CN104311541B - Containing substituted pyrazole compound of ketone and combinations thereof and purposes - Google Patents

Abstract

The present invention relates to the pyrazole compound containing substituted ketone and its pharmaceutically acceptable composition and for preparing treatment and the purposes in the medicine of Xa factor relevant disease.Particularly, the present invention relates to a kind of new pyrazole compound containing substituted ketone, containing the pharmaceutical composition of these compounds and these compounds for preparing the purposes in medicine of the treatment with Xa factor relevant disease.

Description

Containing substituted pyrazole compound of ketone and combinations thereof and purposes

Technical field

The present invention relates to the pyrazole compound containing substituted ketone and its pharmaceutically acceptable composition and for preparing Treatment and the purposes in the medicine of Xa factor relevant disease.Particularly, the present invention relates to a kind of new piperazine containing substituted ketone Pyridine ketone and pyrazole compound, containing the pharmaceutical composition of these compounds and these compounds for prepare treatment and Xa because Purposes in the medicine of sub- relevant disease.

Background of invention

The main practical function of the Xa factor of activation be by producing fibrin ferment to the limited proteolysis of fibrin ferment, For Xa factor in occupation of center in the final general path of blood clotting, it in connection with inherent and external activation equipment System.Fibrin ferment is the final serine protease in the path for produce fibrin clot.Answered by forming factor Compound (Xa factor, factor Ⅴ, Ca²⁺And phosphatide) amplify generation of the fibrin ferment by its precursor.One Xa factor molecule can produce Raw 138 prothrombin molecules (Elodi, a., Varadi, K.:Optimization of conditions for the catalytic effect of the factor IXa–factor VIII complex:Probable role of the complex in the amplification of blood coagulation.Thromb.Res.1979,15,617- 629), so suppression Xa factor may be more more effective than making thrombin inactivation in the interference in blood coagulation system.

It is therefore desirable to have effect and special Xa factor inhibitor are used as potential valuable therapeutic agent to treat thrombus Embolism illness.The present invention relates to new Xa factor inhibitor；Preferably there are improved pharmacological characteristics；More preferably have more High Xa factor inhibitory activity and more preferable selectivity；And/or the characteristic for preferably having the advantage that and improving, but it is unlimited In, pharmacy characteristic (such as solubility, permeability and the adaptability to Sustained-release formulations), volume requirements (such as relatively low dosage and/ Or dosage once a day), reduce with peak valley characterize haemoconcentration factor (such as clearance rate and/or volume of distribution), increase The factor (such as protein binding, volume of distribution) of active agent concentration, the factor of the tendency of reduction clinical medicine interphase interaction are (such as Cytochrome P 450 enzymes suppress or induction), reduce adverse side effect possibility the factor (medicine outside such as serine protease Selectivity, possible chemistry or metabolic response of science and limited CNS permeability) and improvement production cost or feasible Property factor (as synthesis difficulty, the number of chiral centre, chemical stability and the simplicity of operation).

Abstract of invention

The present invention provides a kind of compound or its pharmaceutical composition, can effectively suppress Xa factor, treat associated disease Disease.

On the one hand, the present invention relates to the alloisomerism of the compound shown in compound or formula (I) of the one kind as shown in formula (I) Body, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Prodrug,

Wherein, R¹For C_1-6Alkyl, C_1-6Alkyl-C (=O)-, C_1-6Alkyl-O-C (=O)-or amino-C (=O)-；

Each R²It independently is hydrogen, C_1-6Alkyl, C_1-6Alkoxy or C_1-6Alkylamino；

WhenFor singly-bound when, X CH₂Or NH；

WhenFor double bond when, X is CH or N；With

N is 0,1,2 or 3.

In certain embodiments, R¹For C_1-4Alkyl, C_1-4Alkyl-C (=O)-, C_1-4Alkyl-O-C (=O)-or amino-C (=O)-；With

R²For hydrogen, C_1-4Alkyl, C_1-4Alkoxy or C_1-4Alkylamino.

In further embodiments, R¹For methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, isobutyl group, methyl-C (=O)-, ethyl-C (=O)-, propyl group-C (=O)-, isopropyl-C (=O)-, butyl-C (=O)-, methyl-O-C (=O)-, Ethyl-O-C (=O)-, propyl group-O-C (=O)-, isopropyl-O-C (=O)-, butyl-O-C (=O)-or amino-C (=O)-； With

R²For hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, isobutyl group, methoxyl group, ethyoxyl, propoxyl group, Isopropoxy, butoxy, tert-butoxy, isobutoxy, methylamino, ethylamino, the third amino, isopropylamino, fourth amino, tertiary fourth ammonia Base or i-butylamino.

In further embodiments, the present invention includes the structure of one of：

Or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolism production Thing, pharmaceutically acceptable salt or prodrug.

On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition to include of the present invention any A kind of compound.

In certain embodiments, described pharmaceutical composition is further comprising pharmaceutically acceptable carrier, excipient, dilution Agent, assistant agent, medium or its combination.

In other embodiment schemes, described pharmaceutical composition further includes the anticoagulation of non-Xa factor suppression Agent, anti-platelet agents, thrombin inhibitor, thrombolytic agent, fibrinolytic agent or its combination.

In other embodiment schemes, described pharmaceutical composition, it further presses down comprising second of Xa factor Preparation.

On the other hand, compound of the present invention and described pharmaceutical composition prepare be used to preventing, treat, mitigate or Delay sugared unstable angina, acute coronary syndrome, onset miocardial infarction, recurrent cardiac infarction, ischemic sudden death, Transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease, venous thronbosis, dvt shape Into, thrombophlebitis, arterial embolism, coronary artery thrombosis formation, cerebral artery thrombosis formation, cerebral embolism, renal embolism, lung bolt Fill in and saturating by (a) artificial valve or other implants, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, (e) blood Blood is exposed to the use in the medicine of thrombus caused by other processes for promoting thrombotic artificial surface by analysis or (f) On the way.

Another aspect of the present invention is related to the method for preparation, separation and the purifying for the compound that formula (I) is included.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.

The detailed description of the invention

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.The one of document, patent and the similar material combined Or more it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.

It will further be appreciated that some features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also be provided in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with arbitrarily suitable sub-portfolio in single embodiment.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.

Unless otherwise indicated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS versions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.

There is obvious conflict unless otherwise indicated or in context, article " one " used herein and " one (kind) " It is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or more than one The article of (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to has more than one component quilt Consideration is used or used in the embodiment of the embodiment.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by It is people to try object.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms McGraw-Hill Book Company,New York,1984；and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc.,New York,1994.

Many organic compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, represent molecule on one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is (+) or d compound is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity when, It may occur in which such case.

Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of there is at least 50% enantiomeric excess, at least at least 60% enantiomeric excess, 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer It is excessive.

According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits .Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains a double bond, substituent may be E or Z configurations；If contain dibasic cycloalkanes in compound Base, the substituent of cycloalkyl may have cis or trans configuration.

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

What term " dynamic isomer " or " tautomeric form " referred to have different-energy can build (low by low energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.For example, proton tautomer (protontautomer), also referred to as proton translocation mutually makes a variation Structure body (prototropic tautomer) is included by proton migration the mutual inversion of phases that carries out, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.

As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " being optionally substituted " this term with " substituted or non-substituted ".It is general and Speech, term is " substituted " to represent that institute is substituted to one or more of structure hydrogen atom by specific substituent.Unless its other party Face shows that an optional substituted radical can be substituted in each commutable position of group.When given structural formula Middle more than one position can be substituted by one or more substituents selected from specific group, then substituent can be with identical or not Substitute with ground in each position.Wherein described substituent can be, but be not limited to, hydrogen, deuterium, oxo (=O), halogen, cyanogen Base, nitro, hydroxyl, sulfydryl, amino, fragrant amino, aminoalkyl, alkyl, alkyl sulfenyl, hydroxy alkyl, haloalkyl, cycloalkanes Base, heterocyclic radical, aryl and heteroaryl.

In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, It can both refer in different groups, not influenceed mutually between expressed specific option between same-sign, can also table Show in identical group, do not influenceed mutually between expressed specific option between same-sign.Such as structureR in both²Specific option is unaffected between each other, meanwhile, occur multiple R in same structure², Multiple R²Between specific option be independent of each other, i.e. R²Specific option can be with identical, can also be different.

In each several part of this specification, the substituent that the present invention discloses compound discloses according to radical species or scope.It is special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C_1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for being somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

The group of the present invention is used alone and it is connected with other groups in use, the group is all with of the present invention fixed Justice.For example, alkyl be used alone definition and alkyl-C (=O)-, the alkane mentioned in alkyl-O-C (=O)-or alkyl alkoxy Base define it is identical, all with definition of the present invention.

Terminology used in the present invention " alkyl " or " alkyl group ", expression contain 1 to 20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the substituent institute that the alkyl group can be described optionally by one or more present invention Substitution.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains 1-12 carbon atom；In other embodiments, alkyl group contains 1-6 carbon atom；In other embodiment, alkane Base group contains 1-4 carbon atom；Also in some embodiments, alkyl group contains 1-3 carbon atom.The reality of alkyl group Example includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, 3- methyl isophthalic acids-butyl, 3- hexyls, n-heptyl, n-octyl etc..

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom； In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more The substituent that the present invention describes is substituted.

Term " alkylamino " represents that alkyl group is connected by nitrogen-atoms with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkylamino radicals contain 1-12 carbon atom.In an embodiment party In case, alkylamino radicals contain 1-6 carbon atom；In another embodiment, alkylamino radicals contain 1-4 carbon atom； In another embodiment, alkylamino radicals contain 1-3 carbon atom.The alkylamino radicals can be optionally one or more The substituent that the present invention describes is substituted.

TermOrRepresent singly-bound or double bond.

Term " amino " is expressed as-NH₂。

When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description of group in general refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.

Term " prodrug " used in the present invention, represent a compound and be converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.Completely begged on pro-drug By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical 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 and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:It is 1-19. described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of included N group is formed.Water-soluble or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.

Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (slow down or prevent mitigate disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stablizes body Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refers to prevention or delay disease or disease Breaking-out, generation or the deterioration of disease.

Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

The inorganic acid of salt can be obtained by its derivative to be included such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.

The organic acid of salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

The inorganic base that salt can be obtained by its derivative includes, such as the metal of the I races of ammonium salt and periodic table to XII races. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.

The organic base that salt can be obtained by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Some organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.

The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by making the free alkali form and chemistry of these compounds It is prepared by the suitable acid reaction of metered amount.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.

In addition, compound disclosed by the invention including their salt, with their hydrate forms or can also include it The form of solvent (such as ethanol, dimethyl sulfoxide (DMSO), etc.) obtains, for their crystallization.The present invention discloses compound Inherently or by design solvate can be formed with pharmaceutically acceptable solvent (including water)；Therefore, it is contemplated that Including solvation and unsolvated form.

As described in the present invention, substituent draws a key connection to the member ring systems formed on the ring at center (such as formula (a) institute Show) represent substituent R⁵It can be substituted any commutable position on ring.For example, formula (a) is represented on W1 rings or W2 rings Any position that may be substituted can be substituted.

The composition of the compounds of this invention, preparation and administration

The invention provides the pharmaceutical composition suitable for compounds medicinal, comprising one or more present invention.The medicine Compositions can also further include pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or its combination. Described pharmaceutical composition can be used for preventing, treat, mitigate or delay unstable angina, acute coronary syndrome, just Make up one's mind muscle infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstruction Property arterial disease, venous thronbosis, dvt formation, thrombophlebitis, arterial embolism, coronary artery thrombosis shape Into, cerebral artery thrombosis formation, cerebral embolism, renal embolism, pulmonary embolism and by (a) artificial valve or other implants, (b) indwelling Blood is exposed to and promotes thrombotic labor statement by conduit, (c) support, (d) cardiopulmonary bypass, (e) haemodialysis or (f) Thrombus caused by other processes in face, especially, it has good inhibiting effect to Xa factor.

The compounds of this invention can be administered alone or be applied with one or more combination with other therapeutic agents.Pharmaceutical composition is more entered Anticoagulant, anti-platelet agents, the blood coagulation enzyme level suppressed comprising second of Xa factor inhibitor and/or non-Xa factor to one step Agent, thrombolytic agent, fibrinolytic agent.

When available for treating, the compounds of this invention of therapeutically effective amount, especially formula (I) compound and its pharmaceutically may be used The salt of receiving can be given as unprocessed chemicals, and the active component for being alternatively arranged as pharmaceutical composition provides.Therefore, this hair The pharmaceutical composition that bright content provides includes the compounds of this invention of therapeutically effective amount, especially formula (I) compound or its pharmacy Upper acceptable salt and one or more pharmaceutically acceptable carriers, diluent or excipient.Term as used herein " is controlled Treatment effective dose " refers to the total amount for being enough each active component for showing significant patient benefit.When using individually activity into When point being administered alone, the term only refers to the composition.When combination application, and though the term then refer to combination, sequentially or simultaneously to During medicine, all cause the combined amount of the active component of therapeutic effect.The compounds of this invention, especially formula (I) compound and its pharmacy Upper acceptable salt is as described above.From compatible with preparation other compositions and in the sense that its recipient is harmless, carrier, Diluent or excipient must be acceptable.According to the another aspect of present invention, also provide for preparing pharmaceutical preparation Method, this method include by the compounds of this invention, especially formula (I) compound or its pharmaceutically acceptable salt with it is a kind of or A variety of pharmaceutically acceptable carriers, diluent or excipient mix.Term " pharmaceutically acceptable " used in the present invention Refer to such compound, raw material, composition and/or formulation, they are applied to and patient in the range of rational medicine judgement Tissue contact and without excessive toxicity, excitant, allergy or the other problemses symmetrical with rational interests/Hazard ratio and simultaneously Disease is sent out, and effective for given application.

When present invention composition include present invention compound and one or more other treatment medicines or During the combination of prophylactic agent, the dosage level of compound and other medicine accounts for normal administration generally in monotherapy scheme The about 10-150% of dosage, more preferably account for the about 10-80% of normal dosage.Pharmaceutical preparation is suitable to by any suitable way Footpath is administered, for example, by oral (including oral cavity or sublingual), rectum, nose, part (including oral cavity, sublingual or percutaneous), vagina or It is parenteral (including in subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, breastbone, in intrathecal, focus, the bet of intravenous or corium Penetrate or be transfused) approach.Can prepare this kind of preparation by any known method of art of pharmacy, for example, by by active component with carrying Body or excipient mixing.It is preferred that oral administration or drug administration by injection.

Easily it can in a unit be provided and can lead to for the pharmaceutical composition using the compounds of this invention Any method well-known in the art is crossed to prepare.All methods include making active component with forming one or more auxiliary elements Carrier the step of being combined.Generally, pharmaceutical composition is prepared by the following method：Make active component and liquid carrier or in small, broken bits Solid-state carrier or both be combined equably and nearly, then, if it is desired, the product is formed required preparation. In pharmaceutical composition, the active target compound comprising enough amounts produces desired effect with the process to disease or situation Fruit.

Pharmaceutical composition containing active component can be adapted for oral form, for example, as tablet, lozenge, sugared agent, Water slurry or oil suspension, dispersible pulvis or granule, emulsion, hard capsule or syrup or elixir.It is intended for mouth Take the composition that uses can according to known to pharmaceutical composition production field any method and prepare.Such composition can Include one or more reagents selected from sweetener, flavoring agent, colouring agent and preservative, it is therefore an objective to provide pharmaceutically graceful sum Tasty preparation.

Tablet includes the activity with being mixed suitable for manufacturing other atoxic pharmaceutically acceptable excipient of tablet Composition.These excipient can be, for example, inert diluent, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate； Granula and disintegrant, such as cornstarch or alginic acid；Adhesive, such as starch, gelatin or Arabic gum；And lubricant, it is such as stearic Sour magnesium, stearic acid or talcum.Tablet can be uncoated, or they can be coated with by known technology and delayed in the gastrointestinal tract Disintegration and absorption and thereby provide the long period continuous action.For example, such as glycerin monostearate or two hard can be used The time delay material of glycerol.They can also pass through the skill described in U.S. Patent number 4256108,4160452 and 4265874 Art and be coated with the osmotic therapeutic tablets to be formed for control release.

Formulations for oral use is alternatively arranged as hard gelatin capsule and provided, wherein active component and such as calcium carbonate, Calcium phosphate or the mixing of kaolinic inert solid diluent；Or provided as Perle, wherein active component and water or Such as the oil medium of peanut oil, liquid paraffin or olive oil mixes.

Water slurry includes the active material mixed with suitable for manufacturing the excipient of water slurry.Such excipient is outstanding Floating agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxyl-propyl methylcellulose, sodium alginate, polyethylene-pyrrolidines Ketone, bassora gum and gum arabic；Dispersant or wetting agent can be naturally occurring phosphatide, such as lecithin, or alkylene oxide With the condensation product such as polyoxyethylene stearic acid ester of aliphatic acid, or oxirane and long-chain fatty alcohol such as 17 ethyleneoxies 16 The condensation product of alcohol, or oxirane and the condensation product such as polyoxyethylene sorbitol list derived from aliphatic acid and the partial ester of hexitol Oleate, or oxirane and such as polyethylene sorbitan list oil of the condensation product derived from aliphatic acid and the partial ester of hexitan Acid esters.The water slurry can also include one or more preservatives, and (such as ethyl-para-hydroxybenzoate or P-hydroxybenzoic acid are just Propyl ester), one or more colouring agents, one or more flavoring agents and one or more sweeteners (such as sucrose or saccharin).

Oil suspension can be by the way that active component to be suspended in the plant of such as peanut oil, olive oil, sesame oil or coconut oil Prepared in oil or in the mineral oil of such as atoleine.Oil suspension can include thickener, such as beeswax, hard paraffin or spermaceti Alcohol.Those sweeteners and flavoring agent such as set forth above can be added to provide tasty oral formulations.These compositions can By adding the antioxidant of such as ascorbic acid come anti-corrosion.

Suitable for being provided and dispersant or moistening by adding water to prepare the dispersible pulvis or granule of water slurry The active component of agent, suspending agent and the mixing of one or more preservatives.Suitable dispersant or wetting agent and suspending agent pass through Those already mentioned above carry out exemplary illustration.Other excipient, such as sweetener, flavoring agent and colouring agent also may be present.

The pharmaceutical composition of the present invention can be in the form of oil in water emulsion.Oil phase can be such as olive oil or peanut oil Vegetable oil or such as atoleine mineral oil or these mixture.Suitable emulsifying agent can be naturally occurring tree Glue, such as gum arabic or bassora gum；Naturally occurring phosphatide, as soybean, lecithin and derived from aliphatic acid and hexitan Ester or partial ester, such as Arlacel-80；And the condensation product of the partial ester and oxirane, as polyethylene is dehydrated Sorbitol monooleate.Emulsion may also include sweetener and flavoring agent.

Syrup and elixir can be prepared together with the sweetener of such as glycerine, propane diols, sorbierite or sucrose.Such preparation Moderator, preservative and flavoring agent and colouring agent can also be included.

Pharmaceutical composition can be in the form of the water slurry or oil suspension of sterile injectable.The suspension can be according to known Technology, prepared using suitable dispersant or wetting agent and suspending agent already mentioned above.The system of the sterile injectable Agent can also be the solution or suspension of the sterile injectable in the acceptable diluent of nontoxic, parenteral or solvent, example Such as the solution in 1,3 butylene glycol.Workable acceptable medium and solvent are water, Ringer's solution and isotonic Sodium chloride solution.In addition, sterile fixing oil is traditionally used as solvent or suspension media.Therefore, can be used any gentle Fixing oil, including the monoglyceride of synthesis or two glyceride.In addition, the aliphatic acid of such as oleic acid is in the preparation of injectable drug Find purposes.

Pharmaceutical composition can be also used for the suppository form or enema of the rectal administration of medicine.These compositions can pass through Medicine is mixed with suitable nonirritant excipient and prepared, the nonirritant excipient be at normal temperatures solid but It is liquid under rectal temperature and thereby will melts in the rectum to discharge medicine.Such material includes, for example, cupu oil and Polyethylene glycol.

For local use, using the ointment comprising the compounds of this invention, cream, supensoid agent, lotion, powder, molten Liquor, paste, gel, spray, aerosol, oil formulation or transdermal patch.As used herein topical application alsos attempt to Purposes including mouthwash and mouth-wash.

According in general guideline, in order to reach the effect specified, the day of each used active component is oral The scope of dosage is about 0.001 between 1000mg/kg body weight, it is preferable that between about 0.01 to 100mg/kg body weight. Moreover, most preferably, about 1.0 to 20mg/kg body weight it is daily between.For intravenous administration, in the defeated of conventional rate Most preferred dosage range is about 1 per minute to about 10mg/kg body weight during liquid.The compounds of this invention can be with daily Once apply, or can so that at twice, three times or four times are administered daily.

It will be appreciated, however, that can change for the specific dosage level and administration frequency of any particular patient, and will take Certainly in many factors, including the use of the activity of particular compound, the metabolic stability of the compound and effect duration, the age, Body weight, general health, sex, diet, mode of administration and time, rate of discharge, drug regimen, the seriousness of particular condition and just Through treated host.

The compounds of this invention can use with second therapeutic agent, and the second therapeutic agent can be used for treating, prevent, suppress or changing Kind the compounds of this invention disease or situation useful to its, including unstable angina, acute coronary syndrome, just make up one's mind Muscle infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery are obstructive dynamic Arteries and veins disease, venous thronbosis, dvt formation, thrombophlebitis, arterial embolism, coronary artery thrombosis formed, Cerebral artery thrombosis formation, cerebral embolism, renal embolism, pulmonary embolism and led by (a) artificial valve or other implants, (b) indwelling Blood is exposed to and promotes thrombotic artificial surface by pipe, (c) support, (d) cardiopulmonary bypass, (e) haemodialysis or (f) Other processes caused by thrombus.Such second therapeutic agent can by usually used approach and with usually used amount so as to Simultaneously, sequentially or dividually applied with the compounds of this invention.When the compounds of this invention and one or more other drugs are same Phase in use, except the compounds of this invention, preferably comprises such second therapeutic agent.Therefore, pharmaceutical composition bag of the invention Include except the compounds of this invention also includes one or more second therapeutic agents.

Second therapeutic agent include, but are not limited to, and the anticoagulant of second of Xa factor inhibitor and the suppression of non-Xa factor, resist Blood platelet agent, thrombin inhibitor, thrombolytic agent, fibrinolytic agent or its combination.

Wherein compound of the invention and other anti-freezing agent combinations, for example, for every kg patient body weight, Yi Zhong Dosage can be that 7.5mg the second anti-coagulants is arrived in the compound of about 0.1 to 100mg formula (I) and about 1.For a kind of piece Agent formulation, compound of the invention typically can be that each dosage unit has about 5 to arrive 10mg, and the amount of the second anti-agglutinant It is that each dosage unit has about from 1 to 5mg.Wherein, other anti-freezing reagents specifically include, but are not limited to, Eliquis, profit Cut down husky class, Yi Dushaban, shellfish Qu Shaban, dabigatran, bemiparin, Enoxaparin Sodium, tinzaparin sodium, Danaparoid sodium, Pentosan sodium, Nadroparin Calcium, Ardeparin Sodium, Parnaparin Sodium etc..

According in general guideline, the compounds of this invention is administered in combination with a kind of antiplatelet reagent, the agent of in general day Amount can be the antiplatelet that per kilogram patient body weight about 0.01 arrives 150mg to the compound of 25mg formula (I) and about 50 Reagent, the compound of preferably approximately 0.1 to 1mg formula (I) and about 1 to 3mg antiplatelet reagent.

When the compounds of this invention and thrombolytics are administered in combination, in general daily dose can be per kilogram patient body weight about The compound of 0.1 to 1mg formula (I), the dosage of thrombolytics can reduce about 70-80%.

When two or more foregoing second therapeutic agents are applied together with the compound of formula (I), usually, it is contemplated that Additional or collaboration the effect of therapeutic agent, each group in typical daily dose and typical formulation during combined administration The amount divided, relative to usual dosage when being administered alone, can decline.

Especially, when the dosage unit single as one provides, there is change between the active component of combination Learn the possibility of reaction.Due to this reason, when the compound and second therapeutic agent of formula (I) are in a single dosage unit When being combined, their compound method will make the physical contact between active component minimize (being to reduce), although active component Combination is in a single dosage unit.For example, a kind of active component can be enteric coating peridium.Pass through enteric coating peridium one Kind of active component, it is possible to not only minimize the contact between united active component, and it is also possible to control these into A kind of release in the gastrointestinal tract in point is so that one kind of these components does not discharge under one's belt and is discharged in small intestine.Activity Composition it is a kind of can also superscribe influence its sustained release in the gastrointestinal tract and can also be used for reduce united activity into The material of physical contact between point is further, the component of sustained release can also extraly with enteric coating peridium in order to this into Divide and only discharged in enteron aisle.Also another method is related to the formula of joint product, and one of component is held with one kind The polymer peridium of continuous and/or enteric release, and another component is also with for example a kind of hydroxyl of low sticky rank of polymer Propyl methocel (HPMC) or other suitable material coatings known in the field, to reach further separation The purpose of active component.The reaction of polymer peridium pair and other components forms a kind of extra obstruction.

Once understanding present disclosure, the contact between the component of the joint product for making the present invention of these and other is minimum The method of change be for those skilled in the art it will be apparent that no matter they be with single formulation apply or in a separate form Using, but be in the identical time or apply in an identical manner.

The weight of the compounds of this invention and the second active component is than that can change and by the effective dose depending on every kind of composition. Generally, every kind of effective dose will be used.The combination of the compounds of this invention and other active components generally will also in aforementioned range, But the effective dose of every kind of active component in each case, should be used.

The purposes of the compounds of this invention and pharmaceutical composition

In the purposes the invention provides the compound or pharmaceutical composition of the present invention in medicine is prepared, the medicine can For suppressing Xa factor.The medicine can be used for preventing, treat, mitigate or delay unstable angina, acute coronary to move Arteries and veins syndrome, onset miocardial infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, artery sclerosis Disease, periphery obstructive arterial disease, venous thronbosis, dvt formation, thrombophlebitis, arterial embolism, hat Shape Arterial thrombosis, cerebral artery thrombosis formation, cerebral embolism, renal embolism, pulmonary embolism and by (a) artificial valve or other plants Enter thing, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, (e) haemodialysis or (f) to be exposed to blood and promote thrombus Thrombus caused by other processes of the artificial surface of formation.

The treatment method being administered comprising the compounds of this invention or pharmaceutical composition, further comprises to patient to second of Xa Anticoagulant, anti-platelet agents, thrombin inhibitor, thrombolytic agent, the plasmin that factor inhibitors, non-Xa factor suppress Solve agent or its combination.

The present invention compound or pharmaceutically acceptable composition " effective dose " or " effective dose " refer to processing or Mitigate the effective dose that one or more present invention are previously mentioned the severity of illness.The method according to the invention, compound and combination The order of severity that thing can be any dosage and any method of administration to be efficiently used for handling or mitigate disease.Required standard True amount will change according to the situation of patient, and this is depending on ethnic, the age, the general condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or composition can with one or more other therapeutic agents administering drug combinations, such as What the present invention was discussed.

Compound (herein, form of presentation " formula (I) compound and its stereoisomer, the geometrical isomerism of the present invention Body, dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt and prodrug " may be collectively referred to as " compound of the invention "), it can be used for giving birth to Production medical product is used to preventing, treat, mitigate or delaying unstable angina, acute coronary syndrome, initial cardiac muscle stalk Plug, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease Disease, venous thronbosis, dvt formation, thrombophlebitis, arterial embolism, coronary artery thrombosis formation, brain move Arteries and veins thrombosis, cerebral embolism, renal embolism, pulmonary embolism and by (a) artificial valve or other implants, (b) inlying catheter, (c) Support, (d) cardiopulmonary bypass, (e) haemodialysis or (f) by blood exposed to promote thrombotic artificial surface other Thrombus caused by process, including those are described in the invention.Further, compound of the invention can be used for suppress Xa because Son.Thus, compound of the invention can be used for producing a kind of pharmaceuticals for mitigating, preventing, controlling or treating Xa factor institute The illness of mediation.Thus, compound of the invention may be used as the active component of pharmaceutical composition, and the pharmaceutical composition can wrap Formula (I) or the compound representated by formula (II) are included, can also further include at least one pharmaceutically acceptable carrier, figuration Agent, diluent, assistant agent and medium.

General building-up process

Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.

Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd, and Haiyang Chemical Plant, Qingdao are commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMAC N,N' dimethyl acetamide and N, N- Dimethylformamide is to dry to use in advance through anhydrous sodium sulfate.

Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDCl₃、DMSO-d₆、CD₃OD or acetone-d₆(reported for solvent in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, it is wide Peak), dd (doublet of doublets, two are bimodal), dt (doublet of triplets, double triplets).Coupling is normal Number J units are hertz (Hz).

By being equipped with G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrometer determine, G1329A automatic samplers and G1315B DAD detectors Applied to analysis, ESI sources are applied to LC-MS spectrometers.

Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316A TCC (column temperature is maintained at 30 DEG C) Agilent 6120 serial LC-MS spectrometer determine, G1329A automatic samplers and G1315D DAD detectors should For analyzing, ESI sources are applied to LC-MS spectrometers.

Both the above spectrometer is provided with Agilent Zorbax SB-C18 posts, and specification is 2.1 × 30mm, 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；HPLC peak value is by 210nm and 254nm UV-Vis wavelength records reading.The formic acid acetonitrile solution (phase A) and 0.1% formic acid that mobile phase is 0.1% are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1：

Table 1

Time (min)	A(CH3CN, 0.1%HCOOH)	B(H2O, 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 the series of high efficiency liquid chromatograies (HPLC) of Agilent 1100, wherein UV detections At 210nm and 254nm, Zorbax SB-C18 posts, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature is maintained at 40 DEG C.

The use of brief word below is through the present invention：

G grams

Mg milligrams

Mmol mMs

Ml, mL milliliter

L liters

DEG C degree Celsius

¹The NMR spectrum of H NMR hydrogen 1

¹³C NMR carbon-13 magnetic resonance wave spectrums

MS mass spectrums

MHz megahertzs

Hz hertz

DMSO-d₆Deuterated dimethyl sulfoxide

CDCl₃Deuterochloroform

CD₃OD deuterated methanols

Pos.ion cations

Neg.ion anions

ESI electron spray ionisations

M/z mass-charge ratios

PT plasma prothrombin times

The partial thromboplastin time of APTT activation

FXa activated clotting factors ten

Reaction scheme 1

Compound 5 can be prepared by the method that reaction scheme 1 describes.Wherein, R²It is of the present invention fixed to have with n Justice.

Compound 1 and thionyl chloride reaction generation compound 2.Compound 2 exists with compound 3 in alkali (such as sodium hydride) Under, reaction generation compound 4.The ammonolysis of compound 4 obtains compound 5.

Embodiment 1

5- (5- ((the 6H)-yl of 2,4- dimethyl -6- oxopyrimidins -1) indoles -1- formoxyls) -1- (4- methoxyphenyls) - 1H- pyrazole-3-formamides

Step 1) 5- ((the 6H)-yl of 2,4- dimethyl -6- oxopyrimidins -1) indoles -1- t-butyl formates

It is added dropwise into dichloromethane (15mL) solution of 5- amino indole -1- t-butyl formates (469mg, 2.0mmol) The toluene solution (1.1mL, 2.2mmol, 2M) of trimethyl aluminium, reactant mixture are cooled to 0 DEG C after being stirred at room temperature 1 hour, added (Z) -3- acetylaminos but-2-ene acid methyl esters (346mg, 2.2mmol), stirring 2 hours is continued at 0 DEG C.Water (10mL) is added to quench Go out, extracted with dichloromethane (20mL x 2).Merge organic phase, washed with saturated aqueous common salt (20mL), anhydrous sodium sulfate drying. Decompression boil off solvent, crude product purifies (petrol ether/ethyl acetate (v/v)=1/1) through column chromatography, obtain white solid (523mg, 76.5%).

Step 2) 3- (indoles -5- bases) -2,6- dimethyl pyrimidines -4 (3H) -one

To 5- ((the 6H)-yl of 2,4- dimethyl -6- oxopyrimidins -1) indoles -1- t-butyl formates (341mg, 1.0mmol) Methanol (5mL) solution in add water (5mL) solution of potassium carbonate (399mg, 2.16mmol), reactant mixture was stirred at room temperature Extracted after night with dichloromethane (20mL × 2).Merge organic phase, washed with saturated aqueous common salt (20mL × 2), anhydrous sodium sulfate is done It is dry.Decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (v/v)=1/1) through column chromatography, obtains white solid (180mg, 74.7%).

MS(ESI,pos.ion)m/z:242.1(M+1).

Step 3) 5- (chloroformyl) -1- (4- methoxyphenyls) -1H- pyrazoles -3- Ethyl formates

To the dichloromethane of 3- (carbethoxyl group) -1- (4- methoxyphenyls) -1H- pyrazoles -5- formic acid (290mg, 1mmol) Thionyl chloride (595mg, 5mmol) is added dropwise in (15mL) solution, reactant mixture is heated to 85 DEG C and stirred 2 hours.Decompression boils off Solvent, white solid (309mg, 100%) is obtained, be directly used in next step.

Step 4) 5- (5- ((the 6H)-yl of 2,4- dimethyl -6- oxopyrimidins -1) indoles -1- formoxyls) -1- (4- methoxyl groups Phenyl) -1H- pyrazoles -3- Ethyl formates

To the tetrahydrofuran of 3- (indoles -5- bases) -2,6- dimethyl pyrimidines -4 (3H) -one (242mg, 1.0mmol) 60% sodium hydride (80mg, 2.0mmol) is added in (20mL) solution, is stirred at room temperature 30 minutes, then 5- (chloromethanes are added dropwise thereto Acyl group) -1- (4- methoxyphenyls) -1H- pyrazoles -3- Ethyl formates (309mg, 1.0mmol) tetrahydrofuran (5mL), room temperature Continue to be stirred overnight.Add water (15mL) to be quenched, extracted with dichloromethane (30mL × 2), merge organic phase, use saturated aqueous common salt (20mL × 2) are washed, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate through column chromatography (v/v) white solid (348mg, 67.6%)=1/1), is obtained.

MS(ESI,pos.ion)m/z:514.1(M+1).

Step 5) 5- (5- ((the 6H)-yl of 2,4- dimethyl -6- oxopyrimidins -1) indoles -1- formoxyls) -1- (4- methoxyl groups Phenyl) -1H- pyrazole-3-formamides

Sequentially added into tube sealing 5- (5- ((the 6H)-yl of 2,4- dimethyl -6- oxopyrimidins -1) indoles -1- formoxyls) - 1- (4- methoxyphenyls) -1H- pyrazoles -3- Ethyl formates (51mg, 0.1mmol), methanol (3mL) and ammoniacal liquor (4mL), tube sealing, 80 DEG C are heated to stir 6 hours.It is cooled to room temperature, decompression boils off solvent, and crude product purifies (methylene chloride/methanol (v/ through column chromatography V)=15:1) white solid (26mg, 54%), is obtained.

MS(ESI,pos.ion)m/z:485.2(M+1)；

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.33 (d, J=7.1Hz, 1H), 7.46 (d, J=7.2Hz, 2H), 7.19(s,1H),7.05–7.00(m,2H),6.95(s,3H),6.29(s,1H),6.00(s,1H),3.83(s,3H),2.30 (s,3H),2.18(s,3H).

Embodiment 2

1- (4- methoxyphenyls) -5- (5- (2- oxo-piperidine -1- bases) indoles -1- formoxyls) -1H- pyrazoles -3- formyls Amine

Step 1) 5- nitro -1H- indoles -1- t-butyl formates

Two dimethyl dicarbonate fourths are added into dichloromethane (6mL) solution of 5- nitro -1H- indoles (325mg, 2.0mmol) Ester (524mg, 2.4mmol), stirred 5 minutes at 0 DEG C, add catalytic amount DMAP (3mg, 0.025mmol), then stirring 30 minutes is continued in room temperature.Add water (2mL) to be quenched, extracted with dichloromethane (15mL × 3). Merge organic phase, washed successively with water (20mL), saturated aqueous common salt (15mL × 2), anhydrous sodium sulfate drying, decompression boils off molten Agent, greyish white solid (526mg, 100%) is obtained, be directly used in and react in next step.

Step 2) 5- amino indole -1- t-butyl formates

Added into ethyl acetate (8mL) solution of 5- nitro -1H- indoles -1- t-butyl formates (525mg, 2.0mmol) 10% palladium carbon (50mg), is stirred overnight at room temperature under an atmosphere of hydrogen.Filter, filtrate decompression boils off solvent and obtains white solid (469mg, 100%).

Step 3) 5- (2- oxo-piperidine -1- bases) indoles -1- t-butyl formates

At room temperature, to the DMF of 5- amino indole -1- t-butyl formates (469mg, 2.0mmol) 5- bromines valeric chloride (439mg, 2.20mmol) is added dropwise in (10mL) solution, stirs 1 hour, after question response liquid is cooled to room temperature, adds 60% sodium hydride (120mg, 3mmol), reactant mixture room temperature continue stirring 2 hours.Add water (20mL) to be quenched, use dichloro Methane (15mL × 3) extracts.Merge organic phase, washed with saturated aqueous common salt (20mL), anhydrous sodium sulfate drying, decompression boils off molten Agent, crude product obtain white solid (413mg, 65.2%) through column chromatography (petrol ether/ethyl acetate (v/v)=1/1).

Step 4) 1- (indoles -5- bases) piperidines -2- ketone

To methanol (5mL) solution of 5- (2- oxo-piperidine -1- bases) indoles -1- t-butyl formates (341mg, 1.08mmol) Middle water (5mL) solution for adding potassium carbonate (399mg, 2.16mmol), after reactant mixture is stirred overnight at room temperature, uses dichloromethane (20mL × 2) extract.Merge organic phase, washed with saturated aqueous common salt (20mL × 2), anhydrous sodium sulfate drying.Decompression boils off molten Agent, crude product purify (petrol ether/ethyl acetate (v/v)=1/1) through column chromatography, obtain white solid (163mg, 70.0%).

MS(ESI,pos.ion)m/z:217.1(M+1).

Step 5) 5- (chloroformyl) -1- (4- methoxyphenyls) -1H- pyrazoles -3- Ethyl formates

To the dichloromethane of 3- (carbethoxyl group) -1- (4- methoxyphenyls) -1H- pyrazoles -5- formic acid (290mg, 1mmol) Thionyl chloride (595mg, 5mmol) is added dropwise in (15mL) solution, reactant mixture is heated to 85 DEG C and stirred 2 hours.Decompression boils off Solvent, white solid (309mg, 100%) is obtained, be directly used in and react in next step.

Step 6) 1- (4- methoxyphenyls) -5- (5- (2- oxo-piperidine -1- bases) indoles -1- formoxyls) -1H- pyrazoles - 3- Ethyl formates

60% is added into tetrahydrofuran (20mL) solution of 1- (indoles -5- bases) piperidines -2- ketone (216mg, 1.0mmol) Sodium hydride (80mg, 2.0mmol), be stirred at room temperature 30 minutes, then thereto be added dropwise 5- (chloroformyl) -1- (4- methoxybenzenes Base) -1H- pyrazoles -3- Ethyl formates (309mg, 1.0mmol) tetrahydrofuran (5mL), room temperature continues to be stirred overnight.Add water (15mL) is quenched, and is extracted with dichloromethane (30mL × 2), merges organic phase, is washed with saturated aqueous common salt (20mL × 2), anhydrous Sodium sulphate is dried.Decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (v/v)=1/1) through column chromatography, obtained white Solid (352mg, 72.1%).

MS(ESI,pos.ion)m/z:489.1(M+1).

Step 7) 1- (4- methoxyphenyls) -5- (5- (2- oxo-piperidine -1- bases) indoles -1- formoxyls) -1H- pyrazoles - 3- formamides

1- (4- methoxyphenyls) -5- (5- (2- oxo-piperidine -1- bases) indoles -1- formyls are sequentially added into tube sealing Base) -1H- pyrazoles -3- Ethyl formates (49mg, 0.1mmol), methanol (3mL) and ammoniacal liquor (4mL), tube sealing, be heated to 80 DEG C of stirrings 6 hours.It is cooled to room temperature, decompression boils off solvent, and crude product purifies (methylene chloride/methanol (v/v)=15 through column chromatography:1), obtain white Color solid (25mg, 51%).

MS(ESI,pos.ion)m/z:460.2(M+1)；

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.19 (d, J=8.3Hz, 1H), 7.53-7.36 (m, 2H), 7.12- 7.06 (m, 3H), 6.98-6.82 (m, 3H), 5.73 (s, 1H), 3.89 (t, J=7.9Hz, 2H), 3.82 (s, 3H), 3.08 (t, J =7.8Hz, 2H), 1.93 (s, 4H)

Biological activity test

Mankind FXa enzyme levels are tested

The enzymatic activity of mankind's factor Xa (FXa) is determined by the conversion for the specific chromogenic substrates of FXa.It is right This, factor Xa cracks from chromogenic substrate falls p-Nitraniline.This is determined as follows to state and carried out on microwell plate.

Tester is dissolved in 10% dimethyl sulfoxide by various concentrations, taking the μ L of compound 5 and mankind FXa, (10nM is dissolved in 50mM Tris, 150mM NaCl, pH=8.3) 10 μ L mixing, 15min is incubated in 25 DEG C of constant incubators, is added after incubation The μ L of FXa chromophoric substrates (800 μM, sigma) 5, the kinetic test absorbance at 25 DEG C of 405nm.Test substances will be contained Test mixing thing and control mixture without test substances compare and IC are calculated by these data₅₀Value.

Test of anticoagulation in vitro

Compound extends the clotting time of rabbit plasma

1. the preparation of each concentration compound

4 each compound working solutions of μ L (10mM) are taken, the working solution of each concentration is diluted to dimethyl sulfoxide liquid.

2. the preparation of plasma sample

Some rabbits are taken, auricular vein injects 3% pentobarbital solution (30mg/kg) anesthesia, with containing 3.8% sodium citrate 0.2mL vacuum test tube abdominal aorta is taken a blood sample to 2mL, collects multitube, is turned upside down mixing for several times, is stood 10min, in 3000rpm centrifuges 10min, draws each pipe blood plasma, all blood plasma is mixed to same centrifuge tube, often pipe dispenses 1.6mL, puts rapidly Enter -80 DEG C of refrigerators to save backup.

3. sample-adding and measure clotting time PT and APTT

1.5mL EP pipes are got out, often pipe adds 180 μ L plasma specimens；It is corresponding that 4 μ L are separately added into each pipe blood specimen The medicine of concentration, control group add 4 μ L dimethyl sulfoxide solutions, and concussion mixes, 37 DEG C of incubation 5min；It is complete with Sysmex CA1500 Automatic blood coagulation instrument determines PT and APTT；Amount effect curve is drawn, curve is fitted, thus calculating clotting time of sening as an envoy to doubles Test compound concentration (CT₂)。

Inhibitory action and anticoagulation effect in vitro of the compound to people FXa activity

A：1.00nM-10.00nM；B：10.01nM-100.00nM；C：100.01nM-1.00μM；D：1.01μM-10.00μ M；E：10.01μM-50.00μM

Conclusion：This series compound has preferable factor Xa inhibitory activity, while has and extend the clotting time Effect.

The solubility test of compound

Water (10mL) is added into 15mL conical pipes, sample is added in vibration, until sample stops dissolving, 37 DEG C of constant temperature Water-bath shakes 24h, shake speed 40rpm.After shaking terminates, sample is filtered for (0.45 μm, Φ 13mm) through water system miillpore filter, Primary filtrate is discarded, precision pipettes subsequent filtrate (500 μ L), adds dilution acetonitrile-water (500 μ L, v/v=60/40), and the two is mixed It is even, produce need testing solution.

Need testing solution (40 μ L) is taken, is detected using HPLC, sample concentration is calculated by one point external standard method：

Numbering	Compound solubility (mg/mL)
		Embodiment 1	0.96
Embodiment 2	0.83

Conclusion：This series compound has preferable solubility.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description Point is contained at least one embodiment or example of the present invention.In this manual, to the schematic representation of above-mentioned term not Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area Art personnel can be tied the different embodiments or example and the feature of different embodiments or example described in this specification Close and combine.

Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changed, replacing and modification.

Claims (6)

1. a kind of compound, it is having structure：

Or its pharmaceutically acceptable salt.

2. a kind of pharmaceutical composition, described pharmaceutical composition includes the compound described in claim 1.

3. pharmaceutical composition according to claim 2, further comprising pharmaceutically acceptable carrier, excipient or its group Close.

4. pharmaceutical composition according to claim 3, its anticoagulant further suppressed comprising non-Xa factor, resist Blood platelet agent, thrombin inhibitor, thrombolytic agent, fibrinolytic agent or its combination.

5. according to the pharmaceutical composition any one of claim 2-4, it further presses down comprising second of Xa factor Preparation.

6. prepared by the pharmaceutical composition described in any one of compound or claim 2-5 described in a kind of claim 1 For preventing, treating, mitigating or delaying unstable angina, acute coronary syndrome, onset miocardial infarction, the recidivity heart Muscle infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease, phlebothrombosis Formation, thrombophlebitis, arterial embolism, coronary artery thrombosis formation, cerebral artery thrombosis formation, cerebral embolism, renal embolism, lung bolt Fill in and saturating by (a) artificial valve or other implants, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, (e) blood Blood is exposed to the use in the medicine of thrombus caused by other processes for promoting thrombotic artificial surface by analysis or (f) On the way.