CN104277040B

CN104277040B - Containing acyl piperazine ketone substituent pyrazolo piperidone compounds and composition thereof and purposes

Info

Publication number: CN104277040B
Application number: CN201410483239.9A
Authority: CN
Inventors: 文亮; 郑金付; 张瑾; 吴守涛; 袁小凤; 林润锋; 王晓军; 左应林; 张英俊
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2014-09-19
Filing date: 2014-09-19
Publication date: 2016-04-20
Anticipated expiration: 2034-09-19
Also published as: CN104277040A

Abstract

The present invention relates to pyrazolo piperidone compounds and the acceptable composition of pharmacy thereof and for the preparation for the treatment of and the purposes in the medicine of Xa factor relative disease.Especially, the present invention relates to a kind of novel containing acyl piperazine ketone substituent pyrazolo piperidone compounds, pharmaceutical composition containing these compounds and these compounds for the preparation for the treatment of and the purposes in the medicine of Xa factor relative disease.

Description

Containing acyl piperazine ketone substituent pyrazolo piperidone compounds and composition thereof and purposes

Technical field

Background of invention

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.:Optimizationofconditionsforthecatalyticeffectofthefac torIXa – factorVIIIcomplex:Probableroleofthecomplexintheamplifica tionofbloodcoagulation.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).

Abstract of invention

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

On the one hand, the present invention relates to a kind of steric isomer such as formula the compound shown in the compound shown in (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug

Wherein, R ¹for C _1-6alkyl, C _1-6alkyl-C (=O)-, C _1-6alkyl-O-C (=O)-or amino-C (=O)-; With

R ²for C _1-6alkyl, described C _1-6alkyl is replaced by the substituting group that 1,2 or 3 is independently selected from amino, hydroxyl or halogen.

In certain embodiments, R ¹for C _1-4alkyl, C _1-4alkyl-C (=O)-, C _1-4alkyl-O-C (=O)-or amino-C (=O)-; With

R ²for C _1-4alkyl, described C _1-4alkyl is replaced by the substituting group that 1,2 or 3 is independently selected from amino, hydroxyl or halogen.

In further embodiments, R ¹for methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, methyl-C (=O)-, ethyl-C (=O)-, propyl group-C (=O)-, sec.-propyl-C (=O)-, butyl-C (=O)-, methyl-O-C (=O)-, ethyl-O-C (=O)-, propyl group-O-C (=O)-, sec.-propyl-O-C (=O)-, butyl-O-C (=O)-or amino-C (=O)-; With

R ²for methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl or isobutyl-, described methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl and isobutyl-independently of one another by 1,2 or 3 be independently selected from amino, hydroxyl, fluorine, chlorine or bromine substituting group replace.

In further embodiments, the present invention comprises one of them structure following:

Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.

On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises any one compound of the present invention.

In certain embodiments, described pharmaceutical composition comprises pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination further.

In other embodiment schemes, described pharmaceutical composition further comprise non-Xa factor suppress anti-coagulant, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent or its combination.

In other embodiment schemes, described pharmaceutical composition, it further comprises the second Xa factor inhibitor.

On the other hand, compound of the present invention and described pharmaceutical composition are for the preparation of prevention, treatment, alleviate or delay sugared unstable angina, acute coronary syndrome, onset myocardial infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease, venous thrombosis, dvt is formed, thrombophlebitis, arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis is formed, cerebral embolism, renal infarction, pulmonary infarction, with by (a) artificial valve or other implant, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, (e) hemodialysis or (f) by blood in promote other processes of thrombotic artificial surface cause in the medicine of thrombus purposes.

The present invention relates on the other hand the preparation of compound that formula (I) comprises, the method for abstraction and purification.

Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.

The detailed description of the 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, this paper institute should be applied and use to obtain following definition.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 " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, JohnWiley & Sons, description in NewYork:2007, its full content is incorporated to herein by reference.

Except as otherwise noted or in context, have obvious conflict, article used herein " " and " one (kind) " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.

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.

Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-HillDictionaryofChemicalTermsMcGraw-HillBookCompa ny, NewYork, 1984; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, 1994.

Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.

The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.

By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, and can with reference to Jacques, etal., Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981); PrinciplesofAsymmetricSynthesis (2 ^nded.RobertE.Gawley, JeffreyAub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.StereochemistryofCarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S.H.TablesofResolvingAgentsandOpticalResolutionsp.268 (E.L.Eliel, Ed., Univ.ofNotreDamePress, NotreDame, IN1972); ChiralSeparationTechniques:APracticalApproach (Subramanian, G.Ed., Wiley-VCHVerlagGmbH & Co.KGaA, Weinheim, Germany, 2007).

Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (lowenergybarrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer), the mutual conversion undertaken by proton shifting is comprised, as keto-enol isomerization and imine-enamine isomerizations also referred to as Prototropic tautomers (prototropictautomer).Valence tautomerism body (valencetautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.

As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " being optionally substituted " this term and " substituted or non-substituted " this term can exchange use.Generally speaking, term " replacement " represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to, hydrogen, deuterium, oxo (=O), halogen, cyano group, nitro, hydroxyl, sulfydryl, amino, virtue amino, aminoalkyl group, alkyl, alkyl sulfenyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl.

In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.

At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C _1-6alkyl " refer in particular to independent disclosed methyl, ethyl, C ₃alkyl, C ₄alkyl, C ₅alkyl and C ₆alkyl.

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.

Group of the present invention is used alone and is connected with other groups with it when using, and this group all has definition of the present invention.Such as, the definition that alkyl is used alone and alkyl-C (=O)-, the alkyl definition mentioned in alkyl-O-C (=O)-or alkyl alkoxy is identical, all has definition of the present invention.

The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.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, alkyl group contains 1-4 carbon atom; Also in some embodiments, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but is not limited to, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 3-methyl isophthalic acid-butyl, 3-hexyl, n-heptyl, n-octyl etc.

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

Term " amino " is expressed as-NH ₂.

Term " hydroxyl " is expressed as-OH.

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; Boc), carbobenzoxy-(Cbz) (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: TW.Greene, ProtectiveGroupsinOrganicSynthesis, JohnWiley & Sons, NewYork, 1991; AndP.J.Kocienski, ProtectingGroups, Thieme, Stuttgart, 2005.

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.HiguchiandV.Stella, Pro-drugsasNovelDeliverySystems, Vol.14oftheA.C.S.SymposiumSeries, EdwardB.Roche, ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987, J.Rautioetal., Prodrugs:DesignandClinicalApplications, NatureReviewDrugDiscovery, 2008, 7, 255-270, andS.J.Heckeretal., ProdrugsofPhosphatesandPhosphonates, JournalofMedicinalChemistry, 2008, 51, 2328-2345.

" 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.

" 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.Bergeetal., describepharmaceuticallyacceptablesaltsindetailinJ.Pharm aceuticalSciences, described in 1977,66:1-19..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, 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 and monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.

Term as used in the present invention " treatment " any disease or illness, some embodiment middle fingers improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom) wherein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In other embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.

Pharmaceutically useful acid salt can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-semi-lactosi hydrochlorate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. can be comprised by its derivative mineral acid obtaining salt.

Such as acetic acid, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, sulphosalicylic acid etc. can be comprised by its derivative organic acid obtaining salt.

Pharmaceutically acceptable base addition salt can be formed with mineral alkali and organic bases.

Can be comprised by its derivative mineral alkali obtaining salt, the metal of I race to the XII race of such as ammonium salt and periodictable.In certain embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salts.

Can comprise primary amine, secondary amine and tertiary amine by its derivative organic bases obtaining salt, the amine of replacement comprises the amine, cyclic amine, deacidite etc. of naturally occurring replacement.Some organic amine comprises, such as, and Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.

Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " Remington ' sPharmaceuticalSciences ", the 20th edition, MackPublishingCompany, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (HandbookofPharmaceuticalSalts:Properties; Selection; andUse) ", StahlandWermuth (Wiley-VCH, Weinheim, Germany, 2002) other can be found to be suitable for the list of salt in.

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, methyl-sulphoxide (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.

As described in the present invention, substituting group is drawn a key and is connected to the member ring systems (such as formula (a) Suo Shi) that the ring at center is formed and represents substituent R ⁵can replace any commutable position on ring.Such as, formula (a) represents any position that may be substituted on W1 ring or W2 ring and all can be substituted.

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

The invention provides and be suitable for pharmaceutical composition that is medicinal, that comprise one or more compounds of the present invention.This pharmaceutical composition can also comprise pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination further.Described pharmaceutical composition may be used for prevention, treatment, alleviate or delay unstable angina, acute coronary syndrome, onset myocardial infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease, venous thrombosis, dvt is formed, thrombophlebitis, arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis is formed, cerebral embolism, renal infarction, pulmonary infarction, with by (a) artificial valve or other implant, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, e () hemodialysis or (f) are by other process the cause thrombus of blood in the thrombotic artificial surface of promotion, especially, it has good restraining effect to Xa factor.

The compounds of this invention can be used separately or uses with one or more combination with other therapeutic agents.Pharmaceutical composition further comprises anti-coagulant, anti-platelet agents, thrombin inhibitors, thrombolytic agent, the fibrinolytic agent of the second Xa factor inhibitor and/or the suppression of non-Xa factor.

When can be used for treatment, the compounds of this invention for the treatment of significant quantity, especially formula (I) compound and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and the activeconstituents that also can be used as pharmaceutical composition provides.Therefore, the pharmaceutical composition that content of the present invention provides comprises the compounds of this invention for the treatment of significant quantity, especially formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle.Term as used herein " treatment significant quantity " refers to the total amount of each active ingredient being enough to demonstrate significant patient benefit.When using independent activeconstituents individually dosed, this term only refers to this composition.When Combination application, and though this term then refer to combination, successively or simultaneously administration time, all cause the combined amount of the activeconstituents of result for the treatment of.The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt described above.From compatible with other compositions of preparation and harmless to its recipient meaning, carrier, thinner or vehicle must be acceptable.According to the another aspect of content of the present invention, also be provided for the method for useful in preparing drug formulations, the method comprises the compounds of this invention, and especially formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle mix.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope that rational medicine judges, to be applicable to patient tissue contacts and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and to be effective to given application.

When the composition of content of the present invention comprises the combination of the compound of content of the present invention and one or more other treatment medicines or prophylactic agent, the dosage level of compound and other medicine is usually in monotherapy scheme, account for the about 10-150% of bio-occlusion pharmaceutical quantities, more preferably account for the about 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable for by any suitable administration, such as by oral (comprising oral cavity or sublingual), rectum, nose, locally (comprise oral cavity, sublingual or through skin), vagina or parenteral (comprise in subcutaneous, intracutaneous, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional, intravenously or intradermal injection or infusion) approach.This kind of preparation can be prepared, such as, by by activeconstituents and carrier or mixed with excipients by any currently known methods of art of pharmacy.Preferred oral administration or drug administration by injection.

Can provide in a unit easily for using the pharmaceutical composition of the compounds of this invention and prepare by any method well-known in the art.All methods comprise the step that activeconstituents is combined with the carrier forming one or more ancillary components.Usually, pharmaceutical composition is prepared by the following method: make activeconstituents and liquid carrier or solid-state carrier in small, broken bits or both equably and combine nearly, then, if needed, makes this product form required preparation.In pharmaceutical composition, the Active Target Compounds comprising enough amounts is with the effect desired by producing the process of disease or situation.

Pharmaceutical composition containing activeconstituents can be suitable for oral form, such as, as tablet, lozenge, sugared agent, aqeous suspension or oil suspension, dispersible pulvis or granule, emulsion, hard capsule or syrup or elixir.Be intended for the composition orally used to prepare according to the manufacture known any method of pharmaceutical composition production field.Such composition can comprise the reagent that one or more are selected from sweeting agent, odorant, tinting material and sanitas, and object is to provide pharmaceutically graceful with good to eat preparation.

Tablet comprises the activeconstituents mixed mutually with other the atoxic pharmaceutically acceptable vehicle being suitable for manufacturing tablet.These vehicle can be, such as, inert diluent, as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granule and disintegrating agent, as W-Gum or Lalgine; Tackiness agent, as starch, gelatin or gum arabic; And lubricant, as Magnesium Stearate, stearic acid or talcum.Tablet can be not coated, or they are coated with by known technology the disintegration that delays in the gastrointestinal tract and absorb and thus provide the continuous action of long period.Such as, the time delay material of such as glyceryl monostearate or distearin can be used.They are also coated with the osmotic therapeutic tablets formed for Co ntrolled release by the technology described in U.S. Patent number 4256108,4160452 and 4265874.

Preparation for orally using also can be used as hard gelatin capsule and provides, wherein activeconstituents and such as calcium carbonate, calcium phosphate or kaolinic inert solid mixing diluents; Or provide as soft gelatin capsule, wherein activeconstituents mixes with the oil medium of water or such as peanut oil, liquid paraffin or sweet oil.

Aqeous suspension comprises and the active substance being suitable for the mixed with excipients manufacturing aqeous suspension.Such vehicle is suspension agent, such as Xylo-Mucine, methylcellulose gum, hydroxyl-propyl methylcellulose gum, sodium alginate, Polyvinyl-pyrrolidone, tragacanth gum and Sudan Gum-arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, such as Yelkin TTS, or the condensation product of alkylene oxide and lipid acid is as polyoxyethylene stearic acid ester, or oxyethane and long chain aliphatic alcohol are as the condensation product of 17 vinyloxy group hexadecanols, or oxyethane and derive from lipid acid and hexitol the condensation product of partial ester as octadecanoic acid ester of polyethylene glycol, or oxyethane and derive from lipid acid and hexitan the condensation product of partial ester as polyethylene sorbitan monoleate.Described aqeous suspension also can comprise one or more sanitass (as ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl), one or more tinting materials, one or more odorants and one or more sweeting agents (as sucrose or asccharin).

Oil suspension by activeconstituents is suspended in such as peanut oil, sweet oil, sesame oil or Oleum Cocois vegetables oil in or such as whiteruss mineral oil in and prepare.Oil suspension can comprise thickening material, such as beeswax, paraffinum durum or hexadecanol.Such as those sweeting agents set forth above and odorant can be added to provide good to eat oral preparations.These compositions come anticorrosion by the antioxidant adding such as xitix.

The dispersible pulvis or the granule that are suitable for preparing by adding water aqeous suspension provide the activeconstituents mixed with dispersion agent or wetting agent, suspension agent and one or more sanitass.Suitable dispersion agent or wetting agent and suspension agent carry out exemplary illustration by those having mentioned above.Also can there is other vehicle, such as sweeting agent, odorant and tinting material.

The form of all right oil-in-water emulsion of pharmaceutical composition of the present invention.Oil phase can be the vegetables oil of such as sweet oil or peanut oil or the mineral oil of such as whiteruss or these mixture.Suitable emulsifying agent can be naturally occurring natural gum, as Sudan Gum-arabic or tragacanth gum; Naturally occurring phosphatide, as soybean, Yelkin TTS and the ester or the partial ester that derive from lipid acid and hexitan, such as polyoxyethylene-sorbitan mono-oleate; And the condensation product of described partial ester and oxyethane, as polyethylene sorbitan monoleate.Emulsion also can comprise sweeting agent and odorant.

Syrup can be prepared with elixir together with the sweeting agent of such as glycerine, propylene glycol, sorbyl alcohol or sucrose.Such preparation also can comprise negative catalyst, sanitas and odorant and tinting material.

Pharmaceutical composition can the aqeous suspension of sterile injectable or the form of oil suspension.This suspension can according to known technology, use the above suitable dispersion agent that mention or wetting agent and suspension agent and prepare.The preparation of this sterile injectable can also the solution of sterile injectable in nontoxic, the acceptable thinner of parenteral or solvent or suspension, such as, as the solution in 1,3 butylene glycol.Spendable acceptable vehicle and solvent are water, Ringer's solution and isotonic sodium chlorrde solution.In addition, aseptic fixing oil is traditionally used as solvent or suspension medium.Therefore, the fixing oil of any gentleness can be used, comprise direactive glyceride or two glyceryl ester of synthesis.In addition, the lipid acid of such as oleic acid finds purposes in the preparation of injectable drug.

Pharmaceutical composition can also be used for suppository form or the enema of the rectal administration of medicine.These compositions by prepared by medicine and suitable non-irritating mixed with excipients, described non-irritating vehicle be solid at normal temperatures but under rectal temperature be liquid and thus will melt in the rectum to discharge medicine.Such material comprises, such as, and theobroma oil and polyoxyethylene glycol.

Local is used, adopts the ointment, ointment, suspensoid, lotion, powder, solution, paste, gelifying agent, sprays, aerosol, oil formulation or the transdermal patch that comprise the compounds of this invention.As used herein topical application is also intended to the purposes comprising collutory and mouth-washes.

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 every day.Use for intravenous, in the infusion process of conventional rate, most preferred dosage range is about 1 to about 10mg/kg body weight per 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.

But, be to be understood that, can change for the concrete dosage level of any particular patient and administration frequency, and will many factors be depended on, comprise the activity of the particular compound of use, the metabolic stability of this compound and effect duration, age, body weight, general health, sex, diet, mode of administration and time, rate of discharge, drug regimen, the seriousness of particular condition and decent subject host.

The compounds of this invention can use with the second therapeutical agent, described second therapeutical agent can be used for treatment, prevention, suppress or improve the compounds of this invention to its useful disease or situation, comprise unstable angina, acute coronary syndrome, onset myocardial infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease, venous thrombosis, dvt is formed, thrombophlebitis, arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis is formed, cerebral embolism, renal infarction, pulmonary infarction, with by (a) artificial valve or other implant, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, e blood is caused thrombus in other processes of the thrombotic artificial surface of promotion by () hemodialysis or (f).The second therapeutical agent is like this by normally used approach and with normally used amount thus side by side, sequentially or dividually use with the compounds of this invention.When the compounds of this invention and one or more other drugs use the same period, except the compounds of this invention, preferably comprise the second such therapeutical agent.Therefore, pharmaceutical composition of the present invention comprises except the compounds of this invention also comprises one or more the second therapeutical agents.

Second therapeutical agent include, but are not limited to, the anti-coagulant that the second Xa factor inhibitor and non-Xa factor suppress, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent or its combination.

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 the compounds of this invention and thrombolytics combined administration, general per daily dose can be the compound of per kilogram patient body weight about 0.1 to the formula (I) of 1mg, and 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 weight ratio of the compounds of this invention and the second activeconstituents can change and will depend on the effective dose of often kind of composition.Usually, often kind of effective dose will be used.The combination of the compounds of this invention and other activeconstituentss also in aforementioned range, but in each case, will should use the effective dose of often kind of activeconstituents usually.

The purposes of the compounds of this invention and pharmaceutical composition

The invention provides compound of the present invention or pharmaceutical composition is preparing the purposes in medicine, described medicine may be used for suppressing Xa factor.Described medicine may be used for prevention, treatment, alleviate or delay unstable angina, acute coronary syndrome, onset myocardial infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease, venous thrombosis, dvt is formed, thrombophlebitis, arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis is formed, cerebral embolism, renal infarction, pulmonary infarction, with by (a) artificial valve or other implant, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, e blood is caused thrombus in other processes of the thrombotic artificial surface of promotion by () hemodialysis or (f).

Comprise the methods for the treatment of of the compounds of this invention or pharmaceutical composition administration, comprise further patient to the anti-coagulant of the second Xa factor inhibitor, the suppression of non-Xa factor, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent or its combination.

" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.

Compound of the present invention (in this article, form of presentation " formula (I) compound and steric isomer thereof, geometrical isomer, tautomer, mesomeride, racemic modification, enantiomer, diastereomer, oxynitride, hydrate, solvate, meta-bolites and pharmacy acceptable salt and prodrug " can be referred to as " compound of the present invention "), may be used for producing pharmaceutical prod for prevention, treatment, alleviate or delay unstable angina, acute coronary syndrome, onset myocardial infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease, venous thrombosis, dvt is formed, thrombophlebitis, arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis is formed, cerebral embolism, renal infarction, pulmonary infarction, with by (a) artificial valve or other implant, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, e blood in the thrombus that other processes cause promoting thrombotic artificial surface, is comprised that those are described in the invention by () hemodialysis or (f).Further, compound of the present invention may be used for suppressing Xa factor.Thus, compound of the present invention may be used for producing a kind of pharmaceuticals and is used for alleviating, stop, control or treat the illness that Xa factor mediates.Thus, compound of the present invention can be used as the activeconstituents of pharmaceutical composition, this pharmaceutical composition can comprise the compound representated by formula (I), can also comprise the pharmaceutically acceptable carrier of at least one, vehicle, thinner, assistant agent and vehicle further.

General building-up process

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 AldrichChemicalCompany, Inc., ArcoChemicalCompany and AlfaChemicalCompany, 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, dioxane, toluene, ether are through sodium Metal 99.5 backflow drying and obtain.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF 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 CDCl ₃, DMSO-d ₆, CD ₃oD or acetone-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), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, two are bimodal), dt (doubletoftriplets, two triplet).Coupling constant J unit is hertz (Hz).

Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and aG1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315BDAD 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 G1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315DDAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.

Above two kinds of spectrographs are provided with AgilentZorbaxSB-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 Agilent1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, ZorbaxSB-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:

G gram

Mg milligram

Mmol mmole

Ml, mL milliliter

L liter

DEG C degree Celsius

¹hNMR hydrogen 1 NMR (Nuclear Magnetic Resonance) spectrum

¹³cNMR carbon-13 magnetic resonance wave spectrum

MS mass spectrum

MHz megahertz

Hz hertz

DMSO-d ₆deuterated dimethyl sulfoxide

CDCl ₃deuterochloroform

CD ₃oD deuterated methanol

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

FXa activated clotting factor ten

Reaction scheme 1

The method that compound 8 can be described by reaction scheme 1 prepares.Wherein, R ²define as described herein.

Compound 1 and compound 2 close ring in the basic conditions and obtain compound 3.Compound 3 and Isosorbide-5-Nitrae-diiodo-benzene are at alkali (as cesium carbonate, salt of wormwood), under ketone salt (as cuprous iodide) and part (as N, N'-dimethyl ethyl-1,2-diamines) exist, in solvent (as dioxane, toluene), reacting by heating obtains compound 4.Compound 4 and intermediate M1 at alkali (as cesium carbonate, salt of wormwood), ketone salt (as cuprous iodide) and part are (as (1R, 2R)-N, N'-dimethyl-1,2-cyclohexanediamine) exist under, reacting by heating obtains compound 5 in solvent (as dioxane, toluene).Compound 5 and compound 6 are obtained by reacting compound 7 under condensing agent exists.Compound 7 solves compound 8 through ammonia.

Intermediate

1-(4-p-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester

Step 1) 3,3-bis-Chloperastine-2-ketone

At-5 DEG C, 2-piperazine ketone (30g, 303mmol) is dissolved in chloroform (500mL), adds phosphorus pentachloride (150g, 757.5mmol), at-5 DEG C, stir 10 minutes post-heating reflux 2 hours.Be chilled to room temperature, add frozen water (300mL), at room temperature stir 12 hours.Add methylene dichloride (100mL × 2) extraction, merge organic phase, use water (50mL × 2) and saturated aqueous common salt (50mL) washing successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, obtains faint yellow solid (22g, 43.4%).

MS(ESI,pos.ion)m/z:168.0(M+1).

Step 2) morpholinyl-5,6-dihydropyridine-2 (1H)-one

3,3-bis-Chloperastine-2-ketone (22.0g, 131.7mmol) is dissolved in morpholine (80mL).Then be heated to 140 DEG C stir 12 hours.Be chilled to room temperature, pressure reducing and steaming solvent.Thick product, through column chromatography purification (methylene chloride/methanol (v/v)=20/1), obtains white solid (13g, 55%).

MS(ESI,pos.ion)m/z:182.2(M+1).

Step 3) the chloro-2-of (E)-2-(2-(4-p-methoxy-phenyl) hydrazine fork) ethyl acetate

Below-5 DEG C, by Sodium Nitrite (12.2g, 176.8mmol) be dissolved in after in water (60mL), dropwise join in ethanol (41.4mL) solution of P-nethoxyaniline (20g, 162.4mmol) and concentrated hydrochloric acid (41.4mL).Stir at-5 DEG C after 20 minutes, add sodium-acetate (36.42g, 444mmol), the mixing solutions that 2-chloroacetyl acetacetic ester (30mL) is dissolved in (ethanol/water (v/v)=9/1) (450mL) is dripped subsequently.Stir 20 minutes at-5 DEG C after dropwising.Filter, filter cake washes with water.With ethanol/water (v/v)=9/1 mixed solution recrystallization, obtain white solid (25g, 65%).

MS(ESI,pos.ion)m/z:257.0(M+1).

Step 4) 1-(4-p-methoxy-phenyl)-7a-morpholinyl-7-oxo-3a, 4,5,6,7,7a-six hydrogen-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester

By the chloro-2-of (E)-2-(2-(4-p-methoxy-phenyl) hydrazine fork) ethyl acetate (10.1g, 39.5mmol) be dissolved in ethyl acetate (80mL), be cooled to 5 DEG C, add morpholinyl-5,6-dihydropyridine-2 (1H)-one (6.0g, 33mmol).Slowly add ethyl acetate (30mL) solution of triethylamine (18.5mL, 132mmol) again.Rise to stirring at room temperature after 0.5 hour, continue reflux and stir 12 hours.After being chilled to room temperature, add frozen water (50mL).Extract by ethyl acetate (50mL × 3).Merge organic phase, with saturated aqueous common salt (30mL) 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 yellow solid (6.55g, 55%).

MS(ESI,pos.ion)m/z:403.1(M+1).

Step 5) 1-(4-p-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester

By 1-(4-p-methoxy-phenyl)-7a-morpholinyl-7-oxo-3a, 4,5,6,7,7a-six hydrogen-1H-pyrazolo [3,4-c] pyridine-3-acetic acid ethyl ester (6.4g, 16mmol) is dissolved in ethyl acetate (100mL), is cooled to 5 DEG C.Dropwise add dilute hydrochloric acid (30mL, 4M), stir 4 hours at 5 DEG C after dropwising.Pressure reducing and steaming solvent, extracts with methylene dichloride (50mL × 4).Merge organic phase, with saturated aqueous common salt (30mL) 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 (5.1g, 95.0%).

MS(ESI,pos.ion)m/z:316.1(M+1)。

Embodiment 1

(S)-6-(4-(4-(2-hydroxypropanoyl)-2-oxypiperazin-1-base) phenyl)-1-(4-p-methoxy-phenyl)-7-oxo-4; 5; 6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide

Step 1) piperazine-2-ketone

Under room temperature, to 1,2-quadrol (6.01g, ethanol (10mL) solution of 2-ethyl bromoacetate (1.67g, 10mmol) is slowly dripped, after being added dropwise to complete in ethanol (25mL) solution 100mmol), reaction mixture stirring at room temperature 2 hours, add sodium ethylate (680.5mg, 10mmol) again, room temperature continues stirring and spends the night.Pressure reducing and steaming solvent, thick product through column chromatography purification (methylene chloride/methanol/ammoniacal liquor (v/v/v)=9/1/0.1), then obtains yellow solid (0.8g, 79.84%) with acetone recrystallization.

MS(ESI,pos.ion)m/z:101(M+1).

Step 2) 1-(4-iodophenyl) piperazine-2-ketone

Under nitrogen protection; to 1; 4-diiodo-benzene (4g; 12.12mmol), piperazine-2-ketone (0.8g, 8.00mmol), cuprous iodide (0.31g, 1.62mmol), salt of wormwood (3.3g; 24.2mmol) and N; Isosorbide-5-Nitrae-dioxane (30mL) is added in the mixture of N'-dimethyl-ethylenediamine (0.16g, 1.62mmol).Reaction mixture is heated to 110 DEG C and stirs after 8 hours, is chilled to room temperature.Reaction solution is poured onto (50mL) in water, with ethyl acetate (40mL × 3) extraction, merges organic phase, uses water (30mL × 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 (ethyl acetate/petroleum ether (v/v)=1/2), obtains yellow solid (1.88g, 77.0%).

MS(ESI,pos.ion)m/z:303(M+1)；

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.73-7.71(d,J＝8Hz,2H),7.08-7.06(d,J＝8Hz,2H),3.68-3.65(m,4H),3.23-3.20(t,J＝6Hz,4H).

Step 3) 1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxypiperazin-1-base) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl esters

Under nitrogen protection; to 1-(4-p-methoxy-phenyl)-7-oxo-4; 5; 6; 7-tetrahydrochysene-1H-pyrazolo [3; 4-c] Nicotinicum Acidum ethyl ester (0.9g; 2.85mmol), 1-(4-iodophenyl) piperazine-2-ketone (0.78g, 2.38mmol), cuprous iodide (0.09g, 0.47mmol), potassiumphosphate (1.1g; 4.7mmol) with (1R; 2R)-N, N'-dimethyl-1,2-cyclohexanediamine (0.07g; Isosorbide-5-Nitrae-dioxane (5mL) is added in mixture 0.47mmol).Reaction mixture is heated to 120 DEG C and stirs 8 hours, is chilled to room temperature.Add water (15mL) cancellation, with ethyl acetate (15mL × 3) extraction, merge organic phase, use water (15mL × 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 (ethyl acetate/petroleum ether (v/v)=2/3), obtains yellow solid (0.9g, 57.27%).

MS(ESI,pos.ion)m/z:303(M+1).

Step4) (S)-6-(4-(4-(2-hydroxypropanoyl)-2-oxypiperazin-1-base) phenyl)-1-(4-p-methoxy-phenyl)-7-oxo-4; 5; 6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester

To 1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxypiperazin-1-base) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (146.9mg, N 0.3mmol), (S)-2 hydroxy propanoic acid (30mg is added successively in dinethylformamide (3mL) solution, 0.3mmol), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (114mg, 0.3mmol), DIPEA (30mg, 0.24mmol).Reaction mixture, extracts by ethyl acetate (10mL × 3) down in water (10mL) in stirring at room temperature hypsokinesis in 2 hours.Merge organic phase, use water (10mL × 2), saturated aqueous common salt (15mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (methylene chloride/methanol (v/v)=15/1), obtains white solid (90mg, 76%).

MS(ESI,pos.ion)m/z:534.1(M+1).

Step 5) (S)-6-(4-(4-(2-hydroxypropanoyl)-2-oxypiperazin-1-base) phenyl)-1-(4-p-methoxy-phenyl)-7-oxo-4; 5; 6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide

(S)-6-(4-(4-(2-hydroxypropanoyl)-2-oxypiperazin-1-base) phenyl)-1-(4-p-methoxy-phenyl)-7-oxo-4 is added successively in tube sealing; 5; 6; 7-tetrahydrochysene-1H-pyrazolo [3; 4-c] Nicotinicum Acidum ethyl ester (40mg; 0.7mmol) and methyl alcohol (1mL, the 25%) solution of ammonia.Tube sealing, under nitrogen protection, is heated to 70 DEG C and stirs 8 hours.Be chilled to room temperature, pressure reducing and steaming solvent, thick product, through column chromatography purification (methylene chloride/methanol (v/v)=15/1), obtains white solid (8.0mg, 22%).

MS(ESI,pos.ion)m/z:533.3(M+1)；

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.47-7.45(d,J＝8Hz,2H),7.37-7.35(d,J＝8Hz,2H),7.29(m,2H),6.94-6.92((d,J＝8Hz,2H),6.84(s,1H),5.46(s,1H),4.22-4.12(m,2H),3.82(s,3H),3.78-3.67(m,4H),3.40-3.37(t,J＝8Hz,3H),1.45(s,3H).

Biological activity test

Mankind FXa enzyme level is tested

The enzymic activity of mankind's factor Xa (FXa) is by the transformation assay for the specific chromogenic substrate of FXa.To this, p-Nitraniline is fallen in factor Xa cracking from chromogenic substrate.This is determined as follows to state and carries out on microwell plate.

Tester is dissolved in the methyl-sulphoxide of 10% by different concns, (10nM is dissolved in 50mMTris to get compound 5 μ L and mankind FXa, 150mMNaCl, pH=8.3) 10 μ L mix, 15min is hatched in 25 DEG C of constant incubators, FXa chromophoric substrate (800 μMs, sigma) 5 μ L is added, in 25 DEG C of 405nm place kinetic test absorbances after hatching.By the test mixing thing containing test substances and not containing test substances control mixture relatively and calculate IC by these data ₅₀value.

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 (10mM) 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 1.5mLEP pipe, 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 SysmexCA1500 Automatic coagulometer; Draw amount effect curve, matching is carried out to curve, calculate the concentration (CT2) of the test compounds that the clotting time of sening as an envoy to doubles thus.

Compound is to the restraining effect of people FXa activity and anticoagulation effect in vitro

A:1.00nM-10.00nM; B:10.01nM-100.00nM; C:100.01nM-1.00 μM; D:1.01 μM of-10.00 μMs of conclusions: this series compound has good factor Xa inhibit activities, have 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	0.90

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

1. a compound, it is for such as formula the compound shown in (I), or the pharmacy acceptable salt of the compound shown in formula (I),

R ¹for amino-C (=O)-; With

R ²for methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or isobutyl-, described methyl, ethyl, n-propyl, sec.-propyl, normal-butyl and isobutyl-are replaced by the substituting group that 1 is independently selected from amino or hydroxyl independently of one another.

2. compound according to claim 1, comprises one of them structure following:

Or its pharmacy acceptable salt.

3. a pharmaceutical composition, described pharmaceutical composition comprises the compound according to any one of claim 1-2.

4. pharmaceutical composition according to claim 3, comprises pharmaceutically acceptable carrier, vehicle, thinner, vehicle or its combination further.

5. pharmaceutical composition according to claim 4, its further comprise non-Xa factor suppress anti-coagulant, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent or its combination.

6. the pharmaceutical composition according to any one of claim 3-5, it further comprises the second Xa factor inhibitor.

7. the compound according to any one of a claim 1-2 or the pharmaceutical composition described in any one in claim 3-6 are for the preparation of prevention, treatment, alleviate or delay unstable angina, acute coronary syndrome, onset myocardial infarction, recurrent cardiac infarction, ischemic sudden death, transient ischemic attack, apoplexy, arteriosclerosis, periphery obstructive arterial disease, venous thrombosis, dvt is formed, thrombophlebitis, arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis is formed, cerebral embolism, renal infarction, pulmonary infarction, with by (a) artificial valve or other implant, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, (e) hemodialysis or (f) by blood in promote other processes of thrombotic artificial surface cause in the medicine of thrombus purposes.