CN104277039B - Contain the pyrazoles piperidone compounds and composition thereof and purposes that replace butynyl - Google Patents

Abstract

The present invention relates to pyrazoles and 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 replace the pyrazoles of butynyl and 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

Contain the pyrazoles piperidone compounds and composition thereof and purposes that replace butynyl

Technical field

The present invention relates to pyrazoles and 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 replace the pyrazoles of butynyl and 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.

Background of invention

The main practical function of Xa factor of activation is by the limited proteolysis of zymoplasm is produced zymoplasm, and Xa factor occupies central position in the final general path of blood coagulation, and it in connection with inherent with external activate mechanism. Zymoplasm is the final serine protease in the path of generation fibrin clot. By forming Prothrombin Complex Concent-(Xa factor, factor ��, Ca²⁺And phosphatide) amplify zymoplasm by the generation of 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 suppressing in the interference in blood coagulation system the Xa factor may be more effective than making thrombin inactivation.

Consequently, it is desirable to effective and special Xa factor inhibitor is 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 it is not limited to, pharmacy characteristic is (such as solubleness, perviousness and the adaptability to sustained release formula), dosage demand (such as lower dosage and/or dosage once a day), reduce the factor (such as clearance rate and/or volume of distribution) of the haemoconcentration characterized with peak paddy, the factor increasing active medicine concentration is (such as protein binding, volume of distribution), reduce between clinical medicine the factor (suppressing or induction) of the tendency interacted such as cytochrome P 450 enzymes, the factor of possibility reducing adverse side effect is (such 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).

Invention summary

The present invention provides a kind of compound or its pharmaceutical composition, it is possible to effectively suppresses Xa factor, treats 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 front medicine

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

Each R²It is independently hydrogen, oxo, halogen, C_1-6Alkyl or C_1-6Alkoxyl group;

WhenDuring for singly-bound, X is O, NH or CH₂;

WhenDuring for double bond, X is N or CH;

N and m is 0,1,2 or 3 independently of one another; With

R is 0,1,2,3 or 4.

In certain embodiments, the present invention relates to a kind of steric isomer such as formula the compound shown in the compound shown in (II) or formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or front medicine

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

Each R²It is independently hydrogen, oxo, halogen, C_1-4Alkyl or C_1-4Alkoxyl group.

In further embodiments, R¹For 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

Each R²It is independently hydrogen, oxo, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy or isobutoxy.

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 front medicine.

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

In certain embodiments, described pharmaceutical composition comprise further pharmaceutically acceptable carrier, vehicle, thinner, auxiliary dose, vehicle or its combination.

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

In other embodiment schemes, described pharmaceutical composition, it further comprises the 2nd kind of 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 sugar 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 the purposes in the medicine of thrombus by () hemodialysis or (f) in other processes of the artificial surface promoting thrombosis.

The present invention relates on the other hand formula (I) or formula (II) comprises the preparation of compound, 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 term

Describing certain embodiments of the present invention in detail now, the example is by the structural formula enclosed and chemical formula explanation. The invention is intended to contain all replacements, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition. Those skilled in the art will recognize that, many similar with described herein or that be equal to method and material can be used in practice. The present invention is never limited to method as herein described and material. Different from the application or when contradicting (term that includes but not limited to define, term application, described technology, etc.) at one or more of the document combined, patent and analogous material, it is as the criterion with the application.

It is further recognized that some feature of the present invention, for clearly visible, should be described in multiple independent embodiment, but can also provide in combination in single embodiment. Otherwise, the various features of the present invention, for brevity, are described in single embodiment, but can also provide separately or with the sub-portfolio being 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 be incorporated to the present invention.

Unless otherwise indicated, it should application is used to obtain following definition herein. 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 whole content is incorporated to herein by reference.

Unless otherwise illustrating or have obvious conflict in context, 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 enforcement mode 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, the male sex or women), 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.

Stereochemistry used in the present invention definition and rule generally follow 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 activity form, and namely they have the ability that the plane of plane polarized light is rotated. When describing optically active compound, it may also be useful to prefix D and L or R and S represents the absolute configuration of molecule about one or more chiral centre. Prefix d and l or (+) and (-) are used to specify the symbol that plane polarized light caused by compound rotates, wherein (-) or l represent that compound is left-handed. Prefix for (+) or the compound of d be dextrorotation. Concrete steric isomer is an enantiomer, and the mixture of this kind of 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, this kind of situation can occurs.

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 form 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 quantity depending on 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.

Optical antipode can be split into, e.g., by being separated by its diastereoisomeric salt obtained by the method that the racemic modification of any gained end product or intermediate is familiar with by known method by those skilled in the art. The product of racemize can also be separated by chiral chromatography, as, it may also be useful to 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 ��, 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 " tautomerism form " refer to the constitutional isomer building (lowenergybarrier) mutual conversion by low energy 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, such as keto-enol isomerization and imine-enamine isomerizations also referred to as Prototropic tautomers (prototropictautomer). Valency key tautomer (valencetautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss. The specific examples of keto-enol tautomerism is pentane-2,4-diketone and the change of 4-hydroxyl penta-3-alkene-2-keto tautomer. Another example of tautomerism is phenol-keto tautomerism. A specific examples of phenol-keto tautomerism is pyridine-4-alcohol and the change of pyridine-4 (1H)-one tautomer. Unless otherwise noted, all tautomeric forms of the compounds of this invention are all within the scope of the present invention.

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

In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopts in the present invention " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should being interpreted broadly, it both can refer in different group, does not affect mutually between concrete option expressed between same-sign, can also represent in identical group, not affect mutually between concrete option expressed between same-sign. Such as structureAnd structureR in both²Concrete option is not influenced each other, meanwhile, occurs multiple R in same structure², multiple R²Between concrete option be independent of each other, i.e. R²Concrete option can be identical, it is also possible to different.

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 pointing out, the present invention comprises each independent sub-combinations thereof of each member of these radical species and scope. Such as, term " C_1-6Alkyl " refer in particular to independent disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

At each several part of the present invention, describe connection substituting group. When this structure clearly needs linking group, the Ma Kushi variable cited by this group is interpreted as linking group. Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then it is to be understood that " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.

The 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 that 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 replaces containing 1 to 20 carbon atom. 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, the own base of 3-, n-heptyl, n-octyl etc.

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

Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention. Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom. In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom. The substituting group that described alkoxy base can optionally be described by one or more the present invention replaces.

Term " oxo " represents that oxygen links with double bond with the atom of the position of substitution, namely=O, as carbon oxo be-(C=O)-.

Term " amino " represents for-NH₂��

Term "" or "" represent singly-bound or double bond.

Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, it is commonly used to block or protect special functional. Such as; " blocking group of amino " refers to that a substituting group is connected with amino group and blocks or protect the functional of amino in compound; suitable amido protecting group comprises ethanoyl; trifluoroacetyl base; tertiary butoxy carbonyl (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-CH₂CH₂SO₂Ph; cyano ethyl; 2-(trimethylammonium silylation) ethyl; 2-(trimethylammonium silylation) ethoxyl methyl; 2-(tolysulfonyl base) 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 " front medicine ", represents a compound and is converted into the compound shown in formula (I) or formula (II) in body. 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, and namely its acidylate can obtain the compound of prodrug form. other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that the di on parent obtains. can with reference to following 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 the product that concrete compound or its salt is obtained in body by metabolism. The meta-bolites of a compound can be identified by the known technology of art, and its activity can adopt the method for test to characterize by as described in the present invention such. Such product can be by passing through oxidation to drug compound, reduction, hydrolysis, amidated, and de-acyl ammonia effect, esterification, fat abstraction, enzymatic lysis etc. method obtains. Correspondingly, the present invention comprises the meta-bolites of compound, comprises the meta-bolites that the compound of the present invention and Mammals are fully contacted for some time and produced.

" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention. pharmacy acceptable salt at art known by us, such as document: S.M.Bergeetal., describepharmaceuticallyacceptablesaltsindetailinJ.Pharm aceuticalSciences, described in 1977,66:1-19.. the salt of pharmaceutically acceptable nontoxic acid formation comprises, but is not limited to, and the inorganic acid salt formed with amino group reaction has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is such 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, dextrocamphoric acid salt, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonic acid salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, flutter acid salt, pectate, persulphate, 3-phenylpropionic acid salt, picrate, trimethylacetic acid salt, propionic salt, stearate, thiocyanate-, tosilate, undeeanoic acid salt, valerate, etc.. the salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt. The present invention also intends contemplating the quaternary ammonium salt that the compound of the group of 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 ammonium suitable, nontoxic further, the amine positively charged ion that quaternary ammonium salt and anti-counterion are formed, such as halogenide, oxyhydroxide, carboxylate, and 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 the compound of one or more solvent molecule and the present invention is 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 alleviate 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 discernable symptom) or physiology (such as stablizes 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, stearic acid salt, oleate, oxalate, palmitate, flutter acid salt, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-galactosonic acid salt, 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.

Can be formed with mineral alkali and organic bases by acceptable base addition salt.

Can comprise by its derivative mineral alkali obtaining salt, the metal of the I race of such as ammonium salt and periodictable to XII race. 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 salt.

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

The pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety by conventional chemical method. Generally speaking, such salt can by the suitable alkali of the free acid form and stoichiometry that make these compounds (such as the oxyhydroxide of Na, Ca, Mg or K, carbonate, supercarbonate etc.) reaction, or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared. Such reaction carries out usually in water or organic solvent or the mixture of the two. Generally, when suitable, it is necessary to use non-aqueous media such 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) list of the suitable salt of other can be found in.

In addition, compound disclosed by the invention, the salt that comprises them, it is also possible to their hydrate forms or comprise its solvent (such as ethanol, methyl-sulphoxide (DMSO), etc.) form obtain, for their crystallization. The present invention come into the open compound can with the intrinsic ground of pharmaceutically acceptable solvent (comprising water) or by design forming solvate; Accordingly, it is intended to comprise the form with non-solvation of solvation.

As described in the present invention, substituting group draw a key be connected on the ring at center formed member ring systems (such as formula (a) Suo Shi) represent substituent R⁵Can replace the position in any desirable generation on ring. Such as, formula (a) represents any position that may be replaced on W1 ring or W2 ring and all can be replaced.

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

The present invention provides the pharmaceutical composition being suitable for compound medicinal, that comprise one or more the present invention. this pharmaceutical composition can also comprise further pharmaceutically acceptable carrier, vehicle, thinner, auxiliary dose, vehicle or its combination. 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 blood is caused thrombus in other processes of the artificial surface promoting thrombosis by () hemodialysis or (f), especially, Xa factor is had good restraining effect by it.

The compounds of this invention can be used separately or use with one or more combination with other therapeutic agents. Pharmaceutical composition further comprises anti-coagulant that the 2nd kind of Xa factor inhibitor and/or non-Xa factor suppress, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent.

When can be used for treatment, the compounds of this invention for the treatment of significant quantity, especially formula (I) or formula (II) compound and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and also can be used as the activeconstituents of 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) or formula (II) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, thinner or vehicle. Term as used herein " treatment significant quantity " refers to the total amount being enough to demonstrate each active ingredient of meaningful patient's benefit. When using independent activeconstituents individually dosed, this term only refers to this composition. When Combination application, no matter this term then refers to combination, successively or during simultaneously administration, all causes the combined amount of the activeconstituents of result for the treatment of. The compounds of this invention, especially formula (I) or formula (II) compound and pharmacy acceptable salt thereof are described above. From compatible with other compositions of preparation and to, the harmless meaning of its recipient, carrier, thinner or vehicle must be acceptable. Another aspect according to content of the present invention, also it is provided for the method for useful in preparing drug formulations, the method comprises the compounds of this invention, and especially formula (I) or formula (II) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, thinner or vehicle mix even. Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope of reasonable medical judgment, it is applicable to contact with patient tissue and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and it is effective to set purposes.

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 normal dosage, it is more preferable to account for the about 10-80% of normal dosage. 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, skin, in flesh, in intraarticular, synovial membrane, in breastbone, in sheath, intralesional, intravenously or intradermal injection or defeated note) 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: making activeconstituents and liquid carrier or solid-state carrier in small, broken bits or both an equal ground and closely combines, then, if needed, making this product form required preparation. In pharmaceutical composition, the active target compound comprising enough amounts is with the effect desired by the process of disease or situation being produced.

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

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

Preparation for orally using also can be used as hard gelatin capsule and provide, wherein the inert solid mixing diluents of activeconstituents and such as calcium carbonate, calcium phosphate or kaolin; 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 manufacturing the mixed with excipients of aqeous suspension. Such vehicle is suspension agent, such as Xylo-Mucine, methylcellulose gum, hydroxyl-propyl methocel, sodium alginate, polyethylene-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 such as polyoxyethylene stearic acid ester, or oxyethane and long chain aliphatic alcohol are such as the condensation product of 17 vinyloxy group hexadecanols, or oxyethane with must from the condensation product of lipid acid and the inclined ester of hexitol such as octadecanoic acid ester of polyethylene glycol, or oxyethane with must from the condensation product of lipid acid and the inclined ester of hexitan such as polyethylene polyoxyethylene-sorbitan mono-oleate. Described aqeous suspension also can comprise one or more sanitass (such 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 (such as sucrose or asccharin).

Oil suspension is prepared in the vegetables oil of such as peanut oil, sweet oil, sesame oil or Oleum Cocois or in the mineral oil of such as whiteruss by being suspended in by activeconstituents. 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 adding the antioxidant of such as xitix.

Be suitable for preparing the pulvis dispersibled of aqeous suspension or granule provides with dispersion agent or wetting agent, suspension agent and one or more sanitass mix activeconstituents by adding water. 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 the 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, such as Sudan Gum-arabic or tragacanth gum; Naturally occurring phosphatide, such as soybean, Yelkin TTS and must such as, from the ester of lipid acid and hexitan or ester, polyoxyethylene-sorbitan mono-oleate partially; And the condensation product of described inclined ester and oxyethane, such as polyethylene polyoxyethylene-sorbitan mono-oleate. 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 be prepared according to the suitable dispersion agent that known technology, use have been mentioned above or wetting agent and suspension agent. 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. The acceptable vehicle that can use 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 medicine.

Pharmaceutical composition can also be used for suppository form or the enema of the rectal administration of medicine. These compositions are by preparing the mixed with excipients of medicine and suitable nonirritant, and the vehicle of described nonirritant is solid at normal temperatures but is that liquid also thus will melt to discharge medicine in the rectum under rectal temperature. 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 also is intended to comprise the purposes of collutory and mouth-washes.

According to general governing principle, in order to reach the effect specified, each activeconstituents used day oral dosage scope be about 0.001 between 1000mg/kg body weight, it may be preferred that between about 0.01 to 100mg/kg body weight. And, it is most preferable that between about 1.0 to 20mg/kg body weight every day. Using for intravenous, in the infusion process of conventional speed, dosage range most preferably is about 1 to about 10mg/kg body weight every minute. The compounds of this invention to use once a day, or can divide twice with every day, uses for three times or four times.

But, it is to be understood that, concrete dosage level and administration frequency for any particular patient can change, and multiple factor will be depended on, the host that the seriousness of length when comprising the activity of the particular compound of use, the metabolic stability of this compound and effect, age, body weight, general health, sex, diet, mode of administration and time, rate of discharge, drug regimen, particular condition and just standing is treated.

The compounds of this invention can use with the 2nd therapeutical agent, described 2nd 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 artificial surface promoting thrombosis by () hemodialysis or (f). such 2nd therapeutical agent by normally used approach and with normally used amount thus with the compounds of this invention simultaneously, sequentially or point turn up the soil and to use. when the compounds of this invention and one or more other drugs use the same period, except the compounds of this invention, it is preferable that comprise such 2nd therapeutical agent. therefore, the pharmaceutical composition of the present invention comprises except the compounds of this invention also comprises one or more the 2nd therapeutical agents.

2nd therapeutical agent comprises, but is not limited to, anti-coagulant, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent or its combination that the 2nd kind of Xa factor inhibitor and non-Xa factor suppress.

The 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 2nd antithrombotics that the formula (I) of about 0.1 to 100mg or the compound of (II) and about 1 arrive 7.5mg. For a kind of Tabules, the compound of the present invention can be generally that each dose unit has about 5 to 10mg, and the amount of the 2nd anti-agglutinant is that each dose unit has approximately from 1 to 5mg. Wherein, other anti-freezing reagent specifically comprises, but it is not limited to, Eliquis, razaxaban, Yi Dushaban, shellfish Qu Shaban, reaches than adding group, 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 the anti-platelet agents combined administration of one, general per daily dose can be that per kilogram patient body weight about 0.01 arrives the anti-platelet agents of 150mg to the formula (I) of 25mg or the compound and about 50 of (II), it is preferable that the formula (I) of about 0.1 to 1mg or the compound of (II) and about 1 arrive the anti-platelet agents of 3mg.

When the compounds of this invention and thrombolytics combined administration, general per daily dose can be that per kilogram patient body weight about 0.1 arrives the formula (I) of 1mg or the compound of (II), and the dosage of thrombolytics can reduce about 70-80%.

When using together with the compound of two or more aforesaid 2nd therapeutical agents and formula (I) or (II), generally, 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, it is possible to decline to some extent.

Especially, when the dose unit single as provides, there is the possibility that chemical reaction occurs between the activeconstituents of combination. Due to this reason, when the compound of formula (I) or (II) and the 2nd therapeutical agent are in a single dose unit during united, their compound method to be made the minimize physical contact between activeconstituents (namely be, reduce), although activeconstituents is combined 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 contact minimumization between the activeconstituents of associating, but also likely control a kind of release in the gastrointestinal tract in these compositions so that the one of these components does not discharge in stomach and discharges in small intestine. The material that activeconstituents a kind of can also wrap up the physical contact affecting its sustained release in the gastrointestinal tract and can be used for reducing between the activeconstituents of associating is further, the component of sustained release can also 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, one of them component polymer coating of a kind of lasting and/or molten release of intestines, and another component is also with polymer as the HYDROXY PROPYL METHYLCELLULOSE (HPMC) of a kind of low viscosity rank or other suitable material bag quilt known in the field, to reach the object of further isolating active composition. Polymer coating pair defines a kind of obstruction additionally with the reaction of other component.

Once understanding present disclosure, the minimized method of contact between the component of these and other the associating product making the present invention is very obvious for those skilled in the art, no matter they are used with single formulation or use with the form being separated, but be in the identical time or use in an identical manner.

The weight ratio of the compounds of this invention and the 2nd 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 usually also will in aforementioned range, but in each case, it should use the effective dose of often kind of activeconstituents.

The purposes of the compounds of this invention and pharmaceutical composition

Providing the compound of the present invention or pharmaceutical composition in the purposes preparing in medicine in the present invention, 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 artificial surface promoting thrombosis by () hemodialysis or (f).

Comprise the compounds of this invention or the methods for the treatment of of pharmaceutical composition administration, comprise the anti-coagulant, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent or its combination that patient are suppressed to the 2nd kind of Xa factor inhibitor, non-Xa factor further.

The compound of the present invention or " significant quantity " of pharmaceutically acceptable composition or " effective dose " refer to process or alleviate the significant quantity that one or more the present invention mentioned the severity of illness. Method according to the present invention, compound and composition can be any administration amount and any route of administration come effectively for the treatment of or alleviate the severity of disease. Situation according to patient is changed 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.

The compound of the present invention (herein, form of presentation " formula (I) or formula (II) compound and steric isomer thereof, geometrical isomer, tautomer, mesomeride, racemic modification, enantiomer, diastereomer, oxynitride, hydrate, solvate, meta-bolites and pharmacy acceptable salt and front medicine " can be referred to as " compound of the present invention "), it is possible to it is used for prevention for the production of pharmaceutical prod, 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 artificial surface promoting thrombosis by () hemodialysis or (f), comprise those described in the invention. further, the compound of the present invention may be used for suppressing Xa factor. thus, the compound of the present invention may be used for producing the illness that a kind of pharmaceuticals are used for alleviating, stop, control or treat Xa factor and mediate. thus, the 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) or formula (II), it is also possible to comprises the pharmaceutically acceptable carrier of at least one, vehicle, thinner, auxiliary dose and vehicle further.

General building-up process

Generally, the compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein the definition of substituting group is such as formula shown in (I) or formula (II). Reaction scheme and embodiment below are used for the further content illustrating the present invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing other compounds of many present invention suitablely, and other method for the preparation of the compound of the present invention is all contemplated within the scope of the present invention. Such as; the synthesis of the compound according to those non-illustrations of the present invention can successfully be completed by modifying method by the technician of art; as group is disturbed in suitable protection, 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 applicable to the preparation of other compounds of the present invention also generally acknowledgedly.

The embodiments described below, are decided to be degree Celsius unless other aspects show all temperature. Reagent is bought in goods providers such as AldrichChemicalCompany, Inc., ArcoChemicalCompany and AlfaChemicalCompany, it may also be useful to time all through being further purified, unless other aspects show. General reagent is from Xi Long chemical plant, Shantou, and Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu chemical company limited, Qingdao Teng Long chemical reagent company limited, and Qingdao Haiyang chemical plant are bought and obtained.

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, DMAC N,N' dimethyl acetamide and N, dinethylformamide is through the prior Dryly use of anhydrous sodium sulphate.

Hereinafter reacting is generally overlap a drying tube (unless showing in other) under nitrogen or argon gas positive pressure or on anhydrous solvent, 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 Qingdao Haiyang chemical plant. NMR (Nuclear Magnetic Resonance) spectrum is with CDC1₃��DMSO-d₆��CD₃OD or acetone-d₆For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiplet occurs time, abbreviation below will be used: s (singlet, single peak), d (doublet, bimodal), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, wide peak), dd (doubletofdoublets, two are bimodal), dt (doubletoftriplets, two triplet). Coupling constant J unit is hertz (Hz).

Algorithm (MS) data measure by being equipped with the spectrograph of the Agilent6320 series LC-MS of G1312A binary pump and aG1316ATCC (post 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 measure by being equipped with the spectrograph of the Agilent6120 series LC-MS of G1311A quaternary pump and G1316ATCC (post 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 ��m. 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 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(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 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 ��m, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, post temperature remains on 40 DEG C.

The use writing a Chinese character in simplified form 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 NMR (Nuclear Magnetic Resonance) spectrum

MS mass spectrum

MHz megahertz

Hz hertz

DMSO-d₆Deuterated dimethyl sulfoxide

CDCl₃Deuterochloroform

CD₃OD deuterated methanol

Pos.ion positive ion

Neg.ion negative ion

ESI electron spray ionisation

M/z quality charge ratio

PT plasma prothrombin time

The partial thromboplastin time of APTT activation

FXa activated clotting factor ten

Reaction scheme 1

Compound 5 can be prepared by the method that reaction scheme 1 describes. Wherein R²With r, there is definition of the present invention.

Compound 1 and 2, under potassium hydroxide and potassiumiodide exist, reacts to obtain compound 3 in dimethyl sulfoxide (DMSO). Compound 3 and oxalyl chloride, at N, react to obtain compound 4 under dinethylformamide catalysis. Compound 4 reacts to obtain compound 5 with the methanol solution of ammonia.

Intermediate

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

Step 1) 3,3-bis-chlorine piperidines-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. It is chilled to room temperature, adds frozen water (300mL), at room temperature stir 12 hours. Add methylene dichloride (100mL �� 2) extraction, merge organic phase, wash with water (50mL �� 2) and saturated aqueous common salt (50mL) successively, anhydrous sodium sulfate drying. Filtering, pressure reducing and steaming solvent, obtains faint yellow solid (22g, 43.4%).

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

Step 2) 3-morpholinyl-5,6-dihydropyridine-2 (1H)-one

3,3-bis-chlorine piperidines-2-ketone (22.0g, 131.7mmol) is dissolved in morpholine (80mL). Then it is heated to 140 DEG C stir 12 hours. It is 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, after 176.8mmol) being dissolved in water (60mL), dropwise join in ethanol (41.4mL) solution of P-nethoxyaniline (20g, 162.4mmol) and concentrated hydrochloric acid (41.4mL). After stirring 20 minutes at-5 DEG C, add sodium-acetate (36.42g, 444mmol), drip subsequently and add the mixing solutions that 2-chloroacetyl acetacetic ester (30mL) is dissolved in (ethanol/water (v/v)=9/1) (450mL). Stir 20 minutes at-5 DEG C after dropwising. Filtering, 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-pyrazoles also [3,4-c] Nicotinicum Acidum second ester

By the chloro-2-of (E)-2-(2-(4-p-methoxy-phenyl) hydrazine fork) ethyl acetate (10.1g, 39.5mmol) it is dissolved in ethyl acetate (80mL), it is cooled to 5 DEG C, add 3-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. Filtering, 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-pyrazoles also [3,4-c] Nicotinicum Acidum second ester

By 1-(4-p-methoxy-phenyl)-7a-morpholinyl-7-oxo-3a, 4,5,6,7,7a-six hydrogen-1H-pyrazoles also [3,4-c] pyridine-3-ethyl acetate (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. Filtering, 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

1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxo-piperidine-1-base) fourth-2-alkynes-1-base)-4,5,6,7-tetrahydrochysene-1H-pyrazoles also [3,4-c] pyridine-3-carboxamide

Step 1) the bromo-N-of 5-(4-chlorine fourth-2-alkynes base) valeramide

To 4-chlorine fourth-2-alkynes-1-amine (2.06g, methylene dichloride (120mL) solution 20.0mmol) adds triethylamine (8.4mL, 60mmol), it is chilled to-5 DEG C, slowly drip wherein and add 5-bromine valeryl chloride (4mL, methylene dichloride (20mL) solution 30mmol), is warming up to stirring at room temperature 2 hours. Reaction solution is successively with water (30mL �� 2), dilute hydrochloric acid (30mL �� 2,1M), saturated aqueous common salt (25mL) washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, thick product is through column chromatography purification (ethyl acetate), obtain colorless oil (5.33g, 100%).

Step 2) 1-(4-chlorine fourth-2-alkynes base) piperidines-2-ketone

Under nitrogen protection, in tetrahydrofuran (THF) (20mL) solution of the bromo-N-of 5-(4-chlorine fourth-2-alkynes base) valeramide (2g, 7.5mmol), add the sodium hydride (0.76g, 15mmol) of 60%, stirring at room temperature 4 hours. Adding water (10mL) cancellation, methylene dichloride (20mL �� 3) extracts, and merges organic phase, with saturated aqueous common salt (40mL) washing, and anhydrous sodium sulfate drying. Pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains colorless oil (1.00g, 71.9%).

Step 3) 1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxo-piperidine-1-base) fourth-2-alkynes base)-4,5,6,7-tetrahydrochysene-1H-pyrazoles also [3,4-c] Nicotinicum Acidum

Potassium hydroxide (130mg is added successively in the single port bottle of 50mL, 2mmol) with dimethyl sulfoxide (DMSO) (2mL), stirring at room temperature 15 minutes, add 1-(4-methoxyphenyl)-7-oxo-4 more wherein successively, 5,6,7-tetrahydrochysene-1H-pyrazoles also [3,4-c] Nicotinicum Acidum second ester (160mg, 0.5mmol), potassiumiodide (50mg, 0.3mmol) with 1-(4-chlorine fourth-2-alkynes base) piperidines-2-ketone (280mg, 1.5mmol). After reaction mixture stirs 1 hour under nitrogen protection; add water (10mL) cancellation wherein; extract with methylene dichloride (15mL �� 2); merge organic phase; successively with water (10mL), saturated aqueous common salt (15mL) washing, anhydrous sodium sulfate drying. Filtering, filtrate decompression boils off solvent, and thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), obtains faint yellow oily matter (120mg, 54.18%).

MS(ESI,pos.ion)m/z:437.2(M+1).

Step 4) 1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxo-piperidine-1-base) fourth-2-alkynes base)-4,5,6,7-tetrahydrochysene-1H-pyrazoles also [3,4-c] pyridine-3-formyl chloride

1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxo-piperidine-1-base) fourth-2-alkynes base)-4 is added in the single necked round bottom flask of 50mL, 5,6,7-tetrahydrochysene-1H-pyrazoles also [3,4-c] Nicotinicum Acidum (109mg, 0.25mmol), methylene dichloride (3mL) and N, dinethylformamide (1 �� L), oxalyl chloride (32 �� L) is added under stirring at 0 DEG C, continue to stir after 15 minutes, move to stirring at room temperature 3 hours. Reaction solution pressure reducing and steaming solvent, obtains white solid (114mg, 100%). Next step is directly carried out without the need to purifying.

Step 5) 1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxo-piperidine-1-base) fourth-2-alkynes-1-base)-4,5,6,7-tetrahydrochysene-1H-pyrazoles also [3,4-c] pyridine-3-carboxamide

At 0 DEG C, to the methyl alcohol (3mL of ammonia, 2.1mmol, solution 7M) adds 1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxo-piperidine-1-base) fourth-2-alkynes base)-4,5,6,7-tetrahydrochysene-1H-pyrazoles also [3,4-c] methylene dichloride (10mL) solution of pyridine-3-formyl chloride (114mg, 0.25mmol). Moving reaction mixture to stirring at room temperature 6 hours, pressure reducing and steaming solvent, thick product, through column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtains white solid (15mg, 14%).

MS (ESI, pos.ion) m/z:436.1 (M+1);

¹HNMR(400MHz,CDCl₃):��(ppm)7.45(2H,d),6.98(2H,d),6.83(1H,s),5.63(1H,s),4.29-4.32(2H,m),4.23-4.25(2H,m),3.85(3H,s),3.75(2H,t),3.38(2H,t),3.29(2H,t),2.39(2H,t),1.80-1.83(4H,m).

Biological activity test

Mankind's FXa enzyme level is tested

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

Tester is dissolved in the methyl-sulphoxide of 10% by different concns, (10nM is dissolved in 50mMTris to get compound 5 �� L and mankind FXa, 150mMNaCl, pH=8.3) 10 �� L mix, 25 DEG C of constant incubators hatch 15min, FXa chromophoric substrate (800 ��Ms, sigma) 5 �� L is added, in 25 DEG C of 405nm place kinetic test absorbances after hatching. By the test mixing thing containing test substances with do not compare containing the control mixture of test substances and calculate IC by these data₅₀Value.

External anticoagulation is tested

Compound extends the clotting time of rabbit plasma

1. the preparation of each concentration compound

Get the 4 each compound working fluids (10mM) of �� L, it is 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, collecting multitube, turn upside down mixed even several, 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 is pipe packing often, inserts rapidly-80 DEG C of Refrigerator stores for subsequent use.

3. add sample and measure the clotting time PT and APTT

Getting out 1.5mLEP pipe, often pipe adds 180 �� L plasma specimens; Adding the medicine of 4 �� L respective concentration in each pipe blood specimen respectively, control group adds 4 �� L dimethyl sulfoxide solutions, and concussion is mixed even, hatches 5min for 37 DEG C; PT and APTT is measured with SysmexCA1500 Automatic coagulometer; Draw amount effect curve, curve is carried out matching, thus calculate the concentration (CT of the test compounds that the clotting time of sening as an envoy to doubles₂)��

Compound is to the restraining effect of people's FXa activity and external anticoagulation

A:1.00nM-100.00nM; B:100.01nM-1.00 ��M; C:1.01 ��M-10.00 ��Ms; D:10.01 ��M of-50.00 ��Ms of conclusions: this series compound has good factor Xa inhibit activities, have the effect extending the clotting time simultaneously.

The solubleness test of compound

Adding water (10mL) in 15mL tapered tube, 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 ��m, �� 13mm), abandoning just filtrate, precision pipettes continuous filtrate (500 �� L), adds diluent acetonitrile-water (500 �� L, v/v=60/40), the two is mixed even, obtains need testing solution.

Get need testing solution (40 �� L), adopt HPLC detection, by one point external standard method calculation sample concentration:

Numbering	Compound dissolution degree (mg/mL)
		Embodiment 1	0.44

Conclusion: this series compound has good solubleness.

In the description of this specification sheets, at least one embodiment that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to be contained in the present invention in conjunction with concrete feature, structure, material or feature that this embodiment or example describe or example. In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example. And, the concrete feature 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 be carried out combining and combining by the technician of this area.

Although above it has been shown and described that embodiments of the invention, it is understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and above-described embodiment can be changed, revises, replace and modification by the those of ordinary skill of this area within the scope of the invention.

Claims (7)

1. a compound, it has such as formula the structure shown in (II), or the pharmacy acceptable salt of the compound shown in formula (II),

For singly-bound;

For singly-bound;

WhenDuring for singly-bound, X is CH₂;

R¹For amino-C (=O)-;

Each R²It is independently hydrogen, fluorine, methyl, ethyl or propyl group; With

R is 0 or 1.

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

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 or its combination further.

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

6. pharmaceutical composition according to any one of claim 3-5, it further comprises the 2nd kind of Xa factor inhibitor.

7. the compound according to any one of a claim 1-2 or the pharmaceutical composition described in arbitrary item 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 blood is caused the purposes in the medicine of thrombus by () hemodialysis or (f) in other processes of the artificial surface promoting thrombosis.