CN101065378A - Crystalline forms of a pyrazolo[3,4-c]pyridine factor xa inhibitor - Google Patents

Abstract

The instant invention provides crystalline forms of 1-(3-chlorophenyl)-7-oxo-6-[4-(2-oxo-1 (2H)pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and its solvates thereof; processes for the production of such crystalline forms; pharmaceutical compositions comprising such crystalline forms; and methods of treating thromboembolic disorders with such crystalline forms or such pharmaceutical compositions.

Description

Crystal formation as pyrazolo [3, the 4-c] pyridine of factor Xa inhibitor

Invention field

The present invention relates to 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the method of the crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide and solvate thereof, its preparation method, its pharmaceutical composition and treatment thrombotic disease thereof.

Background of invention

The main practical function of activation factor Xa is to produce zymoplasm by thrombogen is carried out limited proteolysis, and is in the critical positions that connects endogenous and exogenous activation mechanism in the final common pathway of blood coagulation.By forming thrombogen combined enzyme agent (factor Xa, factor V, Ca ²⁺And phosphatide) strengthen from this final serine protease during producing fibrin grumeleuse approach of zymoplasm precursor generation zymoplasm.Since the factor Xa that calculates 1 molecule can produce the zymoplasm (Elodi of 138 molecules, S., Varadi, K.:Optimizationof conditions for the catalytic effect of the factor IXa-factor VIIIComplex:Probable role of the complex in the amplification of bloodcoagulation.Thromb.Res.1979,15,617-629), so for disturbing the blood coagulation system, factor Xa is suppressed than making the zymoplasm inactivation may be more effective.

U.S. Patent Application Publication No. 2003/0191115 (it is hereby incorporated by reference) has disclosed 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide (hereinafter referred to as " compound (I) "):

Compound (I) is potent, selectivity coagulation factor xa inhibitors, therefore can be used for prevention or treatment thrombotic disease.

Need the mankind or the animal subjects of this treatment or prevention by the compound (I) that will treat significant quantity, can finish above-mentioned treatment of diseases or prevention.Can implement by it is united as single compound, as the pharmaceutical composition component or with other therapeutical agent with compound (I) treatment.Compound (I) but orally give, continuously venoclysis, intravenous injection gives or give with any other suitable pathways, so that preferably reach prevention is formed zymoplasm from thrombogen by factor Xa inductive required effect.

Do not know to exist the crystal formation of compound (I) in the past always.Need to show the required useful chemistry and the crystal formation of physical properties.Also need to be used for the reliable and reproducible method of preparation, purifying and preparation compound (I), so that its commercialization is feasible.The present invention relates to these aspects and other importance.

Summary of the invention

The invention provides crystal formation of following formula: compound (I) and preparation method thereof; The pharmaceutical composition that comprises this crystal formation; Method with this crystal formation or this medicine composite for curing thrombotic disease:

The embodiment of these crystal formations comprises that those this paper are described as the sign of N-3 crystal formation, N-1 crystal formation and N-2 crystal formation .5SBu-4 crystal formation and P-1 crystalline phase and P-3 crystalline phase.The description particular form used herein for example title of " N-3 " or the like should not be considered as restriction to physics other any material similar or identical with chemical property, but should be interpreted as more suitably that these titles only are identifiers, these identifiers should be explained according to the characteristic information that this paper also provides.

According to following detailed Description Of The Invention, these aspects of the present invention and others will be conspicuous.

The accompanying drawing summary

The present invention illustrates with reference to following description of drawings.

Fig. 1 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the C-13 CP-MAS SSNMR wave spectrogram of the N-3 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

The 1-that Fig. 2 shows observed (room temperature) (3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the x-ray diffractogram of powder (CuK α λ=1.5418 ) of the N-3 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Fig. 3 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl of calculating (22 ℃) and actual measurement (room temperature)]-4,5,6, the x-ray diffractogram of powder (CuK α λ=1.5418 ) of the N-1 crystal formation of pyrazolo [3,4-c] pyridine-3-carboxamide of 7-tetrahydrochysene-1H).

Fig. 4 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl of calculating (22 ℃) and actual measurement (room temperature)]-4,5,6, the x-ray diffractogram of powder (CuK α λ=1.5418 ) of the N-2 crystal formation of pyrazolo [3,4-c] pyridine-3-carboxamide of 7-tetrahydrochysene-1H).

The 1-that Fig. 5 shows observed (room temperature) (3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the x-ray diffractogram of powder (CuK α λ=1.5418 ) of the P-1 crystalline phase of pyrazolo [3,4-c] pyridine-3-carboxamide of 7-tetrahydrochysene-1H).

Fig. 6 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl of calculating (22 ℃) and actual measurement (room temperature)]-4,5,6, the x-ray diffractogram of powder (CuK α λ=1.5418 ) of the .5SBu-4 crystal formation of pyrazolo [3,4-c] pyridine-3-carboxamide of 7-tetrahydrochysene-1H).

Fig. 7 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the differential scanning calorimetric spectrogram of the N-3 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Fig. 8 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the differential scanning calorimetric spectrogram of the N-1 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Fig. 9 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the differential scanning calorimetric spectrogram of the N-2 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Figure 10 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the differential scanning calorimetric spectrogram of the P-1 crystalline phase of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Figure 11 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the differential scanning calorimetric spectrogram of the .5SBu-4 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Figure 12 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the thermogravimetric analysis Thermogram of the N-3 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Figure 13 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the thermogravimetric analysis Thermogram of the N-1 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Figure 14 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the thermogravimetric analysis Thermogram of the N-2 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Figure 15 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the thermogravimetric analysis Thermogram of the P-1 crystalline phase of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Figure 16 shows 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the thermogravimetric analysis Thermogram of the .5SBu-4 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Figure 17 shows observed (room temperature) 1-(3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the x-ray diffractogram of powder (CuK α λ=1.5418 ) of the P-3 crystalline phase of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Detailed Description Of The Invention

At least part of crystal formation that is provided as the compound (I) (especially with its pharmaceutically acceptable form) of new material of the present invention. Term used herein " pharmaceutically acceptable " refers to be applicable to contact tissue and animal tissue and does not have excessive toxicity, excitant, allergy or other problem or complication and have those compounds, material, composition and/or the formulation of rational interests/risk ratio in rational medical judgment scope. In some preferred embodiment, compound (I) is basically pure form. Term used herein " basically pure " refers to that the purity of compound is that compound (I) accounts for more than about 90% (weight) of compound weight, comprise more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99% (weight), also comprise equaling about 100% (weight). Remaining material comprises other form of this compound and/or reaction impurities and/or processes impurity from the processing of its preparation. For example, the crystal formation of compound (I) is regarded as basically pure, then be to be more than 90% (weight) with at this moment known and the measured purity of art-recognized means, wherein impurity is processed in other form of the following material inclusion compound (I) of all the other 10% (weight) and/or reaction impurities and/or processing.

Molecule, atom and/or ion that " polymorph " used herein refers to form crystal have identical chemical composition but the different crystal formation of space arrangement.

" solvate " used herein refers to comprise in addition the crystal formation that one or more solvent molecules mix molecule, atom and/or ion in the crystal structure. Solvent molecule in the solvate can present regularly arranged and/or lack of alignment. Solvate can comprise stoichiometric amount or the solvent molecule of amount of calculation non-chemically. For example, containing non-chemically, the solvate of amount of calculation solvent molecule can be produced by solvent partial loss in the solvate.

" amorphous " used herein refers to not the solid forms of molecule, atom and/or ion that can crystallization. Amorphous solid can not represent definite X-ray diffractogram.

Can use the method for known method of organic synthesis technology personnel and following patent literature instruction to prepare compound (I): patent application discloses No. 2003/0191115, United States Patent (USP) provisional application the 60/613rd, No. 754, the 60/637th, No. 623, the 60/613rd, No. 943 and the 60/613rd, No. 982 and the application (10066-NP, 10067-NP and 10381-NP) of submission simultaneously, whole disclosures of above-mentioned patent are hereby incorporated by reference.

With the DMF solution of methane amide and sodium methylate,, make compound (I) from ethyl ester (II) in 50 ℃～55 ℃.Slowly add ammonium hydroxide at 50-55 ℃.These slurries were cooled to 20-25 ℃ through at least 1 hour, and 20-25 ℃ of maintenance at least 1 hour.With this dope filtration, washing with acetone 1 time is used in water (WPUR) washing 2 times then.Then, products therefrom is 50 ℃ of vacuum-dryings in nitrogen gas stream, obtain P-1.

Crystal form samples can pure basically phase homogeneity provide, and expression exists a large amount of single polymorphic forms and optional a spot of one or more other polymorphic forms.Can pass through such as powder X-ray diffractometry (XRPD) or solid state nmr spectral method technology such as (SSNMR), the more than a kind of polymorphic form that exists in the working sample.For example, the extra peak that exists in the XRPD of experiment measuring figure and simulation XRPD scheme relatively can indicate more than a kind of polymorphic form in the sample.Can go out to simulate XRPD with monocrystalline X ray data computation, referring to Smith, D.K., " A FORTRAN Program for Calculating X-Ray Powder DiffractionPatterns; " Lawrence Radiation Laboratory, Livermore, Califomia, UCRL-7196, in April, 1963.Preferred crystal formation has as noted pure basically phase homogeneity explanation, and the extra peak area that lacks among the simulation XRPD figure accounts for below 10% of total peak area among the XRPD figure of experiment measuring, and is preferred below 5%, more preferably below 2%.Most preferably, the extra peak area that lacks among the simulation XRPD figure accounts for below 1% of total peak area among the XRPD figure of experiment measuring, and then crystal formation has pure basically phase homogeneity.

The method that is used to prepare crystal formation known in the art.Can be prepared by a number of procedures crystal formation, for example comprise from suitable solvent crystallization or recrystallization, from melts distillation, growth, be converted into from other phase solid-state, from crystalization in supercritical fluid and jet spraying.For example, comprise from the technology of solvent mixture crystallization or recrystallization crystal formation make solvent evaporation, reduce the solvent mixture temperature, the supersaturation solvent mixture of molecule and/or salt, plant under crystal seed, add anti-solvent (counter solvent) with the solvent mixture freeze-drying with in solvent mixture.Can adopt the high-throughput crystallization technology to comprise the crystal formation of polymorphic form with preparation.

The sign that comprises the preparation method of medicine crystal, medicine crystal of polymorphic form and medicine crystal is referring to Solid-State Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer and J.G.Stowell, second edition, SSCI, West Lafayette, Indiana, 1999.

For the crystallization technique that adopts solvent, to one or more choice of Solvent usually on deciding such as one or more following factors: the vapor pressure of the solubleness of compound, crystallization technique and solvent.Can adopt combination solvent, for example, compound can be dissolved in first solvent, add anti-solvent again to reduce the solubleness of compound in solution, to provide crystal formation to obtain solution.Anti-solvent is the lower solvent of compound dissolution degree.Be used to prepare the crystalline suitable solvent and comprise polar solvent and non-polar solvent.

In a kind of preparation crystalline method, compound (I) is suspended in suitable solvent and/or stir to obtain slurries, can heat slurries to promote its dissolving.Term used herein " slurries " is meant the saturated solution of compound (I), and this solution also can contain the compound (I) of additional quantity, with at specified temp, obtains the heterogeneity mixture of compound (I) and solvent.For example, in this respect, suitable solvent comprises the mixture of polar aprotic solvent, polar aprotic solvent and non-polar solvent and two or more described solvents.

For example, suitable polar aprotic solvent comprises acetone, methyl ethyl ketone (MEK), 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (DMPU), 1,3-dimethyl-2-imidazolidone (DMI), N-Methyl pyrrolidone (NMP), the N-methylacetamide, the N-methylformamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO) (DMSO), propionitrile, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate (IpOAc), butylacetate (BuOAc), tert.-butyl acetate, hexachloroacetone, two  alkane, tetramethylene sulfone, N, N-dimethyl propylene acid amides, Nitromethane 99Min., oil of mirbane and hexamethylphosphoramide.

For example, suitable polar aprotic solvent comprises pure and mild dibasic alcohol, for example methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, Virahol (IPA), 1-butanols (1-BuOH), 2-butanols (2-BuOH), isopropylcarbinol, the trimethyl carbinol, 2-nitroethyl alcohol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methyl cellosolve, cellosolvo, Diethylene Glycol, 1-amylalcohol, 2-amylalcohol, 3-amylalcohol, neopentyl alcohol, tertiary amyl alcohol, diethylene glycol monomethyl ether, hexalin, phenylcarbinol, phenol and glycerol.

For example, suitable non-polar solvent comprises methyl tertiary butyl ether (MTBE), hexane and heptane.

For example, preferred solvent comprises acetone, ACN, DMSO, DMF, NMP, MEK, 2-BuOH, IPA, IpOAc, MTBE and BuOAc.

Except those above-named examples, content disclosed according to the present invention is applicable to that other solvent of preparation compound (I) slurries is apparent to those skilled in the art.

Crystal seed can be joined any crystalline mixture to promote crystallization.As the technician understood, crystal seed perhaps was used as the means of crystallization control product size distribution as the means of the specific polymorphic form growth of control.Therefore, the calculating of required crystal seed amount is decided on available crystal seed size and required product median size, for example referring to " Programmed cooling ofbatch crystallizers; " J.W.Mullin and J.Nyvlt, Chemical EngineeringScience, 1971,26,369-377.Generally speaking, need the small particle size crystal seed effectively to control crystal growth in the batch of material.Can be by sieving, mill than macrocrystal or micronization or by making the solution micro-crystallization obtain the small particle size crystal seed.Should carefully mill or the micronization crystal makes it not produce any variation (promptly becoming amorphous or other polymorphic form) that departs from required crystal formation aspect degree of crystallinity.

Can under vacuum, filter through overcooled mixture, isolating solid can be with the washing of for example cold recrystallization solvent of suitable solvent, dry in feeding nitrogen, obtain required crystal formation.Can isolating solid be analyzed by suitable light splitting technology or analytical technology (for example SSNMR, DSC, XRPD etc.), formed preferred crystal formation product with conclusive evidence.The crystal formation that obtains is given birth to the volume production of the above fractional dose of about 70% (weight) of initial compound (I) weight of using in this crystallization procedure usually, but more than preferred 90% (weight).In case of necessity, this product can be milled altogether or allow this product sieve to disperse this product by mesh.

Can be directly from the reaction medium of the last treatment step of preparation compound (I), prepare crystal formation.For example, this can be by in the end using compound (I) from wherein crystalline solvent or mixed solvent are finished in the treatment step.Perhaps, can obtain crystal formation by distillation or solvent adding technology.The suitable solvent that is used for this purpose comprises any those solvents as herein described, comprises proton polar solvent (for example alcohol) and aprotic polar solvent (for example ketone).

As rule, reaction mixture can be filtered to remove any unwanted impurity, inorganic salt or the like, again with reaction solvent or recrystallisation solvent washing.Can be with the solution concentration that obtains to remove unnecessary solvent or gaseous component.If adopt distillation, the visual processing factor of the final quantity of the overhead product of Shou Jiing and changing then, for example, these factors comprise container size, stirring capacity or the like, as rule, can before solvent exchange is implemented, reaction solution be distilled to the initial volume of pact { mark (1/10) }.Can be to the reactant sampling analysis, to determine % (weight) product of level of response and conformance with standard treatment technology.If need, add again or remove reaction solvent, with the optimization reactant concn.Preferably final concentration is adjusted into about 50% (weight), forms slurries usually at this point.

Preferably directly solvent is joined in the reaction vessel and need not to distill this reaction mixture.The preferred solvent that is used for this purpose can finally participate in the solvent of lattice for those, and as mentioned above, they are relevant with exchange of solvent.Although factors such as the visual required purity of final concentration, the rate of recovery and changing, the final concentration of compound in the preferred solution (I) is about 4% to about 7%.Reaction mixture can stir after adding solvent, simultaneously heating.Illustrate in passing, reaction mixture stir about 1 hour can be heated to about 70 ℃ simultaneously.Preferably with the reactant filtered while hot, with solvent or its combination washing of reaction solvent, adding.Crystal seed can be joined any crystallization solution to start crystallization.

Various analytical technologies by known to use those of ordinary skills can be distinguished from each other out various forms described herein.These technology include but not limited to solid state nmr (SSNMR) spectral method, x-ray powder diffraction (XRPD), dsc (DSC) and/or thermogravimetry (TGA).

The existence form of compound (I) can be new crystal, solvate and/or the hydrate of pure form.Can adopt various solvents to prepare the solvate of compound (I).For example, preferred solvent comprises polar solvent, comprises polar aprotic solvent and polar aprotic solvent.For example, in a preferred form, the solvent that adopts in the preparation comprises DMF or acetone, preferred acetone.Compound in the solvate (I) can change with the ratio of solvent, and depends on the preparation method of for example selected concrete solvent and solvate.

N-3 (also claiming P-2), N-1 and these 3 kinds of pure crystal formations of N-2 (also claiming P-4), desolvation P-1 and half sec-butyl alcohol solvate .5SBu-4 crystal formation had mutually been identified already.

The N-3 crystal formation is purified crystallization and non-hygroscopic form.In one aspect of the present invention, the feature of the N-3 crystal formation of compound (I) can be C-13 SSNMR wave spectrogram shown in Figure 1.

At different aspect, the feature of N-3 crystal formation can be x-ray diffractogram of powder basically with shown in Figure 2 consistent.

At different aspect, the feature of N-3 crystal formation can be at about 22 ℃ of following x-ray diffractogram of powder and comprises following 2 θ values (CuK α λ=1.5418 ): 8.6 ± 0.2,11.4 ± 0.2,12.3 ± 0.2 and 15.6 ± 0.2.

At different aspect, the feature of N-3 crystal formation can be the middle peak of differential scanning calorimetric spectrogram (Fig. 7) and appears at about 245-253 ℃.

SSNMR and the research of XRPD indexing had proved already that the N-3 crystal formation was monophasic.In analyzing, TGA do not observe obvious weight loss during up to about 250 ℃.Proved already by the accelerated stability research of under 40 ℃/75% relative humidity/opening/4 weeks and 50 ℃/sealing/4 all conditions, carrying out that the N-3 crystal formation was physically very stable.Show that as moisture absorption and dehumidification institute the N-3 crystal formation is non-hygroscopic property, wherein absorb 0.4% moisture observing in 25 ℃, do not observe hysteresis phenomenon up to 95% relative humidity.The N-3 crystal formation tends to form very little aciculiform or bar-shaped primary particle (＜10 μ m).The N-3 crystal formation is more stable than N-1 and N-2 polymorphic form on thermodynamics in 25 ℃ to 60 ℃.

The N-1 crystal formation is from the pure crystal formation of heptane/2-butanol crystallizing under about 60 ℃.In one aspect of the present invention, the feature of the N-1 crystal formation of compound (I) can be unit cell parameters and is substantially equal to down train value:

Unit cell dimension: a=44.272 (1) 

b＝14.3594(4)

c＝20.9164(6)

β＝109.36(1)

Spacer C2/c

Molecule/asymmetry unit 3

Wherein this crystal formation is at+22 ℃ approximately.

At different aspect, it is as shown in table 3 basically that the feature of N-1 crystal formation can be mark atomic coordinate (fractional atomiccoordinate).

At different aspect, the feature of N-1 crystal formation can be the mark atomic coordinate basically shown in table 3a.

At different aspect, the feature of N-1 crystal formation can be x-ray diffractogram of powder basically with shown in Figure 3 consistent.

At different aspect, the feature of N-1 crystal formation can be at about 22 ℃ of x-ray diffractogram of powder and comprises following 2 θ values (CuK α λ=1.5418 ): 4.3 ± 0.2,10.1 ± 0.2,14.3 ± 0.2 and 17.1 ± 0.2.

The N-1 crystal formation is unstable physically, and as under 40 ℃/75% relative humidity/opening/4 weeks and 50 ℃/sealing/4 all conditions, XRPD figure significantly changes indicated in the pressurization stability test of sample.The N-1 crystal formation has experienced solid-state conversion at about 90 ℃, such as wet rank microscopic study (hot-stagemicroscopy study) proof; Be converted into the N-2 crystal formation at about 90 ℃, confirm as monocrystalline XRPD institute.Analyze in about 113 ℃ of a small amount of heat releases of demonstration by DSC (Fig. 8) and TGA heat, this is owing to the solid-state N-2 crystal formation that is converted to, then in the about 255 ℃ extremely about 259 ℃ fusions heat absorptions similar to N-2 crystal formation fusion range.

The N-2 crystal formation is pure crystal formation, and its monocrystalline can obtain from the N-1 crystal formation or the N-3 crystal formation of partial melting in the time of about 250 ℃.By the P-1 solid can be prepared N-2 powder in enormous quantities in about 230 ℃ of heating.In one aspect of the present invention, the feature of the N-2 crystal formation of compound (I) can be unit cell parameters and is substantially equal to down train value:

Unit cell dimension: a=26.004 (1) 

b＝4.063(1)

c＝22.653(1)

β＝115.95(1)

Spacer Pc

Molecule/asymmetry unit 2

Wherein this crystal formation is at+22 ℃ approximately.

At different aspect, it is as shown in table 4 basically that the feature of N-2 crystal formation can be the mark atomic coordinate.

At different aspect, the feature of N-2 crystal formation can be x-ray diffractogram of powder basically with shown in Figure 4 consistent.

At different aspect, the feature of N-2 crystal formation can be at about 22 ℃ of x-ray diffractogram of powder and comprises following 2 θ values (CuK α λ=1.5418 ): 8.8 ± 0.2,11.4 ± 0.2,13.9 ± 0.2,15.7 ± 0.2 and 22.4 ± 0.2.

At different aspect, the feature of N-2 crystal formation can be the middle peak of differential scanning calorimetric spectrogram (Fig. 9) and appears at about 254-258 ℃.

Stability study shows that the N-2 crystal formation is stable physically, does not observe under the stress condition that is stored in 40 ℃/75% relative humidity/5 weeks of opening and 50 ℃/4 weeks of sealing the significant physical change of N-2 crystal form samples.Moisture absorption and dehumidification studies show that the N-2 crystal formation is non-hygroscopic property, do not observe significant moisture absorption (absorbing～1.2% moisture in 25 ℃ under 90% relative humidity) in this research.Proved that also N-2 is stable not as polymorphic form N-3 on thermodynamics, and in slurries, be converted into N-3 in 25 ℃ and 60 ℃.

P-1 is the desolvation phase, and the parent material (potential solvate) that goes out from the reaction mixture crystallization by drying obtains.In slurries, never observe P-1 always, therefore do not have the evidence support that P-1 is confirmed as the direct single-phase and net phase that goes out from this reaction mixture crystallization.SSNMR studies show that P-1 can not be single-phase material.P-1 is converted into the N-3 crystal formation in solvent (for example acetone), and is converted into multiple potential solvate in the different solvents system of slurries.P-1 also can be solid-state is the N-2 crystal formation at 230 ℃ of thermal conversions.P-1 is very unstable physically, and institute shows as accelerated stability, wherein under 40 ℃/75% relative humidity/opening condition, the XRPD of the sample in 3 weeks of pressurizeing is measured (Fig. 5) observe remarkable physical change.DSC heat is analyzed (Figure 10) and is shown that P-1 is the N-2 crystal formation～223 ℃ of fusions at～225 ℃ of recrystallizations, subsequently 255-259 ℃ of fusion.The moisture absorption and the dehumidification of P-1 material studies show that weight increases～16% after moisture absorption under 90% relative humidity, illustrates that P-1 is a water absorbability.

On the one hand, the feature of P-1 can be x-ray diffractogram of powder basically with shown in Figure 5 consistent.

At different aspect, the feature of P-1 can be at about 22 ℃ of x-ray diffractogram of powder and comprises following 2 θ values (CuK α λ=1.5418 ): 5.5 ± 0.2,11.1 ± 0.2,15.4 ± 0.2,16.8 ± 0.2.

The different crystal forms conversion under certain conditions of flow process 1 explanation compound (I).

Flow process 1

P-1 is easy to be converted into N-3 crystal formation (on the thermodynamics more stable pure form) under about 50 ℃ in the different solvents (for example acetone, ACN, DMSO/MTBE) of slurries.Adopt slurry method, make the P-1 material in acetone about 50 ℃ transform down, successfully prepared the N-3 crystal formation the GLP batch (Good Laboratory Practice batch ,～550g).At about 50 ℃, 1% water is joined in the acetone slurry of P-1 crystal formation and still obtain the N-3 crystal formation, but being added slurries, 5% and 10% water obtains P-3 (solvation) material.P-1 also is converted into N-2 crystal formation (physically stable pure form) with solid-state about 230 ℃ of following heating.Subsequently, the N-2 crystal formation is easy to be converted into the N-3 crystal formation room temperature or about 50 ℃ in acetone slurry.Half sec-butyl alcohol solvate .5SBu-4 crystal formation thermal conversion is the N-2 crystal formation.P-1 about 60 ℃ of recrystallizations in sec-butyl alcohol/heptane (1: 2) with dilute concentration obtain N-1 crystal formation (unsettled pure form), and the N-1 crystal formation also is easy to be converted into N-3 in acetone slurry.The N-1 crystal formation also experiences the solid-state N-2 of being converted into crystal formation in about 90-130 ℃ heating.In addition, room temperature or about 50 ℃, by at different solvents system for example MeOH/EtOAc, DMF/H ₂O, DMSO/H ₂O, NMP/H ₂Form slurries among the O, P-1 is converted into potential solvates/hydrates form.P-1, N-1 crystal formation and N-2 crystal formation all are converted into this fact of N-3 crystal formation in slurries, conclusive evidence N-3 crystal formation ℃ is a polymorphic form more stable on the thermodynamics in room temperature to 60, and is preferred form.

At different aspect, the feature of the .5SBu-4 crystal formation of compound (I) can be unit cell parameters and is substantially equal to down train value:

Unit cell dimension: a=10.688 (1) 

b＝15.006(2)

c＝16.041(2)

α＝85.51(1)

β＝83.15(1)

γ＝74.13(1)

Spacer P-1

Molecule/asymmetry unit 2

Wherein this crystal formation is at+22 ℃ approximately.

At different aspect, it is as shown in table 5 basically that the feature of .5SBu-4 crystal formation can be the mark atomic coordinate.

At different aspect, the feature of .5SBu-4 crystal formation can be the mark atomic coordinate basically shown in table 5a.

At different aspect, the feature of .5SBu-4 crystal formation can be x-ray diffractogram of powder basically with shown in Figure 6 consistent.

At different aspect, the feature of .5SBu-4 crystal formation can be at about 22 ℃ of x-ray diffractogram of powder and comprises following 2 θ values (CuK α λ=1.5418 ): 6.1 ± 0.2,8.1 ± 0.2,12.9 ± 0.2,13.4 ± 0.2 and 18.5 ± 0.2.

At different aspect, the feature of .5SBu-4 crystal formation can be the middle peak of differential scanning calorimetric spectrogram (Figure 11) and appears at about 150-200 ℃.

At different aspect, the feature of .5SBu-4 crystal formation can be in the thermogravimetric curve (Figure 16) in about 200 ℃ of weight loss about 7.5%.

The P-3 representative has similar powder collection of illustrative plates thereby has the solvation phase family of phase quasi-crystalline structue.From all kinds of SOLVENTS (for example ETOH, MEOH, ETOAC) crystalline P-3 crystal at high temperature separate with drying after be converted into P-1.Under these circumstances, can only in slurries, observe P-3 always.Still is P-3 from other solvent (for example DMF/ water, NMP/ water) crystalline P-3 after separation and drying.

On the one hand, the feature of P-3 can be x-ray diffractogram of powder basically with shown in Figure 17 consistent.

At different aspect, the feature of P-3 can be at about 22 ℃ of x-ray diffractogram of powder and comprises following 2 θ values (CuK α λ=1.5418 ): 4.9 ± 0.8,5.6 ± 0.8,9.8 ± 0.8,15.4 ± 0.8,17.0 ± 0.8 and 23 ± 0.8.

The preparation of the crystal formation of compound described herein (I) can be become pharmaceutical composition and/or be used for the treatment of and/or prevention method.These methods include but not limited to give separately crystalline compounds (I), or with one or more other medical active agent drug combinations, comprise the promoting agent that can be used for treating disease described herein.

" treatment significant quantity " is meant and comprises when separately or to unite the crystal formation that gives compound (I) serve as effectively to measure during with supressor Xa.If compound (I) and other medicines are united use, compound combination then described herein can produce synergistic combinations.For example referring to Chou and Talalay, Adv.Enzyme Regul.1984,22,27-55 has produced synergy when uniting when the effect that gives compound is higher than the addition effect that compound is given as drug alone.Generally speaking, synergy is the most clearly to be confirmed under the suboptimal concentration at compound.Compare with each component, synergy can show as that cytotoxicity is lower, anti-thrombosis function strengthens or some other beneficial effect of drug combination.

" treatment " used herein comprises the treatment to mammalian diseases state, especially human disease states, comprise: (a) morbid state that exists of prevention Mammals, particularly easily suffer from described morbid state but also do not make a definite diagnosis the morbid state of Mammals existence when ill when Mammals; (b) suppress morbid state, promptly stop its development; And/or (c) state that palliates a disease, promptly cause disappearing of morbid state.

The crystal formation and the pharmaceutical composition thereof of compound (I) can be used for supressor Xa.Therefore, the invention provides the method that is used for the treatment of and/or prevents Mammals thrombus embolism class diseases (being factor Xa relative disease).Generally speaking, thrombotic disease is the circulation disease that caused by coagulation of blood (relates to promptly that scleroproein forms, the disease of platelet activation and/or platelet aggregation).Term used herein " thrombotic disease " comprises artery cardiovascular thromboembolic disease, vein cardiovascular thromboembolic disease and atrium thrombosis embolism class diseases.Term used herein " thrombotic disease " also comprises and is selected from but is not limited to following disease specific: unstable angina or other acute coronary syndrome, atrial fibrillation, first or the recurrent myocardial infarction, the ischemia sudden death, transient ischemic attack, apoplexy, atherosclerosis, occlusive artery disease on every side, venous thrombosis, venous thrombosis, thrombophlebitis, arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis forms, cerebral embolism, renal infarction, pulmonary infarction and the thrombosis that causes because of following situation: (a) heart valve prosthesis implant or other implant; (b) inlying catheter; (c) support, (d) cardiopulmonary bypass; (e) hemodialysis; Or other operation that (f) blood and the thrombotic artificial surfaces of promotion is contacted.It should be noted that thrombosis comprises obturation (for example after the bypass) and inaccessible again (for example during percutaneous transluminal coronary angioplasty or afterwards).Thrombotic disease can be by including but not limited to that following disease causes: atherosclerosis, surgical operation or postoperative complication, long-time ligamentopexis, atrial fibrillation, congenital thrombophilia, cancer, diabetes, medicine or hormonal action and pregnancy complications.The anticoagulation that it is believed that The compounds of this invention is owing to suppressed factor Xa or zymoplasm.

The novel crystal of the present invention that this method preferably includes medicinal significant quantity gives the patient, preferably unites with one or more pharmaceutically acceptable carriers and/or vehicle to give.For example, the relative proportion that can decide activeconstituents and carrier and/or vehicle by solvability and chemical property, selected route of administration and the standard drug practice of material.

Can give the patient with the crystal formation of compound (I), such as oral administered dosage forms such as tablet, capsule (comprising sustained release preparation or time release formulation respectively), pill, pulvis, granule, elixir, tincture, suspensoid, syrup and emulsions.The crystal formation of compound (I) also can intravenously (injecting or infusion), intraperitoneal, subcutaneous or intramuscular form give, and the formulation of all uses is the pharmacy field those of ordinary skill and knows.They can give separately, but give with the pharmaceutical carrier according to selected route of administration and standard drug choice of practice usually.

Certainly, the dosage regimen of the crystal formation of compound (I) will be looked following known facts and be changed, for example the pharmacodynamic profiles of certain drug and administering mode thereof and route of administration; Recipient's species, age, sex, healthy state, health check-up situation and body weight; The nature and extent of symptom; The kind of the treatment of carrying out simultaneously; Therapeutic frequency; Route of administration, patients " renal function and liver function and required effect.Doctor or animal doctor can determine and leave the prescription that is used to prevent, resist or stops the required medicine effective quantity of thrombotic disease development.Can give several unit dosage approximately simultaneously.The dosage of the crystal formation of the compound (I) that is suitable for most preventing or treats can change with the physiologic characteristic of particular patient in the specific crystal formation of form of medication, selected compounds and the treatment.Briefly say, can bring into use low dose, in case of necessity by a small amount of increase until reaching effect required in this situation.

As rule, adult suitable dosage can be about 0.001mg/kg body weight to all combinations and the subgroup of about 1000mg/kg weight range and this scope and closes and wherein concrete dosage.Preferred dosage can pass through to suck about 0.01mg/kg to about 100mg/kg weight range in every day, preferred every day is by oral administration 0.1-70mg/kg body weight, more preferably 0.5-20mg/kg body weight, every day by the about 0.01mg/kg body weight of intravenously administrable to about 50mg/kg body weight, preferred 0.01-10mg/kg body weight.In each concrete case, dosage can be determined according to the distinguished factor (for example age, body weight, general health situation) of acceptor to be treated and other characteristic that can influence this medicament production effect.The crystal formation that can odd-numbered day dosage gives compound (I), or can every day the fractionated dose of 2 times, 3 times or 4 times give total per daily dose.

For with solid form (for example tablet or capsule) oral administration, the crystal formation and the nontoxic pharmaceutically acceptable inert support (for example lactose, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Lin Suanergai, calcium sulfate, N.F,USP MANNITOL, sorbyl alcohol or the like) of compound (I) can be united.

Except described activeconstituents, preferred solid dosage form also can contain the additional component that multiple this paper is called " vehicle ".Comprise thinner, tackiness agent, lubricant, glidant and disintegrating agent in these vehicle.Also can mix tinting material." thinner " used herein becomes big to be used for the material that pressing prepares the tablet of actual size for making volumes of formulation.The example of thinner is lactose and Mierocrystalline cellulose." tackiness agent " used herein is for to be used for making powdery substance to have the material of viscosity to help to guarantee that tablet is kept perfectly and improves the flowability of pulvis after compacting.The example of typical adhesive is lactose, starch and various carbohydrate." lubricant " used herein has several functions, comprises preventing that tablet is attached to pressing device and improved the flowability of saccharoid before compacting or packing.In most of the cases lubricant is a hydrophobic material.Yet, do not wish to use excessive lubricant, because this can cause the preparation slaking to reduce and/or postpone the stripping of medicine." glidant " used herein refers to improve the material of particulate material flowability.The example of glidant comprises talcum powder and colloidal silica." disintegrating agent " used herein can promote solid dosage to decompose after administration or the material or the compounding substances of disintegration for it is joined in the preparation.The material that can be used as disintegrating agent comprises starch, potter's clay, Mierocrystalline cellulose, phycocolloid, natural gum and cross-linked polymer.One group of disintegrating agent that is called " superdisintegrant " is usually with the low-level solid dosage that is used for, and its consumption is 1% (weight)～10% (weight) with respect to the dose unit gross weight usually.Cross-linked carboxymethyl cellulose, polyvinylpolypyrrolidone and Explotab are represented the example of cross-linked cellulose, cross-linked polymer and cross-linking starch respectively.Explotab expands in less than 30 seconds 7 times to 12 times, and effectively disintegration contains its particle.

Be used for preferred disintegrating agent of the present invention and be selected from treated starch, croscarmellose sodium, calcium carboxymethylcellulose and polyvinylpolypyrrolidone.Being used for more preferably disintegrating agent of the present invention is treated starch, for example Explotab.

Preferred vector comprises capsule or the compressed tablets that contains solid pharmaceutical dosage formulation described herein.Preferred capsule agent or compressed tablets form comprise crystal formation and one or more disintegrating agents of the compound (I) for the treatment of significant quantity usually, and the content of disintegrating agent accounts for more than about 10% (weight) of capsule 's content gross weight or tablet total weight amount.

The preferred every capsule of capsule preparations can contain the crystal formation of 5mg to about 1000mg compound (I) of having an appointment.Preferred every of press sheet formulation contains the crystal formation of 5mg to about 800mg compound (I) of having an appointment.More preferably the every capsule of preparation or every contain the 50mg that has an appointment to about 200mg.Preferred capsule or compressed tablets pharmaceutical dosage form comprise the N-1 crystal formation of the compound (I) for the treatment of significant quantity; Tensio-active agent; Disintegrating agent; Tackiness agent; Lubricant; With optional other pharmaceutically acceptable vehicle, for example thinner, glidant or the like; Wherein said disintegrating agent is selected from treated starch; Croscarmellose sodium, calcium carboxymethylcellulose and polyvinylpolypyrrolidone.

For the liquid form oral administration, can be with the crystal formation and for example ethanol, glycerol, water or the like the associating of any oral nontoxic pharmaceutically acceptable inert support of compound (I).Liquid composition can contain sweeting agent, can make said composition more agreeable to the taste.Sweeting agent can be selected from sugar, for example sucrose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, lactose or the like; Or sugared surrogate, for example cyclamate, asccharin, aspartame or the like.If select sugared surrogate as sweeting agent, the amount of then using in the present composition should be less than basically if use the amount of sugar.Consider this point, the consumption of sweeting agent can be about 0.1% (weight) to all combinations and the subgroup of about 50% (weight) scope and this scope and closes and wherein concrete amount.Preferred amounts gets involved about 0.5% (weight) to about 30% (weight) scope.

More preferably sweeting agent is sugar, especially sucrose.The particle diameter that has found that used cane sugar powder has remarkably influenced to the physical appearance of composition finished product and the taste of its final acceptance.During use, the preferably sucrose grain diameter of components is 200 orders to less than all combinations of 325 orders (USS sieve) scope and this scope with subgroup is closed and concrete particle diameter wherein.

Combine with various other components (if needs) that this paper enumerates with aequum by the crystal formation that will be dissolved in the compound (I) in the suitable solvent, refilter degerming, can prepare aseptic parenteral solution.Generally speaking, by sterilized activeconstituents is incorporated in the aseptic solvent that contains dispersion medium and any other required component, can prepare dispersion.Sterilized powder is being used to prepare under the aseptic parenteral solution situation, the preferred preparation method can comprise vacuum-drying and Freeze Drying Technique, can obtain the activeconstituents powder and add from the required any additional component in the sterile filtration solution before it.

If in a single day those of ordinary skills have grasped the same that the instruction of content of the present invention will understand, will lose its crystalline texture during compound (I) dissolving, therefore can be considered compound (I) solution.Yet form of ownership of the present invention all can be used for preparing liquid preparation, for example compound (I) solubilized or be suspended in wherein.In addition, the crystal formation of compound (I) can be incorporated in the solid preparation.

Liquid composition also can contain other conventional ingredient that is useful on the compounding pharmaceutical composition.An example of this composition is a Yelkin TTS.It is used as emulsifying agent in the present composition, consumption is that 0.05% (weight) is closed and wherein concrete amount to all combinations and the subgroup of 1% (weight) scope and this scope.More preferably can adopt the emulsifying agent of about 0.1% (weight) to about 0.5% (weight).The example of spendable other composition is biocide class sanitas, for example phenylformic acid or parabens; Suspension agent, for example colloidal silica; Antioxidant; Local oral narcotic; Correctives; And tinting material.

, in the art technology level, even can from work embodiment provided below, be better understood the selection of these optional members and the level that is used for the present composition thereof.

The crystal formation of compound (I) also can be combined into target medicine carrier with soluble polymer.This polymkeric substance can comprise polyvinylpyrrolidine pyran co-polymer, poly-hydroxypropyl Methacrylamide-phenol, poly-hydroxyethyl-l-asparagine phenol or the polyethylene oxide-polylysine that is replaced by the palmityl residue.In addition, crystalline compounds (I) can be attached to the Biodegradable polymeric that a class is used to reach controlled release drug, for example poly(lactic acid), polyglycolic acid, poly(lactic acid) and co-glycolic acid, poly epsilon caprolactone lactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and crosslinked or amphiphilic hydrogel segmented copolymer.

The gelatine capsule agent of the crystal formation of compound (I) can contain crystalline compounds (I) and liquid or solid composition described herein.The gelatine capsule agent also can contain powder carrier, for example lactose, starch, derivatived cellulose, Magnesium Stearate, stearic acid or the like.Similar thinner can be used for preparing compressed tablets.The two can be prepared as slow release product tablet and capsule, discharges medicine continuously to reach in a few hours.Can give tablet sugar coating or bag film-coat, covering any offensive odour, and make tablet and air insulated, perhaps make the selectivity disintegration in gi tract of casing sheet.

Generally speaking, water, suitable oil, salt solution, dextrose (glucose) aqueous solution and associated sugars solution and dibasic alcohol (for example propylene glycol or polyoxyethylene glycol) all are the suitable carriers of parenteral solution.By crystalline compounds (I) is dissolved in carrier, in case of necessity, adds buffer substance and prepare the solution that is used for the parenteral solution.Antioxidant for example sodium bisulfite, S-WAT or xitix list with or coupling all be suitable stabilizers.Also can use citric acid and salt thereof and EDTA sodium salt.The parenteral solution also can contain sanitas, for example benzalkonium chloride, methyl p-hydroxybenzoate or propylparaben and trichloro-butyl alcohol.

Suitable pharmaceutical carrier is described in Remington ' s Pharmaceutical Sciences, Mack Publishing Co., and its whole disclosures are hereby incorporated by reference.The useful pharmaceutical dosage form that is used to give The compounds of this invention can illustrate as follows:

Capsule

Many units capsule can prepare by filling standard two-segment type hard gelatin capsule, and every capsule contains the Powdered activeconstituents of 100mg (being factor Xa inhibitor), 150mg lactose, 50mg Mierocrystalline cellulose and 6mg Magnesium Stearate.

Gelseal

The mixture that can prepare activeconstituents and digestible oil (for example soybean oil, Oleum Gossypii semen or sweet oil) injects gelatin with it by positive displacement pump and makes soft gelatin capsule, and every capsule contains the 100mg activeconstituents.Then should this capsule washing is dry.

Tablet

Many tablets prepare by ordinary method, cause dose unit to contain 100mg activeconstituents, 0.2mg colloidal silica, 5mg Magnesium Stearate, 275mg Microcrystalline Cellulose, 11mg starch and 98.8mg lactose.Can increase palatability or prolong with suitable coating material and absorb.

Suspensoid

Can prepare the aqueous suspension that is used for oral administration, every 5ml contains the meticulous activeconstituents of 25mg, 200mg Xylo-Mucine, 5mg Sodium Benzoate, 1.0g Sorbitol Solution USP (U.S.P.) and 0.025mg Vanillin.

Injection

By 1.5% (weight) activeconstituents is stirred with 10% (volume) propylene glycol and water, can prepare the parenteral composition that is suitable for drug administration by injection.This solution is sterilized by common technology.

Nasal spray

The agent of preparation aqueous solution, every 1ml contains 10mg activeconstituents, 1.8mg methyl p-hydroxybenzoate, 0.2mg propylparaben and 10mg methylcellulose gum.This solution branch is installed in the 1ml bottle.

Pulmonary inhalation

The uniform mixture of preparation activeconstituents and polysorbate80, the activeconstituents final concentration should be every container 10mg, and the final concentration of polysorbate80 should be 1% (weight) in the container.This mixture branch is installed in each jar, valve is pacified to this jar, add and depress the dichloro tetrafluoro ethane that adds aequum.

The crystal formation of preferred compound (I) can be used as component of the present invention (a), can any formulation (for example above-mentioned formulation) independently give, and also can variously make up (for example aforesaid combination) and gives.In the following description, component (b) is interpreted as representing one or more medicines described herein that are suitable for combination therapy.

Therefore, the crystal formation of compound (I) can use separately, or unites use with other diagnostic reagent, anti-coagulant, anti-platelet agents, fibrinolysis agent, antithrombotic agent and/or Parenogen solvating agent.For example, give factor Xa inhibitor and give standard heparin, low molecular weight heparin, directly thrombin inhibitors (being r-hirudin), acetylsalicylic acid, fibrinogen deceptor antagonists, streptokinase, urokinase and/or tissue plasminogen activator can cause improving antithrombotic and form or thrombolytic effect or efficient.Can give crystal described herein to treat the various animals thrombosis complication of (for example primates comprises the mankind, sheep, horse, ox, pig, dog, rat and mouse).The inhibition of factor Xa not only be can be used for suffering from the anticoagulant therapy of the individuality of thrombotic disease, and also can use when needing to suppress blood coagulation (for example prevent the whole blood of storing from condensing and prevent to be used to condensing of other biological sample of testing or storing) time.Therefore, can be with any factor Xa inhibitor, the crystal formation that comprises compound as herein described (I), join contain or suspect any medium that contains factor Xa or allow its with contain or suspect that any medium that contains factor Xa contacts, and wherein needs factor Xa inhibitor to suppress blood coagulation.

The crystal formation of compound (I) and any antihypertensive drug or cholesterol or lipid can be regulated the medicine associating or be used for the treatment of restenosis, atherosclerosis or hypertension simultaneously.For example, can unite the compound that some example that is used for the treatment of hypertensive medicine comprises following kind with the new crystal of compound of the present invention (I): beta-blocker, ACE inhibitor, calcium-channel antagonists and α receptor antagonist.Can unite some example that is used for the treatment of the unusual medicine of elevated cholesterol or lipid level with The compounds of this invention and comprise compound or the fibrate that is known as the HMGCoA reductase inhibitor.

Therefore, component of the present invention (a) and (b) can be formulated in together in the dose unit (promptly being mixed together in a seed lac wafer, a slice tablet, one bottle of pulvis or the one bottle of liquid agent etc.) as combined prod.When component (a) with when (b) not being formulated in the dose unit together, component (a) can give with component (b) or give with any order simultaneously; For example can give component of the present invention (a) earlier, give component (b) then, perhaps they can give with reverse order.Contain more than a kind of medicine as fruit component (b), then these medicines can give or give with any order together.When not giving simultaneously, component (a) and (b) be preferably in the pitch time of administration in about 1 hour.Component (a) and route of administration preferred oral approach (b).Though preferred ingredient (a) (that is to say by identical approach with component (b), for example all be oral) or formulation give, if needed, they can give by different approach (for example a kind of component in the combined prod can orally give, and another kind of component can intravenously gives) or formulation.

The scope of the invention also comprises the medicine box that can be used for treating various diseases, and this medicine box comprises one or more sterile chambers, and the pharmaceutical composition that comprises new crystal compound (I) of treatment significant quantity is housed in the container.In a single day those skilled in the art have grasped content of the present invention, will understand at an easy rate in this medicine box also to comprise conventional medicine box composition.Available conventional sterilising method well-known to those skilled in the art is sterilized to container.

The present invention is further described with the following examples.All these embodiment are real example.These embodiment shall not be construed as the restriction to the claims scope.

Embodiment

Embodiment 1

(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester prepares P-1 from 1-(3-chloro-phenyl-)-7-oxo-6-

At room temperature, (4-(2-oxo pyridine-1 (2H)-yl) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester is packed in the 20L reactor with 0.690kg 1-(3-chloro-phenyl-)-7-oxo-6-.At room temperature, 6.514kg DMF and 1.565kg methane amide are packed into this 20L reactor.Then this batch of material is heated to 50-55 ℃, 50-55 ℃ of maintenance at least 10 minutes.Add 0.320kg sodium methylate/25% methyl alcohol then, simultaneously this batch temperature is remained on 50-55 ℃.After adding sodium methylate, with this batch of material 50-55 ℃ of maintenance at least 15 minutes.Take online control sample to finish to prove conclusively this reaction.After reaction is finished, added 10% ammonium hydroxide, keep batch temperature simultaneously at 50-55 ℃ through at least 1 hour.Then this batch of material was cooled to 20-25 ℃ through at least 1 hour, 20-25 ℃ of maintenance at least 1 hour.Then, with this dope filtration,, use 6.90kg water (Water USP Bulk) washing for the second time again with 6.90kg water (Water USP Bulk) washing.At last, filter cake 5.458kg washing with acetone is bled this filter cake 1 hour at least.Then should wet solid in nitrogen gas stream 50 ℃ of vacuum-dryings up to obtaining LOD＜2.0%.

Embodiment 2

The preparation of N-1 crystal formation

In 1 liter of Erlenmeyer flask (Erlenmeyer flask), add 2.2g embodiment 1 product, add the 250ml sec-butyl alcohol then.Heat this mixture and make its dissolving (～80 ℃), filter by the thick sinter funnel of 600ml then.Add the 1000ml sec-butyl alcohol, heating is with all retes on the dissolving flask walls.Added the 530ml normal heptane through 15 minutes in batches.Use from preceding batch N-1 crystal formation crystal seed as this solution.40-50 ℃ was not stirred slaking 24 hours on hot plate, and cooling gradually then was 20-25 ℃ of slaking at least 24 hours.

Embodiment 3

The preparation of N-2 crystal formation

Weigh up 635.2mg embodiment 1 product and put into crucible.Crucible is placed on 230 ℃ of smelting furnaces, kept 2 hours at 230 ℃, or up to not observing the P-1 crystal formation via XRPD and DSC.Then with N-2 crystal formation cool to room temperature.Collect 624.7mg N-2 crystal formation.

Embodiment 4

The preparation of N-3 crystal formation

At room temperature, 0.615kg embodiment 1 product is encased in the 20L reactor.Then at room temperature, 9.730kg acetone is packed in this 20L reactor.These slurries are heated to 50-55 ℃.In case this batch of material reaches 50-55 ℃, the 10.0 gram N-3 crystal formations (from preceding batch) that will be dissolved in 150.0 gram acetone are encased in this reactor.Monitor this reactor by Raman, be converted into the N-3 crystal formation to observe the P-1 crystal formation.This batch of material is finished and examined via XRPD up to conversion 50-55 ℃ of stirring.Then this batch of material was cooled to 20-25 ℃ through at least 1 hour, 20-25 ℃ of maintenance at least 1 hour.With this dope filtration, use the 6.50kg washing with acetone then, this filter cake was bled 1 hour at least.Should the 50 ℃ of vacuum-dryings in nitrogen gas stream of wet solid lose＜0.5% then up to obtaining oven dry.

Embodiment 5

.5SBu-4 the preparation of crystal formation

After leaving standstill for a long time, go out the .5SBu-4 crystal formation from the N-1 mother liquor crystallization.This parent solution solvents composition is approximately 30% normal heptane, 70% sec-butyl alcohol.

With Bruker DSX-400,400MHz NMR spectrometer, measure all solids C-13NMR (SSNMR).Adopt high energy proton uncoupling and TPPM pulse sequence and slope amplitude cross polarization (RAMP-CP)/magic angle spinning technology (MAS), obtain high-resolution spectroscopy ((A.E.Bennett etc. at about 12kHz, J.Chem.Phys., 1995,103,6951), (G.Metz, X.Wu and S.O.Smith, J.Magn.Reson.A .1994,110,219-227)).About 70mg sample is filled in zirconium white rotor decorative pattern jar, is used for each experiment.The external application diamantane chemical shift (δ) of high-frequency resonance be made as 38.56ppm (W.L.Earl and D.L.VanderHart, J.Magn.Reson., 1982,48,35-54).

Those of ordinary skills should understand, and look the X-ray diffractogram that the measuring condition that is adopted can obtain measuring error.Particularly, the visual measuring condition that adopts of the intensity of common known X-ray diffractogram and fluctuating.Will be further understood that yet visual exam condition and changing of relative intensity, therefore, the accurate order of intensity should be at the row of consideration.In addition, for conventional X-ray diffractogram, the measuring error of diffraction angle is about below 5% usually, and that this measuring error degree should be thought of as aforementioned diffraction angle institute is intrinsic.Therefore, should be appreciated that crystal formation of the present invention is not limited to provide the crystal formation of the duplicate X-ray diffractogram of describing with accompanying drawing disclosed herein of X-ray diffractogram.Provide any crystal formation with disclosed those the same basically X-ray diffractograms of accompanying drawing all to fall in the scope of the invention.The ability of determining to be essentially consistent X-ray diffractogram is in those of ordinary skills' limit of power.

Adopt Bruker C2 GADDS (General Area Detector Diffraction System, total area detector diffraction system) to obtain X-ray powder diffraction (PXRD) data.Ray be CuK α (40KV, 50mA).The sample detector distance is 15cm.Powdered sample placed 1mm or more in the sealing glass kapillary of minor diameter; Rotate this kapillary image data.Gather the data of 3≤2 θ≤35 °, the sample exposure time was at least 2000 seconds.To the 2 dimension diffraction arc integrations that draw, to draw out 1 traditional dimension PXRD figure, its step-length is 0.02 degree, and 2 θ get involved in 3 to 35 degree, the 2 θ scopes.Perhaps, by the back of the body method of filling out about 200mg is installed to Philips powder x-ray diffraction (PXRD) sample table.This sample transfer is arrived Philips MPD unit (45KV, 40mA, CuK α ₁).At room temperature in 2 to 32 spend 2 θ angles (continuous sweep pattern, scanning speed were 0.03 degree/second, and divergent slit and anti-scatter slit receive slit: 0.2mm, sample spinner: open automatically) image data.

Go up collection monocrystalline X ray data at Bruker-Nonius CAD4 series diffractometer (Bruker Axs, Inc., Madison WI).Be set at 25 angles of elevation reflections and carry out least square analysis by testing diffractometer, draw unit cell parameters.Under constant temperature, use CuK alpha-ray (λ=1.5418 ) with θ-2 θ variable sweep commercial measurement intensity, the data of only gathering lorentz polarization factor (Lorentz-polarization factor).Gather the sample-out count of half sweep time with the scanning extreme value.In Bruker-Nonius Kappa CCD 2000 systems, (λ=1.5418 ) alternately gathers the monocrystalline data with the CuK alpha-ray.At data program software R.Hooft, with the HKL2000 software package intensity data indexing of measuring is handled among the Nonius B.V. (1998).When needs, crystal cools off in the cold flow of Oxford cryogenic system during the image data.

Use the direct method analytic structure, on viewed reflection basis, improve: carried out local little improved SDP software package SDP (structure determination software package with following software, Enraf-Nonius, Bohemia, N.Y.) or crystallograph software package MAXUS (maXus answer and refinement software cover: S.Mackay, C.J.Gilmore, C.Edwards, M.Tremayne, N.Stewart and K.Shankland).MaXus is the computer program that is used for from the diffraction data answer and the crystalline structure of refining.

The atomic parameter (the coordinate factor and temperature factor) that can refine and derive by the complete matrix least square method.Minimization function in refining is a ∑ _w(| F _o|-| F _c|) ²R is defined as ∑ || F|-|F||/∑ | and F _o|, R _w=[∑ _w(| F _o|-| F _c|) ²/ ∑ _w| F _o| ²] ^1/2, wherein w is the suitable weighting function based on error in the observed intensity.Verify difference diagram in all stages of refining.With isotropic temperature factor hydrogen atom is introduced idealized position, but the hydrogen atom parameter remains unchanged.

At TA Instruments ^TMCarry out differential scanning calorimetric analysis (DSC) experiment on the Q1000 type.(about 2-6mg) weighs with the sample in the aluminium dish, and record is accurate to one of percentage milligram, transfers to DSC.To feed nitrogen in the 50ml/ branch clockwise instrument.Gather the data of room temperatures to 300 ℃ with 10 ℃/minute heating rate.With the endotherm(ic)peak mapping of walking downwards.

At TA Instruments ^TMCarry out thermogravimetric analysis (TGA) experiment in the Q500 type.Sample (about 10-30mg) is placed the platinum dish that has before tared.Accurately measure sample weight arrives the thousandth milligram by instrument record.To feed nitrogen in the 100ml/ branch clockwise smelting furnace.Gather the data of room temperatures to 300 ℃ with 10 ℃/minute heating rate.

Prepare the various crystal formations and the solvate thereof of compound (I), seen Table 1.The structure cell data of these examples and other characteristic see Table 2a and table 2b.Analyze according to the monocrystalline X-ray crystallography, draw unit cell parameters.The detailed description of structure cell can be referring to Stout and Jensen, " X-RayStructure Determination:A Practical Guide ", (MacMillian, 1968), the 3rd chapter.

Table 1

Crystal formation	Describe
		N-3	Pure crystal
N-1	Pure crystal
		N-2	Pure crystal
P-1	The desolvation phase
		.5SBu-4	Half sec-butyl alcohol solvate crystals

Table 2a. unit cell parameters

Crystal formation	T (℃)	a()	b()	c()	α°	β°	γ°
								N-1	+22	44.272(1)	14.3594(4)	20.9164(6)		109.36(1)
N-1	-50	44.041(5)	14.280(8)	20.794(2)		109.07(1)
								N-2	+22	26.004(1)	4.063(1)	22.653(1)		115.95(1)
.5SBu-4	-50	10.665(1)	14.923(2)	15.909(2)	85.85(1)	83.00(1)	74.90(1)
								.5SBu-4	+22	10.688(1)	15.006(2)	16.041(2)	85.51(1)	83.15(1)	74.13(1)

Table 2b. unit cell parameters (continuing)

Crystal formation	V( 3)	Z’	SG	R	Z ' solvent site
						N-1	12545.2(6)	3	C2/c	.047	Do not have
N-1	12360(10)	3	C2/c	065	Do not have
						N-2	2152.1(5)	2	Pc	.050	Do not have
.5SBu-4	2424.3(6)	2	P-1	.07	.5sec-BuOH

The form note:

T is the temperature of crystallographic data.

Z ' is the molecule number of each asymmetry unit compound (I).

SG is a crystallographic space groups.

R is the R factor (measurement refine quality).

The mark atomic coordinate of various crystal formations sees Table 3 to table 5a.

Table 3.N-1 crystal formation is in the location parameter and the effective homogeneity temperature factor of room temperature

Atom	x	y	z	B(iso)
					CL1	0.0854	0.3279	0.5025	6.6
O8	0.1369	0.2940	0.3265	5.7
					O26	0.3055	0.4347	0.3733	7.6
N1	0.0700	0.3407	0.2490	4.2
					N2	0.0441	0.3635	0.1945	4.3
N7	0.1526	0.4022	0.2632	4.3
					O17	0.0393	0.5210	0.0633	6.2
N18	0.0054	0.4037	0.0646	5.1
					N25	0.2810	0.3263	0.4189	4.3
C3	0.0555	0.4160	0.1548	4.0
					C4	0.0885	0.4286	0.1832	4.1
C5	0.1135	0.4767	0.1612	4.8
					C6	0.1436	0.4891	0.2229	5.0
C8	0.1305	0.3550	0.2834	4.2
					C9	0.0973	0.3793	0.2427	4.0
C10	0.0646	0.2943	0.3043	3.9
					C11	0.0786	0.3264	0.3695	4.2
C12	0.0701	0.2844	0.4205	4.5
					C13	0.0486	0.2119	0.4083	4.9
C14	0.0349	0.1799	0.3424	5.2
					C15	0.0426	0.2211	0.2900	4.9
C16	0.0328	0.4513	0.0900	4.4
					C19	0.1859	0.3851	0.2987	4.0
C20	0.1979	0.2956	0.3002	4.5
					C21	0.2298	0.2776	0.3376	4.4
C22	0.2492	0.3487	0.3726	4.0
					C23	0.2378	0.4384	0.3690	5.0
C24	0.2059	0.4565	0.3317	4.9
					C26	0.3075	0.3768	0.4173	5.4
C27	0.3369	0.3517	0.4703	6.8
					C28	0.3386	0.2854	0.5163	6.5
C29	0.3111	0.2351	0.5143	5.9
					C30	0.2830	0.2569	0.4655	5.0
CL2	0.0820	-0.3293	0.4983	5.6
					O48	0.1355	-0.3140	0.3362	5.7
O66	0.2699	-0.3890	0.4679	5.4
					N41	0.0678	-0.3119	0.2446	3.9
N42	0.0415	-0.2967	0.1896	4.0

Atom	x	y	z	B(iso)
					N47	0.1490	-0.2393	0.2530	4.0
O57	0.0328	-0.1413	0.0553	5.5
					N58	0.0024	-0.2675	0.0563	4.8
N65	0.2810	-0.2819	0.3985	4.1
					C43	0.0514	-0.2437	0.1479	3.7
C44	0.0840	-0.2242	0.1750	3.8
					C45	0.1075	-0.1719	0.1510	4.4
C46	0.1402	-0.2180	0.1797	5.1
					C48	0.1277	-0.2767	0.2807	3.9
C49	0.0942	-0.2695	0.2364	3.7
					C50	0.0632	-0.3603	0.3003	3.6
C51	0.0760	-0.3267	0.3655	3.8
					C52	0.0682	-0.3731	0.4159	4.1
C53	0.0488	-0.4500	0.4036	4.5
					C54	0.0363	-0.4829	0.3377	4.9
C55	0.0434	-0.4378	0.2853	4.5
					C56	0.0281	-0.2135	0.0824	3.9
C59	0.1828	-0.2493	0.2902	3.9
					C60	0.2025	-0.2930	0.2597	4.8
C61	0.2347	-0.3036	0.2960	4.7
					C62	0.2469	-0.2708	0.3613	4.0
C63	0.2272	-0.2262	0.3915	4.3
					C64	0.1952	-0.2145	0.3556	4.2
C66	0.2903	-0.3442	0.4519	4.3
					C67	0.3243	-0.3533	0.4856	5.0
C68	0.3451	-0.3025	0.4660	5.7
					C69	0.3339	-0.2385	0.4108	5.7
C70	0.3025	-0.2306	0.3785	4.8
					CL3	0.0889	0.0000	0.5092	6.0
O88	0.1407	-0.0225	0.3482	5.4
					O106	0.3093	0.0778	0.3670	6.8
N81	0.0745	0.0071	0.2558	3.8
					N82	0.0492	0.0309	0.2008	4.0
N87	0.1585	0.0543	0.2712	3.8
					O97	0.0450	0.1918	0.0730	5.6
N98	0.0128	0.0693	0.0685	4.9
					N105	0.2874	-0.0044	0.4344	3.8
C83	0.0615	0.0814	0.1617	3.5
					C84	0.0947	0.0910	0.1910	3.7
C85	0.1206	0.1368	0.1711	4.2
					C86	0.1513	0.0796	0.1990	4.1
C88	0.1351	0.0211	0.2952	4.0
					C89	0.1026	0.0417	0.2506	3.6
C90	0.0674	-0.0351	0.3110	3.7
					C91	0.0819	-0.0031	0.3766	3.9
C92	0.0720	-0.0411	0.4269	4.1

Atom	x	y	z	B(iso)
					C93	0.0484	-0.1078	0.4139	4.4
C94	0.0343	-0.1389	0.3483	4.8
					C95	0.0436	-0.1024	0.2961	4.4
C96	0.0392	0.1190	0.0970	3.8
					C99	0.1915	0.0400	0.3116	3.8
C100	0.2015	0.0604	0.3808	4.1
					C101	0.2330	0.0463	0.4200	4.0
C102	0.2550	0.0132	0.3905	3.7
					C103	0.2453	-0.0042	0.3218	4.2
C104	0.2136	0.0082	0.2822	4.1
					C106	0.3133	0.0332	0.4193	4.7
C107	0.3442	0.0142	0.4691	5.3
					C108	0.3473	-0.0361	0.5254	5.6
C109	0.3206	-0.0733	0.5376	5.3
					C110	0.2911	-0.0561	0.4924	4.5
H181	0.0009	0.3424	0.0914	6.2
					H182	-0.0127	0.4250	0.0183	6.2
H581	-0.0006	-0.3306	0.0827	5.8
					H981	0.0089	0.0044	0.0918	6.0
H982	-0.0051	0.0926	0.0224	6.0
					H582	-0.0183	-0.2244	0.0512	4.0

The approximate error of x, y, z is .001 .0003 .0003.

Table 3a.N-1 crystal formation is in-50 ℃ location parameter and effective homogeneity temperature factor

Atom	x	y	z	B(iso)
					CL1	0.0851	0.3260	0.5044	4.0
CL2	0.0817	-0.3307	0.5005	3.2
					CL3	0.0891	-0.0024	0.5115	3.5
O8	0.1369	0.2946	0.3262	3.4
					O17	0.0391	0.5245	0.0641	3.8
O26	0.3062	0.4358	0.3737	4.5
					O48	0.1358	-0.3101	0.3386	3.4
O57	0.0325	-0.1389	0.0558	2.9
					O66	0.2703	-0.3905	0.4672	2.6
O88	0.1411	-0.0227	0.3496	3.1
					O97	0.0445	0.1954	0.0743	3.1
O106	0.3102	0.0784	0.3673	3.9
					N1	0.0699	0.3417	0.2499	2.1
N2	0.0439	0.3625	0.1965	2.2
					N7	0.1530	0.4054	0.2642	2.0
N18	0.0058	0.4031	0.0650	2.7
					N25	0.2811	0.3269	0.4187	1.9
N41	0.0679	-0.3103	0.2455	1.7

Atom	x	y	z	B(iso)
					N42	0.0412	-0.2974	0.1902	2.0
N47	0.1491	-0.2363	0.2535	2.2
					N58	0.0026	-0.2687	0.0567	2.2
N65	0.2811	-0.2810	0.3982	1.9
					N81	0.0746	0.0071	0.2559	1.9
N82	0.0492	0.0309	0.2011	1.9
					N87	0.1591	0.0572	0.2731	2.0
N98	0.0134	0.0689	0.0686	2.2
					N105	0.2880	-0.0050	0.4354	1.8
C3	0.0554	0.4170	0.1559	1.8
					C4	0.0884	0.4303	0.1848	1.7
C5	0.1133	0.4814	0.1613	2.8
					C6	0.1437	0.4917	0.2251	2.8
C8	0.1304	0.3569	0.2835	2.8
					C9	0.0973	0.3828	0.2453	1.8
C10	0.0641	0.2943	0.3053	1.9
					C11	0.0788	0.3267	0.3714	1.9
C12	0.0696	0.2834	0.4217	2.7
					C13	0.0483	0.2077	0.4091	2.4
C14	0.0345	0.1785	0.3427	2.5
					C15	0.0424	0.2219	0.2911	2.5
C16	0.0326	0.4535	0.0908	2.5
					C19	0.1865	0.3867	0.2996	1.5
C20	0.1976	0.2972	0.3008	2.1
					C21	0.2298	0.2772	0.3380	2.1
C22	0.2493	0.3499	0.3717	1.5
					C23	0.2385	0.4399	0.3684	1.9
C24	0.2062	0.4578	0.3308	2.3
					C26	0.3079	0.3766	0.4184	2.8
C27	0.3374	0.3518	0.4716	3.9
					C28	0.3381	0.2827	0.5167	3.6
C29	0.3107	0.2344	0.5139	3.4
					C30	0.2831	0.2554	0.4648	2.6
C43	0.0510	-0.2413	0.1485	1.8
					C44	0.0843	-0.2235	0.1755	1.9
C45	0.1076	-0.1677	0.1526	2.2
					C46	0.1403	-0.2146	0.1796	2.2
C48	0.1271	-0.2768	0.2823	2.1
					C49	0.0942	-0.2664	0.2371	1.9
C50	0.0627	-0.3610	0.2999	1.5
					C51	0.0759	-0.3260	0.3671	1.9
C52	0.0681	-0.3729	0.4171	2.0
					C53	0.0486	-0.4512	0.4051	2.4
C54	0.0353	-0.4836	0.3369	2.8
					C55	0.0429	-0.4372	0.2856	2.2
C56	0.0278	-0.2133	0.0823	2.0

Atom	x	y	z	B(iso)
					C59	0.1828	-0.2461	0.2904	2.3
C60	0.2031	-0.2907	0.2584	2.4
					C61	0.2353	-0.3010	0.2953	2.5
C62	0.2472	-0.2714	0.3609	2.0
					C63	0.2275	-0.2235	0.3926	2.2
C64	0.1953	-0.2127	0.3576	2.2
					C66	0.2902	-0.3425	0.4522	2.0
C67	0.3247	-0.3515	0.4852	2.8
					C68	0.3456	-0.2976	0.4645	3.6
C69	0.3346	-0.2354	0.4107	3.0
					C70	0.3026	-0.2284	0.3783	2.7
C83	0.0614	0.0843	0.1622	1.7
					C84	0.0948	0.0918	0.1913	1.5
C85	0.1211	0.1407	0.1724	1.7
					C86	0.1515	0.0801	0.1994	1.9
C88	0.1355	0.0203	0.2952	2.1
					C89	0.1026	0.0446	0.2510	2.0
C90	0.0672	-0.0352	0.3123	1.7
					C91	0.0819	-0.0037	0.3779	2.0
C92	0.0721	-0.0424	0.4293	2.2
					C93	0.0483	-0.1104	0.4158	2.2
C94	0.0343	-0.1394	0.3490	2.6
					C95	0.0435	-0.1017	0.2964	2.4
C96	0.0389	0.1192	0.0962	1.7
					C99	0.1917	0.0425	0.3124	1.9
C100	0.2019	0.0609	0.3818	2.0
					C101	0.2328	0.0471	0.4213	2.0
C102	0.2558	0.0118	0.3925	2.0
					C103	0.2461	-0.0033	0.3211	2.2
C104	0.2138	0.0110	0.2819	2.0
					C106	0.3142	0.0339	0.4202	2.7
C107	0.3447	0.0163	0.4698	2.6
					C108	0.3478	-0.0346	0.5267	3.2
C109	0.3204	-0.0739	0.5392	2.9
					C110	0.2912	-0.0565	0.4933	2.3
H181	0.0016	0.3415	0.0920	3.6
					H182	-0.0121	0.4224	0.0173	3.6
H581	0.0001	-0.3330	0.0820	3.2
					H582	-0.0165	-0.2479	0.0107	3.2
H981	0.0105	0.0036	0.0919	3.0
					H982	-0.0050	0.0909	0.0217	3.0

Table 4.N-2 crystal formation is in the location parameter and the effective homogeneity temperature factor of room temperature

Atom	x	y	z	B(iso)
					CL1	-0.135841	-0.286717	-0.094687	7.0
CL2	0.308306	0.289608	0.925413	7.3
					O8	-0.180684	-0.553617	0.077453	5.6
O17	0.009131	-0.027751	0.367246	5.6
					O26	-0.444446	-0.547937	-0.064208	7.7
O48	0.353429	0.546521	0.752078	6.2
					O57	0.162822	0.050250	0.460989	9.0
O66	0.620053	-0.050755	0.722031	7.0
					N1	-0.056121	-0.389894	0.158118	5.1
N2	-0.003828	-0.346977	0.210536	5.6
					N7	-0.199990	-0.296448	0.159041	4.2
N18	0.079497	-0.250428	0.339830	7.8
					N25	-0440023	-0.256272	0.027668	3.6
N41	0.227176	0.375554	0.673430	4.3
					N42	0.178579	0.312867	0.617060	4.7
N47	0.368032	0.271293	0.672441	5.7
					N58	0.093937	0.208036	0.491185	4.5
N65	0.613256	0.221664	0.809980	5.3
					C3	-0.018504	-0.250763	0.260794	3.7
C4	-0.077398	-0.251166	0.240606	4.9
					C5	-0.117716	-0.185048	0.272564	5.3
C6	-0.177927	-0.108086	0.220878	5.0
					C8	-0.164648	-0.405370	0.128666	5.0
C9	-0.103337	-0.332311	0.169699	4.4
					C10	-0.050597	-0.465026	0.100091	4.8
C11	-0.090182	-0.340321	0.038024	4.0
					C12	-0.085777	-0.413661	-0.019688	3.6
C13	-0.036756	-0.597854	-0.014695	6.3
					C14	0.005774	-0.710337	0.047541	6.4
C15	-0.002972	-0.649451	0.100182	4.4
					C16	0.029106	-0.176073	0.330744	5.0
C19	-0.259381	-0.293483	0.118954	5.0
					C20	-0.291078	-0.441986	0.152128	5.0
C21	-0.351216	-0.432197	0.119188	5.0
					C22	-0.375655	-0.290739	0.060616	4.7
C23	-0.347355	-0.118093	0.024767	6.0
					C24	-0.285645	-0.157393	0.058200	4.8
C26	-0.468973	-0.365812	-0.035584	4.4
					C27	-0.530692	-0.331465	-0.068999	5.6
C28	-0.557164	-0.193666	-0.038159	5.9
					C29	-0.525554	-0.069547	0.026983	6.0
C30	-0.463141	-0.078130	0.065993	5.0
					C43	0.194036	0.242736	0.571113	5.3

Atom	x	y	z	B(iso)
					C44	0.252850	0.240736	0.594478	3.6
C45	0.289189	0.202874	0.559973	5.0
					C46	0.346467	0.064822	0.610082	6.1
C48	0.333197	0.391199	0.698071	5.0
					C49	0.271483	0.320215	0.655702	4.3
C50	0.223989	0.457358	0.733977	4.5
					C51	0.267853	0.357528	0.795195	5.7
C52	0.254582	0.439889	0.848257	6.f5
					C53	0.208703	0.616242	0.845 896	6.0
C54	0.170704	0.711142	0.786299	5.1
					C55	0.175781	0.634200	0.725267	5.8
C56	0.151595	0.145768	0.505108	5.6
					C59	0.433366	0.282037	0.707701	4.7
C60	0.460060	0.114791	0.769749	5.3
					C61	0.516566	0.119382	0.799476	4.7
C62	0.552226	0.226618	0.773971	4.6
					C63	0.524787	0.407839	0.711379	5.2
C64	0.465724	0.421596	0.680006	5.2
					C66	0.646462	0.096428	0.780012	4.4
C67	0.704829	0.071429	0.811131	7.4
					C68	0.731420	0.182248	0.874211	7.8
C69	0.695375	0.333003	0.902910	6.6
					C70	0.638527	0.369656	0.874228	6.3
H181	0.082900	-0.372500	0.303200	7.0
					H182	0.111100	-0.138100	0.382200	7.0
H581	0.076700	0.301300	0.528100	7.0
					H582	0.054500	0.179300	0.440700	7.1

The mean error of x, y, z is .0004 .003 .0007.

Table 5..5SBu-4 crystal formation is in+22 ℃ location parameter and effective homogeneity temperature factor

Atom	x	Y	z	Occupation rate	B(iso)
						CL1	0.1371	0.9122	0.4673	1.00	13.1
O8	0.2755	0.6426	0.2992	1.00	3.8
						O16	0.7953	0.3504	0.4288	1.00	4.8
O25	-0.0135	0.3813	0.0604	1.00	7.9
						N1	0.5081	0.6259	0.3895	1.00	3.1
N2	0.6264	0.5904	0.4172	1.00	3.4
						N7	0.3167	0.4851	0.3124	1.00	3.2
N17	0.8526	0.4699	0.4759	1.00	4.3
						N24	-0.1272	0.4851	0.1561	1.00	4.0
C3	0.6514	0.4987	0.4137	1.00	3.2
						C4	0.5484	0.4739	0.3825	1.00	3.2
C5	0.5253	0.3857	0.3604	1.00	3.9

Atom	x	Y	z	Occupation rate	B(iso)
						C6	0.3788	0.3997	0.3610	1.00	3.9
C8	0.3404	0.5681	0.3248	1.00	2.9
						C9	0.4587	0.5566	0.3677	1.00	3.0
C10	0.4548	0.7246	0.3829	1.00	3.4
						C11	0.3352	0.7648	0.4239	1.00	4.6
C12	0.2882	0.8591	0.4159	1.00	6.2
						C13	0.3579	0.9145	0.3681	1.00	6.2
C14	0.4782	0.8716	0.3291	1.00	5.9
						C15	0.5281	0.7779	0.3359	1.00	4.7
C16	0.7734	0.4335	0.4401	1.00	3.5
						C18	0.2058	0.4850	0.2712	1.00	3.2
C19	0.1868	0.5280	0.1927	1.00	3.7
						C20	0.0788	0.5271	0.1536	1.00	4.1
C21	-0.0094	0.4814	0.1945	1.00	3.6
						C22	0.0100	0.4349	0.2705	1.00	3.8
C23	0.1173	0.4375	0.3108	1.00	3.6
						C25	-0.1188	0.4305	0.0882	1.00	5.2
C26	-0.2431	0.4384	0.0563	1.00	6.0
						C27	-0.3536	0.4922	0.0905	1.00	6.0
C28	-0.3560	0.5454	0.1597	1.00	6.4
						C29	-0.2422	0.5408	0.1911	1.00	5.4
CL2	1.0582	-0.2150	0.0516	1.00	8.1
						O38	0.5757	0.0366	0.2274	1.00	5.3
O55	0.1058	0.3485	0.5156	1.00	4.3
						N31	0.6557	0.0578	0.0452	1.00	4.4
N32	0.6900	0.0994	-0.0274	1.00	4.5
						N37	0.4225	0.1756	0.2133	1.00	4.5
N54	0.1964	0.1965	0.5492	1.00	4.0
						C33	0.6252	0.1883	-0.0224	1.00	4.0
C34	0.5455	0.2045	0.0546	1.00	4.0
						C35	0.4501	0.2869	0.0930	1.00	5.0
C36	0.3519	0.2490	0.1536	1.00	5.1
						C38	0.5237	0.1039	0.1848	1.00	4.2
C39	0.5682	0.1202	0.0951	1.00	4.0
						C40	0.7080	-0.0398	0.0592	1.00	4.5
C41	0.8415	-0.0755	0.0483	1.00	5.3
						C42	0.8919	-0.1718	0.0596	1.00	5.4
C43	0.8116	-0.2274	0.0792	1.00	5.6
						C44	0.6784	-0.1904	0.0911	1.00	6.2
C45	0.6261	-0.0970	0.0824	1.00	5.4
						C46	0.6411	0.2569	-0.0930	1.00	4.4
N47	0.6871	0.2217	-0.1669	1.00	5.8
						O46	0.6104	0.3398	-0.0793	1.00	5.3
C48	0.3672	0.1729	0.2994	1.00	4.1
						C49	0.2323	0.1933	0.3152	1.00	4.5
C50	0.1764	0.1995	0.3991	1.00	4.4

Atom	x	Y	z	Occupation rate	B(iso)
						C51	0.2559	0.1844	0.4634	1.00	4.0
C52	0.3899	0.1614	0.4470	1.00	4.3
						C53	0.4466	0.1555	0.3645	1.00	4.2
C55	0.1196	0.2838	0.5695	1.00	3.9
						C56	0.0615	0.2901	0.6542	1.00	5.9
C57	0.0837	0.2185	0.7101	1.00	6.6
						C58	0.1672	0.1336	0.6875	1.00	6.8
C59	0.2212	0.1237	0.6071	1.00	5.6
						C95	0.0821	0.0157	0.2131	0.75	11.5
C96	-0.0335	0.0847	0.2368	0.75	15.1
						C97	-0.1987	0.2308	0.2132	0.75	12.0
C98	-0.0723	0.1657	0.1871	0.75	10.1
						O99	0.0405	0.2033	0.1647	0.75	8.2
H171	0.8317	0.5455	0.4861	1.00	3.6
						H172	0.9450	0.4274	0.4975	1.00	3.6
H991	0.0073	0.2694	0.1264	0.75	4.8

The mean error of x, y, z is .003 .002 .003.

Table 5a..5SBu-4 crystal formation is in-50 ℃ location parameter and effective homogeneity temperature factor

Atom	x	Y	z	Occupation rate	B(iso)
						CL1	0.1406	0.9124	0.4721	1.00	9.4
O8	0.2748	0.6424	0.3017	1.00	2.7
						O16	0.7956	0.3499	0.4261	1.00	3.3
O25	-0.0179	0.3812	0.0592	1.00	5.0
						N1	0.5092	0.6259	0.3912	1.00	2.2
N2	0.6289	0.5904	0.4183	1.00	2.4
						N7	0.3167	0.4839	0.3127	1.00	2.2
N17	0.8538	0.4703	0.4764	1.00	3.1
						N24	-0.1302	0.4862	0.1560	1.00	2.8
C3	0.6526	0.4984	0.4132	1.00	2.3
						C4	0.5485	0.4732	0.3822	1.00	2.2
C5	0.5249	0.3847	0.3593	1.00	2.8
						C6	0.3783	0.3980	0.3605	1.00	2.7
C8	0.3402	0.5676	0.3259	1.00	2.1
						C9	0.4586	0.5562	0.3692	1.00	2.1
C10	0.4574	0.7242	0.3846	1.00	2.4
						C11	0.3378	0.7650	0.4274	1.00	3.3
C12	0.2920	0.8595	0.4193	1.00	4.3
						C13	0.3608	0.9152	0.3707	1.00	4.4
C14	0.4820	0.8721	0.3292	1.00	4.2
						C15	0.5320	0.7774	0.3359	1.00	3.3
C16	0.7746	0.4327	0.4387	1.00	2.5
						C18	0.2050	0.4838	0.2709	1.00	2.2

Atom	x	Y	z	Occupation rate	B(iso)
						C19	0.1868	0.5294	0.1926	1.00	2.6
C20	0.0770	0.5294	0.1537	1.00	2.8
						C21	-0.0112	0.4816	0.1937	1.00	2.5
C22	0.0078	0.4334	0.2696	1.00	2.7
						C23	0.1167	0.4351	0.3101	1.00	2.5
C25	-0.1236	0.4322	0.0870	1.00	3.5
						C26	-0.2481	0.4409	0.0553	1.00	4.0
C27	-0.3594	0.4963	0.0909	1.00	4.2
						C28	-0.3595	0.5502	0.1609	1.00	4.4
C29	-0.2441	0.5430	0.1913	1.00	3.7
						CL2	1.0621	-0.2129	0.0488	1.00	5.4
O38	0.5796	0.0366	0.2275	1.00	3.8
						O55	0.1046	0.3481	0.5157	1.00	3.0
N31	0.6567	0.0563	0.0426	1.00	3.2
						N32	0.6908	0.0978	-0.0315	1.00	3.2
N37	0.4237	0.1742	0.2130	1.00	3.2
						N54	0.1932	0.1960	0.5510	1.00	2.9
C33	0.6263	0.1874	-0.0265	1.00	3.0
						C34	0.5474	0.2033	0.0516	1.00	2.9
C35	0.4518	0.2854	0.0917	1.00	3.7
						C36	0.3541	0.2471	0.1534	1.00	3.7
C38	0.5262	0.1033	0.1838	1.00	3.0
						C39	0.5701	0.1187	0.0933	1.00	3.0
C40	0.7092	-0.0410	0.0571	1.00	3.2
						C41	0.8434	-0.0755	0.0460	1.00	3.8
C42	0.8949	-0.1718	0.0575	1.00	3.6
						C43	0.8148	-0.2290	0.0783	1.00	4.0
C44	0.6807	-0.1939	0.0909	1.00	4.0
						C45	0.6266	-0.0986	0.0806	1.00	3.7
C46	0.6427	0.2551	-0.0968	1.00	3.0
						N47	0.6896	0.2198	-0.1718	1.00	4.2
O46	0.6114	0.3388	-0.0834	1.00	3.6
						C48	0.3670	0.1710	0.2992	1.00	2.9
C49	0.2323	0.1906	0.3163	1.00	3.3
						C50	0.1751	0.1965	0.3994	1.00	3.1
C51	0.2544	0.1826	0.4641	1.00	2.8
						C52	0.3887	0.1602	0.4478	1.00	3.1
C53	0.4464	0.1540	0.3655	1.00	3.0
						C55	0.1169	0.2843	0.5709	1.00	2.7
C56	0.0582	0.2927	0.6567	1.00	4.2
						C57	0.0788	0.2217	0.7136	1.00	4.7
C58	0.1617	0.1346	0.6913	1.00	4.9
						C59	0.2169	0.1233	0.6093	1.00	4.1
C95	0.0817	0.0159	0.2147	0.75	6.9
						C96	-0.0333	0.0867	0.2456	0.75	7.5
C97	-0.1991	0.2339	0.2145	0.75	6.4

Atom	x	Y	z	Occupation rate	B(iso)
						C98	-0.0721	0.1654	0.1872	0.75	6.3
O99	0.0385	0.2070	0.1650	0.75	4.7
						H171	0.8317	0.5455	0.4861	1.00	3.6
H471	0.7048	0.2650	-0.2282	1.00	4.9
						H172	0.9450	0.4274	0.4975	0.75	3.6
H472	0.7127	0.1451	-0.1820	1.00	4.9
						H991	0.0073	0.2694	0.1264	0.75	4.8

The mean error of x, y, z is .003 .002 .003

According to above-mentioned disclosure, the present invention also has numerous modifications and variations.Therefore, should be appreciated that in the appending claims scope, enforcement of the present invention is not limited to specific embodiments as herein described.

Claims (32)

1. (1.1-3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2 (H) pyridyl) phenyl]-4,5,6, the N-3 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide is characterized in that SSNMR is basically with shown in Figure 1 consistent.
2. 2. the N-3 crystal formation of claim 1, it is essentially pure form.
3. 3. the N-3 crystal formation of claim 1, wherein pure basically is that purity is more than 90%.
4. 4. the N-3 crystal formation of claim 1 is characterized in that x-ray diffractogram of powder is basically with shown in Figure 2 consistent.
5. 5. the N-3 crystal formation of claim 1, the x-ray diffractogram of powder of this crystal formation in the time of about 22 ℃ comprises following 2 θ values (CuK α λ=1.5418 ): 8.6 ± 0.2,11.4 ± 0.2,12.3 ± 0.2 and 15.6 ± 0.2.
6. 6. the N-3 crystal formation of claim 1 is characterized in that the peak appears at about 245-253 ℃ in the differential scanning calorimetric spectrogram.
7. (7.1-3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the N-1 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide is characterized in that unit cell parameters is substantially equal to down train value:

   Unit cell dimension: a=44.272 (1) 

   b＝14.3594(4)

   c＝20.9164(6)

   β＝109.36(1)

   Spacer C2/c

   Molecule/asymmetry unit 3

   Wherein said crystal formation is at+22 ℃ approximately.
8. 8. the N-1 crystal formation of claim 7 is characterized in that the mark atomic coordinate is as shown in table 3 basically.
9. 9. the N-1 crystal formation of claim 7 is characterized in that x-ray diffractogram of powder is basically with shown in Figure 3 consistent.
10. 10. the N-1 crystal formation of claim 7, this crystal formation comprises following 2 θ values (CuK α λ=1.5418 ) at about 22 ℃ x-ray diffractogram of powder: 4.3 ± 0.2,10.1 ± 0.2,14.3 ± 0.2 and 17.1 ± 0.2.
11. (11.1-3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the N-2 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide is characterized in that unit cell parameters is substantially equal to down train value:

    Unit cell dimension: a=26.004 (1) 

    b＝4.063(1)

    c＝22.653(1)

    β＝115.95(1)

    Spacer Pc

    Molecule/asymmetry unit 2

    Wherein said crystal formation is at+22 ℃ approximately.
12. 12. the N-2 crystal formation of claim 11 is characterized in that the mark atomic coordinate is as shown in table 4 basically.
13. 13. the N-2 crystal formation of claim 11 is characterized in that x-ray diffractogram of powder is basically with shown in Figure 4 consistent.
14. 14. the N-2 crystal formation of claim 11, this crystal formation comprises following 2 θ values (CuK α λ=1.5418 ) at about 22 ℃ x-ray diffractogram of powder: 8.8 ± 0.2,11.4 ± 0.2,13.9 ± 0.2,15.7 ± 0.2 and 22.4 ± 0.2.
15. 15. the N-2 crystal formation of claim 11 is characterized in that the peak appears at about 254-258 ℃ in the differential scanning calorimetric spectrogram.
16. (16.1-3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the P-1 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide is characterized in that x-ray diffractogram of powder is basically with shown in Figure 5 consistent.
17. 17. the P-1 crystal formation of claim 16, this crystal formation comprises following 2 θ values (CuK α λ=1.5418 ) at about 22 ℃ x-ray diffractogram of powder: 5.5 ± 0.2,11.1 ± 0.2,15.4 ± 0.2,16.8 ± 0.2.
18. 18. the P-1 crystal formation of claim 16, the endotherm(ic)peak that it is characterized in that differential scanning calorimetric spectrogram is at about 217 ℃ to about 223 ℃, and exothermic peak is at about 222 ℃ to 225 ℃, and endotherm(ic)peak is at 255 ℃ to about 259 ℃.
19. (19.1-3-chloro-phenyl-)-7-oxo-6-[4-(2-oxo-1 (2H) pyridyl) phenyl]-4,5,6, the .5SBu-4 crystal formation of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide is characterized in that unit cell parameters is substantially equal to down train value:

    Unit cell dimension: a=10.688 (1) 

    b＝15.006(2)

    c＝16.041(2)

    α＝85.51(1)

    β＝83.15(1)

    γ＝74.13(1)

    Spacer P-1

    Molecule/asymmetry unit 2

    Wherein said crystal formation is at+22 ℃ approximately.
20. 20. the .5SBu-4 crystal formation of claim 19 is characterized in that the mark atomic coordinate is as shown in table 5 basically.
21. 21. the .5SBu-4 crystal formation of claim 19 is characterized in that x-ray diffractogram of powder is basically with shown in Figure 6 consistent.
22. 22. the .5SBu-4 crystal formation of claim 19, this crystal formation comprises following 2 θ values (CuK α λ=1.5418 ) at about 22 ℃ x-ray diffractogram of powder: 6.1 ± 0.2,8.1 ± 0.2,12.9 ± 0.2,13.4 ± 0.2 and 18.5 ± 0.2.
23. 23. a pharmaceutical composition, it comprises the compound and the pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.
24. 24. a method that is used for the treatment of thrombotic disease, this method comprise that the compound with the claim 1 of treatment significant quantity has the patient of needs.
25. 25. the method for claim 24, wherein said thrombotic disease are selected from artery cardiovascular thromboembolic disease, vein cardiovascular thromboembolic disease and atrium thrombosis embolism class diseases.
26. 26. the method for claim 24, wherein said thrombotic disease is selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction first, the recurrent myocardial infarction, the ischemia sudden death, transient ischemic attack, apoplexy, atherosclerosis, occlusive artery disease on every side, venous thrombosis, venous thrombosis, thrombophlebitis, arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis forms, cerebral embolism, renal infarction, pulmonary infarction and the thrombosis that causes because of following situation: (a) heart valve prosthesis implant or other implant, (b) inlying catheter, (c) support, (d) cardiopulmonary bypass, (e) hemodialysis, or other operation that (f) blood and the thrombotic artificial surfaces of promotion is contacted.
27. 27. a method that is used to prepare the crystal formation of compound (I), this method comprises the step of compound (I) being made slurries in being selected from following solvent: acetone, ACN, DMSO, DMF, NMP, MEK, 2-BuOH, IPA, IpOAc, MTBE and BuOAc.
28. 28. a method that is used to prepare the N-3 crystal formation of claim 1, this method comprises the step of N-1 crystal formation, N-2 crystal formation or P-1 being made slurries in acetone.
29. 29. the method for claim 28, this method are included in the acetone in the 20-60 ℃ of step of making slurries.
30. 30. the method for claim 28, this method are included in the acetone in the 25-55 ℃ of step of making slurries.
31. 31. a method that is used to prepare the N-3 crystal formation of claim 1, this method also comprises:

    (a) in the presence of MeONa, make compound (II) and HCONH ₂Contact generates compound (I);

    

    (b) slowly add ammonium hydroxide and, obtain the P-1 crystal formation of compound (I) 50 ℃ of vacuum-dryings;

    (c) P-1 is made slurries in acetone, obtain the N-3 crystal formation.
32. 32. the method for claim 31, wherein:

    (b), obtain the P-1 crystal formation of compound (I) in the 50-55 ℃ of slow ammonium hydroxide that adds;

    (c) P-1 is made slurries in 25-55 ℃ in acetone, obtain the N-3 crystal formation.

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