CN103319445B

CN103319445B - Crystalline structure of SGLT2 inhibitor and preparation method thereof

Info

Publication number: CN103319445B
Application number: CN201310259839.2A
Authority: CN
Inventors: J·Z·古古塔斯; H·洛宾格; S·罗摩克里斯纳; P·P·德什潘德; J·T·比恩; 赖佳仁; 王贞棋; P·里布尔; J·A·格罗索; A·A·尼尔希; J·辛格; J·D·迪马科
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2007-12-27
Filing date: 2007-12-27
Publication date: 2016-01-20
Anticipated expiration: 2027-12-27
Also published as: CN101468976A; CN101468976B; CN103319445A

Abstract

Crystalline structure of SGLT2 inhibitor and preparation method thereof.The present invention relates to the physical crystalline structure of formula I: wherein R ¹, R ², R ^2a, R ³and R ⁴as defined herein, particularly

Description

Crystalline structure of SGLT2 inhibitor and preparation method thereof

[0000] the application is divisional application, and the applying date of original application is on December 27th, 2007, application number is 200710300419.9, denomination of invention is " crystalline structure of SGLT2 inhibitor and preparation method thereof ".

Technical field

The present invention relates to the polymorph crystals structure of the free acid of SGLT2 inhibitor, its pharmaceutical composition, prepare this paracrystalline organizations method and by the method for its disease therapy as diabetes.

Background technology

About 100,000,000 people in the whole world suffer from type ii diabetes (NIDDM), it is characterized in that because of the hyperglycemia caused by excessive hepatic glucose generation and periphery insulin resistance, but its basic reason it be unclear that.Development and the β cellular degeneration of the diabetic complication seeing terminal illness can be offset to the Sustainable Control of the plasma glucose levels in diabetic subject's body.

Plasma glucose normally filters in the renal glomerulus of kidney, and is initiatively heavily absorbed in proximal tubule.In kidney, the glucose reuptake of 90% betides in the epithelial cell of S1 sections before renal cortex proximal tubule.SGLT2 may be the major transporter of responsible this reuptake, and SGLT2 is 672 amino acid proteins containing 14 transmembrane segments, and it to be mainly expressed in before Renal proximal tubular in S1 sections.Substrate specificity, sodium dependency, and the location of SGLT2 is consistent with the characteristic of the heavy body of people's cortex Renal proximal tubular of foregoing summary, low affinity, sodium-dependent glucose translocator.In addition, hybrid depletion research prompting SGLT2 is Na main in proximal tubule S1 sections ⁺/ glucose cotransporter, because all sodium-dependent glucose transport activity be in fact encoded in from the mRNA of renal cortex of rats is by suppression to the specific antisense oligonucleotide of rat SGLT2.In the mankind, the sudden change of SGLT2 connects with the renal glycosuria of familial form, and this provides further evidence for SGLT2 plays a major role in kidney sugar heavily absorbs.These patients are normal in kidney form and renal function.In diabetic subject, will be expected to by increasing glucose excretion the suppression of SGLT2 and reduce plasma glucose levels.

When there is no significant gastrointestinal side-effect; in diabetic subject, by increasing the glucose excretion in urine, Normalization of plasma glucose can be made to the Selective depression of SGLT2; increase the susceptibility of Regular Insulin thus, and postpone the development of diabetic complication.

Summary of the invention

An aspect of of the present present invention relates to the crystalline structure of formula I:

The pharmaceutical composition of the crystalline structure containing Compound I, it comprises (S)-propylene glycol ((S)-PG) the structure I a that crystalline form is SC-3,

Crystalline form is (R)-propylene glycol ((R)-PG) the structure I b of SD-3,

Crystalline form is ethanol or the monoethanolamine dihydrate structure I c of SA-1,

Crystalline form is the ethylene glycol structure Id of SB-1,

; With

Crystalline form is the ethylene glycol structure Ie of SB-2,

; And

Prepare the method for these crystalline structure;

With the 1:2 crystalline complex structure I h of L-PROLINE, it is crystalline form 3,

With the 1:1 crystalline complex structure I i of L-PROLINE, it is crystalline form 6,

With the semihydrate structure I j of the 1:1 crystalline complex of L-PROLINE, it is form H .5-2,

; With

With the 1:1 crystalline complex structure I k of L-Phe, it is crystalline form 2,

; And

Use the method as treated diabetes and relative disease at the crystalline structure of Compound I defined herein, Compound I a, compounds ib, Compound I h, Compound I i, Compound I j and Compound I k and Compound II per.

Form is that the formula I of non-crystalline solid is disclosed in United States Patent (USP) the 6th, and in 515, No. 117, its disclosure is all introduced at this by reference.

In addition, in another aspect of this invention, the crystal of the Compound I f with following structure is also provided,

(also referred to as " Isosorbide-5-Nitrae-butine-diol solvent compound " or " butine-diol solvent compound "); With

This paracrystalline organizations of preparation is also provided and uses this paracrystalline organizations to prepare the method for crystalline compounds Ia (S)-PG.

Still in another aspect of this invention, also provide the crystalline compounds Ig with following structure,

It is also referred to as " dimethanol solvate ", and prepares this dimethanol solvate Ig and utilize Ig to prepare the method for crystalline compounds Ia (S)-PG.

Dimethanol solvate Ig and Isosorbide-5-Nitrae-butine-diol solvent compound If can be used as the intermediate preparing formula I crystalline compounds.

In still another aspect of the invention, provide the preparation method of crystalline compounds (the S)-PG (SC-3 crystalline form) of structure I a,

The method comprises the following steps: to provide compd A (as the U.S. Application Serial the 10/745th submitted on December 23rd, 2003, preparing described in the embodiment 17-20 of No. 075), and Compound A structure is:

With alcoholic solvent as methyl alcohol or ethanol, aqueous bases as sodium hydroxide, and if necessary use water, under an inert atmosphere, and if necessary, at high temperature, process compd A; Add sour example hydrochloric acid, neutralization reaction mixture, form the Compound I of following structure,

And with organic solvent, if methyl tertiary butyl ether, acetic acid alkane ester are as ethyl acetate, methyl acetate, isopropyl acetate or butylacetate and (S)-propylene glycol, the reaction mixture of process containing Compound I, the optional crystal seed adding (S)-PG Compound I a (SC-3) in this mixture, forms (S)-PG Compound I a (SC-3 crystalline form).

Still in another aspect of this invention, provide the method for crystalline compounds (the R)-PG (SD-3 crystalline form) of preparation structure I b,

The method is similar to the method for preparation recited above (S)-PG (SC-3 crystalline form) Ia, just replaces (S)-propylene glycol with (R)-propylene glycol.

Still in another aspect of this invention, provide the novel method for the preparation of Compound I a,

The method comprises the step that reduction has the compd B of following structure,

To remove methoxy group, by carrying out as follows: with reductive agent as triethyl silicane (triethylsilylhydride), and activating group---it is that Lewis acid is as BF ₃et ₂o or BF ₃2CH ₃cOOH, is preferably BF ₃2CH ₃cOOH, and organic solvent is as CH ₃cN, and additional water, process compd B is (as the U.S. Application Serial the 10/745th submitted on December 23rd, 2003, prepare described in the embodiment 17 of No. 075), or process recrystallisation solvent compound such as dimethanol solvate Ig or 1,4-butine-diol solvent compound (If), isolates the compound of structure I

And under the existence of such as this kind solvent of t-butyl methyl ether, with (S)-propylene glycol, the crystal seed of optional Compound I a ((S)-PG), process Compound I, to form the magma (crystalslurry) of Compound I a ((S)-PG), and isolate Compound I a ((S)-PG).

Aforesaid method of the present invention is the operation of single tank, and the generation of intermediate is kept to minimum by it, and the yield which results in final crystalline compounds Ia improves and priority.

Crystalline compounds Ia is also referred to as (the S)-propanediol solvate of Compound I, and it is a kind of novel crystal structure, and is a part of the present invention.

The compound (amorphous) of formula B is disclosed in the U.S. Application Serial the 10/745th proposed on December 23rd, 2003, and in No. 075, its disclosure is all introduced by reference at this.

In another aspect of this invention, provide the method preparing single-EtOH-dihydrate (ethanol or EtOH structure) crystalline form SA-1, it has structure I c,

The method comprises dissolves Compound I in ethanol, and solution is cooled to-20 DEG C and form the step of the crystalline form SA-1 of the crystal of formula Ic.

By being dissolved in ethanol by compd A preferably by being heated to boiling, and being formed as the oil product of Compound I, can Compound I being prepared.

In another embodiment of the invention, provide the method for the ethylene glycol bisthioglycolate hydrate structure for the formation of formula Id,

The method comprises the steps: preferably under heating, Compound I is dissolved in containing in water glycol,

Optionally, after cooling, the crystal seed of (S)-propylene glycol crystalline form SC-3 (Ia) is added in above-mentioned solution, and reclaim the crystal of ethylene glycol bisthioglycolate hydrated crystalline form SB-1 (Id).

In the embodiment that the present invention is other, provide the method forming ethylene glycol bisthioglycolate hydrate structure crystalline form SB-2,

The method comprises the steps:

Preferably under heating, Compound I is dissolved in containing in water glycol;

Optionally, after cooling, the crystal seed of single-EtOH-dihydrate form SA-1 (Ic) is added in above-mentioned solution; With

And reclaim the crystal of ethylene glycol bisthioglycolate hydrated crystalline form SB-1 (Ie).

In another embodiment of the invention, provide the method preparing crystallization Isosorbide-5-Nitrae-butine-diol solvent compound If,

It comprises the steps: basic cpd B

Be dissolved in acetic acid alkane ester as ethyl acetate, propyl acetate or butylacetate, or alcohol is as Virahol or butanols, or in water, 2-butyne-Isosorbide-5-Nitrae-glycol is added, the mixture of heating gained in the solution of compd B, until glycol dissolves, cool this mixture, and reclaim the crystal of Isosorbide-5-Nitrae-butine-diol solvent compound If.When solvate If is in acetic acid alkane ester during crystallization, toluene or heptane can be used as solvent resistant.

Isosorbide-5-Nitrae-butine-diol solvent compound If can be separated, and with continuous processing or batch process for the preparation of Compound I or Compound I a, as mentioned below.

In addition, in another aspect of this invention, provide the method preparing crystallization dimethanol solvate Ig,

Wherein said basic cpd B

Use methyl alcohol process, form crystallization dimethanol solvate Ig.

Be still further according to the present invention, provide the method for the preparation of crystallization dimethanol solvate Ig, wherein said basic cpd B is dissolved in the mixture of methanol/toluene, or be dissolved in the mixture of methanol/toluene/heptane, or be dissolved in the mixture of methanol/toluene/ethyl acetate or other acetic acid alkane ester, and inoculate with the crystal seed of dimethanol solvate Ig.

Dimethanol solvate Ig and Isosorbide-5-Nitrae-butine-diol solvent compound If can be used for preparing crystalline compounds Ia as described herein.

In still another aspect of the invention, provide that structure is Ih, preparation method with the 1:2 composite crystal (crystalline form 3) of L-PROLINE,

Described method comprises the steps: the Compound I providing following structure,

Form L-PROLINE at water neutralized alcohol solvent as the solution in methyl alcohol, ethanol or Virahol, this solution is heated to the temperature within the scope of 70 to about 95 DEG C, at alcoholic solvent as in methyl alcohol, ethanol or Virahol, Compound I is processed with the L-PROLINE solution (containing 2 times of L-PROLINE mole numbers to Compound I) of heating, gained solution is cooled to about room temperature, forms Compound I h.

Still in another aspect of this invention, provide for the preparation of structure be Ii, method with the crystalline compounds (crystalline form 6) of L-PROLINE 1:1 compound,

The method comprises the steps: to provide Compound I, with L-PROLINE at alcohol/water solvent as the boiling solution in ethanol/water, process Compound I at alcoholic solvent as the solution (Compound I of use reaches about 5 times of L-PROLINE) in ethanol or methyl alcohol, and by gained mixture cooling (being such as cooled to about-10 to about-25 DEG C), form Compound I i.

Still in another aspect of this invention, provide for the preparation of structure be Ij, method with the crystalline hemihydrate (form H .5-2) of the 1:1 mixture of L-PROLINE, its structure is:

The method comprises the steps: to provide seed crystal (the structure I i with the 1:1 mixture of L-PROLINE, crystalline form 6), by this crystalline form be 6 seed crystal Ii the cooling solution in alcohol/water solvent (-10 to-25 DEG C) mixes with L-PROLINE and Compound I, and gained mixture is cooled at the temperature of about-10 to-25 DEG C, form semihydrate structure I j (form H .5-2).

In still another aspect of the invention, provide for the preparation of structure I k, crystalline form 2, method with the 1:1 crystalline composites of L-Phe,

The method comprises the steps: to form the solution of L-Phe in water, heated at about 70 to about 85 DEG C by this solution, mixing L-Phe solution and Compound I, be heated to about 75 to about 85 DEG C by gained solution, and make gained solution be cooled to room temperature, form Compound I k.

Another aspect of the present invention relates to the crystalline structure of formula II compound,

It is also referred to as (S)-propylene glycol ((S)-PG) crystalline texture II, wherein:

R ¹, R ²and R ^2aindependent is hydrogen, OH, OR ⁵, alkyl ,-OCHF ₂,-OCF ₃,-SR ^5aor halogen;

R ³and R ⁴independent is hydrogen, OH, OR ^5b, alkyl, alkenyl, alkynyl, cycloalkyl, CF ₃,-OCHF ₂,-OCF ₃, halogen ,-CONR ⁶r ^6a,-CO ₂r ^5c,-CO ₂h ,-COR ^6b,-CH (OH) R ^6c,-CH (OR ^5d) R ^6d,-CN ,-NHCOR ^5e,-NHSO ₂r ^5f,-NHSO ₂aryl ,-SR ^5g,-SOR ^5h,-SO ₂r ⁵ⁱ,-SO ₂aryl, or be independently can contain 1 to 4 heteroatomic 5,6 or 7 yuan of heterocycle in ring, described heteroatoms is N, O, S, SO and/or SO ₂, or R ³and R ⁴form 5, the 6 or 7 yuan of carbocyclic rings or heterocycle that condense together with the carbon that they connect, it can contain 1 to 4 heteroatoms in ring, and described heteroatoms is N, O, S, SO and/or SO ₂;

R ⁵, R ^5a, R ^5b, R ^5c, R ^5d, R ^5e, R ^5f, R ^5g, R ^5hand R ⁵ⁱindependent is alkyl; With

R ⁶, R ^6a, R ^6b, R ^6cand R ^6dindependent is hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R ⁶and R ^6aform 5, the 6 or 7 yuan of heterocycles condensed together with the nitrogen that they connect, it is containing 1 to 4 heteroatoms in ring, and described heteroatoms is N, O, S, SO and/or SO ₂.

In addition, according to the present invention, also provide the pharmaceutical composition of the crystalline structure containing Compound II per and prepare the method for this kind of crystalline structure II.

Be still the crystalline structure that another aspect of the present invention relates to formula III compound,

It is also referred to as (R)-propylene glycol ((R)-PG) crystalline texture III, wherein:

R ³and R ⁴independent is hydrogen, OH, OR ^5b, alkyl, alkenyl, alkynyl, cycloalkyl, CF ₃,-OCHF ₂,-OCF ₃, halogen ,-CONR ⁶r ^6a,-CO ₂r ^5c,-CO ₂h ,-COR ^6b,-CH (OH) R ^6c,-CH (OR ^5d) R ^6d,-CN ,-NHCOR ^5e,-NHSO ₂r ^5f,-NHSO ₂aryl ,-SR ^5g,-SOR ^5h,-SO ₂r ⁵ⁱ,-SO ₂aryl, or be independently can contain 1 to 4 heteroatomic 5,6 or 7 yuan of heterocycle in ring, described heteroatoms is N, O, S, SO and/or SO ₂, or R ³and R ⁴form 5, the 6 or 7 yuan of carbocyclic rings or heterocycle that condense together with the carbon that they connect, it is containing 1 to 4 heteroatoms in ring, and described heteroatoms is N, O, S, SO and/or SO ₂;

In addition, according to the present invention, also provide the pharmaceutical composition of the crystalline structure containing compound III and prepare the method for this kind of crystalline structure III.

In still another aspect of the invention, provide the preparation method of crystalline compounds (the S)-PG of structure I I, described method comprises the steps: that the Compound C providing structure following (comprises wherein R ³or R ⁴be alkenyl or alkynyl, all these can be used in the U.S. Application Serial the 10/745th proposed on December 23rd, 2003, and described in the embodiment 17-20 of No. 075 prepared by method),

Wherein R ¹, R ², R ^2a, R ³and R ⁴as mentioned above;

With alcoholic solvent if methyl alcohol and aqueous bases are as sodium hydroxide, and required words also have water, and under inert atmosphere and high temperature, process Compound C, forms the Compound D that structure is following,

And with organic solvent as methyl tertiary butyl ether, alkyl acetate is as ethyl acetate, methyl acetate, isopropyl acetate or butylacetate, and the process of (S)-propylene glycol contains the reaction mixture of Compound D, the optional crystal seed by (S)-PG Compound II per adds in this mixture, forms (S)-PG Compound II per.

Still in another aspect of this invention, provide the method for crystalline compounds (the R)-PG for the preparation of structure III,

The method is similar to the above-mentioned method for the preparation of (S)-PGII, just replaces (S)-propylene glycol with (R)-propylene glycol.

Still in another aspect of this invention, provide the novel method for the preparation of Compound II per,

The method comprises the steps: to go back the following compd E of primary structure,

(it is openly the U.S. Application Serial the 10/745th that on December 23rd, 2003 proposes, No. 075), to remove methoxy group, this reduction be by with reductive agent as triethyl silicane, and activating group---it is that Lewis acid is as BF ₃et ₂o, and organic solvent is as CH ₃cN, Yi Jishui, process compd E is implemented; Isolate the compound of structure D; and at solvent as under t-butyl methyl ether existence; with (S)-propylene glycol, optionally use the crystal seed process Compound D of Compound II per ((S)-PG), form the magma of Compound II per ((S)-PG); And isolate Compound II per ((S)-PG).

Aforesaid method of the present invention is the operation of single tank, and the generation of intermediate is kept to minimum by this operation.

Accompanying drawing explanation

The present invention is set forth by reference to accompanying drawing described below.

Fig. 1 shows (S)-PG crystalline texture Ia---calculating (at 25 DEG C of Imitatings) the x-ray diffractogram of powder case of SC-3 crystalline form and observation (test under room temperature) x-ray diffractogram of powder case.

Observation (test under room temperature) the x-ray diffractogram of powder case of Fig. 2 shows (R)-PG crystalline texture Ib.

-PG crystalline texture IaSC-3 crystalline form that Fig. 3 shows (S) ¹³cNMRCPMAS composes.

Fig. 4 shows (R)-PG crystalline texture of Ib ¹³cNMRCPMAS composes.

Fig. 5 shows thermogravimetric analysis (TGA) curve of (S)-PG crystalline texture---SC-3 crystalline form---of Ia.

Fig. 6 shows thermogravimetric analysis (TGA) curve of (R)-PG crystalline texture---SD-3 crystalline form---of Ib.

Differential scanning calorimetry (DSC) differential thermogram of (S)-PG crystalline texture of the compound that Fig. 7 shows Ia---SC-3 crystalline form---.

Fig. 8 shows differential scanning calorimetry (DSC) differential thermogram of (R)-PG crystalline texture of Ib.

Fig. 9 shows observation (test at room temperature) the x-ray diffractogram of powder case of Isosorbide-5-Nitrae-butine-diol solvent compound crystalline texture If.

Figure 10 shows observation (test at room temperature) the x-ray diffractogram of powder case of dimethanol solvate crystalline texture Ig.Wherein, from the crystalline melting point of DSC: 77.5 DEG C; Second time heat absorption at 250 DEG C is the decomposition due to compound.

Figure 11 shows differential scanning calorimetry (DSC) differential thermogram of Isosorbide-5-Nitrae-butine-diol solvent compound crystalline texture If.

Figure 12 shows differential scanning calorimetry (DSC) differential thermogram of the dimethanol solvate crystalline texture of Ib.

Calculating (at-40 DEG C of Imitatings) the x-ray diffractogram of powder case that Figure 13 shows 1:2L-proline Complex crystalline texture Ih---crystalline form 3, N-1---, mixing (hybrid) (under room temperature) x-ray diffractogram of powder case and observation (test at room temperature) x-ray diffractogram of powder case.

Calculating (at-40 DEG C of Imitatings) the x-ray diffractogram of powder case that Figure 14 shows 1:1L-proline Complex crystalline texture Ii---crystalline form 6, N-1---, mixing (under room temperature) x-ray diffractogram of powder case and observation (test at room temperature) x-ray diffractogram of powder case.

Figure 15 shows calculating (at-40 DEG C of Imitatings) the x-ray diffractogram of powder case of 1:1L-proline(Pro) hemihydrate crystalline structure I j---form H .5-2---, mixing (under room temperature) x-ray diffractogram of powder case and observation (test at room temperature) x-ray diffractogram of powder case.

Figure 16 shows thermogravimetric analysis (TGA) curve of the 1:2L-proline Complex crystalline texture---crystalline form 3, N-1---of Ih.

Figure 17 shows thermogravimetric analysis (TGA) curve of the 1:1L-proline Complex crystalline texture---crystalline form 6, N-1---of Ii.

Figure 18 shows thermogravimetric analysis (TGA) curve of 1:1L-proline(Pro) hemihydrate crystalline structure I j---form H .5-2---.

Differential scanning calorimetry (DSC) differential thermogram that Figure 19 shows 1:2L-proline Complex crystalline texture Ih---crystalline form 3, N-1---.

Differential scanning calorimetry (DSC) differential thermogram that Figure 20 shows 1:1L-proline Complex crystalline texture Ii---crystalline form 6, N-1---.

Figure 21 shows differential scanning calorimetry (DSC) differential thermogram of 1:1L-proline(Pro) hemihydrate crystalline structure I j---form H .5-2---.

Figure 22 is the schematic diagram of continuous reaction apparatus.

Detailed Description Of The Invention

The present invention provides the crystalline texture of the Compound I as novel substance at least partly.

As used herein, term " pharmaceutically acceptable (pharmaceuticallyacceptable) " refers to such compound, material, composition and/or formulation, in the scope of rational medical judgment, their are applicable to and contact tissue of humans and animals, and do not have the problem complication that overdosage toxicity, stimulation, anaphylaxis or other and rational benefit/risk ratio match.Some preferred embodiment in, the crystalline structure of the compounds of this invention I is in substantially pure form.As used herein, term " substantially pure (substantiallypure) " refers to that compound has the purity of about more than 90%, such as, comprise about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% and about 100%.

The ability that compound exists with different crystal structure is called as heteromorphism.As used herein, but " polymorphic form " refers to have identical chemical constitution form the different crystal shape of the spatial disposition of the molecule of crystal, atom and/or ion.Although polymorphic form has identical chemical constitution, but they are different in heap sum geometry arrangement, and can show different physical propertiess, as fusing point, shape, color, density, hardness, deformability, stability, dissolving and similarity.Depend on their temperature-stability relation, two kinds of polymorphic forms can be single-phase transformations or enantiotropic.For single-phase transformation system, when temperature changes, the relative stability between two solid phases remains unchanged.On the contrary, in enantiotrophy system, there is transition temperature, at such a temperature, the stability of two-phase is put upside down.Polycrystalline in (" PolymorphisminPharmaceuticalSolids " (1999) ISBN :)-8247-0237 is theoretical and originate from (TheoryandOriginofPolymorphism)).

The sample of crystalline structure of the present invention can be provided under substantially pure phase homogeneity, and this shows to there are the single crystal structure of primary amount and one or more other crystalline structure of optional minor amount.In the sample to which, the existence of more than one crystalline structure of the present invention can be measured by such as powder x-ray diffraction (PXRD) or solid state nmr spectral method (SSNMR) this kind of technology.Such as, at the PXRD pattern (observation) of experimental measurement with simulation PXRD pattern the comparing of (calculating), the existence at extra peak may show the crystalline structure in the sample to which with more than one.The PXRD of simulation can calculate according to single crystal X-ray data.(see Smith, D.K., " AFORTRANProgramforCalculatingX-RayPowderDiffractionPatte rns, " LawrenceRadiationLaboratory, Livermore, California, UCRL-7196, April1963; Also see Yin.S., Scaringe, R.P., DiMarco, J., Galella, M.andGougoutas, J.Z., AmericanPharmaceuticalReview, 2003,6,2,80).Preferably, crystalline structure has substantially pure phase homogeneity, as by come from extra peak, the total peak area accounted in experimental measurement PXRD pattern less than 10%, preferably less than 5%, more preferably 2% is shown below, and this extra peak does not exist in simulation PXRD pattern.Most preferably have the crystalline structure of the present invention of following substantially pure phase homogeneity, wherein in experimental measurement PXRD pattern, less than 1% of total peak area come from extra peak, this extra peak does not exist in simulation PXRD pattern.

By using various analytical technology well known by persons skilled in the art, various crystalline structure of the present invention as herein described can be distinguished from each other out.These technology include but not limited to solid state nmr (SSNMR) spectral method, x-ray powder diffraction (PXRD), differential scanning calorimetry (DSC) and/or thermogravimetry (TGA).

The preparation of crystalline structure

Crystalline structure of the present invention can be prepared by multiple method, comprise such as from suitable solvent crystallization or recrystallization, distillation, from melt growth, from the solid state transformation of another phase, from crystalization in supercritical fluid and spraying (jetspraying).The technology of crystalline structure crystallization or recrystallization from solvent mixture such as comprises evaporating solvent, reduces the temperature of solvent mixture, the supersaturation solvent mixture of molecule and/or salt is carried out to crystal inoculation, lyophilize solvent mixture and solvent resistant (counter solvent) is added solvent mixture.High yield crystallization technique can be used for preparing the crystalline structure comprising polymorphic form.

What comprise the medicine crystal of polymorphic form, preparation method and medicine crystal is characterized in Solid-StateChemistryofDrugs, S.R.Byrn, R.R.Pfeiffer and J.G.Stowell, the second edition, SSCI, WestLafayette, Indiana, is discussed in 1999.

Seed crystal can be added in any crystalline mixture to promote crystallization.For technicians it is clear that put into crystal seed to be used as the method that control specific crystal structure grows or the method being used as the distribution of crystallization control product particle size.Therefore, the size of available crystal seed and the expectation size of average product particle are depended on to the calculating of required crystal seed amount, such as, as at " Programmedcoolingofbatchcrystallizers; " J.W.MullinandJ.Nyvlt, ChemicalEngineeringScience, 1971, described in 26,369-377.Generally speaking, need undersized crystal seed, effectively to control the growth of crystal in this batch.Undersized crystal seed by compared with the screening of macrocrystal, grinding or micronizing, or can be produced by the micro-crystallization of solution.It should be noted that the grinding of crystal or micronizing can not cause any change (that is, become amorphous or become another kind of polymorphic form) of the degree of crystallinity expecting crystalline structure.

As used herein, term " room temperature " or " RT " represent the envrionment temperature of 20 to 25 DEG C (68-77 ℉).

Generally speaking, as described below prepare crystalline compounds Ia time, will use solvent (one or more) to make crystalline compounds Ia to be formed, crystalline compounds Ia preferably has tap density as described below.

The crystalline compounds of structure I a of the present invention (S-PG) SC-3 according under look like storied reaction (telescopedreaction) preparation shown in scheme I.

Scheme I

From scheme I, with reductive agent as silane (silylhydride), preferred alkyl silane, more preferably triethyl silicane (triethylsilane or triethylsilylhydride), at activating group---described activating group is Lewis acid, as BCl ₃me ₂s, BBr ₃, BF ₃oEt ₂, BCl ₃or BF ₃2CH ₃cOOH, preferred BF ₃oEt ₂or BF ₃2CH ₃cOOH, and organic solvent---as CH ₃cN, CH ₃cN/ toluene or CH ₃cN/ methylene dichloride, methylene dichloride, or under the existence of water, at temperature within the scope of about-15 to about 25 DEG C, preferably within the scope of about 5 to about 10 DEG C, process compd B or If or Ig (being jointly called compd B), wherein compd B is in the form of amorphous solid or crystalline solid (If or Ig), corresponding basic cpd I is formed with reducing compound B

Compound I is separated from reaction mixture, and process by (S)-propylene glycol ((S)-PG) and organic solvent such as alkyl acetate cited hereinbefore, preferably isopropyl acetate or t-butyl methyl ether (MTBE), and optionally use crystal seed process (the crystal seed Ia: the mol ratio of compd B is in about 0.1 to about 10% scope of compound ((S)-PG) Ia, be preferably about 0.5% to about 3%), to form the magma of compound ((S)-PG) Ia, and crystalline compounds ((S)-PG) Ia is separated from this magma.

When the storied reaction carrying out such scheme I, by the mol ratio of silyl reductive agent and compd B that uses in the scope of about 1.2:1 extremely about 4.5:1, preferably about 2:1 to about 4:1, and the mol ratio of the activating group used (Lewis acid) and silyl reductive agent is in the scope of about 1.2:1 to about 4.5:1, preferably about 2:1 to about 4:1.The mol ratio of (the S)-propylene glycol ((S)-PG) used and compd B in the scope of about 0.9:1 to about 1.5:1, preferably about 0.98:1 to about 1.2:1; The mol ratio of the water used and (S)-PG in the scope of about 0.95:1 to about 5:1, preferably about 0.99:1 to about 2:1.

The crystalline compounds ((S)-PG)---crystalline form SC-3---of structure I a of the present invention also can according to scheme II shown below preparation.

Scheme II

Wherein, with alcoholic solvent---as methyl alcohol, ethanol or Virahol, particular methanol---water and aqueous bases---is as alkali metal hydroxide, as NaOH, KOH or LiOH, preferred NaOH, preferably at inert atmosphere as under nitrogen atmosphere, under the high temperature of about 50 to about 85 DEG C, preferably about 60 to about 80 DEG C, process compd A, forms Compound I.

The aqueous bases used and the mol ratio of compd A in the scope of about 3.5:1 to about 5.5:1, preferably about 3:1 to about 5:1.

By the reaction mixture containing Compound I with organic solvent as above as methyl butyl ether (MTBE) or alkyl acetate, preferred isopropyl acetate or MTBE process, to isolate Compound I, by Compound I (S)-propylene glycol process, to form the thick slurry containing crystallized product Ia (S)-PG---crystalline form SC-3---.Optionally, the crystal seed of compound ((S)-PG) Ia is added in reaction mixture.Conventional steps is adopted to be separated with described slurry by crystalline compounds Ia, such as, with organic solvent as hexanaphthene, octane-iso or methylcyclohexane, the slurry of preferred hexanaphthene process Compound I a, and reclaim crystalline compounds Ia.

When forming Compound I a, the mol ratio of (the S)-PG used and Compound I in the scope of about 0.9:1 to about 1.5:1, preferably about 0.98:1 to about 1.2:1.

As shown in before this paper, prepared by the mode that (R)-propanediol solvate Ib of Compound I can be similar to (S)-propanediol solvate Ia accordingly, just replace (S)-propylene glycol with (R)-propylene glycol.

The inventive method for the preparation of list-EtOH-dihydrate (ethanol or EtOH/ structure) crystalline form SA-1 (Compound I c) is shown in scheme III below.

Scheme III

Wherein, then add water by being heated to boiling compd A dissolved in ethanol, the volume ratio of water and ethanol in the scope of about 1:1 to about 3:1, preferably about 1.5:1 extremely about 2.5:1.Add ethanol, and the scope that is cooled to by mixture is at the temperature of about-10 DEG C to about-30 DEG C, preferably about-15 DEG C to about-25 DEG C.Reclaim Compound I c, it is the crystal of single-EtOH-dihydrate.

The inventive method for the preparation of ethylene glycol bisthioglycolate hydrate structure crystalline form SB-1 and crystalline form SB-2 (being respectively Compound I d and Ie) is carried out as follows.

Preparation Compound I d crystalline form SB-1, by compd A being dissolved in containing (water: ethylene glycol is about 1:1 to about 0.4:1 in water glycol, preferably about 0.7:1 to about 0.5:1) middle enforcement, described dissolving is by the temperature within the scope of about 35 to about 55 DEG C, preferably about 40 to about 50 DEG C, and heating about 0.5 is little to be carried out up to about 1 hour up to about 2 hours, preferably about 0.5 are little.Under mixture being cooled to the temperature within the scope of about 10 to about 22 DEG C, preferred about 14 to about 16 DEG C, add the crystal seed of list-EtOH-dihydrochloride dihydrate crystal Ic or ethylene glycol bisthioglycolate hydrate crystal shape SB-1Id, the mol ratio of they and compd A is in about 0.1% to about 10% scope, preferred about 0.5% to about 3%, to form ethylene glycol bisthioglycolate hydrate crystal shape SB-1Id.

According to the present invention, ethylene glycol bisthioglycolate hydrate crystal shape SB-2Ie is formed as follows: be dissolved in by compd A containing (water: ethylene glycol is about 1:1 to about 0.4:1 in water glycol, preferably about 0.7:1 to about 0.5:1), described dissolving is carried out to about 1 hour up to about 2 hours, preferably about 0.30min heating about 1.5 is little by the temperature within the scope of about 35 to about 55 DEG C, preferably about 40 to about 50 DEG C.Under mixture being cooled to the temperature within the scope of about 10 to about 30 DEG C, preferred about 20 to about 25 DEG C, and add the crystal seed of ethylene glycol bisthioglycolate hydrate crystal shape SB-2Ie, the mol ratio of itself and compd A is in the scope of about 0.1% to about 10%, preferred about 0.5% to about 3%, to form ethylene glycol bisthioglycolate hydrate crystal shape SB-2Ie.

Implement according to scheme IV as follows for the preparation of the crystalline form of compd B and the inventive method of If.

Crystallization of the present invention Isosorbide-5-Nitrae-butine-diol solvent compound If is prepared according to reaction scheme IV below.

Scheme IV

Wherein, (it can as the United States Patent (USP) sequence the 10/745th submitted on December 23rd, 2003 to be preferably in the noncrystalline compd B of substantially pure form (such as 50 to 100% purity), No. 075, or United States Patent (USP) the 6th, 515, be prepared described in No. 117) mix with toluene/alkyl acetate (as ethyl acetate), and this mixture is heated to about 50 to about 70 DEG C, at temperature within the scope of preferred about 55 to about 65 DEG C, add 2-butyne-1, 4-glycol, as above-mentioned heating, until glycol dissolves, add the crystal seed of Compound I f, this mixture is cooled, form the crystal of Compound I f.

In the optional method preparing crystalline compounds If, under high temperature within the scope of about 50 to about 70 DEG C, preferably about 55 to about 65 DEG C, compd B is dissolved in alkyl acetate (as butylacetate) or alkyl acetate/heptane (0.5:1 to 1.5:1) mixture, add 1,4-butine-glycol, and mixture is cooled to room temperature, form the crystal of Compound I f.

In a preferred embodiment, Compound I f crystallization from the mixture of compd B and toluene/alkyl acetate (ethyl acetate), the volume ratio of the toluene that this mixture contains and alkyl acetate is in the scope of about 1:1 to about 19:1, preferably about 4:1 to about 9:1.The mixture of toluene/alkyl acetate will comprise enough toluene, to make the mol ratio of itself and compd B within the scope of about 40:1 to about 90:1, and preferably about 60:1 to about 80:1, thus Isosorbide-5-Nitrae-butine-diol solvent compound If can be formed.

Adopt the crystal seed of Compound I f, more easily can realize crystallization and form Isosorbide-5-Nitrae-butine-diol solvent compound If, the amount of the crystal seed of Compound I f, based on the weight of initial compounds B, is about 0.1 to about 10%, preferably about 0.5 to about 3%.

Another preferred embodiment in, Compound I f (it can be purified or can not be purified) crystallization from the mixture of compd B and alkyl acetate/heptane (preferred butylacetate/toluene), the crystal seed inoculation of optional crystalline compounds If, the amount of crystalline compounds If crystal seed, based on the weight of initial compounds B, for about 0.1 to about 10%, preferably about 0.5 to about 3%.The alkyl acetate used and the volume ratio of heptane in the scope of about 0.5:1 to about 2:1, preferably about 1:1 to about 1:1.5.

Crystallization Isosorbide-5-Nitrae-butine-diol solvent compound If also can with the continuous processing preparation as shown in scheme IVA.

The synthesis of solvate If comprises two consecutive steps of compd E and Compound D: (1) compd E carries out lithiumation and produces lithiumation intermediate G, and the coupling of (2) lithiumation intermediate G and Compound D.

Scheme IVA

With reference to Figure 22, show schematic process flow diagram (be similar to and be disclosed in United States Patent (USP) the 7th, the schema in 164, No. 015, this patent is incorporated herein by reference).In this embodiment, as carried out under non-Cryogenic Conditions in the whole technique of the preparation Compound I f as shown in scheme IVA.The aromatic reactants E with the group being suitable for Li and halogen exchange is at room temperature stored in the first container 1.Equally at room temperature lithium reagent Q is fed in second container 2.Aromatic reactants E and lithium reagent Q is transferred in the first jacketed type static mixer 5 respectively by pump 3 and 4 from container 1 and 2.In the first mixing tank 5, by water cooler 6, the temperature of reaction producing lithiated anion kind is regulated at about-30 DEG C to about 20 DEG C.

The lithiated anion kind G formed thus is directly fed to the second static mixer 22 from the first mixing tank 5 along common feed line 19.The reactant D of carbonyl substituted is at room temperature fed in the 3rd container 20, and is conveyed through water cooler 26 by pump 21, herein, under reactant D is cooled to the temperature within the scope of about-10 to about-30 DEG C, be then delivered to the second jacketed type static mixer 22.Regulated the reaction producing glycoside products H by the second water cooler 23 in the second mixing tank 22.

Carry out the further process under glycosylation condition, wherein H is fed in conventional reactor 25, in the reactor, is used in the acid treatment H in preferred MSA/MeOH or HCl/MeOH of alcoholic solvent, to form H ' (protodesilyation hemiketal), it is further converted to glucosides B.Further additional operation and the reextraction carried out with the 2-butyne in toluene/EtOAc-Isosorbide-5-Nitrae-glycol (J) and crystallization create crystallized product If.In any follow-up reaction process, under reactor 25 can remain on room temperature or other non-cryogenic temperature.

It is organolithium reagent that the lithium reagent used is expected.Suitable organolithium reagent comprises n-BuLi, s-BuLi and t-BuLi.Other will be obvious to those skilled in the art.

After having reacted, according to the technology (such as precipitation, solvent extraction, recrystallization and chromatography) that organic chemistry filed is extensively known, product If can be expected by abstraction and purification.Go protection product If itself can be useful intermediate or final product.Use method known to those skilled in the art, Compound I f can react further, obtains its pharmaceutically acceptable acid salt or alkali salt.

In the continuous processing design shown in scheme IVA, temperature and reaction times are two important parameters: lithiumation can-30 DEG C (or lower) to as high as under 20 DEG C (or higher), at preferred about-17 ° to about-10 DEG C, run the several minutes reaction times to the several seconds continuously.For follow-up linked reaction, lithium derivative G stream mixes in a mixer with Compound D stream (the 3rd charging) further.Then, if need the extra time to complete reaction, then mixed flow is sent to flow reactor.Linked reaction can under the comparatively high temps of-30 DEG C to-10 DEG C (or higher), preferably about-30 ° to about-20 DEG C, carries out the several minutes reaction times to the several seconds continuously.Then, as described herein, coupling stream is sent to batch reactor for further reaction.Compared with large-scale low temperature batch reactor, in processed continuously situation, utilize the less flow reactor having significant temp and control, lithiumation and linked reaction fully can be combined and are operated at relatively high temperatures.

The service temperature of continuous lithiumation in the above-mentioned methods (can be not limited to this temperature) up to 20 DEG C, preferably-17 to-10 DEG C, produces the expectation lithiumation intermediate G of >95RAP simultaneously.

In linked reaction, at-20 DEG C to-30 DEG C from the coupled product of aforesaid method preferably within the scope of 70-79RAP.

As shown in scheme IVB, Compound I f may be used for preparing crystallization of intermediate A.

Scheme IVB

The preparation of intermediate A

Reference scheme IVB, maintains this temperature under solid chemical compound If, solid DMAP, liquid acetonitrile and liquid acetic acid acid anhydride being heated to the temperature within the scope of about 70 to about 85 DEG C, until reaction terminates.

By this batch of cooling (such as 5 DEG C).Triethyl silicane and boron trifluoride acetic acid mixture or other Lewis acid (as described in about scheme I) are added in reaction mixture.After having reacted, add acetone or other solvent.This batch is heated (such as from about 20 to about 30 DEG C) and keeps, until triethyl silicane is depleted.Add moisture NH ₄oAc, mixes this batch, and makes it precipitate, until upper and lower phase is formed.By distilling acetonitrile with minimum stirring, the batch volume of the product in Fu Shangxiang is reduced.At high temperature (>60 DEG C) adds SDA3A ethanol.

By cooling or cool putting in crystal seed (the Compound I f milled based on wet-milling, nitrogen jet or the 5wt% of previous batch) situation, product A is crystallized out.

Product is by recrystallization from SDA3A ethanol, and it is wet cake or dry cake.

Crystallization dimethanol solvate Ig of the present invention is prepared according to reaction scheme V below.

Plan V

Wherein, (it can as the United States Patent (USP) sequence the 10/745th submitted on December 23rd, 2003 to be preferably in the noncrystalline compd B of substantially pure form (such as 50 to 100% purity), No. 075 or United States Patent (USP) the 6th, 515, be prepared described in No. 117) be dissolved in methyl alcohol, methanol/toluene mixture, methanol/toluene/heptane mixture, methyl alcohol/methyl tertiary butyl ether (MTBE)/heptane mixture, or in the mixture of methanol/toluene/ethyl acetate or other alkyl acetate, with stirring, to form the stock white containing crystallization dimethanol solvate Ig.Utilize conventional steps as filtered, crystallization dimethanol solvate Ig can reclaim from this slurry.

Aforesaid method can at room temperature carry out, although can adopt the high temperature that can reach about 20-25 DEG C, to improve crystallization.

In a preferred embodiment, crystalline compounds Ig from the mixture of methanol/toluene, the methyl alcohol that this mixture has to the volume ratio of toluene at about 6:1 within the scope of about 1:1, preferably about 3:1 to about 5:1.The mixture of methanol/toluene will comprise enough methyl alcohol, to make the mol ratio of itself and compd B within the scope of about 80:1 to about 10:1, and preferably about 40:1 to about 20:1, thus dimethanol solvate Ig can be formed.

Adopt the crystal seed of Compound Ig per, more easily can realize crystallization and form dimethanol solvate Ig, the amount of the crystal seed of Compound Ig per, based on the weight of initial compounds B, is about 0.1% to about 10%, preferably about 0.5% to about 3%.

Another preferred embodiment in, at the crystal seed with crystalline compounds Ig---it is based on the weight of initial compounds B, for about 0.1 to about 10%, preferred about 0.5 to about 3%---when inoculation, Compound Ig per (it can be purified or can not be purified) crystallization from the mixture of methanol/toluene/heptane.The methyl alcohol used and the volume ratio of toluene in the scope of about 1:0.5 to about 1:6, preferably about 1:1.5 to about 1:2.5, and heptane: the volume ratio of toluene in the scope of about 2:1 to about 0.5:1, preferably about 1.3:1 to about 0.5:1.

According to reaction scheme VI below, prepare crystalline complex 1:2L-proline(Pro) Ih of the present invention.

Plan V I

Wherein, the aqueous solution of L-PROLINE is heated to the temperature within the scope of about 70 DEG C to about 90 DEG C, and adds alcoholic solvent, as methyl alcohol, ethanol or Virahol, and preferred Virahol.Added by the solution of Compound I in above-mentioned L-PROLINE solution (it is stirred), wherein used Compound I and the mol ratio of L-PROLINE are about 0.5:1.Solution is slowly cooled to room temperature, and solid is formed during this period.Filter this solution, to remove solid, this solid alcoholic solvent is washed.This solid dry, and reclaim as a white solid, it is 1:2L-proline(Pro) crystalline complex Ih---crystalline form 3, N-1.

According to reaction scheme VII below, prepare crystallization 1:1L-proline Complex Ii of the present invention.

Plan V II

The solution of L-PROLINE in ethanol/water is heated to boiling, and adds the solution of Compound I in ethanol or other alcoholic solvent.Gained solution is cooled to-25 DEG C from-10 DEG C, and in solid formation this period, this solid is the 1:1 crystalline complex Ii with L-PROLINE, adopts ordinary method to be reclaimed.Implementing in the above-mentioned steps for the preparation of 1:1L-proline Complex Ii, the L-PROLINE used and the mol ratio of Compound I are in the scope of about 1:4 to about 1:6.

According to reaction scheme VIII below, prepare crystal L-PROLINE semihydrate composite I j of the present invention.

Plan V III

Wherein, L-PROLINE and the solution of Compound I (4.34g, 10mmol) in ethanol/water are heated to 70 DEG C, produce settled solution.Gained solution is cooled to-25 DEG C from-20 DEG C, and adds the crystal seed with the 1:1 composite I i of L-PROLINE.At-20 DEG C after 3 days, by solid collected by filtration, filter cake cold (-20 DEG C) washing with alcohol.Adopt conventional steps, being reclaimed by gained solid suspension, is white crystalline solid Ij, H0.5-2.

According to reaction scheme IX below, prepare crystal L-Phe composite I k of the present invention.

Scheme IX

L-Phe is dissolved in water under heating.Filter gained solution, and add in ethanol (or other alcohol) solution containing Compound I.Gained solution is heated at the temperature of 70 to 90 DEG C, and makes it slowly cool to room temperature (observing crystal formation at 55 DEG C).Solution is made to experience conventional recycling step.Reclaiming L-Phe composite I k, is white solid, through being accredited as the 1:1 mixture of Compound I and L-Phe.

Provide the following examples, to describe the present invention in further detail.These embodiments illustrate to be considered at present for implementing best mode of the present invention, and it is intended to illustrate the present invention instead of limit the present invention.

The compound of formula I prepare describe, in general terms at United States Patent (USP) 6,414, in 126, specifically describe at United States Patent (USP) 5, in the scheme 1 of 515,117 and embodiment 1.United States Patent (USP) 6,414,126 and United States Patent (USP) 5,515,117 all introduce with it at this by reference.The stable form of formula (I) compound can be solvate (such as hydrate) by crystallization.

Embodiment

The preparation of crystalline structure

Embodiment 1

(S) (the preparation of (S)-PG) Jie Gou – crystalline form SC-3 – formula Ia of-propylene glycol

Compd A as at United States Patent (USP) 6, can be prepared described in the part E of 515,117 embodiments 1.

In the 10-L glass reactor being equipped with thermopair and nitrogen entrance, add MeOH (1.25L), deionized water (3.6L), be the 50%NaOH aqueous solution (205.9ml, 3.899mol) afterwards.Residual NaOH solution water (94ml) in graduated cylinder is transferred to reaction vessel.Add compd A (503.11g, 0.872mol), stir the mixture, and be heated in 1.5h ~ 68 DEG C.After 1h, circulation bath temperature is down to 70 DEG C from 80 DEG C; Internal temperature becomes 65 DEG C.Amount to the HPLC of 3h ¹after Indicator Reaction completes, Compound I AP ~ 99.5.When mixture is cooled to after 25 DEG C, add isopropyl acetate (2.5L).Mixture is stirred 10 minutes, then separate aqueous layer (pH=12.5), organic layers with water (1L) is washed.During this washing, the pH concentrated hydrochloric acid (5.0ml) of two-phase system is adjusted to 6.0, then, and separate aqueous layer. ²collected organic layer in a separate container.By reactor use water (2L), MeOH (2L) washing, and use nitrogen wash.The wet solution of compd B is fed in reactor again, and introduces (S)-propylene glycol ((S)-PG) (67.03g, 0.872 mole).Optionally, in this stage, the crystal seed of (S)-PGIa can be added.Instantaneous crystallization (instantaneouscrystallization) creates thick slurry.After stirring 1h, in 10 minutes, add rapidly hexanaphthene (2.5L), stir and continue 21h.Product is filtered through filter paper (Whatman#5, Buchner funnel 24 " diameter).Filtration is rapidly, and spends about 15 minutes.With mixture (1:1) washing leaching cake of MTBE/ hexanaphthene (2x1L), and dry 0.5h under suction.Solid transfer is sent Simon Rex to pyrex() in dish, and in the baking oven of 25-30 DEG C dry two days of vacuum (25mmHg), until correspond to monohydrate (3.6wt.%) by the water analysis of KF.Obtain (S)-PG product Ia (0.425kg, yield 97%), it is snow-white solid, HPLC ³aP99.7.

Crystal seed can be prepared as follows: Compound I is dissolved in solvent as in MTBE, and with (S)-propylene glycol process gained solution, carries out as above-mentioned, and does not use and add crystal seed.

¹hPLC: post: YMCODS-A (C-18) S3,4.6x50mm.Solvent orange 2 A: 0.2%H ₃pO ₄the aqueous solution.Solvent B:90%CH ₃cN/10%H ₂o; Initial %B=0, final %B=100, gradient timetable 8min; Residence time 3min.Integration stand-by time (integrationstoptime) 11.0min.Flow velocity 2.5ml/min.UV wavelength 220nm.

²in carrying out before being separated and, polluted by NaOH to prevent product.(S)-PG structure of not carrying out neutralizing preparation be slight alkaline [be 8.3 at the suspension (~ 20mg/ml) pH of underwater acoustic wave process].

³hPLC method: mobile phase A: at H ₂0.05%TFA in O.Mobile phase B: the 0.05%TFA in CAN.Post: YMCHydrosphere4.6x150 (3 μ).Gradient: 30-90%B in 45 minutes, stops 5 minutes; Be back to 30%B and reequilibrate 10min.Wavelength: 220nm.Injected slurry volume: 10 μ l.Temperature: envrionment temperature.

Embodiment 1A

(S)-propylene glycol ((S)-PG) structure-crystalline form SC-3 – formula Ia

Step

20g compd A is fed in reactor at ambient temperature and pressure.30mL methyl alcohol and 49.75mL3NNaOH are added in reactor, reaction mixture is heated to 80 DEG C or backflow, and keeps about 2-3 hour, to have reacted <0.5AP.This batch is cooled to 20 DEG C, and is neutralized to pH6.0-7.5 (inlet amount of requirement ~ 1mL/gm) with dense HCl or 1N acetic acid.

Extraction

Be extracted into from reaction mixture by product in 100mL isopropyl acetate, by aqueous phase separation, organic phase washed with water, until conductivity <10mS (inlet amount of ~ 4mL/gm).By aqueous phase separation.

Crystallization

2.8g (1.05eq) (S)-(+)-1,2 propylene glycol is added in reaction mixture.This batch 0.1g Compound I crystal seed is inoculated.Add 160mL hexanaphthene, and this batch is cooled to room temperature to 5 DEG C.Before separation, this batch is made to stir at least 1 hour at room temperature to 5 DEG C.

Be separated and drying

By the 50/50 isopropyl acetate/cyclohexane mixtures washing by volume of the separation cake of each load.By this cake at 30 DEG C, dry in vacuum oven under perfect vacuum.(work as KF=3.6%-4.1%, cake is dry).

Yield=84% (calibration)

Typical purity=99.81AP

Typical case PG content=GC is measured as 15.1-15.8%

Embodiment 2

(R) preparation of-propylene glycol structure-Ib

Utilize and the above-mentioned identical method about (S)-propylene glycol structure I a (embodiment 1), preparation (R)-propylene glycol structure, just use (R)-propylene glycol to replace (S)-propylene glycol.

Embodiment 3

(the preparation of ethanol or EtOH structure) – crystalline form SA-1 – formula Ic of single-EtOH-dihydrate

By being heated to boiling, compd A (1.0g) is dissolved in EtOH (3.0ml), and dilutes this solution with water (7ml).Add 1mlEtOH, and mixture is divided into three parts, for 20 DEG C, crystallization at 5 DEG C He – 20 DEG C.Be cooled to after-10 to-20 DEG C, form crystal, it has M.P.40-41 DEG C.

Embodiment 4 and 5

Ethylene glycol structure-crystalline form SB-1 and SB-2 – is respectively the preparation of formula Id and Ie

For obtaining the polymorphic of ethylene glycol bisthioglycolate hydrate crystal shape SB-1Id, by heating 30min at 45 DEG C, compd A (0.5gm) is dissolved in containing (0.3mL water: 0.5ml ethylene glycol) in water glycol.After being cooled to room temperature, add the crystal seed (10mg) of SB-1.Reaction mixture is stirred 16 hours, white crystalline solid is provided.Filtering crystals, washes with water and drying.For obtaining the polymorphic of ethylene glycol bisthioglycolate hydrate seed crystal shape SB-1Id, compd A is dissolved in containing in water glycol, add (S)-propylene glycol crystal shape SC-3Ia, to obtain ethylene glycol bisthioglycolate hydrate crystal shape SB-1Id (embodiment 4).Filter these crystal and wash with excessive water.

For obtaining the polymorphic of ethylene glycol bisthioglycolate hydrate crystal shape SB-2Ie (embodiment 5), by heating, compd A is dissolved in containing in water glycol.After cooling, add the crystal seed of list-EtOH-dihydrate-crystal shape SA-1-Ic, to obtain ethylene glycol bisthioglycolate hydrate crystal shape SB-2Ie (embodiment 5).Filter these crystal and wash with excessive water.

Crystalline form SB-1's and SB-2 ¹hNMR: ¹hNMR (400MHz, DMSO) δ 1.29 (t, 3H, J=6.98Hz,-CH3) 3.15 (m, 4H), 3.33 (bs, 6H ,-CH2), 3.42 (m, 3H), 3.6 (bdd, J=11.4Hz, 1H), 3.9 (bm, 5H, H-1 ,-2CH ₂), 4.43 (t, 1H, J=7.4Hz, OH); 4.86 (d, 1H, J=2.4, OH), 4.95 (q; 1H ,-OH), 6.82 (d, 2H, J=11.47Hz; Ar-H), 7.8 (d, 2H, J=11.4Hz, Ar-H); 7.22 (dd, 1H, J=2.5Hz, J=11.4Hz, Ar-H); 7.35 (t, 2H, J=10.96, Ar-H; ¹³cNMR (400MHz, DMSO) δ 12.49,59.16,60.61,60.69,68.10,72.51,76.11,78.51,79.02,112.09,125.16,126.47,127.38,128.61,129.02,129.73,135.62,137.48,154.70.

Embodiment 6

(S) preparation of-PG solvate crystalline form SC-3Ia

Under the batch temperature of 8-10 DEG C, under nitrogen atmosphere, boron trifluoride ethyl ether complex (borontrifluoridediethyletherate) (2.3mL, 18.4mmol) and water (0.82mL, 4.6mmol) is added in acetonitrile (12mL).After being kept about 1 hour by said mixture, add triethyl silicane (3mL, 18.4mmol).Gained mixture being kept about 1 hour, being then added in the compd B (as prepared described in embodiment 17) in 10mL acetonitrile.This batch is remained on 5 to 10 DEG C.After determining that reaction completes according to HPLC, with the water-containing acetic acid ammonium (24mL in 200mL water; 85g) quencher reaction mixture.Be separated phase, and be rich in the organic phase of product by dried over sodium sulfate.The under reduced pressure concentrated organic phase being rich in product.

Mixing water (13mg, 0.7mmol, based on 0.3g crude compound B charging), (S)-propylene glycol (56mg, 0.7mmol), t-butyl methyl ether (5mL, the charging of ~ 17mL/g compd B), Compound I a crystal seed (~ 20mg), and keep 1 hour, to form magma.Add hexanaphthene (10mL, 33mL/g compd B (charging)).Dry under vacuum by filtering separation crystallized product (Ia) (4-5%) and at 20-25 DEG C.

Embodiment 7

The preparation of crystallization MeOH solvate Ig

Also at room temperature stirring by pure compound B being dissolved in methyl alcohol, obtaining the crystal of Methanol solvate Ig.Form white slurry after a couple of days, and find that it is crystallization Methanol solvate Ig.

Preparing as during at the crystalline compounds Ia described in embodiment 6, the crystallization two-MeOH solvate Ig so formed can be used for replacing compd B.

Embodiment 8

In 80/20 methanol/toluene, utilize crystal seed, prepare crystallization two-MeOH solvate Ig from unpurified compd B

6g compd B (HPLCAP about 80%) is dissolved in 80/20 methanol/toluene of 15mL.

Add the crystal seed (for about 1% of initial compounds B) of Compound Ig per crystal, and the slurry that mixture cooling is formed containing crystal.

Before separation this slurry is stirred 6 hours.

Find that wet cake is crystallization Methanol solvate If, if but it opens wide placement a few hours, lose degree of crystallinity.

Embodiment 9

In methanol/toluene/heptane, utilize crystal seed, prepare crystallization two-MeOH solvate Ig from unpurified compd B

2.5g compd B (91.5%) is added in the scintillation vial with magnetic stirring bar.

Add 4mL toluene, with dissolved compound Ia.

Add 2mL methyl alcohol.Next, the crystal seed (about 1%) of Compound Ig per crystal is added.

In 30 minutes, add 4mL heptane, and mixture is stirred 12 hours.Buchner funnel is separated wet cake.Find that wet cake is crystallization Methanol solvate Ig.It is dry under vacuo in 30 DEG C.Gained powder loses degree of crystallinity.

Yield=1.7g=74.5% (calibration).The feature XRD figure case of crystal: Figure 10.

Preparing as during at the crystalline compounds Ia described in embodiment 6, the crystallization MeOH solvate Ig so formed can be used for replacing compd B.

Embodiment 10

In toluene/ethyl acetate, use crystal seed, prepare crystallization Isosorbide-5-Nitrae-butine-diol solvent compound If from compd B

Isosorbide-5-Nitrae-butine-diol solvent compound can in alkyl acetate (such as ethyl acetate, propyl acetate or butylacetate), alcohol (such as Virahol, butanols) or even crystallization in water.When in alkyl acetate during crystallization, toluene and heptane serve as solvent resistant.

50g (90.3wt%) compd B is dissolved in 675mL toluene.Solution is heated to 60 DEG C, and adds 75mL ethyl acetate.Add 1.5 equivalent 2-butyne-Isosorbide-5-Nitrae-glycol (=13.3g), and at mixture is remained on 60 DEG C, until butynediol dissolves.Solution is cooled to 55 DEG C, adds the crystal seed (50mg) of the Isosorbide-5-Nitrae-butine-diol compound If of 0.1%.Mixture is kept 1 hour at 55 DEG C.Compound I f starts crystallization.Mixture was cooled to 25 DEG C in 6 hours.Before separation gained is starched stirring 3 hours (mother liquid concentration <3mg/mL), filter, with the washing of 180mL toluene+20mL ethyl acetate, vacuum-drying at 45 DEG C, produces the crystal of Isosorbide-5-Nitrae-butine-diol solvent compound If.

HPLCAP=99.5%。Tire=80.7wt% (to the expectation of 1:1 solvate tire=83.6%).Yield=95%.

Embodiment 11

In butylacetate/heptane, prepare crystallization Isosorbide-5-Nitrae-butine-diol solvent compound If from compd B

At 60 DEG C, 0.5g compd B (91wt%) is dissolved in 3.5mL butylacetate+3.5mL heptane.Add the 2-butyne-Isosorbide-5-Nitrae-glycol of 1.5 equivalents, compound is cooled to room temperature.Gained slurry is stirred 12 hours, filters, and use 1mL1:1 butylacetate: heptane wash, in 50 DEG C, dry under vacuum, the crystal of generation Isosorbide-5-Nitrae-butine-diol solvent compound If.Tire=85.1%.Yield=90%.

Isosorbide-5-Nitrae-butine-diol solvent compound If can be used for replacing compd B, and uses Lewis acid BF ₃2CH ₃cOOH replaces BF ₃oEt ₂, form crystalline compounds Ia.

Embodiment 12

With the 1:2 crystalline complex-structure I h of L-PROLINE, the preparation of crystalline form 3-

The solution of L-PROLINE (11.5g, 100mmol) in 10mL water is heated to 80 DEG C, and adds 100mL Virahol.At room temperature, in the L-PROLINE solution stirred rapidly, the solution of Compound I (21.4g, 50mmol) in 100mL Virahol is added.Form solid, solution is slowly cooled to room temperature.Filtering solution, with using hexanes wash gained solid after Virahol again.This solid is dry under vacuum oven, and produce the white solid of 30.4g containing Compound I, it is and the 1:2 crystalline complex of L-PROLINE (structure I h, crystalline form 3).

Embodiment 13

With the 1:1 crystalline complex-structure I i of L-PROLINE, the preparation of crystalline form 6-

The solution of the L-PROLINE (0.23g, 0.2mmol) in 1.1mL90% ethanol/water is quickly heated up to boiling, and is incorporated in the solution of the Compound I (0.4g, 1mmol) in 4mL ethanol.By gained solid cooled to-20 DEG C of 2h, solid is formed during this period.This solution is at room temperature stored 2 days.Centrifugal to container, remove supernatant liquor.Wash residual solid in 1mLMTBE, and this solid is dry under vacuo, and produce the white solid of 0.025g containing Compound I, it is and the 1:1 crystalline complex of L-PROLINE (structure I i, crystalline form 6).

Embodiment 14

The preparation of the form H .5-2 – structure I j of L-PROLINE Compound I semihydrate

By L-PROLINE (0.23g, 2mmol) and Compound I (4.34g, 10mmol), the solution in 31mL97% ethanol/water quickly heats up to 70 DEG C, produces clear solution.Gained solution is cooled to-20 DEG C, and adds the crystal seed with the Compound I 1:1 composite structure Ii crystalline form 6 of L-PROLINE.At-20 DEG C after 3 days, by solid collected by filtration, with cold (-20 DEG C) washing with alcohol filter cake.By gained solid suspension in 5mL heptane, filter afterwards and use heptane wash, producing 0.3g white solid.By this material (0.02g) from 20/1EtOH/H ₂further crystallization in O, along with slow evaporation and the heating/cooling a little of solvent, to produce larger X-ray gem-quality crystal (qualitycrystal), its every structure cell contains the ratio of 4 molecular compound I, 4 molecule L-proline(Pro) and 2 molecular waters---with the semihydrate (structure I j, form H .5-2) of the 1:1 mixture of L-PROLINE.

Embodiment 15

1:1 crystalline complex-structure I the k of preparation and L-Phe, crystalline form 2

At 80 DEG C, L-Phe (424mg, 2.56mmol) is dissolved in 6mL water.Filter gained solution, and added in the ethanolic soln (6.5mL) containing 1 g of compound I (2.36mmol).Gained solution is heated to 80 DEG C, and makes it slowly cool to room temperature (First Observation is to crystal formation at 55 DEG C).At solution being stored in 4 DEG C.Filtering solution, and with 20% water/washing with alcohol crystal, to produce L-Phe: the mixture of Compound I.From 10mL50% water/ethanol, making this substance crystallization further as above-mentioned, producing 910mg white solid, through being accredited as the 1:1.3 composite structure Ik crystalline form 2 of the Compound I with L-Phe (64%), as passed through ¹hNMR integration surveyed.

Embodiment 16

Compound I f is prepared by continuous lithiumation and linked reaction

Adopt the reaction scheme of the scheme shown in scheme IVA and Figure 22 that is similar to.

-30 DEG C of water coolers of lithiation device 5 (jacketed type static mixer 5) are installed.

-30 DEG C of water coolers of coupler reactor 22 (jacketed type static mixer 22) and the precool heat exchanger device (not being shown in Figure 22) of Compound D/toluene feed are installed.

Continuous lithiumation

Two kinds of chargings of mixing E/THF/ toluene (2.74ml/min) and Q---namely n-BuLi (0.41ml/min)---in hexane, and combined by jacketed type static mixer 5 (-30 DEG C).

Before pumping into D/ toluene feed, toluene (2.96ml/min) is flowed as a supplement in (make-upflow) feeding system, so that the constant that always flows is maintained 6.1ml/min.

Collect sample in the exit of lithiumation static mixer 5, carry out HPLC analysis.Before (a) linked reaction starts, and (b) is after reaction mixture is collected in MSA-MeOH reactor, collected specimens.

Continuous linked reaction

Before mixing with lithiumation stream, by D/ toluene feed (2.96ml/min) by interchanger precooling.

Mix two kinds of streams and G and D, and make them mix by jacketed type static mixer 22 (between-24 DEG C and-30 DEG C).

Reaction stream color manifests micro-yellow.

Collect sample in the exit of mixing tank 22, carry out HPLC analysis.Before and after collecting MSA-MeOH reactor 25, collected specimens.

Methyl glycosidation

At <-10 DEG C, under stirring, linked reaction stream 24 is fed in the 500-ml reactor 25 containing MSA and methyl alcohol or HCl/MeOH.

After collection completes, reaction mixture <-10 DEG C, stir under keep 1 hour again.

Reaction mixture is heated to 35 DEG C.Show until HPLC analyzes, till protodesilyation hemiketal H ' RAP<0.3%, reaction has been considered to (about 6 hours).Reaction is cooled to room temperature (20 DEG C), and reaction mixture is kept 16h, form compd B.

The formation of If crystal

Be used in 2-butyne-Isosorbide-5-Nitrae-glycol (J) the crystallization B in toluene/EtOAc, to produce the crystal of If.

Embodiment 17

The preparation of intermediate A

Solid chemical compound If (50.0g), solid DMAP (1.2g), liquid acetonitrile (450mL) and liquid acetic acid acid anhydride (63mL) are fed in 250ml flask reactor.

Heat this batch (77 DEG C) and keep, until reacted.

Cool this batch (5 DEG C).

Triethyl silicane (72mL) and boron trifluoride acetic acid complex compound (63mL) are fed in reactor.

After having reacted, add acetone (36mL).

This batch warm (21 DEG C) also keeps, until triethyl silicane is consumed.

Add moisture NH ₄oAc (33wt%, 450mL), and this batch of mixing, make it precipitation, until upper and lower phase is formed.

By evaporating acetonitrile with minimum stirring, the batch volume of the product in Fu Shangxiang is reduced.Feed ethanol SDA3A (1L) under high temperature (>60 DEG C).

By cooling or cool putting in crystal seed (the Compound I f milled based on wet-milling, nitrogen gas stream or the 5wt% of previous batch) situation, crystallized product.Typical case is separated with >75% yield for product.

Product is wet cake or dry cake by recrystallization from ethanol SDA3A.

Crystal Structure

Can demonstrate within the scope of reasonable error, similar but not identical analysis and characterization with the crystalline structure of this paper crystalline structure required for protection described in below being equivalent to, this depends on test condition, purity, equipment and other conventional variable well known by persons skilled in the art.

Therefore, can carry out various modifications and changes to the present invention, and not deviate from scope and spirit of the present invention, this will be obvious to those skilled in the art.Consider specification sheets of the present invention disclosed herein and practice, other embodiment of the present invention will be obvious to those skilled in the art.Applicant means specification sheets and embodiment should be considered to exemplary, but not is the restriction to scope.

X-ray powder diffraction

One of skill in the art will appreciate that powder x-ray diffraction pattern can obtain when having measuring error, this depends on adopted measuring condition.Specifically, it is generally known that the intensity of powder x-ray diffraction pattern can fluctuate, this depends on adopted measuring condition.Will be further understood that and depend on test conditions, relative intensity also may change, and therefore, should not consider the scale of precision of intensity.In addition, the measuring error of conventional powder X-ray powder diffraction pattern diffraction angle is typically about 5% or following, and when relating to above-mentioned diffraction angle, the measuring error of this kind of degree should not be paid attention to.Therefore, should be appreciated that crystalline structure of the present invention is not limited to such crystalline structure: it will provide X-ray diffraction pattern identical with the X-powder diffraction pattern described in accompanying drawing disclosed herein.Any crystalline structure of the X-ray diffraction pattern substantially identical with those powder x-ray diffraction patterns disclosed in accompanying drawing is provided to fall within the scope of the invention.Determine that ability that X-powder diffraction pattern is substantially identical is in the scope of those skilled in the art.

(S) semihydrate Ij (H.5-2), the 1:2L-proline Complex Ih of-PG (crystalline form SC-3) Ia, (R)-PGIb, Isosorbide-5-Nitrae-butine-diol solvent compound And if dimethanol solvate Ig, 1:1L-proline Complex and 1:1L-proline Complex Ii structure

About 200mg is filled in Philips powder x-ray diffraction (PXRD) sample chamber.This sample is transferred to PhilipsMPD device (45KV, 40mA, CuK α ₁).Data within the scope of collected at room temperature 2 to 322-θ (continuous sweep pattern, 0.03 degree/second of scanning speed, self defocusing (autodivergence) and anti-scattering slit, receiving slit: 0.2mm, sample spinner: open).

(S) the powder x-ray diffraction pattern difference diagram of-PG (Ia), (R)-PG (Ib) structure in fig 1 and 2.The powder x-ray diffraction pattern difference diagram of Isosorbide-5-Nitrae-butine-diol solvent compound And if dimethanol solvate Ig in figures 9 and 10.1:2L-proline Complex Ih, 1:1L-proline Complex Ii and 1:1L-proline(Pro) semihydrate composite I j structure powder x-ray diffraction pattern be illustrated in respectively in Figure 13,14 and 15.(S) semihydrate Ij (H.5-2), the 1:2L-proline(Pro) semihydrate Ih of-PG (Ia), (R)-PG (Ib), 1:1L-proline Complex and the selection diffraction peak position (number of degrees 2 θ ± 0.2) of 1:1L-proline Complex Ii structure are shown in table 1 below.Under RT, characteristic diffraction peak position (number of degrees 2 θ ± 0.1) is based on the first-rate quality pattern collected with the diffractometer (CuK α) with spinning capillary, and method and other suitable standard well known by persons skilled in the art of its 2 θ NationalInstituteofStandardsandTechnology are calibrated.But relative intensity may change, this depends on crystallographic dimension and form.

Table 1

The PXRD peak (2 θ ± 0.2 °) selected

Solid state nmr

(S) structure of-PG (Ia), (R)-PG (Ib), Isosorbide-5-Nitrae-butine-diol solvent compound And if dimethanol solvate Ig is characterized by solid state NMR techniques.

All solid-state C-13NMR measurement BrukerDSX=400,400MHzNMR spectrometer carries out.Utilize high energy proton decoupling and TPPM pulse sequence and there is the gradient amplitude quadrature polarization (RAMP-CP at magic angle spin (MAS); rampamplitudecrosspolarization); under about 12kHz; obtain high resolving power wave spectrum (A.E.Bennettetal; J.Chem.Phys.; 1995,103,6951; G.Metz, X.WuandS.O.Smith, J.Magn.Reson.A .1994,110,219-227).For each test, use about 70mg sample, this sample is filled in the zirconia rotors of tubular design.Chemical shift (δ) is with reference to being set in 38.56ppm, having the external standard diamantane of high-frequency resonance (W.L.EarlandD.L.VanderHart, J.Magn.Reson., 1982,48,35-54).

Structure (S)-PG and (R)-PG produce ¹³cNMRCPMAS wave spectrum is shown in Fig. 3 and 4.

(S) principal resonance peak that-PG and the solid carbon of (R)-PG are composed is listed in table 1A below and table 2 respectively, and the principal resonance peak of the solid carbon spectrum of Isosorbide-5-Nitrae-butine-diol solvent compound And if dimethanol solvate Ig list in respectively table 2A and 2B below total in.Demonstrate substantially similar ¹³the crystalline structure of CNMR peak position---wherein " substantially similar " refers to the dimensionless number of 10 to 15%---is considered to fall within the scope of the invention (structure set forth below being namely equivalent to).

Table 1A

(S) the proton N MR peak position of-propanediol solvate Ia

¹HNMR(400MHz,d ₆-DMSO)δ1.00(d,3H,J=6.25Hz,PG-CH ₃),1.29(t,3H,J=6.98Hz,-CH ₂C H ₃),3.0-3.30(m,4H,H2,H3,H4,H-5),3.43(m,1H,H-6a),3.53(m,1H),3.69(bdd,H,J=4.4Hz,H-6b),3.9-4.1(m,5H,H-1,-CH ₂,-CH ₂),4.38(d,1H,J=4.5Hz,OH),4.44(dt,2H,J=2.2Hz,J=5.7Hz),4.82(d,1H,J=5.7Hz,-OH),4.94and4.95(2d,2H,2-OH),6.82(d,2H,J=8.6Hz,Ar-H),7.09(d,2H,J=8.6Hz,Ar-H),7.22(dd,1H,J=1.97Hz,8.25Hz,Ar-H),7.31(bd,1H,1.9Hz,Ar-H),7.36(d,1H,J=8.2Hz,Ar-H)。

Table 2

Relative to the SSNMR peak position/δ (in ppm) of TMS (tetramethylsilane)

These data are strictly effective for 400MHz spectrophotometer.

Table 2A

The proton N MR peak position of Isosorbide-5-Nitrae-butine-diol solvent compound If

¹HNMR(400MHz,CDCl ₃)δ1.33(t,3H,J=7.1Hz,-CH ₃),2.90(s,2H,-CH ₂),3.39(s,9H,-OCH ₃),3.4-3.65(m,3H),3.81(bm,2H),3.91(q,2H,J=7.1Hz,-CH ₂),3.97(m,1H),6.73(d,1H,J=8.6Hz,Ar-H),7.02(d,2H,J=8.4Hz,Ar-H),7.25(s,2H,Ar-H),7.34(s,1H,Ar-H); ¹³C(CDCl ₃)δ14,78,38.43,49.14,50.57,61.84,63.34,69.98,72.53,74.63,100.95,114.36,(2),126.64,129.19,129.59,129.71,131.38,134.30,136.61,138.50,157.27.M.P.103.08℃。

Table 2B

The proton N MR peak position of dimethanol solvate Ig

¹hNMR (400MHz, DMSO-D6) δ 1.26 (t, 3H, J=7.1Hz ,-CH ₃), 2.38-2.54 (m, 1H), 2.5 (s, 2H ,-CH ₂), 3.2 (m, 1H), 3.35 (m, 3H ,-OCH ₃), 3.16-3.39 (m, 1H, H-6), 3.41-3.42 (m, 1H, H-6), 3.9 (q, 2H, J=7.2Hz, CH ₂), 4.05 (d, 4H ,-CH ₂), 4.52 (t, 1H), 4.75 (m; 2H), 4.95 (d, 2H), 5.23 (t; 2H), 6.82 (d, 2H, J=8.6Hz; Ar-H), 7.07 (d, 2H, J=8.6Hz; Ar-H) 7.4 (s, 2H, Ar-H); 7.50 (s, 1H, Ar-H); ¹³c (CDCl ₃) δ 14.69,48.28,49.02,60.81,62.84,70.05,74.02,76.81,83.97,100.64,114.23,127.40,128.2,129.44,131.2,131.4,132.45,137.38,138.57,156.84.C ₂₆h ₃₃clO ₉calculating ultimate analysis: Calc(calculate) C59.48, H6.34, Cl6.75; Found(actual measurement) C59.35, H5.97, Cl6.19.

Thermogravimetric analysis

At TAInstruments ^tMthermogravimetric analysis (TGA) test is carried out in model Q500.Sample (about 10-30mg) is placed in the platinum dish previously tared.By the weight of the accurate measure sample of this instrument, and be recorded to thousandth milligram (athousandofamilligram).Under 100mL/min, smelting furnace is purged with nitrogen.Data are collected between room temperature and 300 DEG C, under 10 DEG C/min heating rate.

(S) the TGA curve of-PGIa and (R)-PGIb structure is shown in Fig. 5 and 6.Weight loss corresponds to 1 mole of water and 1 mole of propylene glycol of every mole of analyzed structure.

The TGA curve of 1:2L-proline Complex Ih, 1:1L-proline Complex Ii and 1:1L-proline(Pro) semihydrate composite I j structure is shown in Figure 16,17 and 18.Weight loss corresponds to 1 mole of water and 1 mole of L-PROLINE of every mole of analyzed structure.

Differential scanning calorimetry

(S) the solid state heat behavior of-PGIa, (R)-PGIb, Isosorbide-5-Nitrae-butine-diol solvent compound If, dimethanol solvate Ig, 1:2L-proline(Pro) Ih, 1:1L-proline(Pro) Ii and 1:1L-proline(Pro) semihydrate Ij structure is studied by differential scanning calorimetry (DSC).(S) the DSC curve of-PGIa and (R)-PGIb structure is shown in Fig. 7 and 8.The DSC curve of Isosorbide-5-Nitrae-butine-diol solvent compound And if dimethanol solvate Ig structure is shown in Figure 11 and 12.The DSC curve of 1:2L-proline Complex Ih, 1:1L-proline Complex Ii and 1:1L-proline(Pro) semihydrate Ij structure is shown in Figure 19,20 and 21.

Differential scanning calorimetry (DSC) test is at TAInstruments ^tMcarry out in model Q1000.Weighed samples (about 2-6mg) in aluminium dish, and be accurately recorded to one of percentage milligram, and be transferred to DSC.Under 50mL/min, instrument is purged with nitrogen.Data are collected between room temperature and 300 DEG C, under 10 DEG C/min heating rate.Draw, wherein endotherm(ic)peak down.

But those skilled in the art will notice, in dsc measurement, measure real mutability starting temperature and peak temperature existed to a certain degree, this depends on the speed of heating, crystal shape and purity and other measuring parameter.

Single crystal X-ray analysis

Obtain and pass through the monocrystalline of X-ray diffraction studies (S)-PGIa structure and Isosorbide-5-Nitrae-butine-diol solvent compound If, dimethanol solvate Ig, 1:2L-proline(Pro) Ih, 1:1L-proline(Pro) Ii and 1:1L-proline(Pro) semihydrate Ij structure.

At Bruker-Nonius ¹data collected by CAD4 Series diffractive meter.Carrying out least-square analysis by arranging the test diffractometer of 25 high corner reflections, obtaining unit cell parameters.Utilize CuK α radiation ( ), at a constant temperature, adopt variable sweep (variablescan) commercial measurement intensity, and only lorentz polarization factor is corrected.Collect the background count of scanning end, continue the half of sweep time.Alternatively, in Bruker-NoniusKappaCCD2000 system, utilize CuK α radiation ( ) collect single crystal data.Use Collect package ²in HKL2000 software package ³carry out index editor and the process of surveyed intensity data.

When indicating, during data gathering, in Oxfordcryo system ⁴cold flow in crystals cooled.

By direct method analytic structure, and on the basis of observation reflection, use the SDP with less local modification ⁵software package or crystal routine package MAXUS ⁶structure is refined.

To be refined by full-shape Matrix least square method the atomic parameter (coordinate and temperature factor) of gained.The function be minimized in refining is Σ _w(| F _o|-| F _c|) ².R is defined as Σ || F _o|-| F _c||/Σ | F _o|, and R _w=[Σ _w(| F _o|-| F _c|) ²/ Σ _w| F _o| ²] ^1/2, wherein w is the suitable weighting function based on the error in observed strength.Disparity map (Differencemaps) is checked in all stages of refining.With isotropic temperature factor (isotropictemperaturefactor), hydrogen is introduced in ideal position, but be changed without hydrogen parameter.

(S) unit cell parameters of-PG structure I a crystalline form SC-3 is enumerated in table 3.As used herein, unit cell parameters " molecule/every structure cell " refers to the molecule amount of compound in structure cell.

Table 3

(S) the structure cell data of-PG (Ia)

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(drug molecule of the every structure cell of Z)

_______________________

¹BRUKERAXS,Inc.,5465EastCherylParkwayMadison,WI53711USA

²CollectDatacollectionandprocessinguserinterface:Collect:Datacollectionsoftware,R.Hooft,NoniusB.V.,1998

³Otwinowski,Z.&Minor,W.(1997)inMacromolecularCrystallography,eds.Carter,W.C.Jr&Sweet,R.M.(Academic,NY),Vol.276,pp.307-326

⁴OxfordCryosystemsCryostreamcooler:J.CosierandA.M.Glazer,J.Appl.Cryst.,1986,19,105

⁵SDP,StructureDeterminationPackage,Enraf-Nonius,BohemiaNY11716

Scatteringfactors,includingf’andf’’,intheSDPsoftwareweretakenfromthe”InternationalTablesforCrystallography”,KynochPress,Birmingham,England,1974;Vol.IV,Tables2.2Aand2.3.1

⁶maXussolutionandrefinementsoftwaresuite:S.Mackay,C.J.Gilmore,C.Edwards,M.Tremayne,N.Stewart,K.Shankland.maXus:acomputerprogramforthesolutionandrefinementofcrystalstructuresfromdiffractiondata.

R=residue number (residualindex) (I>2 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 4 below shows the location parameter of (S)-PGIa structure at 25 DEG C.

Table 4

(S)-PG is in the location parameter of T=25 DEG C

Atom	X	Y	Z
				CL	0.7313	0.4674	-0.2101
O5	0.8119	0.5766	-0.0701
				04	0.7202	0.5458	0.0056
03	0.5115	0.3666	-0.0246
				06	0.9646	0.2671	-0.0316
02	0.4895	0.5889	-0.0811
				C2	0.6024	0.5045	-0.0697
C12	0.7946	0.4228	-0.1261
				C5	0.8198	0.6301	-0.0398
O17	0.1633	0.2154	-0.2179
				C8	0.6391	0.7665	-0.1320
C6	0.9425	0.5628	-0.0299
				C3	0.5984	0.5441	-0.0373
C1	0.7059	0.6639	-0.0829
				C7	0.7147	0.6097	-0.1148
C4	0.7190	0.4796	-0.0240
				C10	0.7203	0.5412	-0.1732
C17	0.2586	0.3689	-0.2079
				C19	0.4171	0.6835	-0.2198
C11	0.7959	0.3822	-0.1562
				C9	0.6397	0.7259	-0.1622
C13	0.5535	0.8771	-0.1822
				C14	0.4508	0.6852	-0.1907
C15	0.3841	0.5376	-0.1712
				C16	0.2861	0.3765	-0.1788
C20	0.1012	0.0595	-0.1979
				C18	0.3232	0.5239	-0.2279
C21	0.0030	-0.0944	-0.2137
				O89	0.3708	0.0977	-0.0854
O88	0.1294	0.2019	-0.0742
				C88	0.1652	-0.0245	-0.0920
C89	0.2791	0.0335	-0.1051
				C87	0.0645	-0.1005	-0.1124
O99	0.2722	0.4482	-0.0319
				H21	0.6171	0.2877	-0.0753
H121	0.8544	0.3092	-0.1123
				H51	0.7993	0.8404	-0.0347

Atom	X	Y	Z
				H81	0.5805	0.9176	-0.1225
H61	0.9563	0.6296	-0.0070
				H62	1.0096	0.6774	-0.0422
H31	0.5776	0.7529	-0.0321
				H11	0.6920	0.8863	-0.0793
H41	0.7271	0.2607	-0.0265
				H191	0.4656	0.8069	-0.2353
H111	0.8552	0.2316	-0.1658
				H131	0.5284	1.0619	-0.1717
H132	0.6093	0.9308	-0.2010
				H151	0.4086	0.5437	-0.1488
H161	0.2335	0.2640	-0.1632
				H201	0.1483	-0.1065	-0.1854
H202	0.0535	0.1811	-0.1804
				H181	0.2987	0.5193	-0.2503
H211	-0.0606	-0.2245	-0.2014
				H212	-0.0562	0.0572	-0.2256
H213	0.0387	-0.2305	-0.2306
				H2	0.4362	0.4237	-0.0836
H3	0.4297	0.4310	-0.0299
				H4	0.7387	0.3750	0.0172
H6	0.9827	0.1877	-0.0122
				H881	0.1809	-0.2154	-0.0792
H891	0.2662	0.2151	-0.1200
				H892	0.3059	-0.1396	-0.1196
H871	0.0875	-0.2595	-0.1270
				H872	-0.0137	-0.1453	-0.1008
H873	0.0462	0.0938	-0.1255
				H89	0.4203	-0.0719	-0.0817
H88	0.0653	0.1382	-0.0608
				H991	0.2473	0.6301	-0.0234
H992	0.2108	0.3906	-0.0463

____________________________________________________________________

The unit cell parameters of list-ethanol dihydrate (ethanol or EtOH structure)-crystalline form SA-1, formula Ic-is listed in table 5 below.

Table 5

The structure cell data of ethanol SA-1 (Ic)

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(drug molecule of the every structure cell of Z)

R=residue number (I>3 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 6 below lists crystalline form SA-1 (list-ethanol-dihydrate), and Ic is in the location parameter of-50 DEG C.

Table 6

Crystalline form SA-1 is in the fractional atomic coordinates of T=-50 DEG C

Atom	X	Y	Z
				CL	0.7673	0.0854	-0.4142
O2	0.8652	0.6413	-0.1468
				O5	0.8652	0.6413	-0.1468
O6	1.0613	0.9910	-0.0876
				C2	0.6634	0.5087	-0.1420
O3	0.5964	0.4528	-0.0442
				C1	0.7531	0.6504	-0.1782
O17	0.1965	-0.2110	-0.3797
				O4	0.7928	0.7549	0.0061
C7	0.7605	0.5175	-0.2375
				C3	0.6679	0.6209	-0.0790
C14	0.4816	0.3213	-0.3866
				C10	0.7629	0.2551	-0.3461
C13	0.5827	0.5268	-0.3868
				C8	0.6801	0.5902	-0.2843
C9	0.6770	0.4593	-0.3397
				C6	0.9968	0.7646	-0.0652
C12	0.8423	0.3089	-0.2459
				C4	0.7906	0.6184	-0.0498
C5	0.8704	0.7698	-0.0896
				C15	0.4335	0.2531	-0.3337
C11	0.8449	0.1815	-0.3008
				C17	0.2911	-0.0396	-0.3851
C20	0.141	-0.3384	-0.4319
				C19	0.4321	0.2052	-0.4377
C18	0.3377	0.0255	-0.4384
				C16	0.3405	0.0751	-0.3330
C21	0.0431	-0.5128	-0.4132
				O98	0.3643	0.6071	-0.0516
O88	0.2324	-0.2097	-0.1501
				C89	0.1155	-0.3014	-0.2376
C88	0.2065	-0.4150	-0.1969
				O99	0.4409	0.0604	-0.1784
H21	0.6816	0.2833	-0.1387
				H11	0.7283	0.8620	-01.864
H31	0.6356	0.8307	-0.0805
				H131	0.6184	0.5131	-0.4303
H132	0.5505	0.7308	-0.3806
				H81	0.6182	0.7524	-0.2770

Atom	X	Y	Z
				H61	1.0365	0.5668	-0.0787
H62	1.0037	0.7711	-0.0175
				H121	0.9040	0.2455	-0.2092
H41	0.8196	0.4009	-0.0436
				H51	0.8385	0.9826	-0.0936
H151	0.4692	0.3444	-0.2915
				H111	0.9111	0.0214	-0.3081
H201	0.1146	-0.1875	-0.4650
				H202	0.2075	-0.4764	-0.4514
H191	0.4703	0.2491	-0.4794
				H181	0.3000	-0.0606	-0.4802
H161	0.3071	0.0128	-0.2910
				H3	0.5153	0.5297	-0.0473
H2	0.5091	0.3623	-0.1752
				H211	-0.0028	-0.6153	-0.4507
H212	0.0724	-0.6675	-0.3807
				H213	-0.0204	-0.3772	-0.3928
H6	1.1241	0.9168	-0.1118
				H4	0.8466	0.6527	0.0359
H981	0.3836	0.7445	-0.0185
				H982	0.3063	0.4696	-0.0382
H891	0.0626	-0.4601	-0.2593
				H892	0.0592	-0.1642	-0.2133
H893	0.1534	-0.1727	-0.2709
				H881	0.2834	-0.4603	-0.2200
H882	0.1765	-0.6100	-0.1783
				H88	0.2806	-0.2965	-0.1158
H991	0.3630	-0.0141	-0.1685
				H992	0.4889	-0.1137	-0.1762

The unit cell parameters of ethylene glycol crystalline form SB-1 formula Id is listed in below in table 7.

Table 7

The structure cell data of EG-SB-1 (Id)

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(drug molecule of the every structure cell of Z)

R=residue number (I>3 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 8 lists crystalline form SB-1 (ethylene glycol) Id in the location parameter of-50 DEG C below.

Table 8

Crystalline form SB-1 is in the fractional atomic coordinates of T=-50 DEG C

Atom	X	Y	Z
				CL	0.7590	0.0820	-0.4198
O5	0.8631	0.5990	-0.1537
				O17	0.1901	-0.1911	-0.3791
C13	0.5791	0.5319	-03885
				O3	0.5941	0.4849	-0.0439
C11	0.8381	0.1410	-0.3059
				O4	0.7851	0.8250	-0.0026
C10	0.7531	0.2610	-0.3514
				O2	0.5470	0.4971	-0.1739
C18	0.3341	0.0390	-0.4399
				C14	0.4851	0.3559	-0.3849
C1	0.7451	0.6551	-0.1789
				C12	0.8281	0.2849	-0.2539
C5	0.8711	0.7820	-0.0959
				C19	0.4311	0.2230	-0.4349
C17	0.2810	-0.0380	-0.3919
				C4	0.7791	0.6341	-0.0569
C7	0.7530	0.4769	-0.2399
				C8	0.6751	0.5781	-0.2889
C9	0.6671	0.4150	-0.3429
				C2	0.6601	0.4859	-0.1429
C15	0.4250	0.2791	-0.3379
				C20	0.1391	-0.3181	-0.4309
C21	0.0331	-0.4761	-0.4109
				C3	0.6660	0.6460	-0.0839
C16	0.3341	0.1049	-0.3399
				O6	1.0280	0.4331	-0.0685
O98	0.3689	0.6530	-0.0551
				O99	0.4310	0.0080	-0.1639
C6	0.9880	0.6960	-0.0759
				O88	0.1661	-0.7610	-0.1669
O89	0.0461	-0.2291	-0.2249
				C88	0.1970	-0.5606	-0.1946
C89	0.1423	-0.4698	-0.2450
				H89	-0.0093	-0.1368	-0.2011
H88	0.0999	-0.9161	-0.1930
				H2	0.5081	0.3212	-0.1695
H3	0.5158	0.5512	-0.0479
				H6	1.0592	0.3693	-0.1043
H981	0.3142	0.5218	-0.0410
				H982	0.3908	0.7860	-0.0248
H991	0.4708	-0.1672	-0.1673

Atom	X	Y	Z
				H992	0.3887	0.0065	-0.1290
H41	0.8040	0.4214	-0.0458
				H31	0.6366	0.8606	-0.0878
H51	0.8478	0.9977	-0.1052
				H21	0.6886	0.2707	-0.1389
H11	0.7300	0.8758	-0.1869
				H61	1.0435	0.7903	-0.1069
H62	1.0031	0.7943	-0.0335
				H81	0.6253	0.7679	-0.2848
H111	0.8971	-0.0296	-0.3127
				H121	0.8920	0.2316	-0.2193
H151	0.4529	0.3653	-0.2956
				H161	0.2954	0.0652	-0.2987
H181	0.3033	-0.0383	-0.4826
				H191	0.4696	0.2685	-0.4759
H201	0.1135	-0.1601	-0.4631
				H202	0.1990	-0.4618	-0.4495
H211	-0.0104	-0.5787	-0.4482
				H212	0.0603	-0.6313	-0.3784
H213	-0.0253	-0.3295	-0.3920
				H891	0.0986	-0.6418	-0.2678
H892	0.2033	-0.3761	-0.2733
				H881	0.2163	-0.3858	-0.1655
H882	0.2762	-0.6665	-0.2039
				H131	0.6119	0.5248	-0.4319
H132	0.5566	0.7453	-0.3781

The structure cell data of ethylene glycol crystalline form SB-2 formula Ie are listed in below in table 9.

Table 9

The structure cell data of EG-SB-2 (Ie)

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(drug molecule of the every structure cell of Z)

R=residue number (I>3 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 10 below lists crystalline form SB-2 (ethylene glycol) Id in the location parameter of-50 DEG C.

Table 10

SB-2 is in the fractional atomic coordinates of T=-50 DEG C

Atom	X	Y	Z
				CL	0.7374	0.5149	-0.2111
O1	0.8133	0.9822	-0.0746
				O2	0.5013	0.9285	-0.0845
O4	0.7289	1.0601	0.0035
				O3	0.5256	0.8247	-0.0225
C13	0.5550	0.9627	-0.1935
				O6	0.9728	0.7735	-0.0353
C4	0.7265	0.9455	-0.0262
				C3	0.6074	0.9836	-0.0396
C8	0.6428	0.9915	-0.1422
				C5	0.8145	1.0938	-0.0449
C2	0.6104	0.8706	-0.0710
				C1	0.7042	1.0158	-0.0896
O17	0.1616	0.2406	-0.1894
				C10	0.7254	0.6663	-0.1761
C14	0.4505	0.7632	0.1926
				C12	0.7921	0.6786	-0.1254
C7	0.7155	0.8961	-0.1199
				C17	0.2595	0.4115	-0.1926
C9	0.6431	0.8746	-0.1706
				C11	0.7977	0.5663	-0.1538
C18	0.3043	0.4904	-0.2191
				C6	0.9384	1.0646	-0.0348
C21	0.0106	-0.0544	-0.2044
				C15	0.4002	0.6700	-0.1674
C16	0.3062	0.5028	-0.1664
				C19	0.4048	0.6705	-0.2196
C20	0.1094	0.1211	-0.2133
				O89	0.1914	0.1344	-0.0851
O88	0.0643	-0.3997	-0.0870
				C88	0.0717	-0.2076	-0.1097
C89	0.1793	-0.0404	-0.1104
				O98	0.2861	-0.0622	-0.0315
O99	0.3991	0.4406	-0.0899
				H131	0.5987	0.9339	-0.2163
H132	0.5342	1.1796	-0.1916
				H41	0.7470	0.7230	-0.0250
H31	0.5865	1.2077	-0.0378
				H81	0.5800	1.1634	-0.1366
H51	0.7979	1.3174	-0.0455
				H21	0.6251	0.6488	-0.0697
H11	0.6844	1.2377	-0.0920
				H121	0.8481	0.5958	-0.1080
H111	0.8591	0.3889	-0.1576
				H181	0.2593	0.4179	-0.2399

Atom	X	Y	Z
				H151	0.4420	0.7303	-0.1453
H161	0.2700	0.4433	-0.1446
				H191	0.4500	0.7270	-0.2410
H61	0.9486	1.1532	-0.0124
				H62	0.9940	1.1868	-0.0502
H201	0.0802	0.2769	-0.2296
				H202	0.1742	-0.0142	-0.2253
H211	-0.0281	-0.1580	-0.2236
				H212	0.0418	-0.2183	-0.1889
H213	-0.0522	0.0728	-0.1931
				H2	0.4568	0.7450	-0.0867
H3	0.4455	0.9047	-00257
				H6	0.9900	0.7115	-0.0140
H4	0.7487	0.9051	0.0180
				H891	0.1791	0.0911	-0.1307
H892	0.2524	-0.1815	-0.1307
				H881	0.0688	-0.3227	-0.1317
H882	-0.0006	-0.0646	-0.1095
				H89	0.1389	0.3052	-0.0871
H88	0.0278	-0.3039	-0.0685
				H981	0.2546	-0.0138	-0.0523
H991	0.3186	0.3564	-0.0924
				H992	0.4542	0.2696	-0.0893

The unit cell parameters of Isosorbide-5-Nitrae-butine-diol solvent compound If is listed in table 11 below.

Table 11

The structure cell data of Isosorbide-5-Nitrae-butine-diol solvent compound If

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(the every structure cell molecule amount of Z)

R=residue number (I>2 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 12 lists Isosorbide-5-Nitrae-butine-diol solvent compound If in the location parameter of 25 DEG C below.

Table 12

Isosorbide-5-Nitrae-butine-diol solvent compound If is in the fractional atomic coordinates table of T=25 DEG C

Atom	X	Y	Z
				CL1	0.4766	0.0404	0.0954
O1	0.4009	0.0489	0.4240
				O2	0.2487	0.0360	0.2866
O3	0.3361	0.3116	0.3700
				O4	0.2980	-0.0335	0.5564
C1	0.4341	-0.0386	0.2933
				C2	0.2694	-0.0045	0.4212
C3	0.3808	0.0618	0.4929
				O5	0.2184	-0.1421	0.4159
O6	0.1438	0.7685	0.0893
				C4	0.3553	0.1186	0.3597
C5	0.4405	0.0690	0.1713
				C6	0.4608	-0.0547	0.2314
C7	0.2958	-0.0113	0.3508
				C8	0.3662	0.2182	0.2312
C9	0.3737	0.3483	0.1029
				O7	0.4545	-0.2052	0.5425
C10	0.3205	-0.0595	0.4899
				C11	0.1993	0.4901	0.0635
C12	0.3137	0.4646	0.1010
				C13	0.3863	0.0987	0.2935
C14	0.3927	0.2100	0.1692
				C15	0.4368	-0.0055	0.5534
C16	0.2546	0.3872	0.0663
				C17	0.2011	0.6771	0.0960
C18	0.3867	0.4541	0.3863
				C19	0.3147	0.6507	0.1327
C20	0.2589	0.7579	0.1310
				C21	0.0758	1.0412	0.0907
C22	0.1428	0.9704	0.1110
				O8	0.1617	0.3320	0.3009
C23	0.0884	0.7849	0.2826
				C24	0.1613	0.4969	0.2531
C25	0.1208	0.6569	0.2679
				C26	0.0508	0.9415	0.3041
O9?*	0.0699	1.0883	0.3388
				O10*	0.0921	0.9885	0.3889
H1	0.4482	-0.1199	0.3347
				H2	0.2539	0.1293	0.4275
H3	0.3717	0.2007	0.5020
				H4	0.4923	-0.1485	0.2306
H5	0.3090	-0.1481	0.3449
				H6	0.3335	0.3078	0.2311
H7	0.4083	0.4406	0.1034
				H8	03681	0.2711	0.0573
H9	0.3310	-0.1996	0.4860
				H10	0.1605	0.4349	0.0399
H11	0.4728	0.0808	0.5536

Atom	X	Y	Z
				H12	0.4259	0.0056	0.6018
H13	0.2525	0.2624	0.0444
				H14	0.4194	0.4073	0.4272
H15	0.3705	0.5779	0.3998
				H16	0.4041	0.4724	0.3430
H17	0.3536	0.7062	0.1557
				H18	0.2607	0.8821	0.1533
H19	0.0586	1.0179	0.0384
				H20	0.0746	1.1804	0.1009
H21	0.0510	0.9710	0.1197
				H22	0.1691	1.0491	0.0855
H23	0.1594	0.9831	0.1645
				H24	0.2242	0.1281	0.2970
H25	0.1826	-0.0801	0.4013
				H26	0.2934	0.0916	0.5641
H27	0.4478	-0.2782	0.5791
				H28	0.1742	0.3703	0.3468
H30	0.0208	0.9935	0.2512
				H31	0.0199	0.8683	0.3354
H32	0.2091	0.5518	0.2594
				H33	0.1436	0.4493	0.1953

* atom occupancy (atomicoccupancyfactor) is 0.5, and reason is unordered in crystalline structure of 2-butyne-Isosorbide-5-Nitrae-diol solvent.

Table 13 below lists the unit cell parameters of dimethanol solvate Ig.

Table 13

The structure cell data of dimethanol solvate Ig

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(the every structure cell drug molecule of Z)

R=residue number (I>2 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 14 below lists dimethanol solvate Ig in the location parameter of-50 DEG C.

Table 14

Dimethanol solvate Ig is in the fractional atomic coordinates table of T=-50 DEG C

Atom	X	Y	Z
				CL1	0.4845	0.0519	0.0975
O1	0.3999	0.0334	0.4222
				O2	0.2438	0.0327	0.2837
O3	0.2919	-0.0365	0.5534
				O4	0.2111	-0.1509	0.4115
O5	0.1409	0.7749	0.0877
				O6	0.3348	0.2998	0.3692
C1	0.3785	0.0495	0.4912
				O7	0.4528	-0.2193	0.5428
C2	0.4372	-0.0463	0.2932
				C3	0.3958	0.2046	0.1690
C4	0.3540	0.1054	0.3588
				C5	0.2917	-0.0207	0.3471
C6	0.2638	-0.0141	0.4180
				C7	0.4666	-0.0556	0.2324
C8	0.4348	-0.0197	0.5521
				C9	0.3871	0.0889	0.2923
C10	0.3148	0.4622	0.1014
				C11	0.3669	0.2102	0.2310
C12	0.1971	0.4955	0.0616
				C13	0.3756	0.3437	0.1035
C14	0.3159	-0.0680	0.4873
				C15	0.2003	0.6811	0.0949
C16	0.2533	0.3883	0.0643
				C17	0.4459	0.0675	0.1722
C18	0.3162	0.6471	0.1342
				C19	0.2592	0.7551	0.1318
C20	03858	0.4414	0.3857
				C21	0.0747	1.0555	0.0906
C22	0.1419	0.9708	0.1140
				O8	0.1606	0.3410	0.3030
C23	0.1681	0.4908	0.2528
				O9?*	0.0905	1.0537	0.3488
C24	0.0506	0.9411	0.3047
				O10*	0.0871	0.9637	0.3888
H1	0.3698	0.1882	0.5000
				H2	0.4508	-0.1297	0.3339
H3	0.3403	-0.1573	0.3401
				H4	0.2477	0.1190	0.4240
H5	0.5002	-0.1450	0.2324
				H6	0.4724	0.0642	0.5527
H7	0.4230	-0.0062	0.6000
				H8	0.3330	0.2987	0.2309
H9	0.1568	0.4439	0.0375
				H10	0.4115	0.4344	0.1041
H11	0.3694	0.2681	0.0576
				H12	0.3262	-0.2083	0.4845
H13	0.2507	0.2654	0.0414

Atom	X	Y	Z
				H14	0.3563	0.7000	0.1585
H15	0.2614	0.8773	0.1551
				H16	0.4247	0.3814	0.4147
H17	0.3726	0.5474	0.4136
				H18	0.3943	0.4912	0.3398
H19	0.0589	1.0375	0.0377
				H20	0.0760	1.1934	0.1022
H21	0.0460	0.9899	0.1168
				H22	0.1725	1.0486	0.0933
H23	0.1560	0.9729	0.1681
				H24	0.2910	0.0922	0.5653
H25	0.1707	-0.0975	0.3970
				H26	0.4393	-0.3086	0.5727
H27	0.2166	0.1321	0.2895
				H28	0.1613	0.6164	0.2738
H29	0.1368	0.4726	0.2064
				H30	0.2119	0.4855	0.2441
H31	0.1761	0.3807	0.3503
				H32*	0.1139	1.1530	0.3322
H33*	0.0293	0.8376	0.3371
				H34*	0.0122	1.0286	0.2705
H35*	0.0765	0.8620	0.2691
				H36?*	0.0718	0.8698	0.4154
H37?*	0.0679	1.0520	0.2715
				H38?*	0.0601	0.7968	0.2848
H39?*	-0.0015	0.9590	0.2996

* atom occupancy is 0.5, and reason is unordered in crystalline structure of methanol solvate.

The unit cell parameters of 1:2L-proline Complex-crystalline form 3, formula Ih is listed in table 15 below.

Table 15

The structure cell data of 1:2L-proline Complex (Ih)

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(drug molecule of the every structure cell of Z)

R=residue number (I>3 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 15A below lists 1:2L-proline(Pro) proline(Pro) (Ih) pure (neat) crystalline form N-1 in the location parameter of T=-60 DEG C.

Table 15A

With the fractional atomic coordinates table of the Compound I h1:2 mixture (crystalline form N-1) of L-PROLINE

Atom	X	Y	Z
				Cl1	0.8511	0.3142	0.4683
O2	0.1890	0.4635	0.4796
				O3	0.7564	0.4104	0.2284
O4	0.4729	0.5010	0.2885
				O5	0.4376	0.6313	0.2067
O6	0.8989	0.3300	0.1500
				C7	0.2926	0.3792	0.4153
C8	0.6818	0.2711	0.3799
				C9	0.5724	0.5066	0.2584
C10	0.7120	0.3675	0.3085
				C11	0.6191	0.5325	0.1740
O12	0.5675	0.5324	0.1226
				C13	0.8659	0.4113	0.3834
C14	0.6573	0.3919	0.2567
				C15	0.7888	0.3318	0.4049
C16	0.3975	0.3524	0.4995
				C17	0.5114	0.5240	0.2053
C18	0.7053	0.4187	0.1784
				C19	0.2907	0.3910	0.4630
C20	0.4894	0.2664	0.4264
				C21	0.4996	0.2842	0.4793
C22	0.8273	0.4301	0.3341
				C23	0.2056	0.4854	0.5344
C24	0.8279	0.4316	0.1519
				C25	0.3898	0.3142	0.3967
C26	0.5990	0.1967	0.4055
				C27	0.6395	0.2861	0.3305
C28	0.0776	0.5599	0.5411
				Cl29	0.8615	0.7651	0.4622
O30	0.4735	1.0020	0.2917
				O31	0.4387	1.1337	0.2094
O32	0.7479	0.9028	0.2288
				O33	0.8902	0.8251	0.1497
C34	0.8261	0.9016	0.3336
				C35	0.6485	0.8878	0.2580
O36	0.5610	1.0347	0.1249
				C37	0.6759	0.7507	0.3797
C38	0.5079	1.0262	0.2062
				C39	0.4780	0.7554	0.4220
C40	0.6312	0.7804	0.3315
				O41	0.1584	0.9450	0.4656

Atom	X	Y	Z
				C42	0.7041	0.8583	0.3076
C43	0.3624	0.6994	0.4359
				C44	0.8678	0.8769	0.3809
C45	0.5696	1.0064	0.2602
				C46	0.6975	0.9154	0.1787
C47	0.3635	0.9472	0.4341
				C48	0.6156	1.0330	0.1758
C49	0.2666	0.7602	0.4513
				C50	0.2689	0.8865	0.4494
C51	0.4642	0.8736	0.4176
				C52	0.8214	0.9316	0.1526
C53	0.5864	0.6836	0.4051
				C54	0.7948	0.8027	0.4039
C55	0.1465	1.0758	0.4752
				C56	0.2078	1.0792	0.5264
C73	0.7131	0.5906	0.5918
				C74	0.6549	0.5814	0.5389
Cl75	0.0092	0.3008	0.6072
				O76	0.1209	0.5563	0.8403
O77	0.3970	0.6243	0.7788
				C78	0.2253	0.5273	0.8121
C79	0.3613	0.6922	0.8623
				C80	0.1934	0.3303	0.6884
C81	0.1674	0.4723	0.7614
				C82	0.2412	0.3835	0.7390
C83	-0.0019	0.4492	0.6892
				O84	0.4278	0.7982	0.8605
O85	-0.0213	0.5180	0.9192
				C86	0.0441	0.5055	0.7380
O87	0.7087	0.4793	0.6025
				C88	0.1729	0.5956	0.8909
C89	0.4982	0.4992	0.6339
				C90	0.5097	0.2528	0.6324
C91	0.3008	0.6402	0.8083
				C92	0.3983	0.4301	0.6518
O93	0.3078	0.7393	0.9449
				C94	0.2809	0.2490	0.6650
C95	0.3930	0.3137	0.6470
				C96	0.0746	0.3688	0.6663
C97	0.6122	0.3067	0.6180
				C98	0.2545	0.7117	0.8934
C99	0.6095	0.4314	0.6189
				C100	0.0478	0.6254	0.9173
C110	0.0184	0.8459	0.6019
				O102	0.3952	1.1247	0.7804
O103	0.1147	1.0661	0.8415
				O104	0.6781	0.9872	0.5898
O105	0.4317	1.2935	0.8633

Atom	X	Y	Z
				C106	0.5806	0.9279	0.6059
C107	0.4768	0.8827	0.6738
				C108	0.1859	0.8490	0.6890
C109	0.5840	0.9396	0.6532
				C110	0.3778	0.8134	0.5924
C111	0.2988	1.1454	0.8102
				O112	0.3053	1.2394	0.9473
O113	-0.0298	1.0236	0.9198
				C114	0.1616	0.9797	0.7616
C115	0.4712	0.8729	0.5711
				C116	0.1655	1.0994	0.8923
C117	0.2173	1.0311	0.8129
				C118	0.2502	1.2127	0.8951
C119	0.3763	0.8179	0.6434
				C120	0.0002	0.9826	0.6866
C121	0.6693	0.9881	0.5388
				C122	0.2312	0.8864	0.7377
C123	0.3605	1.1913	0.8637
				C124	0.0428	1.0292	0.7357
C125	0.7936	1.0536	0.5306
				C126	0.0458	1.1266	0.9182
C127	0.0732	0.8975	0.6629
				C128	0.2697	0.7610	0.6655
O129	0.1176	0.8835	0.2145
				N130	0.2152	0.6016	0.2596
C131	0.1172	0.6843	0.2345
				O132	0.2914	0.8241	0.2651
C133	0.1853	0.8095	0.2384
				C134	0.1980	0.6021	0.3121
C135	0.0814	0.6857	0.3187
				C136	0.0075	0.6839	0.2657
O137	0.5811	0.9560	0.8015
				O138	0.7490	1.0434	0.8543
C139	0.7527	0.8332	0.8327
				C140	0.6889	0.9523	0.8297
N141	0.6668	0.7335	0.8097
				C142	0.6961	0.7064	0.7572
C143	0.8711	0.8236	0.8064
				C144	0.8046	0.7903	0.7522
O145	0.2901	0.3199	0.2689
				N146	0.2077	0.0992	0.2607
C147	0.1849	0.3081	0.2401
				O148	0.1224	0.3825	0.2158
C149	0.1134	0.1822	0.2345
				C150	-0.0001	0.1822	0.2639
C151	0.1765	0.0951	0.3122
				C152	0.0624	0.1788	0.3149
C153	0.7503	0.3375	0.8345

Atom	X	Y	Z
				O154	0.7509	0.5453	0.8549
O155	0.5797	0.4581	0.8039
				N156	0.6576	0.2389	0.8101
C157	0.6884	0.4556	0.8306
				C158	0.8656	0.3215	0.8057
C159	0.7926	0.2957	0.7527
				C160	0.6813	0.2179	0.7580
O57	0.2706	0.6596	0.1242
				O58	0.4116	0.7306	0.0823
N59	0.2962	0.9340	0.0695
				C60	0.3243	0.7268	0.1018
C61	0.2366	0.8510	0.0985
				C62	0.2021	0.9562	0.0266
C63	0.0946	0.8269	0.0685
				C64	0.0736	0.9268	0.0393
O65	0.2708	0.1591	0.1241
				O66	0.4177	0.2319	0.0834
N67	0.2949	0.4330	0.0684
				C68	0.2341	0.3504	0.0971
C69	0.3311	0.2307	0.1033
				C70	0.0690	0.4256	0.0394
C71	0.1944	0.4576	0.0266
				C72	0.0916	0.3239	0.0659
C161	0.5540	0.4526	0.9706
				O162	0.4543	0.4603	0.9840
O163	0.6026	0.3671	0.9467
				N164	0.5722	0.6674	0.9975
C165	0.7962	0.6796	1.0284
				C166	0.7705	0.5623	1.0029
C167	0.6633	0.7048	1.0426
				C168	0.6369	0.5668	0.9718
N169	0.5736	1.1664	0.9988
				C170	0.6413	1.0706	0.9734
C171	0.6566	1.2036	1.0440
				C172	0.7913	1.1762	1.0303
C173	0.7728	1.0572	1.0049
				O174	0.5984	0.8670	0.9446
O175	0.4528	0.9612	0.9826
				C176	0.5532	0.9542	0.9687
H104	0.4098	0.4245	0.2757
				H1	0.5933	0.3154	0.2391
H11	0.6757	0.6123	0.1863
				H25	0.3866	0.3009	0.3571
H7	0.2181	0.4202	0.3906
				H16	0.4003	0.3732	0.5389
H21	0.5801	0.2482	0.5031
				H231	0.2065	0.4036	0.5514
H230	0.2944	0.5361	0.5495

Atom	X	Y	Z
				H260	0.5550	0.1248	0.3793
H261	0.6617	0.1611	0.4357
				H22	0.8817	0.4891	0.3161
H27	0.5549	0.2379	0.3095
				H13	0.9521	0.4556	0.4051
H24B	0.8905	0.5029	0.1720
				H24A	0.7945	0.4527	0.1146
H18	0.6455	0.3409	0.1637
				H9	0.6364	0.5818	0.2730
H17	0.4471	0.4497	0.1897
				H6O	0.9902	0.3430	0.1754
H5O	0.3733	0.6344	0.1718
				H12	0.5145	0.6132	0.1167
H730	0.4058	0.9277	0.2777
				H35	0.5824	0.8169	0.2387
H34	0.8870	0.9544	0.3141
				H48	0.6718	1.1140	0.1882
H43	0.3564	0.6038	0.4332
				H49	0.1884	0.7171	0.4650
H51	0.5357	0.9155	0.4000
				H47	0.3640	1.0426	0.4342
H550	0.2010	1.1248	0.4533
				H551	0.0459	1.1049	0.4708
H53A	0.5434	0.6098	0.3796
				H53B	0.6443	0.6506	0.4370
H44	0.9590	0.9156	0.4010
				H40	0.5387	0.7432	0.3119
H46	0.6347	0.8402	0.1631
				H45	0.6370	1.0795	0.2743
H52B	0.8851	1.0006	0.1739
				H52A	0.7895	0.9562	0.1157
H38	0.4415	0.9538	0.1901
				H33O	0.9838	0.8359	0.1739
H36	0.5133	1.1183	0.1197
				H31	0.3740	1.1406	0.1748
H78	0.2893	0.4626	0.8307
				H91	0.2300	0.7037	0.7933
H79	0.4290	0.6296	0.8786
				H73A	0.8131	0.6240	0.5975
H73B	0.6558	0.6475	0.6139
				H97	0.6926	0.2563	0.6062
H90	0.5135	0.1579	0.6334
				H92	0.3254	0.4776	0.6699
H89	0.4904	0.5936	0.6319
				H94B	0.3235	0.1904	0.6915
H94A	0.2237	0.1976	0.6335
				H83	-0.0976	0.4703	0.6701
H86	-0.0138	0.5707	0.7560

Atom	X	Y	Z
				H82	0.3324	0.3549	0.7591
H98	0.1908	0.7806	0.8796
				H88	0.2352	0.5280	0.9067
H100	-0.0156	0.6845	0.8964
				H101	0.0795	0.6672	0.9544
H77O	0.4635	0.5569	0.7921
				H84O	0.4937	0.8202	0.8949
H93O	0.3569	0.8249	0.9503
				H85O	-0.1149	0.5173	0.8950
H117	0.2800	0.9658	0.8316
				H123	0.4233	1.1238	0.8797
H111	0.2317	1.2108	0.7948
				H228	0.3143	0.7048	0.6931
H128	0.2074	0.7050	0.6363
				H12A	0.6658	0.8985	0.5209
H12B	0.5824	1.0343	0.5241
				H915	0.4621	0.8772	0.5316
H909	0.6624	0.9895	0.6775
				H107	0.4780	0.8924	0.7134
H910	0.3024	0.7608	0.5678
				H124	-0.0101	1.0987	0.7537
H120	-0.0905	1.0129	0.6667
				H122	0.3164	0.8472	0.7576
H116	0.2250	1.0292	0.9073
				H926	-0.0153	1.1891	0.8983
H826	0.0798	1.1653	0.9557
				H118	0.1903	1.2849	0.8822
H902	0.4593	1.0560	0.7941
				H105	0.4954	1.3127	0.8984
H112	0.3566	1.3240	0.9528
				H113	-0.1207	1.0256	0.8942
H130	0.0880	0.6513	0.1960
				H930	0.1989	0.5128	0.2411
H131	0.3065	0.6289	0.2579
				H936	-0.0527	0.7614	0.2616
H137	-0.0535	0.6049	0.2555
				H136	0.0202	0.6522	0.3427
H935	0.1160	0.7743	0.3334
				H134	0.1753	0.5137	0.3200
H135	0.2861	0.6352	0.3365
				H944	0.9296	0.9035	0.8114
H143	0.9361	0.7508	0.8190
				H244	0.8750	0.7504	0.7303
H144	0.7682	0.8708	0.7360
				H139	0.7802	0.8212	0.8719
H742	0.7271	0.6158	0.7513
				H842	0.6099	0.7203	0.7306
H541	0.6871	0.6572	0.8300

Atom	X	Y	Z
				H641	0.5726	0.7555	0.8089
H952	0.0994	0.2669	0.3315
				H252	-0.0039	0.1476	0.3381
H150	-0.0603	0.2607	0.2596
				H250	-0.0651	0.1042	0.2518
H151	0.1486	0.0063	0.3177
				H152	0.2600	0.1251	0.3397
H460	0.1968	0.0115	0.2409
				H461	0.3000	0.1287	0.2626
H149	0.0881	0.1498	0.1958
				H161	0.7059	0.1256	0.7481
H160	0.5948	0.2388	0.7319
				H159	0.7564	0.3753	0.7372
H259	0.8547	0.2500	0.7286
				H153	0.7784	0.3252	0.8732
H958	0.9256	0.4012	0.8101
				H959	0.9261	0.2481	0.8168
H957	0.6775	0.1597	0.8286
				H956	0.5646	0.2627	0.8110
H620	0.2066	1.0481	0.0198
				H62	0.2205	0.9003	-0.0057
H640	0.0377	1.0016	0.0607
				H64	0.0037	0.9030	0.0061
H63	0.0897	0.7441	0.0449
				H630	0.0231	0.8249	0.0931
H61	0.2352	0.8932	0.1354
				H590	0.3226	1.0165	0.0923
H59	0.3766	0.8979	0.0586
				H68	0.2264	0.3961	0.1333
H710	0.1967	0.5506	0.0213
				H71	0.2110	0.4051	-0.0068
H700	0.0336	0.4977	0.0623
				H70	-0.0021	0.4046	0.0062
H72	0.0901	0.2437	0.0409
				H720	0.0195	0.3163	0.0900
H670	0.3256	0.5143	0.0915
				H67	0.3726	0.3954	0.0559
H666	0.8439	0.5395	0.9797
				H766	0.7706	0.4978	1.0292
H665	0.8720	0.6797	1.0604
				H765	0.8229	0.7417	1.0042
H767	0.6538	0.7982	1.0537
				H667	0.6468	0.6543	1.0723
H168	0.6429	0.5849	0.9344
				H664	0.4798	0.6384	1.0063
H764	0.5568	0.7339	0.9761
				H170	0.6545	1.0931	0.9372
H673	0.7695	0.9914	1.0304

Atom	X	Y	Z
				H773	0.8485	1.0349	0.9826
H672	0.8184	1.2380	1.0061
				H772	0.8655	1.1783	1.0629
H671	0.6469	1.2971	1.0548
				H771	0.6369	1.1536	1.0734
H669	0.5570	1.2393	0.9763
				H769	0.4876	1.1366	1.0054

The unit cell parameters of the pure crystalline form N-1 of 1:1L-proline Complex (crystalline form 6) formula Ii is listed in table 16 below.

Table 16

The structure cell data of 1:1L-proline Complex (Ii)

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(drug molecule of the every structure cell of Z)

R=residue number (I>3 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 16A below lists 1:1L-proline Complex (Ii) pure crystalline form N-1 in the location parameter of T=-40 DEG C.

Table 16A

With the fractional atomic coordinates table of the Compound I i1:1 mixture of L-PROLINE

Atom	X	Y	Z
				Cl1	0.4598	-0.1973	0.4564
C1	0.5901	-0.2370	0.3766
				C2	0.4455	-0.0618	0.3755
C3	0.4764	-0.1649	0.4212
				C4	0.5631	-0.2563	0.4083
C5	0.5270	-0.1401	0.3597
				C6	0.4236	-0.0847	0.4052
C7	0.3350	0.0181	0.4193
				C8	0.4043	0.1572	0.4619
C9	0.4038	0.1366	0.4305
				C10	0.4700	0.2275	0.4154
O1	0.5531	-0.2303	0.3104
				C11	0.6684	-0.0473	0.3232

Atom	X	Y	Z
				C12	0.6871	-0.1530	0.2745
O2	0.6765	0.0755	0.3403
				C13	0.5634	-0.2137	0.2780
C14	0.5532	-0.1047	0.3260
				C15	0.6982	-0.0231	0.2901
C16	0.5401	-0.3394	0.2628
				O3	0.7021	-0.1304	0.2442
O4	0.8064	0.0378	0.2896
				O5	0.5831	0.4559	0.4668
C17	0.5134	0.3474	0.4583
				C18	0.6039	0.5020	0.4977
C19	0.6740	0.6076	0.4990
				O6	0.6178	-0.4307	0.2703
C20	0.4646	0.2450	0.4744
				C21	0.5212	0.3364	0.4270
Cl2	-0.1014	-0.2193	0.4531
				O7	0.0403	-0.2096	0.3126
C22	0.0502	-0.0977	0.3307
				C23	-0.0026	-0.1191	0.3614
C24	0.1707	-0.0312	0.3288
				C25	0.0641	-0.1848	0.2832
C26	0.1903	-0.1171	0.2772
				C27	0.0159	-0.2652	0.4010
C28	0.0413	-0.3076	0.2646
				O8	0.1732	0.0766	0.3473
C29	0.0527	-0.2262	0.3719
				C30	-0.0488	-0.1911	0.4174
O9	0.2066	-0.1046	0.2477
				C31	-0.1057	-0.0845	0.4057
C32	-0.0805	-0.0464	0.3769
				C33	-0.1758	0.0315	0.4210
C34	-0.0962	0.3657	0.4497
				C35	0.0119	0.1514	0.4289
C36	-0.1670	0.2596	0.4419
				O10	0.0892	0.4864	0.4561
C37	0.0235	0.3777	0.4487
				C38	0.0796	0.2657	0.4373
C39	0.2088	0.4743	0.4694
				C40	0.2378	0.6027	0.4670
C41	-0.1056	0.1472	0.4292
				O11	0.3103	0.0473	0.2955
C42	0.1927	-0.0117	0.2972
				O12	0.1209	-0.4060	0.2699
C43	-0.1355	0.5267	0.3371
				C44	-0.1317	0.4102	0.3168
N1	-0.2217	0.3229	0.3311
				C45	-0.1578	0.4809	0.3661
C46	-0.2328	0.3526	0.3628

Atom	X	Y	Z
				O13	0.0687	0.4002	0.3090
O14	-0.0027	0.2411	0.3344
				C47	-0.0235	0.3422	0.3215
C48	0.3738	0.4173	0.3220
				C49	0.3666	0.5397	0.3405
C50	0.3232	0.5141	0.3706
				O15	0.5678	0.3983	0.3126
O16	0.4793	0.2316	0.3356
				N2	0.2751	0.3408	0.3341
C51	0.2568	0.3858	0.3637
				C52	0.4900	0.3392	0.3227
C53	0.1894	0.5037	0.4979
				H1	0.2977	-0.0348	0.4380
H2	0.5158	0.5126	0.5088
				H3	0.6427	0.4151	0.5106
H4	0.4640	0.2425	0.4980
				H5	0.3557	0.0952	0.4743
H6	0.4028	0.0143	0.3656
				H7	0.4846	-0.0412	0.3172
H8	0.7354	-0.1139	0.3309
				H9	0.6383	0.0438	0.2803
H10	0.7509	-0.2206	0.2829
				H11	0.4937	-0.1547	0.2692
H12	0.4535	-0.3750	0.2689
				H13	0.5440	-0.3256	0.2395
H14	0.5987	0.1273	0.3371
				H15	0.5850	-0.4862	0.2863
H16	0.2740	0.0426	0.4038
				H17	0.7825	-0.0885	0.2400
H18	0.8274	0.0552	0.2680
				H19	0.4902	0.2088	0.3946
H20	0.5540	0.4072	0.4143
				H21	0.6504	-0.2925	0.3665
H22	0.6030	-0.3278	0.4194
				H23	0.2586	-0.1789	0.2863
H24	0.1267	0.0606	0.2892
				H25	0.2335	-0.1001	0.3377
H26	0.0060	-0.0175	0.3198
				H27	-0.0022	-0.1194	0.2737
H28	-0.0459	-0.3511	0.2701
				H29	0.0431	-0.2942	0.2411
H30	0.1118	-0.2782	0.3606
				H31	-0.1170	0.0351	0.3696
H32	0.0467	-0.3485	0.4096
				H33	-0.2543	0.2691	0.4432
H34	-0.1353	0.4445	0.4589
				H35	0.0544	0.0664	0.4241
H36	0.1640	0.2598	0.4365

Atom	X	Y	Z
				H37	-0.2417	0.0673	0.4058
H38	-0.2171	0.0017	0.4412
				H39	0.2698	-0.0400	0.2435
H40	0.3320	0.0534	0.2734
				H41	0.1058	0.1381	0.3420
H42	0.0874	-0.4719	0.2852
				H43	-0.1506	0.4388	0.2950
H44	-0.0541	0.5810	0.3377
				H45	-0.2055	0.5941	0.3310
H46	-0.0797	0.4553	0.3782
				H47	-0.2106	0.5460	0.3796
H48	-0.3210	0.3680	0.3662
				H49	-0.1958	0.2728	0.3734
H50	-0.2972	0.3381	0.3195
				H51	-0.1983	0.2279	0.3269
H52	0.3544	0.4339	0.2980
				H53	0.2791	0.3273	0.3822
H54	0.1634	0.4233	0.3683
				H55	0.4032	0.5053	0.3835
H56	0.2799	0.6038	0.3764
				H57	0.4555	0.5795	0.3393
H58	0.3097	0.6065	0.3283
				H59	0.2013	0.3456	0.3219
H60	0.2977	0.2420	0.3345

1:1L-proline(Pro) semihydrate mixture unit cell parameters is H.5-2Ij listed in table 17 below.

Table 17

With the Compound I mixture hemihydrate crystalline structure cell data H.5-2 of L-PROLINE

The temperature (DEG C) of T=crystal data

Z '=drug molecule number/asymmetric cell

V _m=V (structure cell)/(drug molecule of the every structure cell of Z)

R=residue number (I>2 σ (I))

D _calcthe crystalline density of=calculating

SG=spacer

Table 18 below lists 1:1L-proline(Pro) hemihydrate crystalline location parameter H.5-2Ij.

Table 18

With the Compound I j1:1 mixture hemihydrate crystalline of L-PROLINE H.5-2 in the fractional atomic coordinates table of T=-40 DEG C

Atom	X	Y	Z
				CL1	-0.3207	0.2999	0.1007
O2	-0.0812	0.4445	0.3860
				O3	0.1266	0.3986	0.5119
O4	0.0226	0.1123	0.3131
				O5	0.1988	0.2024	0.4116
C6	-0.0400	0.4518	0.4471
				C7	0.0829	0.3978	0.4505
C8	0.0836	0.2539	0.4134
				O9	0.0185	0.6897	0.4693
C10	0.0320	0.2460	0.3495
				C11	-0.1475	0.3075	0.2867
C12	-0.0536	0.5937	0.4833
				C13	-0.2858	0.1976	0.1996
O14	-0.1314	-0.4139	0.0970
				C15	-0.0913	0.3083	0.3494
C16	-0.2316	0.2099	0.2582
				C17	-0.1691	0.4011	0.2002
C18	-0.1786	-0.0508	0.1507
				C19	-0.3006	-0.0480	0.1494
C20	-0.3629	-0.1768	0.1287
				C21	-0.1830	-0.2916	0.1133
C22	-0.1179	0.4052	0.2576
				C23	-0.1249	-0.1696	0.1325
C24	-0.2541	0.3000	0.1727
				C25	-0.3658	0.0787	0.1687
C26	-0.3038	-0.2938	0.1114
				C27	-0.0150	-0.4216	0.0824
C28	-0.0248	-0.4143	0.0214
				CL29	0.6985	0.3144	0.9332
O30	0.9914	0.4113	0.6104
				O31	0.7834	0.1123	0.6447
O32	0.8541	0.4766	0.7040
				C33	0.7408	0.2570	0.7376
O34	0.9142	0.1720	0.5162
				O35	0.7084	-0.1271	0.5485
C36	0.7611	0.2500	0.6736

Atom	X	Y	Z
				O37	0.8359	0.9717	0.9453
C38	0.7967	0.0998	0.5824
				C39	0.8661	0.3408	0.6732
C40	0.8113	-0.0517	0.5552
				C41	0.6608	0.3487	0.7637
C42	0.8842	0.3295	0.6081
				C43	0.7928	0.2013	0.8324
C44	0.6478	0.3693	0.8244
				C45	0.9041	0.1825	0.5787
C46	0.7116	0.2945	0.8580
				C47	0.7693	0.8565	0.9247
C48	0.6523	0.6699	0.9393
				C49	0.6372	0.6130	0.8784
C50	0.6886	0.6798	0.8418
				C51	0.8079	0.1861	0.7731
C52	0.7539	0.8018	0.8657
				C53	0.7171	0.7906	0.9638
C54	0.8594	1.0293	1.0095
				C55	0.5690	0.4784	0.8512
C56	0.9344	1.1572	1.0187
				CL57	0.1318	0.2860	0.9213
O58	0.2325	0.1474	0.6392
				O59	0.3774	0.4788	0.7078
O60	0.3769	0.1826	0.5107
				O61	0.5074	0.3673	0.6076
C62	0.2155	0.2845	0.7366
				C63	0.2440	0.2856	0.6735
C64	0.2590	0.1866	0.7641
				C65	0.3642	0.3439	0.6737
C66	0.1310	0.6369	0.8752
				C67	0.3659	0.1865	0.5718
C68	0.2203	-0.0149	0.5444
				C69	0.2495	0.6414	0.8737
C70	0.2339	0.1891	0.8206
				C71	0.2440	0.1366	0.5760
C72	0.2691	0.8826	0.9099
				C73	0.3878	0.3310	0.6097
C74	0.0797	0.7646	0.8952
				C75	0.1225	0.3883	0.8232
O76	0.0935	-0.0372	0.5272
				C77	0.1466	0.3834	0.7646
C78	0.1643	0.2886	0.8500
				C79	0.3160	0.7598	0.8907
O80	0.3243	1.0074	0.9263
				C81	0.0564	0.5089	0.8537
C82	0.1501	0.8831	0.9123
				C83	0.4517	1.0168	0.9429
C84	0.4736	1.0085	1.0039

Atom	X	Y	Z
				CL85	0.2353	0.2852	0.0943
O86	0.4643	0.4578	0.3847
				O87	0.6924	0.1640	0.4142
C88	0.4307	0.3235	0.3510
				O89	0.6471	0.3804	0.5135
C90	0.5401	0.2370	0.3503
				O91	0.4314	0.6909	0.4760
C92	0.5025	0.4655	0.4471
				C93	0.3782	0.3234	0.2879
O94	0.3688	-0.3850	0.0770
				C95	0.2412	0.2163	0.2011
O96	0.5177	0.1054	0.3143
				C97	0.5871	0.2380	0.4145
C98	0.5309	0.6092	0.4771
				C99	0.6100	0.3805	0.4525
C100	0.3806	0.3946	0.1963
				C101	0.2856	0.2342	0.2611
C102	0.3122	-0.2671	0.0968
				C103	0.1491	0.1041	0.1716
C104	0.2436	-0.2032	0.0581
				C105	0.2886	0.3016	0.1694
C106	0.3259	-0.2129	0.1566
				C107	0.4243	0.4052	0.2556
C108	0.1916	-0.0835	0.0830
				C109	0.3595	-0.4411	0.0145
C110	0.2039	-0.0262	0.1455
				C111	0.2741	-0.0939	0.1807
C112	0.4263	-0.5693	0.0039
				O113	0.6465	0.6039	0.6797
O114	0.7349	0.7473	0.6386
				N115	0.4575	0.7439	0.6955
C116	0.6529	0.7073	0.6592
				C117	0.5581	0.9376	0.6856
C118	0.4708	0.8468	0.7558
				C119	0.5406	0.7887	0.6584
C120	0.5558	0.9548	0.7523
				O121	0.1830	0.6331	0.6898
O122	0.2453	0.7852	0.6450
				N123	-0.0372	0.6985	0.6789
C124	0.0468	0.7797	0.6565
				C125	0.0382	0.9228	0.6945
C126	0.1683	0.7269	0.6638
				C127	0.0337	0.8955	0.7569
C128	-0.0365	0.7591	0.7436
				N129	-0.3701	-0.1217	0.3442
C130	-0.1562	-0.1273	0.3652
				O131	-0.1554	-0.0439	0.3345
O132	-0.0663	-0.1700	0.3912

Atom	X	Y	Z
				C133	-0.2876	-0.3360	0.3362
C134	-0.2710	-0.1891	0.3727
				C135	-0.3924	-0.1926	0.2793
C136	-0.3216	-0.3192	0.2720
				O137	0.4232	-0.1933	0.3831
O138	0.3366	-0.0501	0.3332
				C139	0.2187	-0.2024	0.3678
N140	0.1226	-0.1310	0.3394
				C141	0.3337	-0.1410	0.3604
C142	0.1992	-0.3502	0.3341
				C143	0.1599	-0.3386	0.2693
C144	0.0885	-0.2109	0.2771
				O145	0.2926	0.5997	0.5452
O146	0.5342	-0.0128	0.4878
				H150	-0.0975	0.3899	0.4641
H151	0.1418	0.4590	0.4337
				H152	0.0313	0.1936	0.4337
H154	0.0862	0.3044	0.3298
				H155	-0.1430	0.6195	0.4745
H156	-0.0310	0.5943	0.5295
				H157	-0.1495	0.2477	0.3663
H158	-0.2539	0.1367	0.2824
				H159	-0.1435	0.4768	0.1772
H160	-0.1255	0.0440	0.1660
				H161	-0.4573	-0.1862	0.1271
H162	-0.0551	0.4859	0.2809
				H163	-0.0294	-0.1642	0.1321
H164	-0.4249	0.0580	0.1988
				H165	-0.4172	0.0974	0.1293
H166	-0.3545	-0.3888	0.0944
				H167	0.0443	-0.3425	0.1127
H168	0.0247	-0.5195	0.0867
				H169	0.0584	-0.4150	0.0027
H170	-0.0829	-0.4910	-0.0091
				H171	-0.0634	-0.3139	0.0169
H176	0.6840	0.2850	0.6494
				H177	0.7179	0.1342	0.5591
H178	0.9431	0.3006	0.6953
				H179	0.8770	-0.0884	0.5846
H180	0.8408	-0.0648	0.5117
				H181	0.6098	0.4044	0.7359
H182	0.8091	0.3693	0.5861
				H183	0.8427	0.1385	0.8583
H184	0.9803	0.1446	0.6000
				H185	0.6091	0.6187	0.9683
H186	0.6794	0.6399	0.7942
				H187	0.8728	0.1192	0.7530
H188	0.7902	0.8541	0.8361

Atom	X	Y	Z
				H189	0.7271	0.8353	1.0122
H190	0.7735	1.0569	1.0277
				H191	0.8986	0.9597	1.0334
H192	0.5005	0.4927	0.8176
				H193	0.5288	0.4505	0.8873
H194	0.9545	1.2094	1.0658
				H195	1.0166	1.1315	1.0008
H196	0.8915	1.2288	0.9952
				H200	0.1797	0.3464	0.6531
H201	0.3128	0.1093	0.7423
				H202	0.4283	0.2823	0.6914
H203	0.4309	0.1186	0.5873
				H204	0.2676	-0.0437	0.5075
H205	0.2503	-0.0734	0.5778
				H206	0.2938	0.5478	0.8573
H207	0.2667	0.1115	0.8435
				H208	0.1813	0.2008	0.5579
H209	0.3311	0.3978	0.5902
				H210	-0.0167	0.7728	0.8951
H212	0.1131	0.4619	0.7424
				H213	0.4107	0.7527	0.8914
H214	0.0235	0.4869	0.8923
				H215	-0.0164	0.5268	0.8227
H216	0.1131	0.9807	0.9295
				H217	0.5000	0.9375	0.9142
H218	0.4930	1.1146	0.9386
				H219	0.5658	1.0153	1.0225
H220	0.4299	1.0899	1.0326
				H221	0.4370	0.9127	1.0082
H223	0.3659	0.2811	0.3724
				H225	0.6059	0.2835	0.3311
H227	0.4295	0.4306	0.4673
				H229	0.5247	0.1893	0.4346
H230	0.5953	0.6489	0.4536
				H231	0.5686	0.6221	0.5232
H232	0.6812	0.4246	0.4357
				H233	0.4161	0.4554	0.1692
H234	0.2450	0.1769	0.2870
				H235	0.0958	0.0890	0.2045
H236	0.0943	0.1338	0.1355
				H237	0.2331	-0.2409	0.0101
H238	0.3791	-0.2651	0.1858
				H239	0.4960	0.4787	0.2767
H240	0.1390	-0.0325	0.0529
				H241	0.2692	-0.4672	-0.0046
H242	0.3958	-0.3734	-0.0080
				H243	0.2899	-0.0523	0.2290
H244	0.4221	-0.6177	-0.0443

Atom	X	Y	Z
				H245	0.5184	-0.5490	0.0216
H246	0.3917	-0.6427	0.0251
				H248	0.4793	0.6449	0.7024
H249	0.6424	0.9714	0.6756
				H250	0.4899	0.9910	0.6668
H251	0.3871	0.8958	0.7636
				H252	0.4974	0.8010	0.7924
H253	0.4998	0.7712	0.6119
				H254	0.6437	0.9322	0.7755
H255	0.5346	1.0526	0.7757
				H257	-0.1244	0.7021	0.6547
H258	0.0245	0.7713	0.6086
				H259	0.1125	0.9882	0.6931
H260	-0.0412	0.9702	0.6791
				H261	0.1221	0.8814	0.7786
H262	-0.0061	0.9737	0.7872
				H263	-0.1266	0.7806	0.7533
H264	0.0003	0.6937	0.7698
				H265	-0.4482	-0.1282	0.3648
H267	-0.2055	-0.3921	0.3406
				H268	-0.3541	-0.3919	0.3515
H269	-0.2776	-0.1726	0.4197
				H270	-0.4835	-0.2219	0.2664
H271	-0.3651	-0.1301	0.2520
				H272	-0.2450	-0.3036	0.2505
H273	-0.3737	-0.4037	0.2429
				H275	0.2126	-0.1876	0.4150
H276	0.0471	-0.1254	0.3631
				H277	0.2819	-0.4071	0.3370
H278	0.1354	-0.4038	0.3515
				H279	0.2344	-0.3225	0.2459
H280	0.1069	-0.4219	0.2420
				H281	-0.0019	-0.2405	0.2681
H282	0.1098	-0.1545	0.2449
				H4O	-0.0494	0.0591	0.3246
H5O	0.2411	0.2106	0.4570
				H3O	0.1948	0.4772	0.5288
H9O	-0.0304	0.7367	0.4370
				H91O	0.4288	0.7378	0.4387
H89O	0.5701	0.3737	0.5359
				H87O	0.7447	0.1972	0.4579
H96O	0.4441	0.0598	0.3281
				H32O	0.7685	0.5088	0.6888
H30	1.0223	0.3832	0.5666
				H34	0.9788	0.0971	0.5019
H35O	0.7109	-0.1813	0.5836
				H60O	0.4380	0.1072	0.4941
H61	0.5322	0.4602	0.6402

Atom	X	Y	Z
				H59O	0.2991	0.5325	0.6984
H76	0.0757	-0.1438	0.5063
				H29N	-0.3483	-0.0232	0.3484
H40N	0.1520	-0.0373	0.3393
				H15N	0.3746	0.7405	0.6748
H23N	-0.0113	0.6018	0.6728
				H946	0.4919	-0.0828	0.4471
H1W	0.2742	0.6734	0.5848
				H846	0.6016	-0.0665	0.5089
H2W	0.3486	0.6479	0.5212

Practicality and combined utilization

A. practicality

Compound of the present invention has the activity of the inhibitor as the sodium dependent glucose translocator be found in mammiferous intestines and kidney.Preferably, compound of the present invention is the selective depressant of kidney SGLT2 activity, therefore may be used for the treatment of relevant disease active in SGLT2 or disorder.

Therefore, compound of the present invention can be given Mammals, preferred people, be used for the treatment of multiple symptom and disorder, it includes but not limited to treatment or delays following advancing of disease or outbreak: diabetes (comprise I type and II type, glucose intolerance (impairedglucosetolerance), insulin resistance, with diabetic complication as ephrosis, retinopathy, neuropathy and cataract), hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipemia, the blood level of free fatty acids or glycerine raises, hyperlipidaemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension.Compound of the present invention also may be used for the blood level increasing high-density lipoprotein (HDL) (HDL).

In addition, utilizing compound of the present invention, can treating as being specified in Johannsson, in J.Clin.Endocrinol.Metab., 82,727-34 (1997), that be referred to as " X syndromes " or metabolic syndrome symptom, disease and illness.

Crystalline compounds (S)-PG (SC-3) (Ia), (R)-PG (SD-3) (Ib), SA-1 (Ic), SB-1 (Id), SB-2 (Ie), 1:2L-proline Complex crystalline form 3 (Ih), 1:1L-proline Complex crystalline form 6 (Ii), 1:1L-proline(Pro) semihydrate mixture form H .5-2 (Ij) and 1:1.3L-phenylalanine mixture crystalline form 2 (Ik) are to be disclosed in United States Patent (USP) the 6th, 515, formulation in No. 117 and dosage give, and it is disclosed in this and is all introduced by reference.

B. combined utilization

The present invention comprises pharmaceutical composition within the scope of it, this pharmaceutical composition comprises independent or combines with pharmaceutical carrier or thinner, as effective constituent, the formula I of significant quantity in treatment, it comprises (S)-PG (crystalline form SC-3, Ia), (R)-PG (crystalline form SD-3, Ib), SA-1 (Ic), SB-1 (Id), SB-2 (Ie), 1:2L-proline Complex crystalline form 3 (Ih), 1:1L-proline Complex crystalline form 6 (Ii), 1:1L-proline(Pro) semihydrate mixture form H .5-2 (Ij) and 1:1.3L-phenylalanine mixture crystalline form 2 (Ik).Optionally, compound of the present invention with independent treatment use, or can be applied with one or more other therapeutic agent.

Be suitable for the known treatment agent included but not limited to compound combined utilization of the present invention other " therapeutical agent (one or more) " for above-mentioned treatment for diseases, it comprises: antidiabetic; Antihyperglycemic agents; Hypolipidemic/lipid lowering agent; Anti-obesity medicine; Hypotensive agent; And appetite-inhibiting agent.

Biguanide class is comprised (such as with the example of the suitable antidiabetic of the compounds of this invention combined utilization, N1,N1-Dimethylbiguanide or phenformin), alpha-glucosidase inhibitors (such as, acarbose or miglitol), insulin type (comprising insulin secretagogue or euglycemic agent), meglitinide (such as, repaglinide), the associating of sulfonylurea (such as, glimepiride, U26452, gliclazide, P-607 and Glipizide), biguanide/U26452 (such as ), other agonist of thiazolidinediones (such as troglitazone, rosiglitazone and pyrrole lattice grin ketone), the inhibitor (aP2) of PPAR-alfa agonists, PPAR-gamma agonist, PPAR α/γ dual agonists, glycogen phosphorylase inhibitors, fatty acid binding protein, glucagon-like-peptide-1 (GLP-1) or GLP-1 acceptor and DPP IV (DPP4) inhibitor.

Believe, the hyperglycemia effect that the combined utilization of formula I and at least one or other antidiabetic drug multiple produces can obtainable effect by being greater than each being used alone in these medicines, and is greater than the additive anti-hyperglycemic effect of the associating that these medicines produce.

The MCC-555 that other suitable thiazolidinediones comprises Mitsubisshi (is disclosed in United States Patent (USP) the 5th, 594, No. 016), Glaxo-Wellcome ' sfaraglitazar (GI-262570), englitazone (CP-68722, or darglitazone (CP-86325 Pfizer), Pfizer, isaglitazone (MIT/J & J), Rui Geliezha (reglitazar) (JTT-501) (JPNT/P & U), RIVOGLITAZONE (rivoglitazone) (R-119702) (Sankyo/WL), liraglutide (NN-2344) (Dr.Reddy/NN) or (Z)-1, two-the 4-[(3 of 4-, 5-dioxy-1, 2, 4- bisoxazoline (oxadiazolidin)-2-base-methyl)] phenoxy group but-2-ene (YM-440, Yamanouchi).

PPAR-alfa agonists, the example of PPAR-gamma agonist and PPAR α/γ dual agonists comprises Mo Geta azoles (muraglitazar), peliglitazar, for Ge Liezha (tesaglitazar) AR-HO39242Astra/Zeneca, GW-501516 (Glaxo-Wellcome), KRP297 (KyorinMerck) and " ANovelInsulinSensitizerActsAsaColigandforPeroxisomeProli feration – ActivatedReceptorAlpha (PPARalpha) andPPARgamma.EffectonPPARalphaActivationonAbnormalLipidM etabolisminLiverofZuckerFattyRats " by Murakami etc., Diabetes, 47, 1841-1847 (1998), at WO01/21602 and United States Patent (USP) 6, 653, disclosed those in 314, their disclosure is introduced into by reference at this, utilize wherein proposed dosage, preferably use in this article and be designated as those compounds preferred.

Suitable aP2 inhibitor comprises the U.S. Application Serial the 09/391st being that on September 7th, 1999 proposes, No. 053 and on March 6th, 2000 propose U.S. Application Serial the 09/519th, disclosed in No. 079 those, adopt this article propose dosage.

Suitable DPP4 inhibitor comprises and is disclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), those in WO99/61431 (PROBIODRUG), as by Hughes etc., Biochemistry, 38 (36), 11597-11603, NVP-DPP728A disclosed in 1999 (1-[[[2-[(5-cyanopyridine-2-base) is amino] ethyl] is amino] ethanoyl]-2-cyano group-(S)-tetramethyleneimine) (Novartis), TSL-225 (tryptophyl-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid is (by Yamada etc., Bioorg. & Med.Chem.Lett.8 (1998) 1537-1540 is open)), as by Ashworth etc., Bioorg. & Med.Chem.Lett., Vol.6, No.22, the disclosed 2-Cyanopyrolidine of pp.1163-1166and2745-2748 (1996) and 4-Cyanopyrolidine, be disclosed in U.S. Application Serial the 10/899th, No. 641, WO01/68603 and United States Patent (USP) 6, 395, compound in 767, adopt the dosage proposed in above-mentioned reference paper.

Other suitable meglitinide (meglitinides) comprises nateglinide (Novartis) or KAD1229 (PF/Kissei).

Glucagon-like-peptide-1 (GLP-1) is comprised with the example of the suitable antihyperglycemic agents of the compounds of this invention combined utilization, as GLP-1 (1-36) acid amides, GLP-1 (7-36) acid amides, GLP-1 (7-37) (as be disclosed in United States Patent (USP) the 5th, 614, in No. 492), and Exenatide (exenatide) (Amylin/Lilly), LY-315902 (Lilly), MK-0431 (Merck), liraglutide (NovoNordisk), ZP-10 (ZealandPharmaceuticalsA/S), CJC-1131 (ConjuchemInc) and the compound be disclosed in WO03/033671.

MTP inhibitor, HMGCoA reductase inhibitor, inhibitor for squalene synthetic enzyme, fiber acid derivative (fibricacidderivatives), ACAT inhibitor, lipoxygenase inhibitor, cholesterol absorption inhibitor, ileum Na is comprised with the example of the suitable hypolipidemic/lipid lowering agent of compound combined utilization of the present invention ⁺in/bile acid cotransporter inhibitor, ldl receptor activity, adjustment, cholic acid intercalating agent, cetp are (such as, CETP inhibitor, as torcetrapib (CP-529414, Pfizer) and JTT-705 (AkrosPharma)), one or more in PPAR agonist (as above-mentioned) and/or nicotinic acid and derivative thereof.

United States Patent (USP) the 5th is disclosed in, 595,872, United States Patent (USP) the 5th as above-mentioned operable MTP inhibitor comprises, 739,135, United States Patent (USP) the 5th, 712,279, United States Patent (USP) the 5th, 760,246, United States Patent (USP) the 5th, 827,875, United States Patent (USP) the 5th, 885,983 and United States Patent (USP) the 5th, those inhibitor in 962, No. 440.

Can comprise as being disclosed in United States Patent (USP) the 3rd with the HMGCoA reductase inhibitor of one or more formula I combined utilization, the U.S.A in 983, No. 140 cuts down spit of fland and related compound; As being disclosed in United States Patent (USP) the 4th, the lovastatin (Mevacor (mevinolin)) in 231, No. 938 and related compound; As being disclosed in United States Patent (USP) the 4th, the Pravastatin in 346, No. 227 and related compound; As being disclosed in United States Patent (USP) the 4th, 448,784 and 4,450, the Simvastatin in No. 171 and related compound.Can include, but are not limited to be disclosed in United States Patent (USP) the 5th by other HMGCoA reductase inhibitor as used herein, the fluvastatin in 354, No. 772; As being disclosed in United States Patent (USP) the 5th, 006,530 and 5,177, the simvastatin in No. 080; As being disclosed in United States Patent (USP) the 4th, 681,893,5,273,995,5,385,929 and 5, the Zarator in 686, No. 104; As being disclosed in United States Patent (USP) the 5th, the atavastatin (itavastatin (nisvastatin) (NK-104) of Nissan/Sankyo) in 011, No. 930; As being disclosed in United States Patent (USP) the 5th, the visastatin (Shionogi-Astra/Zeneca (ZD-4522)) in 260, No. 440, and be disclosed in United States Patent (USP) the 5th, the relevant statins in 753, No. 675; As being disclosed in United States Patent (USP) the 4th, the pyrazole analogs of mevalonolactone (mevalonolactone) derivative in 613, No. 610; As being disclosed in the indenes analogue of the mevalonolactone derivative in PCT application WO86/03488; As being disclosed in United States Patent (USP) the 4th, and 6-in 647, No. 576 [2-(replacement-pyrroles-1-base)-alkyl) pyran-2-one and derivative thereof; SC-45355 (glutaric acid derivatives that a kind of 3-replaces) the dichloro-acetate of Searle; As being disclosed in the imidazoles analogue of the mevalonolactone derivative in No. WO86/07054, PCT application; As being disclosed in French Patent the 2nd, the 3-carboxyl-2-hydroxy-propane-phosphonate derivative in 596, No. 393; As being disclosed in 2,3-disubstituted pyrroles, furans and the thiophene derivant in No. 0221025th, european patent application; As being disclosed in United States Patent (USP) the 4th, the naphthyl analogue of the mevalonolactone derivative in 686, No. 237; As being disclosed in United States Patent (USP) the 4th, the octahydro naphthalene in 499, No. 289; As being disclosed in the keto analog (lovastatin) of the Mevacor (lovastatin) in No. 0142146A2nd, european patent application; Be such as disclosed in United States Patent (USP) the 5th, 506,219 and 5,691, the quinoline in No. 322 and pyridine derivate.

Preferred hypolipidemic is Pravastatin, lovastatin, Simvastatin, Zarator, fluvastatin, simvastatin, atavastatin and ZD-4522.

In addition, for suppressing the phosphinic compounds of HMGCoA reductase enzyme, those as being disclosed in GB2205837, are suitable for and compound combined utilization of the present invention.

Be suitable for inhibitor for squalene synthetic enzyme as used herein to comprise, but be not limited to, be disclosed in United States Patent (USP) the 5th, 712, α-phosphono-sulfonate in No. 396, by Biller etc., J.Med.Chem., 1988, Vol.31, No.10, pp.1869-1871 those disclosed compound, comprise isoprenoid (phosphinyl-methyl) phosphonic acid ester, and other known inhibitor for squalene synthetic enzyme, such as, as at United States Patent (USP) the 4th, 871, 721 and 4, 924, No. 024 and at Biller, S.A., Neuenschwander, K., Ponpipom, M.M., andPoulter, C.D., CurrentPharmaceuticalDesign, 2, disclosed in 1-40 (1996).

In addition, be suitable for other inhibitor for squalene synthetic enzyme as used herein and comprise by P.OrtizdeMontellano etc., J.Med.Chem., tetra-sodium terpenoid disclosed in 1977,20,243-249; As by Corey and Volante, J.Am.Chem.Soc., farnesyl diphosphate analog disclosed in 1976,98,1291-1293 awith tetra-sodium presqualene (PSQ-PP) analogue; By McClard, R.W. etc., J.A.C.S., 1987,109,5544 report phosphinylphosphonates and by Capson, T.L., Ph.D. Dissertation, June, 1987, Dept.Med.Chem.UofUtah, Abstract, TableofContents, pp16,17, the cyclopropane of 40-43,48-51, Summary report.

Fenofibrate, gemfibrozil, clofibrate, benzene zakat, Win-35833, S-8527 and analogue can be comprised with the fiber acid derivative of formula I conbined usage, probucol, and related compound, as being disclosed in United States Patent (USP) the 3rd, in 674, No. 836, probucol and gemfibrozil are preferred, cholic acid intercalating agent, as Colestyramine, colestipol and DEAE-Sephadex ( ), and lipostabil (Rhone-Poulenc), EisaiE-5050 (ethanolamine derivant that N-replaces), imanixil (HOE-402), orlistat (tetrahydrolipstatin, THL), istigmastanyl phosphorylcholine (istigmastanylphos-phorylcholine, SPC, Roche), Tanabe Seiyoku (TanabeSeiyoku), AjinomotoAJ-814 (azulene derivatives), AC-233 (Sumitomo), Sandoz58-035, AmericanCyanamidCL-277,082 and CL-283,546 (2-substituted carbamide derivatives), nicotinic acid, acipimox, Acifran, Liu Suanyan NEOMYCIN SULPHATE, para-aminosalicylic acid, acetylsalicylic acid, as being disclosed in United States Patent (USP) the 4th, poly-(diallyl methylamine) derivative in 759, No. 923, as being disclosed in United States Patent (USP) the 4th, the quaternary amine in 027, No. 009 gathers (chloride) and ionene, and the medicine of other known reduction serum cholesterol.

Can comprise with the ACAT inhibitor of formula I conbined usage and be disclosed in DrugsoftheFuture24,9-15 (1999), in (Avasimibe), " TheACATinhibitor, Cl-1011iseffectiveinthepreventionandregressionofaorticfa ttystreakareainhamsters ", Nicolosietal., Atherosclerosis (Shannon, Irel). (1998), 137 (1), 77-85, " ThepharmacologicalprofileofFCE27677:anovelACATinhibitorw ithpotenthypolipidemicactivitymediatedbyselectivesuppres sionofthehepaticsecretionofApoB100-containinglipoprotein ", Ghiselli, Giancarlo, Cardiovasc.DrugRev. (1998), 16 (1), 16-30, " RP73163:abioavailablealkylsulfinyl-diphenylimidazoleACAT inhibitor ", Smith, C., etal, Bioorg.Med.Chem.Lett. (1996), 6 (1), 47-50, " ACATinhibitors:physiologicmechanismsforhypolipidemicanda nti-atheroscleroticactivitiesinexperimentalanimals ", Krauseetal, Editor (s): Ruffolo, RobertR., Jr., Hollinger, MannfredA., Inflammation:MediatorsPathways (1995), 173-98, Publisher:CRC, BocaRaton, Fla., " ACATinhibitors:potentialanti-atheroscleroticagents ", Sliskovicetal., Curr.Med.Chem. (1994), 1 (3), 204-25, " Inhibitorsofacyl-CoA:cholesterolO-acyltransferase (ACAT) ashypocholesterolemicagents.6.Thefirstwater-solubleACATi nhibitorwithlipid-regulatingactivity.Inhibitorsofacyl-Co A:cholesterolacyltransferase (ACAT) .7.DevelopmentofaseriesofsubstitutedN-phenyl-N '-[(1-phenylcyclopentyl) methyl] ureaswithenhancedhypocholesterolemicactivity ", Stoutetal., Chemtracts:Org.Chem. (1995), 8 (6), 359-62, those inhibitor in orTS-962 (TaishoPharmaceuticalCo.Ltd).

Hypolipidemic can be the upper adjustment of LD2 receptor active, as 1 (3H)-isobenzofuranone, 3-(13-hydroxyl-10-oxygen tetradecyl)-5,7-dimethoxy-(MD-700, TaishoPharmaceuticalCo.Ltd) and cholestane-3-alcohol, 4-(2-propenyl)-(3a, 4a, 5a)-(LY295427, EliLilly).

Comprise SCH48461 (Schering-Plough) with the example of the suitable cholesterol absorption inhibitor of compound conbined usage of the present invention and be disclosed in Atherosclerosis115,45-63 (1995) and J.Med.Chem.41, those inhibitor in 973 (1998).

With the suitable ileum Na of compound conbined usage of the present invention ⁺the cotransport example of protein inhibitor of/cholic acid comprises and is disclosed in DrugsoftheFuture, the compound in 24,425-430 (1999).

15-lipoxidase (15-LO) inhibitor can be comprised with the lipoxygenase inhibitor of formula I conbined usage, such as, as being disclosed in the benzimidizole derivatives in WO97/12615, as being disclosed in the 15-LO inhibitor in WO97/12613, as being disclosed in isothiazolones (isothiazolones) in WO96/38144 and as by " Attenuationofdiet-inducedatherosclerosisinrabbitswithahi ghlyselective15-lipoxygenaseinhibitorlackingsignificanta ntioxidantproperties " such as Sendobry, Brit.J.Pharmacology (1997) 120, 1199-1206 and Cornicelli etc., " 15-LipoxygenaseanditsInhibition:ANovelTherapeuticTargetf orVascularDisease ", CurrentPharmaceuticalDesign, 1999, 5, the inhibitor of 15-LO disclosed in 11-20.

Beta adrenergic blocker, calcium channel blocker (L-type and T-type can be comprised with the example of the suitable antihypertensive drug of the compounds of this invention conbined usage, such as, diltiazem verapamil, nifedipine, amlodipine and mybefradil), diuretic(s) (such as, chlorothiazide, hydrochlorothiazide, flumethiazide, hydrogen fluorine first thiophene, Hydrex, methyl chlorothiazide, trichlormethiazide, polythiazide, benzene thiazine, Uregit tricrynafen, chlorthalidone, Furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitor, ACE inhibitor (such as, captopril, zofenopril, fosinopril, Enalapril, ceranopril, cilazopril, delapril, perindopril, quinapril, Ramipril, lisinopril), AT-1 receptor antagonist (such as, losartan, Irb, valsartan), ET receptor antagonist (such as, sitaxsentan, atrsentan and be disclosed in United States Patent (USP) the 5th, 612,359 and 6,043, the compound in No. 265), dual ET/AII antagonist (such as, being disclosed in the compound in WO00/01389), neutral endopeptidase ((NEP) inhibitor, vasopeptidase inhibitors (dual NEP-ACE inhibitor) (such as omapatrilat and gemopatrilat) and nitrate.

'beta '3 adrenergic agonists, lipase inhibitor, thrombotonin (and Dopamine HCL) reuptake inhibitor, thyroid receptor beta medicine, 5HT2C agonist (as ArenaAPD-356) is comprised with the example of the suitable antiadipositas drug of the compounds of this invention conbined usage, MCHR1 antagonist is as SynapticSNAP-7941 and TakedaT-226926, novel melanocortin receptor (MC4R) agonist, melanin concentrating hormone receptor (MCHR) antagonist (as SynapticSNAP-7941 and TakedaT-226926), galanin receptors instrumentality, orexin (orexin) antagonist, CCK agonist, NPY1 or NPY5 antagonist, NPY2 and NPY4 instrumentality, corticotropin releasing factor agonist, Histamine Receptors-3 (H3) instrumentality, 11-β-HSD-1 inhibitor, adinopectin receptor modulators, monoamine reuptake inhibitors or releasing agent, ciliary neurotrophic factor (CNTF, as Regeneron ), BDNF (neurotrophic factor brain derived greatly), carbachol (leptin) and carbachol receptor modulators, cannaboid-1 receptor antagonist (as SR-141716 (Sanofi) or SLV-319 (Solvay)) and/or anoretics.

Can optionally and the 'beta '3 adrenergic agonists of the compounds of this invention conbined usage comprise AJ9677 (Takeda/Dainippon), L750355 (Merck) or CP331648 (Pfizer), or other known β 3 agonist, as being disclosed in United States Patent (USP) the 5th, 541,204,5,770,615,5,491,134,5,776,983 and 5, those in 488, No. 064.

Can optionally and the example of the lipase inhibitor of the compounds of this invention conbined usage comprise orlistat or ATL-962 (Alizyme).

Can optionally and the thrombotonin of the compounds of this invention conbined usage (and Dopamine HCL) reuptake inhibitor (or serotonin receptor agonist) can be BVT-933 (Biovitrum), sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron).

Can optionally and the example of the thyroid receptor beta compound of the compounds of this invention conbined usage comprise ligands for thyroid receptor, as being disclosed in those compounds in WO97/21993 (U.CalSF), WO99/00353 (KaroBio) and WO00/039077 (KaroBio).

Can optionally and the monoamine reuptake inhibitors of the compounds of this invention conbined usage comprise S-768, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, Sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, Dextrofenfluramine, phentermine, Phenylpropanolamine or Mazindol.

Can optionally and the anoretics of the compounds of this invention conbined usage comprise topiramate (Johnson & Johnson), Dextrofenfluramine, phentermine, Phenylpropanolamine or Mazindol.

Above-mentioned patent and patent application are incorporated to herein by reference.

Other therapeutical agent above-mentioned, when with compound conbined usage of the present invention, such as, can use with those amounts indicated in Physicians ' DeskReference, as above propose that in patent or those skilled in the art measure in addition.

biological data

Formula I is selectivity SGLT2 inhibitor (K _i=1.1nM).

For Compound I a, crystalline structure (S)-PG (crystalline form SC-3) and known SGLT2 inhibitor, in 24 hours, the comparative data of urinating glucose excretion for people is shown in Table 19.

Table 19

Compound I a, crystalline structure (S)-PG (crystalline form SC-3), in 14 days, reduce the fasting plasma glucose level in type ii diabetes individuality (47), as in table 20 in dose-dependent mode.

Table 20

With placebo compared with---it is the minimizing of 1.1wt%---, in during 12 weeks, Compound I a crystalline structure (S)-PG (crystalline form SC-3) achieves the minimizing of 2.5%-3.0% by weight in individual (n=389, BMI>30).Equally, systolic pressure is caused to reduce 2-4mm with the treatment that Compound I a carries out.

Claims

1. the crystalline structure of the Isosorbide-5-Nitrae-butine-diol solvent compound of formula If

It is characterized by one or more substantially equaling following unit cell parameters:

Unit cell dimension

α ⁰＝–

β ⁰＝102.96(1)

γ ⁰＝–

Spacer C2

Molecule/asymmetric cell 1

The measurement of wherein said crystalline structure is carried out at 25 DEG C, and it is characterized by the fractional atomic coordinates substantially as listed in table 12;

Or

Unit cell dimension

α ⁰＝–

β ⁰＝102.924(7)

γ ⁰＝–

Spacer C2

Molecule/asymmetric cell 1

The measurement of wherein said crystalline structure is carried out at-50 DEG C, or has and the proton N MR showing substantially similar peak position listed in 2A.

2. prepare the method as crystallization Isosorbide-5-Nitrae-butine-diol solvent chelate compound If claimed in claim 1,

It comprises:

A) by the compd B of following structure

Mix with toluene and ethyl acetate;

B) described mixture is heated at the temperature within the scope of about 50 DEG C to about 70 DEG C;

C) Isosorbide-5-Nitrae-butine-glycol is added;

D) described mixture is heated, until described glycol dissolves;

E) in solution, add the crystal seed of Compound I f; With

F) cool described mixture, form the crystal of Compound I f.

3. utilize non-cryogenic method, be prepared as follows the method for the compound of structure,

It comprises the following steps in successive processes:

A) at-30 DEG C to about 20 DEG C, lithiation reagent is used, the aromatic reactants E of the following structure of lithiumation,

Form the lithiated anion G of following structure

B) at-30 DEG C to about-10 DEG C, the reactant D of the following structure of coupling above-mentioned lithiated anion kind G and carbonyl substituted,

Form the glucosides H of following structure

C) acid treatment is used in step b) the middle glucosides H prepared, form protodesilyation hemiacetal H '

It is converted into compd B

D) in toluene/EtOAc, with 2-butyne-Isosorbide-5-Nitrae-glycol J process from step c) described compd B, form the crystal of Compound I f.

4. method according to claim 3, wherein said lithiation step carries out at the temperature of about-17 DEG C to about-10 DEG C.

5. method according to claim 4, wherein said lithiation reagent is selected from n-BuLi, s-BuLi and t-BuLi.