CN101468976B

CN101468976B - Crystal morphology of SGLT2 inhibitor and preparation thereof

Info

Publication number: CN101468976B
Application number: CN2007103004199A
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: Bristol Myers Squibb Co
Current assignee: AstraZeneca AB
Priority date: 2007-12-27
Filing date: 2007-12-27
Publication date: 2013-11-20
Anticipated expiration: 2027-12-27
Also published as: CN101468976A; CN103319445B; CN103319445A

Abstract

The invention relates to a crystal structure for an SGLT2 inhibitor and a preparation method thereof. The invention relates to a physical crystal structure for a compound in a formula I, wherein R<1>, R<2>, R<2a>, R<3> and R<4> are defined as the context. The invention in particular relates to a medicine composition containing the structure of the compound I or II, the preparation method, intermediate for preparing the structure, and a method for treating diseases such as diabetes by using the structure.

Description

Crystalline structure of SGLT2 inhibitor and preparation method thereof

Technical field

The present invention relates to the free acid of SGLT2 inhibitor polymorphic crystalline structure, its pharmaceutical composition, prepare the method for this type of crystalline structure and with the method for its treatment disease such 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 due to excessive Hepatic glucose production and periphery insulin resistance, but its basic reason it be unclear that.To the Sustainable Control of the plasma glucose levels in diabetic subject's body, can offset development and the β cellular degeneration of the diabetic complication that sees terminal illness.

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

In the situation that there is no significant gastrointestinal side-effect; in the diabetic subject, the excretion of glucose in urinating by increase, suppress to make plasma glucose normalizing to the selectivity of SGLT2; increase thus the susceptibility of Regular Insulin, 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 compound:

The pharmaceutical composition that contains the crystalline structure of Compound I, it comprise crystalline form be SC-3 (S)-propylene glycol ((S)-PG) structure I a,

Compound I a;

Crystalline form be SD-3's (R)-propylene glycol ((R)-PG) structure I b,

Compounds ib;

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

Compound I c;

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

Ethylene glycol

Compound I d

Crystalline form SB-1; With

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

Ethylene glycol

Compound I e

Crystalline form SB-2; And

The method for preparing these crystalline structure;

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

Compound I h;

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

Compound I i;

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

With

Compound I j

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

Compound I k; And

Use as treat 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 I I the method for diabetes and relative disease.

Form is that the formula I compound of noncrystalline solid is disclosed in United States Patent (USP) the 6th, and in 515, No. 117, its disclosure is by reference in these whole introducings.

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

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

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

Still in another aspect of this invention, also provide the Ig of the crystalline compounds 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 preparing the intermediate of formula I crystalline compounds of the present invention.

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

Compound I a

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

Compd A;

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

Compound I,

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

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

(R)-propylene glycol

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

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

Crystal Ia

(S)-PG(SC-3) ，

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

To remove methoxy group, by following, undertaken: with reductive agent such as triethyl silicane (triethylsilylhydride), and activating group---it is Lewis acid such as BF ₃Et ₂O or BF ₃2CH ₃COOH, be preferably BF ₃2CH ₃COOH, and organic solvent such as CH ₃CN, and additional water, process compd B (as the U. S. application sequence the 10/745th of submitting on December 23rd, 2003, described in the embodiment 17 of No. 075 and prepare), or process for example dimethanol solvate Ig or 1 of recrystallisation solvent compound, 4-butine-diol solvent compound (If), isolate the compound of structure I

And under the existence as this kind solvent of t-butyl methyl ether, with (S)-propane diols, optional with Compound I a ((S)-P crystal seed (v), process Compound I, to form the Compound I a (magma of (S)-PG) (crystal slurry), and isolate Compound I a ((S)-PG).

Aforesaid method of the present invention is single tank operation, and its generation by intermediate is kept to minimum, and this has caused the yield of final crystalline compounds Ia to improve and priority.

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

The compound of formula B (amorphous) is disclosed in the U. S. application sequence the 10/745th that proposes 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 for preparing list-EtOH-dihydrate (ethanol or EtOH structure) crystalline form SA-1, it has structure I c,

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

By preferably by being heated to boiling, compd A being dissolved in ethanol, and form the oily product of Compound I, can prepare Compound I.

In another embodiment of the invention, the method for the ethylene glycol bisthioglycolate hydrate structure that is used to form formula Id is provided,

Ethylene glycol

Crystalline form SB-1 Id

The method comprises the steps: preferably under heating, Compound I to be dissolved in and to contain in water glycol,

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

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

Ethylene glycol

Crystalline form SB-2 Ie

The method comprises the steps:

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

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

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

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

It comprises the steps: basic cpd B

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

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 in, the method for preparing crystallization dimethanol solvate Ig is provided,

Wherein said basic cpd B

With methyl alcohol, process, form crystallization dimethanol solvate Ig.

Be still further according to the present invention, method for the preparation of crystallization dimethanol solvate Ig is provided, wherein said basic cpd B is dissolved in the mixture of methanol/toluene, perhaps be dissolved in the mixture of methanol/toluene/heptane, perhaps 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 structure be Ih, with the preparation method of 1: 2 composite crystal (crystalline form 3) of L-PROLINE,

Compound I h

Described method comprises the steps: to provide the Compound I of following structure,

Compound I,

Form the solution of L-PROLINE in water neutralized alcohol solvent such as methyl alcohol, ethanol or Virahol, this solution is heated to 70 to the temperature in about 95 ℃ of scopes, in alcoholic solvent such as methyl alcohol, ethanol or Virahol, with the L-PROLINE solution (containing 2 times of mole numbers of the L-PROLINE to Compound I) of heating, process Compound I, 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, with the method for the compound crystalline compounds (crystalline form 6) of L-PROLINE 1: 1,

Compound I i

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

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

Compound I j,

The method comprises the steps: to provide seed crystal (the structure I i with 1: 1 mixture of L-PROLINE, crystalline form 6), by this crystalline form, be that the cooling solution (10 to-25 ℃) in alcohol/water solvent mixes with L-PROLINE and Compound I for 6 seed crystal Ii, and the gained mixture is cooling at the temperature of approximately-10 to-25 ℃, 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, with the method for 1: 1 crystalline composites of L-Phe,

Compound I k

The method comprises the steps: to form the solution of L-Phe in water, by this solution approximately 70 to approximately heating under 85 ℃, mix L-Phe solution and Compound I, gained solution is heated to approximately 75 to approximately 85 ℃, 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 ,-OCHE ₂,-OCE ₃, ,-SR ^5aOr halogen;

R ³And R ⁴Independent is hydrogen, OH, OR ^5b, alkyl, alkenyl, alkynyl, cycloalkyl, CE 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 independent of in ring, containing 1 to 4 heteroatomic 5,6 or 7 yuan of heterocycle, and described heteroatoms is N, O, S, SO and/or SO ₂, or R ³And R ⁴Together with carbon that they connect, form 5, the 6 or 7 yuan of carbocyclic rings or the heterocycle that condense, 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 ^6aTogether with nitrogen that they connect, form 5,6 or 7 yuan of heterocycles that condense, it contains 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, the method that the pharmaceutical composition of the crystalline structure that contains Compound I I also is provided and has prepared this kind crystalline structure II.

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

It is also referred to as (R)-propylene glycol ((R)-PG) crystalline texture III, 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 independent of in ring, containing 1 to 4 heteroatomic 5,6 or 7 yuan of heterocycle, and described heteroatoms is N, O, S, SO and/or SO ₂, or R ³And R ⁴Together with carbon that they connect, form 5, the 6 or 7 yuan of carbocyclic rings or the heterocycle that condense, it contains 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, the method that the pharmaceutical composition of the crystalline structure that contains compound III also is provided and has prepared this kind crystalline structure III.

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

Compound C,

R wherein ¹, R ², R ^2a, R3 and R4 as mentioned above;

With alcoholic solvent such as methyl alcohol and aqueous bases such as sodium hydroxide, and essential words also have water, under inert atmosphere and high temperature, process Compound C, form the following Compound D of structure,

Compound D,

And with organic solvent such as methyl tertiary butyl ether, alkyl acetate such as ethyl acetate, methyl acetate, isopropyl acetate or butylacetate, and (S)-propylene glycol is processed the reaction mixture that contains Compound D, choose wantonly the crystal seed of (S)-PG Compound I I is added in this mixture, form (S)-PG Compound I I.

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

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

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

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

(it openly is the U. S. application sequence the 10/745th that on December 23rd, 2003 proposed, No. 075), to remove methoxy group, this reduction is by using reductive agent such as triethyl silicane, and activating group---it is Lewis acid such as BF ₃Et ₂O, and organic solvent such as CH ₃CN, and water, process compd E and implement; Isolate the compound of structure D, and under solvent such as t-butyl methyl ether existence, with (S)-propylene glycol, optional (crystal seed of (S)-PG) is processed Compound D, the formation Compound I I (magma of (S)-PG) with Compound I I; And isolate Compound I I ((S)-PG).

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

The accompanying drawing explanation

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

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

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

Fig. 3 has shown (S)-PG crystalline texture Ia SC-3 crystalline form ¹³C NMR CPMAS spectrum.

Fig. 4 has shown Ib's (R)-PG crystalline texture ¹³C NMR CPMAS spectrum.

Fig. 5 has shown thermogravimetric analysis (TGA) curve of Ia's (S)-PG crystalline texture---SC-3 crystalline form---.

Fig. 6 has shown thermogravimetric analysis (TGA) curve of Ib's (R)-PG crystalline texture---SD-3 crystalline form---.

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

Fig. 8 has shown differential scanning calorimetry (DSC) differential thermogram of Ib's (R)-PG crystalline texture.

Fig. 9 has shown 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 has shown 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 ℃; Heat absorption for the second time under 250 ℃ is the decomposition due to compound.

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

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

Figure 13 has shown 1: 2L-proline(Pro) complex crystallization structure I h---crystalline form 3, N-1---calculating (at-40 ℃ of Imitatings) x-ray diffractogram of powder case, mixing (hybrid) (under room temperature) x-ray diffractogram of powder case and observation (test at room temperature) x-ray diffractogram of powder case.

Figure 14 has shown 1: 1L-proline(Pro) complex crystallization structure I i---crystalline form 6, N-1---calculating (at-40 ℃ of Imitatings) x-ray diffractogram of powder case, mixing (under room temperature) x-ray diffractogram of powder case and observation (test at room temperature) x-ray diffractogram of powder case.

Figure 15 has shown 1: the calculating of 1L-proline(Pro) semihydrate crystalline texture Ij---form H .5-2---(at-40 ℃ of Imitatings) x-ray diffractogram of powder case, mixing (under room temperature) x-ray diffractogram of powder case and observation (test at room temperature) x-ray diffractogram of powder case.

Figure 16 has shown 1 of Ih: 2L-proline(Pro) complex crystallization structure---crystalline form 3, N-1---thermogravimetric analysis (TGA) curve.

Figure 17 has shown 1 of Ii: 1L-proline(Pro) complex crystallization structure---crystalline form 6, N-1---thermogravimetric analysis (TGA) curve.

Figure 18 has shown 1: thermogravimetric analysis (TGA) curve of 1L-proline(Pro) semihydrate crystalline texture Ij---form H .5-2---.

Figure 19 has shown 1: 2L-proline(Pro) complex crystallization structure I h-crystalline form 3, N-1---differential scanning calorimetry (DSC) differential thermogram.

Figure 20 has shown 1: 1L-proline(Pro) complex crystallization structure I i-crystalline form 6, N-1---differential scanning calorimetry (DSC) differential thermogram.

Figure 21 has shown 1: differential scanning calorimetry (DSC) differential thermogram of 1L-proline(Pro) semihydrate crystalline texture Ij---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 as the Compound I of novel substance at least partly.

As used herein, term " pharmaceutically acceptable (pharmaceutically acceptable) " refers to such compound, material, composition and/or formulation, in the scope of rational medical judgment, they are suitable for contacting with the tissue of humans and animals, and the problem complication that does not have overdosage toxicity, stimulation, anaphylaxis or other and rational pros and cons ratio to 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 (substantially pure) " refers to that compound has the approximately purity more than 90%, for example comprises approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99% and approximately 100%.

Compound is called as heteromorphism with the ability that the different crystal structure exists.As used herein, but " polymorphic form " refers to have identical chemical constitution the different crystal shape of spatial disposition that forms molecule, atom and/or the ion of crystal.Although polymorphic form has identical chemical constitution, yet they are different on accumulation and 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 change, the relative stability between two solid phases remains unchanged.On the contrary, in the enantiotrophy system, exist transition temperature, at this temperature, the stability of two-phase is put upside down.Polycrystalline theory and origin (Theory and Origin of Polymorphism) in (" Polymorphism in Pharmaceutical Solids " (1999) ISBN :)-8247-0237).

The sample of crystalline structure of the present invention can be provided under substantially pure phase homogeneity, this shows one or more other crystalline structure of the single crystal structure that exists main amount and the minor amount of choosing wantonly.In sample, the existence of more than one crystalline structure of the present invention can be by measuring such as powder x-ray diffraction (PXRD) or this class technology of solid state nmr spectral method (SSNMR).For example, the PXRD of experimental measurement pattern (observation) and simulation PXRD pattern (calculatings) relatively in, additionally the existence at peak may show the crystalline structure that has more than one in sample.The PXRD of simulation can calculate according to the Single Crystal X-ray data.(referring to Smith, D.K., " A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns; " LawrenceRadiation Laboratory, Livermore, California, UCRL-7196, April 1963; Also referring to Yin.S., Scaringe, R.P., DiMarco, J., Galella, M.and Gougoutas, J.Z., American PharmaceuticalReview, 2003,6,2,80).Preferably, crystalline structure has substantially pure phase homogeneity, as by come from extra peak, account for below 10% of total peak area in experimental measurement PXRD pattern, preferred below 5%, more preferably 2% is shown below, this extra peak does not exist in simulation PXRD pattern.The crystalline structure of the present invention that most preferably has following substantially pure phase homogeneity, wherein in experimental measurement PXRD pattern total peak area below 1%, 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

Can prepare by several different methods by crystalline structure of the present invention, for example comprise 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).Crystalline structure from the technology of crystallization solvent mixture or recrystallization for example comprise evaporating solvent, reduce solvent mixture temperature, to the supersaturation solvent mixture of molecule and/or salt, carry out crystal inoculation, lyophilize solvent mixture and will resist solvent (counter solvent) to add solvent mixture.The high yield crystallization technique can be used for preparing the crystalline structure that comprises polymorphic form.

Comprise polymorphic form medicine crystal, preparation method and medicine crystal be characterized in Solid-State Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer and J.G.Stowell, second edition, SSCI, West Lafayette, Indiana, discussed in 1999.

Seed crystal can be added in any crystalline mixture to promote crystallization.Be clear that for technicians, put into the method that crystal seed is used as controlling the method for specific crystal structure growth or is used as crystallization control product size-grade distribution.Therefore, the calculating of required crystal seed amount is depended on to the size of available crystal seed and the expectation size of average product particle, for example, as at " Programmed cooling of batch crystallizers; " J.W.Mullinand J.Nyvlt, Chemical Engineering Science, 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 can pass through the screening than macrocrystal, grinding or micronizing, or produces by the micro-crystallization of solution.It should be noted that the grinding of crystal or micronizing can not cause expecting any variation (that is, become amorphous or become another kind of polymorphic form) of the degree of crystallinity of crystalline structure.

As used herein, term " room temperature " or 20 to 25 ℃ of (68-77 of " RT " expression

) envrionment temperature.

Generally speaking, as described below, while preparing crystalline compounds Ia, will use solvent (one or more) that crystalline compounds Ia is formed, crystalline compounds Ia preferably has tap density as described below.

Under the crystalline compounds basis of structure I a of the present invention (S-PG) SC-3, look like in the storied reaction shown in scheme I (telescoped reaction) and prepare.

Scheme I

(crystal) compound (Ia ((S)-PG) crystalline form SC-3

From visible scheme I, with reductive agent such as silane (silyl hydride), preferred alkyl silane, more preferably triethyl silicane (triethyl silane or triethylsilyl hydride), 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, approximately-15 to about 25 ℃ of scopes, preferred approximately 5 to the temperature in about 10 ℃ of scopes, process compd B or If or Ig (jointly being called compd B), wherein compd B is in the form of amorphous solid or crystalline solid (If or Ig), with reducing compound B and form corresponding basic cpd I

By Compound I from reaction mixture, separating, and ((S)-PG) and organic solvent are processed as cited hereinbefore alkyl acetate, preferred isopropyl acetate or t-butyl methyl ether (MTBE) with (S)-propylene glycol, and optional (crystal seed of (S)-PG) Ia processes that (crystal seed Ia: the mol ratio of compd B is approximately 0.1 to about 10% scope with compound, be preferably approximately 0.5% to approximately 3%), to form the compound (magma of (S)-PG) Ia, and ((S)-PG) Ia is from separating this magma by crystalline compounds.

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

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

Scheme II

Compd A

Wherein, use 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 under inert atmosphere such as nitrogen atmosphere, at approximately 50 to approximately 85 ℃, preferred approximately 60 to the about high temperature of 80 ℃, process compd A, form Compound I.

The aqueous bases of using and the mol ratio of compd A in the scope of approximately 3.5: 1 to approximately 5.5: 1, preferred approximately 3: 1 to approximately 5: 1.

The reaction mixture that will contain Compound I is with organic solvent as above such as methyl butyl ether (MTBE) or alkyl acetate, preferred isopropyl acetate or MTBE process, to isolate Compound I, Compound I is processed with (S)-propylene glycol, with formation, contained the thick slurry of crystallized product Ia (S)-PG---crystalline form SC-3---.Randomly, (crystal seed of (S)-PG) Ia adds in reaction mixture by compound.Adopt conventional steps that crystalline compounds Ia is separated with described slurry, for example, with organic solvent such as hexanaphthene, octane-iso or methylcyclohexane, preferred hexanaphthene is processed the slurry of Compound I a, and reclaims crystalline compounds Ia.

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

As shown in this paper front, (R)-propylene glycol solvent compound Ib of Compound I can be similar to the mode of (S)-propylene glycol solvent compound Ia accordingly and prepare, and just with (R)-propylene glycol, replaces (S)-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 following scheme III.

Scheme III

The compd A Compound I

List-EtOH-dihydrate

Crystalline form SA-1

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

Following the carrying out of 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).

Preparation Compound I d crystalline form SB-1, to contain by compd A is dissolved in that in water glycol, (water: ethylene glycol is approximately 1: 1 to approximately 0.4: 1, preferred approximately 0.7: 1 to approximately 0.5: 1) middle enforcement, described dissolving is by at approximately 35 to approximately 55 ℃, preferred approximately 40 to the temperature in about 50 ℃ of scopes, heating approximately 0.5 hour to approximately 2 hours, preferred approximately 0.5 hour extremely approximately 1 hour and carry out.Mixture is cooled to approximately 10 to approximately 22 ℃, preferred approximately 14 to the temperature in about 16 ℃ of scopes, the crystal seed that adds list-EtOH-dihydrochloride dihydrate crystal Ic or ethylene glycol bisthioglycolate hydrate crystal shape SB-1 Id, the mol ratio of they and compd A is approximately 0.1% to about 10% scope, preferred approximately 0.5% to approximately 3%, to form ethylene glycol bisthioglycolate hydrate crystal shape SB-1Id.

According to the present invention, the following formation of ethylene glycol bisthioglycolate hydrate crystal shape SB-2Ie: compd A is dissolved in and contains that in water glycol, (water: ethylene glycol is approximately 1: 1 to approximately 0.4: 1, preferred approximately 0.7: 1 to approximately 0.5: 1), described dissolving by approximately 35 to approximately 55 ℃, preferably approximately 40 at heating approximately 1.5 hours to approximately 2 hours, preferred about 0.30min, extremely approximately carried out in 1 hour to the temperature in about 50 ℃ of scopes.Mixture is cooled to approximately 10 to approximately 30 ℃, preferred approximately 20 to the temperature in about 25 ℃ of scopes, and add the crystal seed of ethylene glycol bisthioglycolate hydrate crystal shape SB-2Ie, the mol ratio of itself and compd A is approximately 0.1% to about 10% scope, preferred approximately 0.5% to approximately 3%, to form ethylene glycol bisthioglycolate hydrate crystal shape SB-2Ie.

The inventive method that for the preparation of the crystalline form of compd B is If is implemented according to scheme IV as follows.

According to following reaction scheme IV, prepare crystallization Isosorbide-5-Nitrae-butine of the present invention-diol solvent compound If.

Scheme IV

The compd B crystallization

If

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

In the optional method for preparing crystalline compounds If, at approximately 50 to approximately 70 ℃, preferred approximately 55 to the high temperature in about 65 ℃ of scopes, 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 is from crystallization the mixture of compd B and toluene/alkyl acetate (ethyl acetate), and the toluene that this mixture contains and the volume ratio of alkyl acetate are in the scope of approximately 1: 1 to approximately 19: 1, preferred approximately 4: 1 to approximately 9: 1.The mixture of toluene/alkyl acetate will comprise enough toluene so that the mol ratio of itself and compd B approximately 40: 1 to about 90: 1 scopes, preferred approximately 60: 1 to approximately 80: 1, thus can form Isosorbide-5-Nitrae-butine-diol solvent compound If.

Adopt the crystal seed of Compound I f, can realize more easily that crystallization forms 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, be approximately 0.1 to approximately 10%, preferred approximately 0.5 to approximately 3%.

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

Also can prepare with the continuous processing as shown in scheme IVA by crystallization Isosorbide-5-Nitrae-butine-diol solvent compound If.

Synthetic two consecutive steps that comprise compd E and Compound D of solvate If: (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, shown 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 the whole technique of the preparation Compound I f as shown in scheme IVA, under non-Cryogenic Conditions, carry out.Aromatic reactants E with the group that is suitable for Li and halogen exchange at room temperature is stored in the first container 1.Equally at room temperature lithium reagent Q is fed in second container 2.By aromatic reactants E and lithium reagent Q from

container

1 and 2, by

pump

3 and 4, transferring in the first jacketed type static mixer 5 respectively.In the first mixing tank 5, by water cooler 6, the temperature of reaction that produces the lithiumation anion species is adjusted in to approximately-30 ℃ to approximately under 20 ℃.

The lithiumation anion species G that forms thus directly is fed to the second static mixer 22 from the first mixing tank 5 along conventional transfer limes 19.The reactant D of carbonyl substituted at room temperature is fed in the 3rd container 20, and carries through supercooler 26 by pump 21, herein, reactant D is cooled at approximately-10 to approximately-30 ℃ of temperature in scope, then is delivered to the second jacketed type static mixer 22.In the second mixing tank 22, by the second water cooler 23, regulate the reaction that produces glucosides product H.

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

The lithium reagent expectation of using is organolithium reagent.Suitable organolithium reagent comprises n-BuLi, s-BuLi and t-BuLi.Other will be obvious to those skilled in the art.

After reaction completes, according to the extensive known technology (for example precipitation, solvent extraction, recrystallization and chromatography) of organic chemistry filed, can separate and purifying expectation product If.Removing to protect product If itself can be useful intermediate or final product.Use method known to those skilled in the art, Compound I f can further react, and obtains its pharmaceutically acceptable acid salt or alkali salt.

In the design of the continuous processing shown in scheme IVA, temperature and reaction times are two important parameters: lithiumation can-30 ℃ (or lower) to as high as 20 ℃ (or higher) under, preferably under approximately-17 ° to approximately-10 ℃, move continuously the several minutes reaction times to the several seconds.For follow-up linked reaction, lithium derivative G stream further mixes in mixing tank with Compound D stream (the 3rd charging).Then, if need the extra time in order to complete reaction, mixed flow is sent to flow reactor.Linked reaction can, at-30 ℃ to the comparatively high temps of-10 ℃ (or higher), preferably approximately-30 ° to approximately-20 ℃, be carried 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.With large-scale low temperature batch reactor, compare, in processed continuously situation, utilize and have the less flow reactor that significant temp is controlled, lithiumation and linked reaction can fully be combined and be operated under comparatively high temps.

The service temperature of the continuous lithiumation in aforesaid method can (be not limited to this temperature) up to 20 ℃, preferred-17 to-10 ℃, produces simultaneously the expectation lithiumation intermediate G of>95 RAP.

In linked reaction, under-20 ℃ to-30 ℃ from the coupled product of aforesaid method preferably in the 70-79RAP scope.

As shown in scheme IVB, Compound I f can be for the preparation of crystallization of intermediate A.

Scheme IVB

The preparation of intermediate A

Reference scheme IVB, be heated to solid chemical compound If, solid DMAP, liquid acetonitrile and liquid acetic acid acid anhydride approximately 70 to the temperature in about 85 ℃ of scopes and remain this temperature, until reaction finishes.

Should batch cooling (for example 5 ℃).Triethyl silicane and boron trifluoride acetic acid mixture or other Lewis acid (as described in about scheme I) are added in reaction mixture.After reaction completes, add acetone or other solvent.By this batch heating (for example from approximately 20 to approximately 30 ℃) maintenance, until triethyl silicane is depleted.Add moisture NH ₄OAc, mix this batch, and make its precipitation, until upper and lower phase forms.By following minimum the stirring to distill acetonitrile, batch volume of the product in Fu Shangxiang is reduced.At high temperature (>60 ℃) add SDA3A ethanol.

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

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

According to following reaction scheme V, prepare crystallization dimethanol solvate Ig of the present invention.

Plan V

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

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

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

Adopt the crystal seed of Compound I g, can realize more easily that crystallization forms dimethanol solvate Ig, the amount of the crystal seed of Compound I g, based on the weight of initial compounds B, be approximately 0.1% to approximately 10%, preferred approximately 0.5% to approximately 3%.

In separately-preferred embodiment, with crystalline compounds Ig crystal seed---it is based on the weight of initial compounds B, for approximately 0.1 to approximately 10%, preferred approximately 0.5 to approximately 3%---in the situation of inoculation, Compound I g (it can be purified or can not be purified) is from crystallization the mixture of methanol/toluene/heptane.The methyl alcohol that uses and the volume ratio of toluene in the scope of approximately 1: 0.5 to approximately 1: 6, preferred approximately 1: 1.5 to approximately 1: 2.5, and heptane: the volume ratio of toluene in the scope of approximately 2: 1 to approximately 0.5: 1, preferred approximately 1.3: 1 to approximately 0.5: 1.

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

Plan V I

Wherein, the aqueous solution of L-PROLINE is heated to approximately 70 ℃ to the temperature in about 90 ℃ of scopes, and adds alcoholic solvent, as methyl alcohol, ethanol or Virahol, and preferred Virahol.The solution of Compound I is added in above-mentioned L-PROLINE solution (it is stirred), and the Compound I of wherein using and the mol ratio of L-PROLINE are approximately 0.5: 1.Solution is slowly cooled to room temperature, and solid forms during this period.Filter this solution, to remove solid, this solid is washed with alcoholic solvent.Dry this solid, and reclaim with the form of white solid, it is 1: 2L-proline(Pro) crystalline complex Ih---crystalline form 3, N-1.

According to following reaction scheme VII, prepare crystallization 1 of the present invention: 1L-proline(Pro) composite I i.

Plan V II

Solution by 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 ℃ from-10 ℃, this period solid form, this solid be and 1: 1 crystalline complex Ii of L-PROLINE that the employing ordinary method reclaims it.Implementing for the preparation of 1: in the above-mentioned steps of 1L-proline(Pro) composite I i, the L-PROLINE that uses and the mol ratio of Compound I are in the scope of approximately 1: 4 to approximately 1: 6.

According to following reaction scheme VIII, 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 ℃, produce settled solution.Gained solution is cooled to-25 ℃ from-20 ℃, and adds the crystal seed with 1: 1 composite I i of L-PROLINE.At-20 ℃ after lower 3 days, by solid collected by filtration, filter cake is with cold (20 ℃) washing with alcohol.Adopt conventional steps, by gained solid suspension recovery, be white crystalline solid Ij, H0.5-2.

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

Scheme IX

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

The following examples are provided, to advance-to walk to describe in detail the present invention.These embodiment have showed that present consideration is be used to implementing best mode of the present invention, and it is intended to illustrate the present invention rather than limits 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) 5,515, in 117 scheme 1 and embodiment 1.United States Patent (USP) 6,414,126 and United States Patent (USP) 5,515,117 by reference at this with its whole introducings.The stable form of formula (I) compound can be solvate (for example hydrate) by crystallization.

Embodiment

The preparation of crystalline structure

Embodiment 1

(S)-propylene glycol ((S)-PG) structure-

The preparation of crystalline form SC-3-formula Ia

In the 10-L glass reactor that is equipped with thermopair and nitrogen entrance, adding MeOH (1.25L), deionized water (3.6L), is the 50%NaOH aqueous solution (205.9ml, 3.899mol) afterwards.Residual NaOH solution with 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 ℃.After 1h, the circulation bath temperature is down to 70 ℃ from 80 ℃; Internal temperature becomes 65 ℃.Amount to the HPLC of 3h ¹After Indicator Reaction completes, Compound I AP～99.5.When mixture is cooled to after 25 ℃, add isopropyl acetate (2.5L).Mixture was stirred 10 minutes, then separate water layer (pH=12.5), organic layer water (1L) is washed.During this washing, the pH of two-phase system is adjusted to 6.0 with concentrated hydrochloric acid (5.0ml), then, separates water layer.2 in independent container collected organic layer.By reactor 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).Randomly, in this stage, can add the crystal seed of (S)-PG Ia.Instantaneous crystallization (instantaneous crystallization) has produced 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 approximately 15 minutes.With the MTBE/ hexanaphthene (2 * 1L) mixture (1: 1) washing leaching cake, and the suction under dry 0.5h.By solid transfer to pyrex (sending Simon Rex) dish, and in the baking oven of 25-30 ℃ dry two days of vacuum (25mm Hg), until the water analysis by KF is corresponding to monohydrate (3.6wt.%).Obtain (S)-PG product Ia (0.425kg, yield 97%), it is the snowy white solid, HPLC ³AP 99.7.

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

¹HPLC: post: YMC ODS-A (C-18) S3,4.6 * 50mm.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 time 8min; Residence time 3min.Integration stand-by time (integration stop time) 11.0min.Flow velocity 2.5ml/min.UV wavelength 220nm.

。

³HPLC method: mobile phase A: the 0.05%TFA in H2O.Mobile phase B: the 0.05%TFA in CAN.Post: YMC Hydrosphere 4.6 * 150 (3 μ).Gradient: 30-90%B in 45 minutes stopped 5 minutes; Be back to 30%B reequilibrate 10min.Wavelength: 220nm.Inject volume: 10 μ l.Temperature: envrionment temperature.

Embodiment 1A

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

Step

The 20g compd A is fed to reactor under envrionment temperature and pressure in.30mL methyl alcohol and 49.75mL 3N NaOH are added in reactor, reaction mixture is heated to 80 ℃ or backflow, and keeps about 2-3 hour, so that reaction completes<0.5AP.Should batch be cooled to 20 ℃, and be neutralized to pH 6.0-7.5 (inlet amount of requirement～1mL/gm) with dense HCl or 1N acetic acid.

Extraction

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

Crystallization

By 2.8g (1.05eq) (S)-(+)-1,2 propylene glycol add in reaction mixture.This batch inoculated with 0.1g Compound I crystal seed.Add the 160mL hexanaphthene, and should batch be cooled to room temperature to 5 ℃.Before separating, make this batch stirring at least 1 hour under room temperature to 5 ℃.

Separate and drying

By the 50/50 isopropyl acetate/hexanaphthene mixture washing by volume of the separation cake of each load.By this cake dry in vacuum oven under 30 ℃, under perfect vacuum.(work as KF=3.6%-4.1%, cake is done).

Yield=84% (not calibration)

Typical case purity=99.81AP

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

Embodiment 2

(R) preparation of-propylene glycol structure-Ib

R-propylene glycol Ib

Utilize and 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 list-EtOH-dihydrate (ethanol or EtOH structure)-crystalline form SA-1-formula Ic

The compd A Compound I

By being heated to boiling, compd A (1.0g) is dissolved in EtOH (3.0ml), and water (7ml) dilutes this solution.Add 1ml EtOH, and mixture is divided into to three parts, for 20 ℃, 5 ℃ and-20 ℃ of lower crystallizations.Be cooled to after-10 to-20 ℃, forming crystal, it has M.P.40-41 ℃.

Embodiment

4 and 5

Ethylene glycol structure-crystalline form SB-1 and SB-2-

Be respectively the preparation of formula Id and Ie

For obtaining the polymorphic of ethylene glycol bisthioglycolate hydrate crystal shape SB-1 Id, by under 45 ℃, heating 30min, compd A (0.5gm) is dissolved in and contains (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 was stirred 16 hours, white crystalline solid is provided.Filter crystal, wash with water and drying.For obtaining the polymorphic of ethylene glycol bisthioglycolate hydrate seed crystal shape SB-1Id, compd A is dissolved in and contains in water glycol, add (S)-propylene glycol crystal shape SC-3 Ia, 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-2 Ie (embodiment 5), by heating, compd A is dissolved in and contains 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-2 Ie (embodiment 5).Filter these crystal and wash with excessive water.

Crystalline form SB-1 and SB-2's ¹H NMR: ¹H NMR (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-3 Ia

Compd B

At batch temperature of 8-10 ℃, under nitrogen atmosphere, in acetonitrile (12mL), add boron trifluoride ethyl ether complex (borontrifluoride diethyletherate) (2.3mL, 18.4mmol) and water (0.82mL, 4.6mmol).After said mixture being kept approximately to 1 hour, add triethyl silicane (3mL, 18.4mmol).The gained mixture was kept approximately 1 hour, then be added in the compd B (as in preparation described in embodiment 17) in the 10mL acetonitrile.Should batch remain on 5 to 10 ℃.After according to HPLC, determining that reaction completes, with the water-containing acetic acid ammonium (24mL in 200mL water; 85g) quencher reaction mixture.Separate phase, and by dried over sodium sulfate, be rich in the organic phase of product.Under reduced pressure concentrate the organic phase that is 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 kept 1 hour, to form magma.Add hexanaphthene (10mL, 33mL/g compd B (charging)).Dry (4-5%) and under 20-25 ℃ of lower vacuum by filtering separation crystallized product (Ia).

Embodiment 7

The preparation of crystallization MeOH solvate Ig

By pure compound B being dissolved in methyl alcohol and at room temperature stirring, obtain the crystal of methanol solvate compound Ig.After a couple of days, form white slurry, and find that it is crystallization methanol solvate compound Ig.

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

Embodiment 8

In 80/20 methanol/toluene, utilize crystal seed,

From unpurified compd B, prepare crystallization two-MeOH solvate Ig

6g compd B (HPLC AP approximately 80%) is dissolved in 80/20 methanol/toluene of 15mL.

Add Compound I g crystal crystal seed (for initial compounds B approximately 1%), and mixture is cooling and form the slurry that contains crystal.

Before separation, should starch and stir 6 hours.

Find that wet cake is crystallization methanol solvate compound If, if but its open wide and place a few hours lose degree of crystallinity.

Embodiment 9

In methanol/toluene/heptane, utilize crystal seed,

From unpurified compd B, prepare crystallization two-MeOH solvate Ig

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 (approximately 1%) that adds Compound I g crystal.

In 30 minutes, add the 4mL heptane, and mixture was stirred 12 hours.On the Buchner funnel, separate wet cake.Find that wet cake is crystallization methanol solvate compound Ig.It is dry under vacuum in 30 ℃.The gained powder loses degree of crystallinity.

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

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

Embodiment 10

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

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

50g (90.3wt%) compd B is dissolved in 675mL toluene.Solution is heated to 60 ℃, and adds the 75mL ethyl acetate.Add 1.5 equivalent 2-butyne-Isosorbide-5-Nitraes-glycol (=13.3g), and mixture is remained under 60 ℃, until butynediol dissolves.Solution is cooled to 55 ℃, adds the crystal seed (50mg) of Isosorbide-5-Nitrae-butine of 0.1%-diol compound If.Mixture was kept 1 hour under 55 ℃.Compound I f starts crystallization.Mixture was cooled to 25 ℃ in 6 hours.(mother liquid concentration<3mg/mL), filtration, with 180mL toluene+20mL ethyl acetate washing, 45 ℃ of lower vacuum-dryings, produce the crystal of Isosorbide-5-Nitrae-butine-diol solvent compound If the gained slurry to be stirred to 3 hours before separating.

HPLC?AP＝99.5％。Tire=80.7wt% (expectation to 1: 1 solvate tire=83.6%).Yield=95%.

Embodiment 11

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

At 60 ℃, 0.5g compd B (91wt%) is dissolved in 3.5mL butylacetate+3.5mL heptane.Add the 2-butyne-Isosorbide-5-Nitrae of 1.5 equivalents-glycol, compound is cooled to room temperature.The gained slurry was stirred 12 hours, filter, and with 1: 1 butylacetate of 1mL: heptane wash, dry under 50 ℃, 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 BF32CH ₃COOH replaces BF ₃OEt ₂, form crystalline compounds Ia.

Embodiment 12

With 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 ℃, and adds the 100mL Virahol.At room temperature, in the L-PROLINE solution of rapid stirring, add the solution of Compound I (21.4g, 50mmol) in the 100mL Virahol.Form solid, solution is slowly cooled to room temperature.Filtering solution, with after Virahol, with hexane, washing the gained solid again.This solid is dry under vacuum oven, produce the white solid that 30.4g contains Compound I, it is 1: 2 crystalline complex (structure I h, crystalline form 3) with L-PROLINE.

Embodiment 13

With 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 1.1mL 90% ethanol/water is quickly heated up to boiling, and be incorporated in the solution of the Compound I (0.4g, 1mmol) in 4mL ethanol.To-20 ℃ of 2h, solid forms during this period by the gained solid cooled.This solution was at room temperature stored 2 days.Centrifugal to container, remove supernatant liquor.Wash residual solid in 1mL MTBE, and this solid is dry under vacuum, produce the white solid that 0.025g contains Compound I, and it is 1: 1 crystalline complex (structure I i, crystalline form 6) with L-PROLINE.

Embodiment 14

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

Solution in 31mL 97% ethanol/water quickly heats up to 70 ℃ by L-PROLINE (0.23g, 2mmol) and Compound I (4.34g, 10mmol), produces clear solution.Gained solution is cooled to-20 ℃, and adds the crystal seed with 1: 1 composite structure Ii crystalline form 6 of Compound I of L-PROLINE.At-20 ℃ after 3 days, by solid collected by filtration, with cold (20 ℃) washing with alcohol filter cake.By the gained solid suspension, in the 5mL heptane, filter afterwards and use heptane wash, produce the 0.3g white solid.By this material (0.02g) from 20/1 EtOH/H ₂In O, advance-walk crystallization, be accompanied by the slow evaporation of solvent and a little the heating/cooling, to produce larger X ray gem-quality crystal (quality crystal), 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 1: 1 mixture of L-PROLINE.

Embodiment 15

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

Under 80 ℃, L-Phe (424mg, 2.56mmol) is dissolved in 6mL water.Filter gained solution, and it is added and contains 1 and digest in the ethanolic soln (6.5mL) of compound I (2.36mmol).Gained solution is heated to 80 ℃, and makes it slowly cool to room temperature (arriving crystal formation at 55 ℃ of lower First Observations).Solution is stored under 4 ℃.Filtering solution, and with 20% water/washing with alcohol crystal, to produce L-Phe: the mixture of Compound I.From 10mL 50% water/ethanol as above-mentionedly advance-walk to make this substance crystallization, generation 910mg white solid, through being accredited as have L-Phe 1: 1.3 composite structure Ik crystalline form 2 of Compound I of (64%), as pass through ¹H NMR integration is surveyed.

Embodiment 16

By continuous lithiumation and linked reaction, prepare Compound I f

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

-30 ℃ of water coolers of lithiation device 5 (jacketed type static mixers 5) are installed.

-30 ℃ 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

Mix E/THF/ toluene (2.74ml/min) and Q two kinds of chargings of---i.e. n-BuLi in hexane (0.41ml/min)---, and by jacketed type static mixer 5 (30 ℃) combination.

Before pumping into the D/ toluene feed, toluene (2.96ml/min) is flowed to (make-up flow) as a supplement and send in system, constant maintains 6.1ml/min always flowing.

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

Continuous linked reaction

With before lithiumation stream mixes, D/ toluene feed (2.96ml/min) is passed through to the interchanger precooling.

Mixing two kinds of streams is G and D, and by jacketed type static mixer 22 (between-24 ℃ and-30 ℃), they is mixed.

On the reaction stream color, manifest micro-yellow.

Sample is collected in exit at mixing tank 22, carries out the HPLC analysis.Before collecting MSA-MeOH reactor 25 and afterwards, collected specimens.

The methyl glycosidation

<-10 ℃, under stirring, linked reaction stream 24 is fed in the 500-ml reactor 25 that contains MSA and methyl alcohol or HCl/MeOH.

After collection completes, reaction mixture<-10 ℃, kept again 1 hour under stirring.

Reaction mixture is heated to 35 ℃.Until HPLC the analysis showed that, till desilylation hemiketal H ' RAP<0.3%, reaction has been considered to (approximately 6 hours).Reaction is cooled to room temperature (20 ℃), and reaction mixture is kept to 16h, form compd B.

The formation of If crystal

Be used in 2-butyne-Isosorbide-5-Nitrae in toluene/EtOAc-glycol (J) crystallization B, 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 ℃) and keep, until reaction completes.

Cooling this batch (5 ℃).

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

After reaction completes, add acetone (36mL).

Warm this batch (21 ℃) also keeps, until triethyl silicane is consumed.

Add moisture NH ₄OAc (33wt%, 450mL), and mix this batch, make it precipitation, until upper and lower phase forms.

By following minimum the stirring to evaporate acetonitrile, batch volume of the product in Fu Shangxiang is reduced.At the lower feed ethanol SDA3A (1L) of high temperature (>60 ℃).

By cooling or put in crystal seed (the Compound I f that mills based on wet-milling, nitrogen gas stream or the 5wt% of previous batch) situation cooling, crystallized product.The product typical case is separated with>75% yield.

Product is from being wet cake or dried cake by recrystallization ethanol SDA3A.

Crystal Structure

Be equivalent to and followingly describedly with the crystalline structure of this paper crystalline structure required for protection, can demonstrate in the reasonable error scope, similar but not identical analysis and characterization, this depends on test condition, purity, equipment and other variable commonly used 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.The applicant means specification sheets and embodiment should be considered to exemplary, but not is the restriction to scope.

The X-ray powder diffraction

One of skill in the art will appreciate that the powder x-ray diffraction pattern can be in the situation that have measuring error and obtain, this depends on the measuring condition that adopts.Particularly, be known that usually the intensity of powder x-ray diffraction pattern can fluctuate, this depends on the measuring condition that adopts.Should advance-walk understanding, depend on test conditions, relative intensity also may change, and therefore, should not consider the accurate grade of intensity.In addition, the measuring error of conventional powder X-ray powder diffraction pattern diffraction angle be typically approximately 5% or below, when relating to above-mentioned diffraction angle, the measuring error of this kind degree should not paid attention to.Therefore, should be appreciated that crystalline structure of the present invention is not limited to such crystalline structure: it will provide and the identical X-ray diffraction pattern of the X-powder diffraction pattern described in accompanying drawing disclosed herein.Provide with any crystalline structure of the essentially identical X-ray diffraction pattern of disclosed those powder x-ray diffraction patterns of accompanying drawing to fall within the scope of the invention.Determine that the essentially identical ability of X-powder diffraction pattern is in those skilled in the art's scope.

(S)-PG (crystalline form SC-3) Ia, (R)-PG Ib, Isosorbide-5-Nitrae-butine-diol solvent compound And if dimethanol solvate Ig, 1: the semihydrate Ij (H.5-2), 1 of 1L-proline(Pro) mixture: 2L-proline(Pro) composite I h and 1: 1L-proline(Pro) composite I i structure

About 200mg is filled in Philips powder x-ray diffraction (PXRD) sample chamber.This sample is transferred to Philips MPD device (45KV, 40mA, Cu K α 1).Under room temperature, collect the data (continuous sweep pattern, scanning speed 0.03 degree/second, self defocusing (auto divergence) and anti-scatter slit, receiving slit: 0.2mm, sample spinner: open) in 2 to 32 2-θ scopes.

(S) the powder x-ray diffraction pattern of-PG (Ia), (R)-PG (Ib) structure is illustrated in Fig. 1 and 2 respectively.The powder x-ray diffraction pattern of Isosorbide-5-Nitrae-butine-diol solvent compound And if dimethanol solvate Ig is illustrated in respectively in Fig. 9 and 10.1: 2L-proline(Pro) composite I h, 1: 1L-proline(Pro) composite I i and 1: 1L-proline(Pro) semihydrate composite I j structure the powder x-ray diffraction pattern be illustrated in respectively in Figure 13,14 and 15.

(S)-PG (Ia), (R)-PG (Ib), 1: the semihydrate Ij (H.5-2), 1 of 1L-proline(Pro) mixture: 2L-proline(Pro) semihydrate Ih and 1: the selection diffraction peak position (number of degrees 2 θ ± 0.2) of 1L-proline(Pro) composite I i structure is shown in following table 1.Under RT, characteristic diffraction peak position (number of degrees 2 θ ± 0.1) is based on using the first-rate quality pattern of collecting with rotation diffractometer capillaceous (CuK α), and its 2 θ calibrates with method and other suitable standard well known by persons skilled in the art of National Institute of Standards andTechnology.Yet relative intensity may change, and this depends on crystallographic dimension and form.

Table 1

The PXRD peak (2 θ ± 0.2 °) of selecting

(S)-PG(Ia)	(R)-PG(Ib)	H.5-2,1: 1 L-PROLINE (semihydrate) (Ij)	N-1,1: 2 L-PROLINE (Ih)	1: 1 L-PROLINE (Ii) of N-1
					3.8	3.9	3.9	3.3	3.9
7.6	8.0	8.8	6.5	9.5
					8.1	8.7	15.5	8.6	15.4
8.7	15.3	15.8	15.7	15.7
					15.2	15.6	16.5	16.4	15.9
15.7	17.2	17.8	17.2	17.5
					17.1	19.2	19.4	18.9	18.7
18.9	19.9	19.7	19.8	19.7
					20.1	20.3	20.8	20.2	20.3

?Solid state nmr

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

All solid-state C-13NMR measure and use Bruker DSX=400, and 400MHz NMR spectrometer carries out.Utilize high energy proton decoupling and TPPM pulse sequence and the gradient amplitude crossed nicols (RAMP-CP with magic angle spin (MAS), ramp amplitude crosspolarization), under about 12kHz, obtain high resolving power wave spectrum (A.E.Bennett et al, J.Chem.Phys., 1995,103,6951; G.Metz, X.Wu and S.O.Smith, J.Magn.Reson.A .1994,110,219-227).For each test, use about 70mg sample, this sample is filled in the zirconium white rotor of tubular design.Chemical shift (δ) with reference to being set in 38.56ppm, have high-frequency resonance the external standard diamantane (W.L.Earl and D.L.VanderHart, J.Magn.Reson., 1982,48,35-54).

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

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

Table 1A

(S) the proton N MR peak position of-propylene glycol solvent compound Ia

¹H?NMR(400MHz，d _6-DMSO)δ1.00(d，3H，J＝6.25Hz，PG-CH3)，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)，4.94?and?4.95(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

SSNMR peak position/δ (in ppm) with respect to TMS (tetramethylsilane)

?(S)-PG	?(R)-PG
		δ/ppm	δ/ppm
16.2 17.6 39.3 60.9 63.3	15.8 17.6 39.0 60.9 63.2

?

(S)-PG	(R)-PG
		δ/ppm	δ/ppm
69.8 76.9 78.7 79.4 113.8 123.6 129.3 130.5 132.0 135.7 139.1 158.0	67.4 69.7 77.3 79.2 79.8 113.3 123.6 129.0 130.4 132.0 135.6 139.2 157.9

These data are strictly effective for the 400MHz spectrophotometer.

Table 2A

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

¹H?NMR(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

¹H NMR (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 ₉The calculating ultimate analysis: Calc (calculating) C59.48, H6.34, Cl6.75; Found (actual measurement) C59.35, H5.97, Cl6.19.

Thermogravimetric analysis

At TA Instruments ^TMIn model Q500, carry out thermogravimetric analysis (TGA) test.Sample (about 10-30mg) is placed in the platinum dish that had before tared.By the weight of the accurate measure sample of this instrument, and be recorded to thousandth milligram (a thousand of a milligram).With nitrogen, under 100mL/min, purge smelting furnace.Between room temperature and 300 ℃, under 10 ℃/min heating rate, collect data.

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

The TGA curve of 1: 2 L-PROLINE composite I h, 1: 1 L-PROLINE composite I i and 1: 1 L-PROLINE semihydrate composite I j structure is shown in Figure 16,17 and 18.Weight loss is corresponding to 1 mole of water and 1 mole of L-PROLINE of every mole of analyzed structure.

Differential scanning calorimetry

(S)-PG Ia, (R)-PG Ib, Isosorbide-5-Nitrae-butine-diol solvent compound If, dimethanol solvate Ig, 1: 2L-proline(Pro) Ih, 1: 1L-proline(Pro) Ii and 1: the solid state heat behavior of 1L-proline(Pro) semihydrate Ij structure is studied by differential scanning calorimetry (DSC).(S) the DSC curve of-PG Ia and (R)-PG Ib 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 12.1: 2L-proline(Pro) composite I h, 1: 1L-proline(Pro) composite I i and 1: the DSC curve of 1L-proline(Pro) semihydrate Ij structure is shown in Figure 19,20 and 21.

Differential scanning calorimetry (DSC) test is at TA Instruments ^TMIn model Q1000, carry out.The sample (about 2-6mg) of weighing in the aluminium dish, and accurately be recorded to one of percentage milligram, and be transferred to DSC.With nitrogen, under 50mL/min, purge instrument.Between room temperature and 300 ℃, under 10 ℃/min heating rate, collect data.Draw, wherein endotherm(ic)peak down.

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

Single-crystal x-X-ray analysis X

Obtain and pass through X-ray diffraction studies (S)-PG Ia 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: the monocrystalline of 1L-proline(Pro) semihydrate Ii structure.

At Bruker-Nonius ¹On CAD4 series diffractometer, collect data.By the test diffractometer setting to 25 high corner reflections, carry out least-square analysis, obtain unit cell parameters.Utilize Cu K α radiation (λ=1.5418 ), under steady temperature, adopt θ-2 θ variable sweep (variable scan) commercial measurement intensity, and only lorentz polarization factor is carried out to the school distance.Collect the background count of scanning end, continue half of sweep time.Alternatively, on Bruker-Nonius Kappa CCD 2000 systems, utilize Cu K α radiation (λ=1.5418

) collection monocrystalline data.Use the Collect package ²In the HKL2000 software package ³Carry out index editor and the processing of the intensity data of surveying.

When indication, during data gathering, in Oxford cryo system ⁴Cold flow in crystals cooled.

By the 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.

^1/2, wherein w is based on the suitable weighting function of the error in observed strength.In all stages of refining, check disparity map (Difference maps).With isotropic temperature factor (isotropictemperature factor), hydrogen is introduced in ideal position, but be changed without the hydrogen parameter.

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

Table 3

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

Structure

T

a(

)

b( )

c( )

α°

β°

γ°

?V _m

Z’

?SG

?Dcalc

R

?Ia(S)-PG

25

11.2688(8)

4.8093(3)

46.723(3)

90

?90

?633

1

?P2 ₁2 ₁2 ₁

?1.319

.069

The temperature of T=crystallization data (℃)

Z '=drug molecule number/asymmetric cell

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

---------------------------

¹BRUKER?AXS，Inc.，5465?East?Cheryl?Parkway?Madison，WI?53711?USA

²Collect?Data?collection?and?processing?user?interface：Collect：Data?collection?software，R.Hooft．Nonius?B.V.，1998

³Otwinowski，Z.&?Minor，W.(1997)in?Macromolecular?Crystallography，eds.Caner，W.C.Jr?&?Sweet，R.M.(Academic，NY)，Vol.276，pp.307-326

⁴Oxford?Cryosystems?Cryostream?cooler：J.Cosier?and?A.M.Glazer，J.Appl.Cryst.，1986，19，105

⁵SDP,Structure?Determination?Package，Enraf-Nonius，Bohemia?NY?11716Scattering?factors，including?f’and?f”，in?the?SDP?software?were?taken?from?the”International?Tables?forCrystallography”，Kynoch?Press，Birmingham，England，1974；Vol.IV，Tables?2.2A?and?2.3.1

⁶maXus?solution?and?refinement?software?suite：S.Mackay，C.J.Gilmore，C.Edwards，M．Tremayne，N.Stewart，K.Shankland．maXus：a?computer?program?for?the?solution?and?refinement?of?crystal?structuresfrom?diffraction?data.

R=residue number (residual index) (I>2 σ (I))

D _CalcThe crystalline density of=calculating

The SG=spacer

Following table 4 has shown the location parameter of (S)-PG Ia structure under 25 ℃.

Table 4

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

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	?O.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

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

Table 5

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

Crystalline form

T°

a(

)

b(

)

c( )

α°

β°

γ°

Z’

?SG

?V _m

?R

?D _calc

?Ic?SA-1

-50

?11.519(1)

4.799(1)

22.648(1)

-

94.58(1)

-

1

?P2 ₁

?624

?1.307

?0.05

The temperature of T=crystallization 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

The SG=spacer

Following table 6 has been enumerated crystalline form SA-1 (list-ethanol-dihydrate), and Ic is in the location parameter of-50 ℃.

Table 6

Crystalline form SA-1 is in the mark atomic coordinate of T=-50 ℃

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 following table 7.

Table 7

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

Crystalline form

?T°

a(

)

b(

)

c(

)

α°

β°

γ°

Z’

SG

V _m

R

D _calc

Id?SB-1

-50

11.593(8)

4.766(5)

22.78(3)

?-

93.38(9)

-

1

P2 ₁

628

.19

1.340

The temperature of T=crystallization 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

The SG=spacer

Below table 8 enumerated crystalline form SB-1 (ethylene glycol) Id in the location parameter of-50 ℃.

Table 8

Crystalline form SB-1 is in the mark atomic coordinate of T=-50 ℃

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
				?H12l	?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	-O.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 following table 9.

Table 9

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

Crystalline form

T°

a(

)

?b(

)

c(

)

α°

β°

γ°

Z’

?SG

V _m

?R

?D _calc

?Ie?SB-2

-50

11.4950(1)

?4.7443(1)

44.4154(5)

-

1

?P2 ₁2 ₁2 ₁

606

?.050

?1.390

The temperature of T=crystallization 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

The SG=spacer

Following table 10 has been listed crystalline form SB-2 (ethylene glycol) Id in the location parameter of-50 ℃.

Table 10

SB-2 is in the mark atomic coordinate of T=-50 ℃

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 following table 11.

Table 11

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

Crystalline form	T	a( )	b( )	c( )	α°	β°	γ°	?Z’	SG	V _m	R	D _calc
													YD-1(If)	25	21.576(7)	6.755(1)	18.335(5)	-	102.96(1)	-	?1	C2	651	.055	1.339
YD-1(If)	-50	21.537(4)	6.7273(6)	18.267(3)	-	102.924(7)	-	?1	C2	645	.054	1.352

The temperature of T=crystallization data (℃)

Z '=drug molecule number/asymmetric cell

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

R=residue number (I>2 σ (I))

D _CalcThe crystalline density of=calculating

The SG=spacer

Below table 12 listed Isosorbide-5-Nitrae-butine-diol solvent compound If in the location parameter of 25 ℃.

Table 12

Isosorbide-5-Nitrae-butine-diol solvent compound If is in the mark atomic coordinate table of T=25 ℃

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

Following table 13 has been listed the unit cell parameters of dimethanol solvate Ig.

Table 13

The structure cell data of dimethanol solvate Ig

Crystalline form

T

a(

)

b(

)

c(

)

α°

β°

γ°

?Z’

SG

V _m

R

D _calc

?M2-1(Ig)

-50

20.948(3)

6.794(2)

18.333(2)

-

102.91(2)

-

?1

C2

636

.038

1.314

The temperature of T=crystallization 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

The SG=spacer

Following table 14 has been listed dimethanol solvate Ig in the location parameter of-50 ℃.

Table 14

Dimethanol solvate Ig is in the mark atomic coordinate table of T=-50 ℃

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
				?H367 ^*	?0.0718	?0.8698	?0.4154
?H377 ^*	?0.0679	?1.0520	?0.2715
				?H387 ^*	?0.0601	?0.7968	?0.2848
?H397 ^*	?-0.0015	?0.9590	?0.2996

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

1: 2L-proline(Pro) mixture-crystalline form 3, the unit cell parameters of formula Ih is listed in following table 15.

Table 15

1: the structure cell data of 2L-proline(Pro) mixture (Ih)

Crystalline form

T°

a(

)

b(

)

c(

)

α°

?β°

?γ°

?Z’

?SG

?V _m

?R

?D _calc

N-1(Ih)

-60

10.311(1)

11.334(1)

27.497(1)

95.94

?99.22

?90

?4

?P1

?789

?0.1

?1.343

The temperature of T=crystallization 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

The SG=spacer

Following table 15A has listed 1: 2L-proline(Pro) proline(Pro) (Ih) pure (neat) crystalline form N-1 is in the location parameter of T=-60 ℃.

Table 15A

1: 2 mixture of Compound I h with L-PROLINE

The mark atomic coordinate table of (crystalline form N-1)

Atom	X	Y	Z
				?C11	?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
				?C129	?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
?C175	?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	?1.297l	?1.0548
				?H771	?0.6369	?1.1536	?1.0734
?H669	?0.5570	?1.2393	?0.9763
				?H769	?0.4876	?1.1366	?1.0054

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

Table 16

1: the structure cell data of 1L-proline(Pro) mixture (Ii)

Crystalline form

T°

a( )

?b(

)

c(

)

α°

?β°

γ°

Z’

?SG

?V _m

R

D _calc

N-1(Ii)

-40

?11.441(1)

?10.235(1)

45.358(1)

90

?90

?2

?P2 ₁2 ₁2 ₁

?664

?0.08

?1-311

The temperature of T=crystallization 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

The SG=spacer

Following table 16A has listed 1: the pure crystalline form N-1 of 1L-proline(Pro) mixture (Ii) is in the location parameter of T=-40 ℃.

Table 16A

Mark atomic coordinate table with 1: 1 mixture of Compound I i of L-PROLINE

Atom	X	Y	Z
				?C11	?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
?01	?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
?C12	?-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	?013734
?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 following table 17.

Table 17

Compound I mixture with L-PROLINE

The structure cell data of semihydrate form H .5-2

Crystalline form

T℃

a(

)

b(

)

c(

)

α°

β°

γ°

?Z’

SG

?V _m

R

D _calc

?H.5-2

-40

11.539

10.199

23.183

103.96

97.16

90.25

?4

P ₁

?656

.06

1.349

The temperature of T=crystallization 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

The SG=spacer

Following table 18 has been listed the location parameter of 1: 1 L-PROLINE semihydrate form H .5-2Ij.

Table 18

1: 1 mixture of Compound I j with L-PROLINE

Semihydrate form H .5-2 is in the mark atomic coordinate table of T=-40 ℃

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
?H1?56	?-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
				?H1?83	?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 as the activity that is found in the inhibitor of the sodium dependent glucose translocator in mammiferous intestines and kidney.Preferably, compound of the present invention is the selective depressant of kidney SGLT2 activity, therefore can be for the disease relevant with the SGLT2 activity or disorderly treatment.

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 (impaired glucose tolerance), insulin resistance, with diabetic complication such as ephrosis, retinopathy, neuropathy and cataract), hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipemia, the blood levels of free fatty acids or glycerine raises, hyperlipidaemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension.Compound of the present invention also can be for increasing the blood levels of high-density lipoprotein (HDL) (HDL).

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

Crystalline compounds (S)-PG (SC-3) (Ia), (R)-PG (SD-3) (Ib), SA-1 (Ic), SB-1 (Id), SB-2 (Ie), 1: 2L-proline(Pro) mixture crystalline form 3 (Ih), 1: 1L-proline(Pro) mixture 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 and dosage in No. 117 give, and it is disclosed in this and is all introduced by reference.

B. combined utilization

The present invention comprises pharmaceutical composition in its scope, that this pharmaceutical composition comprises is independent or that with pharmaceutical carrier or thinner, combine, as effective constituent, the formula I compound 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(Pro) mixture crystalline form 3 (Ih), 1: 1L-proline(Pro) mixture 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).Randomly, compound of the present invention can be with independent treatment application, or with one or more other therapeutical agent combined utilization.

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

With the example of the suitable antidiabetic of the compounds of this invention combined utilization, (for example comprise the biguanide class, N1,N1-Dimethylbiguanide or phenformin), alpha-glucosidase inhibitors (for example, acarbose or miglitol), insulin type (comprising insulin secretagogue or euglycemic agent), meglitinide (for example, repaglinide), sulfonylurea (for example, glimepiride, U26452, gliclazide, P-607 and Glipizide), biguanide/U26452 associating (Glucovance for example

), other agonist and DPP IV (DPP4) inhibitor of inhibitor (aP2), glucagon-like-peptide-1 (GLP-1) or the GLP-1 acceptor of thiazolidinediones (for example troglitazone, rosiglitazone and pyrrole lattice grin ketone), PPAR-alfa agonists, PPAR-gamma agonist, PPAR α/γ dual agonists, glycogen phosphorylase inhibitors, fatty acid binding protein.

Believe, the hyperglycemia effect that the combined utilization of formula I compound and at least a or multiple other antidiabetic drug produces will be greater than using separately each in these medicines can obtainable effect, and the cumulative hyperglycemia effect of the associating that produces greater than these medicines.

Phenoxy group but-2-ene (YM-440, Yamanouchi).

the 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-HO39242 Astra/Zeneca, GW-501516 (Glaxo-Wellcome), KRP297 (Kyorin Merck) and by " ANovel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-ActivatedReceptor Alpha (PPAR alpha) the and PPAR gamma.Effect on PPAR alpha Activationon Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats " of Murakami etc., Diabetes, 47, 1841-1847 (1998), at WO 01/21602 and United States Patent (USP) 6, 653, in 314 disclosed those, their disclosure is introduced into by reference at this, utilize the dosage that wherein proposes, the preferred use is designated as preferred those compounds in this article.

Suitable aP2 inhibitor comprises and is the U. S. application sequence the 09/391st that proposed on September 7th, 1999, No. 053 and the U. S. application sequence the 09/519th that proposes on March 6th, 2000, those disclosed in No. 079, the dosage that adopts this article to propose.

-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.1163-1166 and 2745-2748 (1996) and 4-Cyanopyrolidine, be disclosed in U. S. application sequence the 10/899th, No. 641, WO 01/68603 and United States Patent (USP) 6, compound in 395,767, adopt the dosage that proposes in above-mentioned reference paper.

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

with the example of the suitable antihyperglycemic agents of the compounds of this invention combined utilization, comprise glucagon-like-peptide-1 (GLP-1), as GLP-1 (1-36) acid amides, GLP-1 (7-36) acid amides, GLP-1 (7-37) (as is 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 (Zealand PharmaceuticalsA/S), CJC-1131 (Conjuchem Inc) and be disclosed in the compound in WO 03/033671.

with the example of the suitable hypolipidemic/lipid lowering agent of compound combined utilization of the present invention, comprise the MTP inhibitor, HMG CoA reductase inhibitor, inhibitor for squalene synthetic enzyme, fiber acid derivative (fibric acidderivatives), the ACAT inhibitor, lipoxygenase inhibitor, cholesterol absorption inhibitor, ileum Na+/cholic acid cotransporter inhibitor, on the ldl receptor activity, adjust, the cholic acid intercalating agent, cetp (for example, the CETP inhibitor, as torcetrapib (CP-529414, Pfizer) and JTT-705 (Akros Pharma)), one or more in PPAR agonist (as above-mentioned) and/or nicotinic acid and derivative thereof.

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

Can comprise with the HMG CoA reductase inhibitor of one or more formulas I compound combined utilization as be disclosed in United States Patent (USP) the 3rd, the U.S.A in 983, No. 140 cuts down spit of fland and related compound; As be disclosed in United States Patent (USP) the 4th, lovastatin (Mevacor (mevinolin)) and related compound in 231, No. 938; As be disclosed in United States Patent (USP) the 4th, Pravastatin and related compound in 346, No. 227; As be disclosed in United States Patent (USP) the 4th, and 448,784 and 4,450, Simvastatin and related compound in No. 171.Other HMG CoA reductase inhibitor includes, but are not limited to be disclosed in United States Patent (USP) the 5th as used herein, the fluvastatin in 354, No. 772; As be disclosed in United States Patent (USP) the 5th, and 006,530 and 5,177, the simvastatin in No. 080; As be disclosed in United States Patent (USP) the 4th, and 681,893,5,273,995,5,385,929 and 5,686, the Zarator in No. 104; As be disclosed in United States Patent (USP) the 5th, the atavastatin (itavastatin of Nissan/Sankyo (nisvastatin) (NK-104)) in 011, No. 930; As be 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 be disclosed in United States Patent (USP) the 4th, the pyrazole analogs of mevalonolactone (mevalonolactone) derivative in 613, No. 610; As be disclosed in the indenes analogue of the mevalonolactone derivative in PCT application WO 86/03488; As be disclosed in United States Patent (USP) the 4th, the 6-[2-(replacement-pyrroles-1-yl) in 647, No. 576-alkyl) pyran-2-one and derivative thereof; The SC-45355 of Searle (glutaric acid derivatives that a kind of 3-replaces) dichloro-acetate; As be disclosed in the imidazoles analogue of the mevalonolactone derivative in No. WO86/07054, PCT application; As be disclosed in French Patent the 2nd, the 3-carboxyl in 596, No. 393-2-hydroxyl-propane-phosphonate derivative; As being disclosed in 2 in No. 0221025th, european patent application, 3-disubstituted pyrroles, furan are fed and thiophene derivant; As be disclosed in United States Patent (USP) the 4th, the naphthyl analogue of the mevalonolactone derivative in 686, No. 237; As be disclosed in United States Patent (USP) the 4th, the octahydro naphthalene in 499, No. 289; As be disclosed in the keto analog (lovastatin) of the Mevacor (lovastatin) in No. 0,142,146 A2, european patent application; With as be disclosed in United States Patent (USP) the 5th, 506,219 and 5,691, quinoline and pyridine derivate in No. 322.

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

In addition, be used to suppressing the phosphinic compounds of HMG CoA reductase enzyme, as be disclosed in those in GB 2205837, be suitable for and compound combined utilization of the present invention.

being suitable for inhibitor for squalene synthetic enzyme as used herein comprises, but be not limited to, be disclosed in United States Patent (USP) the 5th, 712, α-phosphono in No. 396-sulfonate, 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, for example, 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., and Poulter, C.D., CurrentPharmaceutical Design, 2, disclosed in 1-40 (1996).

In addition, being suitable for other inhibitor for squalene synthetic enzyme as used herein comprises by P.Ortiz deMontellano etc., J.Med.Chem., the disclosed tetra-sodium terpenoid of 1977,20,243-249; As by Corey and Volante, squalene (PSQ-PP) analogue before J.Am.Chem.Soc., 1976,98,1291-1293 disclosed farnesyl diphosphate analogue A and tetra-sodium; By McClard, R.W. etc., J.A.C.S., 1987,109,5544 the report the phosphinyl phosphonic acid esters and by Capson, T.L., doctorate paper, June, 1987, Dept.Med.Chem.U of Utah, Abstract, Table of Contents, pp 16,17,40-43,48-51, the cyclopropane of Summary report.

can comprise with the fiber acid derivative that formula I compound of the present invention is combined use fenofibrate, gemfibrozil, clofibrate, benzene zakat, Win-35833, S-8527 and analogue, probucol, and related compound, as be disclosed in United States Patent (USP) the 3rd, in 674, No. 836, probucol and gemfibrozil are preferred, the cholic acid intercalating agent, as Colestyramine, colestipol and DEAE-Sephadex (Secholex

, Policexide

), and lipostabil (Rhone-Poulenc), Eisai E-5050 (ethanolamine derivant that N-replaces), imanixil (HOE-402), orlistat (tetrahydrolipstatin, THL), istigmastanyl phosphorylcholine (istigmastanylphos-phorylcholine, SPC, Roche), Tanabe Seiyoku (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivatives), AC-233 (Sumitomo), Sandoz 58-035, American Cyanamid CL-277, 082 and CL-283, 546 (2-substituted carbamide derivatives), nicotinic acid, acipimox, Acifran, Liu Suanyan NEOMYCIN SULPHATE, para-aminosalicylic acid, acetylsalicylic acid, as be disclosed in United States Patent (USP) the 4th, 759, poly-(diallyl methylamine) derivative in No. 923, as be disclosed in United States Patent (USP) the 4th, 027, quaternary amine in No. 009 gathers (chlorination diallyl dimethyl ammonium) and ionene, and the medicine of other known reduction serum cholesterol.

Ureas with enhanced hypocholesterolemicactivity "; Stout et al., Chemtracts:Org.Chem. (1995), 8 (6); 359-62, those inhibitor in or TS-962 (TaishoPharmaceutical Co.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, Taisho Pharmaceutical Co.Ltd) and cholestane-3-alcohol, 4-(2-propenyl)-(3a, 4a, 5a)-(LY295427, Eli Lilly).

The example of combining the suitable cholesterol absorption inhibitor of use with compound of the present invention comprises SCH48461 (Schering-Plough) and is disclosed in Atherosclerosis 115,45-63 (1995) and J.Med.Chem.41, those inhibitor in 973 (1998).

The suitable ileum Na that combines use with compound of the present invention ⁺The cotransport example of protein inhibitor of/cholic acid comprises and is disclosed in Drugs of the Future, the compound in 24,425-430 (1999).

the lipoxygenase inhibitor that can combine with formula I compound use comprises 15-lipoxidase (15-LO) inhibitor, for example, as be disclosed in the benzimidizole derivatives in WO 97/12615, as be disclosed in the 15-LO inhibitor in WO 97/12613, as be disclosed in WO 96/38144 isothiazolones (isothiazolones) and as by " Attenuation of diet-induced atherosclerosis in rabbits with a highlyselective 15-lipoxygenase inhibitor lacking significant antioxidant properties " such as Sendobry, Brit.J.Pharmacology (1997) 120, 1199-1206 and Cornicelli etc., " 15-Lipoxygenase and itsInhibition:A Novel Therapeutic Target for Vascular Disease ", Current PharmaceuticalDesign, 1999, 5, disclosed 15-LO inhibitor in 11-20.

the example that can combine with the compounds of this invention the suitable antihypertensive drug of use comprises beta adrenergic blocker, calcium channel blocker (L-type and T-type, for example, diltiazem

, verapamil, nifedipine, amlodipine and mybefradil), diuretic(s) (for example, chlorothiazide, hydrochlorothiazide, flumethiazide, hydrogen fluorine first thiophene, Hydrex, methyl chlorothiazide, trichlormethiazide, polythiazide, the benzene thiazine, Uregit tricrynafen, chlorthalidone, Furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitor, ACE inhibitor (for example, captopril, zofenopril, fosinopril, Enalapril, ceranopril, cilazopril, delapril, perindopril, quinapril, Ramipril, lisinopril), AT-1 receptor antagonist (for example, losartan, Irb, valsartan), ET receptor antagonist (for example, 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 (for example, being disclosed in the compound in WO 00/01389), neutral endopeptidase ((NEP) inhibitor, vasopeptidase inhibitors (dual NEP-ACE inhibitor) (for example omapatrilat and gemopatrilat) and nitrate.

the example of combining the suitable antiadipositas drug of use with the compounds of this invention comprises 'beta '3 adrenergic agonists, lipase inhibitor, thrombotonin (and Dopamine HCL) reuptake inhibitor, Tiroidina beta receptor medicine, 5HT2C agonist (as Arena APD-356), MCHR1 antagonist such as Synaptic SNAP-7941 and TakedaT-226926, novel melanocortin receptor (MC4R) agonist, melanin concentrating hormone receptor (MCHR) antagonist (as Synaptic SNAP-7941 and Takeda T-226926), the galanin receptors instrumentality, orexin (orexin) antagonist, the CCK agonist, NPY1 or NPY5 antagonist, NPY2 and NPY4 instrumentality, the corticotropin releasing factor agonist, Histamine Receptors-3 (H3) instrumentality, 11-β-HSD-1 inhibitor, the adinopectin receptor modulators, monoamine reuptake inhibitors or releasing agent, ciliary neurotrophic factor (CNTF, AXOKINE as Regeneron

), BDNF (large brain derived neurotrophic factor), carbachol (leptin) and carbachol receptor modulators, cannaboid-1 receptor antagonist (as SR-141716 (Sanofi) or SLV-319 (Solvay)) and/or anoretics.

The 'beta '3 adrenergic agonists of combining use with the compounds of this invention be can choose wantonly and AJ9677 (Takeda/Dainippon), L750355 (Merck) or CP331648 (Pfizer) comprised, or other known β 3 agonists, as be 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.

The example of combining the lipase inhibitor of use with the compounds of this invention be can choose wantonly and orlistat or ATL-962 (Alizyme) comprised.

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

The example that can choose the Tiroidina beta receptor compound of combining use with the compounds of this invention wantonly comprises ligands for thyroid receptor, as is disclosed in those compounds in WO 97/21993 (U.Cal SF), WO 99/00353 (KaroBio) and WO00/039077 (KaroBio).

The monoamine reuptake inhibitors of combining use with the compounds of this invention be can choose wantonly and S-768, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, Sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, Dextrofenfluramine, phentermine, Phenylpropanolamine or Mazindol comprised.

Can choose the anoretics of combining use with the compounds of this invention wantonly and comprise topiramate (Johnson & Johnson), Dextrofenfluramine, phentermine, Phenylpropanolamine or Mazindol.

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

Above-mentioned other therapeutical agent, when with compound of the present invention, combining while using, for example can use with those amounts of indicating in Physicians ' Desk Reference, such as in top institute propositions patent or the other mensuration of those skilled in the art.

Biological data

Formula I compound 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 the glucose excretion for the people is shown in Table 19.

Table 19

Medicine	Dosage	Glucose output	24 hours
				Sergliflozin (She Gelie is clean)	?200mg?500mg	?12g?17g
AVE?2268	?1200mg?2000mg	?14g?21g
			Compound I a crystalline structure (S)-PG (crystalline form SC-3)	?5mg?20mg	?～32g?～64g

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) in dose-dependent mode, at table 20.

Table 20

Medicine	Dosage/sky	Average accumulated urine glucose (in 24hrs, gram)
			Placebo	The 1st day 5mg of the-1 day 5mg of 5mg the 14th day	222
Compound I a crystalline structure (S)-PG (crystalline form SC-3)	The 1st day 5mg of the-1 day 5mg of 5mg the 14th day	14035
			The 1st day 25mg of the-1 day 25mg of 25mg the 14th day	27368	?

?

The 1st day 100mg of the-1 day 100mg of 100mg the 14th day

?4?82?66

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

Claims

1. the crystalline structure of the formula Ia compound for the treatment of significant quantity is in wound healing, X syndromes, atherosclerosis, hypertension or the hypertriglyceridemia of preparation treatment diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delay or for increasing the application in the medicine of the hdl level in Mammals, the crystalline structure of described formula Ia compound is:

By substantially equaling following unit cell parameters, characterize:

Unit cell dimension

α ⁰＝90

β ⁰＝90

γ ⁰＝90

Spacer=P2 ₁2 ₁2 ₁

Molecule/asymmetric cell=1

The measurement of wherein said crystalline structure is at room temperature carried out, and it is by substantially characterizing as mark atomic coordinate listed in table 4.

2. application according to claim 1, wherein said crystalline structure are further by following sign: under room temperature, comprise 2 θ values The x-ray diffractogram of powder case, described 2 θ values are selected from 3.8 ± 0.1,7.6 ± 0.1,8.1 ± 0.1,8.7 ± 0.1,15.2 ± 0.1,15.7 ± 0.1,17.1 ± 0.1,18.9 ± 0.1 and 20.1 ± 0.1.

3. the crystalline structure of the formula Ia compound for the treatment of significant quantity is in wound healing, X syndromes, atherosclerosis, hypertension or the hypertriglyceridemia of preparation treatment diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delay or for increasing the application in the medicine of the hdl level in Mammals:

By following sign: solid-state ¹³C NMR wave spectrum, it has substantially similar peak position 16.2,17.6,39.3,60.9,63.3,69.8,76.9,78.7,79.4,113.8,123.6,129.3,130.5,132.0,135.7,139.1 with 158.0ppm, and it is to be zero mensuration on the 400MHz spectrometer, with respect to TMS.

4. the described application of according to claim 1-3 any one, wherein said crystalline structure are further by following sign:

The differential scanning calorimetry analysis chart, it has heat absorption in 50 ℃ to 78 ℃ scopes.

5. the described application of according to claim 1-3 any one, wherein said crystalline structure are further by following sign:

Differential scanning calorimetry analysis chart as shown in Figure 7.

6. the described application of according to claim 1-3 any one, wherein said crystalline structure are further by following sign:

Thermogravimetric analysis curve, wherein about room temperature to 240 ℃ have approximately 18.7% weight loss.

7. the described application of according to claim 1-3 any one, wherein said crystalline structure are further by following sign:

Thermogravimetric analysis curve as shown in FIG. 5.

8. the described application of according to claim 1-3 any one, wherein said crystalline structure are further by following sign:

Proton N MR, it has and the basic similarly peak position that is listed in table 1A.

9. the described application of according to claim 1-3 any one, it is in substantially pure form wherein said crystalline structure.

10. the described application of according to claim 1-3 any one, wherein said medicine are used for the treatment of wound healing, X syndromes, atherosclerosis or the hypertension of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delay or for increasing the hdl level in Mammals.

11. the described application of according to claim 1-3 any one, wherein said medicine is used for the treatment of hypertriglyceridemia.

12. pharmaceutical composition, its comprise, formula Ia compound significant quantity that combine with one or more therapeutical agents crystalline structure, described one or more therapeutical agents are selected from antidiabetic, antiadipositas drug, antihypertensive drug, antiatherosclerotic and lipid lowering agent, and the crystalline structure of described formula Ia compound is:

By substantially equaling following unit cell parameters, characterize:

Unit cell dimension

α ⁰＝90

β ⁰＝90

γ ⁰＝90

Spacer=P2 ₁2 ₁2 ₁

Molecule/asymmetric cell=1

13. pharmaceutical composition according to claim 12, wherein said crystalline structure are further by following sign: under room temperature, comprise 2 θ values

The x-ray diffractogram of powder case, described 2 θ values are selected from 3.8 ± 0.1,7.6 ± 0.1,8.1 ± 0.1,8.7 ± 0.1,15.2 ± 0.1,15.7 ± 0.1,17.1 ± 0.1,18.9 ± 0.1 and 20.1 ± 0.1.

14. pharmaceutical composition, its comprise, formula Ia compound significant quantity that combine with one or more therapeutical agents crystalline structure, described one or more therapeutical agents are selected from antidiabetic, antiadipositas drug, antihypertensive drug, antiatherosclerotic and lipid lowering agent, and the crystalline structure of described formula Ia compound is:

15. the described pharmaceutical composition of according to claim 12-14 any one, wherein said one or more therapeutical agents are selected from N1,N1-Dimethylbiguanide, Regular Insulin, sulfonylurea, thiazolidinedione and DPP IV (DPP4) inhibitor.

16. the described pharmaceutical composition of according to claim 12-14 any one, wherein said one or more therapeutical agents are N1,N1-Dimethylbiguanide.

17. one kind for the preparation of as in claim 1-9 any one the method for defined crystalline structure, comprise the compound that makes formula A

In organic solvent, with alkali and (S)-propylene glycol reaction, produce the crystalline structure of described formula Ia compound, the crystal seed of the crystalline structure of wherein said formula Ia compound is added in reaction mixture, so that the crystalline compounds of described formula Ia can form.

18. one kind for the preparation of as in claim 1-9 any one the method for defined crystalline structure, it comprises the compd B that makes structure following,

With reductive agent, under the existence of activating group, react, to form the following Compound I of structure,

Under organic solvent exists, make Compound I and (S)-propylene glycol reaction, randomly to the crystal seed that adds the crystalline structure of described formula Ia compound in reaction mixture, to form the crystalline structure of described formula Ia compound

19. a method for preparing as the crystalline structure of formula Ia compound as described in defined in claim 1-9 any one, it comprises

Make the Compound I f that structure is following

At Dimethylamino pyridine, CH ₃CN exists lower and acetic anhydride, forms

Make above-claimed cpd and reductive agent at activating group and CH ₃There is lower reaction in CN, forms the Compound I of following structure,

Under the existence of organic solvent, make above-claimed cpd and alkali, then with (S)-propylene glycol reaction, optional crystal seed to adding the crystalline structure of described formula Ia compound in reaction mixture, form the crystalline structure of described formula Ia compound

20. as defined method in claim 19, the compound of wherein said formula If is provided as the crystalline structure of the compound of described formula If

By one or more that substantially equal following unit cell parameters, characterized:

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 under 25 ℃, and it is by substantially characterizing as mark atomic coordinate listed in table 12;

Perhaps

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 under-50 ℃.

21. as defined method in claim 20, wherein said reductive agent is alkyl silane, and described activating group is Lewis acid.

22. as defined method in claim 20, wherein said reductive agent is triethyl silicane, and described activating group is BF ₃OEt ₂Or BF ₃2CH ₃COOH.

23. the described method of according to claim 20-22 any one, prepared by the method that comprises the following steps by the crystalline structure of wherein said formula If compound:

A) by the compd B of following structure

With toluene and ethyl acetate, mix;

B) approximately 50 ℃ to the described mixture of heating at the temperature in about 70 ℃ of scopes;

C) add Isosorbide-5-Nitrae-butine-glycol;

D) heat described mixture, until described glycol dissolves;

E) to the crystal seed that adds Compound I f in solution; With

F) cooling described mixture, form the crystal of the crystalline structure of described formula If compound.

24. the described method of according to claim 20-22 any one, the crystalline structure of wherein said formula If compound is by non-cryogenic method preparation, and described non-cryogenic method comprises the following steps in successive processes:

A) under non-cryogenic temperature, use lithiation reagent, the aromatic reactants E of the following structure of lithiumation,

Form the lithiumation negatively charged ion G of following structure

B) under non-cryogenic temperature, the reactant D of the following structure of coupling above-mentioned lithiumation anion species G and carbonyl substituted,

Form the glucosides H of following structure

C) with acid treatment at step b) in the glucosides H of preparation, formation desilylation hemiacetal H '

It is converted into compd B

With

D), in toluene/EtOAc, process from step c with 2-butyne-Isosorbide-5-Nitrae-glycol J) described compd B, form the crystal of the crystalline structure of described formula If compound.

25. method according to claim 24, wherein said lithiumation step is extremely approximately carried out at the temperature of 20 ℃ at approximately-30 ℃.

26. method according to claim 24, wherein said lithiumation step is carried out at the temperature of approximately-17 ℃ to approximately-10 ℃.

27. method according to claim 26, wherein said lithiation reagent is selected from n-BuLi, s-BuLi and t-BuLi.

28. method according to claim 24, wherein said coupling step carries out at the temperature of approximately-300 to approximately-10 ℃.