TWI357330B - Mixture of crystalline forms of triazolo (4,5-d) p - Google Patents

Description

[1357330 VI. OBJECTS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the initial form of chemical compounds, particularly crystalline and non-morphological 'more particularly four crystalline forms and one non-a non-day form . More particularly, the present invention relates to a process for the preparation of such a swell state, comprising a medicinal composition of a compound which is crystalline and/or non-曰X and a daily form' and a therapeutic use of such a form. [Prior Art]

It is important that the drug substance is in a form that can be conveniently controlled and handled in the formulation of the pharmaceutical composition. Pots and knives are important not only from the point of view of commercial viability, but also from the subsequent manufacture of pharmaceutical formulations containing active compounds. The chemical stability of the active ingredients, solid state stability, and storage of life are also very important factors. The drug substance and compositions containing the same should be effectively stored for a substantial period of time without exhibiting significant changes in the physico-chemical characteristics of the active ingredient (e.g., its chemical composition, density, hygroscopicity, and solubility). In addition, it is also important to provide a drug that is as pure as possible. Amorphous materials may have significant problems with this point. For example, this material is generally more difficult to control and blend than crystalline materials, providing unreliable solubility and often found to be unstable and chemically impure. Those skilled in the art will appreciate that the above problems can be solved if the drug is readily available in a stable crystalline form. Accordingly, in the manufacture of commercially viable and pharmaceutically acceptable pharmaceutical compositions, it is desirable to provide as much as possible a substantially crystalline and stable form of the drug. However, it should be noted that this goal is not always complete. In fact, in general, it is not possible to predict the crystallization behavior of a compound separately from the molecular, nominal σ configuration, and it is usually only experimentally determined. 147303.doc fI357330 Platelet adhesion and coagulation is the initial state of arterial thrombosis. Although the process of adhering to the surface of the endothelium may play an important role in repairing the damaged wall, the platelet aggregation caused by it can precipitate the acute thrombus of the deadly vascular bed, causing high myocardial infarction and unstable angina. The situation of mortality. The success of interventions to prevent or slow these conditions, such as thrombolysis and vasodilation, is also compromised by closure or reclosure caused by platelets. Adenosine 5'-diphosphate (ADP) has been found to be a key mediator of thrombosis. ADP-induced platelet aggregation is caused by a receptor subtype located on the platelet cell membrane. The main drug of PST receptor (also known as P2YADp or p2TAC) involves conduction coagulation/activation and is a G·protein coupled receptor that is not yet capable of reproduction. The musical characteristics of this sensation have been circulated in 'For example, Humphries et al. Br. J. Pharmacology (1994), 135, 1057-1063, and Fagura et al. Br. J. Pharmacology (1998) 124, 157 -164 reference material. It has recently been shown that antagonists of this receptor provide significant improvements over other antithrombotic agents (see J. Med. Chem. (1999) 42, 213). International Patent Application WO 9905143 discloses in its entirety a series of three-vomit [4,5-d] mouth biting compounds having activity as p2T (P2Yadp or P2Tac) antagonists. The compound of formula (i) (described below) contains the general scope of International Patent Application No. WO 9905 143 ' but is not specifically disclosed herein. This compound appears to be highly effective as a P2T (Ρ2γΑΕ)ρ or P2TAC) antagonist. It also has an amazing high-tech Chen Dai's qualitative and bioavailability. SUMMARY OF THE INVENTION Accordingly, the present invention is directed to a compound of the formula (1) in a substantially crystalline form: 147303.doc 1357330 HO- 0

N

H〇 OH

N

F Formula (I) is conventionally known as 3,4·: fluorophenyl=:[心卿S*, 2R*), 3 is called 2,3·three saliva [ή], :] Amine is called propionate Base) _ diol. ))-5_(2_hydroxyethoxy)cyclopentane- The compound of the formula (1) can be present in four types of 不 η 吝曰 吝曰 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , Homogeneous polycrystalline 11, homogeneous polycrystalline m, and homogeneous polycrystalline iv. More homogeneity: 曰曰 is a special crystalline form of the compound. The same physical properties of the same compound and the relatively amorphous state are significant. The chemical and pharmaceutical treatment effects of the natural compound, especially when preparing or using the compound on an industrial scale. In a preferred embodiment of the invention, the preferred crystalline form of the compound of formula (1) is a polymorphous polymorphous π, a polycrystalline polymorph III, and a polymorph IV. In an alternative aspect of the invention, the preferred crystalline form of the compound of formula (1) is a homopolymorph I. In another aspect of the invention, the preferred crystalline form of the compound of formula (1) is isomorphous polymorph II. In another aspect of the invention, the preferred crystalline form of the compound of formula (1) is a polymorph III. 147303.doc 1357330 In another aspect of the invention, the preferred crystalline form of the compound of formula (1) is a homogeneous polymorph IV. In another aspect of the invention, the compound of formula (1) is substantially amorphous - There are three-dimensional long-range orders that are usually present in crystalline grievances (for example, polymorphisms), and that the molecular positions in the amorphous form are essentially random (see BC 1^〇4). j. Pharm Sci. (1997) 86 1. The amorphous form of the compound of formula (1) is called morphology. σ has isolated the compound of formula (I) into crystalline and amorphous forms. It is substantially or essentially free of water ("dehydration, form). Therefore, in one of the hairy samples of the present invention, a crystalline form or an amorphous form of the dehydrated form is provided - a compound of the formula (1). The above pure and essentially dehydrated morphology " does not exclude the presence of some solvents in the lattice structure or outside the lattice structure, including water. The dehydrated form has less than 个4 water molecules per molecule (less than 40). /〇水水). The dehydrated form contains less than 〇1 water molecules per molecule. Homogeneous polycrystals I, II, III, and may refer to their melting origin, powder \_ray diffraction pattern, and/or single crystal Χ ray The data is different. Lu homomorphic I has a stimuli starting point of 14 6 -15 2 C when it is in a substantially pure and essentially dehydrated form, for example, about 15 1. 同. Homogeneous polymorph II is in its essence. In the case of pure and essentially dehydrated form, it has a melting starting point of 13 6-139 C, for example, about 137 5. [. Polymorph III has a purity of 127-132 ° C when it is substantially pure and essentially dehydrated. The refining starting point, for example, about ηη: The homogenous polyfluorene IV has a melting starting point of about 139 ° C when it is substantially pure and essentially dehydrated. The form α is generally before melting. The glassy sputum is then transferred to one of the above homogeneous polymorphic forms, for example, homogeneous polymorph II. The melting point is determined using a differential scanning calorimeter (DSC) of a Perkin Elmer DSC7 instrument. The melting point is defined as significant from the baseline. Change, and by Perkin Elmer Pyris software measurement. It should be understood that alternative readings of melting point may be generated by other forms of the device' or by using conditions other than those described herein. Therefore, the number quoted is not an absolute value. Those skilled in the art should understand that The exact value is affected by the purity of the compound 'sample weight, heating rate, and particle size. The same polycrystalline I has 5.3 (±0.1.), 20.1 (±) when it is substantially pure and essentially dehydrated. 0".), 2〇7〇(±〇1〇), 21〇〇(±〇1〇), and 21.3. (±〇·ΐ.) 2ΘThe χ-ray powder diffraction pattern with high intensity specific peaks. More preferably, the 'substantially pure and essentially dehydrated polymorph is present at 53. (±0.1.), 8,0. (±〇.1.), 9.6. (Turk.1.), 13.9. (±0.1.), and 15.3. (Soil 0.1.), 2°.1.0 (±0.1), 20_7〇 (±0.1.), 21.0. (±0.1.)' 21_30 (±0.1°), 26.2. (±〇·ι.), and 27 5. (Turkish 1〇) 20 X-ray diffraction pattern with high intensity specific peaks. Homogeneous polymorph II has a pH of 5.5° (±〇.1.), 13 5 when it is in a substantially pure and essentially dehydrated form. (Turkish 1〇), 18 3. (Turkish 1〇), 22 7. (Turkish 1〇), and 24.3° (士士.1.) 2Θ X-ray powder diffraction pattern with high intensity specific peaks. More preferably, the substantially pure and essentially dehydrated polycrystalline II has a modulus of 5.5. (±0.1.), 6.8. (±〇.1〇), 1〇 6. (±〇 1〇), 13.5. (±0.1.), 14.9. (±0.1.), 18.3. , 19.2. (±0.1.), 22.7. (±0.1.), 24.3. 147303.doc 1357330 (±0.1°) and 27.1° (±0.1.) 2Θ χ-ray diffraction pattern with high intensity specific peaks. Homogeneous polycrystal III has a temperature of 14.0 when it is in a substantially pure and substantially dehydrated form. (±0.1.), 17.4. (±0.1.), 18.4. (±0.1.), 21.4. (±0.1.) 'and 24.1. (±0·1°) 2ΘThe χ-ray powder diffraction pattern with high intensity specific peaks. More preferably, the substantially pure and essentially dehydrated polycrystalline germanium has a value of 5.6. (±0·1〇), 12.5. (±0.1.), 14.0. (士〇.1〇), 17 4〇 (±〇 1〇), 18.4. (±0.1.), 21.4. (±0.1.), 22.2. (±〇.1.), 22.9. (±0".), 24.1. (±0.1.), and 24.5^0". 2) χ with a high intensity specific peak, the radiation line diffraction pattern. Homogeneous polycrystalline IV has a 4.9 when it is in a substantially pure and essentially dehydrated form. (±0.1.), 9.2. (±0.1.), 11.6. (±(M.), 15 6. (Turkish 1〇), and 16.4. (±0.). 2) χ-ray powder diffraction pattern containing high intensity specific peaks. More preferably, the quality is pure and Intrinsically dehydrated homogenous polycrystalline Ι ν is at 49 (±0.1.), 6.0 (±〇.1〇), 9.2 (±〇.1〇), ".6. (土〇1〇) , 12 8. (±0.1.), 15.6. (±〇·ΐ.), 16 4. (Turkish.), 17 2. (±〇), and ι〇 (±0.1°) 2ΘTwo The χ-ray diffraction pattern of the intensity-specific peak. The 形态 form α has an X-ray powder diffraction pattern without sharp peaks when it is in a substantially pure and essentially dehydrated form. Homogeneous polymorph II, homogeneous polycrystalline m, homogenous Polycrystalline IV, and 形态α χ ray diffraction data were obtained using a Siemens D5000 device. Homogeneous polycrystalline X-ray diffraction data was obtained using a PhiHps x, Pert MPD machine. It should be understood that 'different devices and/or conditions can cause A slightly different data is produced. Therefore, the 'referenced number is not an absolute value. 147303.doc 1357330 In an alternative state of the invention, a solvated form can be formed, for example, a hydrated form (π The compound "). Thus, in the state of the present invention, a hydrate of a compound of the formula (I) is provided in a crystalline form. The hydrate has 0.8 or more water molecules (80% or more of hydration) per molecule of the compound. The hemihydrate has from 0.4 to 0.8 water molecules (40-80% hydrate) per molecule of the molecule. In another state of the invention, any mixture of crystalline and/or amorphous forms of the compound of formula (I) is provided. Preferably, the mixture has a homopolymorph I, a homopolymorph II, a polymorph III, a polymorph IV, and/or a morphology a. More preferably, the present invention provides a polymorph II and a polymorph III. In a further feature of the invention, there is provided a process for the preparation of a crystalline form of a compound of formula (I) by crystallization of a compound of formula (I) from a suitable solvent. Preferably, the solvent is selected from the group consisting of: ethanol, ethyl acetate An ester, isopropanol, isooctane, acetonitrile, water, or a mixture thereof. More preferably, the solvent is selected from the group consisting of: ethanol, ethyl acetate, isopropanol, isooctyl, water, or a mixture thereof, suitably, a solvent Selected from: a mixture of sterol and water, B Alcohol, ethyl acetate, a mixture of ethanol and water, a mixture of isopropanol and water, a mixture of ethyl acetate and isooctane, and acetonitrile. The compound of formula (I) can be prepared by a method similar to that described in WO 9905 143 patent. In order to initiate crystallization, it is necessary to crystallize the compound of formula (I). In order to obtain the selected polymorph, it is necessary to seed the desired polymorphism. The compound of formula (I) can be crystallized from a suitable solvent system. This is accomplished, for example, by cooling, by evaporation of the solvent, and/or by addition of an anti-solvent (wherein the solvent of the formula (I) is poorly dissolved; examples of suitable anti-solvents include heptane or isooctane) to obtain supersaturation. The crystallization temperature and time vary depending on the concentration of the compound in the solution, the solvent system used in 147303.doc 1357330, and the crystallization method employed. The compound of formula (I) in crystalline form can be isolated from the above reaction mixture using techniques known to those skilled in the art, for example, by decantation, filtration or centrifugation. Similarly, the crystalline form of the compound of formula (I) can be dried according to known procedures. The recrystallization step can be carried out using the same or different solvent systems to reduce more impurities, such as amorphous materials, chemical impurities, or to convert crystalline forms from one polymorphic to another, or to hydrate. Or dehydrated form. In addition, the removal of amorphous material may require an adjustment step to expose the solid to high humidity. Preferably, the crystallization is carried out directly from the reaction solution. Alternatively, the crystallization is carried out by a subsequent solution. In a further feature of the invention, there is provided a method of preparing a homogeneous polycrystal' which comprises a polycrystalline polycrystal derived from a homogeneous polycrystalline η! The slow crystal growth results in a plurality of homogeneous seed crystals, and the reaction mixture containing the compound of the formula (1) and a suitable mixed solvent system (e.g., methanol/water) is used for seeding. In other features of the invention, a process for preparing a homogeneous polycrystalline η is provided which comprises crystallizing in a suitable solvent such as ethyl acetate. In a further feature of the invention, there is provided a process for the preparation of a homogeneous polycrystalline Hr which comprises crystallizing in a suitable solvent such as an alcohol, for example, ethanol or isopropanol (dog, especially a crystalline polycrystalline m seeding, Or a compound of the formula (1) is slurried in a suitable solvent such as hydrazine. In other features of the invention, there is provided a method of preparing a homogeneous polycrystal, which comprises crystallizing from a suitable solvent such as acetonitrile, particularly homogenous Crystallization of crystal IV, or the compound of formula (1) in a suitable solvent such as acetonitrile; 147303.doc -10-. - Other animals of the present invention &&&& A method for preparing homogeneous polycrystalline π homogenous multi-day III, a compound white/, 3', for example, a compound of formula (1) at 5_65. The temperature of 〇 is in the "6 aliphatic alcohol/aqueous solvent system, preferably Destruction mo day in Π>Α/水): Other features of this month 'provide a method of making a substantially amorphous form of a compound comprising the use of a suitable solvent system, such as 'ethanol/water' Cold; East dry or mouth-dried solution of the compound of formula (1). " Substantially none, means less than 1% by weight of other homogeneous polycrystals, preferably less than W 50 / 〇. In other aspects of the invention 'providing - a compound obtained by any of the above methods.' ☆, crystalline and/or amorphous form (1) The compound is pH (ρ2γZhe or p2TAC). The human and inner group antagonists. Therefore, the compound of formula (1) in crystalline and/or amorphous form can be used for treatment, including combination therapy. In particular, the compound of formula (1) in crystalline form is indicated for the treatment or prevention of arterial thrombosis complications in patients with coronary, cerebrovascular or peripheral blood vascular diseases. Arterial thrombosis complications may include unstable angina, arteriosclerosis Aortic thrombosis complications, such as thrombosis or vascular obstruction, temporary ischemic attack, peripheral golden tube disease, myocardial infarction with or without thrombolysis, interference due to arteriosclerosis (eg, vasodilation, including coronary vasodilation) Arterial complications, surgical or mechanical damage caused by (PTCA), endarterectomy, stent placement, vesicles, arteries, and other vascular grafting procedures External or surgical trauma tissue using 'reconstruction surgery, including skin and tendon', thrombotic complications, diffusion of thrombosis / platelet depletion conditions, such as disseminated submucosal coagulation, thrombocytopenia ^7303^00 1357330 less purpura hemolytic uremic Symptoms, thrombotic complications of sepsis, adult respiratory distress syndrome, antiphospholipid syndrome, heparin-induced thrombocytopenia and pre-pregnancy toxemia/gestational toxemia, or venous thrombosis, such as deep vein thrombosis, venous obstruction, Blood conditions, such as myeloproliferative diseases, including thrombocytopenia, sickle cell disease; or prevention of mechanically induced platelet activation, such as cardiopulmonary bypass and in vitro cell membrane oxidation (prevention of microthrombotic), mechanically induced platelet activation in vitro, such as for preservation Blood products, such as blood plate concentrates, or shunt obstructions, such as renal dialysis and plasma depletion, secondary to blood & damaged/inflamed thrombus, such as vasculitis, arteritis, glomerulonephritis ^ k intestinal disease and Organ transplant rejection, such as migraine, the condition of Raynaud's disease, in which platelets cause blood Under the process conditions of disease wall inflammatory diseases, such as atherosclerosis, blood class formation / development, becomes narrower / longer narrowed and other inflammatory conditions such as asthma, in which platelets and the plate-derived factors involved in the immune disease process diseases. Other indications include treating (10) the disease and preventing tumor growth and spread. According to other aspects of the invention, there is provided a crystalline and/or amorphous form of a compound of formula (1) for use in a human or animal body treatment. According to an additional feature of the invention, a crystalline and/or amorphous form of a compound of formula (1) is provided as a pharmaceutical agent. Preferably, the crystallized and/or amorphous form of the formula (1)-α is used as a western medicine for anti-pH (p2YADp4p2TAc) and endosomes in a warm-blooded animal such as human. More preferably, the compound of the formula (1) in a crystalline and/or amorphous form is used as a pharmaceutical agent for treating or preventing arterial (four) complications in a patient having coronary artery, cerebrovascular or peripheral gray tube disease in a warm-blooded animal such as a human. According to the invention, the invention provides a crystalline and/or amorphous form of the compound of the formula (I) 147303.doc 1357330. The use of a pharmaceutical agent as a P2T (P2YADP or P2TAC) receptor antagonist. In particular, it is more known 1 Use of a compound of formula (I) for crystallization and/or amorphous form for the treatment of a patient having a disease of the sacral artery, cerebrovascular or peripheral vascular disease or a medical agent for preventing complications of arterial blood tests. The invention also provides a method of treating or preventing arterial thrombotic complications in a patient having coronary, cerebrovascular or peripheral vascular disease, comprising administering a therapeutically effective amount of crystallization and/or amorphous to a person suffering or susceptible to the disease. Formula (1) Compound. The compound of the formula (1) which strikes the crystalline and/or amorphous form may be in the form of a solution, a suspension, a pro-aerosol, and a dry powder formulation &, Example #, applied locally to the lung and/or the airway; or systematically' For example, oral administration in the form of a medicinal tablet, a pill, a capsule, a sugar, a syrup, a powder, or a granule, or a sterilized parenteral solution (4), a subcutaneous administration, or a reading agent for rectal administration. , or apply in the brain. The pharmaceutically acceptable diluent, adjuvant and/or carrier pharmaceutical composition of the compound of the formula (1) in a crystalline and/or amorphous form, either directly or as a compound of the formula (1) comprising a crystalline φ and/or a non-M cancer Apply. Accordingly, other features of the present invention provide a pharmaceutical composition of a compound of formula (1) in a crystalline and/or amorphous form in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. It is particularly preferred to be a composition free of materials which can cause adverse reactions such as negative allergic reactions. Dry powder formulations of the compound of formula (1) in crystalline and/or amorphous form and pressurized HFA gas-soluble can be applied by sputum or nasal inhalation. For the purpose of inhalation, it is desirable to finely divide the compound of the formula (1) in a crystalline and/or amorphous form. Compounds of formula (1) in crystalline and/or amorphous form may also be administered by dry powder inhalers. The inhaler can be a 147303.doc -13- single or multiple dose inhaler and can be a breath actuated dry powder inhaler. One possibility is to mix the finely divided crystalline and/or amorphous form of the compound with the carrier material, for example, mono-, di- or polysaccharides, sugar alcohols and other 7L alcohols. Suitable carriers include sugars and powders. Alternatively, the compound of formula (1), which is 'finely divided, aB and/or amorphous, can be coated with other substances. The powder mixture may also be added to hard gelatin capsules each containing the desired amount of active crystalline and/or amorphous form of the compound of formula (1). Another possibility is to treat the finely divided powder into a sphere that ruptures during the inhalation step. This spheroidized powder can be filled into a multi-dose inhaler drug, such as 'known as Turbuhaler%, where the dosage unit will be in the menstrual period. Ten doses, which are then inhaled by the patient. This system delivers the compound of the active formula (1) with or without a carrier = mass to the patient. A pharmaceutical composition comprising a compound of the formula (I) which is crystalline and/or amorphous may conveniently be an oral tablet, a granule, a syrup, a syrup, a powder, or a granule; a non-gastrointestinal or subcutaneous solution of a bacterium; A medicinal suspension for enteral administration or a suppository for rectal administration. For oral administration, the compound of formula (J) in crystalline and/or amorphous form may be admixed with an adjuvant or carrier, for example, lactose, sucrose, glucose alcohol, mannitol, such as horse starch, corn starch or starch. a starch of starch, a cellulose derivative, a binder such as gelatin or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium hard calcium citrate, polyethylene glycol, wax, paraffin, etc. It is then compressed into tablets. If it is desired to coat the tablet, the core prepared as above may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a volatile organic solvent or aqueous solvent. 147303.doc -14- In order to prepare a soft gelatin capsule, the knot can be blended, for example, vegetable oil or a compound of the formula (1) of the formula (1), for example, an alcohol, a powder, a fiber Cut biopterin Glucitol 'mannose can hold the compound's particles and gelatin' to contain the compound particles. The liquid or semi-solid formulation of the music is also filled into the hard gelatin sac. Liquid for oral application

The liquid mouth 0 may be in the form of a sugar residue or a suspension, for example, a solution of a compound of the formula (1) in a σΒ曰 and/or a non-曰曰 form, and the balance being a mixture of sugar 2 alcohol, glycerin, and propylene glycol. Optionally, the liquid product may contain coloring agents, flavoring agents, saccharin, and methylcellulose as a thickening agent, or other excipients known to those skilled in the art. It should be understood that sample analysis using particles larger than 30 microns in size and non-single-aspect ratio may affect the relative intensity of the peaks. Those skilled in the art should also appreciate that the position of the reflection is affected by the precise height of the sample at the diffractometer and the zero correction of the diffractometer. The surface polarity of the sample also has a small effect. Therefore, the proposed diffraction pattern data is not an absolute value.

The invention is described by the following non-limiting examples. [Examples] Example 1 The homomorphic polymorphic form I {lS-[la, 2a, 3p(lS*, 2R*), 5p]}-3-(7-{[2-(3,4 --fluorobenzene) ))cyclopropyl]amino}-5-(propylthio)-3Η-1,2,3 -three·»Sit[4,5-d]·pyrimidine _3_yl)-5-(2- Hydroxyethoxy)cyclopentane·ι,2·diol Part 1 The compound of formula (1) (2 mg) in the form of polymorph II is heated and cooled in DSC in the following manner: 35 to 143 to 35 to I48 to 35 to 148 to 35t. 147303.doc -15· 1357330 This annealing process results in the crystallization of pure polymorphous I, as indicated by DSC. Part 2 A solution comprising a compound of formula (I), 5 mg/g methanol, 7.3 mg/g water, and a small amount of homogeneous polycrystalline I seed crystallized at 30 °C. XRPD and DSC have demonstrated that substantially pure polycrystalline I has been formed. Example 2 [lS-[lα,2α,3β(lS*,2R*),5β]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropene) in the form of polymorphism II Amino}-5-(propylthio)-3Η-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl)-5-(2-hydroxyethoxy) ring Pentane-1,2-diol A gas-like (150 μl) was added to 45 mg of the compound of formula (1), and the mixture was warmed to dissolve in a steam bath. The resulting solution was allowed to stand to crystallize overnight and dried under flowing nitrogen. XRPD and DSC confirmed the formation of substantially pure polymorph II. Example 3 {18-[1〇1,2〇1,30(15*,211*),53]}-3-(7-{[2-(3,4-difluorobenzene) in the form of polymorphic polymorphism 111 Cyclopropyl]amino}-5-(propylthio)-311-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl)-5-(2-hydroxyethyl Ethoxy)cyclopentane-1,2-diol Ethanol (200 microliters) was added to 10 mg of the compound of formula (I) and the mixture was warmed to dissolve via a steam bath. The resulting solution was allowed to stand to crystallize overnight. XRPD and DSC confirmed the formation of substantially pure polymorphs II and III. This material was used for seeding on a larger scale: 191 mg of the homogeneous polycrystal II was deuterated in 1 ml of a 50% aqueous solution of isopropyl alcohol. 15 mg of mixed polycrystalline II/III seeds were added to the slurry. Complete conversion to homogeneous polycrystal III occurred after 2 days, as confirmed by XRPD. Example 4 147303.doc -16- 1357330 Homogeneous polycrystalline ιν morphology, {ls 彻, 2a, 3(3(ls*, 2R*) 5i3]}_3_(7_{[2_ (3,4·difluorophenyl) Cyclopropyl]aminopurine 5-(propylthio)-3Η-1,2,3-triazole [4,5-d] "Bitter-3-yl"-5-(2-carbylethoxy) Cyclopentene], 2·diol acetonitrile (0.12 ml) was added to 10 mg of the compound of the formula (1), and the mixture was warmed to dissolve in a steam bath. The warming solution was slowly cooled in a hot water jacket to form crystals. It is dried under nitrogen. XRPD shows that it is a unique homogeneous polycrystal. Example 5 The homomorphic form a {lS-[la,2a,3β(lS*,2R*),5β]}-3-(7-{[ 2-(3,4-difluorophenyl)cyclopropyl]amino}_5_(propylthio)_3h_i,2,3-triazole[4,5-d]-pyrimidin-3-yl)-5- (2-Hydroxyethoxy)cyclopentanediol The compound of the formula (I) (21 8 mg) was dissolved in 50% aqueous ethanol (24 ml). The solution was added dropwise to another 14.5 ml of water. The solution was then freeze dried using a Virtis instrument under the following conditions (vacuum 2170 mTorr, time 20.2 hours, condensation temperature -52 ° C, ambient temperature 20.3 ° C). Reference Example 1 {lS-[la, 2a, 3 0(lS*, 2R*), 5p]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino}-5 -(propylthio)-3Η-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2- Glycol {3aR-[3acx,4a,6a(lR*,2S*),6aa]}-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl]amine 5- 5-(propylthio)-3H-l,2,3_tris[4,5-d]-propound·3-yl}-tetrahydro-2,2-dimethyl-4H-cyclo a solution of pentane-1,3-dioxo-4-yl)oxy]ethanol (method A, 0. 59 g) in trifluoroacetic acid (15 ml) and water (15 ml) The reaction mixture was carefully added to a solution of sodium bicarbonate (21 g 147303.doc -17 - 1357330) in water (150 ml) and stirred for 3 min. The mixture was extracted with ethyl acetate to dry and evaporate. The residue was purified (EtOAc EtOAc (EtOAc) elute =3.3), 7.39-7.21 (2H, m), 7.10-7.00 (1H, m), 5.12 (1H, d, J=6.4), 5.05 (1H, d, J=3.6), 4.96 (1H, q, J=9.0), 4.62-4.54 (2H, m), 3.95 (1H, br s), 3.79-3.73 (1H, m), 3.55-3.47 (4H, m), 3.20-3.13 (1H, m), 2.98-2.81 (2H, m), 2.63 (1H, dt, J=13.6, 8.5 ), 2.29-2.21 and 2.16-2.09 (1H, m), 2.07-2.00 (1H, m), 1.73-1.33 (4H, m), # 0.99 (3H, t, J=7.4). Preparation of the starting materials The raw materials are commercially available or readily prepared from known materials by standard methods. For example, the following reactions are descriptions of some of the starting materials for the above reactions, but are not limiting. -

Method A {3aR-[3aoc,4a,6a(lR*,2S*),6aa]}_2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl]amino) -5-(propylthio)-3Η-1,2,3-triazole [4,5-d]-pyrimidine-3-yl}}-tetra--2,2-dimethyl- 4H-cyclo Pentyl-1,3-dioxo-4-yl)oxy]ethanol Add DIBAL-H® (1.0 己烷 solution of hexane, 5.15 ml) to {3aR-[3aa,4a,6a( 1R*,2S*) ,6aa]}-{[6-(7·{[2-(3,4-difluorophenyl)cyclopropyl]amino-5-(propylthio)-3Η-1,2,3 -3 η sit [4,5-d]-mouth bit-3-yl}_ four mice-2,2-·-methylpenta-1,3-oxo-4-yloxy]acetic acid methanol (Method B , 0.76 g) of ice-cold solution in THF (1 mL), and the solution was stirred at this temperature for 2 hr. The reaction mixture was concentrated in vacuo and the residue was crystalljjjjjjjjj A saturated aqueous solution of sodium potassium tartrate (75 mL) was added and the mixture was vigorously stirred for 16 hours. The organics were collected and re-extracted (2 x 50 mL) with ethyl acetate. The combined organics were dried and concentrated, and the residue was purified (jjjjjjjjj MS (APCI) 563 (M+H+, 100%).

Method B {3aR-[3aa, 4ot, 6a(lR*, 2S*), 6aa]}-{[6-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino -5-(propylthio)-3Η-1,2,3_tris-[4,5-d]-indan-3-yl}-tetrahydro-2,2-dimethyl-4H-cyclopentyl Methyl-1,3-dioxo-4-yl)oxy]acetate in [3aR-(3aa,4a,6a,6aa)]-({6-[7-bromo-5-(propylthio))- 3H-1,2,3-triazole [4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimercapto-4H-cyclopentyl 1,3-dioxo-4- Methyl alcohol oxy)acetate (method d, 0.80 g) and (1R-trans)-2-(3,4-difluorophenyl)cyclopropylamine, [RJR'R*)]. A mixture of % dihydroxysuccinic acid ester (1:1) (Method C '0.61 g) in dioxane (25 mL) was added N,N-diisopropylethylamine (0.85 mL). The resulting solution was stirred at room temperature for 6 hours and then concentrated in vacuo. Purification (Si 〇 2 'isohexan: ethyl acetate 3:1 as a solvent) gave the title compound as colorless foam (0.77 g). MS (APCI) 591 (M+H+, 100%).

Method C (1R-trans)-2-(3,4-difluorophenyl)cyclopropylamine, [R-(R*,R*)]-2,3-dihydroxysuccinate 〇 : 1)

The title compound can be prepared according to the procedures described in the WO 9905143 patent. Method D

[3aR-(3aa,4a,6a,6aa)]-({6-[7-bromo-5-(propylthio)-3Η-1,2,3-three 147303.doc -19- 1357330 azole [4 ,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-diindolyl-4H-cyclopenta-1,3-dioxo-4-ol}oxy)acetic acid decyl ester [3aR-( 3aa,4ct,6a,6aa)]-({6-[7-Amino-5-(propylthio)-3H- 1,2,3-triazole [4,5-(1]-pyrimidine-3) -yl]-tetrahydro-2,2-dimethyl-4^1-cyclopentyl-1,3-dioxo-4-ol}oxy)acetic acid methyl ester (method e, gram) and isovaleronitrile ( 2.4 ml). The title compound (0.44 g) was obtained eluted eluted eluted MS (APCI) 502/4 (M+H+), 504 (100%). *

Method E

[38 ft - (33〇1,4〇6,6〇1,6&〇〇]-({6-[7-amino-5-(propylthio)-311-1,2,3-three Methyl [4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-di-f--4H-cyclopenta-1,3-dioxo-4-ol}oxy)acetate [3aR-(3aa,4a,6a,6aa)]-6-[7-Amino-5-(propylthio)-3Η· 1,2,3-tris[4,5-d]-pyrimidine_ 3_yl]-tetrahydro-2,2-diindolyl-4-indole-cyclopentyl 1,3-dioxo-4·ol (Method F, 〇.5 gram) in THF (25 mL) 〇° The solution of C was added to a butyl clock (0.62 ml of 2,5 N hexane). After 20 minutes, the suspension was calcined with bismuth acetoxyacetate (0 34 g) (according to Biton's Tetrahedron, I" Prepared by a solution of 5, 51, 10513) in THF (10 ml). The resulting solution was warmed to room temperature and then concentrated and purified (si〇2, ethyl acetate: hexane 4: 6 as solvent) The title compound (〇25g) was obtained. MS (APCI) 439 (M+H+, 1〇〇〇/0).

Method F

[3&11_(3&〇1,4〇1,6〇1,6 buckle)]_6_[7_Amino_5_(propylthio)-311-1,2,3-triazole [4,5_d ]-pyrimidin-3-yl]-tetrahydro-2,2-diindolyl-4H-cyclopenta-1,3-dioxo. 147303.doc _20· 1357330 4-alcohol [aR (3aa,4a,6a, 6act)]-6-[7-chloro-5-(propylthio)_3-1,2,3-tris[4,5 d]-%.疋·3_基]_tetrahydro-2,2_dimercapto_4H-cyclopenta-ι,3-dioxy-4-ol (Method G, 13.2 g) in TUF (0.8 mL ammonia (5 mL)) 200 ml) stirred for 2 hours, then concentrated to dryness and the residue was partitioned between water and ethyl acetate

. The organics were dried and concentrated to give title compound (l. MS (APCI) 367 (M+H+, 100%) 〇 Method G

[3aR-(3aa,4a,6ot,6aa)]-6-[7-chloro-5-(propylthio)_3H-1,2,3-triazole[4,5-d]-pyrimidine_3_ 4-tetrahydrodimethyl·4Η-cyclopenta-l,3-dioxo-4-ol isoprenonitrile (1.1 ml) was added to [3aR-(3aa,4ot,6(x,6aa)]-6 -{[5l$yl-6-chloro-2-(propylthio)-pyrimidin-4-yl]aminotetrahydro-2,2 dimethyl-4 Η·cyclopenta-1,3-dioxo-4 - a solution of the alcohol (method η, 2.0 g) in acetonitrile (1 mL), and the solution was heated at 70 ° C for 1 hour. The cooled reaction mixture was concentrated and purified (Si 〇 2, ethyl acetate: : 3 as a dissolving agent) to provide the title compound (1.9 g). MS (APCI) 386 (M+H+, 100%). Method Η [3&11-(33〇6,4〇1,6〇1,6&amp ;〇〇]-6-{[5-Amino-6-gas-2-(propylthio)-pyrimidin-4-yl]amino}-tetrahydro-2,2-diindolyl-4-indole Ethyl phthalate, 3-dioxo-4-ol, iron powder (3.0 g) was added to [3aR-(3aa,4a,6a,6aa)]-6-{[6-gas-5-nitro-2-( Propylthio)-°t °-4-yl]amino}-tetrahydro-2,2·dimethyl-4H-cyclopenta-1,3-dioxo-4-ol (Method I '2.7 g a stirred solution of acetic acid (1 ml). After stirring for 2 hours, it was concentrated to a half volume, diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated to afford titled 147303.doc -21 · 1357330 (2.0 g). MS (APCI) 375 (M+H+, 100%).

Method I

[3aR-(3aa,4a,6a,6aa)]-6-{[6-chloro-5-nitro-2-(propylthio)-pyrimidin-4-yl]amino}-tetrahydro- 2,2-Dimercapto-4H-cyclopenta-1,3-dioxo-4-ol [3&11-(3 〇1,4〇^,6〇1,6压〇1)]- 6-Aminotetrahydro-2,2-dimethyl-411-cyclopenta-1,3-dioxo-4·ol, hydrogen salt (method J, 10.0 g) and N,N-diisopropyl B A solution of the amine (35 mL) in EtOAc (EtOAc) The mixture was filtered and the solution was added to a solution of 4,6-dioxa-5-nitro-2-(propylthio)pyrimidine (WO 9703084), 25.6 g) in THF (1 mL) over 1 hour. , and stirring for another 2 hours. The solvent volume was reduced in vacuo and ethyl acetate (1000 mL) was added. The mixture was washed with EtOAc (EtOAc m. MS (APCI) 405 (M+H+, 100%).

Method J

[3 Wang 11-(33〇1,4〇1,6〇1,63〇〇]-6-aminotetrahydro-2,2-dimethyl-411-cyclopenta-1,3-dioxo- 4-alcohol, hydrochloride salt [1ΙΙ-(1α, 2β, 3β, 4α)]-2,3,4-trihydroxycyclopentenyl quinone imidocarbonic acid, hydrazine (1,1-dimethylethyl) The vinegar (method oxime, 17.4 g) was stirred in 6 M HCl (100 mL) / decyl alcohol (500 mL) for 18 hours. The mixture was evaporated and then azeotroped with toluene (4 x 200 mL) to give a colorless powder. 7 g). This solid was suspended in acetone (250 ml) containing 2,2-dimethoxypropane (25 ml) and concentrated HCl (0.2 ml) and then heated under reflux for 2 hours. The mixture was cooled and evaporated. And azeotrope with toluene (3 x 200 ml). The residue was dissolved in 2% aqueous acetic acid and stirred for 2 hrs. The mixture was evaporated and azeotroped with toluene (4 χ 2 mM) to provide 147303.doc -22- 1357330 title compound (10_1 g) MS (APCI) 174 (M+H+, 100%).

Method K

[1ΙΙ-(1α,2β,3β,4α)]-2,3,4-trihydroxycyclopentenyl quinone imidocarbonic acid, hydrazine (1,1-dimethylethyl) ester in (1R- Cis)-indole (1,1-dimethylethyl) 4 -hydroxy-2-epoxypentenyl iminodicarbonate (method L, 17.1 g) in THF (500 ml) / water (50 ml The solution was added to ruthenium-fluorenyl ruthenium-ruthenium-oxide (9.4 g) followed by osmium tetroxide (10 ml, 2.5% tributanol solution). The mixture was stirred at room temperature for 4 days and then dried over sodium hydrogensulfite (6.0 g). The suspension was filtered through celite, and the product was purified (jjjjjjjjjjjjjjjjjjjjjjj , 1.46-1.60 (1H, m), 1.97-2.05 (1H, m), 3,.55-3.58 (1H, m), 3.66-3.73 (1H, m), 4.11-4.21 (2H, m), 4.54 (1H, d, J=4.8), 4.56 (1H, d, J=5.9), 4.82 (1H, d, J=4.6).

Process L (1R-cis)-indole (1,1-dimethylethyl)_4-hydroxycyclopentenyl quinone iminodicarbonate in sodium hydride washed with ether (6 % suspension in oil) ; 031 g) In a suspension of THF (30 ml), hydrazine iodide (1, dimethyl dimethyl ester) (1.84 g) was added. The mixture was stirred at 40 ° C for 1 hour. Then, at the temperature of the mixture, (1S-cis-M-ethoxycarbonyl-2-cyclopentene-ethanol (0.5 g) and hydrazine (triphenylphosphine) palladium (〇) (〇_18 g) were added to the mixture. The reaction mixture was stirred for 24 hours and then purified (EtOAc EtOAc: EtOAc: EtOAc: EtOAc: 1.61 (1H,ddd, 147303.doc •23· 1357330 J-12.3, 7·7, 6.4), 2'54 (1H,dt,J=12.6, 7.4), 4.51-4.57 (1H, m), 4.86 ( 1H, tq, J = 8.0, 1.8), 4.91 (1H, d, J = 5.4), 5.71-5.77 (2H, m). Example 2 The following describes the compound of formula (1) in crystalline and/or amorphous form (hereinafter referred to as A representative pharmaceutical dosage form for Compound X) for therapeutic or prophylactic use in humans: (a) Ingot I Compound X Lactose Ph. Eur Croscarmellose Nano mg/Plastic 100 182.75 12.0 Yuxi Li Starch Slurry (5% w/v aggregate) 2.25 magnesium stearate 3 〇 (b) medicinal ingot II compound X lactose Ph.Eur Croscarmellose sodium mg / drug key 50 223.75 6.0 maize starch slurry (5% w/v mass material) polyethylene Base p than terpene ketone 15.0 2.25 stearin Magnesium 3 billion (c) drug ingot III Compound X Lactose Ph.Eur Croscarmellose sodium cloak g / key drug 1.0 93.25 4.0 147303.doc -24 1357330

Corn starch paste (5% w/v slurry) magnesium stearate (d) capsule compound X lactose Ph.Eur magnesium stearate

(e) Injection I Compound X 1N sodium hydroxide solution 0.1N hydrochloric acid Polyethylene glycol 400 Water for injection to 100% (1) Injection II Compound X Sodium phosphate BP 0.1N sodium hydroxide solution Water for injection to 100%

(g) Injection III Compound X Sodium Phosphate BP Citric Acid Polyethylene Glycol 400 Water for Injection to 100% 0.75 1.0 mg/capsule 10 488.5 1.5 (50 mg/ml) 5.0% w/v 15.0% w/v (Adjust pH To 7.6) 4.5% w/v (10 mg/ml) 1.0% w/v 3.6% w/v 15.0% v/v (1 mg/ml, buffered to pH 6) 0.1% w/v 2.26% w/v 0.3 8% w/v 3.5% w/v 147303.doc -25- 1357330 Note The above formulations can be obtained by conventional procedures well known in the art of medicine. For example, tablets (a)-(c) may be enteric coated by conventional methods to provide a coating of cellulose acetate phthalate. NMR spectra were measured on a Varian Unity Inova 3 00 or 400 spectrometer; NMR data were quoted in the form of delta values for the main diagnostic protons, expressed in parts per million (ppm) relative to tetramethyl decane (TMS) as an internal standard, used throughout Dimethyl hydrazide (DMSO-56) is used as a solvent unless otherwise indicated; for example, chemical transfer only refers to the main rotamer to show the presence of rotamers in the proton NMR spectrum; coupling constant (J) in Hz Said. Mass spectra (MS) were measured as follows: EI spectra were obtained on a VG 70-250S or Finnigan Mat Incos-XL spectrometer, FAB spectra were obtained on a VG 70-250 SEQ spectrometer, and ESI and APCI were obtained on a Finnigan Mat SSQ7000 or Micromass Platform spectrometer. Preparative HPLC separations are typically carried out using Novapak®, Bondapak® or Hypersil® columns packed with BDSC-18 reverse phase vermiculite. Flash chromatography (indicated by (Si02) in the example) was performed using Fisher Matrix, 35-70 microns. Shorthand THF. Tetrahydropyrene XRPD X-ray powder diffraction DSC differential scanning calorimeter [Simple illustration] Figure 1.1 is an X-ray diffraction pattern of homogeneous polycrystalline I using Philips 147303.doc -26- 1357330 The XTert MPD machine takes at 1. Scanning range up to 40. 2 ,, 〇〇 2 〇 20 increments for 2 or 5 seconds exposure θ_θ configuration to obtain β Χ _ ray by using 4 〇 volts and 50 mA operating copper long-fine focus tube produce. The wavelength of the χ•ray is 1.5406 angstroms. Figure 1.2 shows the homogenous polycrystalline π χ ray diffraction pattern, which is used in a heart-printed 8 D5000 machine at 2. To the scanning range of 3〇〇2Θ, the increment of each 〇·〇2〇2Θ is 4 sec. The χ-ray is generated by a copper length of 45 volts and 4 mA amps. The wavelength of the χ-ray is 丨54〇6 Å. The data was collected using a zero background in which ~1 〇 mg of compound was placed. The holder is made of a single crystal ray which has been cut along a non-diffractive plane and then polished to an optically flat finish. The X-ray incidence on this surface is cancelled by the Blerger extinction. Figure 1.3 shows a homogenous polycrystalline Χ2 Χ ray diffraction pattern using the Siemens D5000 machine described above. Figure 1.4 shows the χ-ray diffraction pattern of a homogeneous polycrystalline iv using the Siemens D5000 machine described above. Figure 1.5 is a χ-ray diffraction pattern of Form α using the Siemens D5000 machine described above. Figure 2 shows DSC plots of homogeneous polycrystals I, η, ΠΙ, and Iv, and morphology a, obtained using a Perkin Elmer DSC 7 instrument. The disc type is aluminum with a perforated cover. The sample weighs 1 to 3 mg. The procedure was carried out under a stream of nitrogen (3 〇 ml/min) and the temperature range of the study was 3 〇 ° c to 325. (:, at a rate of 1 per minute (TC fixed temperature increase rate. 147303.doc -27-

Claims (1)

1357330 VII. Patent application scope: 1. A mixture of compounds of formula (I) Patent application No. 099108726 Replacement of Chinese patent application scope (September 1st) Λ HO OH (I) The sputum is characterized by having a substantially crystalline form (soil 0.1.), 13.5. (±0.1.), 18.3. (±〇 1〇), 22 7. (Gentry 1〇) and 24 3. (Soil 0.1°) 2ΘThe χ-ray powder diffraction pattern containing a specific peak of the south intensity; or characterized by 5.5° (±0.1.), 6.8. (Turkish 1〇), 1〇 6. (土〇). η 5. (Soil 0.1.), 14.9. (±(M.), 18.3. (Gentry)), 19 2. (±〇1〇), 22 7. (±0.1.) , 24.3 (±0.1.) and 27". (Turkish 1〇) 2Θ X-ray with a specific peak A line diffraction pattern; or characterized by a differential scanning calorimeter curve having a melting starting point in the range of 136-139 ° C, and a compound of formula (1) characterized by 14 〇. (10)". ), 17 4. (10) ), 21.4° (±(U.), and 24”. (±()1.) 2θ contains a high-intensity specific ray-ray powder diffraction pattern; or is characterized by a value of 5.6. (土〇.Ι>125. 2 (= ! ), 22'2° (士 0.1.), 22·9. (士 0.1.), 24". (±0.1.), and ten = 〇士〇10) 20 with a specific peak χ ray around The pattern, or the characteristic is poor " for the calorimeter curve has a melting starting point in the range of 12 7 - i 3 2 〇, 147303-100092] d〇 (1357330 the mixture is substantially free of any other polymorph a compound of the formula (r). 2. A mixture of the claimed items, which is used as a medical agent for preventing arterial thrombosis complications in patients with coronary artery, cerebrovascular or peripheral A tube disease. A pharmaceutical composition for arterial thrombosis complications in a patient having a sacral artery, a cerebrovascular or a peripheral vascular disease, comprising a mixture of a pharmaceutically acceptable adjuvant, a diluent or a carrier, as in the case of a mixture of the applicants. The use of a mixture of claim R for the manufacture of a medicament for the treatment of coronary, cerebrovascular or peripheral vascular disease The disease: complications of arterial blood tests. 147303-1000921.doc