TWI330082B - Crystalline form of triazolo(4,5-d)pyrimidine compound and method of preparing the same - Google Patents

Description

1330082 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to a form of a chemical compound, particularly a crystal and a non-morphology, more particularly, four crystal forms and a non-crystalline (four). The invention further relates to a process for the preparation of such a form, comprising a pharmaceutical composition of a compound in crystalline and/or amorphous form and the therapeutic use of such a form. [Prior Art]

In the formulation of the pharmaceutical composition, it is important that the drug substance is in a form in which it can be conveniently controlled and handled. It is important not only from the point of view of commercial viable processes, but also from the subsequent manufacture of pharmaceutical formulations containing active compounds. The chemical stability, solid state stability, and shelf life of the active ingredients 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 physical-chemical characteristics of the active ingredient (e.g., '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 formulate than crystalline materials to provide unreliable solubility, and the work: found to be unstable and chemically impure. Those skilled in the art should understand that if the music is easily obtained in a stable crystalline form, the above problems can be solved. Therefore, in the manufacture of commercially viable and pharmaceutically acceptable pharmaceutical compositions, it is desirable to provide: crystallization of crystalline and stable forms of the drug. However, it should be noted that this goal is not always complete. In fact, in general, it is impossible to predict the crystallization behavior of a compound by the molecule (4), and it is usually only determined by experiments.

O:\IOO\IOOI34.DOC 1330082 Platelet adhesion and coagulation is the initial condition of arterial thrombosis. Although the process of platelet adhesion to the surface of the endothelium may play an important role in repairing the damaged wall, it triggers the acute blood test closure of the platelet adhesion, which can cause a high death rate such as myocardial infarction and restless angina. The situation of the rate. 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 the ρ2τ receptor subtype located on the platelet cell membrane. The PZT receptor (also known as !>2¥八〇1> or Ρ2Τα〇 main drug involves conduction coagulation/activation, and is a protein coupling receptor that is not yet able to reproduce. The pharmacology of this receptor The features are described, for example, in Humphries et al., Br. J. Pharmacology (1994), 113, 1057-1063, and by Fagura et al., Br. J. Pharmacology (1998) 124, 157-164. It is shown that the antagonist of this receptor provides superiority over other antithrombotic agents.

Significant improvement (see J. Med. Chem. (1999) 42, 213). International Patent Application WO 9905 143 discloses in its entirety a series of triazole [4,5-d]pyrimidine compounds having activity as ρ2τ (p2Yadp or P2Tac) antagonists. The compound of formula (I) (described below) contains the general scope of international patent application WO 9905143, but is not specifically disclosed herein. This compound appears to be highly effective as a p2T (P2Yadp or P2Tac) antagonist. It also has an amazing high-tech Chen Dai's qualitative and bioavailability. SUMMARY OF THE INVENTION Accordingly, the present invention relates to a compound of the formula (1) in a substantially crystalline form:

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H0 OH The compound of formula (I) is conventionally named as {lS-[la, 2a, 3p(lS*, 2R*),

5β]Ρ3-(7_{[2-(3,4-difluorophenyl)cyclopropyl]amino}5•(propylthiol broad 1'2'3纟[4'5_(1;1_〇 ^_3_基)_5_(2·transethoxymethane)cyclopentane _ 1,2-diol. The compound of formula (1) can exist in four different substantially crystalline forms, which are called homogeneous polycrystalline I, and homogeneous. Crystal η, the same as polycrystalline ΠΙ ' and the same polymorphic ν ν. The homomorphic polycrystal is a special crystalline form of the compound. The different physical properties of the same and different amorphous states are significant.

The ground is affected by the chemical and pharmaceutical treatment of the compound, especially when the compound is prepared or used on an industrial scale. In one aspect of the invention, the preferred crystalline form of the compound of formula (") is a polymorph I, a polymorph II, a polycrystalline germanium, and a polymorph IV. In an alternative aspect of the invention, the preferred crystalline form of the compound of formula (I) is a homopolymorph I. In another aspect of the invention, the preferred crystalline form of the compound of formula (I) is a polymorph II. In another aspect of the invention, the preferred crystalline form of the compound of formula (I) is a polymorph III.

O:\100\100134.DOC In another aspect of the invention, the preferred crystalline form of the compound of formula (1) is a polymorph IV. In another aspect of the invention, the compound of formula (1) is in a substantially amorphous form. In the amorphous form, the two-dimensional long-range order usually exists in the crystalline form (for example, polymorphism), and the molecular positions in the amorphous form are random on the surface (see BC Hancoci<^G Zografi J. Pharm. Sci· (1997) 86 1. The amorphous form of the compound of formula (I) is called form α. We have isolated the compound of formula (I) into crystalline and amorphous forms. It is either anhydrous or intrinsically free ("dehydrated" morphology.) Therefore, in one aspect of the invention, a compound of formula (1) in a crystalline form or an amorphous form in a dehydrated form is provided. The noun "substantially pure Essentially dehydrated morphology" does not exclude the presence of solvents in the lattice structure or outside the lattice structure, including water. The dehydrated form has less than 4 water molecules per molecule (less than 40% hydration). Preferably, the dehydrated form contains less than one water molecule per molecule of molecules. The homogeneous polycrystals I, II, III, and 1 may refer to their melting origin, powder X-ray diffraction pattern, and/or single crystal germanium _ Different from ray data. Polymorph I has a melting initiation point of 146-152 ° C when it is in a substantially pure and essentially dehydrated form, for example, about 15 Å (:. Polymorph II is in a substantially pure and dehydrated form on the f) , having a melting starting point of 136-139 ° C, for example, about 137 5 < t. With the beak 曰曰 III in its substantially pure and essentially dehydrated form, it has 127-132. , about 132〇c. The homogenous Ba IV has O:\IOO\IOOI34.DOC -9- 1330082, which is a melting starting point of about 139 ° C when it is in a substantially pure and essentially dehydrated form. The glass is transferred prior to melting and then crystallized into one of the above homogeneous polymorphic forms, for example, 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 a significant change from baseline. And measured by the Perkin Elmer Pyris software. It should be understood that alternative readings of melting point may be produced by other forms of equipment, or by using conditions other than the conditions described herein. Therefore, the 'referenced number is not an absolute value. This artist should The exact value of the melting point is affected by the purity of the compound, the weight of the sample, the heating rate, and the particle size. • Homogeneous polycrystal 1 has a 5.3° (±0.1°) when it is in a substantially pure and essentially dehydrated form. 20.1° (±0.1°), 20.7° (±〇.1〇), 21.〇° (±0.1°) ', and 21·3. (土ο·1.) 2Θ X-rays containing specific peaks of high intensity Powder diffraction pattern. More preferably, the 'substantially pure and essentially dehydrated polymorph is present at 53. (±0.1.), 8.0. (±0.1.), 9.6. (10)". ), 13 9. (Turkish 1〇), and 15 3. ·· (土ο·1.), 20丄. (±〇.1), 20.7. (±ο.ι.), 21.0. (〇土"), 21 3. (±0.1.), 26.2 (±0".), and 27.5. (±〇.1〇) X-ray diffraction pattern of high intensity specific peaks. Homogeneous polymorph II has a pH of 5.5 when it is in a substantially pure and essentially dehydrated form. (±0.1.), 13,5. (±0".), 18.3. (Turkish 1〇), 22 7. (Turkish 1〇) -, and 24.3. (9), 1. 2) A powder diffraction pattern containing a high intensity specific peak. More preferably 4; substantially pure and essentially dehydrated homogenous polycrystalline π is at 55. (±0.1.), 6.8. (±0.1.), 10.6. (earth (Μ.), 13 5. (Turkish 1〇), 14 9. (±0.1°) ^ 18.3« (±〇.1〇) > 19.2° (±0.1〇) , 22 7〇 (± 〇1〇) ^ 24 3〇O:\100\100134.DOC -10- 1330082 (±0.1°) and 27.1. (±0.1.) 2Θ χ-ray diffraction pattern with high intensity specific peaks. Homogeneous polycrystalline III In the case of a substantially pure and substantially dehydrated form, it has 14.0 (soil 0.1), 17.4 (±0.1), 18.4 (±〇.1), 21.4 (±0 1), and 24.1. (±〇,1.) 2Θ X-ray powder diffraction pattern containing a specific peak of high intensity. More preferably, the substantially pure and essentially dehydrated homomorphic polycrystal m has a value of 5.6 (±〇.1.), 12.5. (±0.1.), 14.0. (±0.1.), 17.4. (±〇1〇)

, 18.4. (±〇.1〇), 21.4〇 (±0.1.), 22.2. (±〇.1〇), 22_9. (±0.1.), 24.1 (±〇.1.), and 24.5. (±〇·1.) 2Θχ-ray diffraction pattern with high intensity specific peaks. Homogeneous 曰a曰IV has a value of 4.9 when it is substantially pure and essentially dehydrated. (±0.1.), 9.2. (±0.1.), U.6. (±〇 1〇), 15 6. (Turkish 1〇), and 16.4. (±0.1.) 2ΘThe χ-ray powder diffraction pattern with high intensity specific peaks. More preferably, the homogenous polycrystalline IV with a pure and essentially dehydrated quality is at 4.9.

(±0.1.), 6.0. (±0.1.), 9.2. (±〇.1〇), U.6. (±〇·1〇), 12·8〇 (soil 0.1.), 15.6. (±〇·1.), 16.4. (±0.1.), 17.2. (±0.1.), and 18.1 ο (±0.1°) 2Θ A χ-ray diffraction pattern containing a specific peak of high intensity. Form a has an X-ray powder diffraction pattern that does not contain sharp peaks when it is in a substantially pure and substantially dehydrated form. Homogeneous polymorph II, homogeneous polycrystalline m, homogeneous polycrystalline IV, and morphological ai χ ray diffraction data were obtained using a Siemens D5 〇〇〇 device. The X-ray diffraction data for homogeneous polycrystal 1 was obtained using a Philips x, Pert MPD machine. It should be understood that 'different devices and/or conditions can result in slightly different data. Therefore, the quoted number is not an absolute value.

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-1U 1330082 In an alternative state of the invention, a solvated form, e.g., a hydrated form hydrate π), may be formed. Therefore, in the state of the present invention, a hydrate of the compound of the formula (I) in a crystalline form is provided. The hydrate has 0.8 or more water molecules (80% or more hydration) per molecule of the compound. The hemihydrate has from 4 to 0.8 water molecules (40-80% hydration) per molecule of the molecule.

In another aspect of the invention, any mixture of crystalline and/or amorphous forms of the compound of formula (1) 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 any mixture of polycrystalline II and polycrystalline 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, isopropanol, isooctane, acetonitrile, water, or mixtures thereof. More preferably, the solvent is selected from the group consisting of: ethanol, ethyl acetate, isopropanol, isooctyl, water, or a mixture thereof. Suitably, the solvent is selected from the group consisting of: a mixture of methanol and water, ethanol, ethyl acetate, ethanol, and water. a mixture, a mixture of isopropyl alcohol and water, a mixture of ethyl acetate and isooctane, and acetonitrile. Compounds of formula (1) can be prepared by methods analogous to those described in WO 9905 143. In order to initiate crystallization, it is necessary to crystallize the compound of the formula (I). In order to obtain a homogeneous polycrystal of choice, it is necessary to seed the same polymorphism as desired. The compound of formula (I) can be crystallized from a suitable solvent system, for example, by cooling, by solvent evaporation, and/or by an anti-solvent (wherein the solvent of formula (I) is poorly dissolved; examples of suitable anti-solvents include heptane Or the addition of isooctane) is supersaturated to complete. The crystallization temperature and time vary depending on the concentration of the compound in the solution, the solvent system used for OA100\I00134.DOC -12-1330082, and the crystallization method employed. The compound of the formula (1) in a crystalline form can be isolated from the above reaction mixture by a technique known to those skilled in the art, for example, by decantation or filtration, and the compound of the formula (1) in a crystalline form can be dried in accordance with known procedures. The recrystallization step can be carried out using the same or different solvent systems, such as impurities, such as amorphous materials, chemical impurities, or conversion of the crystalline form from a polymorphic polymorph to another polycrystalline transformation, or Become water $ σ or dehydrated form. Furthermore, in order to remove the amorphous material, an adjustment step may be required 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 comprising seed crystals obtained from the slow crystal growth of homomorphic polycrystals derived from polymorphs, and using the same Seeding a reaction mixture comprising a compound of formula (1) and a suitable mixed solvent system (such as methanol/water). •• Other features of the invention, a method for preparing a homogeneous polycrystalline η, which is contained in, for example, ethyl acetate Crystallization in a suitable solvent. In a further feature of the invention, there is provided a process for the preparation of a polymorph III which comprises crystallization in a suitable solvent such as an alcohol, for example, ethanol or isopropanol (oxime), especially homogenous Crystallization of polycrystalline m or slurry of a compound of formula (1) in a suitable solvent such as IPA. In a further feature of the invention, there is provided a process for the preparation of a polymorph IV comprising crystallization from a suitable solvent such as acetonitrile, in particular Sown with polycrystalline IV, sa, or compound of formula (1) in a suitable solvent such as acetonitrile

O:\100MOOI34.DOC -13- 1330082 period. A further feature of the invention provides a process for the preparation of a homopolymorphic polymorph II which comprises, for example, a compound of formula (1) at 5-65. (The temperature is slurried in a Cl-6 aliphatic alcohol/aqueous solvent system (preferably IPA/water) 1-1 〇 day β. In other features of the invention, a formula for producing a substantially amorphous form is provided (I) A method of a compound comprising lyophilizing or spray drying a solution of a compound of formula (1) using a suitable solvent system, such as 'ethanol/water'.

The term "substantially absent" means less than 10% of other homogeneous polycrystals, preferably less than 5%. In other aspects of the invention, a compound obtained by any of the above methods is provided. The compound of formula (1) in crystalline and/or amorphous form is a P2T (P2Yadp4 P2Tac) receptor antagonist. Thus, the compound of formula (1) in crystalline and/or amorphous form can be used in therapy, including combination therapy. The compound of formula (1), in particular 'crystalline form, is indicated for the treatment or prevention of arterial thrombosis complications in patients with coronary, cerebrovascular or peripheral blood I® disease. Arterial thrombosis complications may include unstable angina, aortic thrombosis complications of arteriosclerosis, such as blood stasis or vascular obstruction, temporary ischemic attack, peripheral vascular disease, myocardial infarction with or without thrombolysis, due to arteries Sclerosing disease interventions (such as vasodilation • surgery, including coronary vasodilation (PTCA), endarterectomy) • stent placement, coronary artery, and other vascular grafting procedures, arterial complications, surgery or Mechanical damage (such as accidental or surgical trauma tissue using 'reconstruction surgery, including skin and tendon) thrombosis complications, diffusion thrombosis / platelet depletion conditions, such as disseminated subcutaneous coagulation, blood stasis platelet reduction O: \ lOOMOOl34.DOC -14· 1330082 Less purple spot syndrome 'dissolving jk uremia syndrome' thrombosis complications of sepsis, adult respiratory distress syndrome 'antiphospholipid syndrome, heparin induced thrombocytopenia and surnamed toxemia / collateral toxemia, or vein Gray examinations, such as deep vein thrombosis, venous obstruction, blood conditions, such as myeloproliferative diseases, including small blood Reduced disease, sickle cell disease; or prevent mechanically induced activation of living platelets, such as cardiopulmonary bypass and in vitro cell membrane oxidation (prevention of microthrombotic disease), mechanically induced platelet activation in vitro, such as for preservation of blood products, such as I, blood plate concentrates , or shunt obstruction, such as renal dialysis and plasma removal, secondary to vascular damage/inflammation of thrombosis, such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ transplant rejection, such as migraine, Raynaud's disease A condition of a phenomenon in which platelets cause a inflammatory disease process under the blood vessel wall, such as atherosclerotic blood group formation/development, narrowing/re-narrowing, and other inflammatory conditions such as stagnation, in which platelet and platelet-derived factors are involved. Immune disease is too much. Other indications include treatment of the disease and prevention of tumor growth and spread. In accordance with 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. Further, according to an additional feature of the present invention, a compound which is a medicinal agent and/or a non-daily morphological formula (I) is provided. Preferably, the formula (1) is crystalline and/or amorphous. The substance acts as a medical agent against Pa or ρ2Τα〇 and endosomes in a warm-blooded animal such as human. More preferably, the formula (1) of the crystalline and/or amorphous form is a medical agent for treating a disease of a coronary artery, a cerebrovascular disease or a disease of the heart, or preventing a thrombosis of an arterial thrombus in a warm-blooded animal such as a human. According to the invention of the invention, a compound of the formula (1) which provides a crystalline and/or amorphous form is further provided.

O:\IOO\100I34.DOC -15- 1330082

Use as a pharmaceutical agent for Ph (P2Yadp or P2TAC) receptor antagonists. In particular, the compound of formula (I) which further provides a crystalline and/or amorphous form is useful for the manufacture of a pharmaceutical agent for treating or preventing arterial thrombotic complications in a patient having coronary, cerebrovascular or peripheral vascular disease. 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 non-susceptibility to a person suffering from or susceptible to the disease. Crystal form (work) compound. The compound of formula (1) having a combination of aa and/or amorphous form may be in the form of a solution, suspension, HFA aerosol, and dry powder formulation, for example, topically applied to the lungs and/or airways; or systemically, for example, Oral administration in the form of a bond, pill, capsule, syrup, powder, or granule, or sterilized parenteral solution: or suspension parenteral administration, subcutaneous administration, or rectal administration in the form of a suppository, or brain Apply medicine internally. The compound of the formula (1) in the form of 曰曰 and/or amorphous form may be applied directly or as a pharmaceutical composition comprising a pharmaceutically acceptable diluent, an adjuvant and/or a carrier of a compound of the formula (1) comprising a crystalline and/or amorphous form. medicine. Accordingly, other features of the present invention provide a pharmaceutical composition comprising a compound of formula (1) comprising a crystalline and/or amorphous form in combination with a pharmaceutical, a diluent, an adjuvant and/or a carrier. It is particularly preferred to be a composition free of materials which can cause adverse reactions such as negative allergic reactions. The dry powder of the compound of the formula (1) in the form of crystallization and/or amorphous % can be used for administration by oral or nasal inhalation. & Inhalation, it is desirable to have a finely divided compound of formula (1) in the form of == and/or amorphous form, and the compound of formula (1) which is not in the form of a compound can also be applied by a dry powder inhaler. Inhaler can be

O:\IOO\100I34.DOC 1330082 Single or multiple dose inhalers' and may be a breath actuated dry powder inhaler. One possibility is to mix the finely divided crystalline and/or amorphous form of the compound of formula (1) with a carrier material, for example, a mono-, di- or polysaccharide, a sugar alcohol or other polyol. Suitable carriers include sugars and starches. Alternatively, the compound of formula (1) in a finely divided crystalline and/or amorphous form may be coated with other materials. 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 (I).

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 drug reservoir of a multi-dose inhaler, for example, as known from Turbuhaler 8, wherein the dosage unit will meter the desired dose' which is then inhaled by the patient. This system delivers the active compound of formula (1) with or without a carrier material to the patient. The pharmaceutical composition of the compound of the formula (1) comprising crystalline and/or amorphous oxime may conveniently be an oral drug, a syrup, a syrup, a powder, or a granule; a sterilized parenteral or subcutaneous solution, a parenteral administration Suspension, or rectal administration of suppositories. In order to take the 'crystalline and/or amorphous form of the drug, the compound of formula (1) can be used as an adjuvant or carrier, for example, lactose, sucrose, glucose alcohol, mannitol, such as horse mash, corn granules or Branched starch temple powder, cellulose derivative two wins or polyethylene base ... 嗣 point mixture, and such as stearic acid town two, polyethylene glycol 'soil, chain burning hydrocarbons and other lubricants, and then pressed fruit: The core prepared as above may be coated with concentrated sugar titanium or the like. Or: 筚 = Arabian Yao, gelatin, talc powder 'suitable polymer for dioxidation · Valley in volatile organic solvents or aqueous solvents

O:\IOO\l0O134.DOC -17. 丄330082 β For the preparation of soft gelatin capsules, the compound of formula (1) in crystalline and/or amorphous form may be blended, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules can be shaped with the above-mentioned music! For example, lactose, sucrose, glucose alcohol, mannitol, starch, cellulose derivatives, or gelatin, which contain the granules of the compound, can also be filled into the hard gelatin kicker with a liquid or semi-solid formulation of the drug.

The liquid preparation for oral use may be in the form of a syrup or suspension, for example, a solution containing a compound of the formula (1) in a crystalline and/or amorphous form, the balance being a mixture of hydrazine and ethanol water, glycerin, and propylene glycol. Optionally, the liquid system πσ may contain colorants, flavoring agents, saccharin, and carboxymethylcellulose as a thickening agent, or other excipients known to those skilled in the art. It will be appreciated that sample analysis using particles larger than 30 microns and non-single aspect ratios may affect the relative intensity of the peaks. Those skilled in the art should also understand that the position of the reflection is corrected by the precise height of the sample at the diffractometer and the zero of the diffractometer.

The shirt is ringing. 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 US_[la 2a 3i3(ls:j!, 2R!) 8), 5i^_3_(7_{[2_(3,4_monophenyl)cyclopropyl] Amino}-5-(propylthio)-3Η-1,2,3-triazole [4,5-d]-penetrating _3_yl)5(2hydroxyethoxy)cyclopentane·12 Glycol Part 1 The compound of formula (I) (2 mg) in the form of a homogeneous polymorph II is heated and cooled in DSC in the following manner: 35 to 143 to 35 to 148 to 35 to 148 to 35 °C. 〇:\100VI0OI34.DCM: • 18 · 1330082 This annealing process results in the crystallization of pure polymorphous I, as indicated by DSC. Part 2 contains a solution of the compound of formula (I), 5 mg/g of methanol, with 7.3 mg/g of water, and a small amount of homogeneous polycrystalline I seed crystallized at 3 ° C. XRPD and DSC confirm that substantially pure homogeneity has been formed. Crystal j. Example 2

{lS-[la,2a,3p(lS*,2R*),5p]}-3-(7.{[2. (3,4-difluorophenyl)cyclopropyl] in the form of polymorphic polymorphism II Amino}_5_(propylthio)_311_123_triazolo[4,5-d]-pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol will be gas Imitation (150 microliters) was added 45 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 and dried under flowing nitrogen. XRPD and DSC confirmed the formation of substantially pure polycrystalline η. Example 3

{lS-[la,2ot,3P(lS*,2R*),5p]}-3-(7-{〇(3,4-difluorophenyl)cyclopropyl]amino group in the form of polymorphic III }·5_(propylthio-3-triaz[4,5-d]-pyrimidin-3-yl)-5·(2-hydroxyethoxy)cyclopentane-1,2-diol ethanol (200 Microliters) 10 mg of the compound of formula (I) was added, and the mixture was warmed to dissolve in a steam bath. The resulting solution was allowed to stand to crystallize overnight. XRPD and DSC confirmed that substantially pure polymorphs II and III had been formed. Preparation for larger scale seeding: 191 mg of homopolymorph II was slurried in 1 ml of 50% aqueous isopropanol solution. 15 mg of mixed polycrystalline II/III seeds were added to the slurry. Complete conversion to homogeneous polycrystal III, as confirmed by XRPD Example 4 〇: MOOMOOI34.DOC -19- 1330082 Homogeneous polymorphic 1乂 form {18-[1〇1,2〇1,邛(18*,211* ), 50]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino}_5_(propylthio)_3H1,2 3•triazole [4,5- d]-pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-12 diol acetonitrile (0.12 ml) was added to 1 mg of the compound of formula (1), and The mixture was warmed to dissolve. The warming solution was slowly cooled in a hot water jacket. The resulting crystals were dried under nitrogen. XRPD showed it to be a homogeneous homogeneous polycrystal.

Example 5 [lS-[la, 2a, 3p(lS*, 2R*), 50] p3. (7. U2_(3,4-fluoro-based) 3⁄4 propyl]amino}- 5-(propylthio)-3H-1,2,3 -=sal[4,5-d]- shie-3-yl)-5-(2-carbylethoxy)cyclopentane _1 , 2_diol The compound of formula (I) (21 8 mg) was dissolved in 50% aqueous ethanol (24 ml). To this solution was added dropwise another 14.5 ml of water. The resulting saturated solution was then subjected to cold image drying using a Virtis apparatus under the following conditions (vacuum 2170 mTorr, carry-over time 20.2 hours, condensation temperature - 52 eC, ambient temperature 20.3.

Reference Example 1 {lS-[la, 2a, 3p(lS*'2R*), 5P]}-3-(7-{[2-(3,4·difluorophenyl)cyclopropyl]amino} -5-(propylthio)-311-1,2,3-tris[4,5-(1]-mouth _3_yl) 5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol {3aR-[3aa,4a,6a(lR*,2S*),6aa]}-2-[6-({7-[2-(3,4-diphenylphenyl)cyclopropane Amino-5-(propylthio)-3Η_1,2,3-triazole[4,5-d]-唆唆·3-yl}•tetrahydro-2,2-dimercapto-4H- Cyclopentyl-1,3-dioxo-4-yl)oxy]ethanol (Method A '0.59 g) in a solution of trifluoroacetic acid (15 mL) and water (15 mL) 30 minutes. Carefully add the reaction mixture to a solution of sodium bicarbonate (21 g 〇:\l〇0\10〇134.D〇C -20-1330082) in water (150 ml) and stir 3 The mixture was extracted with ethyl acetate, dried and evaporated. EtOAc EtOAc (EtOAc) 523 (M+H+, 100%); NMR: 8.95 (1H, d, J=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 = l3.6, 8.5), 2.29-2.21 and 2.16-2.09 (1H, m), 2.07-2.00 (ih, m), 1.73.1.33 (4H, m) 0.99 ( 3H, t, J = 7.4). The raw materials for the preparation of the raw materials are commercially available or can be prepared from known materials by standard methods. For example, the following reactions are descriptions of some of the raw materials used in the above reaction, but are not limited.

Method A. Lu {3&仗-[3&〇1,4〇1,6〇1(111*,28*),6&〇1]}-2-[6-({7-[2-( 3,4-difluorophenyl)cyclopropyl]amino-5-(propylthio)_3Η·12,3_triazole [4 5 d]pyrimidine % group}-tetrahydro-2,2-dimethyl Addition of DIBAL-H® (M-solution, 5 15 ml) to {3仏[3 commit, 4«plus (111*,28*),6_}_{[6_(7_{[2_(3,4-difluorophenyl)cyclopropyl]amino-5-(propylthiotriazole [4 5_d]-pyrimidine · 3-yl}_tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3.dioxy)oxy] decyl alcohol (method oxime, 0.76 g) in THF (1 mL) ice cold The solution, and the solution was stirred at this temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc After vigorous stirring for 16 hours, the organics were collected and re-extracted with ethyl acetate (2×50 mL). The combined organics were dried and concentrated, and the residue was purified (Si 〇 2, isohexane: ethyl acetate 〖: 1 as a dissolving agent) Produce The title compound (0.63 g) .MS (APCI) 563 (M + H +, 100%).

Method B

{3aR-[3aa, 4oc, 6a(lR*, 2S*), 6aa]}-{[6-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-5 -(propylthio)-3Η-1,2,3-triwa[4,5-d]-pyrimidin-3-yl}·tetrahydro-2,2-dimethyl-4H-cyclopenta-1, Methyl 3-dioxo-4-yl)oxy]acetate in [3aR-(3aa,4a,6ot,6aa)]-({6-[7-indol-5-(propylthio))-3H-1 , 2,3·triazole [4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-4-ol}oxygen Ethyl acetate (method d, 0.80 g) and (1R-trans)-2-(3,4-difluorophenyl)cyclopropylamine, [R-(R*,R*)]_2,3-di N,N-Diisopropylethylamine (0.85 mL) was added to a mixture of succinimide (1:1) (Method C </ RTI> </ RTI> <RTIgt; The resulting solution was stirred at room temperature for 6 hours and then concentrated in vacuo. Purification (Si 2 , isohexane: ethyl acetate 3:1 as solvent) gave the title compound as colourless foam (0.77 g). MS (APCI) 591 (M+H+, 100%).

Method C (111-trans)-2-(3,4-difluorophenyl)cyclopropylamine, [11-(11*,11*)]-2,3-dihydroxysuccinate (1:1)

The title compound can be prepared according to the procedures described in WO 9905 143. Method D

[3aR-(3aa,4a,6a,6aa)]-({6-[7-bromo-5-(propylthio)-3Η-1,2,3-three OA100M00134.DOC -22- 1330082 0 sitting [ 4,5-&lt;1]-mouth-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxo-4-ol}oxy)acetic acid decyl ester [3aR-(3aa,4a,6oc,6aa)]-({6-[7-Amino-5-(propylthio)-3H-1,2,3-tris[4,5-&lt;1 ]- mouth bite _3-yl]-tetrahydro-2,2-dimethyl-411-cyclopenta-1,3-dioxo-4-ol}oxy)acetic acid methyl ester (method ugly, 1_1 g) And isovaleronitrile (24 ml) was heated in bromoform (30 ml) at 80 °C for 30 min. The cooled reaction mixture was purified (Si〇2' ethyl acetate: iso-hexane 1 : 4 as a dissolving agent) to provide the standard

Compound (0_44 g). MS (APCI) 502/4 (M+H+), 504 (100 ❶/〇).

Method E

[3aR-(3aa,4a,6a,6aa)]-({6-[7-Amino-5-(propylthio))3H-1,2,3-triazole[4,5-d]-pyrimidine Methyl-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-4-ol}oxy)acetate

[3aR-(3aa,4a,6a,6aa)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-tris-[4,5-d]-pyrimidine Benzyl-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-4-ol (Method F, 0.50 g) in THF (25 mL) Add butyl lithium (0.62 ml of 2.5 N hexane). After 20 minutes, the suspension was burned with dioxane to oxidize the oxyacetic acid (0.34 g) (according to Biton's Tetrahedron, 1995, 51, 10513). The title compound (0.25 g) was obtained from EtOAc (EtOAc). MS (APCI) 439 (M+H+, 100%).

Method F

[3aR-(3aa,4a,6ot,6aa)]-6-[7-Amino-5-(propylthio)_3H-1,2,3-triazole[4,5-d]-pyrimidine-3 -yl]-tetrahydro-2,2-dimercapto-4H-cyclopenta-1,3-dioxo-O:\100M00134.DOC -23- 1330082 4-alcohol [3aR-(3aa,4a,6cx, 6aa)]-6-[7-chloro-5-(propylthio)-3Η-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2 -Dimethyl-4H-cyclopenta-1,3-dioxo-4-alcohol (Method G, 13.2 g) was stirred in THF (200 mL) EtOAc (EtOAc) The residue was distributed between water and ethyl acetate. The organics were dried <RTI ID=0.0> MS (APCI) 367 (M+H+, 100%) °

Method G

[3aR-(3aa'4a,6a,6aa)]-6-[7-chloro-5-(propylthio)·3Η-1,2,3·triazole [4,5-d]·pyrimidin-3-yl ]-tetrahydro-2,2-dimethyl-4-anthracene-cyclopenta-1,3-dioxo-4-ol added isovaleronitrile (1.1 ml) to [3&amp;11-(3&amp;〇6,4〇 1,6〇1,6&amp;〇1)]-6-{[5-Amino-6-gas·2-(propylthio)-pyrimidin-4-yl]amino}-tetrahydro-2,2 - Dimercapto-4 Η-cyclopenta-1,3-dioxo-4-ol (method Η ' 2.0 g) in acetonitrile (1 mL), and the solution was heated at 70 ° C for 1 hour. The cooled reaction mixture is concentrated and purified (Si〇2, acetic acid, ethyl acetate, isopropanol 1:3 as a dissolving agent) to provide the title

Compound (1.9 g). MS (APCI) 386 (M+H+, 100%). Method Η [3&amp;11-(3,4〇1,6〇1'6&amp;〇〇]-6-{[5-Amino-6-chloro-2-(propylthio)-pyrimidine_ 4- Amino]-tetrahydro-2,2-dimethyl-4-anthracene-cyclopenta-indole, 3-dioxy-4-ol added iron powder (3.0 g) to [3&amp;11-(;^〇1 ,4〇1,6〇1,6&amp;〇〇]-6_{[6-gas-5-nitro-2-(propylthio)-pyrimidin-4-yl]amino}-tetrahydro-2, 2_Dimercapto_4Η•cyclopenta-1,3-dioxy-4·ol (Method I, 2-7 g) in a stirred solution of acetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hr. To a half volume, diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated to afford titled: EtOAc: EtOAc: EtOAc: +H+, 1001⁄4).

Method I

[3aR-(3atx,4a,6a,6aa)]-6-{[6-gas-5-terminal-2-(propylthio)_mouth bite-4-yl]amino}tetrazine_2, 2_Dimethyl-411-3⁄4戍-1,3-oxo-4-ol

[3&amp;-(3&amp;〇1,4〇6,6〇〇,63〇〇]-6-aminotetrahydro-2,2_didecyl_4^cyclopenta-1,3-di Oxy-4-ol, a solution of the hydrochloride salt (Method J, 10.0 g) and N,N-diisopropylethylamine (35 mL) in THF (600 mL) A solution of 4,6-dichloro-5-nitro-2-(propylthio) coughidine (WO 9703084), 25.6 g of a solution in THF (1000 ml) was added over 1 hour, and stirred 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%) 〇 Method J

[3 ugly 11-(33〇6,4(1,6〇1,6 ugly]-6-aminotetrahydro-2,2-dimethyl-41^cyclopenta-1,3-diox -4-ol, hydrogen salt [1Κ·-(1α, 2β, 3β, 4α)]-2,3,4-trihydroxycyclopentenyl quinone iminodicarbonate, hydrazine (1,1-dimethyl Ethyl ester (method oxime, 17.4 g) was stirred in 6 M HCl (1 mL) / methanol (500 mL) for 18 hours. The mixture was evaporated and then azeotroped (4 x 200 mL) to give a colorless powder. (8.7 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. Evaporation and azeotrope with toluene (3 χ 200 ml). The residue was dissolved in 20% aqueous acetic acid and stirred for 2 hours. The mixture was evaporated and azeotroped with toluene (4 χ 2 〇〇ml) to provide the standard O:\100U OOJ34.DOC - 25- 1330082 Compound (10.1 g). MS (APCI) 174 (M+H+, 100%).

Method K

[1R-(1 α,2β,3β,4α)]·2,3,4-trihydroxycyclopentenyl quinone iminocarbonate, hydrazine (1,1-dimethylethyl) ester

(1R-cis)-indole (1,1-dimethylethyl)-4-hydroxy-2-cyclopentenyl quinone iminodicarbonate (method L, 17.1 g) in THF (500 mL) A solution of /water (50 ml) was added to N-hydrazinyl-N-oxide (9.4 g) followed by tetraoxide (10 mL, 2.5% solution in hexanes). 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 (EtOAc) (EtOAc (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjj , 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).

Method L

(1R-cis)-indole (1,1-dimethylethyl)-4-hydroxy-2-cyclopentenyl quinone iminodicarbonate in sodium hydride washed with ether (60% suspension in oil) To a suspension of THF (30 ml) was added hydrazinium dicarbonate (1,1-dimethylethyl) ester (1.84 g). The mixture was stirred at 40 ° C for 1 hour. Then, at the temperature of the week, (1S-cis)-4-ethyloxy-2-cyclopentan-1-ol (〇.5g) and hydrazine (triphenylphosphine)palladium (〇) are added to the mixture. 18 grams). The reaction mixture was stirred for 24 hours then purified (EtOAc, EtOAc (EtOAc) NMR: i.43 (18H, s), 1.61 (1H,ddd, 〇Al00\I00I34.DOC •26- 1330082 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 a representative pharmaceutical dosage form of a compound of formula (I) (hereinafter referred to as Compound X) containing a crystalline and/or amorphous form for therapeutic or prophylactic use in humans:

(a) Ingot I mg / medicinal compound X 100 Lactose Ph. Eur 182.75 Croscarmellose sodium 12.0 Magnolia starch slurry (5% w/v slurry) 2.25 Magnesium stearate (b) Tablet II Compound X Lactose Ph. Eur Croscarmellose Sodium sulphate Thai powder powder (5% λγ/ν loading) 3.0 mg/drug 50 223.75 6.0 15.0 Polyvinyl P Piroprofen magnesium stearate (c) Tablet III Compound X Lactose Ph.Eur Croscarmellose Nano 2.25 3.0 mg / drug key 1.0 93.25 4.0 OMOO\100134.DOC •27 1330082

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 Hydrogen 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 (adjustment 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 O:\lO0UOO134.DOC -28 1330082 Note The above formulations can be obtained by well-known 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 300 or 400 spectrometer; NMR data were quoted as the delta value of the primary diagnostic proton, expressed in parts per million (ppm) relative to the tetramethyl sulphur (TMS) as an internal standard. It uses total dimethyl hydrazine (DMSO-56) 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 ) is expressed in Hz. 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. Inter-write THF Tetrahydrofuran XRPD X-ray powder diffraction DSC differential scanning calorimeter [Simple diagram] Figure 1.1 is an X-ray diffraction pattern of homogeneous polycrystalline I using Philips O:\I00\100134.DOC •29 - 1330082 The X'Pert MPD machine is available in a scan range of 1° to 40. 2Θ, with a Θ-Θ configuration of 2 or 5 seconds exposure in increments of 0.02. X-rays were produced by copper long-fine focus tubes operating at 40 volts and 50 milliamps. The X-ray wavelength is 1.5406 angstroms.

Figure 1.2 is an X-ray diffraction pattern of a homogeneous polycrystalline II using a Siemens D5000 machine at 2. The scan range to 30. 2 , is obtained for every 0.02. 2 Θ increment of 4 sec exposure. X-rays are produced by copper long-fine focus tubes operating at 45 volts and 40 milliamps. The X-ray wavelength is 1.5406 angstroms. The data was collected using a zero background in which ~10 mg of compound was placed. The holder is made of a single crystal crucible that 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 an X-ray diffraction pattern of polycrystalline III using the Siemens D5000 machine described above. Figure 1.4 shows an X-ray diffraction pattern of homogeneous polycrystalline IV using the Siemens D5000 machine described above.

Figure 1.5 is an X-ray diffraction pattern of Form a using the Siemens D5000 machine described above. Figure 2 shows DSC plots of homogeneous polycrystals I, II, III, 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 (30 ml/min) and the temperature range of the study was from 30 ° C to 325 ° C at a fixed temperature increase rate of 10 ° C per minute. O:\100\100134.DOC -30-

Claims (1)

1330082 May) = Patent application No. 094107365 Chinese patent application scope replacement (99 years X. Patent application scope: - Compound of formula (I): HN HO OH (1) F is characterized in that it is substantially pure polycrystalline π, which is characterized by 5.5. (±0.1.), 13.5. (±0.1.), 18.3. (±0.1.), 22.7. (±0.1°) and 24.3. (±0.1.) 2Θ X-ray powder diffraction pattern containing high intensity specific peaks. 2. A compound of formula (I) according to claim 1 which is present in a dehydrated form having substantially less than 0.4 water molecules per compound molecule. 3. A compound of formula (I) according to claim 1 which is characterized by being 5.5. (Turk. 1.), 6.8. (±0.1.), 10.6. (±0.1.), 13.5. (Soil 0.1.), 14.9. (±0.1.), 18.3. (±0.1 0), 19.2. (±0.1.), 22-7. (±0.1.), 24.3. (±0·1.) and 27.1 0 (±〇_1°) 2θ X-ray diffraction pattern containing high intensity specific peaks. 4. A compound of formula (I) according to claim 1 or 2, characterized in that the differential scanning calorimeter curve has a melting starting point in the range of from 136 to 139 °C. 5. A compound of the formula (I) according to claim 1, which is a hydrate form having 8 or more water molecules per molecule of the compound. 6. A process for the preparation of a compound of formula (I) according to claim 1, wherein the compound of formula (1) is 100134-990506. The DOC 1330082 system is crystallized from ethyl acetate. 7. A compound according to claim 1 or 2 which is used as a pharmaceutical agent. 8. A pharmaceutical composition comprising a solid pharmaceutically acceptable adjuvant, diluent or carrier according to any one of claims 1-5. A pharmaceutical composition for preventing an arterial thrombosis complication of a patient having a coronary artery, a cerebrovascular or a peripheral vascular disease, which comprises the solid compound according to any one of claims [5]. 10. Use of a solid compound according to any one of claims (1) for the manufacture of a medicament for preventing arterial blood stasis complications in a patient having coronary artery, cerebrovascular or peripheral vascular disease. 11. Use of a solid compound as claimed in any of claims 5 to 5 for the manufacture of a medicament for the treatment of arterial thrombosis complications in a patient having a coronary artery, a cerebral choroid or a peripheral syringle. I00134-990S06.DOC 1·