TW201034672A - Mixture of crystalline forms of triazolo (4,5-D) pyrimidine compound - Google Patents

Abstract

The invention provides new forms of a chemical compound, processes for their preparation, their use as medicaments, and compositions containing them.

Description

201034672 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to the form of chemical compounds, particularly crystalline and non-morphological 'more particularly four crystalline forms and crystalline forms. The invention further relates to a process for the preparation of such a form, & a pharmaceutical composition comprising a compound of crystalline and/or amorphous form' and 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. 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., 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 generally provides an unreliable degree of rotation than the crystalline material (4) (10) (4), and is 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. Therefore, in the manufacture of commercially viable and pharmaceutically acceptable pharmaceutical compositions, it is desirable to provide a drug of substantially crystalline and stable form as much as possible, and this goal is not always complete. In fact, — " and Syria, it is impossible to predict the crystallization behavior of a compound by its molecular structure alone, and it is usually only experimentally determined. 147303.doc 201034672 Platelet adhesion and coagulation is the initial state of arterial thrombosis. Although the process of platelet adhesion to the surface of the endothelium may play an important role in repairing damaged wall, the platelet aggregation caused by it may precipitate acute thrombus closure of the fatal vascular bed, resulting in high mortality such as myocardial infarction and unstable angina. Feelings = . 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 subtype of the Τ2Τ receptor on the platelet cell membrane. The main drug of Ρπ receptor (also known as P2Yadp or P2Tac) involves conduction coagulation/activation, and is a protein-coupled receptor that is not yet able to reproduce. The pharmacological characteristics of this Cannes are described, for example, in Humphries et al., Br. J. Pharmacology (1994), 113, ι 57_1〇63, and Fagura et al. Br. J. Pharmacology (1998) 124, 157 -164 reference material. It has recently been shown that the antagonist of this receptor provides a significant improvement over other antithrombotic agents (see J. Med. Chem. (1999) 42, 213). International Patent Application No. 9905143 discloses a series of triazole [4,5-d]pyrimidine compounds having an antagonist activity as 1>21(1)2¥8 1)1> or P2TAC. The compound of formula (1) (described below) contains the general scope of International Patent Application No. 9905 143' 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: 1473〇3.d〇i 201034672

HO

HN^n7

The formula (1) of β is known as: 5β]}-3-(7-{[2-(3,4< lphenyl)cyclopropyl]amino}_5_(propylthio)_

3Η-1,2,3·three spit [4,5-d]-penetrating _3_yl)_5_(2_ mercaptoethoxy)cyclopentane _ 1,2-diol. The compound of formula (I) may exist in four different substantially crystalline forms, which are referred to as polymorph I, polymorph II, polymorph, and polymorph IV. The isomorphic polycrystal is a particularly crystalline form of the compound. The different physical properties of the homomorphic polymorphic forms and the relatively amorphous state are significant in the chemical and pharmaceutical treatment of the compounds, especially when the compounds are prepared or used on an industrial scale. In one aspect of the invention, the preferred crystalline form of the compound of formula (1) is in the form of benzoid I, polymorphic π, polycrystalline germanium, and polymorph IV. In an alternative aspect of the invention, the preferred crystalline form of the compound of formula (I) is a homopolymorph I. In still 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 201034672 In another aspect of the invention, the preferred crystalline form of the compound of formula (1) is a polymorph IV. In still another aspect of the invention, the compound of formula (1) is in a substantially amorphous form. In the amorphous form, usually one of the crystal length forms (for example, polymorphism) does not exist in one dimension, and the position of each other in the amorphous form is random (see B·C. 1^〇呔和(} ZografiiL pharm. Sci· (1997) 86 1. The amorphous form of the compound of formula (1) is called form α. We have isolated the compound of formula (I) into crystalline and amorphous forms. Absent or absent ("dehydrated" form). Thus, in one aspect of the invention, a compound of formula (I) is provided in a crystalline form or an amorphous form in a dehydrated form. Using nouns, substantially pure and essential The upper dehydrated form " does not exclude the presence of some solvent within the lattice structure or outside of the lattice structure, including water. The dehydration profile has less than 0.4 water molecules per molecule (less than 40 / hydrazine). Preferably, the 'dehydrated form is less than 〇 each water molecule per molecule. The homogeneous polycrystals I, II, III, and 1 can refer to their melting origin, powder χ-ray diffraction pattern, and/or single Different from crystal X-ray data. Polymorph I has a melting origin of 146-152 ° C when it is in a substantially pure and essentially dehydrated form, for example, about 1. The polymorph II has 13 6 in its substantially pure and essentially dehydrated form. -13 9 The melting starting point of C, for example, about 13 7 5 ° C. The homogeneous polycrystalline III has a simplification starting point of 12 7 -13 2 C when it is in a substantially pure and essentially dehydrated form 'for example, about 13 2. Homogeneous polymorph IV has a melting starting point of about 139 ° C when it is in a substantially pure and essentially dehydrated form. Form °1 generally undergoes glass transfer before smelting and then crystallizes above The homomorphic polymorphic form - for example, a homogeneous polycrystalline π. The melting point is determined using a Perkin Elmer 峨 7 instrument differential scanning performance meter (DSC). The melting starting point is defined as where the baseline changes significantly, and by Perkin Elmer Pyris Software measurement. It should be understood that alternative readings for refining points may be generated by other forms of farming or by using conditions other than those described herein, and the numbers quoted are not absolute values. Those skilled in the art should understand , the exact value of the melting point It is affected by the purity of the compound, the weight of the sample, the heating rate, and the particle size. The homopolymorph I has a purity of 5.3 〇 (±0"., 20" (±〇1) when it is in a substantially pure and essentially dehydrated form. .), 2〇7. (〇土〇.), 21 〇. (±〇"〇) and 21.3(9).1.) 20 X-ray powder diffraction pattern containing high-strength special materials. More preferably 'substance The same f polycrystal i which is dehydrated in the upper pure and the present f has 5.3 ( soil 0·1.), 8.G. (±(M.), 9.6 (10).1), 13.9. (10)]. ), and 15 3. (±〇·1°), 2G.1·. (±(M), 2〇.7.(9)".), 21 Q. (10)". ), η 3. (±〇.1.), 26.2. (±(U.), and 27 5. (Turkish.)) (9) X-ray diffraction pattern containing a specific peak of high intensity. The homomorphic polycrystalline yttrium has a substantially pure and dehydrated form on the f. 5.5 (±〇.1.), 13.5. (±〇1〇), 18 3. (Gentry, η 7. (Turkish., and 24.3. (±(U.) 2Θ) containing high intensity specific peaks a ray powder diffraction pattern. More preferably, the substantially pure and essentially dehydrated homogeneous polycrystalline cookware is at 55 (±0.1.), 6.8 (±0.1), 10.6. (士〇1〇), 13 5. (10) 1〇), 9. (±0.1.), 18.3. (±〇·ι.), 19.2. (±(U.), 22 7. (±〇1.), 24 3. 147303. Doc 201034672 (Soil 0.1.) and 27.1Μ±0·1°) 2Θ X-ray diffraction pattern with high intensity specific peaks. Homogeneous polycrystal III has a purity of 14.0 when it is in a substantially pure and essentially dehydrated form. ±0.1.), 17.4. (±0.1.), 18.4. (Turkish 1〇), 21 4. (+〇, ι〇), and 24.i. (ed.) 2 高 high intensity specific peak 乂The ray powder diffraction pattern. More preferably, the substantially pure and essentially dehydrated polycrystalline Ι π has a value of 5.6. 0.1), 12.5 (±0.1), 14.0 (±〇1), 17 4〇 (±〇ι〇), 18.4 (±0.1), 21.4 (±0)., 22.2. (±〇1〇), 22 9. (土〇ι〇), 24.1. (soil 0.1.), and 24.5. (soil 0.1.) 2Θ _ray diffraction pattern containing high intensity specific peaks. Homogeneous polycrystalline IV When it is in a substantially pure and essentially dehydrated form, it has 4.9 (±0_1.), 9.2 (±0.1), U_6 (±〇1〇), and 15.6 (〇1〇), And 16.4. (±0.1.) 2 χ χ 粉末 powder diffraction pattern containing high intensity specific peak. More preferably, substantially pure and essentially dehydrated homogeneous polycrystalline 1 ¥ at 49. (±0.1.), 6.0 (±0".), 9.2〇(±0·1〇), u 6. (土〇ι〇), 12 8〇 (±0.1.), 15.6° (±(M.), 17 2 (( 〇 〇 绕 、 、 ± ± ± ± ± ± ± 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线 射线Ray powder diffraction pattern. Homogeneous polycrystalline π, homogeneous polycrystalline germanium, homogeneous polycrystalline 1 ¥, and morphological shot Diffraction data obtained using Siemens D5000 equipment. Polymorphism X- ray diffraction data obtained using the device. It should be appreciated, different apparatus and / or conditions may result in slightly different data generation. Therefore, the number quoted is not an absolute value. 147303.doc 201034672 • In an alternative state of the invention, a solvate form, for example, a water-form hydrate hydrate, can be formed. Thus, in the state of the invention, a hydrate of a compound of formula (I) is provided. The hydrate has 〇8 or more water molecules (80% or more hydrates) per molecule of the compound. The hemihydrate has 0.4 to 0.8 water molecules (4 〇 80% hydrate) per molecule of the compound. 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, a homogenous 11, a polymorph 111, and a homogeneous Crystal IV, and/or Form a. More preferably, the present invention provides any mixture of homopolymorphs and homopolycrystals m. In a further feature of the invention, there is provided a process for the preparation of a crystalline form of a compound of formula (1) 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, isooctane, 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. Mixing ◎ 16, a mixture of isopropyl alcohol and water, a mixture of acetic acid and isooctane, and acetonitrile. Compounds of formula (I) can be prepared by methods analogous to those described in U.S. Patent No. 5,5,143. In order to introduce, ',.曰曰, 播种 is to be crystallized with the compound of formula (1). In order to obtain a homogeneous polycrystal of choice, it is necessary to seed the same polymorphism as desired. The compound of formula (1) can be crystallized from a suitable solvent system, for example, by cooling, evaporation by solvent, and/or by a magical agent (wherein the solvent of the formula (1) is poorly dissolved; examples of suitable antisolvents include heptane or isooctane The addition of the burnt) is completed by the excess. The crystallization temperature and time vary depending on the concentration of the compound in the solution, the solvent system used in 147303.doc 201034672, and the crystallization method employed. The crystalline form of the compound of formula (I) can be isolated from the above reaction mixture using techniques known to those skilled in the art', e.g., by decantation, filtration or centrifugation. The compound of the formula (I) in a similarly crystalline form can be dried in accordance with 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 the crystalline centroid from a homogeneous polycrystal to another polycrystalline transformation, or to become Hydrated or dehydrated form. In addition, 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 another feature of the invention, there is provided a method of preparing a homogeneous polycrystalline ι comprising a seed crystal of a plurality of polycrystalline germanium obtained by slow crystal growth of a polymorph I obtained from a polymorph 11 , and using the same The reaction mixture comprising the compound of formula (1) and a suitable mixed solvent system (such as methanol/water) is sown. In a further feature of the invention, there is provided a process for the preparation of a homopolycrystalline fluorene which comprises crystallization 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 homopolymorphic m comprising crystallization in a suitable solvent such as an alcohol, for example ethanol or isopropanol (IPA), especially in the crystallization of homogeneous polycrystalline m crystals. Or the compound of formula (1) is slurried in a suitable solvent such as IPA. In a further feature of the invention, there is provided a process for the preparation of a homopolycrystal comprising crystallization from a suitable solvent such as acetonitrile, in particular a crystal of homogeneous polycrystalline IV, or a compound of formula (1) in a suitable solvent such as acetonitrile. Slurry 147303.doc -10· 201034672 . Other features of the invention provide a method for preparing a homopolymorph without polymorph II comprising, for example, a compound of formula (1) at a temperature of 5 valent in a Cl. 6 aliphatic alcohol/aqueous solvent system (preferably IPA / water) in the pulping day. In a further feature of the invention, a method of making a compound of formula (1) in a substantially amorphous form is provided which comprises using a suitable solvent system such as 'ethanol/water, cold; east drying or (10) drying a solution of the compound of formula (1). The term "substantially free" means less than 10% of other polymorphic polymorphs, preferably less than ^ 5%. In other aspects of the invention, there is provided a compound obtained by any of the methods described above. The compound of formula (1) in crystalline and/or amorphous form is Ρ2Τ (ρ2γ guess or ρ2τ^ receptor antagonist). Thus, the compound of formula (1) in crystalline and/or amorphous form can be used in therapy, including combination therapy. In particular, crystallization The morphological formula (1) is indicated for the treatment or prevention of arterial thrombotic complications in patients with coronary, cerebrovascular or peripheral blood stenosis. Arterial thrombosis complications may include unstable stenosis, arteriosclerosis and aorta Thrombosis complications, such as blood tests or blood stasis, stroke, transient ischemic attack, peripheral vascular disease, myocardial infarction with or without thrombolysis, interference due to arteriosclerosis (eg, vasodilation, including coronary vasodilation) PTCA), endarterectomy, stent placement, coronary arteries, and other vascular grafting procedures; sacral arterial complications, surgical or mechanical damage (such as tissue use for accidental or surgical trauma, reconstruction surgery, including Thrombosis complications of skin and tendon), conditions of blood stasis/platelet depletion, such as disseminated subcutaneous coagulation, thrombotic platelets 147303.doc -11- 201034672 Less purple spot syndrome, 35 groups of hemolytic uremic syndrome, sputum complications of ▲ syndrome, adult respiratory distress syndrome, anti-lipidemia syndrome, heparin-induced thrombocytopenia and pre-pregnancy toxemia/gestational toxicity Hemorrhage, or venous thrombosis, such as deep veins ▲• suppository venous obstruction, blood conditions, including thrombocytopenia, sickle cell disease; or such as myeloproliferative diseases, including prevention of mechanically induced platelet activation, such as cardiopulmonary bypass In vitro cell membrane oxidation (prevention of micro-blood detection) mechanically induced platelet activation in vitro, such as for preservation of blood products, such as 'blood plate concentrates, or shunt obstruction, such as f dialysis and de-plasma method secondary to vascular damage/inflammation Thrombosis, such as colitis, arteritis, glomerular nephritis, inflammatory bowel disease and n-graft rejection, such as migraine, the phenomenon of Raynaud's disease's disease caused by platelets in the sputum of 4 tube wall under the inflammatory disease process' Such as the formation / development of atherosclerosis, narrowing / narrowing and other inflammatory conditions such as asthma, which ▲ small plate and platelet derived factors And immune disease processes.Other indications include treating CNS diseases 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 the additional features of the invention, it is provided as a (four) agent crystal and/or a non-formula (1). It is preferably a crystalline and/or amorphous form (1) which is a mouth-like substance as a warm-blooded animal such as human. Contrast ^ (p2YADp or pi): a medical agent of the body. More preferably, a crystalline and/or amorphous form (1) chemical cooperation: in a warm-blooded animal such as humans with coronary, cerebrovascular or weekly treatment or prevention A pharmaceutical agent for complication of arterial thrombosis. According to the present invention, a compound of the formula (1) is provided in a crystalline and/or amorphous form. 147303.doc 201034672 • A pharmaceutical agent for the P2T (P2Yadp or P2Tac) receptor antagonist Uses. Beta, in particular, a more available, crystalline and/or amorphous form of a compound of formula (1) for the manufacture of a medicament for the treatment or prevention of complications of arterial embolus in patients with coronary, cerebral or peripheral vascular disease. use. This month also provides methods for treating or preventing arterial thrombosis complications in patients with coronary motility, cerebral ash or peripheral vascular disease, including the treatment of a therapeutically effective amount of a person suffering from or susceptible to the disease and / or amorphous form of the compound of formula 1. The compound of formula (1) in 〇, crystalline and/or amorphous form may be in the form of a solution, suspension, HFA aerosol, and dry powder formulation, for example, to the lungs and/or airways. Sputum application 'or systematically, for example, oral administration in the form of tablets, pills, capsules, syrups, powders, or granules, or sterilized parenteral solutions, suspensions for parenteral administration, subcutaneous administration Or in the form of a test for rectal administration or intracerebroventricular administration. The compound of the formula (1) in a crystalline and/or amorphous form may be administered directly or as a pharmaceutical composition comprising a pharmaceutically acceptable diluent, adjuvant and/or carrier in a compound of formula (1) comprising crystalline oxime and/or amorphous form. Accordingly, other features of the present invention provide a pharmaceutical composition comprising 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 aerosols can be administered by oral 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 (I) in crystalline and/or amorphous form may also be administered by dry powder inhalers. The inhaler can be a single or multiple dose inhaler of 147303.doc -13- 201034672 and can be a breath actuated dry powder inhaler. A possibility is to mix the finely divided crystalline and/or amorphous form of the compound of formula (1) with a carrier material, for example, mono-, _ ^ early- or a polysaccharide, sugar alcohol or other polyol. Suitable carriers include sugars and source powders. 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 the hard alum capsules, each containing the desired amount of the 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 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. A pharmaceutical composition comprising a compound of the formula (1) which is crystalline and/or amorphous (IV) may conveniently be an oral drug, a granule, a capsule, a syrup, a powder, or a granule; a sterilized parenteral or subcutaneous solution, a parenteral administration Suspension, or rectal administration of suppositories. J Oral Xerox 'crystalline and / or amorphous form of the compound of formula (1) can be used as a drug or as a carrier, for example, lactose, sucrose, glucose alcohol, mannitol, such as potato 4 powder, corn starch or branch powder a powder of a temple, a cellulose derivative, a binder such as gelatin or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, stearic acid, polyethylene glycol, earth, chain burned hydrocarbon, etc., and then pressed Chengle ingots. 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, dioxide: when:: the drug can be coated to dissolve in volatile organic Solvent or Aqueous Solvent 147303.doc •14- 201034672 For the preparation of soft phosphine, it is available for the user, capsule, crystalline and/or amorphous form of compound (I), for example, in the form of oil or polyethylene. alcohol. Hard gelatin capsules can be used as excipients for the use of escaping tablets, such as lactose, sucrose, glucose alcohol, mannitol, dinosaur powder, transport main 〇 '·, 素素 complaint organisms, or gelatin, containing compounds Particles. Also °: The liquid or I solid formulation of the drug is filled into hard gelatin capsules. The liquid product to be applied may be in the form of a syrup or suspension, a solution of the compound of the formula (1) in the form of yang and/or amorphous, and the balance being sugar

A mixture of alcohol glycerin and propylene glycol. Optionally, the liquid may contain 3 colorants, flavoring agents, saccharin, and ester methylcellulose as a bulking agent, or other excipients known to those skilled in the art. It will be appreciated that sample analysis using particles larger than 3 〇 microns and non-single aspect ratios may affect the relative intensity of the peaks. Those skilled in the art should also understand that the 'reflection position 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. [Embodiment] Example 1 Homogeneous polymorph 1 form {18-[1〇^, 2〇1, 30(18*,211*), 50]}-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-I,2-diol fraction 1 The compound of formula (1) (2 mg) in the form of polymorph 11 is heated and cooled in DSC in the following manner: 35 to 143 to 35 to 148 to 35 to 148 to 35. Hey. • 15-147303.doc 201034672 This annealing process results in the crystallization of pure polymorphism, as indicated by DSC. Part 2 A solution comprising a compound of formula (I), 5 mg/g of sterol, with 7.3 mg/g water, and a small amount of homogeneous polycrystalline I seed crystallized at 3 〇〇c. XRPD and DSC have proven to be substantially pure polycrystalline j. Example 2 {lS-[la,2a,3p(lS*,2R*;),5p]}-3-(7-{[2-(3,4-difluorophenyl)) ring of the isomorphous polymorph II form Propyl]amino}_5_(propylthiobu 311_丨, 2,3-triazole[4,5-d]-pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane _丨, 2_diol chloroform (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 overnight and dried under flowing nitrogen. XRPD and DSC confirmed Substantially pure polymorphic π has been formed. Example 3 Homogeneous polymorphic III morphology {lS-[la,2a,3p(is*,2R*),5p]}-3-(7-{[2_ (3, 4-monofluorophenyl)cyclopropyl]amino}_5_(propylthio)_3仏1,2,3_triazole[4,5-d]-pyrimidine_3·yl)_5_(2_hydroxyethyl Ethyl)cyclopentane-diol Ethanol (200 microliters) was added to 10 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. xrpd* DSC confirmed that substantial Pure homogeneous polycrystals 11 and 11] [. This material is used for seeding larger scale preparations: 191 mg of polymorphous polymorph II is slurried in 1 ml of 50 ❶ /. isopropanol in water. Into 15 mg of mixed polycrystalline Π/ΙΠ seeds. Complete conversion to homomorphic poly III after 2 ,, as confirmed by XRPD. Example 4 147303.doc • 16 · 201034672 Homogeneous polymorphic IV morphology {lS-[ La,2a,3p(lS*,2R*),5P]}-3-(7-{[2 (3,4-difluorophenyl)cyclopropyl]amino}_5_(propylthio)_3Η_ι, 2,3_=唉[4,5-d]-pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane 4,2-diol acetonitrile (0-12 ml) was added to 10 mg (I) a compound, and the mixture is warmed to dissolve in a steam bath. The warming solution is slowly cooled in a hot water jacket. The resulting crystals are dried under nitrogen. XRPD shows that it is a unique homogeneous polycrystal. a form of {lS-[la, 2a, 3p(lS*, 2R*), 5p]}-3-(7_{[2 (3,4-difluorophenyl)cyclopropyl]amino}_5- (propylthiotriterpene [4,5-d]-" densely -3-yl)-5-(2-carbylethoxy)cyclopentanol~ι, 2_diol will give formula (I) The compound (218 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 used under the following conditions. Is freeze-dried (2170 mTorr vacuum intake line time 20.2 hours, condensed temperature -52 ° C, the peripheral temperature of 20.3 ° C). Reference Example 1 {lS-[la, 2oc, 3p(lS*, 2R*), 5p]}-3-(7-{[2-(3,4-difluorophenyl)cyclo)]amino} -5-(propylthio)-311-1,2,3-tris-[4,5-(1]-. dimethyl-3-yl), 5-(2-hydroxyethoxy)cyclopentane -l,2-diol {3aR-[3aa,4a,6a(lR*,2S*),6aa]}-2-[6-({7-[2-(3,4-digas)) J-propyl]amino-5-(propylthio)_3H-1,2,3-tris-[4,5-d]-n-dens. 3-yl}-tetrahydro-2,2-di a solution of methyl-4H-cyclopenta-1,3-dioxo-4-yloxy]ethanol (method A, 0.59 g) in trifluoroacetic acid (15 ml) and water (15 ml) 30 min. The reaction mixture was carefully added to a solution of sodium bicarbonate (21 g 147303.doc -17- 201034672) in water (150 ml) and stirred for 3 min. The mixture was extracted with ethyl acetate. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) , 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=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). The starting materials are either 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-[3aa,4a,6a(lR*,2S*),6aot]}-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl]amine Base - 5-(propylthio)-3Η-1,2,3 -three 0 sitting [4,5-d] - mouth bite-3·yl}-tetrahydro-2,2-dimercapto-4H- Cyclopentyl-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(lR*,2S*) ),6aoc]},{[6-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino-5-(propylthio)-3Η-1,2,3- Triazolo[4,5-d]-pyrimidin-3-yl}-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-4-yl)oxy]acetic acid methanol ( Method B, 0.76 g of an ice cold solution in THF (1 mL), and the mixture was stirred at this temperature for 2 hr. The reaction mixture was concentrated in vacuo and residue was dissolved in ethyl acetate 147303. A saturated aqueous solution of sodium potassium tartrate (75 mL) was added and the mixture was stirred vigorously 16 hr. The organics were collected and re-extracted (2 x 50 mL) with ethyl acetate. The combined organics were dried and concentrated, and then purified (jjjjjjjj MS (APCI) 563 (M+H+, 100%).

Method B {3&11-[3&〇1,4〇^6〇6(111*,28*),63〇〇}_{[6-(7,{[2_(3,4-difluoro] Cyclopropyl]amino-5-(propylthio)-3Η-1,2,3-triazole[4,5-d]-pyrimidin-3-yl}-tetrahydro-2,2-di Methyl-4H-cyclopenta-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-(1]-pyrimidin-3-yl]-tetrahydro-2,2-diindolyl-411-cyclopenta-1 , 3-dioxo-4-ol}oxy)acetic acid decyl ester (method d, 〇. 80 g) and (1R-trans)·2-(3,4-difluorophenyl)cyclopropylamine, [rjr' r*)]. To a mixture of methylene chloride (25 ml), N,N-diisopropylethylamine (0.85 ml) was added. The resulting solution was stirred at room temperature for 1 hour and then concentrated in vacuo. Purification (Si 2 , isohexane: ethyl acetate 3:1 as a solvent) gave the title compound as a colorless foam (yield: 77 g). MS (APCI) 591 (M+H+, 1〇〇〇/0).

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

The title compound can be prepared according to the procedures described in the PCT Patent No. 9905143. Method D

[3aR-(3aa,4a,6a,6aa)H{6-[7-bromo-5-(propylthio)·3Η_12,3_III147303.doc -19- 201034672 嗤[4,5-d]-pyrimidine -3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-4-ol}oxy) decyl acetate

[3aR-(3aa,4ot,6a,6aa)]-({6-[7-Amino-5-(propylthio)-3H-1,2,3-triazole[4,5-d]- Pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-4-ol}oxy)acetic acid decyl ester (method e, 1.1 g) and isoprene The nitrile (2.4 ml) was heated in bromo (30 mL) at EtOAc (EtOAc (EtOAc) g)) MS (APCI) 502/4 (M+H+), 504 (100%). Method E

[3aR-(3aa,4a,6a,6aa)]-({6-[7-Amino-5-(propylthio)-3Η-1,2,3-triazole[4,5-d]- Methylpyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-4-alcohol}oxy)acetate in [3aR-(3aot,4a,6a ,6aa)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2 , 2-Dimethyl-4H-cyclopenta-1,3-dioxo-4-ol (method F, 0, 50 g) in THF (25 mL) EtOAc (m.) Hexane). After 20 minutes, the suspension was treated with a solution of difluoromethane succinyl acetoxyacetate (0 34 g) (prepared according to the method of Biton's Tetrahedron, 1995, 51, 10513) in thF (10 ml). The resulting solution was warmed to rt then EtOAc (EtOAc:EtOAc) MS (APCI) 439 (M+H+, 1 〇〇〇/〇) 〇

Method F

[3&11-(33〇1,4〇1,6〇1,6&〇〇]-6-[7-amino-5-(propylthio)-311-1,2,3-three saliva [4,5-d]-pyrimidine_3_yl]_tetrahydro-2,2-diindenyl_4H_cyclopentane-1,3-dioxo-147303.doc 201034672 4-alcohol [3aR_(3aa, 4a,6a,6ao〇]-6-[7-chloro-5-(propylthio)-3Η-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydrogen _2,2_Dimethyl·4H_cyclopenta-1?-dioxo-4-ol (Method G, 13.2 g) was given for 2 hours in raF (200 ml) containing 〇88 ammonia (5 ml) 'then concentrated to dryness and the residue is distributed between water and ethyl acetate

. The organics were dried and concentrated to give title compound (1·5 g). MS (APCI) 367 (M+H+, 100%) 〇 Method G

[3&11-(33〇6,4〇^6〇1,6&〇〇]-6-[7-chloro-5-(propylthio)-3«:-1,2,3-triazole [4,5-d]-Pyrimidin-3-yl]-tetrahydro-2,2-diindole_4H_cyclopentaoxy-4-ol Addition of isoamyl 3 (1.1 ml) to [3aR-( 3aot, 4a, 6a, 6aa)]-6-{[5-amino-6-chloro-2-(propylthio)-pyrimidin-4-yl]aminopurine tetrahydro-2,2 dimethyl_ 4H_cyclopenta-1,3-dioxo-4-ol (method H, 2 gram) in a bet (1 〇〇 ml) solution, and the solution is at 70. (: heating for 1 hour. The cooled reaction mixture Concentration and purification (Si 2 , ethyl acetate: hexanes: hexanes: 3) eluted to afford the title compound (1.9 g). MS (APCI) 386 (M+H+, 100%). 33〇[,416〇1,6°)]_6_{[5_Amino_6_chloro_2_(propylthio)-pyrimidin-4-yl]amino}-tetrahydro-2,2-dimethyl Base-4Η-cyclopenta-1,3-dioxo-4-ol adds iron powder (3.0 g) to [3311_(3 commit, 4〇1,6〇1,6 buckle)]_6_{[6_氯_ 5-nitro-2-(propylthio)-pyrimidin-4-yl]amino}_tetrahydro-2,2-dimethyl-7 Η-cyclopentane 1,3-dioxo-4-ol (method) I, 2.7 g) in a stirred solution of acetic acid (1 mL). The mixture was stirred at room temperature for 2 hours, 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 · 201034 672 (2.0 g). (APCI) 375 (M+H+, 100%).

Method I

[3aR-(3aa,4a,6a,6aa)]-6-{[6-gas-5-nitro-2-(propylthio)-°3⁄4 ate-4-yl]amino}-tetrazine- 2,2-Dimethyl-4Η·ί 戊-1,3-dioxo-4-ol

[3&11-(3&〇1,4〇1,6〇[,63〇〇]-6-aminotetrahydro-2,2-dimethyl-411-cyclopenta-1,3-di Oxy-4-ol 'hydrochloride salt (method J '10_0g) was stirred with ν, Ν-diisopropylethylamine (35 ml) in THF (600 mL) for 1 hour. A solution of 4,6-dioxa-5-nitro-2-(propylthio)pyrimidine (WO 9703084), 25.6 g of a solution in THF (1 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&11-(3&〇1,4〇1,6〇1,6已〇〇]-6-aminotetrahydro-2,2-dimethyl-411-cyclopenta-1,3-di Oxy-4-ol, hydrogen salt [1ΙΙ-(1α,2β,3β,4α)]-2,3,4-trihydroxycyclopentylidene iminodicarbonate '贰(1,1-dimethyl Ethyl) (Method κ, 174 g) was stirred in 6 μl of HCl (1 mL) / methanol (500 mL) for 8 hours. The mixture was evaporated and then azeotroped with toluene (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. 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 h. The mixture was evaporated and azeotroped with toluene (4 χ 2 mL) to afford 147303.doc -22- 201034672 10.1 g) MS (APCI) 174 (M+H+, 100%).

Method K

[1Κ·-(1α,2β,3β,4α)]-2,3,4-trihydroxycyclopentenyl quinone iminodicarbonate 'Wu (1,1-dimethylethyl)@ 1R-cis)-Home (1,1-Methylethyl)-4-yl-2-cyclopentyl-bromoimidodicarbonate (Method L, 17.1 g) in THF (500 mL) / A solution of water (50 ml) was added with hydrazine-methylmorphine oxide (9.4 g) followed by osmium tetroxide (10 ml, 2.5% solution of t-butanol;). 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 purified (EtOAc EtOAc EtOAc (EtOAc) 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) °

Method L (1R-cis)-indole (1,1-dimercaptoethyl)_4·hydroxy-2-cyclohexyl quinone iminodicarbonate in sodium hydride washed with ether (60% in oil) Suspension; 1.3 1 g) In a suspension of THF (30 ml) was added hydrazinium dicarbonate (丨, dimethylideneethyl) ester (1.84 g). The mixture was stirred at 40 ° C for 1 hour. Then at the ambient temperature, (1S-cis)-4-ethenyloxy-2-cyclopentene-nonanol (0.5 g) and hydrazine (triphenylphosphine)palladium (〇) (〇.18) were added to the mixture. Gram). The reaction mixture was stirred for 24 hr then purified (EtOAc EtOAc:EtOAc:EtOAc NMR: 1.43 (18H, s), 1.61 (1H, ddd 147303.doc • 23- 201034672 J=12_3, 7.7, 6.4), 2.54 (1H, dt, J=i2.6, 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) 〇' Example 2, 3, σ day and/or Formula of day-to-day form α) Compound (hereinafter referred to as compound X) 'Used for human treatment or sputum form. Representative medical dose for fly prevention purposes mg/ingot 100 182.75 12.0 2.25 3.0 mg/drug; 50 223.75 6.0 15.0 2.25 3.0 mg / medicinal 1.0 93.25 4.0 (a) Ingot I Compound X Lactose Ph.Eur Croscarmellose Sodium Yutai Thai Temple Powder (5% w/v slurry) Magnesium stearate (b) Tablet II Compound X Lactose Ph.Eur Croscarmellose Sodium Yutai Thai Temple Powder (5 % w / v slurry) Polyvinylpyrrolidone magnesium stearate (c) Tablet III Compound X Lactose Ph.Eur Croscarmellose #3 147303.doc -24- 201034672

〇玉蜀黍 starch slurry (5% w/v slurry) 0.75 magnesium stearate 1.0 (d) capsule mg/capsule compound X 10 lactose Ph.Eur 488.5 magnesium stearate 1.5 (e) injection I (50 mg / ML) Compound X 5.0% w/v 1N sodium hydroxide solution 15.0% w/v 0.1N hydrochloric acid (adjusted pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f) Injection 11 (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v 0.1 N sodium oxide solution 15.0% v/v Water for injection to 100% (g) Injection 111 (1 mg/ml, Buffer to pH 6) Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 400 3.5 % w/v Water for injection to 100% 147303.doc -25 201034672 Note above Formulations can be obtained by conventional procedures well known in the art of medicinal techniques. For example, tablets (a)-(c) may be enteric coated by conventional methods to provide a coating of cellulose acetate phthalate. The NMR light lf is measured on a Varian Unity Inova 3 00 or 400 spectrometer; the NMR data is quoted in the form of a delta value for the main diagnostic proton, expressed in parts per million (ppm) relative to the tetramethyl decane (TMS) as an internal standard, the use of which Total dimethyl hydrazine (DMSO-56) as solvent 'unless otherwise indicated; for example, only the chemical transfer of the main rotamer indicates the presence of a rotamer in the proton NMR spectrum; the coupling constant (J) Hz is indicated. 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 Description] Figure 1.1 shows the X-ray diffraction pattern of homogeneous polycrystalline I using Philips 147303.doc -26- 201034672. The X'Pert MPD machine takes at 1. The scan range to 40. 2 , is increased by 0.02. 2 .. The amount is 2 or 5 seconds of exposure Θ-Θ configuration. 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 shows an X-ray diffraction pattern of homogeneous polycrystalline II, which was obtained using a Siemens D5000 machine for a scan range of 2° to 30° 2 ,, with a 秒-Θ configuration of 4 seconds exposure per 0.02 ο 2θ increment. X-rays are produced by copper long-fine focus tubes operating at 45 volts and 40 milliamps. The X-ray wavelength is 1 · 5,406 angstroms. Number ® is based on a zero background collection using a compound that is placed ~10 mg. 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 the form α, which uses the above-mentioned Siemens

Q D5000 machine. 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. 147303.doc -27-

Claims (1)

201034672 VII. Patent application scope: 1. A mixture of compounds of formula (I), ❹ F F A compound of formula (1) wherein it has a substantially crystalline form is characterized by a 5 5 . (±〇·η2θ X-ray powder diffraction pattern containing high intensity specific peaks; or characterized by 5.5. (±(M°), 6.8. (±0.n, 1〇6. (土〇η,Η 5 (±0.1°)^ 14.9° (10.10).18.3^(10.10).19^^0^), 22 70 (10) (7) ^ soil ^ and (1) ^ soil core ^ contains a specific peak of the - ray diffraction pattern · ' or characterized by a differential scanning calorimeter curve having a melting point in the range of 136-139 ° C, and the compound of formula (1) is characterized by 14. Hey. (Gentry.), 174. (±〇 1〇), ΜΙ (±0.1), 21.4. (Soil 0.1.), and 24.!. (Tufts 1.) 2θ X-ray powder diffraction pattern containing high intensity specific peaks; or characterized by 5 6 . (9)a. ), ^. (土°·1.), 14·0. (士 0.1.), 17.4. (±0.1.), 18.4. (±(U.), 214. (―Ο.1), 22.2. (土Ο.1.), 22.9. (±0.1.), 24.1. (±(U.), and 24.^ (±〇 . ι ) Θ 射线 绕 绕 绕 帛 帛 帛 帛 帛 帛 帛 帛 帛 帛 帛 帛 et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et Medicinal agent 3. A medical music composition, the sentence will be mixed with a mixture of seven 匕3, such as δ月求求, to receive an adjuvant, diluent or carrier. σ商乐可4·If request 3 A pharmaceutical composition for preventing arterial thrombotic complications in a patient having coronary artery, cerebral blood, or peripheral vascular disease. 5. A mixture of claim 1 in the manufacture of medicine and m. For the treatment of arterial gold complication in patients with coronary artery, cerebrovascular or peripheral ' & bloody disease. 147303.doc