TWI294427B - Crystalline form of a triazolo [4,5-d] pyrimidine compound and process for making the same - Google Patents

Description

1294427 A7 B7 V. DESCRIPTION OF THE INVENTION (1) The present invention relates to the form of a chemical compound, particularly crystalline and non-morphological, and more particularly to four crystalline forms and one amorphous form. The present invention further relates to this form (manufacturing method, a pharmaceutical group of compounds containing crystalline and/or amorphous forms) and the therapeutic use of such a form. Printed by the Consumer Standards Bureau of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the back side first) Precautions and then fill in this page. In the formulation of pharmaceutical compositions, it is important that the drug substance is conveniently controlled. It is important not only from the point of view of commercially viable process, but also by subsequent manufacture. The chemical formulation of the compound is also a very important factor in the chemical stability, solid state stability, and shelf life of the active ingredient. The drug substance and the composition containing the same should be effectively stored for a relatively long period of time without presentation. Significant changes in the physical-chemical characteristics of the active ingredient (eg, 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 exist at this point. A major problem. For example, this material is generally more difficult to control and blend than crystalline materials, providing unreliable solubility, and It is often found to be unstable and chemically impure. Those skilled in the art should be aware that if the drug is readily available 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 Providing 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 structure, and it is usually only experimentally determined. Adhesion and coagulation are the initial conditions 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, the platelet aggregation caused by it can precipitate the acute thrombus of the deadly vascular bed. The scale applies to the Chinese National Standard (CNS) A4 specification (21GX297 羡 1294427 V. Invention Description (closed 'causes the high mortality rate such as myocardial infarction and unstable angina. To prevent or slow down these conditions (such as thrombosis) The success of interference with lysis and vasodilation is also blocked by platelets Re-closure and damage. Adenosine 5,-diphosphate (ADP) has been found to be a key mediator of thrombosis. ADP-induced platelet aggregation is caused by p-T receptor/human type located on the platelet cell membrane. The main drug of Ρ2τ^ (also known as P2Yadp or P2Tac) involves conduction coagulation/activation, and is a G-protein coupled receptor that is not yet reproducible. The pharmacological characteristics of this receptor have been described, for example, Humphries et al., Br. J. Pharmacology (1994), 113, 1057-1063, and Fagura et al., Br. J. Pharmacology (1998) 124, 157_164. Recently, it has been shown that this receptor is confronted. The agent provides significant improvements over other antithrombotic agents (see J. Med. Chem. (1999) 42, 213). International Patent Application WO 9905 143 discloses, in its entirety, a series of triterpene [4,5-d], lake compounds having activity as ρ2τ (P2Yadp or P2TAC) antagonists. The compound of the formula (I) (described below) comprises one of the ranges of the international patent application WO 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 amazingly high metabolic stability and bioavailability. Accordingly, the present invention relates to a compound of the formula (I) in a substantially crystalline form: . — (Please read the notes on the back and then fill out this page) Ordered by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs, Printed by the Cooperatives - 5 - Paper Size Applicable to Chinese national standards (CNS > A4 specification (210X297 mm) 1294427 V. Invention description (3)

HO formula (1) compound known ib> named horse · {lS, [la, 2oc, 3p (lS*, 2R*), 5β]} 3 (7乂[2-(3,4·difluorophenyl) Cyclopropyl]amino group propyl (propylthio) 3 Η 1'2'3 嗤[4,5-d]-, pyridine·3_yl)·5_(2_carbylethoxy)cyclopentyl Pit-1,2-diol. (1) The compound may exist in four different substantially crystalline forms, which are referred to as homopoly, 1, polymorph, polymorph III, 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 significantly affected by the chemical and pharmaceutical treatment of the compounds, particularly 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 printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs. _丨丨ΓΙ._丨| · — (Please read the notes on the back and fill out this page. ) hn^\7

N N

H〇 OH is homogeneous polycrystalline 1, homogeneous polycrystalline II, homogeneous polycrystalline germanium, and homogeneous polycrystalline IV. In an alternative aspect of the invention, the preferred crystalline form of Compound I of Formula (1) is a homogeneous polymorph I 0. In another aspect of the invention, the preferred crystalline form of the compound of Formula (1) is a homogeneous polymorph II.

1294427 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. INSTRUCTION DESCRIPTION (4) In another aspect of the invention, the preferred crystalline form of the compound of formula (I) is a polymorph III. ~ In another aspect of the invention, the preferred crystalline form of the compound of formula (I) is a polymorph IV. In another aspect of the invention, the compound of formula (1) is substantially amorphous. In the amorphous form, it is usually present in the crystalline form (for example, polymorphism). The two-dimensional long-range order does not exist, and the position of each other in the amorphous form is free from random (see B·C. Hancock and J. G. ZograH

Pham·Sci· (1997) 86 !. The amorphous form of the compound of formula (1) is referred to as the form α. The compound of formula (I) has been isolated into crystalline and amorphous forms. These forms may be substantially or essentially free of water ("dehydrated" form). Therefore, in one aspect of the present invention, a compound of the formula (1) in a crystalline form or an amorphous form in a dehydrated form is provided. The use of the term "substantially pure and essentially dehydrated form" does not exclude the presence of solvents other than or within the lattice structure, including water. The dehydrated form has less than 4 water molecules per molecule (less than 40% hydration). Preferably, the dehydration form is less than 〇; 1 water molecule per molecule of the molecule. The homomorphic polycrystals I, II, III, and IV can be distinguished by reference to their melting origin, powder enthalpy-ray diffraction pattern, and/or single crystal X-ray data. The homopolymorph I has a melting initiation point of 146-152 C, for example, about 151, when it is in a substantially pure and substantially dehydrated form. The same polymorph II has a starting point of 136-139 C', for example, about 135 when it is in a substantially pure and essentially dehydrated form. This paper scale applies to Chinese national standards (CNS M4 specifications (210X297 mm) (please read the notes on the back and fill out this page)

Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing 1294427 A7 ___ B7 V. INSTRUCTIONS (5) Homogeneous polycrystal III has 1 2 7 -1 3 2 C when it is in a substantially pure and essentially dehydrated form: The beginning of the valley, for example, about 1 3 2 °c. Homogeneous polycrystalline IV has a melting initiation point of typically about 1 39 ° C when it is in a substantially pure and substantially dehydrated form. The form α is generally subjected to glass transfer prior to melting and then crystallized into one of the above homomorphic polymorphic forms, for example, polycrystalline π. The melting point was measured using a differential scanning calorimeter (DSC) of a Perkin Elmer DSC7 instrument. The melting point was defined as the significant change from baseline and was measured by Perkin Elmer Pyds software. It will be appreciated that alternative readings of melting points may be produced by other forms of means, or by using conditions other than those described herein. Therefore, the number quoted is not absolute. Those skilled in the art will appreciate that the precise melting point is affected by the purity of the compound, the weight of the sample, the rate of heating, and the particle size. Homogeneous polymorph I has a 5.3° (±0.1°) > 20.1° (±0.1°) > 20.7° (±0.1°) - 21.0° (±0.1) in its substantially pure and essentially dehydrated form. °), and 21.3 ° (±0.1.) 2 χ high-intensity specific peaks of the χ-ray powder diffraction pattern. More preferably, 'substantially pure and essentially dehydrated polycrystalline! Has a total of 5. 3. (Soil 0.1.), 8.0. (Soil 0.1.), 9.6. (Soil 0.1.), 13.9. (Soil 0.1.), and 15.3. (士0_1〇), 20.1·. (±0.1), 20·7ο (±〇·ιο), 21.0. (±0.1〇), 21.3. (soil 0.1 °), 26.2. (±0.1.), and 27.5. (±0.1.) 2Θ X-ray diffraction pattern containing a specific peak of high intensity. Homogeneous polymorph II has a pH of 5.5 when it is in a substantially pure and essentially dehydrated form. (±〇·ι.), 13.5. (±〇.1.), i 8.3. (±0.1.), 22.7. (±0.1 〇), and 24·3° (soil 0.1.) 2ΘSpecial peak with high intensity χ ray powder diffraction pattern -8 - 5 sheet scale applicable ϊΛ ϊΛ standard (CNS) Α 4 specification (210X297 mm Τ I :_|.——#! (Please read the notes on the back and fill out this page) Order 1294427 A7

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs. More preferably, the homogeneous polycrystalline 11 which is substantially pure and essentially dehydrated is at 5.5 C (:0·1.), 6.8. (Turkish·1.), 10.6. (±0.1.), 13.5. (土0".), (±0.1〇). 18 30 (*〇.!〇). 19&gt;2〇(^.^), 22^0 24 3〇(±0·1°) and 27” . (±(Μ.) 2Θ ray diffraction pattern containing a specific peak of high intensity. The same polymorph III has a purity of 14.0 (±0.1.), 17.4 (±0.1). .), 18.4. (±0·1Ί, 21 4. (Turkish 1〇) Ann and 24·1 (Turkish·ι) 2ΘIncluding 鬲 intensity specific 乂 乂 射线 粉末 粉末 粉末 粉末 粉末 粉末 粉末 粉末 粉末 粉末 粉末 粉末 粉末 粉末The homogenous polycrystalline III which is substantially pure and essentially dehydrated has a value of 5.6 (±0.1), 12.5 (Turkish "", 14 〇. (Turkish 1〇), 17 4. (Turkish 1 〇), 18·4. (±〇·ΐ.), 21.4. (Soil 0.1.), 22.2. (Soil 0.1.), 22.9. (±〇.1〇), 24·1° (±0.1°) And 24.5. (±0.1.) 2Θ 射线· ray diffraction pattern containing high intensity specific peaks. Homogeneous polycrystalline IV has 4.9 (±0”) when it is substantially pure and essentially dehydrated. 9.2 (±0.1.), 11:6 (±0".), 15 6. (Gentry). and 16.4. (±〇·ι.) 2Θ X-ray powder winding with high intensity specific peak Shooting pattern. More preferably 'substantially pure and essentially dehydrated homogeneous polycrystalline IV 4.9 (±0.1), 6.0 (soil 0.1), 9.2 (±0.1), 11.6 (±0.1), 12.8 (±0.1), 15.6 (±〇·1.) , 16.4 (±0.1.), 17.2 (±0.1.), and 18.1° (±0·1°) 2Θ X-ray diffraction pattern containing high intensity specific peaks. Form α is essentially pure and essential In the case of dehydration, it has an X-ray powder diffraction pattern without sharp peaks. X-ray diffraction data of polymorph II, polymorph III, polymorph IV, and form α are obtained using a Siemens D5000 device. Polycrystalline I-9 _ This paper scale applies to China National Standard (CNS) ΜSpecifications (210'x297 DON) I——!——φ! (Please read the notes on the back and fill out this page again) -'' Ll 1294427 V. INSTRUCTIONS (7) A7 B7 χ-ray diffraction data is obtained using a Philips x, Pert mpd machine. It should be understood that different <devices and/or conditions can cause slightly different data. Therefore, the number quoted is not Absolutely 値. In the alternative state of the invention, a solvent-forming form can be formed, for example, water $~ (water). Thus, in the state of the present invention, the hydrate of the compound of the formula (1) is provided as having 〇·8 ^ or more water molecules (8 G% or more of hydration) per compound molecule. The hemihydrate is Each compound has from 0.4 to 0.8 water molecules (4 〇 -8 % hydration). In another state of the invention, a crystalline and/or amorphous form of the formula (1) is provided as a mixture. Preferably, the mixture has a homopolymorphous polymorph II, a homopolymorphic polymorph, and/or a morphology a. More preferably, the present invention provides a homopolymorphic Any mixture. In a further feature of the invention, there is provided a process for producing a crystalline form of the compound of formula (1) by crystallization of a compound of formula (1) from a suitable solvent. Preferably, the horse drop agent 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, 1 propanol, 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. The Mixed Foods Department of the Central Bureau of Standards and Staff Consumer Cooperatives prints 3⁄4 ml!——Φ! (Please read the notes on the back and fill out this page), 11 substances, a mixture of isopropyl alcohol and water, ethyl acetate and isooctyl acetate Mixture I and acetonitrile. Compounds of formula (1) can be prepared by methods analogous to those described in the WO 9905143 patent. In order to initiate crystallization, it is necessary to crystallize the compound of the 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 by a suitable solvent system, for example, by cooling, borrowing

This paper scale is suitable for the financial industry (CNS) A4 specifications (210X297 mm 1294427 Ministry of Economic Affairs Central Bureau of Standards Bureau staff consumption cooperatives printed A7 B7 V. Inventions (8) Solvent evaporation, and / or by anti-solvent ( (I) a solvent in which the compound is poorly dissolved; an addition of a suitable anti-solvent includes heptane or isooctane), which is obtained by supersaturation. The crystallization temperature and time are regarded as the concentration of the compound in the solution, the falling agent system used, and The crystallization method is different. The compound of the formula (I) in a crystalline form can be isolated from the above reaction mixture by techniques known to those skilled in the art, for example, by decantation, filtration or centrifugation. Similarly, the form of the crystalline form ( I) The compound 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 the crystalline form from a homogeneous polycrystal to Another polycrystalline transformation, either in a hydrated or dehydrated form. In addition, in order to remove the amorphous material, an adjustment step may be required to fix Exposure to high humidity. The car is also good, the crystallization is carried out directly from the reaction solution. Or, the crystallization is carried out by the subsequent; the gluten solution. In other features of the invention, a method for preparing a homopolycrystalline strontium is provided, which comprises The slow junction of homopolycrystalline ruthenium from the polymorphous polycrystal II is obtained by seeding two or more homogeneous polycrystalline J seeds, and using the reaction mixture containing the compound of the formula (1) and a suitable mixed solvent system (such as methanol/water) In a further feature of the invention, there is provided a process for preparing a homogeneous mass comprising crystallization in a suitable solvent such as ethyl acetate. In other features of the invention, soil provides a preparation; The method comprises: crystallization in a suitable solvent such as an alcohol, and the alcohol alcohol is especially sown by homogenous crystallization, or 2-11 - the paper size is 21 297 ϋ (please read the precautions on the back) Fill in this page) « HI I 0 Order 1294427 V. INSTRUCTIONS (9) Slurry in a suitable solvent such as IPA. Method, JL: Other characteristics, provide a crystal of the preparation of a polycrystalline 1V square IV: Such as: ^ Crystallization of a suitable solvent, especially during the period of polymorphism (IV) The compound of formula (1) is polymerized in a suitable solvent such as acetonitrile, and it is characterized by the fact that it produces a homogeneous polymorphism of polymorphism II. Including, for example, the compound of formula (1) is slurried in a 1-6 aliphatic fresh/aqueous solvent system (preferably hydrazine/water) at a temperature of from 5 to 65. In the other features of the invention, Provided is a method of making a substantially amorphous form of a mash, comprising a solution of a compound of formula (1) using a suitable solvent system, for example, ethanol/water, freeze drying or spray drying. Other homopolycrystals of 〇%, preferably less than 5% 〇, in other aspects of the invention, a compound obtained by any of the above methods is provided. The Central Bureau of Standards of the Ministry of Economic Affairs, the Consumer Cooperatives, prints crystalline and/or amorphous forms. (1) The compound is a Prr (P2Yadp or P2TAC) vincent antagonist. Thus, crystalline and/or amorphous forms of the formula can be used in therapy, including combination therapy. In particular, the crystalline form of the compound of formula (I) is indicated for the treatment or prevention of arterial thrombotic complications in patients with coronary, cerebrovascular or peripheral vascular disease. Arterial thrombosis complications may include unstable angina, aortic thrombosis complications of arteriosclerosis, such as thrombosis or vascular obstruction, temporary ischemic attack, peripheral vascular disease, myocardial infarction with or without thrombolysis, due to arteriosclerosis Disease intervention (such as vasodilation, including coronary vasodilation (PTC A), intra-arterial-12 paper scale applicable to China National Standard (CNS) Μ specification (210 X297 mm) Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives 1294427 A7 --- ____B7 ______ V. Description of the invention (1〇) Arterial complications, surgical or mechanical damage (such as accidents or caused by membranous resection, stent placement, coronary artery, and other vascular grafting) Tissue use of surgical trauma, reconstruction surgery, including skin and tendon) thrombotic complications 'diffuse thrombus / platelet depletion components, such as disseminated submuscular coagulation, blood test thrombocytopenic purpura hemolytic uremic syndrome, thrombosis complications of sepsis 'Adult respiratory distress syndrome, antiphospholipid syndrome, heparin burst thrombocytopenia and before Toxicemia/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 mechanical discharge of living platelets Activation, such as cardiopulmonary bypass and in vitro cell membrane oxidation (prevention of microthrombotic disease), mechanical in vitro platelet activation, such as for preservation of blood products such as 'blood plate concentrates, or shunt obstruction, such as renal dialysis and plasma depletion' Second to vascular damage/inflammation of thrombosis, such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ transplant rejection, such as migraine, Lei disease phenomenon, in which platelets cause inflammatory diseases under the blood vessel wall Conditions of the process, such as atherosclerotic blood formation/development, narrowing/re-narrowing and other inflammatory conditions, such as asthma, in which platelet and platelet-derived factors are involved in the immune disease process. Other indications include treatment of CNS disease and prevention of cancer Growing and spreading. According to other aspects of the invention, a method for treating human or animal body is provided Crystalline and/or amorphous form of the compound of formula (I). According to an additional feature of the invention, a crystalline and/or amorphous form of a compound of formula (I) is provided as a pharmaceutical agent. Preferably, it is crystalline and/or amorphous. Formula (1) Compound as a warm-blooded animal such as human against p2T (P2Yadp or P2Tac) -13- This paper scale applies Chinese S standard (CNS) A4 specification (210X297 public) ---- • ----- (Please read the precautions on the back and then fill out this page), 11 1294427 V. INSTRUCTIONS (11) The pharmaceutical agent of the party body. More preferably, the crystalline and/or amorphous form of the compound (1) is used as a human A warm-blooded animal that treats or prevents arterial thrombosis complications in patients with coronary, cerebrovascular, or peripheral vascular disease. According to the present invention, there is further provided a use of a compound of the formula (1) in a crystalline and/or amorphous form for the manufacture of a pharmaceutical agent as a (P2 YADP or P2Tac) receptor antagonist. In particular, the compound of formula (1) 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 provides a method for treating or preventing arterial thrombosis complications in a patient having coronary artery, cerebrovascular or peripheral vascular disease, which comprises administering a therapeutically effective amount of crystal and/or amorphous to a person suffering from or susceptible to the disease. a compound of formula (I). The compound of formula (1) in a crystalline and/or amorphous form may be in the form of a solution, a suspension, a sol, and a dry powder formulation, for example, for the lungs and/or airways; or, or, for example, a tablet, Pills, capsules, sugar: 22: 1 granule heart form oral administration, or sterilized non-gastrointestinal enteral administration 'subcutaneous application' or rectal drug in the form of suppository, or intracerebral administration. The Ministry of Economic Affairs Central Bureau staff consumption cooperatives print and = and crystal form (1) compounds can be directly or as long as the crystal / θ day / corpse (1) compound combination of pharmaceutical acceptable diluents, adjuvants and / or carriers Pharmaceutical composition is applied. Therefore, the other special (four)-supplied species of the present invention comprise a crystalline and/or amorphous form of a drug-receiving diluent, an adjuvant, and/or a two-component composition, which is not included in the composition. A composition of materials that can be reacted in a face-to-face manner (such as a negative allergic reaction). This paper is suitable for national standards (-14· Ministry of Economic Affairs, Central Bureau of Health, Bureau of Consumers, Cooperatives, Printing 1294427 V. Inventions (η), The dry powder formulation of the compound of the formula (1) and the pressurized A gas mixture may be administered by oral or nasal inhalation. For inhalation, it is desirable to crystallize,/or amorphous form. The compound of formula (I) is finely divided. The compound of formula (1) which is crystallized and/or non-daily can also be applied by dry powder inhaler. The inhaler can be a single or vaccination inhaler, and can be inhaled by a breath-activated dry powder. The present invention is a mixture of finely divided crystalline and/or amorphous forms of a compound and a carrier material, for example, mono-, di- or polysaccharide, sugar alcohol f, other polyterpene alcohol. Suitable carriers include sugar and starch. Or, fine = d crystal and / or amorphous The formula (U compound can be coated with other substances. The powder mixture can also be added to hard gelatin capsules, each containing the desired dose of active crystalline and/or amorphous form ruthenium (I) compound. 2 possibilities To treat the finely divided powder into a sphere at the time of the inhalation step. The spheroidized powder can be filled into a multi-dose inhaler drug, for example, known as Turbuhaler®, wherein the dosage unit measures the amount of the dose, Then, it is inhaled by the patient. The system delivers the compound of the active formula (1) to the patient with or without a carrier. The pharmaceutical composition comprising the compound of crystalline and/or amorphous 2 (1) can be conveniently used as an oral tablet. Le pill, capsule, sugar paddle, powder, or granule; bacteriostatic non-gastrointestinal or subcutaneous solution, parenteral medicinal suspension, or rectal medicinal suppository. For oral administration, crystallization and/or amorphous form The compound of the formula (1) may be incorporated with an adjuvant or a carrier, for example, lactose, sucrose, glucose alcohol, mannitol, starch such as horse starch, corn starch or branched starch, cellulose derivative, such as Glue or polyethyl fluorenyl ruthenium bismuth with the same adhesive, and such as iron stearate 'stearic acid #5, polyethylene glycol, insects, key burning smoke and other lubricants, and then pressed) A4 specifications ( .------------ (Please read the notes on the back and fill out this page) Order -15- 1294427 A7 B7 V. Invention Description (13) Reduce the tablet. For example, I (please first) Read the precautions on the back and fill in the page) Solution, JL can be coated with the drug, the core prepared as above can be coated with concentrated sugar, etc. Or: with =, gum arabic, gelatin, slippery, dioxide The appropriate polymer can be coated with a compound of the formula (1) in a volatile organic solvent or an aqueous solvent, which can be incorporated into a human M ^ gelatin capsule, in a crystalline and/or amorphous form, for example, for a pharmaceutical tablet. Shaped Jingjing. Hard gelatin capsules can contain granules of the compound, such as alcohol, powder, fiber, sugar, sucrose, glucose, mannose, derivatives, or gelatin. Also: Ai's night sorrow or semi-solid formulation is filled into hard gelatin capsules. The liquid product to be applied may be in the form of a syrup or suspension, for example, a solution of the compound of the formula (1) in 7 or amorphous form, and the balance being a mixture of glycerol and propylene glycol. Optionally, the liquid t may contain coloring agents, flavoring agents, saccharin, and carboxycellulose, as a thickening agent, or other excipients known to those skilled in the art. Fig. 1 is a homogenous polycrystalline ray diffraction pattern using a Philips = P: rt MPD machine at 1. To 4 〇. 2Θ scan range, 〇2 per 。. (9) The configuration is obtained by increasing the exposure of 2 or 5 seconds. χ• Rays are produced by copper long-fine focus tubes operating in volts and 5 mA. The wavelength of the χ-ray is 1.5406 angstroms. Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs Figure 1_2 shows the homogenous polycrystalline Π2Χ•ray diffraction pattern, which is used at 2 to 3 s using the siemens D5〇0〇 machine. The scan range of μ is obtained by Θ-Θ configuration with 4 seconds of exposure per μ increment. X-rays are produced by a copper length _ fine focus tube operating at 45 volts and 4 amps milliamperes. The X-ray has a wavelength of 154 〇 6 angstroms. The data was collected using a zero background in which ~10 mg of compound was placed. The holder is from the single 16-paper scale applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm). The Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing 1294427 A7 _ B7 V. Invention Description (14) 矽 矽, It is 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 3.3 is 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 05000 machine described above. Figure 2 shows dsc plots of homogeneous polycrystals I, π, ιΠ, and IV, and morph α, which were obtained using a Perkin Elmer DSC 7 instrument. The disc type is the cover 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 (rc to 325 χ: at a fixed temperature increase rate of 10 ° C per minute. It should be understood that 'the use size is larger than 30 μm and non-single Sample analysis of the aspect ratio of the particles may affect the relative intensity of the peaks. Those skilled in the art should also understand that the 'reflection position is subject to the sample at the precise height of the diffractometer and the zero calibration of the diffractometer. The surface polarity of the sample also has a small effect. Therefore, the proposed diffraction pattern data is not considered as an absolute enthalpy. The present invention is described by the following non-limiting examples. Example 1] Aminopropylthio)-3Η-1,2,3-three-trimone ethane Part of the decane-1,2-diol 1 I use II — II!——#! (Please read the notes on the back and fill out this page), π 1294427 Α7 Β7 V. Invention Description (1S) Read the instructions on the back and then fill out this page. Heat and cool the compound of formula (I) (2 mg) in the form of polymorph II in DSC in the following manner: 35 to 143 to 35 to 148 to 35 to 148. 35 °C. This annealing process results in the crystallization of pure polycrystalline 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 The morphology of the polymorphic 11 (18-"1〇6,2〇^38 (18*, 2 feet*), 58113彳7-111-(3,4-difluorophenyl)pyridyl 1 Amine}-5-(propylthio)_311-1.2.3-di 1丨1 2 3 4,5 6-dl-pyrimidine-3·yl ethoxylate cyclopentane-i,2-diol Chloroform (150 μL) was added to 45 mg of the compound of formula (I), and the mixture was warmed to dissolve in a steam bath. The resulting solution was allowed to stand for crystallisation overnight and dried under flowing nitrogen. XRPD and DSC were confirmed to be substantially pure. Homogeneous polycrystalline germanium. Example 3 Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printed 1 Polycrystalline III Shaped Bear (1S-"1f7.?rY 3iU1S* 2 U.2 - (3^4- a mouse base) Cyclopropyl 1Aminopropylthio)-3H-1.2J" 3 逵丄4,5_dl_pyrimidine·3-hydroxylethyl 1)cyclopentane u-two drunk 4 Add ethanol (200 μl) 1 mg of the compound of formula (1), and the mixture was warmed to dissolve by steaming. The resulting solution was allowed to stand to crystallize overnight. XRpi and DSC sides: Substantially pure polycrystalline η and in have been formed. This material was used to sown a larger scale preparation: 191 mg of homopolycrystalline π was slurried in 1 ml of a 5 〇0/isopropanol aqueous solution. To this slurry was added 5 mg of mixed polycrystalline II/III seeds. After 2 days, complete conversion to homomorphic polycrystalline m occurs, as in 6 -18-1294427 A7 B7 5. Inventive Note (16) XRPD confirmed. Example 4 U2_(3'4_d ^ΛΛΜ^ΑΛΜ propylthio)-3Η-1,2,3^ 魏魏基乙气) Cyclodecane-I·2-two drunk acetonitrile (〇·12 halo) 1 mg of the compound of formula (1), and the mixture was warmed to dissolve via a steam bath. The warming solution was slowly cooled in a hot water jacket. The resulting crystals were dried under nitrogen. XRPD shows that it is unique and polycrystalline. Example 5 JD - morphological form α {1S_" i[_2-(3,4-difluorophenyl)cyclopropanyl 1 amine group 5•(propylthiol μη·) 2 Gui I4,5-d Hydroxyethane gas) pentane _12·di &amp; The compound of formula (I) (218 mg) was dissolved in 50% aqueous ethanol (24 ml). To this solution was added dropwise another 14.5 ml of water. The solution was then freeze-dried using a Virtis instrument under the following conditions (2170 mTorr, 20.2 hours, condensation temperature _52 ° C, ambient temperature 20.3. 参考. Reference Example 1 ilS-na, 2a.3Rns* ?R* ), 5B1) -3-(7-{r2-r3.4^ m, printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs, ------------------ f Please read the back Note: Please fill in this page j. 1 Amino}-5-(propylthio)-3Η-1,2,3 -3. Sit "4.5-dl-. Close attack: 1-(2-hydroxy-ethane) A port of pentane-1,2-diol {3aR-[3aa,4a,6oc(lR*,2S*),6aa]}-2-[6-({7-[2-(3,4_: i phenyl)cyclopropyl]amino- 5-(propylthio)_3Η·1,2,3_三峻[4,5-d]i-trident-3-yl}-tetrahydro-2,2 -Dimethyl-411-% penta-1,3-oxo_4_yl)oxy]ethanol-19- This paper scale applies to China Quasi (CNS) M specification (210X297 mm) 1294427 A7 B7 V. Description of the invention (17) (Method A, 0.59 g) A solution of trifluoroacetic acid (15 ml) and water (15 ml) was stirred at room temperature 3 0 The reaction mixture was carefully added to a solution of sodium hydrogencarbonate (2 g) in water (150 ml) and stirred for 30 min. The mixture was extracted with ethyl acetate, dried and evaporated. Ethyl acetate as a solvent to provide the title compound (0.44 g). MS (APCI) 523 (M+H+, 100 〇 / 〇); 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 (ih d J = 3.6), 4.96 (1H, q, 9.0), 4.62-4.54 (2H, m), 3.95 (1H, br s)5 3.79^3.73 (1H? m)5 3.55-3.47 (4H? m)? 3.20-3.13 (1Η, 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 (ih, m) 1.73-1.33 (4H, m), 0.99 (3H, t, J = 7.4). 'Preparation of raw materials 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 |jaR-『3aa,4a,6a( !R*,2S*^6aa1 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page)) Cyclopropylamine Base-5--(propylthio)-3H-l,H triazolyl on tetrahydro-2,2-dimethyl-4H-cyclopentane&quot; Will DIBAL-H, hexane 1.0 Μ solution, 5.15 ML) plus {3aR-[3aa,4a,6a(lR*,2S*),6aa]}-{[6-(7-{[2-(3,4-dioxa*yl)cyclopropyl]amine _5-(propylthio)-3Η-1,2,3 -threeπ[4,5-d]-P from luki}-tetrachloro-2,2-dimethyl-4H-cyclopentyl -1,3-Dioxy-4-yloxy]B-20- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294427 A7 B7 V. Description of invention (18) Alcohol ( Method B, 0.76 g of ice cold solution in THF (1 mL), and the mixture was stirred at this temperature for 2 hours. The reaction mixture was concentrated in vacuo and residue was dissolved in ethyl acetate (EtOAc). A saturated aqueous solution of sodium potassium tartrate (75 mL) was added and the mixture was stirred for 16 hours. The organics were collected and re-extracted with ethyl acetate (2 X 50 mL). The combined organics were dried and concentrated, and purified (EtOAc mjjjjjjjj MS (APCI) 563 (M+H +, 100%).

Method B base) 3⁄4 propyl 1 amino- 5-(propylthio)-3Ή-1,2,3 - three-seat [~4,5-d〗 _ mouth secret _3_ kibu four 氪-2, 2-Dimethyl-4H-cyclopenta-1,3-dioxo-4U.yl group 1 ^Coolli. In [3&amp;11-(3 Brunei 6,4〇6,6〇6,6&amp;〇 〇]-({6-[7-bromo-5-(propylthio)-311-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]•tetrahydro-2, Methyl 2-dimethyl-4H-cyclopenta-1,3-dioxo-4-ol}oxy)acetate (method 〇, 〇.80 g) and (111-re)-2-(3,4 -difluorophenyl)cyclopropylamine, [R-(R*,R*)]-2,3-dihydroxysuccinate (1:1) (Method C, 0.61 g) in di-methane ( A mixture of 25 ml) was added with N,N-diisopropylethylamine (0.85 ml). The resulting solution was stirred at room temperature for 16 hr then concentrated and concentrated. Purified (Si02, isohexane: ethyl acetate 3:1 as solvent) To give the title compound as a colorless foam (0.77 g). MS (APCI) 591 (M+H' 100%

Method C ^_1 wei-trans)-2-(3,4-difluoroanthracene, cyclopropylamine, "11-(^*^*)) 2.3-diindole succinate (1 : Π -21 - This paper scale applies to Chinese national standards (CNS>A4 specifications (2丨0&gt;&lt;297 public Chu)!111!——#! (Please read the notes on the back and fill out this page) Consumer Cooperatives Printed 1294427 Α7 Β7 Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printing 5, Inventions (19)

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

Il§K3aa,4a,6a,6jjg^({6-"7-bromo-5-(砬砬某-3Η-1,2,3-^ 生丄jj-cm症-3_基^四ι_2, 2-Dimethyl-4Η_瑗戍-13·di t alcohol} gas base) acetic acid brewing [3&amp;ΙΙ-(3αα,4α,6α,6αα)]·({6-[7_amino-5- (propylthio)-3H-1,2,3-diazole[4,5-d].pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3 Methyl 2-dioxo-4-ol}oxy)acetate (method e, gram) and isovaleronitrile (2.43⁄4 liter) in m-form (3 liters) heated at go t for 3 minutes. The reaction mixture was purified (EtOAc EtOAc (EtOAc:EtOAc:EtOAc)

Method E jXaR-(3aa?4a76a,6aa)]-^{6-r7·-^ ^ -5-( ^ ^ V3H-K2.3-iazole "4,5-d-pyrimidine.21 dimethyl Dioxa-4-ol}oxy)acetamidine in [3aR-(3aa,4a,6a,6aa)]-6_[7_amino-5-(propylthio)-3H-1,2,3 -Triazole [4,5-d]. Pyrimidine _3 -yl]•Tetraindole-2,2-dimethyl-4H·cyclopenta-1,3-dioxo-4-ol (Method F, 〇· 50 g) A solution of THF (25 ml) at 0 ° C was added to a butyl bell (0.62 mL of 2.5 N hexane). After 20 minutes, the suspension was methyl trifluoromethanesulfonate oxyacetate (0·34 g according to Biton

Prepared by a solution of Tetrahedron, 1995, 5 1,10513) 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) to afford the title compound ( 〇·25 -22- This paper scale applies to the Chinese National Standard (CNS) 〉Α4 specifications (210X297 mm) H.- II ...... I - - - ...... - I -- HI I- - 1 ^14 , \ one one, (please read the back first) Note: Please fill out this page again) Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing 1294427 A7 ____B7_ — — V. Invention Description (20) gram). MS (APCI) 439 (M+H +, 100%) 〇

Method F Amine-5-(procarbazole [4,5-(1~|_pyrimidin-3-篡1-tetraon|-2,2-dimethyl-41~1-ring"^-1, .O. oxy-4-ol [3aR-(3aoc,4a,6a,6aa)]_6-[7-chloro-5-(propylthiol·l 31^1,2,3·triazole [4,5 -d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl- 4H-cyclopenta-1,3-dioxo-4-ol (Method G, 13.2 g) in 0.88 ammonia (5 ml) The THF (200 liters) was stirred for 2 hr then concentrated to dryness and the residue was crystalljjjjjjjjjjjjjjjjjjjjjj + H+,100%) 〇

Method G

[3aR-(3aa, 4a, 6a, 6aa, l-6-r7-.5-Γ and 摹,

LiA: dl·pyrimidin-3-yl μ tetraoxo-2,2·dimethyl hydrazine _4Η·瑗 -1-1 raw isoprenonitrile (1.1 ^: liter) was added to [3aR-(3aa,4a,6a,6aa) )]-6-{[5^$: -6-chloro-2-(propylthio)-pyrimidin-4-yl]amino}-tetrahydro-2,2-dimethyl-4H-cyclopentyl - 1,3-dioxo-4-ol (method η, 2.0 g) in acetonitrile (100 mM) in amps &amp; and the solution was heated at 70 ° C for 1 hour. The cooled reaction mixture was concentrated to dryness (yield: EtOAc, ethyl acetate: hexanes: hexanes: 3) to afford the compound (1·9 g). MS (APCI) 386 (M+H+, 100%). Method 〇 〇 & & & & & & & & & & & & & & & & & & & & & & & & & & & _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Base 1 amine base tetrahydro-2,2·dimethyl UH-cyclopentane-1,3-dioxo-23- This paper scale applies to Chinese national standards (CNS>Α4 specifications (210X297 public 羡) ----- -------- (Please read the notes on the back and fill out this page again), can be 丨1· Department of Economics, Central Bureau of Standards, Staff Consumer Cooperatives, Printing 1294427 A7 B7_ — 1-5, invention description (21) Powder (3.0 g) was added [3aR-(3aa,4a,6a,6aa)]-6-{[6-gas-5-nitro-2-(propylthio)-pyrimidin-4-yl]amino} a stirred solution of tetrahydro-2,2·dimethyl-4H-cyclopenta-1,3-dioxo-4-ol (Method I, 2.7 g) in acetic acid (100 mL). After 2 hours, it was concentrated to a half volume of EtOAc (EtOAc) EtOAc (EtOAc). .

Method I r3aR-(3aa.4a,6a,6aa)l-6-(r6-氪-5-nitro-2-pyridylthio)-pyridin-4-one 1 amine ab 1-2, 2-Dimethyl-4H-cyclopenta-1,3-dihydro-4-ol [3&amp;11-(3 〇6,4〇1,6〇6,6&amp;〇〇]-6-amine Tetrahydro-2,2-dimethyl-411-cyclopenta-1,3-dioxo-4-ol, hydrochloride salt (method J, 10.0 g) and N,N-diisopropylethylamine ( 3 5 ml) a solution of THF (600 ml) was stirred for 1 hour. The mixture was filtered and the solution was added 4,6-di-5-nitro-2-(propylthio)pyrimidine (WO 9703084) over 1 hour. Patent, 25.6 g) in THF (1000 mL), and stirred for 2 hours. The solvent volume was reduced in the helium and ethyl acetate (1000 mL) was added. The mixture was washed with water and EtOAc (EtOAc m. MS (APCI) 405 (M + H +, 100%).

Method J

[3aR-(3aa,4cx,6a,6aa)]-6-Aminotetrahydro-2,2-dimethyl-4Η_cyclopenta-1,3-dioxo-4-ol, hydrochloride salt [1ΙΙ_(1α , 2β53β,4α)]-2,3,4_trisylcyclopentanyl quinone iminodicarbonate 'Wu (1,1-dimethylethyl) cool (method Κ, 17.4 g) in 6M HCl ( L〇〇ml)/methanol (500 ml) was stirred for 18 hours. Evaporate the mixture and then with A-24 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 Gongdong) ' ----- -------------- (please smell Read the back of the note and fill out this page), ιτ 1294427 A7 ____ B7 V. Inventions (22) (Please read the notes on the back and fill out this page)

The benzene was azeotroped (4 X 2003⁄4 liters) to give a colorless powder (7.8 g). This solid was suspended in acetone containing 2,2·dimethoxypropane (25 ml) and concentrated HCl (0.2 ml) (250 liters) and then heated under reflux for 2 hours. The mixture was cooled, evaporated and azeotroped with toluene (3 X 200 mL). The residue was dissolved in 2 〇〇 / 0 aqueous acetic acid and stirred for 2 hr. The mixture was evaporated and azeotroped with toluene (4×2 s) to afford title compound (10·1 g). MS (APCI) 174 (Μ + Η +, 100%). Method K m(lcx, 2^3 0,4001^3,4-trihydroxycyclodecenyl imine, a diterpene 丄贰 丄贰 (M-dimethyl ethane, ester in (1R cis)-wu ( 1,1_monomethylethyl)-4-trans-yl-2-cyclopentanyl-iminodicarbonate (method L, 17.1 g) was added in THF (500 ml) / water (50 ml) N-methylmorpholine-N-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 sodium sulfite (6) </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; s), 1.46-1.60 (1H, m), 1.97-2.05 (1H, m), 3.55-3.5 8 (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, d5 4.6) 中央 Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperative Print

Method L (1R-cis)-oxime (1,1 dimethylethyl)-4-mercapto-2-cyclopentene oxime iminodicarbonate in sodium hydride washed with ether (in oil 60 % suspension (0.31 g) in a suspension of THF (30 ml) with ruthenium dibromide (1,1-dimethylethyl) -25 - This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1294427 A7 B7 V. Description of invention (23) Vinegar (1.84 g). The mixture was stirred at 40 ° C for a few hours. Then at the ambient temperature, (1S-cis)-4-ethenyloxy-2-cyclopentene-indole-ol (〇5g) and hydrazine (triphenylphosphine) are added to the mixture (〇·18) Gram). The reaction mixture was stirred for 24 hours then purified (EtOAc EtOAc (EtOAc:EtOAc) NMR: 1.43 (18H, s), 161 (1H, ddd, j = 12.3, 7.7, 6.4), 2·54 (1H, dt, J = 12.6, 7. 4), 4.51-4.57 (1H, m)5 4.86 ( 1H, tq, J = 8.0, 1.8), 4·91 (1H, d, 5.4), 5.7 Bu 5.77 (2H, m) 〇 Example 2 The following describes the compound of formula (1) containing crystalline and/or amorphous forms ( Hereinafter referred to as Compound X), a representative pharmaceutical dosage form for therapeutic or prophylactic use in humans: I----------- (Please read the notes on the back and fill out this page)

1T Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printing Pharmaceutical Ingots I gram / medicinal compound X 100 Lactose Ph.Eur 182.75 Croscarmellose Sodium 12.0 Magnolia starch slurry (5% w/v slurry) 2.25 Stearic acid town 3.0 Ingot II mg / medicinal compound X 50 Lactose Ph.Eur 223.75 Croscarmellose Na 6.0 -26 - This paper scale applies to Chinese national standard (CNS M4 specification (210X297 public) 1294427 A7 B7 V. Invention description (24) Yuxi Hall slurry Material (5% w/v slurry) 15.0 Polyvinylpyrrolidone 2.25 Stearic acid 3.0 Ingot III mg/medicine ingot X 1.0 Lactose Ph.Eur 93.25 Croscarmellose Steel 4.0 Corn starch slurry (5% w/v pulp) Material) 0.75 Magnesium Stearate 1.0 Capsules mg/capsule Compound X 10 Lactose Ph.Eur* 488.5 Magnesium Stearate 1.5 (Please read the notes on the back and fill out this page) Printed by the Central Bureau of Standards and Staff Consumer Cooperatives of the Ministry of Economic Affairs ( e) Injection I Compound X 1N sodium hydroxide solution 0.1 N Hydrochloric acid polyethylene glycol 400 Water for injection to 100% (50 mg/ml) 5.0% w/v 15.0% w/v (adjust pH to 7.6) 4.5 % w/v -27- Paper scale applicable to Chinese national standard (CNS>A4 specification (210X297 mm) 1294427 A7 B7 V. Invention description (25) (f) Injection π Compound X Sodium phosphate BP 0.1N sodium hydroxide solution Water for injection to 100% (g Injection III compound X sodium sulphate BP citric acid polyethylene glycol 400 water for injection to 100 ° / 〇

Formulations above 1 L can be obtained by conventional procedures well known in the art of medicinal techniques. For example, the drug bonds (a)-(c) may be enteric coated by conventional methods to provide a coating of cellulose acetate phthalate. Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (10 mg/m well) 1.0% w/v 3.6% w/v 15.0% v/v Πmg/ml, buffered to pH 6) 0.1 % w/v 2.26% w /v 0.38% w/v 3.5% w/v (Please read the notes on the back and fill out this page) NMR spectra are measured on a Varian Unity Inova 300 or 400 spectrometer; NMR data is quoted in the form of a delta 値 of the main diagnostic proton It is expressed in parts per million (ppm) of tetramethyl decane (TMS) as an internal standard, which uses total dimethyl hydrazine (DMS046) as a solvent unless otherwise indicated; for example, only the main rotation The chemical transfer of the structure shows the presence of rotamers in the proton NMR spectrum; the coupling constant (J) is expressed in Hz. 28· This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1294427 A7 B7 V. Description of invention (26) Mass spectrometry (MS) is measured as follows: EI spectrum in VG 70-250S or Finnigan Mat Incos-XL spectrometer The FAB spectra were obtained on a VG 70-250 SEQ spectrometer, and the 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 examples) was performed using Fisher Matrix vermiculite, 35-70 microns. Shorthand THF Tetrahydropyrene XRPD X-ray powder diffraction DSC differential scanning calorimeter (please read the back note first and then fill out this page) Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperative Print -29- This paper scale applies to China Standard (CNS) A4 specification (210'〆297 mm)

Claims (1)

y\ λ|- ^ ·_ I, Shiyi _8 ^ r> 1294 pick 7G1 号 号 专利 专利 专利 _ _ _ 申请 申请 申请 申请 申请 申请 、 、 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请 申请Compound of formula (1) It is selected from the group consisting of: a compound of formula (I) characterized by being at 5.3. (Turkish.), 2〇". (Turk.), 20.7. (±〇·ΐ.)' 21·〇. (Turkish 1〇), and 21 3. (Turkish ι〇) 2θ X-ray powder diffraction pattern containing a specific peak of high strength; a compound of the formula (I) characterized by 14·〇. (士〇η, 17 4. (Turkish 1〇) 18.4. (±〇·1.), 21·4. (〇土〇.), and 24". (土〇ι〇) 2θ contains high and specific a X-ray powder diffraction pattern of peaks; and a compound of formula (I) characterized by being 49. (±〇1}, 9.2. (〇1〇), u ^ (〇〇.1°), 15· 6° (±〇·1.), and 16.4. (Soil 0.1.) 2Θ X-ray powder diffraction pattern containing a specific peak of high intensity. 2. According to the compound of formula (1) of the scope of the patent application, which is substantially The dehydrated form exists. 3. The compound of the formula (1) according to the scope of the patent application is characterized by 53. (Turkish·10), 8·0ο (±〇.1〇), 9.6 (±0.1.), 13.9〇(±〇.1〇), 15 3. (±0.1), 20.1 (±〇·10), 2〇.7〇(土0·1ο), 21.0ο (土〇·ι〇), 2ΐ· 30 71178-961108.doc _ 1 ^ This paper scale applies to China National Standard (CNS) Α4 specification (210X297 metric tons) 1294427 &amp;, patent application scope A8 B8 C8 D8 (±0·1°), 26·2° ( ±〇·ΐ.), and 27·5. (±0.1°) 2ΘX-ray diffraction pattern with high intensity specific peak 4. A compound according to formula (I) of claim 3, characterized in that the differential scanning calorimeter curve has a melting starting point in the range of from 14 to 152 ° C. 5 according to the scope of claim 1 ( I) a compound characterized by being 5.6 (±0·1ο), 12.5 (±〇·1〇), 14·0ο (±0.1〇), 17.4 (±〇·1〇), 18·4〇 (±0·1ο), 21:4ο (Turkish·ι〇), 22·2〇 (Earth 0·1〇), 22·9ο (±〇·1〇), 24·1〇 (土°·1 .), and 24·5〇(±〇·ΐ〇) 2Θ. 6. The compound of formula (I) according to item 5 of the patent application, characterized in that the differential scanning calorimeter curve has a range of 127-132. The starting point of melting. • The compound of formula (I) according to item 1 of the patent application is characterized by 4.9 (±0·1.), 6·0ο (±〇.1〇), 9 2. (〇 ”), 116〇 (士〇1〇), 12 8. (±0·1ο), 15.6〇 (±〇·ι), 16.4〇 (Gentry)., 17_2. (±〇·ι〇) And 18 1 〇 (±0.1 °) 2 又 ray diffraction pattern containing high intensity specific peaks. • Compound according to formula (I) of claim 7 Wherein a differential scanning calorimeter melting curve having a starting point of about 139 ° C. 9. A compound of the formula (1) according to the first aspect of the patent application, which is in the form of a hydrate. A method of preparing a compound of the formula (1) according to the scope of the patent application of the present invention, wherein the compound of the formula (I) is crystallized from a solvent selected from the group consisting of low-carbon alcohol, acetonitrile, water or a mixture thereof. A method according to the first aspect of the invention, wherein the solvent is selected from the group consisting of ethanol, ethyl acetate, isopropanol, isooctane, acetonitrile, water, or a mixture thereof. 71178-961108.doc 2_ 卞仔平哼哼油中中|同彳样ymis) λ 1 (1丨丨丨丨μ览) 1 1294427 VI. Applying for patent Fanyuan 12· According to Zhongming patent scope i! In the method, the solvent is selected from the group consisting of a mixture of methanol and water, ethanol, a mixture of ethanol and water, a mixture of isopropyl alcohol and water, a mixture of ethyl acetate and isooctane, and acetonitrile. 13. The method according to any one of claims 1 to 12, which is for the manufacture of a compound according to claim 3 or 4 wherein the solvent is a mixture of methanol and water. 14. A method of producing a compound according to claim 3 or 4, which uses seeds. 15. The method of claim 14, wherein the seed is prepared by melting a compound according to claim 3 or 4 of the patent application. The method according to any one of claims 1 to 12, which is for use in the manufacture of a compound according to claim 5 or 6 wherein the alcohol is dissolved. 17. A method of producing a compound according to claim 5 or 6 which comprises a compound of formula (I) in the range of 5 to 65. The temperature of the crucible is slurried in the IPA/water solvent system. The method according to any one of claims 1 to 12, which is to manufacture a compound according to claim 7 or 8 of the patent application, and the second: is acetonitrile. And a bathing agent. 19. A compound according to any one of claims 1 to 9, a remedy. , as a pharmaceutical composition for the prevention of coronary artery, cerebrovascular or peripheral vascular disease in human arterial thrombosis, which includes the Chinese Standard (CNS) Α 4 specification according to the application of the bite = the paper scale (210X297 mm). 1294427 6. The compound of any one of items 1 to 9 of the patent application A8 B8 C8 D8 J range is incorporated with a pharmaceutically acceptable adjuvant, diluent or carrier. Use of a compound according to any one of claims 1 to 9 for the manufacture of a pharmaceutical agent for preventing arterial thrombosis complications in a patient having coronary artery, cerebrovascular or peripheral vascular disease. A pharmaceutical composition for preventing tumor growth and spread, which comprises a compound according to any one of claims 1 to 9. And a use of a compound according to claims 1 to 9 in the manufacture of a pharmaceutical agent for preventing tumor growth and spread. 71178-961108.doc -4- ____;____^ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)·