TW200812968A - Novel crystalline forms 2 639 - Google Patents

Abstract

The present invention relates to 6-(4-{[(benzylsulfonyl)amino] carbonyl}piperidin-1-yl)-5-cyano-2-methylnicotinic acid ethyl ester, form I and II, to processes for preparing such compounds, to their utility as P2Y12 inhibitors and as anti-thrombotic agents etc, their use as medicaments in cardiovascular diseases as well as pharmaceutical compositions containing them.

Description

200812968 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention provides 6-(4-{[(sulfonyl)amino]carbonyl}hexahydroacridinyl> 5-cyano-2-methyl A novel crystalline form of nicotinic acid ethyl ester, its use as a pharmaceutical agent, a composition comprising the same, and a method of preparing the same. [Prior Art] Initial event in platelet adhesion and agglutination arterial thrombosis. Although platelet adhesion The process to the subendothelial surface may play an important role in repairing the damaged vessel wall, but the resulting platelet aggregation may suddenly lead to an acute thrombotic occlusion of the extremely important vascular bed, which leads to high morbidity events (eg myocardial infarction) And unstable angina). The success of interventions to prevent or reduce such conditions (such as thrombolysis and angioplasty) is also impaired by platelet-mediated occlusion or severe occlusion. Hemostasis is caused by platelet aggregation, coagulation And a tight balance between fibrinolysis to control thrombosis under pathological conditions (eg, atherosclerotic plaque rupture) initially It is caused by platelet adhesion, activation and agglutination. This not only leads to the formation of platelet embolism, but also leads to the exposure of negatively charged phospholipids on the outer platelet membrane, which promotes blood coagulation. The inhibition of the accumulation of initial platelet plugging is expected to reduce blood. Detection and reduction of the number of cardiovascular events 'This is confirmed by, for example, the antithrombotic effects of aspirin (BMJ 1994; 308: 81-106 Antiplatelet Trialists,

Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: Prevention of death, myocardial infarction, and stroke by prolonged antipalatelet therapy in 121551.doc 200812968 various categories of patients) 血小板 Platelet activation/agglutination can be induced by a variety of different agonists. However, different intracellular signaling pathways must be activated to achieve complete platelet aggregation, which is mediated via G-proteins Gq, G12/i3, and Gi (Platelets, edited by AD Michelson, Elsevier Science 2002, ISBN 012-493951-1; 197-213 · D Woulfe et al., Signal transduction during the initiation, extension, and perpetuation of platelet plug formation). In platelets, G. protein-coupled receptor P2Y12 (formerly known as platelet P2T, P2Tae, or P2Yeye receptor) transmits signals via G彳, resulting in decreased intracellular cAMP and complete agglutination (Nature 2001; 409: 202-207) G Hollopeter et al., Identification of the platelet ADP receptor targeted by antithrombotic drugs). The ADP released from the dense particles will be positively fed back to the P2Y12 receptor to enable complete agglutination. The clinical use of clopidogrel provides clinical evidence for the pivotal role of the ADP-P2Y12 feedback mechanism, which is a thienopyridine prodrug whose active metabolite selectively and irreversibly binds to the P2Y12 receptor. This has been shown in some clinical trials to effectively reduce the risk of cardiovascular events in at-risk patients (1^11〇61 1996; 348:1329-39: CAPRIE Steering committee, A randomised, blinded,trial of clopidogrel Versatile aspirin in patients at risk of ischaemic events (CAPRIE); N Engl J Med 2001; 345 (7): 494-502): The Clopidogrel in Unstable Angina to prevent Recurrent Events Trial Investigators. Effects of clopidogrel in 121551.doc 200812968 addition To aspirin in patients with acute coronary syndromes without ST-segment elevation.) The clinical benefit of clopidogrel therapy in these studies is accompanied by an increase in clinical bleeding rate. Published data indicate that reversible P2Y12 antagonists can provide a high clinical benefit while reducing the risk of bleeding compared to thienopyridine (Sem Thromb Haemostas 2005; 31 (2): 195-204, van Giezen & RG Humphries Preclinical and clinical studies with selective reversible direct P2Y12 antgonists) o Accordingly, it is an object of the present invention to provide an effective, reversible and selectable P2Y12-antagonist as an antithrombotic agent. In the formulation of pharmaceutical compositions, it is important that the drug substance is in a form that can be conveniently handled and processed. This is important not only from the standpoint of obtaining a commercially viable manufacturing process, but also from the subsequent manufacture of pharmaceutical formulations comprising the active compound. Moreover, in the manufacture of oral pharmaceutical compositions, it is important to provide a drug that is reliable, reproducible, and stable in plasma concentration profile after administration to the patient. The chemical stability, solid state stability and "shelf life" of the active ingredients are also important factors. The drug substance and the composition comprising the same should be effective for a relatively long period of time, and the active ingredient does not exhibit significant changes in physicochemical properties (e.g., chemical composition, density, water absorption, and solubility). Amorphous materials may present problems in this regard. For example, such materials are generally more difficult to handle and formulate, their solubility is unreliable, and often less stable. Therefore, it is important to provide a substantially crystalline and stable form of the drug as much as possible in the manufacture of a commercially viable and pharmaceutically acceptable pharmaceutical composition. [Inventive content] Now, we have surprisingly discovered the crystalline form of the present invention. Reversible and selective P2Y12 antagonist. The compounds of the present invention surprisingly exhibit beneficial properties which make them particularly suitable for use in the treatment of the diseases/conditions set forth below. Examples of this specialized benefit feature are high performance, high selectivity, and advantageous therapeutic windows. [Embodiment] The first aspect of the present invention is: In the first embodiment, 6-(4-{[(benzylsulfonyl)amino]carbonyl}hexahydropyridin-1-yl)·5-cyanide Formula I of ethyl-2-methylnicotinate ethyl ester having the following XRPD-peak: 〇3.54 α-value, A (Angstrom) relative intensity, % 7.12 18.63 19.64 Therefore, the first aspect of the present invention The first embodiment is characterized by exhibiting XRPD-peaks at values of approximately 24.9, 12.4, 4.76, 4.52, 4.09, and 2.65 angstroms (A). The first embodiment of the first aspect of the present invention is also characterized by having an XRPD-peak at about 2-251 (°) 3.54, 7.12, 18.63, 19.64, 21.71 and 33.85 as follows. A second embodiment of the first aspect of the invention, 6-(4-{[(benzylsulfonyl)amino]amino}hexahydroσ-pyridin-1-yl)·5-cyano-2- Methyl smear acid type I has the following XRPD-peak: angle 2-θ° d-value, relative intensity of angstrom, % 3.54 24.9 " 1〇〇7.12 ^ 12.4 14 13.39 6.6 5 14.07 6.3 4 14.76 ' 6.0 4 18.32 4.84 4 18.63 4.76 9 ~ 19.64 4.52 6 20.79 4.27 4 21.71 4.09 33.85 2.65 2 41.14 2.19 2 Therefore, the second embodiment of the first aspect of the invention is characterized by approximately 24·9, 12.4, 6.6. , 6.3, 6.0, 4.84, 4.76, 4.52, 4.27, 4.09, 2.65, and 2.19 angstroms (A) D-values have XRPD-peaks. The second embodiment of the first aspect of the present invention may also be characterized by the following approximately 2-theta (°) 3.54, 7.12, 13.39, 14.07, 14.76, 18.32, 18.63, 19.64, 20.79, 21.71, There are xRpd_ peaks at 33.85 and 41.14. A third embodiment of the first aspect of the invention, 6-(4-{[(benzylsulfonyl)amino]carbonyl}hexahydroacridin-1-yl)-5-cyano-2-yl Type I of ethyl nicotinic acid ethyl ester has the following XRPD-peak: 121551.doc -10- 200812968 Angle 2-θ° d-value, human (Angstrom) relative intensity, % 3.54 24.9 100 7.12 12.4 14 10.69 8.3 1 13.39 6.6 5 14.07 6.3 4 14.76 6.0 4 17.89 4.95 2 18.32 4.84 4 18.63 4.76 9 19.31 4.59 3 19.64 4.52 6 20.11 4.41 1 20.56 4.32 3 20.79 4.27 4 21.23 4.18 2 21.51 4.13 4 21.71 4.09 11 23.17 3.84 3 23.38 3.80 2 24.07 3.69 1 25.08 3.55 3 26.26 3.39 2 26.56 3.35 1 26.80 3.32 2 27.81 3.20 1 28.53 3.13 2 33.85 2.65 2 41.14 2.19 2

Accordingly, the third embodiment of the first aspect of the present invention is characterized by approximately 24.9, 12.4, 8.3, 6.6, 6.3, 6.0, 4.95, 4.84, 4.76, 4.59, 4.52, 4.41, 4.32, 4.27, 4.18. , 4.13, 4.09, 3.84, 3.80, 3.69, 3.55, 3.39, 3.35, 3.32, 3.20, 3.13, 2.65 and 2.19 angstroms (A) D-values have XRPD-peaks. The third embodiment of the first aspect of the invention is characterized by the following approximately 2-theta 3.54, 7.12, 10_69, 13.39, 14.07, 14.76, 17.89, 18.32, 18.63, 19.31, 19.64, 20.11, 20.56, 20.79. 121551.doc -11 - 200812968 21.23, 21·51, 21.71, 23.17, 23.38, 24.07, 25.08, 26·26, 26.56, 26.80, 27.81, 28.53, 33.85 and 41.14 have XRPD peaks. A fourth embodiment of the first aspect of the invention, 6-(4_{[(benzylsulfonyl)amino]carbonyl}hexahydropyridin-1-yl)-5-cyano-2-methyl Formula I of ethyl nicotinic acid is characterized according to any of the preceding embodiments of the first aspect of the invention wherein the XRPD peak having the greatest relative intensity is at a d-value of about 24.9 humans (Angstroms). A fifth embodiment of the first aspect of the present invention, 6-(4-{[(benzylsulfonyl)amino]carbonyl}hexahydropyridin-1-yl)-5-cyano-2-methyl cigarette Formula I of ethyl hydroxy acid is characterized by having an XRPD-spectrum substantially as shown in Figure 1. Another (second) aspect of the invention is: 6·(4_{[(benzylsulfonyl)amino]carbonyl}hexahydrou-bipyridyl-fluorenyl-pyridyl-cyano-2_indenylnicotinic acid Type II of ethyl ester has the following XRPD peaks in the first embodiment: angle 2-θ° d-value, human (Angstrom) relative intensity, % 6.76 13.1 100 10.00 8.8 5 14.39 6.2 "- 19.08 4.65 20.37 4.36 2Α ~ - Thus, the first embodiment of the second aspect of the invention is characterized by exhibiting xRPD-peak 0 at approximately 13·1, 8·8, 6.2, 4.65 and 4_36 angstroms (A)D_ values. In the first embodiment, [6-(4-{[(benzylsulfonyl)amino]carbonyl}hexahydropyridin-1-yl)-5-cyano-2-methylnicotine The shape of the acid ethyl ester 121551.doc -12- 200812968 The formula II is also characterized by having an xrpd peak at about 1., 丨 19.08 and 20.37. · In the second aspect of the present invention - in the case of the example, only 6-(4-{indolyl)amino]amino}hexahydro-peri-bityl-)-only ^^^ π g. cyano-2_methylnicotine Acetate type 11 has the following XRPD peaks: Self-twist angle 2-Θ0 —-——-------- 6J6 ^ Οοο Relative strength, % 21 cut: 5 — 3 ~ 13.40 — 14.39 6.6 ^- Γ 14?76 i 19Ό8 Ϊ9Α3 ~ 〇«^ Γ 60 ^ ^— 4.56 —^' 6 [1 4 — ^ i 20.37 2L60 25A6 - - - - - - - Therefore, the fourth aspect of the present invention is 4.36 ^ 4 ΤΪ - Ϊ 5 Γ - - -- ~ ~ - ^ J ^ ^ 5 L___ 3ZZII ^ ^ 丨 two embodiments are characterized by Ο Ο about 13.1 XRPD-peaks were present at 8.8, 6.6, 6.2, 2, 6.0, 4.65, 4.56, 4.36, 4·ΐι and 3·50 angstroms (A) D-values. In the second embodiment of the second aspect of the present invention, [6-(4_{[(benzylidene)amino)carbonyl}hexahydropyridin-1-yl)-5-cyano-2-indolyl The type II of ethyl alkaliate is characterized by having an XRPD peak at about 2-theta (°) of 6.7ό, 10·00, 13·40, 14.39, 14.76, 19.08, 19.43, 20.37, 21.60 and 25.46. In a third embodiment of the second aspect of the invention, 6-(4-{[(indenyl)amino]carbonyl}hexahydropyridin-1-yl)-5-cyanoindole nicotinic acid Type II of acetamidine has the following XRPD peaks: 121551.doc -13- 200812968

The xrPD-peak is present at a 3.21 angstrom (A) D-value. Q This third embodiment of the second aspect of the invention, [6-(4-{[(benzylsulfonyl)amino]] anoyl}hexahydro-yl)-5-cyano-2. The type II of the base cigarette is characterized by the following approximately 2_θ(0)6·76, 9.51, 9.68, 10.00, 13.40, 13.55, 14.18, 14.39, 14.76, 19.08, 19.43, 20.37, 21.60 &gt There are XRPD peaks at 22-90, 23.27, 24.63, 24.89, 25.46, 25.74 and 27.73. A fourth embodiment of the second aspect of the present invention, 6-(4-{[(benzylsulfonyl)amino]carbonyl}hexahydro 0-pyridin-1-yl)-5-cyano-2-indole Types of ethyl nicotinic acid ethyl ester 121551.doc -14- 200812968 II is characterized according to any of the foregoing embodiments of the second aspect of the invention, wherein the XRPD peak with the greatest relative intensity is located at approximately 131 persons (Angstrom ) at the d-value. A fifth embodiment of another aspect of the invention, [6_(4_{[(benzylsulfonyl)amino]carbonyl}hexahydroacridin-1-yl)-5-cyano-2-methylnicotine Formula II of the acid ethyl ester is characterized by having an xrpd spectrum substantially as shown in Figure 2. Another aspect of the invention is a process for the preparation of the above crystalline form I, which process comprises the steps of: a) compound 6-(4_{[(benzylsulfonyl)amino) at ambient temperature or by reflux Ethyl carbonyl}hexahydropyridin-1-yl)-5-cyano-2-methylnicotinate is dissolved or suspended in ethyl acetate; b) the solution obtained from a) is optionally subjected to transparent filtration; c Crystallizing the substance dissolved or suspended in the solution or suspension obtained from step a) or step b), and this is carried out as appropriate during cooling to room temperature; d) filtering the obtained crystalline product and Separation. A further aspect of the present invention is a process for preparing the above crystalline form, which comprises the steps of: a) introducing a compound 6_(4_{[(benzylsulfonyl)amino) at ambient temperature or by refluxing Ethyl carbonyl}hexahydroacridin-1-yl)-5-cyano-2-indenyl nicotinic acid is dissolved or suspended in chloroform or tetrahydrofuran; b) The solution obtained from step a) is optionally filtered as appropriate c) crystallizing the substance dissolved or suspended in the solution or suspension obtained from the step or step b), and this is carried out in the process of cooling to room temperature as in the case of 121551.doc -15-200812968; d) adding a non-solvent such as ethanol as appropriate; e) filtering and separating the obtained crystalline product. 6_(4·{[( 酿 酿 ) ) 胺 } } } } } } } } } } } } } } } } } 六 六 六 六 六 六 六 六 六 六 六 另外 另外 另外Additional Properties Listed below·· Any of its embodiments* has the following aspects for the first aspect of the invention:

Ο (I) When characterized by thermogravimetric analysis, at 25°. In the range of 2 steps of the Trent, a weight loss of approximately 8%.8% occurs, and/or (Π) when borrowed under a flowing nitrogen in a closed cup with a pinhole at a rate of 1 〇, When characterized by differential scanning calorimetry, the melting temperature (Tm) begins at about 194 charge and/or the associated melting endotherm is about 96 J/g; and/or (III) when stored at 80% RH (environment), Adsorbs less than 〇2% moisture. * For the type II, that is, the second aspect of the invention, any of the embodiments has: (1) when characterized by thermogravimetric analysis, 'appears about 0.2% in the range from 25 to 2 〇 5 Weight loss, and/or (II) is 1 Torr in a closed cup with pinholes under flowing nitrogen. When the heating rate of [: /min is characterized by differential scanning calorimetry, the melting temperature (Tm) starts at about 193 ° C and/or the associated melting endotherm is about 1 〇 5 j / g. Pharmacological data Functional inhibition of the P2Yi2 receptor can be measured by using a cell membrane derived from P2 transfected CHO-cells 121551.doc -16-200812968, as follows. Functional inhibition of P2Y12 signaling induced by 2-Me-S-ADP: Diluting 5 μg of membrane in 200 μl of 200 mM NaC 1 mM MgCl 2 , 50 mM HEPES (pH 7.4), 0.01% BSA, 30 μg /ml saponin and 10 μΜ

In GDP. An agonist of ECso concentration (2-methyl-thio-adenosine diphosphate), a test compound of the desired concentration, and 〇·1 pCi 35S-GTPyS were added thereto. The reaction was allowed to proceed at 30 ° C for 45 minutes. The sample was then transferred to a GF/B filter using a cell harvester and washed with wash buffer (5 Tris (pH 7.4), 5 mM MgCl2, 50 mM NaCl). The filter is then covered by the scintillator and counted as the number of 35S-GTPYS retained by the filter. The maximum activity is the value measured in the presence of the agonist and the minimum activity is the value measured in the absence of the agonist, which is the value obtained by subtracting the measured value of the non-specific activity. The effect of the compound at various concentrations is based on the following equation y = A + ((BA) / (l + ((C / x) AD)))) and the calculated IC50, where A is the plateau of the curve, also That is, the final minimum y value B is the top of the plateau of the curve, that is, the final maximum threshold C is the X value in the middle of the curve. When a+b = 1〇〇, this represents the value of i〇g ec50. D is the tilt factor. The X value originally known for the X system. y is the initially known y value. The compounds of the present invention are active at a concentration of about 4 _ or less when tested in the illustrated 2-Me-S-ADP-induced P2Y12 signal-inducing assay of 121551.doc 17·200812968. The compounds of the invention act as P2Yu receptor antagonists and are therefore useful in therapy. According to another aspect of the invention, a compound of the invention is provided for use in therapy. • In another example, the use of a compound of the invention is provided for the manufacture of a medicament for the treatment of platelet agglutination disorders. Another step in the present invention

In a sad form, the use of a compound of the invention for the manufacture of a medicament for inhibiting a P2Y" receptor is provided. /Equivalent a system is used for treatment, especially adjuvant therapy, in particular, they are not useful as Platelet activation, agglutination and degranulation inhibitors, platelet deagglomeration promoters, antithrombotics or for treatment or prevention: unstable angina, coronary angioplasty (PTCA), myocardial infarction, peripheral blood private bath solution, Primary arterial thrombotic complications of atherosclerosis, such as blood-forming or embolic stroke, transient ischemic attack, peripheral blood disease, myocardial infarction with or without thrombolysis, by interventional atherosclerosis Arterial complications caused by H disease 'Examples angioplasty, endarterectomy, endovascular stent placement, coronary and other vascular graft procedures, thrombotic complications of surgery or mechanical injury, for example, after accident or surgical trauma Tissue remediation, orthopedic surgery, including skin and muscle flaps, conditions with diffuse thrombosis/platelet depletion, for example, diffusion Intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, thrombotic complications of septicemia, adult respiratory distress syndrome, antiphospholipid syndrome, heparin-induced thrombocytopenia, and 121551.doc -18- 200812968 "= work/eclampsia, or venous thrombosis, such as deep vein thrombosis, venous obstructive disease, hematological disorders, for example, bone marrow hyperplasia, including thrombocytosis, sickle cell disease; or for prevention in vivo Mechanically induced platelet activation, for example, cardiopulmonary bypass and extracorporeal membrane type artificial oxygenation (prevention of small thrombus), in vitro mechanically induced platelet activation, Ο

QJ is used to preserve blood products, such as platelet concentrates, or bypass closures: for example, in renal transfusion and plasmapheresis, secondary to vascular injury/cases, vasculitis, arteritis, glomerulonephritis, inflammation Thrombosis of septic disease and S transplant rejection, such as migraine headaches, Raynaud's phenomenon, conditions in which platelets may contribute to the process of essential inflammatory diseases in the blood vessel wall, for example, atheroma formation/progression, stenosis / restenosis and for other inflammatory symptoms, such as asthma, I platelets and small plate source factors involved in the immune disease process. According to the present invention, the use of the compound of the present invention for the manufacture of an agent for treating the above diseases is provided. In particular, the compounds of the present invention are useful for the treatment of myocardial infarction, thrombotic stroke, transient blood clots, peripheral fistula disease, and colic, especially unstable angina. The invention also provides a method of treating the above diseases, which method comprises administering to a patient suffering from such a disease a therapeutically effective amount of a compound of the invention. x In another aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of the invention and a pharmaceutically acceptable adjuvant, diluent and/or carrier. Such compounds can be administered topically in the form of solutions, suspensions, hydrofluorinated aerosols and dry powders 121551.doc -19- 200812968 (eg, administration to the lungs and/or airways 0 'eg, in the form of tablets, pills, Capsules, syrups, powders or granules are administered orally or in the form of a sterile parenteral solution or suspension in the form of a (4) intestinal administration, or administered subcutaneously, or administered in the form of a test for rectal administration. The compound of the present invention can be administered alone or as a pharmaceutical composition (including a compound of the present invention in combination with a pharmaceutically acceptable thinner < diluent, adjuvant or carrier) Ο 。. Particularly preferred are compositions which do not contain a substance which causes an adverse reaction (for example, an allergic reaction). The dry powder formulation of the compound of the present invention and the pressurized hydrofluorocarbon aerosol can be used by oral or nasal. For inhalation, it is desirable that the compound is ground. The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or multiple dose inhaler and may be A respiratory start dry powder inhaler. It is possible to mix the ground compound with a carrier (for example, a monosaccharide, a disaccharide or a polysaccharide, a sugar alcohol or another polyol). Suitable carriers include sugars and starches. The compound may be coated with another substance. The powder mixture may also be dispensed into a hard gelatin capsule, each capsule containing the desired amount of the active compound. Another collateral is the processing of the ground powder into a sphere, which The sphere is decomposed during inhalation. The spheroidized powder can be filled into a multi-dose inhaler (e.g., 'the one known as Turbuhaler®') in a drug reservoir, one of which doses the desired dose inhaled by the patient. With this system, the active compound with or without a carrier is delivered to the patient. 121551.d〇( -20- 200812968 A pharmaceutical composition comprising a compound of the invention may conveniently be administered to a lozenge, pill, capsule, syrup, powder or granule for oral administration; sterile parenteral or subcutaneous injection A solution, a suspension for parenteral administration or a suppository for rectal administration. For oral administration, the active compound can be combined with an adjuvant or carrier (for example, lactose, sucrose, sorbitol, mannitol, Starch (such as potato starch, corn starch or amylopectin), cellulose derivatives), binders (such as gelatin or polyvinylpyrrolidone) and lubricants (such as magnesium stearate, calcium stearate, polyethylene) The diol, beeswax, paraffin, and the like are blended and then compressed into a tablet. If a tablet is to be coated, the core prepared by the method explained above may be a concentrated sugar solution (which may include, for example, Arabic) Coated with gum, gelatin, talc, titanium white, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a volatile organic solvent or aqueous solvent. The compound may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound, using any of the above-mentioned excipients for lozenges (eg, lactose, sucrose, sorbus) Alcohol, mannitol, starch, cellulose derivative or gelatin. The liquid or semi-solid formulation of the drug may also be filled into a hard gelatin capsule. The liquid formulation for oral administration may be in the form of a syrup or suspension. a form comprising, by way of example, a solution comprising the compound, the balance being a mixture of sugar and ethanol, water, glycerol and propylene glycol, as the case may be, the liquid formulation may comprise a coloring agent, a flavoring agent, a saccharin and as an increase The carboxymethylcellulose of the thickener or other excipient known to those skilled in the art. 121551.doc -21 - 200812968 The invention will be further illustrated by the following non-limiting examples. Mass spectra were recorded on a Finnigan LCQ Duo ion trap mass spectrometer (LC-ms) equipped with an electrospray interface or recorded in LC-ms consisting of WatersZQ using an LC-Agilent 1100 LC system. On the system, a Varian Mercury VX 400 spectrometer operating at a frequency of 400 to 1 H and a Varian (" UNITY plus 400, 500 and 600 spectrometer operating at 400, 500 and 600 Hz respectively) were subjected to 1H NMR. The chemical shift was given in ppm using the solvent as an internal standard. Chromatography was performed using Biotage Shishuang 40S, 40M, 12i or Merck Silicone 60 (0·063·0·200 mm). Standard glass column was used. Flash chromatography on a plastic column or on a Biotage Horizon system. HPLC separation in a microwave reactor using a Kromasil C8 10 micron column on a Waters YMC-ODS AQS_3 (120 A, 3 x 500 mm) or on a Waters Delta Prep Systems The reaction can be performed in Personal Chemistry Smith Creator, Smith Synthesizer or Ο

Implemented in Emrys Optimizer.

The XRPD experiment was carried out on a D8 Advance diffractometer (Bruxer AXS - GmbH, Karlsruhe, Germany) with a Bragg-Brentano geometry and equipped with a VANTEC-1 position: a sensitive detector (PSD). Nickel-filtered Cu Κα radiation was used. Approximately 10 mg of these samples were placed on a zero background holder (矽 crystal). Use continuous scan mode to 〇_〇 17. The step size and the 0.5 second step are collected in the range of 1-50. 2 。. Apply a variable (V20) divergence slit and a 12 mm detection slit, which is equivalent to a wide detection window of 3.47° 121551.doc -22- 200812968. Test the sample with or without an internal standard. (The diffraction pattern shown in Figures 1 and 2 does not require an internal standard). List of abbreviations used: abbreviated explanation br generalized value BSA bovine serum albumin, d double DMF dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol HOBt 1-hydroxybenzotriazole Hz Hertz J Coupling constant m Multiple MeOH methanol O MHz mega mega mL ml: MS mass spectrometry; q quadruple rt room temperature s single line t triple TBTU tetrafluoroboric acid > 1-[(111-1,2,3-benzotriazole- 1-Based 121551.doc -23· 200812968 Oxygen)(dimethylamino)-methylene]-N-methylmethylammonium THF Tetrahydrofuran Example 1 6-(4·{[(~ 醯 )))] Carbonyl}hexa-argon ratio bite)_5-cyanomethylnicotinic acid ethyl ester 6-chloro-5-cyano-2-methylnicotinate ethyl ester (47.5 g, 211 mmol) at room temperature Add the solution of triethylamine (58.36 g, 577 mmol) in Et〇H (3 14 ml) to the stirred N_(benzylsulfonyl)hexahydropyridinium-4. Methionine (53.55 g, 189.7 mmol, see Comparative Example 2 (b)) and EtOH (10 〇t liter) mixture, and the mixture was heated to i〇〇t (bath temperature, in 40 minutes) Inside, 20-100 ° C, 100 After 15 minutes at ° C, then cool to room temperature for 15 minutes. A solution of KHS04 (142.93 g in 900 ml of water) was added to precipitate a product. The precipitate was filtered and washed with water (2×250 mL). The crude product was slurried in 50% EtOH (1200 mL) and heated at 5 ° C (bath temperature) for 2 hours and 45 minutes, then stirred at room temperature overnight. Filtration gave the crude product which was further washed by stirring at 25% EtOH (1600 mL) for 2 hours at 50 ° C and then stirring at 20 ° C for 20 hours with 20% EtOH (1000 mL). Attempts to purify the material by using a 50% EtOH/water solution were unsuccessful because it dissolved too much of the product). The solid obtained after the above washing (89% pure) was dissolved in 700 ml of EtOAc at 70 ° C, and the solution was allowed to stand at room temperature overnight to crystallize. The crystals were filtered and washed with EtOAc (EtOAc) (EtOAcjjjjjjjjj -1-yl)_5- 121551.doc -24- 200812968 Ethyl cyano-2.methylnicotinate. Yield: 54.94 g. The recrystallized solid in EtcAc& mother liquor gave 10.50 g again. The yield was 65.44 g (73%). This product can also be crystallized from CHC13. NMR (400 MHz5 CDC13): δ 1.38 (3Η5 t, J=7.0 Ηζ)5 1.77- L91 (4Η,m), 2.37-2.44 (1Η,m), 2.73 (3Η,s), 3.10-3.17 (2H, m), 4.33 (2H, q, J = 7.0 Hz), 4.64 - 4.68 (4H, m), 7.36-7. 41 (5H, m), 8.36 (1H, s). MS m/z : 471 (M+l) 〇

Ο

The product obtained from crystallization in EtOAc (formula) is characterized by the presence of a peak at about "and the relative intensity values" in the χ-ray powder diffraction (XRPD) measurement, and the homemade pulp. The characteristics of the product obtained by crystallization in CHC13 (Formula H) are set forth in Table 2 below. The formula π can also be prepared as follows. · Only the crude product of Example 1 (crude product) 82 g (174 3 mmol) under reflux (67. 〇) Dissolved in 300 ml of anhydrous tetrahydrogenate. The resulting solution was kept transparent and allowed to crystallize during cooling to room temperature. At room temperature, 300 ml of ethanol was slowly added to After gently mixing the crystal slurry, after Μ hours, the crystal was filtered off. The crystal product was washed with ethanol and dried under vacuum at 40 ° C. Yield: 7 g. Stable type). The methyl group produces a mixture of Forms I and II. This procedure gives the crystalline form 11 (thermodynamic tetrahydrofuran in place of the THF in the above procedure).

121551.doc -25- 200812968 11.59 7.6 0.6 13.39 6.6 5 14.07 6.3 4 14.29 6.2 0.9 14.76 6.0 4 16.98 5.2 0.2 17.89 4.95 2 18.32 4.84 4 18.63 4.76 9 19.31 4.59 3 19.64 4.52 6 20.11 4.41 1 20.56 4.32 3 20.79 4.27 4 21.23 4.18 2 21.51 4.13 4 21.71 4.09 11 22.33 3.98 0.6 ^ Λ Z丄丄/ 3.84 3 23.38 3.80 2 24.07 3.69 1 25.08 3.55 3 25.73 3.46 0.4 26.26 3.39 2 26.56 3.35 1 26.80 3.32 2 27.34 3.26 0.3 27.81 3.20 1 28.53 3.13 2 28.82 3.09 0.6 29.34 3.04 0.8 29.87 2.99 0.9 30.29 2.95 0.8 31.25 2.86 0.6 31.74 2.82 0.5 32.59 2.75 0.9 33.85 2.65 2 34.38 2.61 0.7 35.16 2.55 0.4 35.65 2.52 0.2 36.26 2.48 0.5 37.49 2.40 0.4 38.42 2.34 0.4 38.76 2.32 0.3 40.02 2.25 0.6 40.91 2.20 0.8 41.14 2.19 2 43.80 2.07 0.4 44.33 2.04 0.5 44.88 2.02 0.4 121551.doc -26- 200812968 Table 1. 6-(4-{[(> continuation) amino group] a few base} six rat σ than bite-1 - XRPD peak of type I of 5-)-methyl- 2-methylnicotinate

Angle 2-θ° d-value, human (Angstrom) relative intensity, % 6.76 13.1 100 9.51 9.3 2 9.68 9.1 2 10.00 8.8 5 12.30 7.2 0.4 13.40 6.6 3 13.55 6.5 1 13.74 6.4 0.8 14.18 6.2 1 14.39 6.2 6 14.76 6.0 4 15.19 5.8 0.4 16.22 5.5 0.3 18.02 4.92 0.6 18.79 4.72 0.5 19.08 4.65 6 19.43 4.56 5 20.37 4.36 24 21.60 4.11 3 22.20 4.00 0.8 22.90 3.88 2 23.27 3.82 1 23.95 3.71 0.8 24.63 3.61 2 24.89 3.57 2 25.46 3.50 3 25.74 3.46 3 26.06 3.42 0.6 26.97 3.30 0.5 27.28 3.27 0.8 27.73 3.21 2 28.49 3.13 0.7 31.43 2.84 0.3 34.30 2.61 0.9 41.45 2.18 0.9 Table 2: 6-(4-{[(benzylsulfonyl)amino]carbonyl}hexahydroacridine-1- XRPD peak of type II of 5-(cyano-2-methylnicotinate) ethyl ester. These crystalline forms are further characterized by one of the following listed or at 121551.doc -27- 200812968

Additional properties: (i) For type I (1) when characterized by thermogravimetric analysis, from 205 ° C at 25 ° C

In the characterization, the melting temperature (Tm) is not dissolved and the endotherm is about 96 J/g; and/or the absorption is less than 0.2% wet (ΙΠ) when stored at 80% RH (environment).

(i) For Type II (I) when characterized by thermogravimetric analysis, from 25. Approximately 0.2% weight loss occurs in the range of 2〇5〇c, and/or (Π) when heated under a flowing nitrogen atmosphere in a closed cup with pinholes at a heating rate of 10 ° C / min When characterized by differential scanning calorimetry, the melting temperature (Tm) begins at about 193 ° C and/or the associated melting endotherm is about 105 J/g. Comparative Example 2 N-~Immediately hexanitrogen 11 to bite _ 4 ·Artemisamine (a) 4-{[(benzylidene)amino]peptidyl}hexa-argon" than bite-1-carboxylic acid Tributylidazole was added to triethylamine (591 g, 5840 mmol) to 1-(tris-butoxycarbonyl)hexahydropyridine-4-carboxylic acid (448 g, B54) at room temperature under nitrogen atmosphere. Milliol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in a stirred suspension in THF (3000 mL). 15 121551.doc -28- 200812968 Hours after adding '1 phenyl ketone decylamine (352 g, stored in 丨fan ml THF '2056 house Moule) solution and overnight to remove the solvent under 35 m A thick rice gray slurry (about 2500 ml) is given. Et〇AC (3500 ml) was added followed by an aqueous HCl solution (1960 ml of 3·6 M HCl and 1960 ml of water). The aqueous phase was removed and the organic phase was washed with 2 x 1500 mL 1 M EtOAc. The organic phase was cooled to give a H?m precipitate which was filtered. Most of the solvent was removed in vacuo to give a thick, beige-gray slurry. EtOH (50%, 4000 mL) was added and the slurry was stirred for 5 h. The precipitated product was filtered, washed with 50% EtOAc (EtOAc: EtOAc (EtOAc) ] Hexahydropyridine·1_carboxylic acid tert-butyl ester. The yield is 584 g (78 〇 / 〇). 'H NMR (400 MHz, CDC13): δ 1.46 (9Η, s), 1.54-1.61 (2H, m), 1·70_1·74 (2H, m), 2·19_2·27 (1H, m), 2 · 68_2·75 (2H, m), 4.07-4.12 (2H, m), 4·66 (2H, s), 7.32-7.41 (5H, m), 7.54 (1H, br s). (b) N-(benzyl decyl)hexa-argon" is a 4-butane-pyridylcarboxamide. The ester (583 g, 1524 mmol) was suspended in formic acid (3000 mL), and the reaction mixture was stirred for 20 minutes. The reaction mixture was foamed, and gas was formed, and the formic acid (500 ml) was used to wash off the walls of the reaction vessel. Foam. After 2 hours the foaming was stopped and the reaction was clarified and a little solid remained. The reaction was stirred overnight and 2500 mL of formic acid was removed in vacuo. Water (1 mL) was added and the reaction was filtered. The solution was added with water (3000 ml). A saturated aqueous ammonium hydroxide solution (total addition of 390 ml, pH from 3·10 to 121551.doc -29-200812968 6.1 〇) was used to neutralize the acidic solution' and at the end point ( pH=6i〇) A large amount of product precipitate formed. The mixture was stirred overnight and the precipitate was filtered and washed with water (1000 ml) dried in vacuo to give N-(sulfonyl) as a white powder. Hexahydropyridine _4_formamide. Yield 372 4 g (87%) 〇H NMR (400 MHz, DMSO-d6): δ 1. 60-1.72 (2H5 m), 1.75- 1.84 (2H, m), 2.10-2.19 (lH, m), 2.77-2.87 (2H, m), 3.10-3.18 (2H, m), 4·23 (2H, s), 7.18-7.28 (5H, m), 8·17 (1H, br s) 〇 [Simple description of the diagram] Figure 1 shows the 6-(4_) obtained by the method of "general experimental procedure" {[(( sulfonyl)amino]carbonyl hydrazine hexahydro. Bipyridin-1-yl)-5-cyano-2-methyl niacin acid S S is an XRPD diffraction pattern of Formula I. Figure 2 shows the XRPD of the 6-(4-{[(benzylsulfonyl)amino]carbonyl}hexahydropyridin-1-yl)cyano-2-indenyl nicotinic acid ethyl ester type obtained by the same method. Shooting. 121551.doc

Claims (1)

200812968 X. Patent application scope: 1. A type I of 6H{[(benzylsulfonyl)amino]carbonylindole hexahydroacridine-fluorenyl cyanomethylnicotinate ethyl ester, characterized in that XRPD-peaks were presented for 24 Q λ 1 ^ 12·4, 4.76, 4.52, 4·09, and 2.65 angstroms (A) D-values. 2. The crystalline form I of the substance of claim 1 characterized in that it is about 24.9, 12.4, 6.6, 6.3, 6.00, 4.84, 4.76, 4.52, 4.27, 4.09, XRPD-peaks were present at 2.65 and 2.19 angstroms (A) D-values. 3. The crystalline form I of the substance of claim 1 characterized in that it is about 24.9, 12·4, 8.3, 6.6, 6.3, 6.0, 4.95, 4.84, 4.76, 4.59, 4.52, 4.41, 4.32, 4.27, 4.18, 4.13, 4.09, 3.84, 3.80, 3.69, 3.55, 3.39, 3·35, 3·32, 3·20, 3·13, 2.65 and 2·19 angstroms (A) D-value The XRPD-peak is presented. 4. The crystalline form I of the substance as claimed, characterized in that it has an XRPD-spectrum substantially as shown in Figure 1. 5. A type of π, which is 6-(4-{[(benzylidene)amino]carbonyl}hexahydro, 唆-丨-yl)-5-cyano-2-indenyl nicotinic acid ethyl ester, It is characterized by exhibiting another 1^〇-peak at approximately 0·1, 8·8, 6.2, 4.65, and 4.3 6 angstroms (in). 6. The crystalline form II of the substance of claim 5, which is characterized by being about 13.1, 8.8, 6.6, 6.2, 6.0, 4.65, 4.56, 4.36, 4.11 and 3. 5 〇 The XRPD peak is present at the angstrom (A) D-value. 7. The crystalline form II of the substance of claim 5, characterized by being about 13.1, 9·3, 9·1, 8·8, 6.6, 6.5, 6.2, 6.2, 6.0, 4.65, 4.56, 4.36, 4.11, 3.88, 3.82, 3.61, 3.57, 3.50, 3.46 121551.doc 200812968 and 3.21 angstroms (A) D-values exhibit XRPD peaks. 8. The crystalline form of the substance of claim 5, characterized by having an XRPD spectrum as substantially as shown in Figure 2. 9. A method of preparing a compound according to any one of claims 1 to 4, The method comprises the steps of: μ a) dissolving the compound benzylsulfonyl)amino]carbonyl}hexahydropyridinium-yl)-cyanoquinone nicotinic acid ethyl ester at ambient temperature or by refluxing or Suspended in ethyl acetate; b) transparently transition the solution obtained from a); c) crystallize the substance dissolved or suspended in the solution or suspension obtained from step a) or step b) And the method of preparing the compound of any one of claims 5 to 8, which comprises the method of preparing the compound obtained according to any one of claims 5 to 8, which comprises: The following steps: a) the compound benzylsulfonyl)amino]carbonyl}hexahydropyridin-1-yl)-5-cyano-2-indenyl nicotine at ambient temperature or by reflux West Day gluten solution or suspension in chloroform or tetrahydrofuran; b) The solution obtained from a) is transparent as appropriate C) crystallization of the substance dissolved or suspended in the solution or suspension obtained from step a) or step b), and this is carried out as appropriate during cooling to room temperature; d) adding a non-solvent as appropriate , e.g., ethanol; e) filtering and separating the obtained crystalline product. 121551.doc 200812968 • A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and an adjuvant, diluted The combination of the agent and the carrier of the invention, wherein the compound of any one of claims 1 to 8 is used for the treatment, and the use of the compound of any one of the items 8 to 8 The use of a compound for the treatment of a platelet agglutination disorder. 14. Use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for inhibiting the P2Y12 receptor. 〇 121551.doc