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WO2008004945A1 - Nouvelles formes cristallines i et ii - Google Patents

Nouvelles formes cristallines i et ii Download PDF

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Publication number
WO2008004945A1
WO2008004945A1 PCT/SE2007/000645 SE2007000645W WO2008004945A1 WO 2008004945 A1 WO2008004945 A1 WO 2008004945A1 SE 2007000645 W SE2007000645 W SE 2007000645W WO 2008004945 A1 WO2008004945 A1 WO 2008004945A1
Authority
WO
WIPO (PCT)
Prior art keywords
xrpd
peaks
approximate
benzylsulfonyl
cyano
Prior art date
Application number
PCT/SE2007/000645
Other languages
English (en)
Inventor
Soren Andersen
Carl-Johan Aurell
Caroline Eriksson
Carl-Gustav Sigfridsson
Fredrik Zetterberg
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/SE2006/000832 external-priority patent/WO2007008140A1/fr
Priority claimed from US11/622,606 external-priority patent/US20080027104A1/en
Priority claimed from SE0700083A external-priority patent/SE0700083L/xx
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2008004945A1 publication Critical patent/WO2008004945A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention provides novel crystalline forms of 6-(4-
  • Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub -endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina. The success of interventions used to prevent or alleviate these conditions, such as thrombolysis and angioplasty is also compromised by platelet mediated occlusion or re- occlusion. Haemostasis is controlled via a tight balance between platelet aggregation, coagulation and fibrinolysis.
  • Thrombus formation under pathological conditions like e.g. arteriosclerotic plaque rupture, is firstly initiated by platelet adhesion, activation and aggregation. This results not only in the formation of a platelet plug but also in the exposure of negatively charged phospholipids on the outer platelet membrane promoting blood coagulation. Inhibition of the build-up of the initial platelet plug would be expected to reduce thrombus formation and reduce the number of cardiovascular events as was demonstrated by the anti- thrombotic effect of e.g. 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 antiplatelet therapy in various categories of patients.).
  • Platelet activation/aggregation can be induced by a variety of different agonists. However, distinct intracellular signalling pathways have to be activated to obtain full platelet aggregation, mediated via G-proteins Gq, G12/13 and G 1 (Platelets, AD Michelson ed, Elsevier Science 2002, ISBN 0-12-493951-1; 197-213: D Woulfe, et al.
  • the G-protein coupled receptor P2Y 12 (previously also known as the platelet P ⁇ r, P2T ao , or P2Y O yc receptor) signals via Gi, resulting in a lowering of intra- cellular cAMP and Ml aggregation (Nature 2001; 409: 202-207 G Hollopeter, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs.)- Released ADP from dense- granules will positively feedback on the P2Y 12 receptor to allow full aggregation.
  • the drug substance In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but
  • the drug substance, and compositions containing it should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active component, e.g. its chemical composition, density, hygroscopicity and solubility.
  • Amorphous materials may present problems in this regard. For example, such materials are typically more difficult to handle and to formulate, provide for unreliable solubility, and are often found to be more unstable.
  • the crystalline forms of the invention are reversible and selective P2Y 12 antagonists.
  • the compounds of the invention unexpectedly exhibit beneficial properties that render them particularly suitable for use in the treatment of diseases/conditions as described below. Examples of such beneficial properties are high potency, high selectivity, and an advantageous therapeutic window.
  • Figure 1/2 shows the XRPD diffractogram of 6-(4-
  • Figure 2/2 shows the XRPD diffractogram of 6-(4-
  • a first aspect of the present invention is: 6-(4- ⁇ [(benzylsulfonyl)amino]carbonyl ⁇ i ⁇ eridin- l-yl)-5-cyano-2-methylnicotinic acid ethyl ester, form I in a first embodiment having the following XRPD peaks:
  • this first embodiment of the first aspect of the invention can be characterized by the presence of XRPD-peaks at approximate d- values of; 24.9, 12.4, 4.76, 4.52, 4.09 and 2.65 Angstrom (A).
  • This first embodiment of the first aspect of invention can also be characterized by having XRPD peaks at the following approximate 2-Theta, °; 3.54, 7.12, 18.63, 19.64, 21.71 and 33.85.
  • 6- (4- ⁇ [(benzylsulfonyl)amino]carbonyl ⁇ iperidin-l-yl)-5-cyano-2-methyh ⁇ cotmic acid ethyl ester, form I, is having the following XRPD peaks:
  • this 2nd embodiment of the first aspect of the invention can be characterized by the presence of XRPD-peaks at approximate d- values of; 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 Angstrom (A).
  • This 2nd embodiment of the first aspect of the invention can also be characterized by having XRPD peaks at the following approximate 2-Theta, °; 3.54, 7.12, 13.39, 14.07, 14.76, 18.32, 18.63, 19.64, 20.79, 21.71, 33.85 and 41.14.
  • this 3rd embodiment of the first aspect of the invention can be characterized by the presence of XRPD-peaks at approximate d- values of; 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, s 3.32, 3.20, 3.13, 2.65 and 2.19 Angstrom (A).
  • This 3rd embodiment of the first aspect of the invention can also be characterized by having XRPD peaks at the following approximate 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, 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.
  • ⁇ [(benzylsulfonyl)ammo]carbonyl ⁇ piperidin-l-yl)-5-cyano-2-methyhiicotinic acid ethyl ester, form I is characterized as according to anyone of the preceding embodiments of the first aspect of the invention, wherein, the XRPD peak having the largest relative intensity is situated at the approximate d- value of 24.9 A (Angstrom).
  • Another (second) aspect of the present invention is:
  • this first embodiment of the second aspect of the invention can be characterized by the presence of XRPD-peaks at approximate d-values of; 13.1, 8.8, 6.15, 4.65 and 4.36 Angstrom (A).
  • This first embodiment of the second aspect of the invention [6-(4- ⁇ [(benzylsulfonyl)amino]carbonyl ⁇ piperidin-l-yl)-5-cyano-2-methyhiicotinic acid ethyl ester, form II] can also be characterized by having XRPD peaks at the following approximate 2-Theta, °; 6.76, 10.00, 14.39, 19.08 and 20.37.
  • 6- (4- ⁇ [(benzylsulfonyl)amino]carbonyl ⁇ piperidin- l-yl)-5-cyano-2-methylnicotinic acid ethyl ester, form DL, is having the following XRPD peaks:
  • this second embodiment of the second aspect of the invention can be characterized by the presence of XRPD-peaks at approximate d-values of; 13.1, 8.8, 6.6, 6.15, 6.0, 4.65, 4.56, 4.36, 4.11 and 3.50 Angstrom (A).
  • This second embodiment of the second aspect of the invention [6-(4- ⁇ [(benzylsulfonyl)amino]carbonyl ⁇ piperidin-l-yl)-5-cyano-2-methylnicotmic acid ethyl ester, form H] can also be characterized by having XRPD peaks at the following approximate 2-Theta, °; 6.76, 10.00, 13.40, 14.39, 14.76, 19.08, 19.43, 20.37, 21.60 and 25.46.
  • 6-(4- ⁇ [(benzylsulfonyl)amino]carbonyl ⁇ piperidin-l-yl)-5-cyano-2-methylnicotinic acid ethyl ester, form ⁇ is having the following XRPD peaks:
  • this 3rd embodiment of the second aspect of the invention can be characterized by the presence of XRPD-peaks at approximate D- values of; 13.1, 9.3, 9.1, 8.8, 6.6, 6.5, 6.24, 6.15, 6.0, 4.65, 4.56, 4.36, 4.11, 3.88, 3.82, 3.61, 3.57, 3.50, 3.46 and 3.21 Angstrom (A).
  • This 3rd embodiment of the second aspect of the invention [6-(4- ⁇ [(benzylsulfonyl)amino]carbonyl ⁇ piperidin- l-yl)-5-cyano-2-methylnicotinic acid ethyl ester, form BE] can also be characterized by having XRPD peaks at the following
  • I 5 ester, form EL is characterized as according to anyone of the preceding embodiments of the second aspect of the invention, wherein the XRPD peak having the largest relative intensity is situated at the approximate d- value of 13.1 A (Angstrom).
  • a further aspect of the present invention is a process for the preparation of the 25 crystalline form I above, comprising the steps of: a) dissolving or suspending the compound 6-(4-
  • Another further aspect of the present invention is a process for the preparation of the crystalline form II above, comprising the steps of: a) dissolving or suspending the compound 6-(4- ⁇ [(beri2ylsulfonyl)amino]carbonyl ⁇ piperidin- l-yl)-5-cyano-2-methyh ⁇ cotinic acid ethyl ester in chloroform or tetrahydrofuran at ambient temperature or by refiuxing; b) optionally clear filtering a solution obtained in step a); c) allowing the material dissolved or suspended in the solution or suspension obtained from step a) or step b) to crystallize optionally during cooling to room temperature; d) optionally adding a non- solvent such as ethanol; e) filtering and isolating the crystalline product obtained.
  • crystalline forms of 6-(4- ⁇ [(benzylsulfonyl)amino]carbonyl ⁇ piperidin-l-yl)-5-cyano-2- methyhiicotinic acid ethyl ester may be further characterised by the presence of one or more of the additional properties listed below:
  • thermogravimetric analysis when characterised by thermogravimetric analysis, a weight loss of approx. 0.2 % occurs in the range from 25 0 C up to 205 0 C, and/or QI) when characterised by differential scanning calorimetry, at a heating rate of 1O 0 C per minute in a closed cup with a pinhole under flowing nitrogen, a melting temperature (Tm) having an onset at about 193 0 C and/or an associated endotherm of melting of about 105 J/g.
  • Tm melting temperature
  • Functional inhibition of- the P2Y 12 receptor can be measured by in vitro assays using cell membranes from P2Y 12 transfected CHO -cells, the methodology is indicated below.
  • Functional inhibition of 2-Me- S-ADP induced P2Y 12 signalling 5 ⁇ g of membranes were diluted in 200 ⁇ l of 20OmM NaCl, ImM MgCi, 5OmM HEPES (pH 7.4), 0.01% BSA, 30 ⁇ g/ml saponin and lO ⁇ M GDP. To this was added an EC 80 concentration of agonist (2- methyl- thio- adenosine diphosphate), the required concentration of test compound and 0.1 ⁇ Ci 35 S-GTPyS.
  • D is the slope factor
  • x is the original known x values.
  • y is the original known y values.
  • the compounds of the invention have an activity, when tested in the functional inhibition of 2-Me-S-ADPinducedP2Y 12 signalling assay described, at a concentration of around 4 ⁇ M or below.
  • the compounds of the invention act as P2Y 12 receptor antagonists and are therefore useful in therapy.
  • a compound of the invention for use in therapy.
  • the compounds of the invention for the manufacture of a medicament for treatment of a platelet aggregation disorder.
  • a compound of the invention for the manufacture of a medicament for the inhibition of the P2Y 12 receptor.
  • the compounds are useful in therapy, especially adjunctive therapy, particularly they are indicated for use as: inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation, antithrombotic agents or in the treatment or prophylaxis of unstable angina, coronary angioplasty (PTCA), myocardial infarction, perithrombolysis, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischaemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopaenic
  • the use of a compound according to the invention in the manufacture of a medicament for the treatment of the above disorders is further provided.
  • the compounds of the invention are useful for treating myocardial infarction, thrombotic stroke, transient ischaemic attacks, peripheral vascular disease and angina, especially unstable angina.
  • the invention also provides a method of treatment of the above disorders which comprises administering to a patient suffering from such a disorder a therapeutically effective amount of a compound according to the invention.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention in combination with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • the compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, by subcutaneous administration, or by rectal administration in the form of suppositories or transdermally.
  • the compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
  • Dry powder formulations and pressurised HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol.
  • Suitable carriers include sugars and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler e.g. that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active compound with or without a carrier substance is delivered to the patient.
  • the pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral or subcutaneous solutions, suspensions for parenteral administration or suppositories for rectal administration.
  • the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • the compound may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol , mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • IH NMR measurements were performed on a Varian Mercury VX 400 spectrometer, operating at a IH frequency of 400 and Varian UNITY plus 400, 500 and 600 spectrometers, operating at IH frequencies of 400, 500 and 600 respectively. Chemical shifts are given in ppm with the solvent as internal standard. Chromatography was performed using Biotage silica gel 40S, 40M, 12i or Merck silica gel 60 (0.063-0.200mm). Flash chromatography was performed using either standard glass- or plastic-columns column or on a Biotage Horizon system. HPLC separations were performed on a Waters YMC-ODS AQS-3 120 Angstrom 3 x 500 mm or on a Waters Delta Prep Systems using Kromasil C8, 10 ⁇ m columns.
  • V20 divergence slit and a detector slit of 12mm, corresponding to a 3.47° wide detector window were applied. Samples were tested with and without an internal standard. (Diffractogram shown in Figures 1/2 and 2/2 are without internal standard). Presented 2-Theta- and d- values are adjusted in relation to internal standard.
  • Form II The product obtained from crystallization in EtOAc (Form I) was characterised by the presence, in X-ray powder diffraction (XRPD) measurements, of peaks at about the 2- Theta-, d- and relative intensity values detailed in Table 1 below and the product obtained from slurry/crystallization in CHQ (Form II) in Table 2 below.
  • Form II may also be prepared as follows:
  • Example 1 (crude), 82 g (174.3 mmoles) was dissolved in 300 ml of dry tetrahydrofuran (THF) at reflux (6TC). The resulting solution was clear filtered warm and allowed to crystallise during cooling to room temperature. At room temperature, 300 ml of ethanol was added slowly to the gently stirred crystal slurry. After 2-3 hours the crystals were filtered off. The crystalline product was washed with ethanol and dried in vacuum at 4O 0 C. Yield: 70g.
  • THF dry tetrahydrofuran
  • Tm melting temperature
  • Triethylamine (591 g, 5840 mmol) was added to a stirred suspension of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t.
  • a solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was added after 1.5 hours and the stirring was continued over night. The solvent was removed in vaccuo to give a thick grey-beige slurry (volume about 2500 mL).
  • EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2 x 1500 mL I M HCl. The organic phase was cooled to O 0 C which gave a precipitate of HOBt that was filtered off. Most of the solvent was removed in vaccuo to give a thick grey- white slurry. EtOH (50 %, 4000 mL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off , washed with 50 % EtOH ( 500 mL + 2 x 1500 mL) and dried in a vaccum oven at 25 °C to give tert-butyl 4-

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  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne les formes I et II de l'ester d'éthyle d'acide 6-(4-{[(benzylsulfonyl)amino]carbonyl}pipéridin-1-yl)-5-cyano-2-méthylnicotinique, des procédés de préparation de ces composés, leur utilité comme inhibiteurs de P2Y12 et comme agents anti-thrombotiques, etc., leur utilisation comme médicaments contre les maladies cardiovasculaires, ainsi que des compositions pharmaceutiques les contenant.
PCT/SE2007/000645 2006-07-04 2007-07-02 Nouvelles formes cristallines i et ii WO2008004945A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
PCT/SE2006/000832 WO2007008140A1 (fr) 2005-07-13 2006-07-04 Nouveaux analogues de la pyridine
SEPCT/SE2006/000832 2006-07-04
US11/622,606 US20080027104A1 (en) 2006-07-04 2007-01-12 Novel Crystalline Forms 2
US11/622,606 2007-01-12
SE0700083A SE0700083L (sv) 2006-07-04 2007-01-15 Nya kristallina former 2
SE0700083-9 2007-01-15

Publications (1)

Publication Number Publication Date
WO2008004945A1 true WO2008004945A1 (fr) 2008-01-10

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PCT/SE2007/000645 WO2008004945A1 (fr) 2006-07-04 2007-07-02 Nouvelles formes cristallines i et ii

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WO (1) WO2008004945A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010005384A1 (fr) * 2008-07-07 2010-01-14 Astrazeneca Ab Analogues de cétone pyridine et leur utilisation dans le traitement de troubles cardiovasculaires
WO2010005385A1 (fr) * 2008-07-07 2010-01-14 Astrazeneca Ab Dérivés de pyridine substitués par 2-amino-6-alkyle utiles comme inhibiteurs de p2y12

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003854A1 (fr) * 1997-07-18 1999-01-28 Novartis Ag Modification de la forme cristalline d'un derive n-phenyl-2-pyrimidineamine, procede de preparation et d'utilisation de ce dernier
WO2002030902A1 (fr) * 2000-10-13 2002-04-18 Akzo Nobel N.V. Formes cristallines d'hydrochlorure de 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]piperazine
WO2006073361A1 (fr) * 2005-01-06 2006-07-13 Astrazeneca Ab Nouveaux composes de pyridine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003854A1 (fr) * 1997-07-18 1999-01-28 Novartis Ag Modification de la forme cristalline d'un derive n-phenyl-2-pyrimidineamine, procede de preparation et d'utilisation de ce dernier
WO2002030902A1 (fr) * 2000-10-13 2002-04-18 Akzo Nobel N.V. Formes cristallines d'hydrochlorure de 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]piperazine
WO2006073361A1 (fr) * 2005-01-06 2006-07-13 Astrazeneca Ab Nouveaux composes de pyridine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010005384A1 (fr) * 2008-07-07 2010-01-14 Astrazeneca Ab Analogues de cétone pyridine et leur utilisation dans le traitement de troubles cardiovasculaires
WO2010005385A1 (fr) * 2008-07-07 2010-01-14 Astrazeneca Ab Dérivés de pyridine substitués par 2-amino-6-alkyle utiles comme inhibiteurs de p2y12

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