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(12) United States Patent (10) Patent No.: US 7,034,160 B2 Woodward Et Al

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(12) United States Patent (10) Patent No.: US 7,034,160 B2 Woodward Et Al USOO703416OB2 (12) United States Patent (10) Patent No.: US 7,034,160 B2 Woodward et al. (45) Date of Patent: Apr. 25, 2006 (54) CRYSTALLINE FORMS OF A FACTOR XA (52) U.S. Cl. ....................................... 54.6/332: 514/357 INHIBITOR (58) Field of Classification Search ................ 514/351, 514/357: 546/332 (75) Inventors: Rick G. Woodward, Harleysville, PA See application file for complete search history. (US); David S. Teager, Marcus Hook, PA (US) (56) References Cited (73) Assignee: Aventis Pharmaceuticals Inc., U.S. PATENT DOCUMENTS Bridgewater, NJ (US) 6,080,767 A * 6/2000 Klein et al. ................. 514,357 (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. WO WO 97.241.18 7/1997 OTHER PUBLICATIONS (21) Appl. No.: 10/404,678 Halebian et al. J of Pharm Sci., (1969), 58, pp. 911-929.* (22) Filed: Apr. 1, 2003 Chemical & Engineering news, Feb. 2003, pp. 32-35.* US Pharmacopia, 1995, pp. 1843-1844.* (65) Prior Publication Data Concise Encyclopedia Chemistry, pp. 872-873 (1993).* Brittain et al., Polymorphism in Pharmaceutical Solids, NY: US 2003/0225144 A1 Dec. 4, 2003 Marcel Dekker, Inc., 1999, pp. 183-226, 228-330.* Related U.S. Application Data * cited by examiner (63) Continuation of application No. PCT/US01/31087, Primary Examiner Patricia L. Morris filed on Oct. 4, 2001. (74) Attorney, Agent, or Firm—Joseph D. Rossi (60) Provisional application No. 60/238.316, filed on Oct. 5, 2000. (57) ABSTRACT (30) Foreign Application Priority Data The present invention relates to novel crystalline forms of an inhibitor of Factor Xa, processes for its preparation, com Apr. 10, 2001 (GB) .................................... O108903 positions comprising it, and its therapeutic use. (51) Int. Cl. C07D 213/89 (2006.01) 4 Claims, 2 Drawing Sheets U.S. Patent Apr. 25, 2006 Sheet 1 of 2 US 7,034,160 B2 OZZ0||200206||08|| |''DIH 0 Z| (Wu) dn Spu MolleeH U.S. Patent Apr. 25, 2006 Sheet 2 of 2 US 7,034,160 B2 O C O O C O O r CN Sl US 7,034,160 B2 1. CRYSTALLINE FORMS OF AFACTOR XA INHIBITOR (I) This application is a continuation application of Interna tional Application Number PCT/US01/31087, filed Oct. 4, 2001, which, in turn, is entitled to the benefit of, and claims priority from earlier filed U.S. Application No. 60/238.316, filed Oct. 5, 2000, and Great Britain Application Number 0108903.6, filed Apr. 10, 2001, the contents of all of which are incorporated herein by reference. 10 FIELD OF THE INVENTION The present invention relates to novel crystalline forms of an inhibitor of Factor Xa, and its production and use. 15 BACKGROUND OF THE INVENTION N-(aminomethyl) phenylpropyl amide compounds, includ Factor Xa is the penultimate enzyme in the coagulation ing Compound (I), are disclosed in commonly assigned U.S. cascade. Inhibition of Factor Xa may be achieved, for Pat. No. 6,080,767, which is based on an application that example, by direct complex formation between a suitable claims priority benefit under 35 U.S.C. S. 371 of Interna inhibitor and the enzyme and is therefore independent of the tional application Serial No. PCT/US96/20770 (designating plasma co-factor antithrombin III. Effective factor Xa inhi the United States) filed Dec. 23, 1996, which, in turn, claims bition may be achieved by administering compounds by oral priority benefit of U.S. Provisional application Ser. No. administration, continuous intravenous infusion, bolus intra 60/009,485 filed Jan. 2, 1996. venous administration or any other Suitable route Such that it preferably achieves the desired effect of preventing the 25 Treatment and/or prevention of the foregoing pathological Factor Xa induced formation of thrombin from prothrombin. conditions may be accomplished by administering a thera Anticoagulant therapy is often indicated for the treatment peutically effective amount of Compound (I) to a patient in and prophylaxis of a variety of thrombotic conditions of need of such treatment and/or prevention. Treatment with both the venous and arterial vasculature. In the arterial Such forms of Compound (I) may be accomplished by its use system, abnormal thrombus formation is primarily associ 30 alone, as an ingredient of a pharmaceutical composition, or ated with arteries of the coronary, cerebral and peripheral in combination with one or more other medications. Com vasculature. The diseases associated with thrombotic occlu pound (I) may be administered enterally or parenterally in sion of these vessels include, for example, acute myocardial Solid or liquid dosage forms. infarction (AMI), unstable angina, thromboembolism, acute Crystalline forms of Compound (I) have not been known vessel closure associated with thrombolytic therapy and 35 to exist previously. There exists a need for crystalline forms percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication which may exhibit desirable and beneficial chemical and and bypass grafting of the coronary (CABG) or peripheral physical properties. There also exists a need for reliable and arteries. reproducible methods for the manufacture, purification, and Chronic anticoagulant therapy may also be beneficial in formulation of Compound (I) to permit its feasible commer preventing the vessel luminal narrowing (i.e., restenosis) 40 cialization. The present invention is directed to these, as well that often occurs following PTCA and CABG, and in the as other important ends. maintenance of vascular access patency in long-term hemo dialysis patients. With respect to the venous vasculature, SUMMARY OF THE INVENTION pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee 45 Accordingly, the present invention is directed, in part, to and hip surgery (deep vein thrombosis, or DVT). DVT novel crystalline forms of Factor Xa inhibitors. Specifically, further predisposes the patient to a higher risk of pulmonary in one embodiment, there are provided novel crystalline thromboembolism. A systemic, disseminated intravascular forms of Compound (I): coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and 50 cancer. This condition may be characterized by a rapid consumption of coagulation factors and their plasma inhibi (I) tors which may result in the formation of life-threatening clots throughout the microvasculature of several organ sys tems. The indications discussed above include some, but not all, of the possible clinical situations where anticoagulant 55 therapy may be warranted. Those experienced in this field are well aware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy. Both free Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and 60 phospholipid) may be inhibited by N-(aminomethyl) phe nylpropyl amide compounds. A particularly promising N-(aminomethyl) phenylpropyl amide compound is methyl (2R,3R)-2-3-amino(imino)methylbenzyl-3-(4- (1-oxido-4-pyridinyl)benzoylaminobutanoate, i.e., the 65 in particular in pharmaceutically acceptable form. compound of formula (I) (hereinafter referred to as “Com These and other aspects of the invention will become pound (I)): more apparent from the following detailed description. US 7,034,160 B2 3 4 BRIEF DESCRIPTION OF THE DRAWINGS paring the salts. Preferably, the salts of the present invention comprise about one equivalent of acid for about each FIG. 1 is a graphical representation of a differential equivalent of Compound (I). scanning calorimetry thermogram of the 2-butanol hemisol The acid addition salts of Compound (I) may be prepared vate of methyl (2R,3R)-2-3-amino(imino)methylben by dissolving the free base in aqueous or aqueous-alcohol Zyl-3-4-(1-oxido-4-pyridinyl)benzoylaminobutanoate Solution or other Suitable solvents containing the appropriate hydrochloride. acid or to which the appropriate acid is added, and isolating FIG. 2 is a graphical representation of an X-ray powder the salt by evaporating the solution, or by reacting the free diffraction pattern of the 2-butanol hemisolvate of methyl base and acid in an organic solvent, in which case the salt (2R,3R)-2-3-amino(imino)methylbenzyl-3-4-(1- 10 may separate directly and/or may be obtained by concen oxido-4-pyridinyl)benzoylaminobutanoate hydrochloride. tration of the solution. In accordance with preferred embodiments of the inven DETAILED DESCRIPTION OF THE tion, Compound (I) may be present in the novel crystals as INVENTION a solvate. A wide variety of solvents may be employed in the 15 preparation of the solvates of Compound (I). Preferred The present invention provides, at least in part, crystals of Solvents include, for example, polar solvents, including Compound (I) (i.e., methyl (2R,3R)-2-3-amino(imino)me polar protic and polar aprotic solvents. In preferred form, the thylbenzyl-3-4-(1-oxido-4-pyridinyl)-benzoyl Solvent employed in the preparation of the Solvates is aminobutanoate) as a novel material, in particular in phar selected from the group consisting of alcohols, ethers and maceutically acceptable form. The term “pharmaceutically nitriles. Suitable alcohols for use in the preparation of acceptable', as used herein, refers to those compounds, Solvates of Compound (I) include, for example, methyl materials, compositions, and/or dosage forms which are, alcohol, ethyl alcohol, propyl alcohols, including n-propyl within the scope of Sound medical judgment, Suitable for alcohol and i-propyl alcohol, and butyl alcohols, including contact with the tissues of human beings and animals n-butyl alcohol, t-butyl alcohol, iso-butyl alcohol, and sec without excessive toxicity, irritation, allergic response, or butyl alcohol (i.e., 2-butanol). Preferred among these alco other problem complications commensurate with a reason 25 hols are secondary butyl alcohols, with 2-butanol being able benefit/risk ratio. In certain preferred embodiments, more preferred. The 2-butanol employed in the solvates may Compound (I) is in substantially pure form.
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