Preparation Process of Plasma Kallikrein Inhibitor

Abstract

Processes for preparing and purifying a compound of formula I, or a salt thereof, are provided, JPEG2022541398000022.jpg60152 where the subscript m is an integer from 0 to 3, Each R a is (C3-C8) cycloalkyl, (C1-C4) haloalkyl, halogen, -OH, -OR 1 , -SH, -SR 1 , -S(O)R 1 , -S(O)2R 1 , -SO2NH2, -C(O)NH2, -C(O)NHR 1 , -C(O)N(R 1 )2, -C(O)R 1 , -C(O)H, -CO2H, -CO2R 1 , -NO2, -NH2, -NHR 1 , -N(R 1 )2, wherein each R 1 are independently (C1-C8) alkyl; L is a linking group selected from the group consisting of a single bond or CH2; Q a , Q b , and Q c are N, S, O and C(R q ), and each R q is H, C 1-8 independently selected from the group consisting of alkyl, halogen, and phenyl, and Q a , Q b , Q c and the ring having Y as a vertex is a five-membered ring having two double bonds, and Y is selected from the group consisting of C and N.

Description

Technical Field

[0001] The present invention relates to a production process and a purification process of a plasma kallikrein inhibitor, and a compound useful for those processes.

Background Art

[0002] Although thrombus formation is essential to prevent blood loss and enable the repair of damaged blood vessels, which is a process known as hemostasis, there is a risk of becoming pathological if the thrombus occludes the blood vessel and deprives the tissue of oxygen. Arterial thrombosis, which is the occlusion of an artery by a thrombus, most often occurs at the site of atherosclerotic plaques that have ruptured or ulcerated (V. Kou et al., Mt Sinai J Med (2006) 73: 449-68). Specific occlusion of the coronary artery results in acute coronary syndromes including unstable angina and myocardial infarction (MI).

[0003] Fibrin clots can be generated by the activation of one of two distinct pathways, the intrinsic and extrinsic pathways, which converge on a common coagulation pathway (R.G. Macfarlane, Nature (1964) 202:498-99; E.W. Davie et al., Science (1964) 145:1310-12; K. Joseph et al., Adv Immunol (2005) 86:159-208). Experimental data suggest that both PK-deficient and FXII-deficient individuals, although having no bleeding phenotype, have a major impairment in clot formation via the intrinsic pathway (O.D. Ratnoff et al., J Clin Invest (1955) 34:602-13; R.W. Colman, (2001) in “Hemostasis and Thrombosis: Basic Principles and Clinical Practice” (R.W. Colman et al., eds., Lippincott, Williams & Wilkins, Philadelphia, Pa., pp.103-122); E.D. Rosen et al., Nature (1997) 390:290-94; W.E. Hathaway et al., Blood (1965) 26:521-32; A.S. Lawrie et al., Clin Lab Haematol (1998) 20:179-86; and S.M. Bates et al., Circulation (2005) 112:53-60). In the intrinsic pathway, binding to a surface activates a small amount of factor XII (FXII) to FXIIa, which then proteolytically activates plasma kallikrein (PK) through proteolysis. Importantly, PK subsequently generates more FXIIa within a feedback loop, which then activates factor XI (FXI) to FXIa, linking to the common pathway.The initial activation of the intrinsic pathway is through a small amount of FXIIa that activates a small amount of PK. However, it is the subsequent feedback activation of FXII by PK that controls the degree of activation of the intrinsic pathway, and thus it is downstream coagulation (W.E. Hathaway et al., Blood (1965) 26:521-32).

[0004] Current treatments for acute MI or ischemic stroke in the hospital setting require emergency measures to dissolve occlusive thrombi and enable reperfusion (restoration of blood flow). One common way to do this is by administering to the patient a fibrinolytic drug such as tissue plasminogen activator (t-PA) or streptokinase, which leads to the generation of active plasmin from plasminogen. Plasmin cleaves the fibrin network of the thrombus and thus causes thrombolysis. Such fibrinolytic drugs are the most frequently used therapeutic agents worldwide for reperfusion. However, thromboembolic recurrence is highly associated with fibrinolytic therapy, and subsequent reocclusion rates can be as high as 50% in some studies (F. Zijlstra et al., N Engl J Med (1993) 328:680-84; B.R. Brodie et al., Circulation (1994) 90:156-62; G.W. Stone et al., Circulation (1999) 99:1548-54; H. Tamai et al., Am Heart J (2004) 147:E9; F.W. Verheugt et al., J Am Coll Cardiol (1996) 27:766-73).

[0005] Patients who have had an acute MI show clinical evidence of a hypercoagulable (procoagulant) state. This hypercoagulability paradoxically worsens in those undergoing fibrinolytic therapy. In such treated patients, an increase in thrombin generation is observed, as assessed from thrombin-antithrombin III (TAT) levels that are up to two-fold higher compared to the already high levels observed in those receiving only heparin (H.M. Hoffmeister et al., Circulation (1998) 98:2527-33). The increase in thrombin is proposed to be due to activation of the intrinsic pathway via plasmin. Activation of the intrinsic pathway via plasmin is known to occur in blood (G.A. Ewald et al., Circulation (1995) 91:28-36), and it has been suggested that this occurs as a result of direct activation of FXII by plasmin.

[0006] It is not only fibrinolytic-induced hypercoagulability that leads to an increased rate of reocclusion; it is also thought to be due, at least in part, to the major weakness of fibrinolytic therapy in not being able to achieve complete fibrinolysis of the thrombus (E.C. Keeley et al., Lancet (2003) 361:13-20). Another problem with fibrinolytic therapy is that it is associated with a three-fold increased risk of intracranial haemorrhage (ICH) (V. Menon et al., Chest (2004) 126:549S-575S; Fibrinolytic Therapy Trialists’ Collaborative Group, Lancet (1994) 343:311-22). Therefore, an adjunctive anticoagulant therapy that does not increase the risk of bleeding but inhibits the formation of new thrombin would be highly beneficial.

[0007] Administration of an irreversible inhibitor of FXII to wild-type mice has been found to lead to a reduction in occluded blood vessels and a decrease in ischemic cortical injury, and inhibition of FXII is protective against arterial thrombosis such as that which occurs during acute MI or thrombotic stroke (WO 2006 / 066878 pamphlet). However, peptide pharmaceuticals have numerous weaknesses, including limitations in their application to acute tests due to their short half-lives, intravenous administration requiring medical intervention, and the generation of anti-peptide antibodies by patients undergoing treatment.

[0008] Plasma kallikrein is also implicated in diabetic macular edema and diabetic retinopathy (A. Clermont et al., Diabetes (2011) 60:1590-98; J. A. Phipps et al., Hypertension (2009) 53:175-81); hereditary angioedema due to C1 inhibitor deficiency (A. Banerji et al., N Engl J Med (2017) 376:717-28; E. Aygoren-Pursun et al., N Engl J Med (2018) 379(4):352-62); acute liver injury (M. Li et al., Biochem Biophys Res Commun (2018) 504(4):857-64); inflammation and anaphylaxis (L. Bender et al., Front Immunol (2017) 8:1115); hemorrhagic changes and worsening of cerebral edema after treatment with recombinant tissue plasminogen activator (tPA) (F. Simao et al., Blood (2017) 129(16):2280-90); and chemically sensitized kidney injury (H. Wang et al., J Immunotoxicol (2016) 13(4):567-79).

[0009] Suitable plasma kallikrein inhibitors have been developed (Sinha et al., WO 2008 / 016883 pamphlet; US Patent No. 8,258,170). However, there remain unaddressed requirements in the manufacturing processes of such compounds. SUMMARY OF THE INVENTION

[0010] The inventors have invented a compound of Sinha et al. (U.S. Patent No. 8,258,170, the entire disclosure of which is incorporated herein by reference), a novel process for preparing novel intermediates, and a novel purification process for providing the plasma kallikrein inhibitor of Sinha et al. in a pharmaceutically suitable form.

BRIEF DESCRIPTION OF THE INVENTION

[0011] Definitions Unless otherwise specified, the following terms used in this specification and the claims have the meanings set forth below.

[0012] The term "alkyl", unless otherwise specified, means a straight-chain or branched-chain hydrocarbon group having the specified number of carbon atoms (i.e., C1-C8 means 1 to 8 carbons), either alone or as part of another substituent. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. For each definition herein (e.g., alkyl, alkoxy, alkylamino, alkylthio, alkylene, haloalkyl), when no prefix indicating the number of backbone carbon atoms in the alkyl portion is included, the group or portion thereof has 12 or fewer backbone carbon atoms.

[0013] The term "alkylene" means a divalent group derived from an alkane, such as exemplified by -CH2CH2CH2CH2-, either alone or as part of another substituent. Typically, an alkyl (or alkylene) group is considered to have 1 to 12 carbon atoms. "Lower alkyl" or "lower alkylene" generally refers to a shorter-chain alkyl or alkylene group having 6 or fewer carbon atoms.

[0014] The term "cycloalkyl" refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., (C3-C6) cycloalkyl), and being fully saturated or having one or fewer double bonds between the vertices of the ring. One or two C atoms may optionally be substituted by a carbonyl. "Cycloalkyl" also includes bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. When a prefix indicating the number of ring carbon atoms in the cycloalkyl is not included, the group or a portion thereof has 8 or fewer ring carbon atoms.

[0015] The terms "alkoxy", "alkylamino", and "alkylthio" (or thioalkoxy) are used in their conventional meanings and refer to an alkyl group linked to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Further, with respect to a dialkylamino group, the alkyl portions may be the same or different and may be combined to form a 3- to 7-membered ring with the nitrogen atom to which each is linked. Thus, the group represented as "-NR a R b " includes piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

[0016] The term "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, alone or as part of another substituent, unless otherwise specified. Further, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-C4 haloalkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0017] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with acids or bases that are relatively non-toxic depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base in neat or a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include primary, secondary and tertiary amines such as substituted amines, cyclic amines, natural amines and the like, for example arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid in neat or a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid or phosphorous acid and the like, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid (see, for example, S.M. Berge et al., J Pharm Sci (1977) 66:1-19). Certain compounds of the present invention contain both basic and acidic functionalities that enable the compound to be converted to either a base addition salt or an acid addition salt. The term "pharmaceutically acceptable" means that the carrier, diluent or additive must be compatible with the other ingredients of the formulation and not harmful to the recipient.

[0018] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified amounts of the specified ingredients.

[0019] General The compounds of formula I prepared by the process of the present invention are useful as plasma kallikrein (PK) inhibitors for the prevention and treatment of blood coagulation such as thrombosis, and PK-dependent diseases and conditions. For example, this compound inhibits the formation of thrombin by the intrinsic pathway, thus reducing the risk of new pathogenic thrombus formation (reocclusion), and also improves reperfusion induced by fibrinolysis when administered as adjuvant therapy with a fibrinolytic regimen. Compound 1 of formula 1 is also useful for treating other diseases and disorders mediated by plasma kallikrein, such as, for example, diabetic macular edema, diabetic retinopathy, hereditary angioedema due to C1 inhibitor deficiency, acute liver injury, inflammation and anaphylaxis, hemorrhagic changes and exacerbation of cerebral edema after treatment with recombinant tissue plasminogen activator (tPA), and chemically sensitized kidney injury.

[0020] Process for preparing the compounds of formula I Compounds of formula I The compounds of formula I were prepared by the process of the present invention.

Chemical formula

[0021] In some embodiments, Y is N, and Q a , Q b , and Q c are each independently C(R q ). In some embodiments, each R q is methyl. In some embodiments, each Q b is CH, and Q a and Q c are each C-CH3. In some embodiments, Y and Q c are each N, and Q a and Q b are each independently C(R q ). In some embodiments, Y and Q b are each N, and Q a and Q c are each independently C(R q ). In some embodiments, Y and Q b are each N, and Q a and Q c are each C-H. In some embodiments, L is -CH2-, m is 0, 1, or 2, and R a are each independently halogen.

[0022] In some embodiments, the compound of formula I is

Chemical formula

[0023] In some embodiments, the compound of formula I is 1-benzyl-N-(4-carbamimidoyl-benzyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0024] Preparation method The process of the present invention is optimized to a sufficient extent for commercialization in terms of yield and purity. The compound of formula IV is obtained from a commercial source or prepared from commercially available precursor compounds by methods known in the art.

Chemical formula

Chemical formula

[0025] A. Process 1: (A) A compound of formula IV is coupled with 4-aminomethyl-benzonitrile using 1-propanephosphonic acid cyclic anhydride (T3P®) and triethylamine (Et3N) in an aprotic solvent to produce a compound of formula III. In some embodiments, T3P® is provided as a 50% ethyl acetate solution. The compound of formula IV and 4-aminomethyl-benzonitrile may be provided in approximately equimolar amounts, or one reactant may be provided in an excess in the range of about 0.2 to about 5 equivalents compared to the other reactant. In some embodiments, the ratio of the compound of formula IV to 4-aminomethyl-benzonitrile is about 0.2 to about 5, about 0.5 to about 2, about 0.9 to about 1.2, or about 1.0.

[0026] T3P® may be provided in a similar range of ratios. In some embodiments, the ratio of T3P® to the compound of formula IV may be about 0.5 to about 5, about 0.8 to about 4, about 1.0 to about 3, about 1.2 to about 2.0, and about 1.2 to about 1.8.

[0027] Triethylamine may also be provided in a certain range of ratios to the compound of formula IV. In some embodiments, the ratio of Et3N to the compound of formula IV is about 0.5 to about 10, about 1 to about 8, about 2 to about 5, and about 3 to about 5.

[0028] In some embodiments, the aprotic solvent may be dichloromethane (DCM), tetrahydrofuran (THF), methyl ethyl ketone (MEK), dimethyl sulfoxide (DMSO), ethyl acetate (EtOAc), methyl t-butyl ether (MTBE), and mixtures thereof. In some embodiments, the aprotic solvent is DCM.

[0029] The reaction is carried out in a temperature range where the selected solvent is liquid. In some embodiments, the reaction temperature is from about 0 °C to about 100 °C. In some embodiments, the reaction temperature is from about 15 °C to approximately the reflux temperature of the selected aprotic solvent. In some embodiments, the reaction temperature is from about 20 °C to about 80 °C. In some embodiments, the reaction temperature is from about 20 °C to about 30 °C.

[0030] The reaction time is generally the length of time required for the reaction to substantially complete, which may vary with the specific reactants, aprotic solvent, and reaction temperature selected. In some embodiments, the reaction time is from about 30 minutes to about 48 hours. In some embodiments, the reaction time is from about 1 hour to about 24 hours. In some embodiments, the reaction time is from about 4 hours to about 12 hours. In some embodiments, the reaction time is from about 6 hours to about 10 hours. In some embodiments, the reaction time is about 8 hours.

[0031] In some embodiments, the reaction is carried out under an inert atmosphere or under anhydrous conditions. In some embodiments, the reaction is carried out under a nitrogen atmosphere.

[0032] (B) The compound of formula III is purified by extraction. Generally, (i) an aprotic solvent containing the compound of formula III is combined with water, (ii) mixed well (e.g., by stirring or shaking), (iii) the organic layer and the aqueous layer are separated, (iv) the aqueous layer is removed, and (v) the organic layer is dried to remove water. These steps may be repeated together or individually, one, two, or more than three times. Further, the water may also contain salts such as NaCl, NaHCO3, and the like. The aqueous layer may also be extracted with an organic solvent such as DCM, and the organic solvent can be combined with the other organic layer obtained. This organic layer may then be dried over a suitable drying agent such as sodium sulfate.

[0033] In some embodiments, the compound of Formula III in DCM is stirred with water, the layers are separated, then stirred with 10% aqueous NaHCO3, separated, stirred with saturated aqueous NaCl, separated, and then dried over Na2SO4. In some embodiments, the dried organic layer is concentrated under reduced pressure, taken up in acetone, washed with water, filtered, suction dried, and then vacuum dried (or dried under reduced pressure) to provide the purified compound of Formula III. The drying step may be carried out at an elevated temperature, for example, above about 25 °C, above about 30 °C, above about 35 °C, above about 40 °C, above about 45 °C, above about 50 °C, above about 55 °C, and above about 60 °C. The drying temperature is generally below the melting point of the compound of Formula III and may be below about 150 °C, below about 120 °C, below about 100 °C, below about 90 °C, below about 80 °C, below about 75 °C, below about 70 °C, and below about 65 °C.

[0034] B. Process 2: (A) The compound of Formula III is then contacted with hydroxylamine (NH2OH) or a salt thereof in the presence of a weak base in a suitable solvent to provide the compound of Formula II. In some embodiments, the hydroxylamine is hydroxylamine hydrochloride. Hydroxylamine or the hydroxylamine salt is added to the reaction in a ratio of about 10 to about 0.5 relative to the compound of Formula II.

[0035] In some embodiments, the ratio of NH2OH or the salt to Formula II is about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1. In some embodiments, the ratio is at least about 0.5, about 1, about 2, or about 3.

[0036] In some embodiments, the weak base is triethylamine or diisopropylamine. The weak base is added to the reaction in a ratio of about 10 to about 0.5 relative to the compound of Formula II. In some embodiments, the ratio of the weak base to Formula II is about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1. In some embodiments, this ratio is at least about 0.5, about 1, about 2, or about 3.

[0037] In some embodiments, the solvent is ethanol, isopropanol, methanol, DCM, EtOAc, or a mixture thereof. In some embodiments, the reaction temperature is a high temperature such as, for example, above about 25°C, above about 30°C, above about 35°C, above about 40°C, above about 45°C, above about 50°C, above about 55°C, above about 60°C, above about 65°C, and above about 70°C. The reaction temperature is generally below the reflux temperature of the selected solvent and may be less than about 120°C, less than about 100°C, less than about 90°C, less than about 80°C, less than about 75°C, less than about 70°C, and less than about 65°C.

[0038] The reaction time is generally the length of time required for the reaction to substantially complete, which may vary with the specific reactants, aprotic solvent, and reaction temperature selected. In some embodiments, the reaction time is from about 30 minutes to about 48 hours. In some embodiments, the reaction time is from about 1 hour to about 24 hours. In some embodiments, the reaction time is from about 4 hours to about 12 hours. In some embodiments, the reaction time is from about 6 hours to about 10 hours. In some embodiments, the reaction time is about 7 hours.

[0039] (B) The solution of the compound of formula II is then (i) concentrated, (ii) the compound is precipitated by adding water, (iii) the solid is filtered, (iv) washed, and (v) dried to provide the purified compound of formula II. In some embodiments, (i) the concentration results from heating the solution containing the compound of formula II, reducing the pressure, or both. In some embodiments, the solution is concentrated to a volume of about 20% of the volume of the reaction mixture by heating under reduced pressure. Then water (ii) is added to the concentrated solution and the mixture is stirred to precipitate the solid compound of formula II. The resulting solid is (iii) filtered, (iv) washed with water, and (v) dried.

[0040] In some embodiments, the solid is dried by suction filtration, drying under reduced pressure, drying at high temperature, or a combination thereof. In some embodiments, the solid is first dried by suction filtration and then dried under reduced pressure at high temperature to provide the purified compound of Formula II.

[0041] Process 3: (A) The compound of Formula II is then subjected to reduction conditions in a protic solvent at high temperature to provide the crude compound of Formula I. In some embodiments, the reduction conditions include catalytic hydrogenation. In some embodiments, Raney nickel and hydrogen are used for catalytic hydrogenation. In some embodiments, the protic solvent is acetic acid. This process may provide the compound of Formula I as an acetate.

[0042] In some embodiments, the high temperature reaction temperature is greater than about 30°C, greater than about 35°C, greater than about 40°C, greater than about 45°C, greater than about 50°C, greater than about 55°C, and greater than about 60°C. The reaction temperature is generally below the reflux temperature of the solvent and less than about 120°C, less than about 100°C, less than about 90°C, less than about 80°C, less than about 75°C, less than about 70°C, less than about 65°C, less than about 60°C, and less than about 55°C. In some embodiments, the reaction temperature is about 50°C to about 55°C.

[0043] In some embodiments, in catalytic hydrogenation, a metal catalyst is utilized. In some embodiments, the metal catalyst contains nickel. In some embodiments, the metal catalyst contains Raney nickel. The amount of catalyst used may vary depending on the selected catalyst and other reaction conditions. In some embodiments, the amount of Raney nickel used (expressed as mol% based on the amount of the compound of Formula II) is at least about 1 mol%, at least about 5 mol%, at least about 10 mol%, at least about 15 mol%, at least about 20 mol%, at least about 25 mol%, at least about 30 mol%, at least about 35 mol%, at least about 40 mol%, at least about 45 mol%, at least about 50 mol%, or at least about 60 mol%.

[0044] The amount of hydrogen used (expressed as kg pressure per cm of catalyst) also varies depending on the amount of catalyst selected and other reaction conditions. In some embodiments, the amount of hydrogen is at least about 1 kg / cm 3 , at least about 2 kg / cm 3 , at least about 3 kg / cm 3 , at least about 4 kg / cm 3 , at least about 5 kg / cm 3 , at least about 6 kg / cm 3 , at least about 7 kg / cm 3 , at least about 8 kg / cm 3 , at least about 9 kg / cm 3 , at least about 10 kg / cm 3 , at least about 11 kg / cm 3 , at least about 12 kg / cm 3 , at least about 15 kg / cm 3 , at least about 20 kg / cm 3 , at least about 25 kg / cm 3 , or at least about 32 3 is. In some embodiments, in this reaction, about 20 mol% of Raney nickel and about 10 kg / cm 3 of H2 are utilized.

[0045] The reaction time is generally the length of time required for the reaction to be substantially complete and may vary with the specific conditions selected and the reaction temperature. In some embodiments, the reaction time is at least about 30 minutes, at least about 1 hour, at least about 4 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 16 hours, at least about 20 hours, or at least about 24 hours. In some embodiments, the reaction time is less than about 48 hours, less than about 40 hours, less than about 36 hours, less than about 30 hours, less than about 24 hours, less than about 18 hours, or less than about 14 hours. In some embodiments, the reaction time is about 12 hours.

[0046] ​(B) The crude compound of formula I reaction mixture is (i) filtered, (ii) the residue is washed with a first solvent, (iii) concentrated to about 10-20% of the reaction mixture volume, and (iv) the reaction mixture is treated with a second solvent in which the compound is poorly soluble, (v) filtered, and (vi) dried to provide a semi-purified product.

[0047] The first solvent (step ii) may be a lower alkyl alcohol, dimethyl sulfoxide (DMSO), or dimethylformamide (DMF). In some embodiments, the first solvent is methanol or ethanol. In some embodiments, the second solvent (step iv) is ethyl acetate. The filtration process (steps i and v) may include suction filtration and may further include washing the solids with an additional second solvent.

[0048] In some embodiments, the drying process (step vi) may include suction drying, drying under reduced pressure, drying at an elevated temperature, or a combination thereof. In some embodiments, the drying process may include suction drying followed by drying under reduced pressure at a temperature of at least 35°C. In some embodiments, the reduced pressure is less than 600 mmHg, less than 500 mmHg, less than 400 mmHg, less than 300 mmHg, or less than 200 mmHg.

[0049] In some embodiments, the drying temperature is at least about 40°C, at least about 45°C, or at least about 50°C. The drying temperature is less than the melting point of the compound of formula I and less than the decomposition temperature of the compound of formula I. In some embodiments, the drying temperature is less than about 120°C, less than about 110°C, less than about 100°C, less than about 90°C, less than about 80°C, less than about 70°C, or less than about 65°C.

[0050] (C) The semi - refined product at this point may still contain unacceptable amounts of nickel (or other catalytic metals). To further purify the product, the dried solid is (i) treated with water, (ii) heated at a high temperature, stirred to form a slurry, (iii) cooled, (iv) filtered, (v) dried for a first time, (vi) incorporated into a mixture of ethanol and acetic acid, (vii) heated to a holding temperature, (viii) cooled, (ix) filtered, and (x) dried for a second time to provide a product depleted in nickel. In some embodiments, the high temperature in step ii is at least about 30 °C, at least about 35 °C, at least about 40 °C, at least about 45 °C, at least about 50 °C, at least about 55 °C, at least about 60 °C, or at least about 65 °C. In some embodiments, the high temperature is less than about 100 °C, less than about 90 °C, less than about 80 °C, less than about 70 °C, or less than about 65 °C. In some embodiments, the high temperature is about 55 °C.

[0051] In some embodiments, the filtering step in step iv includes a suction filtering step and a washing step with water. In some embodiments, the drying step in step v includes a suction drying step and a subsequent drying step under reduced pressure at a temperature of at least 35 °C. In some embodiments, the reduced pressure is less than 600 mmHg, less than 500 mmHg, less than 400 mmHg, less than 300 mmHg, or less than 200 mmHg.

[0052] In some embodiments, the drying temperature in step v is at least about 40 °C, at least about 45 °C, or at least about 50 °C. The drying temperature is less than the melting point of the compound of formula I and less than the decomposition temperature of the compound of formula I. In some embodiments, the drying temperature is less than about 120 °C, less than about 110 °C, less than about 100 °C, less than about 90 °C, less than about 80 °C, less than about 70 °C, or less than about 65 °C. In some embodiments, the drying temperature in step v is about 45 °C.

[0053] In step vi, the ratio of ethanol to acetic acid may range from about 1:20 to about 20:1. In some embodiments, the ratio is about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1, v / v ethanol:acetic acid. In some embodiments, the holding temperature in step vii is at least about 30°C, at least about 35°C, at least about 40°C, at least about 45°C, at least about 50°C, at least about 55°C, at least about 60°C, or at least about 65°C. In some embodiments, the holding temperature is approximately the reflux temperature of the solvent mixture of ethanol and acetic acid, or less than about 80°C, less than about 75°C, less than about 70°C, less than about 65°C, or less than about 60°C. In some embodiments, the holding temperature is approximately the reflux temperature of this solvent mixture.

[0054] In some embodiments, the mixture is maintained at the holding temperature for a time of at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, at least about 120 minutes, at least about 150 minutes, at least about 240 minutes, or at least about 3 hours. In some embodiments, the time is less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes. In some embodiments, the time is about 1 hour.

[0055] The cooling in step viii is carried out over a time of at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, or at least about 2 hours. The final temperature in step viii is less than about 35°C, less than about 30°C, less than about 25°C, less than about 20°C, less than about 15°C, less than about 10°C, or less than about 5°C. In some embodiments, the final temperature in step viii is approximately ambient temperature.

[0056] In some embodiments, step viii further includes the step of stirring the mixture. The drying step of step ix may further include the step of washing with a lower alkyl alcohol. In some embodiments, the filtered solid is washed with ethanol. The drying step of step x may include the step of suction drying, drying under reduced pressure, drying at a high temperature, or a combination thereof.

[0057] In some embodiments, the drying process of step x includes suction drying, followed by drying under reduced pressure at a temperature of at least 35°C. In some embodiments, the reduced pressure is less than 600 mmHg, less than 500 mmHg, less than 400 mmHg, less than 300 mmHg, or less than 200 mmHg. In some embodiments, the drying temperature of step x is at least about 40°C, at least about 45°C, or at least about 50°C. The drying temperature is less than the melting point of the compound of formula I and less than the decomposition temperature of the compound of formula I. In some embodiments, the drying temperature is less than about 120°C, less than about 110°C, less than about 100°C, less than about 90°C, less than about 80°C, less than about 70°C, or less than about 65°C. In some embodiments, the drying temperature of step x is about 45°C.

[0058] In some embodiments, steps vi - x are repeated 1, 2, or 3 times. In some embodiments, steps vi - x are repeated 1 time.

[0059] D. Process 4: (A) The nickel-depleted product of Process 3 is further purified by (i) contacting this compound with a first solvent, (ii) raising the mixture to a first elevated temperature, (iii) adding a second solvent, (iv) cooling the resulting mixture to the crystallization temperature, (v) stirring the mixture, (vi) filtering the solids, and (vii) drying the solids to provide the compound of Formula I in pure anhydrous crystalline form. In some embodiments, the first solvent in step (i) is methanol, ethanol, 1-propanol, or 2-propanol, or a mixture thereof. In some embodiments, the lower alkyl alcohol is methanol.

[0060] The first elevated temperature in step (ii) is at least about 30 °C, at least about 35 °C, at least about 40 °C, at least about 45 °C, at least about 50 °C, at least about 55 °C, at least about 60 °C, or at least about 65 °C. The elevated temperature is below the reflux temperature of the first solvent, or below about 80 °C, below about 75 °C, below about 70 °C, below about 60 °C, below about 55 °C, below about 50 °C, below about 45 °C, below about 40 °C, or below about 35 °C. In some embodiments, the elevated temperature is about 55 °C.

[0061] In some embodiments, step (ii) further includes maintaining the mixture at or near the elevated temperature until the compound of Formula I is completely dissolved and a clear solution is formed. In some embodiments, step (ii) further includes slowly cooling the solution to a second elevated temperature. In some embodiments, the second elevated temperature is about 5 °C, about 10 °C, about 15 °C, or about 20 °C lower than the first elevated temperature. The second elevated temperature is about 5 °C, about 10 °C, about 15 °C, about 20 °C, or higher than about 20 °C.

[0062] In some embodiments, step (ii) also includes filtering the solution.

[0063] The second solvent in step iii is MTBE or THF. In some embodiments, the second solvent is MTBE. In some embodiments, the first solvent and the second solvent are anhydrous. In some embodiments, the second solvent is added slowly over a long period of time. In some embodiments, the long period of time in step ii is at least about 20 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes, at least about 105 minutes, at least about 120 minutes, at least about 150 minutes, at least about 180 minutes, or at least about 240 minutes. The long period of time is less than about 24 hours, less than about 18 hours, less than about 12 hours, less than about 8 hours, less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, or less than about 1 hour. In some embodiments, the long period of time is about 2 hours.

[0064] In some embodiments, step iii further includes adding seed crystals. The ratio of the first solvent to the second solvent may vary from about 1:20 to about 20:1, v / v. In some embodiments, the ratio of MeOH to MTBE is about 5:1, about 4:1, about 3:1, about 2.7:1, about 2.5:1, about 2.3:1, about 2:1, about 1.5:1, about 1.3:1, about 1.2:1, about 1:1, about 1:1.5, about 1:2, about 1:3, or about 1:4.

[0065] The crystallization temperature in step iv is about 35 °C or lower, less than about 30 °C, less than about 25 °C, less than about 20 °C, less than about 15 °C, less than about 10 °C, or less than about 5 °C. In some embodiments, the crystallization temperature is about 25 °C. Cooling occurs over a long period of time. In some embodiments, the cooling time in step iv is at least about 20 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes, at least about 105 minutes, at least about 120 minutes, at least about 150 minutes, at least about 180 minutes. In some embodiments, the cooling time is from about 45 minutes to about 90 minutes.

[0066] In some embodiments, step v further includes adding an additional amount of a second solvent over an extended period of time. In some embodiments, the extended period of time for step (v) is at least about 20 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes, at least about 105 minutes, at least about 120 minutes, or at least about 150 minutes. The extended period of time is less than about 24 hours, less than about 18 hours, less than about 12 hours, less than about 8 hours, less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, or less than about 1 hour.

[0067] The filtering step of step vi can further include washing the solids with an additional amount of the second solvent. The drying step of step vii can include suction drying, drying under reduced pressure, drying at an elevated temperature, or combinations thereof. In some embodiments, the drying process of step x includes suction drying and subsequently drying under reduced pressure at a temperature of at least 35°C. In some embodiments, the reduced pressure is less than 600 mmHg, less than 500 mmHg, less than 400 mmHg, less than 300 mmHg, or less than 200 mmHg. In some embodiments, the drying temperature of step vii is at least about 40°C, at least about 45°C, or at least about 50°C. The drying temperature is less than the melting point of the compound of formula I and less than the decomposition temperature of the compound of formula I. In some embodiments, the drying temperature is less than about 120°C, less than about 110°C, less than about 100°C, less than about 90°C, less than about 80°C, less than about 70°C, or less than about 65°C. In some embodiments, the drying temperature of step vii is about 45°C.

[0068] Intermediates useful in the process The compounds of formula II and formula III are useful in the preparation of the compound of formula I,

Chemical formula

Chemical formula

[0069] Formulation The compounds of formula I are formulated and administered according to methods known in the art. The pharmaceutical compositions containing the active ingredient may be, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, self-emulsifying agents as described in U.S. Patent Application No. 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders and effervescent tablets, and may be in a form suitable for oral use.

[0070] Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can include one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives in order to obtain pharmaceutically sophisticated and palatable preparations. Tablets contain an active ingredient mixed with non-toxic pharmaceutically acceptable additives suitable for the manufacture of tablets. These additives can be inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate, etc.; granulating and disintegrating agents such as corn starch or alginic acid, etc.; binders such as PVP, cellulose, PEG, starch, gelatin or gum arabic, etc.; and lubricants such as magnesium stearate, stearic acid or talc, etc. These tablets may or may not be coated, or may be coated enterically or in another manner by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. They can also be coated by the techniques described in U.S. Patent No. 4,256,108, U.S. Patent No. 4,166,452 and U.S. Patent No. 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0071] Formulations for oral use can also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, etc., or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil, etc. Further, emulsions can be prepared with non-aqueous miscible components such as oil, etc. and stabilized with surfactants such as mono-diglycerides, PEG esters, etc.

[0072] The aqueous suspension contains an active material mixed with additives suitable for the production of the aqueous suspension. Such additives are suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth gum and gum arabic, etc., and the dispersing agent or wetting agent is a natural phosphatide such as lecithin, or a condensate of alkylene oxide and fatty acid such as polyoxyethylene stearate, or a condensate of ethylene oxide and long-chain aliphatic alcohol such as heptadecaethyleneoxycetanol, or a condensate of ethylene oxide and a partial ester derived from fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or a condensate of ethylene oxide and a partial ester derived from fatty acid and hexitol anhydride such as polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0073] The oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, solid paraffin or cetyl alcohol. To obtain a palatable oral preparation, sweeteners and flavoring agents such as those shown above can also be added. These compositions can also be preserved by the addition of an antioxidant such as ascorbic acid.

[0074] The dispersible powder or granule suitable for the preparation of the aqueous suspension by the addition of water provides an active ingredient mixed with a dispersing agent or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing agents or wetting agents, and suspending agents are exemplified by those already described above. Other additives such as sweeteners, flavoring agents and colorants may also be present.

[0075] The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be natural gums such as gum arabic or tragacanth gum, natural phosphatides such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensates of this partial ester with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0076] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain demulcents, preservatives, and flavoring and coloring agents. Oral solutions can be prepared, for example, in combination with cyclodextrins, PEGs and surfactants.

[0077] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated using the suitable dispersing or wetting agents and suspending agents described above according to known techniques. The sterile injectable preparation may be a solution or suspension for sterile injection as a solution in a non-toxic parenterally acceptable diluent or solvent, for example in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are also conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid are also used in the preparation of injections.

[0078] The compounds of formula I can also be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature and is thus thought to melt in the rectum and release the drug. Such materials include cocoa butter and polyethylene glycol. Furthermore, the compounds can be administered via delivery to the eye by means of solutions or ointments. Still further, transdermal delivery of the subject compounds can be achieved by means of iontophoresis-type patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are used. As used herein, topical application includes the use of mouthwashes and gargles.

[0079] The compounds of formula I can be formulated for attachment in a medical device that can include any of a variety of conventional grafts, stents including stent grafts, catheters, balloons, baskets or other devices that can be placed or permanently implanted into a body cavity. As one particular example, it would be desirable to have a device and method for delivering the compounds of the present invention to a body region being treated by an interventional procedure.

[0080] Inhibitors of Formula I can be attached inside medical devices such as stents and reach the treatment site for the treatment of a part of the body. The stent is used as a delivery medium for a therapeutic agent (i.e., a drug). Intravascular stents are generally permanently implanted into coronary or peripheral blood vessels. The stent designs include those of U.S. Patent No. 4,733,655 (Palmaz), U.S. Patent No. 4,800,882 (Gianturco), and U.S. Patent No. 4,886,062 (Wiktor). Such designs include both metal and polymer stents, as well as self-expanding and balloon-expandable stents. Also, for example, as disclosed in U.S. Patent No. 5,102,417 (Palmaz), as well as International Publication No. 91 / 12779 pamphlet (Medtronic, Inc.) and International Publication No. 90 / 13332 pamphlet (Cedars-Sanai Medical Center), U.S. Patent No. 5,419,760 (Narciso, Jr.) and U.S. Patent No. 5,429,634 (Narciso, Jr.), stents can also be used to deliver drugs at the contact site with the vascular structure.

[0081] The term "deposited" means that the inhibitor is coated, adsorbed, positioned, or incorporated in another manner into the device by methods known in the art. For example, the inhibitor can be embedded in a polymer material that covers or extends over the medical device and released therefrom ("matrix type"), or surrounded by it and released therethrough ("reservoir type"). In the latter example, one or more of the methods known in the art for producing such materials can be used to trap the inhibitor inside the polymer material or couple it to the polymer material. In other formulations, the inhibitor may be linked to the surface of the medical device without the need for coating by a separable bond and release over time, and can also be removed by an active mechanical or chemical process, or in a permanently immobilized form that presents the inhibitor at the implantation site.

[0082] The polymer may be either a biostable polymer or a bioabsorbable polymer depending on the desired release rate or degree of desired polymer stability. However, unlike biostable polymers, bioabsorbable polymers are considered not to remain in the body for a long time after implantation and not to cause any harmful, chronic local responses. Therefore, bioabsorbable polymers are preferred for this embodiment. Bioabsorbable polymers that can be used include poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoester, polyphosphoester urethane, poly(amino acid), cyanoacrylate, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-ester) (e.g., PEO / PLA), polyalkylene oxalate, polyphosphazene, and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, poly ε-caprolactone, polyhydroxybutyric acid, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylate, crosslinkable or amphiphilic block copolymers of hydrogels, and other suitable bioabsorbable polymers known in the art, but are not limited thereto.Also, biostable polymers with relatively low chronic tissue reactivity, such as polyurethane, silicone, and polyester, can be used, and if they can dissolve and cure or polymerize on a medical device, polyolefins, polyisobutylene, and ethylene-α-olefin copolymers; acrylic polymers and copolymers, halogenated vinyl polymers and copolymers, such as polyvinyl chloride, etc.; polyvinyl pyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether, etc.; polyhalogenated vinylidene, such as polyvinylidene fluoride and polyvinylidene chloride, etc.; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatics, such as polystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and with olefins, such as ethylene-methyl methacrylate copolymer, acrylonitrile-styrene copolymer, ABS resin, and ethylene-vinyl acetate copolymer, etc.; pyran copolymers; polyhydroxy-propyl-methacrylamide-phenol; polyhydroxyethyl-aspartoamide-phenol; polyethylene oxide-polylysine substituted by palmitoyl residues; polyamides, such as nylon 66 and polycaprolactam, etc.; alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and other polymers such as carboxymethyl cellulose can also be used.

[0083] The polymer and the semipermeable polymer matrix can also be formed as shaped articles such as valves, stents, tubes, artificial organs, and the like. Typically, the polymer is applied by spin coating, dipping, or spraying onto the surface of the implantable device. Other methods known in the art can also be utilized for this purpose. Spraying methods include conventional methods and microdeposition methods using inkjet-type dispensers. Further, photolithography can be used to attach the polymer onto the implantable device in order to place the polymer only on specific portions of the device. This coating of the device provides a uniform layer around the device, thereby improving the diffusion of various analytes through the coating of the device.

[0084] The compound of Formula 1 can be formulated for release from the polymer coating into the environment in which the medical device is placed. For example, the compound is released in a controlled manner over a long time frame (e.g., several months) using at least one of several well-known techniques involving a polymer carrier or layer for controlling elution. Some of these techniques are described in U.S. Patent Application Publication No. 2004 / 0243225, the entire disclosure of which is incorporated herein by reference in its entirety.

[0085] Furthermore, for example, as described in U.S. Patent No. 6,770,729, which is incorporated herein by reference in its entirety, the reaction conditions of the reagents and polymer compositions can be manipulated to control the release of the inhibitor from the polymer coating. For example, the diffusion coefficient of one or more polymer coatings can be adjusted to control the release of the inhibitor from the polymer coating. In one variation of this subject matter, the ability of an analyte present in the environment in which the medical device is disposed (e.g., an analyte that promotes the disintegration or hydrolysis of a portion of the polymer) to access one or more components within the polymer composition (and thereby, for example, to regulate the release of the inhibitor from the polymer coating) can be regulated by controlling the diffusion coefficient of one or more polymer coatings. Some embodiments of the present invention include devices having multiple polymer coatings, each having multiple diffusion coefficients. In such embodiments of the process, the release of the inhibitor from the polymer coating can be regulated by the multiple polymer coatings.

[0086] The release of the inhibitor from the polymer coating can be controlled by adjusting one or more properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds or the pH of the polymer composition. For example, certain polymer compositions can be designed to release the inhibitor in response to a decrease in the pH of the polymer composition. Alternatively, certain polymer compositions can be designed to release the inhibitor in response to the presence of hydrogen peroxide.

[0087] Embodiments One aspect of the present invention is a process for preparing a compound of Formula I, or a salt thereof,

Chemical formula

[0088] In some embodiments, the reduction conditions include Raney nickel and H2. In some embodiments, the reduction conditions include about 10 to about 40 mol% of Raney nickel and about 2 to about 20 kg / cm 3 of H2. In some embodiments, the reduction conditions include about 20 mol% of Raney nickel and about 10 kg / cm 3 of H2.

[0089] In some embodiments, this reduction condition further includes acetic acid as a solvent and heating at a temperature of about 30°C to about 70°C. In some embodiments, this temperature is about 50°C to about 65°C.

[0090] In some embodiments, this heating is carried out for about 15 minutes to 2 hours. In some embodiments, this heating is carried out for about 15 minutes to 1 hour. In some embodiments, this heating is carried out for about 30 minutes.

[0091] In some embodiments, this process further includes forming an aqueous slurry of this crude product at a temperature of about 25°C to about 70°C to provide a nickel-depleted product. In some embodiments, this temperature is about 50°C to about 60°C. In some embodiments, this slurry is stirred for about 1 hour.

[0092] In some embodiments, this process further includes heating this nickel-depleted product in a solvent to further remove nickel. In some embodiments, this solvent includes a mixture of ethanol and acetic acid. In some embodiments, this solvent includes a mixture of methanol, dimethylglyoxime, and methyl-t-butyl ether.

[0093] In some embodiments, the compound of formula II is exposed to hydroxylamine or a salt thereof under basic conditions with the compound of formula III.

Chemical formula

[0094] In some embodiments, this basic condition includes triethylamine and ethanol. In some embodiments, this basic condition further includes heating at a temperature of about 50°C to about 75°C. In some embodiments, this basic condition includes heating at a temperature of about 60°C to about 65°C. In some embodiments, this heating is carried out for about 3 hours to about 12 hours. In some embodiments, this heating is carried out for about 7 hours. In some embodiments, about 3 equivalents of hydroxylamine and triethylamine are used per equivalent of the compound of formula III.

[0095] In some embodiments of the present invention, the compound of formula III is obtained by exposing the compound of formula IV to 4-(aminomethyl)benzonitrile hydrochloride under aprotic conditions.

Chemical formula

[0096] In some embodiments, this aprotic condition includes triethylamine in dichloromethane. In some embodiments, this aprotic condition further includes 1-propanephosphonic anhydride (T3P®) in ethyl acetate. In some embodiments, this aprotic condition includes incubating the compound of formula IV with 4-(aminomethyl)benzonitrile hydrochloride and 1-propanephosphonic anhydride at a temperature of about 5°C to about 39°C. In some embodiments, this temperature is about 20°C to about 30°C. In some embodiments, this aprotic condition further includes stirring for 1 to 6 hours. In some embodiments, this aprotic condition further includes stirring for 3 hours.

[0097] In some embodiments, the compound of formula I is

Chemical formula

[0098] In some embodiments, the compound of formula I is 1-benzyl-N-(4-carbamimidoyl-benzyl)-1H-pyrazole-4-carboxamide or a salt thereof. In some embodiments, the compound of formula I is 1-benzyl-N-(4-carbamimidoyl-benzyl)-1H-pyrazole-4-carboxamide acetate.

Examples

[0099] Examples The following examples are provided by way of illustration and are not intended to limit the claimed invention. In the following examples, concentration under reduced pressure is carried out at 500 - 600 mmHg unless otherwise specified. The following abbreviations are used: DCM = dichloromethane; MeOH = methanol; EtOH = ethanol; AcOH = acetic acid; EtOAc and AcOEt = ethyl acetate; T3P® = 50% 1-propanephosphonic anhydride in EtOAc; MTBE = methyl t-butyl ether.

[0100] Example 1: Synthesis of the compound of formula IV The compound of formula IV is purchased from a commercial source or prepared by the methods described below or other methods known in the art.

Chemical formula

[0101] In the formula, the subscript m is an integer from 0 to 3, each R a is (C3-C8) cycloalkyl, (C1-C4) haloalkyl, halogen, -OH, -OR 1 , -SH, -SR 1 , -S(O)R 1 , -S(O)2R 1 , -SO2NH2, -C(O)NH2, -C(O)NHR 1 , -C(O)N(R 1 )2, -C(O)R 1 , -C(O)H, -CO2H, -CO2R 1, -NO2, -NH2, -NHR 1 , -N(R 1 )2, independently selected from the group consisting of, each R 1 is independently (C1-C8) alkyl, L is a linking group selected from the group consisting of a single bond or CH2, Q a , Q b , and Q c are each members independently selected from the group consisting of N, S, O and C(R q ), each R q is H, C 1-8 alkyl, halogen and phenyl, independently selected from the group consisting of, and Q a , Q b , Q c and this ring having Q as ring vertices is a 5-membered ring having two double bonds, and

[0102] Ethyl 1H-pyrazole-4-carboxylate (23.5 g, 1 equivalent) and acetone (587 mL) were charged into a round-bottom flask at 20-25 °C under a N2 atmosphere, and the mixture was stirred for 10 minutes. Then, K2CO3 (70.4 g, 3 equivalents) was added. The whole reaction mixture was cooled to 0-5 °C, and benzyl bromide (28.66 g, 1.1 equivalents) was added very slowly at 0-5 °C over 15 minutes. The reaction mixture was warmed to 20-25 °C, heated to 50-60 °C, and maintained at that temperature for 3 hours. After the reaction was complete (monitored by HPLC), the reaction mixture was concentrated under reduced pressure at 45-50 °C, quenched with 10% NaOH, and extracted with DCM (117 mL). The aqueous layer was separated, back-extracted with DCM (117 mL), the combined organic layers were dried over sodium sulfate, and concentrated under reduced pressure at 45-50 °C. Petroleum ether or n-heptane (117 mL) was added to the concentrate, stirred for 1 hour, filtered, and concentrated under reduced pressure at 40-45 °C for 12 hours to produce ethyl 1-benzyl-1H-pyrazole-4-carboxylate (32.5 g).

[0103] Ethyl 1-benzyl-1H-pyrazole-4-carboxylate (30 g) and methanol (300 mL) were charged into a 3 L round-bottom flask, and the resulting solution was stirred at 24 °C for 10 minutes. Subsequently, KOH (14.6 g, 2 equivalents) was added, and the mixture was heated to 65 - 70 °C and maintained for 4 hours. After the reaction was completed (judged by HPLC), the reaction mixture was concentrated under reduced pressure to 40 - 60 mL at 45 - 50 °C. The resulting residue was dissolved in water (300 mL) and extracted with DCM (2 × 150 mL). The aqueous layer was separated and acidified to pH 2 with 6N HCl. The precipitated solid was filtered, washed with water (30 mL), and concentrated under reduced pressure at 45 - 50 °C for 12 hours to afford 1-benzyl-1H-pyrazole-4-carboxylic acid (19.5 g) as a light brown solid with a purity of 99.1% by HPLC. 1 HNMR (400 MHz, DMSO-d6): δ 5.36 (s, 2H), 7.26 - 7.37 (m, 5H), 7.83 (s, 1H), 8.38 (s, 1H), 12.33 (broad s, 1H).

[0104] Other compounds of formula IV are prepared by a similar method with appropriate changes to the benzyl and pyrazole components as required.

[0105] Example 2: Synthesis of the compound of formula III The compound of formula III with substituents as described in Example 1 above is prepared as described below.

Chemical formula

[0106] DCM (285 mL) and 4-aminomethyl-benzonitrile hydrochloride (19.2 g, 1.2 equivalents) were charged into a 3 L round-bottom flask, and the mixture was cooled to 0 °C. Triethylamine (39.4 g, 3 equivalents) was added at 0 °C, and the resulting mixture was stirred for 30 minutes. Next, 1-benzyl-1H-pyrazole-4-carboxylic acid (19 g, 1 equivalent) was added at 0 - 5 °C, and the temperature was raised to 20 - 25 °C. 50% Ethyl acetate solution of 1-propanephosphonic anhydride (T3P®, Spectrochem, 72 mL, 1.28 equivalents) was added, and the mixture was stirred at 20 - 25 °C for 3 hours. After the reaction was completed, water (95 mL) was added and stirred for 10 - 15 minutes, and the organic layer was separated. The aqueous layer was extracted again with DCM (95 mL), and the combined organic layers were washed with water (95 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to about 40 mL. Then, acetone (95 mL) was added, and the mixture was co-distilled until only 20 - 30 mL remained in the pot. Then, water (285 mL) was added and stirred at 20 - 25 °C for 1 hour. The resulting solid was filtered, washed with acetone:water (1:3 v / v, 10 mL), and suction-filtered and dried under reduced pressure at 45 - 50 °C for 12 hours to give 1-benzyl-N-(4-cyano-benzyl)-1H-pyrazole-4-carboxamide (26.9 g, 94%) as a bright brown solid with a purity of 98.51% by HPLC. 1 1H NMR (400 MHz, DMSO-d6): δ 4.49 (d, J = 5.9 Hz, 2H), 5.37 (s, 2H), 7.27 - 7.38 (m, 5H), 7.48 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.95 (s, 1H), 8.31 (s, 1H), 8.77 (t, J = 5.9 Hz, 1H).

[0107] Other compounds of formula III are prepared by the same method using the other compounds prepared in Example 1.

[0108] Example 3: Synthesis of the compound of formula II The compound of formula II with substituents as described in Example 1 above is prepared as described below.

Chemical formula

[0109] Ethanol (250 mL) and 1-benzyl-N-(4-cyanobenzyl)-1H-pyrazole-4-carboxamide (25 g) were charged into a 1 L round-bottom flask at 20 - 25 °C under a nitrogen atmosphere. Hydroxylamine hydrochloride (16.3 g, 3 equivalents) and triethylamine (24.64 g, 3 equivalents) were added to the reaction mixture at 20 - 25 °C. The mixture was then heated to 60 - 65 °C and maintained at that temperature for 7 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to about 30 - 50 mL at 45 - 50 °C. Then water (250 mL) was added and the mixture was stirred at ambient temperature for 30 minutes. The resulting solid was filtered, washed with water (125 mL), filtered by suction to dryness, and further dried under reduced pressure by suction at 45 - 50 °C for 12 hours to give 1-benzyl-N-(4-(N-hydroxycarbamimidoyl)benzyl)-1H-pyrazole-4-carboxamide (25.5 g, 92.3% yield) as a pale yellow solid with a purity of 95.41% by HPLC. 1 HNMR (400 MHz, DMSO-d6): δ 4.40 (d, J = 5.9 Hz, 2H), 5.34 (s, 2H), 5.76 (broad, 2H), 7.25 - 7.37 (m, 7H), 7.61 (d, J = 8.2 Hz, 2H), 7.91 (s, 1H), 8.27 (s, 1H), 8.63 (t, J = 5.9 Hz, 1H), 9.57 (broad s, 1H).

[0110] Other compounds of formula II are prepared by the same method using the other compounds prepared in Example 2.

[0111] Example 4: Synthesis of the compound of formula I The compound of formula I with substituents as described in Example 1 above is prepared as described below.

Chemical formula

[0112] Acetic acid (2100 g) and 1-benzyl-N-(4-(N-hydroxycarbamimidoyl)benzyl)-1H-pyrazole-4-carboxamide (200 g) were stirred in a hydrogenation apparatus at 25 °C for 10 - 15 minutes.

[0113] Raney nickel (40 g) and water (1 volume) were stirred in a flask and allowed to precipitate for 5 minutes. The water was decanted, another volume of water was added, stirred, allowed to precipitate for 5 minutes, and then decanted. Acetic acid (1 volume) was added, the mixture was stirred for 10 minutes, then allowed to precipitate for 5 minutes, and then decanted. The Raney nickel was charged into the hydrogenation apparatus together with acetic acid (1 volume). The reaction mixture was heated to 60 °C and hydrogen was applied for 30 minutes (10 Kg pressure).

[0114] The resulting mixture was cooled to ambient temperature and the resulting solid was suction filtered over Celite® for 30 minutes. The solid was washed with MeOH (784 g), concentrated to 1 - 2 volumes, and charged with EtOAc (2 L). The mixture was stirred at 25 °C for 1 hour, suction filtered, washed with EtOAc (400 g), and suction dried for 2 hours. The product was further dried at 25 °C for 2 hours and then at 25 °C under reduced pressure (<300 mmHg), followed by drying at 45 °C for 12 hours under reduced pressure (<300 mmHg) to produce 1-benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide acetate (220 g) as the crude product.

[0115] Other compounds of formula I are prepared by the same method using the compound prepared in Example 3.

[0116] Example 5: Purification The dried product (219 g) was cooled to 25 °C, charged into a round-bottom flask together with water (2190 mL), and stirred for 10 minutes to form a slurry. The slurry was heated to 55 °C over 20 minutes, stirred at that temperature for 1 hour, cooled to 25 °C over 20 minutes with stirring, and further stirred at 25 °C for 30 minutes. The solid was filtered, washed with water (220 mL), and suction dried for 2 hours. The product was dried again at 45 °C for 12 hours under reduced pressure (<300 mmHg), cooled to 25 °C, and charged into a round-bottom flask. Anhydrous ethanol (1250 g) and acetic acid (183 g) were added thereto, and the mixture was heated to the reflux temperature (75 °C) over 30 minutes and refluxed for 30 minutes. Then the mixture was slowly cooled to 25 °C over 30 minutes, stirred at 25 °C for 45 minutes, filtered, washed with EtOH, and suction dried at 25 °C for 2 hours. Then the product was dried at 45 °C for 10 hours under reduced pressure (<300 mmHg).

[0117] The dried product (143 g) was cooled to 25 °C, charged into a round-bottom flask together with anhydrous ethanol (1027 g) and acetic acid (150 g), and the mixture was heated to the reflux temperature (75 °C) over 30 minutes and refluxed for 1 hour. Then the mixture was slowly cooled to 25 °C over 45 minutes, stirred at 25 °C for 45 minutes, filtered, washed with EtOH, and suction dried at 25 °C for 2 hours. Then the product was dried at 45 °C for 12 hours under reduced pressure (<300 mmHg) to give purified 1-benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide acetate (126 g, 56% yield, purity 99.6% by HPLC) having less than 30 ppm of nickel.

[0118] Example 6: Pure Crystal Form 1 A mixture of the crude 1-benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide acetate (Compound 1, 10 g) in MeOH (450 mL) was charged into a 2 L round-bottom flask and the mixture was heated to 50 - 55 °C to obtain a clear solution. The solution was maintained at 50 - 55 °C for 30 minutes, filtered and charged into the reactor at 50 - 55 °C. MTBE (450 mL) was slowly added at 50 - 55 °C and the mixture was cooled to 25 °C over 1 hour. A white suspension was observed as it cooled. MTBE (450 mL) was slowly added at 20 - 25 °C and the resulting mixture was stirred for 16 hours, filtered and washed with MTBE (10 mL). The product was dried under reduced pressure at 50 - 55 °C for 24 hours to give the pure 1-benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide acetate in the anhydrous crystalline polymorphic form (“Form 1”) as an off-white solid (8.25 g, 82.5% yield). The purity of the product was >99% by HPLC and it contained <14.5 ppm nickel. 1 HNMR (300 MHz, DMSO-d6): δ 1.71 (s, 3H), 4.47 (d, J = 5.4 Hz, 2H), 5.36 (s, 2H), 7.26 - 7.37 (m, 5H), 7.46 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.92 (s, 1H), 8.29 (s, 1H), 8.77 (broad s, 1H), 10.34 (broad s, 3H). 13 CNMR (75 MHz, DMSO-d6): δ 24.7, 41.7, 55.0, 118.4, 127.4 (2C), 127.5 (2C), 127.8 (2C), 128.2 (2C), 128.6 (2C), 131.6, 136.8, 145.2, 161.8, 165.7, 176.5.

Claims

1. A process for preparing a compound of formula I or a salt thereof, 【Chemical Formula 1】 wherein the compound of formula I is 【Chemical Formula 2】 and the process comprises (a) subjecting a compound of formula II to catalytic hydrogenation to provide a compound of formula I as a crude product, wherein the compound of formula II is 【Chemical Formula 3】 and in the formula, the subscript m is 0, L is CH₂, Qa and Qb are each C(Rq), and each Rq is H, Qc is N, and Y is N.

2. The catalytic hydrogenation comprises Raney nickel and H 2 The method according to claim 1.

3. The catalytic hydrogenation further comprises acetic acid as a solvent and heating at a temperature of 30 °C to 70 °C. The method according to claim 1 or 2.

4. The temperature is 50 °C to 65 °C. The method according to claim 3.

5. The heating is carried out for 15 minutes to 2 hours. The method according to claim 3 or 4.

6. The heating is carried out for 30 minutes. The method according to any one of claims 3 to 5.

7. The method according to any one of claims 2 to 4, further comprising forming an aqueous slurry of the crude product at a temperature of 25 °C to 70 °C to provide a product depleted in nickel.

8. The temperature is 50 °C to 60 °C. The method according to claim 7.

9. The method according to claim 8, wherein the slurry is stirred for 1 hour.

10. The method according to claim 7 or 8, further comprising heating the product in which nickel has been depleted in a solvent to further remove nickel.

11. The method according to claim 10, wherein the solvent comprises a mixture of ethanol and acetic acid.

12. The method according to claim 10, wherein the solvent comprises a mixture of methanol, dimethylglyoxime, and methyl-t-butyl ether.

13. A method according to any one of claims 1 to 12, comprising binding a compound of formula III to hydroxylamine or a salt thereof under basic conditions to provide the compound of formula II, wherein the compound of formula III is 【Chemical Formula 4】 and providing the compound of formula II.

14. The method according to claim 13, wherein the basic conditions comprise triethylamine and ethanol.

15. The method according to claim 14, wherein the basic conditions further comprise heating at a temperature of 50 °C to 75 °C.

16. The method according to claim 15, wherein the basic conditions comprise heating at a temperature of 60 °C to 65 °C.

17. The method according to claim 15 or 16, wherein the heating is carried out for 3 hours to 12 hours.

18. The method according to any one of claims 15 to 17, wherein the heating is carried out for 7 hours.

19. The method according to any one of claims 13 to 16, using 3 equivalents of hydroxylamine and triethylamine per equivalent of the compound of formula III.

20. The method according to any one of claims 13 to 19, comprising reacting a compound of formula IV with 4-(aminomethyl)benzonitrile hydrochloride under aprotic conditions to provide the compound of formula III, wherein the compound of formula IV is 【Chemical 5】 as follows.

21. The method according to claim 20, wherein the aprotic conditions include triethylamine in dichloromethane.

22. The method according to claim 20 or 21, wherein the aprotic conditions further include 1-propanephosphonic anhydride in ethyl acetate.

23. The method according to any one of claims 20 to 22, wherein the aprotic conditions include incubating the compound of formula IV with 4-(aminomethyl)benzonitrile hydrochloride and 1-propanephosphonic anhydride at a temperature of 5 °C to 39 °C.

24. The method according to claim 23, wherein the temperature is 20 °C to 30 °C.

25. The method according to claim 23 or 24, wherein the aprotic conditions further include stirring for 1 to 6 hours.

26. The method according to any one of claims 23 to 25, wherein the aprotic conditions further include stirring for 3 hours.

27. The method according to any one of claims 1 to 24, wherein the compound of formula I is 1-benzyl-N-(4-carbamimidoyl-benzyl)-1H-pyrazole-4-carboxamide acetate.

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