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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
• • 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
• • 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
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• • 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
  • A61P7/10—Antioedematous agents; Diuretics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• Coagulation is the process by which blood forms clots, for example to stop bleeding.
• the physiology of coagulation is somewhat complex insofar as it includes two separate initial pathways, which converge into a final common pathway leading to clot formation.
• prothrombin is converted into thrombin, which in turn converts fibrinogen into fibrin, the latter being the principal building block of cross- linked fibrin polymers which form a hemostatic plug.
• the contact activation or intrinsic pathway the other is known as the tissue factor or extrinsic pathway.
• the intrinsic pathway begins with formation of a primary complex on collagen by high-molecular- weight kininogen (HMWK), prekallikrein, and FXII (Factor XII; Hageman factor).
• HMWK high-molecular- weight kininogen
• FXII Factor XII
• FIX Factor IX
• Activated plasma kallikrein also cleaves HMWK to release the potent vasodilator peptide bradykinin. It is also able to cleave a number of inactive precursor proteins to generate active products, such as plasmin (from plasminogen) and urokinase (from prourokinase). Plasmin, a regulator of coagulation, proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.
• MI myocardial infarction
• thrombin-antithrombin III TAT
• TAT thrombin-antithrombin III
• Plasma kallikrein inhibitors also have therapeutic potential for treating hereditary angioedema (HAE).
• HAE is is a serious and potentially life-threatening rare genetic illness, caused by mutations in the Cl -esterase inhibitor (C1INH) gene, located on chromosome 1 lq.
• C1INH Cl -esterase inhibitor
• HAE is inherited as an autosomal dominant condition, although one quarter of diagnosed cases arise from a new mutation.
• HAE has been classed as an orphan disease in Europe, with an estimated prevalence of 1 in 50,000.
• One aspect of the invention relates to a crystalline salt of Compound I,
• the present invention provides a pharmaceutical composition, comprising a crystalline salt of Compound I, and one or more
• the pharmaceutical preparations may be for use in treating or preventing a condition or disease characterized by aberrant plasma kallikrein activity.
• FIG. 1 is an X-ray powder diffraction (XRPD) pattern of Compound I * 2(HC1).
• FIG. 2 is a spectrum showing a TG-IR analysis of Compound I * 2(HC1).
• FIG. 3 shows plasma concentration of Compound I * 2(HC1) versus time profiles on Day 7 after once per day (QD) oral administration of Compound I * 2(HC1) at 125, 250, and 500 mg QD; and on Day 14 after QD oral administration of Compound I * 2(HC1) at 350 mg QD.
• the invention provides a crystalline salt of Compound I,
• Compound l is a potent inhibitor of plasma kallikrein, described in WO
• physicochemical properties of the compound including but not limited to solid state properties (e.g., crystallinity, hygroscopicity, melting point, or hydration), pharmaceutical properties (e.g., solubility/dissolution rate, stability, or compatibility), as well as
• the crystalline form of Compound I exhibits beneficial pharmacokinetic properties as well; the uniformity of the crystal form leads to a consistent and predictable pharmacokinetic profile.
• the polymorph of the crystalline salt is characterized by X- ray powder diffraction (XRPD).
• Q represents the diffraction angle, measured in degrees.
• the diffractometer used in XRPD measures the diffraction angle as two times the diffraction angle Q.
• the diffraction patterns described herein refer to X-ray intensity measured against angle 20.
• the peak value at the diffraction angle 0, or at two times the diffraction angle 0 (20), may exhibit a minor measurement error due to the XRPD instruments or the conditions under which the measurement is taken. Accordingly, in certain embodiments, the characteristic peaks in the XRPD pattern have a value of °20 ⁇ 0.2°. In certain
• the characteristic peaks in the XRPD pattern have a value of °20 ⁇ 0.1°. In certain embodiments, the characteristic peaks in the XRPD pattern have a value of °20 ⁇ 0.06°.
• the crystalline salt of Compound I has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20 ⁇ 0.2°) of 5.3, 9.0, and 22.0. In certain embodiments, the crystalline salt of Compound I has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20) of 5.3, 9.0, and 22.0.
• the crystalline salt has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20 ⁇ 0.2°) of 5.3, 9.0, 19.8,
• the crystalline salt has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20) of 5.3, 9.0, 19.8,
• the crystalline salt has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20) of 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3.
• XRPD X-ray powder diffraction
• the crystalline salt of Compound I has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20 ⁇ 0.2°) of 5.28, 8.96, and 22.01. In certain embodiments, the crystalline salt of Compound I has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20) of 5.28, 8.96, and 22.01.
• the crystalline salt has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20 ⁇ 0.2°) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.
• the crystalline salt of Compound I has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°20) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.
• the crystalline salt of Compound I is complexed with water in a molar ratio of 1 :2 crystalline salt to water.
• the crystal lattice does not comprise molecules of water.
• the crystalline salt of Compound I is complexed with water in a molar ratio of 1 :2.5 crystalline salt to water.
• the crystal lattice does not comprise molecules of water.
• the crystalline salt of Compound I has a thermogravimetric- infrared spectrum substantially similar to that shown in Fig. 2.
• substantially pure refers to a crystalline polymorph that is greater than 90% pure, meaning that it contains less than 10% of any other compound, including the corresponding amorphous compound or an alternative polymorph of the crystalline salt.
• the crystalline polymorph is greater than 95% pure, or even greater than 98% pure.
• the crystalline salt of Compound I has characteristic peaks in the XRPD pattern at values of two theta ( ° 20) as described herein above and is substantially pure.
• the crystalline salt form can be at least 90% pure, preferably at least 95% pure, or more preferably at least 98% pure.
• the crystalline salt of Compound I has an XRPD pattern that is substantially the same as that shown in Fig. 1 and is substantially pure.
• the crystalline salt form can be at least 90% pure, preferably at least 95% pure, or more preferably at least 98% pure.
• the crystalline salt is a hydrochloride salt, e.g., a
• the first organic solvent comprises a polar aprotic solvent, such as acetonitrile, N,N-dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), diethyl ether, ethyl acetate, isopropyl acetate, methylethyl ketone, methyl tert-butyl ether (MTBE), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran.
• a polar aprotic solvent is methyl tert-butyl ether.
• the first organic solvent further comprises a non-polar solvent.
• Non-polar solvents include, for example, benzene, heptaine, hexanes, and toluene. In certain embodiments, the non-polar solvent is toluene.
• the acid is hydrochloric acid.
• the second organic solvent is a polar protic solvent, such as ethanol, methanol, 2-propanol, 1 -butanol, water, or any combination thereof.
• a polar protic solvent such as ethanol, methanol, 2-propanol, 1 -butanol, water, or any combination thereof.
• the polar protic solvent is methanol.
• the mixture comprising a salt of Compound I formed in step b) is a solution.
• the mixture comprising the salt of Compound l is a solution
• the step of crystallizing the salt from the mixture comprises bringing the solution to supersaturation to cause Compound I to precipitate out of solution.
• bringing the mixture comprising the salt of Compound I to supersaturation comprises the slow addition of an anti-solvent, such as heptanes, hexanes, ethanol, or another polar or non-polar liquid miscible with the organic solvent, allowing the solution to cool (with or without seeding the solution), reducing the volume of the solution, or any combination thereof.
• bringing the mixture comprising the salt of Compound I to supersaturation comprises adding an anti-solvent, cooling the solution to ambient temperature or lower, and reducing the volume of the solution, e.g., by evaporating solvent from the solution.
• allowing the solution to cool may be passive (e.g., allowing the solution to stand at ambient temperature) or active (e.g., cooling the solution in an ice bath or freezer).
• the preparation method further comprises inducing crystallization.
• the method can also comprise the step of drying the crystals, for example under reduced pressure.
• inducing precipitation or crystallization comprises secondary nucleation, wherein nucleation occurs in the presence of seed crystals or interactions with the environment (crystallizer walls, stirring impellers, sonication, etc.).
• inducing crystallization comprises seeding the solution with crystalline seeds of the salt of Compound I.
• washing the crystals comprises washing with a liquid selected from anti-solvent, acetonitrile, ethanol, heptanes, hexanes, methanol,
• anti-solvent means a solvent in which the salt crystals are insoluble, minimally soluble, or partially soluble.
• the addition of an anti-solvent to a solution in which the salt crystals are dissolved reduces the solubility of the salt crystals in solution, thereby stimulating precipitation of the salt.
• the crystals are washed with a combination of anti-solvent and the organic solvent.
• the anti solvent is water, while in other embodiments it is an alkane solvent, such as hexane or pentane, or an aromatic hydrocarbon solvent, such as benzene, toluene, or xylene.
• washing the crystals comprises washing the crystalline salt of Compound I with a solvent or a mixture of one or more solvents, which are described above.
• the solvent or mixture of solvents is cooled prior to washing.
• the method further comprises drying the crystalline salt.
• crystalline salts described herein may be made according to the above- described method.
• carrier and“pharmaceutically acceptable carrier” as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration.
• pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
• auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used.
• suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.
• a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention.
• the at least one additional pharmaceutically active agent can be an agent useful in the treatment of a disease or condition characterized by aberrant plasma kallikrein activity.
• the at least one additional pharmaceutically active agent can be an anti coagulation agent, an anti-platelet agent, or a thrombolytic agent.
• Anti coagulation agents prevent the coagulation of blood components and thus prevent clot formation, for example in atrial fibrillation.
• Anticoagulants include, but are not limited to, heparin, warfarin, coumadin, dicumarol, phenprocoumon, acenocoumarol, ethyl biscoumacetate, hirudin, bivalarutin, direct thrombin inhibitors, and indandione derivatives.
• Thrombolytic agents lyse clots that cause thromboembolic phenomena such as stroke, myocardial infarction, and pulmonary thromboembolism.
• Thrombolytic agents include, but are not limited to, plasminogen, a2-antiplasmin, streptokinase, antistreplase, TNK, tissue plasminogen activator (tPA), and urokinase.
• Tissue plasminogen activator includes native tPA and recombinant tPA, as well as modified forms of tPA that retain the enzymatic or fibrinolytic activities of native tPA.
• compositions of the invention can be prepared by combining one or more crystalline salts of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.
• the invention provides a pharmaceutical composition that is formulated for the prophylactic or therapeutic treatment of a disease or condition characterized by aberrant plasma kallikrein activity.
• the present invention provides compounds that inhibit the formation of thrombin via the intrinsic pathway and thus reduce the risk of new pathogenic thrombus formation (vessel occlusion or reocclusion) and also improve fibrinolytic-induced reperfusion when given as adjunctive therapy with a fibrinolytic regimen.
• Diseases and conditions that can be treated using the compounds of the present invention include, but are not limited to, stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post fibrinolytic treatment condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular
• small polypeptide PK inhibitor DX-88 alleviates edema in patients with hereditary angioedema (HAE).
• HAE hereditary angioedema
• bradykinin B2 receptor antagonist Icatibant
• Icatibant is also effective in treating HAE. Bork, K. et al. (2007) J. Allergy Clin. Immunol. 119:1497-1503. Because plasma kallikrein generates bradykinin, inhibition of plasma kallikrein is expected to inhibit bradykinin production.
• DX-88 reduced brain edema, infarct volume, and neurological deficits in an animal model of ischemic stroke. Storini, C. et al. (2006) J Pharm. Exp. Ther. 318:849-854. Cl- inhibitor reduced infarct size in a mouse model of middle cerebral artery occlusion
• plasma kallikrein inhibitor P8720 has been found to reduce inflammation in an acute and chronic rat model of inflammatory bowel disease (IBD). Stadnicki, A. et al. (1998) FASEB J. 12:325-33; Stadnicki, A. et al. (1996) Dig. Dis. Sci.
• CCMK H-D-Pro-Phe-Arg-chloromethylketone
• Cl -inhibitor an inhibitor of PK and FXII and a physiological inhibitor
• LPS lipopolysaccharide
• Clinical improvement was observed in sepsis patients treated with Cl- inhibitor. Zeerleder, S. et al. (2003) Clin. Diagnost. Lab. Immunol. 10:529-35; Caliezi, C., et al. (2002) Crit. Care Med. 30:1722-8; and Marx, G. et al. (1999) Intensive Care Med.
• prePK levels are higher in diabetics, especially those with proliferative retinopathy, and correlate with fructosamine levels. Gao, B.-B., et al. (2007) Nature Med. 13: 181-8; and Kedzierska, K. et al. (2005) Archives Med. Res. 36:539- 43. PrePK is also found to be highest in those with a sensorimotor neuropathy. Christie,
• PrePK levels are elevated in diabetics and are associated with increased blood pressure. PrePK levels independently correlate with the albumin excretion rate and are elevated in diabetics with
• Bl receptor antagonists can also prevent streptozotocin- treated mice from developing hyperglycemia and renal dysfunction. Zuccollo, A. et al. (1996) Can. J. Physiol. Pharmacol. 74:586-9.
• the invention provides a crystalline salt of Compound I, for use as a medicament.
• the invention provides methods of treating or preventing a disease or condition characterized by aberrant plasma kallikrein activity.
• the method includes the step of administering to a subject in need thereof a therapeutically effective amount of a crystalline salt of Compound I, thereby treating or preventing the disease or condition characterized by aberrant plasma kallikrein activity.
• a crystalline salt of Compound I thereby treating or preventing the disease or condition characterized by aberrant plasma kallikrein activity.
• “treat,”“treating,” and“treatment” as used herein means prevent, halt or slow the progression of, or eliminate a disease or condition in a subject. In some embodiments“treat,”“treating,” and“treatment” means halt or slow the progression of, or eliminate a disease or condition in a subject. In some embodiments,“treat,”“treating,” and “treatment” means reducing at least one objective manifestation of a disease or condition in a subject.
• an effective amount refers to an amount that is sufficient to bring about a desired biological effect.
• terapéuticaally effective amount refers to an amount that is sufficient to bring about a desired therapeutic effect.
• inhibitor means decrease by an objectively measurable amount or extent. In various embodiments“inhibit” means decrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to relevant control. In one embodiment “inhibit” means decrease 100 percent, i.e., halt or eliminate.
• a subject refers to a mammal.
• a subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate.
• a subject is a human.
• the invention provides a crystalline salt of
• Compound I for treatment of a disease or condition characterized by aberrant plasma kallikrein activity is provided.
• the invention provides the use of a crystalline salt of Compound I for the manufacture of a medicament for use in treatment of a disease or condition characterized by aberrant plasma kallikrein activity.
• a“disease or condition characterized by aberrant plasma kallikrein activity” refers to any disease or condition in which it is desirable to reduce plasma kallikrein activity. For example, it may be desirable to reduce plasma kallikrein activity in the setting of inappropriate activation or hyperactivation of kallikrein. As another example, it may be desirable to reduce plasma kallikrein activity in the setting of a hypercoagulable state. As another example, it may be desirable to reduce plasma kallikrein activity in the setting of tissue ischemia that is associated with the presence or formation of thrombus.
• hemorrhage blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, brain edema, increased albumin excretion, macroalbuminuria, and nephropathy.
• the disease or condition characterized by aberrant plasma kallikrein activity is angioedema.
• the disease or condition characterized by aberrant plasma kallikrein activity is acquired angioedema or hereditary angioedema (HAE).
• HAE hereditary angioedema
• Acquired Angioedema (Caldwell JR, et al. Clin Immunol Immunopathol. 1972; 1 :39- 52) is characterized in several ways, including by acquired deficiency of Cl inhibitor (Cl-INH), hyperactivation of the classical pathway of human complement and angioedema symptoms mediated by bradykinin released by inappropriate activation of the contact-kinin system.
• AAE may be present in two forms, AAE type 1 (which is normally associated with another disease) and AAE type II, which is normally associated with an autoimmune disease.
• AAE may be caused by a number of factors, including, but not limited to, autoimmune diseases (for example, the production of anti-ClINH antibodies) or by an acquired mutation in Cl INH.
• the crystalline salts of Compound I may be used to treat side effects of angiotensin converting enzyme (ACE) inhibitor treatments.
• ACE angiotensin converting enzyme
• the disease or condition characterized by aberrant plasma kallikrein activity is hereditary angioedema (HAE).
• HAE hereditary angioedema
• the hereditary angioedema is Type I hereditary angioedema.
• the hereditary angioedema may be Type II hereditary angioedema.
• the hereditary angioedema may be Type III hereditary angioedema.
• the crystalline salt of Compound I is used for prophylactic treatment of HAE. In other embodiments, the crystalline salt of Compound I is used for acute treatment of HAE.
• the crystalline salt of Compound I is used for the prevention or treatment of angioedema attacks in a subject with HAE. In certain embodiments, the crystalline salt of Compound I is used as a preventive treatment to reduce the frequency of angioedema attacks in a subject with HAE. In other embodiments, the crystalline salt of Compound I is used for the treatment of an acute angioedema attack in a subject with HAE. In certain embodiments, the disease or condition characterized by aberrant plasma kallikrein activity is stroke.
• the disease or condition characterized by aberrant plasma kallikrein activity is acute myocardial infarction.
• the disease or condition characterized by aberrant plasma kallikrein activity is blood loss during cardiopulmonary bypass.
• the disease or condition characterized by aberrant plasma kallikrein activity is selected from the group consisting of retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age- related macular degeneration, and proliferative retinopathy.
• the crystalline salts of Compound I described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes. Additional routes of administration are also contemplated by the invention.
• compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of a given unit dosage form.
• amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
• the tablets, troches, pills, capsules, and the like may also contain the following diluents and carriers: binders such as gum tragacanth, acacia, corn starch or gelatin;
• excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
• a liquid carrier such as a vegetable oil or a polyethylene glycol.
• Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form.
• tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
• a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
• any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
• the active compound may be incorporated into sustained-release preparations and devices.
• the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
• Solutions of the active compound can be prepared in water or physiologically acceptable aqueous solution, optionally mixed with a nontoxic surfactant.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active compound which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
• the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
• the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
• the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.
• Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
• methods of preparation can include vacuum drying and the freeze drying techniques, which yield a powder of the active compound plus any additional desired ingredient present in the previously sterile-filtered solutions.
• the crystalline salts of Compound I may be applied in pure form, i.e., when they are prepared in liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
• Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
• Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the crystalline salts of the invention can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
• Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
• the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
• Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
• Useful dosages of the crystalline salts of Compound I can be determined, at least initially, by comparing their in vitro activity and in vivo activity in animal models.
• the amount of the crystalline salt of Compound I required for use in treatment will vary not only with the particular crystalline salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
• a suitable dose will be in the range of from about 0.5 to about 100 mg/kg body weight of the recipient per day, e.g., from about 3 to about 90 mg/kg of body weight per day, from about 6 to about 75 mg per kilogram of body weight per day, from about of 10 to about 60 mg/kg of body weight per day, or from about 15 to about 50 mg/kg of body weight per day.
• Crystalline salts of Compound I can be conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, 10 to 750 mg, 50 to 500 mg, 75 mg to 350 mg, 75 mg to 300 mg, 75 mg to 250 mg, 75 mg to 200 mg, 75 mg to 175 mg, 75 mg to 150 mg, 75 mg to 125 mg, 100 mg to 750 mg, 100 mg to 500 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, 100 mg to 175 mg, 100 mg to 150 mg, 100 mg to 125 mg, 125 mg to 350 mg, 125 mg to 300 mg, 125 mg to 250 mg, 125 mg to 200 mg, 125 mg to 175 mg, 125 mg to 150 mg, including, for example, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg,
• the invention provides a composition comprising a crystalline salt of Compound I formulated in such a unit dosage form.
• the desired dose may conveniently be presented in a single dose or as divided doses to be administered at appropriate intervals, for example, as two, three, four or more sub- doses per day.
• the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
• Crystalline salts of Compound I can also be administered in combination with other therapeutic agents, for example, other agents that are useful for treating or preventing ischemia, blood loss, or reperfusion injury.
• Other delivery systems can include time-release, delayed release, or sustained release delivery systems such as are well-known in the art. Such systems can avoid repeated administrations of the active compound, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. Use of a long-term sustained release implant may be desirable. Long-term release, as used herein, means that the delivery system or is implant constructed and arranged to deliver therapeutic levels of the active compound for at least 30 days, and preferably 60 days.
• the crystalline salts of Compound I may be formulated for depositing into a medical device, which may include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other device that can be deployed or
• a crystalline salt of Compound I may be deposited within a medical device, such as a stent, and delivered to the treatment site for treatment of a portion of the body.
• Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs).
• Intravascular stents are generally permanently implanted in coronary or peripheral vessels.
• Stent designs include those of U.S. Pat. No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S. Pat. No. 4,886,062 (Wiktor).
• Such designs include both metal and polymeric stents, as well as self-expanding and balloon-expandable stents.
• Stents may also be used to deliver a drug at the site of contact with the vasculature, as disclosed in U.S. Pat. No. 5,102,417 (Palmaz), U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634 (Narciso, Jr.), and in International Patent Application Nos. WO 91/12779 (Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai
• the term“deposited” means that the active compound is coated, adsorbed, placed, or otherwise incorporated into the device by methods known in the art.
• the compound may be embedded and released from within (“matrix type”) or surrounded by and released through (“reservoir type”) polymer materials that coat or span the medical device.
• the compound may be entrapped within the polymer materials or coupled to the polymer materials using one or more the techniques for generating such materials known in the art.
• the compound may be linked to the surface of the medical device without the need for a coating, for example by means of detachable bonds, and release with time or can be removed by active mechanical or chemical processes.
• the compound may be in a permanently immobilized form that presents the compound at the implantation site.
• the active compound may be incorporated with polymer compositions during the formation of biocompatible coatings for medical devices, such as stents.
• the coatings produced from these components are typically homogeneous and are useful for coating a number of devices designed for implantation.
• the polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability, but frequently a bioabsorbable polymer is preferred for this embodiment since, unlike a biostable polymer, it will not be present long after implantation to cause any adverse, chronic local response.
• Bioabsorbable polymers that could be used include, but are not limited to, 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 acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, cross linked or amphipathic block copolymers of hydrogels, and other suitable bioabsorbable poplymers known in the art.
• PEO/PLA polyalkylene oxalates
• biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyortho
• polyvinylpyrrolidone polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymer; polyhydroxy-propyl- methacrylamide-phenol; polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide- polylysine substituted with palmitoyl residues; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins, poly
• the crystalline salt of Compound I is coupled to a polymer or semipermeable polymer matrix that is formed as a stent or stent- graft device.
• polymers are applied to the surface of an implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be utilized for this purpose. Methods of spraying include traditional methods as well as microdeposition techniques with an inkjet type of dispenser. Additionally, a polymer can be deposited on an implantable device using photo-patterning to place the polymer on only specific portions of the device. This coating of the device provides a uniform layer around the device which allows for improved diffusion of various analytes through the device coating.
• the active compound is formulated for release from the polymer coating into the environment in which the medical device is placed.
• the compound is released in a controlled manner over an extended time frame (e.g., months) using at least one of several well-known techniques involving polymer carriers or layers to control elution. Some of these techniques are described in U.S. Patent Application 2004/0243225 Al, the entire disclosure of which is incorporated herein in its entirety.
• the reagents and reaction conditions of the polymer compositions can be manipulated so that the release of the active compound from the polymer coating can be controlled.
• the diffusion coefficient of the one or more polymer coatings can be modulated to control the release of the compound from the polymer coating.
• the diffusion coefficient of the one or more polymer coatings can be controlled to modulate the ability of an analyte that is present in the environment in which the medical device is placed (e.g. an analyte that facilitates the breakdown or hydrolysis of some portion of the polymer) to access one or more
• Yet another embodiment of the invention includes a device having a plurality of polymer coatings, each having a plurality of diffusion coefficients. In such embodiments of the invention, the release of the active compound from the polymer coating can be modulated by the plurality of polymer coatings.
• the XRPD pattern was collected with a PANalytical X'Pert PRO MPD
• TG analyses were performed using a TA Instruments Discovery thermogravimetric analyzer with an IR furnace. Temperature calibration was performed using nickel and AlumelTM. Each sample was placed in an aluminum pan. The sample was hermetically sealed, the lid pierced, then inserted into the TG furnace. The furnace was heated under nitrogen. The acquisition scan rate is recorded in the thermogram header, while the heating range can be determined from the individual plot.
• TG-IR Thermogravimetric infrared analysis was performed on a TA Instruments Q5000 IR thermogravimetric (TG) analyzer interfaced to a Magna-IR 560® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, a potassium bromide (KBr) beamsplitter, and a mercury cadmium telluride (MCT-A) detector.
• the FT-IR wavelength verification was performed using polystyrene, and the TG calibration standards were nickel and AlumelTM. The sample was placed in a platinum sample pan, and the pan was inserted into the TG furnace.
• the TG instrument was started first, immediately followed by the FT-IR instrument.
• the TG instrument was operated under a flow of helium at 90 and 10 cc/min for the purge and balance, respectively.
• the furnace was heated under helium at a rate of 20 °C/minute to a final temperature of 350 °C.
• IR spectra were collected approximately every 16 seconds for approximately 13 minutes. Each IR spectrum represents 16 co-added scans collected at a spectral resolution of 4 cm -1 . Volatiles were identified from a search of the High
• Step-2 Preparation of tert-butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c)
• Step-3 Preparation of tert-butyl 3-(5-(5-((3- cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d)
• Step-4 Preparation of l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e)
• the insoluble crude product was purified by flash column chromatography [silica gel, eluting with chloroform/CMA80 (1 :0 to 2:1)] to afford l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e).
• the pure product was dissolved in methanol (10 mL) and added 4 N HC1 (aq.
• Example 4 Large-Scale Synthetic & Crystallization Protocol for Compound I * 2(HC1 )
• Aqueous hydrochloric acid (38.1 kg, 32.3 L, 2.14 equiv.) was charged to a clean and empty crystallization vessel, methanol (228.9 kg, 39.5 equiv.) was added, and the contents were cooled to -7 ⁇ 3°C.
• a solution of Compound I free base (approx. 101.8 kg; 180.9 moles) in MTBE (approx. 1,300 L) was filtered through a polish filter into the crystallization vessel at temperature -5 ⁇ 5°C. After rinse with MTBE, pre-weighed Compound I » 2(HCl) seed crystals (1.39 kg, 0.012 equiv.; Example 3) were charged to the crystallization vessel via the manhole.
• the vessel content was heated to 30-33°C, and the agitation speed was set to 25-50 rpm. After confirmed crystallization, the slurry was agitated for another three to four hours. The product slurry was transferred to centrifuge and isolated by centrifugation. The product was washed with MTBE (585 L). After dry spinning the wet product, Compound I*2(HC1), it was discharged from the centrifuge, and the product was dried at ⁇ 40°C under vacuum in a cone drier. Product Compound I » 2(HCl) yield: 100 kg; 157.4 mol; approx. 85%.
• the XRPD pattern of Compound I » 2(HCl) is shown in Fig. 1.
• Compound I » 2(HCl) has characteristic peaks in its XRPD pattern at values of two theta (°2Q) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.
• TG-IR analysis indicated two, distinct weight loss regions: the first was completed by 125 °C while the second began at approximately 208 °C.
• IR analysis of the off gasses from this experiment detected only trace amounts of water at the initial weight loss while HC1 gas was detected at the 208°C event. No other solvents were detected in the sample.
• Compound I * 2(HC1) completed their respective dose regimens and were available for assessment of PK parameters at either Day 7 or Day 14.
• Plasma Compound I * 2(HC1) concentration versus time profiles on Day 7 after QD oral administration of Compound I * 2(HC1) at 125, 250, and 500 mg QD, and on Day 14 after QD oral administration of Compound I * 2(HC1) at 350 mg QD, are shown in FIG. 3.
• Table 1 provides a summary of plasma pharmacokinetic parameters [the maximum (peak) plasma drug concentration (Cmax), time (observed time point) to reach maximum (peak) plasma drug concentration following drug administration (Tmax), the observed trough plasma concentration at the end of the dosing interval (Ctau), and the area under the plasma concentration-time curve over the dosing interval (AUCtau)] following 7 or 14 days of multiple oral doses of Compound I * 2(HC1).
• Table 1 Summary of plasma pharmacokinetic parameters following 7 or 14 days of multiple oral doses of Compound I * 2(HC1) in healthy subjects (Day 7 or Day 14).

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