Oral pharmaceutical preparations containing 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives

Abstract

Pharmaceutical formulations are provided that include a 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide 12-LOX inhibitor with improved solubility for oral administration. Also provided are pharmaceutical formulations that include a selective 12-LOX inhibitor amorphously dispersed in a material selected from vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), aminomethyl acrylate copolymer (Eudragit EPO), hydroxypropyl methylcellulose E3 (HPMC E3), or a combination thereof, and have a high drug load of 30% or more, comprising 40-80% of the total solid content of the formulation. Alternatively, the formulations contain additives, such as surfactants (sodium lauryl sulfate), crystallization inhibitors, or pH adjusters, in an amount of up to 20% of the total solid content of the formulation.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international patent application claims priority to U.S. Provisional Patent Application No. 63 / 382,032, filed November 2, 2022, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Lipoxygenases are a class of nonheme iron-containing enzymes that regiospecifically and stereospecifically oxidize polyunsaturated fatty acid substrates, such as arachidonic acid (AA) and linoleic acid (LA) (Solomon, et al. Chem. Biol. 1997, 4, 795-808; Brash, J. Biol. Chem. 1999, 274, 23679-23682). The positions at which these cis,cis-1,4-pentadiene substrates are oxidized correspond to the required lipoxygenase activity. Three major human lipoxygenases, 5-LOX, 12-LOX, and 15-LOX-1, oxidize the C-5, C-12, and C-15 positions, respectively. Lipoxygenases are involved in the first critical step in cascades of metabolic pathways, and their products (eicosanoids) are precursors to hormones such as leukotrienes and lipoxins that mediate a wide variety of cellular functions (Serhan, et al. Chem. Rev. 2011, 111, 5922-5943). Consequently, lipoxygenase enzymes and their bioactive metabolites (e.g., hydroxyeicosatetraenoic acid (HETE) and leukotriene A4) have been implicated in various inflammatory diseases and cancer.

[0003] 12-LOX exists as three isoenzymes: platelet, leukocyte, and epidermal; leukocyte 12-LOX is found in rats, mice, pigs, and cattle, but not in humans (Yamamoto Biochim. Biophys. Acta. 1992, 1128, 117-131; Funk et al. FEBS Lett. 1997, 402, 162-166).

[0004] 12-LOX has been demonstrated to play a role in many diseases and / or conditions, such as skin diseases and platelet hemostasis, transplantation / xenotransplantation, cancer (including, but not limited to, prostate cancer, colorectal cancer, breast cancer, and lung cancer), type 1 and type 2 diabetes, diabetic kidney disease (diabetic nephropathy), diabetic neuropathy, diabetic retinopathy, lupus, cardiovascular disease (including, but not limited to, myocardial infarction, congestive heart failure, heart failure, and stroke), thrombosis, heparin-induced thrombocytopenia (HIT), Alzheimer's disease, non-alcoholic steatohepatitis, insulin resistance, and inflammation.

[0005] A 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide-based scaffold was identified and used for medicinal chemistry optimization and biological characterization, as described in Luci, DK. et al. J. Med. Chem. 2014, 57, 495-506 and U.S. Patent Nos. 10,266,488 and 10,752,581. This optimization yielded several highly potent and selective 12-LOX inhibitors, such as N-(benzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide (Compound 1), N-(benzo[d]oxazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide (Compound 2), and 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-isopropylphenyl)benzenesulfonamide (Compound 3).

[0006] A challenge with the therapeutic use of 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide and related 12-LOX inhibitors is their low aqueous solubility (less than 5 μM). There is a need for pharmaceutical formulations of 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide 12-LOX inhibitors.

[0007] Relatively insoluble compounds, i.e., compounds with a water solubility of less than 200 μg / mL, may exhibit promising pharmaceutical activity, but their development as pharmaceuticals presents challenges, especially in oral dosage forms. Non-aqueous solvents can be used in oral pharmaceutical formulations to dissolve water-insoluble drugs. However, these organic solvents, which are considered chemically and biologically inert, may exhibit pharmacological and toxicological effects. These methods are often insufficient to solubilize sufficient amounts of drugs for oral formulations. Furthermore, only therapeutic compounds dissolved in body fluids can penetrate biological barriers and reach their sites of action on proteins or cell surfaces or within specific intracellular structures. Summary of the Invention

[0008] The present application provides pharmaceutical formulations for oral administration, including oral administration, comprising 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide 12-LOX inhibitors. The method of administering these formulations as therapeutic agents in the treatment or prevention of 12-LOX-mediated diseases and disorders by oral administration is preferred.

[0009] In one embodiment, the pharmaceutical formulation comprises: -Compound 1

[0010] [ka] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In one embodiment, the pharmaceutical formulation comprises: -Compound 2

[0012] [ka] or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, and a pharmaceutically acceptable carrier.

[0013] In one embodiment, the pharmaceutical formulation comprises: -Compound 3

[0014] [ka] or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, and a pharmaceutically acceptable carrier.

[0015] In one embodiment, the pharmaceutical formulation comprises a compound of formula (I)

[0016] [ka] (In the formula, R1 is methoxy; R2 is H, R3 can comprise 2-benzothiazole, 4-methyl-2-benzothiazole, 6-fluoro-2-benzothiazole, 6-methoxy-2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 2-thiophene, 4-methyl-2-thiazole, 5-methyl-2-thiazole, 4,5-methyl-2-thiazole, 4-phenyl-2-thiazole, 3-quinoline, 8-isoquinoline, phenyl, 1,4-biphenyl, 1-naphthalene, 2-naphthalene, 3-piperazine-phenyl, 4-piperidine-phenyl, 3-piperidine-phenyl, 2-pyridine, 3-pyridine, 4-piperazine-3-pyridine, 3-tert-butyl-phenyl, 3-morpholine-phenyl, 4N-boc-piperidine-3-phenyl, and 3-isopropyl-phenyl), or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, and a pharmaceutically acceptable carrier.

[0017] In one embodiment, the pharmaceutical formulation can include a pharmaceutically acceptable carrier that is a polymer.

[0018] In one embodiment, the pharmaceutically acceptable carrier is a polymer selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), aminomethacrylate copolymer (Eudragit EPO), hydroxypropylmethylcellulose E3 (HPMC E3), or a combination thereof.

[0019] In one embodiment, the pharmaceutically acceptable carrier is a polymer in an amount of about 40% to 80% of the total solids content. The pharmaceutically acceptable carrier can be a polymer in an amount of about 40% to 60%, 50% to 80%, 40% to 50%, or 60% to 70% of the total solids content. The pharmaceutically acceptable carrier can be polymer in an amount of about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% of the total solids content.

[0020] In one embodiment, the polymer is vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) in an amount of about 40-80% of the total solids content.

[0021] In one embodiment, the compound of formula (I) is present in the pharmaceutical formulations described herein in an amount of about 1 mg to about 1,000 mg. The compound of formula (I) can be present in the pharmaceutical formulations described herein in an amount of about 1 mg to 100 mg, 250 mg to 500 mg, or 250 mg to 750 mg. The compound of formula (I) can be present in the pharmaceutical formulations described herein in an amount of about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 2 30mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375m g, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550 The amount may be 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 625mg, 655mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1,000mg.

[0022] In one embodiment, Compound 1 is present in the pharmaceutical formulations described herein in an amount of about 1 mg to about 1,000 mg. Compound 1 can be present in the pharmaceutical formulations described herein in an amount of about 1 mg to 100 mg, 250 mg to 500 mg, or 250 mg to 750 mg. Compound 1 can be present in the pharmaceutical formulations described herein in an amount of about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230m g, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 30 5mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550m The amount may be 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 625mg, 655mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1,000mg.

[0023] In one embodiment, Compound 2 can be present in the pharmaceutical formulations described herein in an amount of about 1 mg to about 1,000 mg. Compound 2 can be present in the pharmaceutical formulations described herein in an amount of about 1 mg to 100 mg, 250 mg to 500 mg, or 250 mg to 750 mg. Compound 2 can be present in the pharmaceutical formulations described herein in an amount of about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230m g, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 30 5mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550m The amount may be 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 625mg, 655mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1,000mg.

[0024] In one embodiment, Compound 3 can be present in the pharmaceutical formulations described herein in an amount of about 1 mg to about 1,000 mg. Compound 3 can be present in the pharmaceutical formulations described herein in an amount of about 1 mg to 100 mg, 250 mg to 500 mg, or 250 mg to 750 mg. Compound 3 can be present in the pharmaceutical formulations described herein in an amount of about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230m g, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 30 5mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550m The amount may be 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 625mg, 655mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1,000mg.

[0025] In one embodiment, the pharmaceutical formulation may further comprise a pharmaceutically acceptable carrier, additive, excipient, preservative, solvent, buffer, or mixtures thereof.

[0026] In one embodiment, the pharmaceutical formulation may be suitable for oral administration.

[0027] In one embodiment, the pharmaceutical preparation may be formulated for use as a therapeutic agent in the treatment or prevention of 12-LOX mediated diseases and disorders.

[0028] In one embodiment, a pharmaceutical composition for treating or preventing a 12-LOX mediated disease and / or disorder may comprise the pharmaceutical formulation described herein.

[0029] In one embodiment, a pharmaceutical composition for reducing PAR1-AP or PAR4-AP induced platelet aggregation may comprise a pharmaceutical formulation described herein.

[0030] In one embodiment, a pharmaceutical composition for reducing PAR4-AP-induced calcium mobilization may comprise a pharmaceutical formulation described herein.

[0031] In one embodiment, a pharmaceutical composition for reducing PAR4-AP-induced calcium mobilization may comprise a pharmaceutical formulation described herein.

[0032] In one embodiment, the pharmaceutical preparation is formulated for oral administration.

[0033] In one embodiment, a method for treating or preventing a 12-LOX mediated disease and / or disorder may comprise administering to a mammal in need thereof a pharmaceutical formulation described herein.

[0034] In one embodiment, a method for reducing PAR1-AP or PAR4-AP induced platelet aggregation may comprise orally administering to the mammal a pharmaceutical formulation described herein.

[0035] In one embodiment, a method for reducing PAR4-AP-induced calcium mobilization may comprise orally administering to the mammal a pharmaceutical formulation described herein.

[0036] In one embodiment, a method for treating U46619-induced and FcγRIIa-mediated platelet aggregation may comprise orally administering to the mammal a pharmaceutical formulation described herein.

[0037] In one embodiment, the mammal is a human.

[0038] In one embodiment, a subject in need thereof has a 12-LOX mediated disease and / or disorder.

[0039] In one embodiment, the 12-LOX mediated disease and / or condition is selected from the group consisting of skin diseases and platelet hemostasis, transplantation / xenotransplantation, cancer, optionally prostate cancer, colorectal cancer, breast cancer and lung cancer, type 1 and type 2 diabetes, diabetic nephropathy, optionally diabetic nephropathy, diabetic retinopathy, lupus, cardiovascular disease, optionally myocardial infarction, congestive heart failure, heart failure and stroke, thrombosis, heparin-induced thrombocytopenia (HIT), Alzheimer's disease, non-alcoholic steatohepatitis, insulin resistance, and inflammation. The 12-LOX mediated disease and / or condition can be a combination of skin disease and platelet hemostasis, transplantation / xenotransplantation, cancer, optionally prostate, colorectal, breast and lung cancer, type 1 and type 2 diabetes, diabetic nephropathy, optionally diabetic nephropathy, diabetic retinopathy, lupus, cardiovascular disease, optionally myocardial infarction, congestive heart failure, heart failure and stroke, thrombosis, heparin-induced thrombocytopenia (HIT), Alzheimer's disease, non-alcoholic steatohepatitis, insulin resistance, and / or inflammation. [Brief explanation of the drawings]

[0040] [Figure 1] 1 shows microevaporative dissolution analysis of all spray-dried dispersion (SDD) prototypes of Compound 1 in pH 6.8 phosphate buffer. [Figure 2] A comparison of the top spray dried dispersion (SDD) prototype alone with Compound 1 alone is shown. [Figure 3]Mouse PK is shown using Compound 1 alone (triangles) or at an SDD of 30 mg / kg (diamonds) or 100 mg / kg (squares) suspended in 0.5% methylcellulose. DETAILED DESCRIPTION OF THE INVENTION

[0041] definition As used herein, "therapeutically effective amount" refers broadly to an amount of a compound disclosed herein effective in preventing, ameliorating, treating, or delaying the onset of a disease or condition.

[0042] As used herein, a "prophylactically effective amount" refers to an amount of a compound disclosed herein effective to inhibit the development or progression of a disorder.

[0043] The present disclosure is not limited to the specific embodiments described below, as variations of the specific embodiments may be made and still fall within the scope of the appended claims. The terminology used is for the purpose of describing the specific embodiments and is not intended to be limiting.

[0044] 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide derivatives 12-lipoxygenase inhibitors Described herein are oral formulations comprising 12-LOX inhibitors.

[0045] The pharmaceutical formulations described herein comprise a selective 12-lipoxygenase (12-LOX) inhibitor. In one embodiment, the selective 12-LOX inhibitor is a 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide derivative. In a specific embodiment, the 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide derivative is a compound of formula (I):

[0046] [ka] wherein R1 is methoxy, R2 is H, and R3 is selected from the group consisting of 2-benzothiazole, 4-methyl-2-benzothiazole, 6-fluoro-2-benzothiazole, 6-methoxy-2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 2-thiophene, 4-methyl-2-thiazole, 5-methyl-2-thiazole, 4,5-methyl-2-thiazole, 4-phenyl-2-thiazole, 3-quinoline, 8-isoquinoline, phenyl, 1,4-biphenyl, 1-naphthalene, 2-naphthalene, 3-piperazine-phenyl, 4-piperidine-phenyl, 3-piperidine-phenyl, 2-pyridine, 3-pyridine, 4-piperazine-3-pyridine, 3-tert-butyl-phenyl, 3-morpholine-phenyl, 4N-boc-piperidine-3-phenyl, and 3-isopropyl-phenyl.

[0047] In one embodiment, the pharmaceutical formulation comprises Compound 1:

[0048] [ka] or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the pharmaceutical formulation comprises Compound 2:

[0050] [ka] or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the pharmaceutical formulation comprises Compound 3:

[0052] [ka] or a pharmaceutically acceptable salt thereof.

[0053] The pharmaceutical formulations described herein include a compound of formula (I) or a salt, or a combination thereof.

[0054] The present disclosure further relates to pharmaceutical formulations comprising a pharmaceutically acceptable carrier and at least one selective 12-LOX inhibitor compound described herein. In preferred embodiments, the carrier is a polymer, preferably vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), aminomethacrylate copolymer (Eudragit EPO), or hydroxypropylmethylcellulose E3 (HPMC E3).

[0055] Compounds 1, 2, and 3 were previously identified as selective 12-LOX inhibitors, for example, in US Pat. No. 10,266,488.

[0056] [ka]

[0057] These compounds have low solubility in water. The following compares the oral bioavailability of Compound 1 in suspension (Table 1) and solution (Table 2).

[0058] [Table 1]

[0059] [Table 2]

[0060] Intravenous formulations use cyclodextrins (CDs) to enhance solubility. However, drug loadings below 10% are not suitable for oral formulations. We explored new approaches to oral formulation without guidance from the art, including lipid solubility screening in various non-aqueous vehicles, self-microemulsifying systems with oils, surfactants, and cosurfactants, amorphous solid dispersions by hot melt and spray drying, micronization, and in silico screening of supercritical fluid nanoparticle engineering. Minimal improvements in aqueous solubility and dissolution rate were observed in all cases except for non-aqueous vehicles and spray-dried dispersions. While non-aqueous vehicles may offer improved solubility, rapid in vivo precipitation limited oral bioavailability in animals, as seen in Table 2. We found that spray-dried dispersions (SDD) were the most promising technique, improving water solubility by orders of magnitude and demonstrating adequate oral bioavailability in rodent and canine models. Pharmaceutically acceptable carriers can be polymers.

[0061] formulation Surprisingly, the inventors found that most solvents utilized in the prior art did not dissolve Compound 1 to an adequate level for efficient spray drying or polymer:drug loading. THF was the most suitable solvent and could be combined with other solvents, such as acetone, ethanol, and water, to enable dissolution of the drug, polymer, and excipients in the formulation. Furthermore, maximizing drug loading in the amorphous dispersion was essential given the expected dosage of the product. The inventors found that Kollidon VA64, Eudragit EPO, and HPMC E3 enabled drug loadings of 35% or higher in the amorphous dispersion. Surprisingly, higher drug loading levels for Kollidon VA64 and Eudragit EPO improved in vitro dissolution results when comparing 25% and 35% drug loadings (Figure 2). HPMC E3 enabled drug loadings of up to 40%, and in vitro dissolution remained similar at drug loadings of 20–40% in this polymer matrix.

[0062] The formulations include a compound described herein and a weight / weight solid composition of 35% Compound 1:55% Kollidon VA64:10% sodium lauryl sulfate (SLS), 35% Compound 1:65% Eudragit EPO, or 40% Compound 1:60% HMPC E3.

[0063] We found that higher drug loading improved SDD performance (Figure 2). We found that SDD formulations exhibited good animal bioavailability, approximately 14% to 37% in rodents and approximately 50% in dogs. SDD formulations showed a 28- to 100-fold increase in bioavailability compared to suspensions.

[0064] The pharmaceutically acceptable carrier may be a polymer. The pharmaceutical formulations described herein may include a polymer selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), aminomethacrylate copolymer (Eudragit EPO), hydroxypropylmethylcellulose E3 (HPMC E3), or a combination thereof.

[0065] The pharmaceutical formulations described herein may contain polymer in an amount of about 40% to 80% of the total solid content. The pharmaceutical formulations described herein may contain polymer in an amount of about 40% to 60%, 50% to 80%, 40% to 50%, or 60% to 70% of the total solid content. The pharmaceutical formulations described herein may comprise polymer in an amount of about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% of the total solids content.

[0066] The pharmaceutical formulations described herein may contain vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) in an amount of about 40-80% of the total solids content.

[0067] The pharmaceutical formulation may further contain other acceptable carriers or additives in amounts that do not alter the properties of the formulation, including vegetable oils such as peanut oil, cottonseed oil, sesame oil, and the like, as well as organic solvents, glycerol, and surfactants.

[0068] In one embodiment, the pharmaceutical formulation contains at least 30% drug, preferably 35% or more drug, in the final amorphous polymer matrix.

[0069] The compounds described herein can be present in any suitable amount in the pharmaceutical formulations described herein. Those skilled in the art can easily determine the appropriate concentration of the compound to include in the pharmaceutical formulation, depending on various factors, including the dosage and route of administration. The pharmaceutical formulations useful in the present invention can contain an amount of the compounds described herein in an amount effective to treat or prevent the condition, disorder, or disease of the subject being treated.

[0070] A compound described herein, e.g., a compound of Formula (I), optionally Compound 1, Compound 2, Compound 3, or a mixture thereof, may be present in the pharmaceutical formulation in an amount of at least 5%, 10%, 15%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the composition of the final amorphous spray-dried dispersion.

[0071] The compounds described herein may be present in a pharmaceutical formulation in an amount of about 1 mg to 1,000 mg. The compounds described herein may be present in a pharmaceutical formulation in an amount of about 1 mg to 100 mg, 250 mg to 500 mg, or 250 mg to 750 mg. The compounds described herein may be present in a pharmaceutical formulation in an amount of about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 59 65mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg , 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310 mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 3 85mg, 390mg, 395mg, 400mg, 405mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg , 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 625 mg, 655 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1,000 mg.

[0072] The inventors surprisingly discovered that the solubility of Compound 1 is significantly enhanced and maintained in phosphate buffer or simulated intestinal fluid over periods ranging from 10 to 120 minutes. Because solubility is maintained after the initial dissolution event, the compound has time to be absorbed from the gastrointestinal tract.

[0073] Amorphous spray-dried dispersions are produced using standard spray drying techniques known to those skilled in the art. Compound 1: Kollidon VA64: SLS 35:55:10 is prepared by creating a solvent solution containing THF, methanol, and water in a ratio of 90:5:5. Compound 1, Kollidon VA64, and SLS are added to the solvent solution in a ratio of 35:55:10, with a total solids content of 2.65%. The solids are mixed until dissolved, and then spray-dried using a Buchi B-290. The solids are collected and analytically characterized. Eudragit EPO and HPMC E3 formulations are produced using similar techniques known to those skilled in the art.

[0074] The 35:55:10 Compound 1: Kollidon VA64:SLS SDD was administered up to the maximum feasible dose (MFD) of 700 mg / kg due to the viscosity of the suspension and dose volume limitations. No saturation of Cmax or AUC was observed up to the MFD in SDD administration.

[0075] The formulations described herein have demonstrated solid state stability. For example, after 7 months of storage at RT (room temperature (approximately 25°C)), the formulations showed no change in amorphous state. Over 18 months of storage at room temperature still resulted in no change in amorphous state. This stability over a year and a half was unexpected. Furthermore, the formulations demonstrated dose suspension stability. A 3 mg / mL suspension was prepared and analyzed for various quality attributes. After 3 days, there was no change in related substances or crystallinity by XRD.

[0076] In addition to the compounds disclosed herein, pharmaceutical formulations may contain at least one suitable auxiliary agent, including, but not limited to, diluents, crystallization inhibitors, isotonicity agents, water structuring or disintegrating agents, polymers, ion-pairing agents, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. Pharmaceutically acceptable auxiliary agents are preferred. Examples and methods for preparing such sterile solutions are well known in the art and can be found in well-known literature, such as, but not limited to, REMINGTON'S PHARMACEUTICAL SCIENCES (Adejare, Ed., 23rd Edition, Academic Press. (2020); Handbook of Pharmaceutical Excipients, 9th Edition, Pharmaceutical Press (2020)). Pharmaceutically acceptable carriers suitable for the mode of administration, solubility, and / or stability of the compound can be routinely selected.

[0077] Pharmaceutical excipients and additives useful in the pharmaceutical formulations described herein also include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars; and polysaccharides or sugar polymers), which can be present alone or in combination and range from 1 to 99.99% by weight or volume, alone or in combination. Exemplary protein excipients include serum albumins, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, and casein. Exemplary amino acid components that can also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, and aspartame.

[0078] The pharmaceutical formulations described herein may also include additional therapeutic agents, such as argatroban, and may include, but are not limited to, other therapeutic agents or combinations thereof.

[0079] The additional therapeutic agent may be an additional 12-LOX inhibitor. The 12-LOX inhibitor may be an organic compound, an inorganic compound, a biological compound (e.g., a protein or fragment thereof, an antibody or fragment thereof, a nucleic acid, a nucleic acid analog, a sugar, or a peptide), or any combination thereof. The 12-LOX inhibitor may also be synthetic or naturally occurring. Selective 12-LOX inhibitors are described in U.S. Patent Nos. 10,266,488 and 10,752,581.

[0080] The mixing ratio of 12-LOX inhibitors can be optimized to provide the greatest therapeutic effect.

[0081] Additional medications include, but are not limited to, antithrombotic agents such as argatroban, fondaparinux, lepirudin, bivalirudin, danaparoid, and drotrecogin alfa; antidiabetic drugs such as exenatide, albiglutide, pramlintide, semaglutide, lixisenatide, and dulaglutide. Combinations with direct-acting oral anticoagulants, including, but not limited to, apixaban, dabigatran, rivaroxaban, and edoxaban, are also contemplated.

[0082] The formulations can be supplied in unit-dose or multi-dose containers as powder in capsules, powder in bottles, stick packs, or powder in sachets. The formulations can be combined with other external excipients and compressed into tablets or filled into empty capsule shells to produce dosage units. Solutions and suspensions suitable for oral administration can be prepared from spray-dried powders, granules, and tablets. Spray-dried powders can be sprinkled on food or administered with meals.

[0083] Methods of preparing pharmaceutical formulations containing particular amounts of active ingredients will be known to those skilled in the art, or will become apparent in light of this disclosure. Methods of preparing such pharmaceutical formulations may incorporate other suitable pharmaceutical excipients and their formulations, as described in REMINGTON'S PHARMACEUTICAL SCIENCES, supra.

[0084] Methods for preparing the pharmaceutical preparations described herein are manufactured by known methods, including conventional mixing, dissolving, and spray-drying processes.

[0085] Administration and Dosage Those skilled in the art will understand that the pharmaceutically effective amount of the pharmaceutical formulations described herein administered to a patient in need thereof can be determined empirically or by standards currently recognized in the medical field. It will be understood that when administered to a human patient, the total daily dosage of the compounds described herein will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors: the type and extent of cellular response to be achieved; the activity of the specific agent or composition used; the specific agent or composition used; the patient's age, weight, general health, sex, and diet; the time, route of administration, and excretion rate of the agent; the duration of treatment, drugs used in combination with or concurrently with the specific agent; and similar factors well known in the medical field. It is well within the skill of one of ordinary skill in the art to initiate dosages of an agent at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0086] The administration route and effective dose of the pharmaceutical formulation containing the compound are also disclosed. The preferred administration route is oral. The pharmaceutical formulations described herein can be administered in unit dosage form as a powder in a capsule, a powder in a bottle, a stick pack, or a powder in a sachet. The formulations can be combined with other external excipients and compressed into tablets or filled into empty capsule shells to produce dosage units. The compounds described herein can be administered in combination with other pharmaceuticals in various protocols to effectively treat diseases.

[0087] The pharmaceutical formulations can be administered in a single daily dose, or the total daily dose can be administered in divided doses two, three, or four times daily. Doses can be administered for a week, a month, or several months, over 3, 6, 9, or 12 months, or at intervals known in the art and deemed clinically relevant. For example, the pharmaceutical formulations described herein can be administered for 7, 14, 21, 28, or 35 days. The daily dosage of the formulations can vary over a wide range, from about 1 to about 1,000 mg per patient per day, more specifically, from about 200 to about 700 mg, preferably about 600 mg per day. The dosage range, as determined by a physician, can be adjusted to achieve clinically relevant plasma and / or serum concentrations.

[0088] Specifically, the pharmaceutical formulations described herein can be administered at least once a day for several weeks, months, or years. In one embodiment, the pharmaceutical formulations are administered at least once a day for several weeks to several months. In one embodiment, the pharmaceutical formulations are administered once a day for at least one year or more.

[0089] In one embodiment, the pharmaceutical formulations described herein may be administered orally. An oral dosage may include about 1 to 1,000 mg of a 12-LOX inhibitor in the pharmaceutical formulation. The oral dosage of the 12-LOX inhibitor described herein may be about 10 to 100 mg, 250 to 500 mg, 750 to 1,000 mg, or 500 to 750 mg. Oral dosages of the 12-LOX inhibitors described herein may be about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, The dosage may be 00, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1,000 mg.

[0090] The pharmaceutical formulations described herein can be administered to any animal that can experience the beneficial effects of the compounds of the invention, with administration to humans being preferred.

[0091] The dosage administered will depend upon the age, health, and weight of the recipient, type of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0092] Therapeutic and preventative methods for 12-LOX-mediated diseases / disorders The present disclosure further provides a method for treating or preventing a 12-LOX-mediated disease or disorder, comprising administering to a mammal a therapeutically or prophylactically effective amount of a pharmaceutical formulation described herein.

[0093] The 12-LOX-mediated diseases or disorders to be treated or prevented are typically diseases or disorders in which the production of 12-hydroxyeicosatetraenoic acid (12-HETE) is involved in the onset or progression of the disease or disorder. 12-LOX-mediated diseases and disorders include those in which 12-LOX is a direct mediator of the disease or disorder, and those in which inhibition of 12-LOX provides a therapeutic effect in the treatment or prevention of the disease or disorder.

[0094] Methods for treating or preventing a 12-LOX-mediated disease or disorder can include administering to a mammal a therapeutically or prophylactically effective amount of any of the compounds of formula (I), or a salt thereof, in a pharmaceutical formulation. In one embodiment, the compound in the formulation is Compound 1.

[0095] In one embodiment, the 12-LOX is human 12-LOX.

[0096] The 12-LOX mediated disease or disorder may be selected from the group consisting of type 1 diabetes, type 2 diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, lupus, cardiovascular disease, Alzheimer's disease, non-alcoholic steatohepatitis, platelet hemostasis, skin disease, heparin-induced thrombocytopenia, thrombosis, and cancer.

[0097] The cancer may be selected from the group consisting of prostate cancer, colorectal cancer, breast cancer, and lung cancer. In one embodiment, the cancer is a hematological cancer.

[0098] The cardiovascular disease may be selected from the group consisting of congestive heart failure, myocardial infarction, and stroke. The cardiovascular disease may be a mixture of congestive heart failure, myocardial infarction, and stroke.

[0099] A method for treating or preventing type 1 and / or type 2 diabetes can include administering to a mammal a therapeutically or prophylactically effective amount of any of the compounds described herein, e.g., a compound of formula (I), Compound 1, Compound 2, Compound 3, or a mixture thereof, or a salt thereof, in a pharmaceutical formulation.

[0100] A method for treating or preventing thrombosis can include orally administering to the mammal a pharmaceutical formulation containing a therapeutically or prophylactically effective amount of any of the compounds described herein, or salts thereof.

[0101] A method for reducing PAR1-AP or PAR4-AP-induced platelet aggregation may include orally administering to the mammal a pharmaceutical formulation described herein containing a therapeutically or prophylactically effective amount of any of the compounds described herein, e.g., a compound of formula (I), compound 1, compound 2, compound 3, or a mixture thereof, or a salt thereof.

[0102] A method for reducing PAR4-AP-induced calcium mobilization may include orally administering to the mammal a pharmaceutical formulation containing a therapeutically or prophylactically effective amount of any of the compounds described herein, or a salt thereof.

[0103] A method for treating U46619-induced and FcγRIIa-mediated platelet aggregation may comprise orally administering to the mammal a pharmaceutical formulation comprising a therapeutically or prophylactically effective amount of any of the compounds described herein, or a salt thereof.

[0104] 12-LOX inhibitors can be used, for example, in transplantation / xenotransplantation procedures where pancreatic islets are treated ex vivo prior to transplantation to improve survival.

[0105] Methods for treating or preventing a disease or disorder involving the FcγRIIa-mediated pathway are provided, comprising orally administering a pharmaceutical formulation described herein. Such diseases or disorders may be immune-mediated thrombocytopenia and thrombotic disorders. Examples of immune-mediated thrombocytopenia and thrombotic disorders include, but are not limited to, heparin-induced thrombocytopenia (HIT), antiphospholipid syndrome, sepsis syndrome, therapeutic or diagnostic monoclonal antibody-associated thrombosis, and thrombotic thrombocytopenic purpura. In some aspects, methods for inhibiting platelet activation and methods for preventing or treating thrombosis are disclosed herein.

[0106] The method for inhibiting or reducing platelet activation can comprise contacting platelet with a pharmaceutical preparation comprising an effective amount of the compound described herein.In some embodiments, platelet activation is immune-mediated.In some embodiments, immune-mediated platelet activation is caused by the activation of FcγRIIa receptor.

[0107] The method for treating or preventing thrombotic events, myocardial infarction or stroke can comprise orally administering to a subject in need thereof a pharmaceutical preparation comprising an effective amount of the compound described herein.Immune-mediated platelet activation can lead to thrombus formation, which can cause arterial clotting and lead to stroke, myocardial infarction, organ infarction, limb gangrene, or other serious complications.

[0108] The subject may exhibit one or more risk factors for immune-mediated thrombocytopenia and thrombosis disorders. The subject may be undergoing or have recently undergone heparin therapy. The subject may have undergone orthopedic surgery. It is known in the art that orthopedic surgery patients are at a higher risk of developing HIT than patients receiving heparin for other medical reasons.

[0109] A method for treating or preventing a 12-LOX-mediated disease and / or disorder can involve administering a pharmaceutical formulation containing Compound 1, Compound 2, Compound 3, or a combination thereof to a subject in need thereof. The subject in need thereof can be a mammal. In a preferred embodiment, the subject in need thereof is a human.

[0110] The 12-LOX-mediated disease and / or disorder can be type 1 diabetes, type 2 diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, lupus, cardiovascular disease, Alzheimer's disease, nonalcoholic steatohepatitis, platelet hemostasis, skin disease, heparin-induced thrombocytopenia, thrombosis, or cancer.

[0111] A method for treating a patient suffering from immune-mediated thrombocytopenia can include administering to a subject in need thereof a pharmaceutical formulation comprising Compound 1, Compound 2, Compound 3, or a combination thereof.

[0112] A method for treating a patient suffering from a thrombotic disorder, comprising orally administering to a subject in need thereof a pharmaceutical formulation comprising Compound 1, Compound 2, Compound 3, or a combination thereof.

[0113] Formulation method The compounds described herein, eg, compounds of formula (I), eg, Compound 1, Compound 2, and Compound 3, exhibit poor solubility in water.

[0114] While preferred embodiments have been illustrated and described in detail herein, various modifications, additions, and substitutions can be made thereto without departing from the spirit of the invention, and are therefore deemed to be within the scope of the invention as defined in the following claims. Moreover, to the extent not already indicated, it will be understood by those skilled in the art that any one of the various embodiments described and illustrated herein can be further modified to incorporate features shown in any of the other embodiments disclosed herein.

[0115] The following examples illustrate embodiments and aspects of the present invention. It will be apparent to those skilled in the relevant art that various modifications, additions, and substitutions can be made without changing the spirit or scope of the present invention, and such modifications and variations are encompassed within the scope of the present invention as defined in the following claims. The following examples are not intended to limit the present invention in any way. [Example]

[0116] Example 1 Development of an oral formulation of compound 1 Previously, all oral administration of Compound 1 was performed using 100% PEG 300 as the vehicle. While this vehicle was sufficient for short-term efficacy studies, we needed a more robust and clinically relevant formulation for the longer-term dosing regimens required for the mouse efficacy model. To date, we have tested doses of Compound 1 as a suspension in 0.5% methylcellulose, but oral bioavailability in both mice and rats was less than 5%. These results necessitated the testing of alternative formulations, such as amorphous spray-dried dispersions (SDDs), which formulate Compound 1 with different polymers to improve solubility and oral bioavailability.

[0117] We used an approach that included solvent screening, analytical method development, polymer matrix and excipient screening, aqueous solubility and stability assessment, drug loading and yield optimization, and pharmacokinetic (PK) studies in rodents.

[0118] The solubility in organic solvents relevant for spray drying was investigated (Table 1) and showed that THF with EtOH in water was preferred (85 / 10 / 5).

[0119] [Table 3]

[0120] Next, a number of different polymer systems were screened with varying drug loadings and surfactants to determine which provided the best dissolution. These studies showed that Compound 1: Kollidon VA64: SLS (35:55:10) significantly improved the dissolution of Compound 1, as compared to Compound 1 alone in Figures 1 and 2.

[0121] Compound 1: Kollidon VA64:SLS (35:55:10) SDD was scaled up to approximately 65 g, which was sufficient for the PK and efficacy studies outlined below. Stability studies demonstrated no change after 18 months of room temperature storage. Furthermore, as a 3 mg / mL solution, no changes in related substances or crystallinity by XRD were observed after 3 days.

[0122] Example 2 PK parameters and dose linearity in mice We identified an SDD formulation with significantly improved dissolution in vitro (Figures 1 and 2) and confirmed that this improvement was observed in vivo (Figure 3). We performed PK studies in mice and rats using a formulation of Compound 1:KollidonVA64:SLS (35:55:10). Oral exposure in mice was significantly improved, as shown in Figure 3 and Table 4.

[0123] [Table 4]

[0124] Example 3 Preparation of spray-dried dispersions A Buchi B-290 spray dryer was used to generate spray-dried prototypes of Compound 1. The formulations of the spray-dried dispersions are reported in Table 5.

[0125] [Table 5]

[0126] The target amounts of THF, MeOH, and water were dispensed into an appropriately sized container and the mixer was turned on to create a vortex. The target amount of Compound 1 was added to the container. The solution was mixed until all of the API was dissolved. The API solution was passed through a 200 mesh screen. The target amounts of Kollidon VA64 and SLS were added to the container. The solution was mixed until all of the polymer and SLS were dissolved. In 6, the solution was spray dried using the following parameters:

[0127] [Table 6]

[0128] The spray-dried dispersion recovered from the spray dryer was dried using a conventional heat oven at 40°C for 12 hours (secondary drying). Samples were collected before and after drying for residual solvent (THF, MeOH) content. The dried material was characterized for assay, impurities, p-XRD, and DSC.

[0129] Taken together, these data demonstrate that we have successfully designed a clinically relevant formulation of Compound 1 that can be utilized for efficacy studies and therapeutic purposes. The formulation is not only stable and well-tolerated, but also provides excellent exposure of Compound 1 in mice, as shown in Table 4. In addition to examining PK in mice, we tested Compound 1 in rats and dogs. Compound formulations were specifically relevant in GLP toxicity studies. These studies revealed excellent and reproducible exposure in both rats and dogs (F% 20-50%). We were surprisingly able to administer up to 700 mg / kg in rats.

[0130] All references cited herein are incorporated by reference to the same extent as if each reference was specifically and individually indicated to be incorporated by reference. The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by virtue of prior invention.

[0131] It will be understood that each of the above-described elements, or two or more together, may find useful application in other types of methods different from those described above. Without further analysis, the foregoing description makes the gist of the present disclosure sufficiently clear that others, by applying their current knowledge, can readily adapt the present disclosure to various applications without omitting features that, in view of the prior art, constitute essential features of the general or specific aspects of the present disclosure as set forth in the appended claims. The foregoing embodiments are presented by way of example only. The scope of the present disclosure is limited only by the following claims.

Claims

1. 1. A pharmaceutical formulation comprising: -Compound 1 【Chemical 1】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. 1. A pharmaceutical formulation comprising: -Compound 2 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, and a pharmaceutically acceptable carrier.

3. 1. A pharmaceutical formulation comprising: -Compound 3 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, and a pharmaceutically acceptable carrier.

4. Compounds of formula (I): 【Chemistry 4】 (In the formula, R １ is methoxy, R ２ is H, R ３ are 2-benzothiazole, 4-methyl-2-benzothiazole, 6-fluoro-2-benzothiazole, 6-methoxy-2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 2-thiophene, 4-methyl-2-thiazole, 5-methyl-2-thiazole, 4,5-methyl-2-thiazole, 4-phenyl-2-thiazole, 3-quinoline, 8-isoquinoline, phenyl, 1,4-biphenyl, 1-naphthalene, 2-naphthalene 1. A pharmaceutical formulation comprising a compound selected from the group consisting of 4-N-boc-piperazine-3-phenyl, 3-piperazine-phenyl, 4-piperidine-phenyl, 3-piperidine-phenyl, 2-pyridine, 3-pyridine, 4-piperazine-3-pyridine, 3-tert-butyl-phenyl, 3-morpholine-phenyl, 4N-boc-piperidine-3-phenyl, and 3-isopropyl-phenyl), or a pharmaceutically acceptable salt, or a diastereomer thereof, and a pharmaceutically acceptable carrier.

5. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the pharmaceutically acceptable carrier is a polymer.

6. 6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the pharmaceutically acceptable carrier is a polymer selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), aminomethacrylate copolymer (Eudragit EPO), hydroxypropylmethylcellulose E3 (HPMC E3), or a combination thereof.

7. 7. The pharmaceutical formulation of any one of claims 1 to 6, wherein the pharmaceutically acceptable carrier is a polymer in an amount of about 40% to 80% of the total solid content.

8. 8. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable carrier is a polymer in an amount of about 40% to 60%, 50% to 80%, 40% to 50%, or 60% to 70% of the total solids content.

9. 9. The pharmaceutical formulation of any one of claims 1 to 8, wherein the pharmaceutically acceptable carrier is a polymer in an amount of about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% of the total solids content.

10. 10. The pharmaceutical formulation according to any one of claims 1 to 9, wherein the polymer is vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) in an amount of about 40-80% of the total solids content.

11. The pharmaceutical formulation of any one of claims 1 to 10, wherein the compound of formula (I) is in an amount of about 1 mg to about 1,000 mg.

12. 12. The pharmaceutical formulation of any one of claims 1 to 11, wherein the compound of formula (I) is in an amount of about 1 mg to 100 mg, 250 mg to 500 mg, or 250 mg to 750 mg.

13. The compound of formula (I) may be administered in the form of a dose of about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg , 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240m g, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315m g, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390 mg, 395mg, 400mg, 405mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein the amount of the compound is 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 625 mg, 655 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1,000 mg.

14. 14. The pharmaceutical formulation of any one of claims 1 to 13, wherein Compound 1, Compound 2, Compound 3, or a combination thereof is in an amount of about 1 mg to about 1,000 mg.

15. 15. The pharmaceutical formulation of any one of claims 1 to 14, wherein Compound 1, Compound 2, Compound 3, or a combination thereof is in an amount of about 1 mg to 100 mg, 250 mg to 500 mg, or 250 mg to 750 mg.

16. Compound 1, Compound 2, Compound 3, or a combination thereof, is administered in an amount of about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg g, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 31 0mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385 mg, 390mg, 395mg, 400mg, 405mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg , 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 625 mg, 655 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1,000 mg.

17. The pharmaceutical formulation of any one of claims 1 to 16, wherein the formulation further comprises a pharmaceutically acceptable carrier, additive, excipient, preservative, solvent, buffer, or a mixture thereof.

18. The pharmaceutical formulation according to any one of claims 1 to 17, wherein the formulation is suitable for oral administration.

19. 19. The pharmaceutical preparation of any one of claims 1 to 18, formulated for use as a therapeutic agent in the treatment or prevention of 12-LOX mediated diseases and disorders.

20. A pharmaceutical composition for treating or preventing 12-LOX mediated diseases and / or disorders, comprising the pharmaceutical formulation of any one of claims 1 to 19.

21. A pharmaceutical composition for reducing PAR1-AP or PAR4-AP-induced platelet aggregation, comprising the pharmaceutical preparation according to any one of claims 1 to 19.

22. A pharmaceutical composition for reducing PAR4-AP-induced calcium mobilization, comprising the pharmaceutical formulation according to any one of claims 1 to 19.

23. A pharmaceutical composition for reducing PAR4-AP-induced calcium mobilization, comprising the pharmaceutical formulation according to any one of claims 1 to 19.

24. The pharmaceutical composition according to any one of claims 20 to 23, wherein the pharmaceutical preparation is formulated for oral administration.

25. A method for treating or preventing 12-LOX mediated diseases and / or disorders, comprising administering the pharmaceutical formulation of any one of claims 1 to 19 to a mammal in need thereof.

26. A method for reducing PAR1-AP or PAR4-AP induced platelet aggregation, comprising orally administering to said mammal the pharmaceutical formulation of any one of claims 1 to 19.

27. A method for reducing PAR4-AP induced calcium mobilization, comprising orally administering to said mammal the pharmaceutical formulation of any one of claims 1 to 19.

28. A method for treating U46619-induced and FcγRIIa-mediated platelet aggregation, comprising orally administering to said mammal a pharmaceutical formulation according to any one of claims 1 to 18.

29. The method of any one of claims 25 to 28, wherein the mammal is a human.

30. The method of any one of claims 25 to 29, wherein the subject in need thereof has a 12-LOX mediated disease and / or disorder.

31. 31. The method of any one of claims 25 to 30, wherein the 12-LOX mediated disease and / or condition is selected from the group consisting of skin diseases and platelet hemostasis, transplantation / xenotransplantation, cancer, optionally prostate, colorectal, breast and lung cancer, type 1 and type 2 diabetes, diabetic nephropathy, optionally diabetic nephropathy, diabetic retinopathy, lupus, cardiovascular diseases, optionally myocardial infarction, congestive heart failure, heart failure and stroke, thrombosis, heparin-induced thrombocytopenia (HIT), Alzheimer's disease, non-alcoholic steatohepatitis, insulin resistance, and inflammation, etc.

Images