12-Lipoxygenase inhibitors for treating lupus

Abstract

Methods for treating lupus using a therapeutically effective amount of a selective 12-lipoxygenase inhibitor are disclosed. In some embodiments, the 12-lipoxygenase inhibitor is N-(benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide or a related benzylsulfonamide compound.

Description

[Background technology]

[0001] Lupus is a chronic autoimmune disease that causes systemic inflammation in multiple organs. The etiology of lupus is unknown, but it is suspected to result from multiple causes, including genetics, biological sex (women are more affected than men), and environmental factors. Lupus is typically characterized by active acute exacerbations followed by periods of remission. Lupus affects the skin and joints, but can also affect other organs, including the kidneys, pleura, pericardium, and brain. Skin symptoms include rash, hair loss, and stomatitis, which may worsen with exposure to sunlight. Joint symptoms include swollen and stiff joints and arthritis. Lupus-associated kidney damage includes lupus nephritis and urinary system disorders, including proteinuria. While lupus does not commonly affect the brain, patients with brain involvement have reported headaches, dizziness, and seizures. Lupus patients also often have low red blood cell counts. Inflammation of the pleura of the heart and lungs and the pericardium causes pleurisy and pericarditis in lupus patients. Lupus patients generally feel unwell and tired, and may lose weight.

[0002] Types of lupus include, for example, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE) (CLE includes, for example, acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), intermittent cutaneous lupus erythematosus, and chronic cutaneous lupus), lupus nephritis, drug-induced lupus, and neonatal lupus. Approximately 70% of all lupus cases are SLE. In patients with CLE, symptoms are generally limited to the skin. More than 90% of lupus patients are women.

[0003] Lupus is commonly treated with NSAIDs, steroids, immunosuppressants, and hydroxychloroquine in combination with lifestyle modifications such as diet and sun protection to avoid acute exacerbations. There is a growing need for effective treatments.

[0004] Lipoxygenases are a group 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; Blash, 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 committed steps in cascades of metabolic pathways, and their products (eicosanoids) are precursors to hormones such as leukotrienes and lipoxins that mediate a wide range of cellular functions (Serhan, et al. Chem. Rev. 2011, 111, 5922-5943). As such, lipoxygenase enzymes and their bioactive metabolites (e.g., hydroxyeicosatetraenoic acid (HETE) and leukotriene A4) have been implicated in certain inflammatory diseases and cancer.

[0005] 12-Lipoxygenase (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; Fink et al. FEBS Lett. 1997, 402, 162-166). Specifically, 12-LOX has been implicated in a variety of conditions, including cancer, type I and type II diabetes (including diabetic kidney disease and diabetic neuropathy), thrombosis (including heparin-induced thrombocytopenia or HIT), inflammatory diseases, neuronal damage associated with acute ischemic stroke, skin diseases, transplantation, Alzheimer's disease, Fc region receptor (FcγRIIa)-mediated platelet activation, PAR4-AP-induced platelet aggregation, antiphospholipid syndrome; sepsis syndrome; immunoglobulin gamma Fc region receptor (FcγRIIa)-associated thrombocytopenia, and nonalcoholic steatohepatitis (NASH). Exemplary 12-LOX inhibitors used to treat the above diseases or conditions are described in U.S. Patent Nos. 10,266,488, 10,752,581, and 11,274,077. The 12(S)-lipoxygenase inhibitor N-(1,3-benzothiazol-2-yl)-4-[(2-hydroxy-3-methoxyphenyl)methylamino]benzenesulfonamide (ML355) and certain of its analogs prevent thrombosis in vitro and in vivo (see, e.g., Adili et al. Arterioscler Thromb Vasc Biol. 2017;37:1828).

[0006] There remains a need for treatments for lupus that have not previously been shown to be linked to 12-LOX. Summary of the Invention

[0007] The present invention provides a method for treating or preventing lupus, comprising administering to a mammal a therapeutically or prophylactically effective amount of a selective 12-LOX inhibitor.

[0008] In a specific embodiment, the method comprises administering to a subject a selective 12-LOX inhibitor compound of formula (I):

[0009] [ka] wherein R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, F, Cl, Br, amine, nitrogen dioxide, indole, alkoxy, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, F, Cl, Br, hydroxyl, amine, and methoxy;

[0010] R3 is selected from the group consisting of phenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, thiazole, benzothiazole, benzoxazole, imidazole, benzimidazole, thiophene, 1-naphthalene, 2-naphthalene, pyridine, quinoline, isoquinoline, 4N-boc-piperidine-3-phenyl, oxazole, benzothiophene, parathiazine, furan, pyran, chromene, benzofuran, pyrrole, pyrazole, pyrazine, pyrimidine, triazine, indole, purine, and phthalazine, each of which is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, F, Cl, Br, hydroxyl, amine, alkoxy, phenyl, cycloalkyl, aryl, piperazine, piperidine, pyridine, morpholine, pyrrolidine, pyrazolidine, imidazolidine, and thiomorpholine.

[0011] Alternatively, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof may be used.

[0012] In specific embodiments, R3 is 2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 4-methyl-2-benzothiazole, 2-thiophene, 4-methyl-2-thiazole, 5-methyl-2-thiazole, 5-phenyl-2-thiazole, 4,5-dimethyl-2-thiazole, phenyl, 1-naphthalene, 2-naphthalene, 1,4-biphenyl, 3-piperazine-phenyl, 4-piperazine-phenyl, 4-piperidine-phenyl, 4-piperazine-3-pyridine, 6-methyl- Selected from the group consisting of 3-pyridine, 3-quinoline, 8-isoquinoline, 2-pyridine, 3-pyridine, 3-tert-butyl-phenyl, 6-methoxy-2-benzothiazole, 6-fluoro-2-benzothiazole, 4-phenyl-2-thiazole, 3-morpholine-phenyl, 4N-boc-piperidine-3-phenyl, 3-piperidine-phenyl, 3-isopropyl-phenyl, 3-methoxy-phenyl, 5-methyl-3-isoxazole, 2-pyrimidine, and 1,3-bi-phenyl.

[0013] In another embodiment, the compound of formula (II):

[0014] [ka] wherein X is selected from the group consisting of O, S, NH, and C; R1 and R2 are independently selected from the group consisting of H, halogen, hydroxyl, alkoxy, and alkyl; R3 to R6 are independently selected from the group consisting of H, halogen, hydroxyl, alkoxy, and alkyl. or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0015] In another aspect, the present invention provides a compound of formula (III):

[0016] [ka] wherein R1 and R2 are independently selected from the group consisting of H, halogen, and alkoxy; and further wherein R1 and R2 are not both H; R4 and R5 are independently selected from the group consisting of H, alkyl, phenyl, and optionally substituted phenyl. or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0017] In another aspect, the present invention provides a compound of formula (IV):

[0018] [ka] wherein R1 and R2 are independently selected from the group consisting of H, halogen, and alkoxy; R3 and R4 are independently H, phenyl, optionally substituted phenyl, tert-butyl, isopropyl, and

[0019] [ka] is selected from the group consisting of X is NH, O and

[0020] [ka] selected from the group consisting of or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0021] In one embodiment, R4 is

[0022] [ka] If X is not NH, then

[0023] In another aspect, the present invention provides a compound of formula (V):

[0024] [ka] wherein X is selected from the group consisting of N, C, S, and O; R1-R6 are independently selected from the group consisting of H, alkyl, and alkoxy. or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0025] In one embodiment, X is C and R1-R6 are H.

[0026] In one embodiment, X is N and R1-R6 are H. In another aspect, the present invention provides a compound of formula (VI):

[0027] [ka] wherein X is selected from the group consisting of N, C, S, and O; R1-R6 are independently selected from the group consisting of H, alkyl, and alkoxy. or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0028] In one embodiment, X is C and R1-R6 are H.

[0029] In one embodiment, X is N and R1-R6 are H.

[0030] In another aspect, the present invention provides a compound of formula (VII):

[0031] [ka] wherein X is selected from the group consisting of N, C, S, and O; R1-R3 are independently selected from the group consisting of H, alkyl, and alkoxy. or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0032] In certain embodiments, the 12-LOX inhibitor is

[0033] N-(benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide,

[0034] N-(benzo[d]oxazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0035] N-(1H-benzo[d]imidazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0036] 4-(2-hydroxy-3-methoxybenzylamino)-N-(thiophen-2-yl)benzenesulfonamide,

[0037] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(5-phenylthiazol-2-yl)benzenesulfonamide,

[0038] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-methoxyphenyl)benzenesulfonamide,

[0039] 4-(2-hydroxy-3-methoxybenzylamino)-N-(isoquinolin-8-yl)benzenesulfonamide,

[0040] 4-(2-hydroxy-3-methoxybenzylamino)-N-phenylbenzenesulfonamide,

[0041] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-1-yl)benzenesulfonamide,

[0042] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-2-yl)benzenesulfonamide,

[0043] N-([1,1'-biphenyl]-4-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0044] N-([1,1'-biphenyl]-3-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0045] N-(3-(tert-butyl)phenyl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0046] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(6-methoxybenzo[d]thiazol-2-yl)benzenesulfonamide,

[0047] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-phenylthiazol-2-yl)benzenesulfonamide,

[0048] tert-butyl 4-(3-(4-((2-hydroxy-3-methoxybenzyl)amino)phenylsulfonamido)phenyl)piperidine-1-carboxylate,

[0049] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-isopropylphenyl)benzenesulfonamide,

[0050] N-(6-fluorobenzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0051] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-(piperazin-1-yl)phenyl)benzenesulfonamide,

[0052] 4-(2-hydroxy-3-methoxybenzylamino)-N-(4-(piperazin-1-yl)phenyl)benzenesulfonamide, and

[0053] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-(piperidin-4-yl)phenyl)benzenesulfonamide,

[0054] or a pharmaceutically acceptable salt thereof.

[0055] In another embodiment, the 12-LOX inhibitor is N-(benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide.

[0056] In one embodiment, the lupus is systemic lupus erythematosus.

[0057] In another embodiment, the 12-lipoxygenase inhibitor is formulated for parenteral administration.

[0058] In certain embodiments, the 12-lipoxygenase inhibitor is dissolved in a hydroxyalkylated β-cyclodextrin.

[0059] In another embodiment, the 12-lipoxygenase inhibitor is formulated for oral administration.

[0060] In a further embodiment, the present invention provides a method of treating lupus with (2S,3S,4S,5R,6S)-6-(2-(((4-(N-(benzo[d]thiazol-2-yl)sulfamoyl)phenyl)amino)methyl)-6-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (a metabolite of ML-355, also known as ML-355 glucuronide), or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0061] It is to be understood that this invention is not limited to the particular methods described herein, as these may vary, and that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to limit the scope of the invention.

[0062] For therapeutic use, the "salts" of the compounds of the invention are physiologically acceptable, i.e., they are derived from a physiologically acceptable acid or base. However, salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. Accordingly, all salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.

[0063] "Diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers differ in physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical techniques such as electrophoresis and chromatography.

[0064] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0065] The term "pharmaceutically acceptable carrier," as used herein, refers to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents known in the art for use with pharmaceutical active substances. Except insofar as any conventional media or agent is incompatible with the compound, its use in the therapeutic compositions is contemplated.

[0066] The phrase "therapeutically effective amount" refers to an amount of a compound disclosed herein that is effective in preventing, ameliorating, treating, or delaying the onset of a disease or condition and / or inhibiting the onset or progression of a disorder. This term also includes reduction or amelioration of one or more symptoms.

[0067] "Alkyl" is a C1-C6 hydrocarbon having normal, secondary, tertiary, or cyclic carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, tert-butyl, etc.

[0068] An "alkenyl" is a C2-C6 hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-CH5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0069] An "alkynyl" is a C2-C6 hydrocarbon having normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Examples include, but are not limited to, acetylenyl (-C≡CH) and propargyl (-CH2C≡CH).

[0070] "Cycloalkyl" refers to a saturated, unsaturated, or aromatic ring system having, for example, 3 to 8 carbon atoms, preferably 3 to 7 carbon atoms, and more preferably 3 to 6 carbon atoms. Examples include, but are not limited to, cyclopentenyl and cyclohexenyl. Cyclic alkyl groups can be unsubstituted or further substituted.

[0071] "Heterocycloalkyl" refers to a saturated, unsaturated, or aromatic ring system containing at least one N, O, S, or P. Thus, heterocycles encompass heteroaryl groups. As used herein, heterocycles include, but are not limited to, those described in Paquette, Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky et al., Comprehensive Heterocyclic Chemistry (Pergamon Press, 1996); and 82 J. Am. Chem. Soc. 5566 (1960).Exemplary heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxide tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isoquinolinyl isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, isothiazolyl, isoxozolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, a Examples include quinuclidinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

[0072] "Aryl" means a monovalent aromatic hydrocarbon radical of 6 to 20 carbon atoms derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Common aryl groups include, but are not limited to, benzene, substituted benzene, naphthalene, anthracene, biphenyl, etc.

[0073] "Heteroaryl" means a monovalent aromatic radical derived by removing a hydrogen atom from a carbon atom of a parent aromatic ring system, and composed of one or more carbon atoms and one or more atoms selected from N, O, S, or P. Heteroaryl groups can be monocyclic rings having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), or bicyclic rings having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). Heteroaryl bicyclic rings have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 heteroatoms selected from N and S) arranged as a bicyclo[5,6] or [6,6] system. Heteroaryl groups can be attached to the drug scaffold via a stable covalent bond through carbon, nitrogen, sulfur, phosphorus, or other atoms. Heteroaryl groups include, but are not limited to, pyridyl, dihydropyridyl isomers, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.

[0074] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although preferred methods and compositions are described, methods and compositions similar or equivalent to those described herein can also be used in the practice or testing of the present invention.

[0075] 12-lipoxygenase inhibitors In one embodiment, the present invention provides a method for treating lupus, comprising administering to a mammal a therapeutically or prophylactically effective amount of either a 12-LOX inhibitor compound.

[0076] A compound or agent is considered a 12-LOX inhibitor if it reduces the function or activity of 12-LOX by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. 12-LOX inhibitors can be organic compounds, inorganic compounds, biological compounds (e.g., proteins or fragments thereof, antibodies or fragments thereof, nucleic acids, nucleic acid analogs, saccharides, or peptides), or any combination thereof. 12-LOX inhibitors can be synthetic or naturally occurring.

[0077] In one embodiment, the 12-LOX inhibitor is selective for 12-LOX and has little or no activity against other LOX isoforms, such as 15-LOX.

[0078] Exemplary selective 12-LOX inhibitors are described in U.S. Patent Nos. 10,266,488, 10,752,581, and 11,274,077, and include ML-355. These compounds are described herein. The methods of the present invention further include ML-355 glucuronide, a metabolite of ML-355, whether or not it is a 12-lipoxygenase inhibitor.

[0079] Other non-limiting 12-LOX inhibitors include ETYA (CAS No.: 1191-85-1), baicalein (CAS No.: 491-67-8), 15(S)-HETrE (CAS No.: 13222-49-6), caffeic acid (CAS No.: 331-39-5), CDC (CAS No.: 132465-11-3), esculetin (CAS No.: 305-01-1), ethyl 3,4-dihydroxybenzylidenecyanoacetate (CAS No.: 1 Examples of suitable hydroxybenzoates include hydroxybenzoates (CAS No. 32464-92-7), ETI (CAS No. 13488-22-7), ferulic acid (CAS No. 1135-24-6), gossypol (CAS No. 303-45-7), 2-TEDC (CAS No. 132465-10-2), hinokitiol (CAS No. 499-44-5), 8,11,14-eicosatrienoic acid (CAS No. 34262-64-1), daphnodrin A, ML355, and combinations thereof. The chemical structure of ML355 is described in Luci et al. (J. Med. Chem. 2014, 57, 495-506), the entire contents of which are incorporated by reference.

[0080] 12-LOX inhibitors are also disclosed in, for example, US20130096159, WO1990012008, US6217875, US4605669, US4623661, CA1327204, US20070111965, US4897422, US20060193797, US5120752, US5112848, US5574062, EP0416609, US4822811, EP0456760, US4761403, JP2013526576A, the contents of each of which are incorporated herein by reference for their teachings of 12-LOX inhibitors.

[0081] In specific embodiments, the 12-LOX inhibitor compound is a compound of Formula (I)-(VII) described herein, or a salt, enantiomer, mixture of enantiomers, or diastereomer thereof.

[0082] In certain embodiments, exemplary 12-LOX inhibitors for the treatment of lupus are described in US 10,266,488 and include the following compounds:

[0083] N-(benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide,

[0084] N-(benzo[d]oxazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0085] N-(1H-benzo[d]imidazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0086] 4-(2-hydroxy-3-methoxybenzylamino)-N-(thiophen-2-yl)benzenesulfonamide,

[0087] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(5-phenylthiazol-2-yl)benzenesulfonamide,

[0088] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-methoxyphenyl)benzenesulfonamide,

[0089] 4-(2-hydroxy-3-methoxybenzylamino)-N-(isoquinolin-8-yl)benzenesulfonamide,

[0090] 4-(2-hydroxy-3-methoxybenzylamino)-N-phenylbenzenesulfonamide,

[0091] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-1-yl)benzenesulfonamide,

[0092] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-2-yl)benzenesulfonamide,

[0093] N-([1,1'-biphenyl]-4-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0094] N-([1,1'-biphenyl]-3-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0095] N-(3-(tert-butyl)phenyl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0096] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(6-methoxybenzo[d]thiazol-2-yl)benzenesulfonamide,

[0097] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-phenylthiazol-2-yl)benzenesulfonamide,

[0098] tert-butyl 4-(3-(4-((2-hydroxy-3-methoxybenzyl)amino)phenylsulfonamido)phenyl)piperidine-1-carboxylate,

[0099] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-isopropylphenyl)benzenesulfonamide,

[0100] N-(6-fluorobenzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0101] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-(piperazin-1-yl)phenyl)benzenesulfonamide,

[0102] 4-(2-hydroxy-3-methoxybenzylamino)-N-(4-(piperazin-1-yl)phenyl)benzenesulfonamide, and

[0103] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-(piperidin-4-yl)phenyl)benzenesulfonamide,

[0104] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0105] In a preferred embodiment, the compound is ML-355 (N-(benzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide).

[0106] In another embodiment, the compound is ML-355 glucuronide.

[0107] It is further understood that the above compounds and salts may form solvates or may exist in substantially uncomplexed forms, such as anhydrous forms. When the solvent incorporated in the solvate is water, the molecular complex is a hydrate. Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitriles, and the like. These compounds may also exist in polymorphic forms. Formulation, Administration, and Dosage

[0108] The present invention further relates to treating lupus, or a symptom thereof, by administering to a patient in need thereof at least one compound of Formulas (I)-(VII) described herein. Routes of administration and effective dosages for pharmaceutical compositions containing the compounds are also disclosed. The compounds of the present invention can be administered in combination with other pharmaceutical agents in various protocols to effectively treat the disease. formulation

[0109] In addition to the compounds disclosed herein, the pharmaceutical compositions of the present disclosure can further comprise at least one of any suitable auxiliary agent, including, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, and the like. Pharmaceutical compositions containing the compounds, their salts and hydrates can be prepared by any method well known in the pharmaceutical art. Generally, such preparative methods include the step of bringing into association the 12-LOX inhibitor or a pharmaceutically acceptable salt thereof with the carrier or excipient, and / or one or more accessory ingredients, and then shaping and / or packaging the product into a desired single or multiple dose unit, as necessary and / or desired.

[0110] In any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules. This can be achieved by conventional protecting groups such as those described in Protective Groups In Organic Chemistry (1973); and Greene and Wuts, Protective Groups In Organic Synthesis (1991). The protecting groups can be removed at a convenient subsequent stage using methods well known in the art.

[0111] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions of the invention may vary depending on the nature, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. The compositions used in the methods of the invention may contain 0.001% to 100% (w / w), 0.01% to 100%, 0.01% to 75%, 0.01% to 50%, 0.01% to 25%, 0.01% to 10%, and 0.01 to 5% of the active ingredient.

[0112] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may contain a diluent. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0113] In certain embodiments, the pharmaceutical composition used in the method of the present invention may contain a granulating agent and / or dispersing agent. Exemplary granulating agents and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate, sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0114] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may contain a binder. Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish mist, panwar gum, ghatti gum, psyllium mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate, and larch-derived arabogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, wax, water, alcohol, and / or mixtures thereof.

[0115] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may contain a preservative. Non-limiting examples of preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0116] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention can include an antioxidant. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0117] In certain embodiments, the pharmaceutical composition used in the method of the present invention may contain a chelating agent. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antibacterial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0118] In certain embodiments, the pharmaceutical composition may contain a buffering agent together with the 12-LOX inhibitor or its salt. Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluvate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0119] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may contain a lubricant. Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0120] Parenteral Dosage Forms In one embodiment, the novel compounds described herein can be administered in parenteral dosage forms. As used herein, the term "parenteral" includes, but is not limited to, subcutaneous injections, intravenous, intramuscular, intraperitoneal injection, or infusion techniques.

[0121] In one embodiment, the parenteral pharmaceutical formulations described herein comprise a compound described herein and a pharmaceutically acceptable carrier.

[0122] In one embodiment, a parenteral pharmaceutical formulation can contain a liquid carrier comprising a vegetable oil, such as peanut oil, cottonseed oil, or sesame oil, as well as organic solvents, PEG, propylene glycol, glycerol, and surfactants. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents, such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0123] In another embodiment, the parenteral pharmaceutical formulation is aqueous. In one embodiment, the aqueous parenteral pharmaceutical formulation comprises at least 50% water, preferably 70% or more water.

[0124] In another embodiment, the pharmaceutical carrier comprises a solubilizing agent, hi certain embodiments, the solubilizing agent is a 2-hydroxyalkylated β-cyclodextrin, such as hydroxyethyl β-CD, hydroxypropyl-β-CD, hydroxybutyl β-CD, or sulfobutylether-β-cyclodextrin.

[0125] The pharmaceutically acceptable 2-hydroxyalkylated β-cyclodextrin can be present in any suitable amount in the aqueous parenteral pharmaceutical formulations described herein. The pharmaceutically acceptable 2-hydroxyalkylated β-cyclodextrin can be present in an amount of about 5% to 50% w / v. For example, the pharmaceutically acceptable solubilizer, optionally HP-β-CD, can be present in an amount of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w / v. In certain embodiments, HP-β-CD can be present in an amount of about 10% to about 40%, about 20% to about 40%, about 30% to about 40%, about 10% to about 30%, or about 10% to about 20% of the total formulation. In one embodiment, the 2-hydroxyalkylated β-cyclodextrin can be present in an amount of about 25% w / v of the total formulation.

[0126] For parenteral administration, sterile solutions and suspensions are preferred.If intravenous administration is desired, isotonic preparations containing suitable preservatives are generally used.Pharmaceutical preparations can be parenterally administered by injection of pharmaceutical preparations containing the compound dissolved in an inert liquid carrier such as sterile water or other pharmaceutically acceptable diluents.

[0127] Pharmaceutical compositions or formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of sterile liquid carriers, such as water for injection, saline, dextrose in water (D5W), and lactated Ringer's solution, immediately prior to use. Extemporaneous preparation immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above.

[0128] Parenteral formulations may further comprise at least one of any suitable auxiliary agent, including, but not limited to, diluents, crystallization inhibitors, tonicity agents, water structure-forming or -disrupting agents, polymers, ion-pairing agents, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, and the like. Pharmaceutically acceptable auxiliary agents are preferred. Examples and methods for preparing such sterile solutions are well known in the art and include, but are not limited to, REMINGTON'S PHARMACEUTICAL SCIENCES (Adejare, Ed., 123rd Edition, Academic Press. (2020)), Handbook of Pharmaceutical Excipients, 9 th Edition, Pharmaceutical Press (2020)). Pharmaceutically acceptable carriers can be selected in a conventional manner to suit the administration route, solubility, and / or stability of the compound.

[0129] Pharmaceutical excipients and additives useful in the parenteral pharmaceutical formulations described herein include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides such as monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derived sugars such as alditols, aldonic acids, and esterified sugars; and polysaccharides or sugar polymers), which may be present alone or in combination in amounts ranging from 1 to 99.99% by weight or volume. Examples of 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.

[0130] Carbohydrate excipients suitable for the pharmaceutical formulations described herein for parenteral administration include, but are not limited to, monosaccharides such as dextrose, fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides such as lactose, sucrose, trehalose, and cellobiose; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, and starch; and alditols such as mannitol, xylitol, maltitol, lactitol, sorbitol (glucitol), and myo-inositol.

[0131] Pharmaceutical formulations containing the compounds described herein may also contain a pH adjuster. The pH adjuster may be a base, optionally sodium hydroxide. The pH adjuster may also be an acid, optionally hydrochloric acid.

[0132] In one embodiment, the present disclosure provides stable parenteral pharmaceutical formulations, as well as preserved solutions and formulations containing preservatives, and multi-purpose preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one compound disclosed herein in a pharmaceutically acceptable formulation. Pharmaceutical formulations according to the present disclosure may optionally contain at least one known preservative. Preservatives include, but are not limited to, aqueous diluents containing phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparabens (methyl, ethyl, propyl, butyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof. Any suitable concentration or mixture known in the art can be used, e.g., 0.001-5%, or any range or value therein. Non-limiting examples include no preservatives, 0.1-2% m-cresol, 0.1-3% benzyl alcohol, 0.001-0.5% thimerosal, 0.001-2.0% phenol, 0.0005-1.0% alkylparaben(s).

[0133] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservatives, may also be added. When used, the amount of osmolality adjusters most frequently used ranges from 0.1 to 1% (w / v). Non-limiting examples of osmolality adjusters include sodium chloride, glycerin, boric acid, calcium chloride, dextrose, and potassium chloride. The formulation may contain a local anesthetic to alleviate potential pain during injection. If necessary, a physiologically acceptable buffer may be added to improve pH control. Pharmaceutical formulations may encompass a wide range of pH, such as from about pH 4 to about pH 10, specifically from about pH 5 to about pH 9, and more specifically from about pH 7.0 to about pH 9.0. In one embodiment, the pH of the formulations described herein is from about 8.4 to about 8.7.

[0134] The compositions of the present invention can be administered parenterally in the form of liposomes. As is well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes can be used. The compositions of the present invention in the form of liposomes can contain stabilizers, preservatives, excipients, etc. in addition to the peptide inhibitors of the present invention. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are well known in the art (see Prescott, ed., Meth. Cell Biol. 14:33 (1976)). Liposomes, methods for their manufacture, and methods of use are described in U.S. Pat. Nos. 4,089,8091 (process for preparing liposomes), 4,233,871 (methods relating to biologically active substances in lipid vesicles), 4,438,052 (process for preparing mixed micelles), 4,485,054 (large multilamellar vesicles), 4,532,089 (giant liposomes and methods therefor), 4,897,269 (liposomal drug delivery systems), and 5,820,880 (liposomal formulations).

[0135] Intravenous administration can include bolus or sustained release. For example, a single bolus can be administered, multiple divided doses can be administered over time, or the dose can be relatively reduced or increased depending on the exigencies of the therapeutic situation. Parenteral compositions can be advantageously formulated in dosage unit form for ease of administration and uniformity of dosage.

[0136] Oral Dosage Forms Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, dragees, sachets or tablets each containing a predetermined amount of the compound; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; as an oil-in-water or water-in-oil emulsion; as a bolus, and the like.

[0137] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch, or tapioca starch, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0138] Suitable pharmaceutically acceptable excipients for oral dosage forms include corn starch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose, and similar substances. Pharmaceutical compositions containing compounds and / or their salts can contain one or more pharmaceutically acceptable excipients known in the art. Formulations include oral films, orally disintegrating tablets, effervescent tablets, and granules or beads that can be sprinkled on food or mixed with liquid as a slurry or poured directly into the mouth.

[0139] For oral administration, the compositions can also optionally contain sweeteners, including, but not limited to, sucrose, fructose, sodium saccharin, sucralose (SPLENDA®), sorbitol, mannitol, aspartame, sodium cyclamate, and the like, and combinations thereof.

[0140] The oral compositions of the present invention include sustained-release or controlled-release formulations. These can be, for example, diffusion-controlled formulations, dissolution-controlled formulations, disintegration formulations, osmotic pump systems, or ionic resin systems. Diffusion-controlled systems contain water-insoluble polymers that control the flow of water and subsequently release the dissolved drug from the dosage form. Dissolution-controlled products control the dissolution rate of the drug by using slowly dissolving polymers or by microencapsulating the drug with varying thicknesses to control release. Disintegration formulations control drug release by the rate of disintegration of the carrier matrix. Osmotic pump systems release the drug based on the constant influx of water through a semipermeable membrane into a reservoir containing an osmotic agent. Using ion-exchange resins to bind the drug allows for controlled drug release via the ionic environment in the digestive tract upon swallowing.

[0141] Tablets can be produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be produced by compressing a free-flowing compound, such as a powder or granules, mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant in a suitable machine. Molded tablets can be produced by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide sustained or controlled release of the compound contained therein.

[0142] In other embodiments, pharmaceutical compositions containing a 12-LOX inhibitor or a salt thereof are administered as a liquid oral dosage form. Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain auxiliary substances such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with a solubilizing agent, such as Cremophor™, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0143] The aqueous suspensions, emulsions and / or elixirs for oral administration of the present invention may be formulated with various sweeteners, flavoring agents (such as, but not limited to, orange or lemon flavor), coloring agents (such as dyes, natural colors or pigments), in addition to diluents such as water, glycerin, and various combinations thereof, as described herein.

[0144] Topical and Mucosal Dosage Forms Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops, or other ophthalmic formulations, or other forms known to those skilled in the art. Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or oral gels.

[0145] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide the topical and mucosal dosage forms encompassed herein are well known to those skilled in the art of pharmaceuticals and depend on the specific tissue to which a particular pharmaceutical composition or dosage form is to be applied. In one embodiment, excipients include, but are not limited to, non-toxic, pharmaceutically acceptable excipients such as water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions, or gels. Wetting agents or humectants can also be added to pharmaceutical compositions and dosage forms.

[0146] The pharmaceutical preparations described herein can be prepared by known methods, including conventional mixing, dissolving, or lyophilization processes. Thus, an aqueous pharmaceutical composition can be obtained by combining an active compound with a solid excipient, optionally adding suitable auxiliary agents for solid dosage forms, if desired or necessary, followed by grinding the resulting mixture and processing the granular mixture.

[0147] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of the active ingredient is approximately equal to the dose of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dose, such as, for example, one-half or one-third of such a dose.

[0148] Administration The pharmaceutical compositions of the present invention can be administered to any animal that can benefit from the beneficial effects of the compounds of the present invention. Such animals include humans and non-human animals such as domestic animals (e.g., dogs). In a preferred embodiment, the patient is a human.

[0149] The present invention further relates to administering at least one compound disclosed herein by routes including, but not limited to, oral, parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intraperitoneal, intra-articular capsule, intrachondral, intracavity, intra-cerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, intravaginal, intrarectal, buccal, sublingual, intranasal, iontophoretic, or transdermal means.

[0150] The pharmaceutical compositions of the present invention are administered to a subject by methods well known in the art, and the dosage administered will depend on the age, health, and weight of the recipient, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the effect desired.

[0151] Dosage In general, the compounds disclosed herein can be used alone or in combination with other therapeutic agents at appropriate dosages determined by routine testing to achieve optimal efficacy while minimizing potential toxicity. Pharmaceutical formulations useful in the present invention can contain a compound(s) according to the present invention in an amount effective to treat or prevent the condition, disorder, or disease of the subject being treated. As a non-limiting example, human or veterinary therapeutic agents can be administered in a one-time or periodic dose of a compound of the present invention at a dose of 0.0001 to about 50,000 mg per patient per day. More specifically, the range can be about 0.001 mg / kg to 500 mg / kg, about 0.1 to 500 mg / kg, 0.1 to 100 mg / kg, about 1.0 to 100 mg / kg, about 1.0 to 75 mg / kg, about 1.0 to 50 mg / kg, about 1.0 to 25 mg / kg, or about 1.0 to 10 mg / kg per kg of body weight per day for an adult (approximately 60 kg). Furthermore, the dosage can be about 0.5-10 mg / kg per day, about 1.0-5.0 mg / kg per day, 5.0-10 mg / kg per day, or an equivalent dose determined by a physician to achieve a clinically meaningful serum concentration.

[0152] Dosage regimens using 12-LOX can be selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal or hepatic function, and the particular compound being used. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0153] Optimal precision in achieving a drug concentration within a range that provides maximum efficacy with minimal toxicity may require a regimen based on the kinetics of compound availability to one or more target sites. Drug distribution, equilibrium, and excretion can be considered when determining the optimal concentration for a treatment regimen. The dosage of the compounds disclosed herein can be adjusted when combined to achieve the desired effect. On the other hand, the dosages of these various therapeutic agents can be independently optimized and combined to achieve synergistic results, resulting in less pathology than when either agent is used alone.

[0154] In particular, the toxicity and therapeutic efficacy of the compounds disclosed herein are measured, for example, by LD 50 (50% lethal dose of the population) and ED 50 The LD (the dose at which 50% of a population is therapeutically effective) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 The therapeutic index can be expressed as a ratio of . Compounds with a large therapeutic index are preferred unless the cytotoxicity of the compound is the desired activity or therapeutic outcome. Compositions that exhibit toxic side effects can be used, but targeting such compounds to the site of the affected tissue via a delivery system can minimize the potential for damage to uninfected cells, thereby reducing side effects. In general, the compounds of the present invention can be administered in a manner that maximizes efficacy and minimizes toxicity.

[0155] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably administered at an ED400 dose with little or no toxicity. 50 The therapeutically effective dose of any compound used in the methods of the invention can be estimated initially from cell culture assays. A dose can be formulated in animal models to compare the IC20 determined in cell culture with the IC10 determined in cell culture. 50 A circulating plasma concentration range that includes the concentration of the test compound that achieves half-maximal inhibition of symptoms can be obtained. This information can be used to accurately determine useful doses in humans. Plasma concentrations can be measured by high performance liquid chromatography.

[0156] More specifically, the pharmaceutical composition may be administered in a single dose per day, or the total daily dose may be administered in divided doses two, three, or four times per day. Doses may be administered over a period of one week, one month, or several months, 3, 6, 9, or 12 months, or at intervals known in the art, such as during acute exacerbations, as deemed clinically meaningful. Because lupus is a chronic disease, administration of 12-LOX inhibitors may continue throughout the patient's lifetime.

[0157] Combination therapy In another embodiment of the present invention, the compounds of the present invention can be co-administered to a patient in need thereof with another active ingredient with known side effects for treating lupus, including systemic lupus erythematosus. Such agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, antibodies, antimalarials, and immunosuppressants. Examples of such agents include conventional NSAIDs, COX-2 inhibitors, and salicylates (such as aspirin). Antimalarials include, but are not limited to, chloroquine, hydroxychloroquine, chloroquine phosphate, mefloquine, halofantrine, doxycycline, proguanil, quinidine gluconate, artesunate, atovaquone, primaquine and primaquine phosphate, and quinacrine. Corticosteroids include, but are not limited to, prenisone, betamethasone, methylprednisolone acetate, hydrocortisone, and dexamethasone. Immunosuppressants include, but are not limited to, methotrexate, cyclophosphamide, azathioprine, voclosporin, and mycophenolate mofetil.

[0158] Exemplary antibodies include, but are not limited to, anti-CD6 antibodies, anti-CD20 antibodies, anti-CD28 antibodies, anti-IL12 antibodies, anti-IL23 antibodies, anti-BDCA2 antibodies, anti-CD52 antibodies, anti-CD74 antibodies, rituximab, aniflomab, and belimumab, or combinations thereof.

[0159] The additional therapeutic agent may be solubilized or suspended in the pre-concentrate (before dilution with the diluent), added to the pre-concentrate before dilution, added to the pre-concentrate after dilution, or added to the diluent before mixing with the pre-concentrate. The additional therapeutic agent may also be co-administered as part of a separate dosage form to achieve a therapeutic effect. Optionally, the additional therapeutic agent(s) may be present in a first solubilized amount and a second solubilized (suspended) amount. Such additional therapeutic agent(s) may be any agent(s) that has a therapeutic or other effect when administered to an animal, particularly a mammal, such as drugs, nutrients, and diagnostic agents.

[0160] Treatment effect The methods of the invention can be used to treat patients with one or more symptoms of lupus, including, but not limited to, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, central nervous system (CNS) lupus, cardiovascular symptoms, pulmonary symptoms, hepatic symptoms, hematologic symptoms, gastrointestinal symptoms, musculoskeletal symptoms, neonatal lupus erythematosus, pediatric systemic lupus erythematosus, drug-induced lupus erythematosus, or complement deficiency syndromes resulting in lupus symptoms.

[0161] Exemplary symptoms associated with lupus that can be prevented, alleviated, or ameliorated using a 12-LOX inhibitor include, but are not limited to, joint pain and stiffness; muscle aches, pain, or weakness, fever; fatigue; skin symptoms (e.g., skin erythema, including "butterfly" rash); abnormal weight loss or weight gain; anemia; neurological or neuropsychiatric symptoms (e.g., thought disorder, memory loss, confusion, depression, headache, seizures, stroke); kidney damage (e.g., nephritis, e.g., glomerulonephritis); chest pain; sun or light sensitivity; hair loss; Raynaud's phenomenon. vascular lesions or other vascular symptoms), as well as biological concomitants of lupus disclosed herein or known in the art (e.g., immune complexes, elevated levels of cytokines (e.g., interferons (e.g., type I interferons, e.g., IFN-α and / or IFN-β), interleukins (e.g., IL-6, IL-8, IL-1, and IL-18) and TNF-α), elevated levels of lupus-associated antibodies (e.g., antinuclear antibodies (e.g., anti-Smith antibodies, anti-double-stranded DNA (dsDNA) antibodies, anti-U1 RNP, SS-a (or anti-Ro), SS-b (or anti-La), antiphospholipid antibodies, anti-ssDNA antibodies, anti-histone antibodies, or anticardiolipin antibodies), and overexpression of IFN-inducible genes.

[0162] According to some embodiments, treatment of lupus with a 12-LOX inhibitor compound of the present disclosure results in improved renal function, a decrease in serum anti-dsDNA antibody levels, a decrease in serum anticardiolipin antibody levels, an increase in serum complement factor C3 levels, and an increase in serum complement factor C4 levels. Each possibility represents a separate embodiment of the present invention.

[0163] Without wishing to be bound by any theory or mechanism, it is believed that administration of the compositions of the present invention to a subject with lupus may increase the expression of Toll-like receptor 9 and / or pro-inflammatory cytokines, including, but not limited to, CD19 in the patient. + / CD27 + This can result in decreased expression of IL-1, IL-6, IL-17 and interferon-γ in B cells.

[0164] A reduction in acute exacerbations or the length of time between acute exacerbations compared to before treatment with a 12-LOX inhibitor is also considered a treatment outcome.

[0165] While preferred embodiments have been shown and described in detail herein, it will be apparent to those skilled in the art that various modifications, additions, substitutions, and the like may be made without departing from the spirit of the invention, and are therefore deemed to be within the scope of the invention as defined in the claims that follow. Furthermore, those skilled in the art will understand that, unless already indicated, any one of the various embodiments described and shown herein can be further modified to incorporate features shown in any of the other embodiments disclosed herein.

[0166] All patents and other publications cited throughout this specification, including but not limited to literature references, issued patents, published patent applications, and pending patent applications, are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodology described in such publications that might be used in connection with the technology described herein.

[0167] The following examples illustrate some embodiments and aspects of the present invention. It will be apparent to those skilled in the art that various modifications, additions, substitutions, etc. can be made without altering 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.

[0168] The technology described herein is further illustrated by the following examples, which should not be construed as further limiting in any way.

Claims

1. A method for treating or preventing lupus, comprising administering to a patient in need thereof an effective amount of a selective 12-lipoxygenase inhibitor and a pharmaceutically acceptable carrier.

2. The 12-lipoxygenase inhibitor is a compound of formula (I): 【Chemical 1】 (In the formula, R １ and R ２ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, F, Cl, Br, amine, nitrogen dioxide, indole, alkoxy, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each of which is selected from the group consisting of C １ ~C ６ Alkyl, C １ ~C ６ Alkenyl, C １ ~C ６ optionally substituted with one or more substituents selected from the group consisting of alkynyl, F, Cl, Br, hydroxyl, amine, and methoxy; R ３ is selected from the group consisting of phenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, thiazole, benzothiazole, benzoxazole, imidazole, benzimidazole, thiophene, 1-naphthalene, 2-naphthalene, pyridine, quinoline, isoquinoline, 4N-boc-piperidine-3-phenyl, oxazole, benzothiophene, parathiazine, furan, pyran, chromene, benzofuran, pyrrole, pyrazole, pyrazine, pyrimidine, triazine, indole, purine, and phthalazine, each of which is selected from the group consisting of C １ ~C ６ Alkyl, C １ ~C ６ Alkenyl, C １ ~C ６ optionally substituted with one or more substituents selected from the group consisting of alkynyl, F, Cl, Br, hydroxyl, amine, alkoxy, phenyl, cycloalkyl, aryl, piperazine, piperidine, pyridine, morpholine, pyrrolidine, pyrazolidine, imidazolidine, and thiomorpholine; or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

3. R ３ However, 2-benzothiazole, 2-benzoxazole, 2-benzimidazole, 4-methyl-2-benzothiazole, 2-thiophene, 4-methyl-2-thiazole, 5-methyl-2-thiazole, 5-phenyl-2-thiazole, 4,5-dimethyl-2-thiazole, phenyl, 1-naphthalene, 2-naphthalene, 1,4-biphenyl, 3-piperazine-phenyl, 4-piperazine-phenyl, 4-piperidine-phenyl, 4-piperazine-3-pyridine, 6-methyl-3-pyridine, 3-quinolinyl 3. The method of claim 2, wherein the aryl group is selected from the group consisting of 2-pyrimidine, 8-isoquinoline, 2-pyridine, 3-pyridine, 3-tert-butyl-phenyl, 6-methoxy-2-benzothiazole, 6-fluoro-2-benzothiazole, 4-phenyl-2-thiazole, 3-morpholine-phenyl, 4N-boc-piperidine-3-phenyl, 3-piperidine-phenyl, 3-isopropyl-phenyl, 3-methoxy-phenyl, 5-methyl-3-isoxazole, 2-pyrimidine, and 1,3-bi-phenyl.

4. The 12-LOX inhibitor is N-(benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide, N-(benzo[d]oxazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide, N-(1H-benzo[d]imidazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide, 4-(2-hydroxy-3-methoxybenzylamino)-N-(thiophen-2-yl)benzenesulfonamide, 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(5-phenylthiazol-2-yl)benzenesulfonamide, 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-methoxyphenyl)benzenesulfonamide, 4-(2-hydroxy-3-methoxybenzylamino)-N-(isoquinolin-8-yl)benzenesulfonamide, 4-(2-hydroxy-3-methoxybenzylamino)-N-phenylbenzenesulfonamide, 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-1-yl)benzenesulfonamide, 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-2-yl)benzenesulfonamide, N-([1,1'-biphenyl]-4-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide, N-([1,1'-biphenyl]-3-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide, N-(3-(tert-butyl)phenyl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide, 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(6-methoxybenzo[d]thiazol-2-yl)benzenesulfonamide, 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-phenylthiazol-2-yl)benzenesulfonamide, tert-butyl 4-(3-(4-((2-hydroxy-3-methoxybenzyl)amino)phenylsulfonamido)phenyl)piperidine-1-carboxylate, 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-isopropylphenyl)benzenesulfonamide, N-(6-fluorobenzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide, 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-(piperazin-1-yl)phenyl)benzenesulfonamide, 4-(2-hydroxy-3-methoxybenzylamino)-N-(4-(piperazin-1-yl)phenyl)benzenesulfonamide, and 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-(piperidin-4-yl)phenyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

5. 2. The method of claim 1, wherein the 12-lipoxygenase inhibitor is N-(benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide.

6. The method according to any one of claims 1 to 5, wherein the lupus is systemic lupus erythematosus.

7. The method of any one of claims 1 to 6, wherein the 12-lipoxygenase inhibitor is formulated for parenteral administration.

8. 8. The method of claim 7, wherein the 12-lipoxygenase inhibitor is dissolved in a hydroxyalkylated β-cyclodextrin.

9. 10. The method of claim 1, wherein the treatment is amelioration of one or more symptoms of lupus.

10. 10. The method of claim 9, wherein the condition is lupus nephritis.

11. A method for treating or preventing lupus, comprising administering to a patient in need of such treatment or prevention an effective amount of (2S,3S,4S,5R,6S)-6-(2-(((4-(N-(benzo[d]thiazol)-2-yl)sulfamoyl)phenyl)amino)methyl)-6-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

12. 12. The method of claim 11, wherein the lupus is systemic lupus erythematosus.

13. 13. The method of claim 12, wherein the treatment is the amelioration of one or more symptoms of systemic lupus erythematosus.

14. 14. The method of claim 13, wherein the condition is lupus nephritis.

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