12-lipoxygenase inhibitors for treatment of lupus

Abstract

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

Description

Background of the Invention

[0002] Lupus is a chronic autoimmune disease that causes systemic inflammation in multiple organs. The cause of lupus is unknown, but multiple factors are suspected, including genetics, sex (women are more susceptible than men), and environmental factors. Lupus is typically characterized by active flare-ups followed by periods of remission. Lupus can affect the skin and joints, as well as other organs, including the kidneys, pleura, pericardium, and brain. Skin problems include rashes, hair loss, and mouth ulcers, which may be exacerbated by sun exposure. Joint problems include swelling, stiffness, and arthritis. Kidney problems associated with lupus include lupus nephritis and urinary tract problems (including proteinuria). Although symptoms such as headaches, dizziness, and seizures have been reported in lupus patients with brain damage, lupus rarely affects the brain. People with lupus also often have low red blood cell counts. Inflammation of the pleura and pericardium of the heart and lungs in lupus patients leads to pleurisy and pericarditis. People with lupus often feel unwell and fatigued, and lose weight.

[0003] 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. For CLE patients, symptoms are usually limited to the skin. More than 90% of lupus patients are women.

[0004] Lupus is typically treated with NSAIDs, steroids, immunosuppressants, and hydroxychloroquine, along with lifestyle changes such as diet and sun protection to avoid flare-ups. There is a growing need for effective treatments.

[0005] Lipoxygenases are a class of enzymes containing non-heme iron that regio- 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 essential lipoxygenases. The three major human lipoxygenases are 5-LOX, 12-LOX, and 15-LOX-1, which oxidize at the C-5, C-12, and C-15 positions, respectively. Lipoxygenases are involved in the first step of a series of metabolic pathways, and the products of these enzymes (eicosanoic acids) are precursors of hormones such as leukotrienes and lipoxins, which mediate a variety of cellular functions (Serhan et al. Chem. Rev. 2011, 111, 5922-5943). Therefore, lipoxygenases and their bioactive metabolites (such as hydroxyeicosatetraenoic acid (HETE) and leukotriene A4) are associated with certain inflammatory diseases and cancer.

[0006] 12-Lipoxygenase (12-LOX) exists as three isoenzymes: platelet-type, leukocyte-type, and epidermal-type. Leukocyte-type 12-LOX is present 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). In particular, 12-LOX is associated with a variety of conditions, such as cancer, type I and type II diabetes (including diabetic nephropathy 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; thrombocytopenia associated with immunoglobulin gamma Fc region receptor (FcγRIIa) and non-alcoholic steatohepatitis (NASH). Exemplary 12-LOX inhibitors for the treatment of the aforementioned 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 have been shown to prevent thrombosis in vitro and in vivo. See, for example, Adili et al. Arterioscler Thromb Vasc Biol. 2017;37:1828.

[0007] There is an ongoing need for treatment of lupus, but no link has been found between lupus and 12-LOX. Summary of the Invention

[0008] The present invention provides a method for treating or preventing lupus, comprising administering a therapeutically or prophylactically effective amount of a selective 12-LOX inhibitor to a mammal.

[0009] In a specific embodiment, a selective 12-LOX inhibitory compound of formula (I) is used in the method:

[0010]

[0011] 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, 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;

[0012] 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-piperidin-3-phenyl, oxazole, benzothiophene, p-thiazine, furan, pyran, chroman, benzofuran, pyrrole, pyrazole, pyrazine, pyrimidine, triazine, indole, purine, phthalazine; 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, alkoxy, phenyl, cycloalkyl, aryl, piperazine, piperidine, pyridine, morpholine, pyrrolidine, pyrazolidine, imidazolidine and thiomorpholine;

[0013] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0014] In a specific embodiment, R3 is selected from the group consisting of 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-piperidinyl-phenyl, 4-piperazine-3-ylpiperidinyl, 4-piperidinyl-phenyl, 4-piperidinyl-3-ylpiperidinyl ... -pyridine, 6-methyl-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-morpholino-phenyl, 4N-boc-piperidin-3-phenyl, 3-piperidin-phenyl, 3-isopropyl-phenyl, 3-methoxy-phenyl, 5-methyl-3-isoxazole, 2-pyrimidine and 1,3-biphenyl.

[0015] In another embodiment, a method of treating lupus with a compound of formula (II) is provided:

[0016]

[0017] wherein X is selected from the group consisting of O, S, NH and C:

[0018] wherein R1 and R2 are independently selected from the group consisting of H, halogen, hydroxy, alkoxy and alkyl;

[0019] wherein R3 to R6 are independently selected from the group consisting of H, halogen, alkoxy and alkyl;

[0020] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0021] In another aspect, the present invention includes compounds of formula (III):

[0022]

[0023] wherein R1 and R2 are independently selected from the group consisting of H, halogen, and alkoxy, and wherein R1 and R2 are not both H;

[0024] wherein R4 and R5 are independently selected from the group consisting of H, alkyl, phenyl, and optionally substituted phenyl;

[0025] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0026] In another aspect, the present invention includes compounds of formula (IV):

[0027]

[0028] wherein R1 and R2 are independently selected from the group consisting of H, halogen, and alkoxy;

[0029] wherein R3 and R4 are independently selected from H, phenyl, optionally substituted phenyl, tert-butyl, isopropyl and The group composed of

[0030] wherein X is selected from NH, O and the group formed;

[0031] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0032] In one embodiment, when R4 is When X is not NH.

[0033] In another aspect, the present invention includes compounds of formula (V):

[0034]

[0035] wherein X is selected from the group consisting of N, C, S and O;

[0036] wherein R1 to R6 are independently selected from the group consisting of H, alkyl and alkoxy;

[0037] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0038] In one embodiment, X is C and R1 to R6 are H.

[0039] In one embodiment, X is N and R1 to R6 are H. In another aspect, the present invention includes compounds of formula (VI):

[0040]

[0041] wherein X is selected from the group consisting of N, C, S and O;

[0042] wherein R1 to R6 are independently selected from the group consisting of H, alkyl and alkoxy;

[0043] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0044] In one embodiment, X is C and R1 to R6 are H.

[0045] In one embodiment, X is N and R1 to R6 are H.

[0046] In another aspect, the present invention includes compounds of formula (VII):

[0047]

[0048] wherein X is selected from the group consisting of N, C, S and O;

[0049] wherein R1 to R3 are independently selected from the group consisting of H, alkyl and alkoxy;

[0050] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0051] In specific embodiments, the 12-LOX inhibitor is selected from the group consisting of:

[0052] N-(Benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide;

[0053] N-(Benzo[d]oxazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0054] N-(1H-benzo[d]imidazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0055] 4-(2-Hydroxy-3-methoxybenzylamino)-N-(thiophen-2-yl)benzenesulfonamide;

[0056] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(5-phenylthiazol-2-yl)benzenesulfonamide;

[0057] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-methoxyphenyl)benzenesulfonamide;

[0058] 4-(2-hydroxy-3-methoxybenzylamino)-N-(isoquinolin-8-yl)benzenesulfonamide;

[0059] 4-(2-Hydroxy-3-methoxybenzylamino)-N-phenylbenzenesulfonamide;

[0060] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-1-yl)benzenesulfonamide;

[0061] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-2-yl)benzenesulfonamide;

[0062] N-([1,1'-biphenyl]-4-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0063] N-([1,1'-biphenyl]-3-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0064] N-(3-(tert-butyl)phenyl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0065] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(6-methoxybenzo[d]thiazol-2-yl)benzenesulfonamide,

[0066] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-phenylthiazol-2-yl)benzenesulfonamide,

[0067] tert-Butyl 4-(3-(4-((2-hydroxy-3-methoxybenzyl)amino)phenylsulfonamido)phenyl)piperidine-1-carboxylate;

[0068] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-isopropylphenyl)benzenesulfonamide;

[0069] N-(6-Fluorobenzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0070] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-(piperazin-1-yl)phenyl)benzenesulfonamide;

[0071] 4-(2-hydroxy-3-methoxybenzylamino)-N-(4-(piperazin-1-yl)phenyl)benzenesulfonamide; and

[0072] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-(piperidin-4-yl)phenyl)benzenesulfonamide,

[0073] or a pharmaceutically acceptable salt thereof.

[0074] In another specific embodiment, the 12-lipoxygenase inhibitor is N-(benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide.

[0075] In one embodiment, the lupus is systemic lupus erythematosus.

[0076] In another embodiment, the 12-lipoxygenase inhibitor is formulated for parenteral administration.

[0077] In one embodiment, the 12-lipoxygenase inhibitor is dissolved in a hydroxyalkylated β-cyclodextrin.

[0078] In another specific embodiment, the 12-lipoxygenase inhibitor is formulated for oral administration.

[0079] 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

[0080] It is to be understood that the present invention is not limited to the particular methods and the like described herein, as these methods may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.

[0081] For therapeutic use, a "salt" of the compounds of the invention will be physiologically acceptable, i.e., the salt will be derived from a physiologically acceptable acid or base. However, salts of physiologically unacceptable acids or bases may also be used to prepare or purify physiologically acceptable compounds. Therefore, all salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.

[0082] "Diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical methods, such as electrophoresis and chromatography.

[0083] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0084] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, antimicrobial agents, antifungal agents, isotonic agents, and absorption delaying agents well known in the art for pharmaceutically active substances. Unless any conventional media or agent is incompatible with the compound, its use in the therapeutic compositions is contemplated.

[0085] The expression "therapeutically effective amount" refers to an amount of a compound disclosed herein that is effective for preventing, ameliorating, treating a disease or disorder, or delaying its onset, and / or for inhibiting the onset or progression of a disorder. This term also includes alleviating or ameliorating one or more symptoms.

[0086] "Alkyl" is a C1-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, tert-butyl, and the like.

[0087] "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 (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2), etc.

[0088] "Alkynyl" is a C2-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one unsaturated site, i.e., a carbon-carbon sp triple bond. Examples include, but are not limited to, acetylene (-C=-CH) and propargyl (--CH2C=CH) and the like.

[0089] "Cycloalkyl" is a saturated, unsaturated, or aromatic ring system containing, 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. Cycloalkyl groups can be unsubstituted or further substituted.

[0090] "Heterocycloalkyl" means a saturated, unsaturated, or aromatic ring system containing at least one N, O, S, or P. Thus, heterocycle includes heteroaryl. As used herein, heterocycle includes, but is 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-present), particularly Volumes 13, 14, 16, 19, and 28; KATRITZKY et al., COMPREHENSIVE HETEROCYCLIC CHEMISTRY (Pergamon Press, 1996); and 82 J. AM. CHEM. S. OC.5566 (1960). Heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, thiooxytetrahydrothiophenyl, 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, isophenyl benzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrenyl, pyrazolyl, pyrazolyl, pyrazolinyl, piperazinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

[0091] "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived from a carbon atom of a parent aromatic ring system by removing one hydrogen atom. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzenes, naphthalene, anthracene, biphenyl, and the like.

[0092] "Heteroaryl" means a monovalent aromatic group of one or more carbon atoms and one or more atoms selected from N, O, S, or P, derived by removing one hydrogen atom from an atom of a parent aromatic ring system. A heteroaryl group can be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicyclic ring 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 arranged as a bicyclic [4,5], [5,5], [5,6], or [6,6] system (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 9 to 10 ring atoms arranged as a bicyclic [5,6] or [6,6] system (8 to 9 carbon atoms and 1 to 2 heteroatoms selected from N and S). Heteroaryl groups can be bound to the drug stent via stable covalent bonds to 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, furyl, thiofuranyl, thienyl and pyrrolyl.

[0093] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. Although preferred methods and compositions have been described, any methods and compositions similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0094] 12-Lipoxygenase inhibitors

[0095] In one embodiment, the present invention provides a method of treating lupus comprising administering to a mammal a therapeutically or prophylactically effective amount of any 12-LOX inhibiting compound.

[0096] 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, carbohydrates, or peptides), or any combination thereof. 12-LOX inhibitors can also be synthetic or naturally occurring.

[0097] In one embodiment, the 12-LOX inhibitor is selective for 12-LOX and has little activity against other LOX isoforms (eg, 15-LOX).

[0098] Exemplary selective 12-LOX inhibitors are described in U.S. Pat. Nos. 10,266,488, 10,752,581, and 11,274,077 and include ML-355. These compounds are listed herein. The methods of the present invention also include ML-355 glucuronide (a metabolite of ML-355), whether or not it is a 12-lipoxygenase inhibitor.

[0099] 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. 132464-92- 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-eicosatriynoic acid (CAS No.: 34262-64-1), daphnodorin A, ML355, and combinations thereof. The chemical structure of ML355 is disclosed in Luci et al. (J Med Chem. 2014, 57, 495-506), the contents of which are incorporated by reference in their entirety.

[0100] 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, each of which is incorporated by reference for its teachings regarding 12-LOX inhibitors.

[0101] In specific embodiments, the 12-LOX inhibiting compound is a compound of Formula (I)-(VII) described herein, or a salt, enantiomer, mixture of enantiomers, or diastereomer thereof.

[0102] In specific embodiments, exemplary 12-LOX inhibitors for the treatment of lupus are described in US 10,266,488 and include the following compounds:

[0103] N-(Benzo[d]thiazol-2-yl)-4-[(2-hydroxy-3-methoxybenzyl)amino]benzenesulfonamide;

[0104] N-(Benzo[d]oxazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0105] N-(1H-benzo[d]imidazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0106] 4-(2-Hydroxy-3-methoxybenzylamino)-N-(thiophen-2-yl)benzenesulfonamide;

[0107] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(5-phenylthiazol-2-yl)benzenesulfonamide;

[0108] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-methoxyphenyl)benzenesulfonamide;

[0109] 4-(2-hydroxy-3-methoxybenzylamino)-N-(isoquinolin-8-yl)benzenesulfonamide;

[0110] 4-(2-Hydroxy-3-methoxybenzylamino)-N-phenylbenzenesulfonamide;

[0111] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-1-yl)benzenesulfonamide;

[0112] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(naphthalen-2-yl)benzenesulfonamide;

[0113] N-([1,1'-biphenyl]-4-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0114] N-([1,1'-biphenyl]-3-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0115] N-(3-(tert-butyl)phenyl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide,

[0116] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(6-methoxybenzo[d]thiazol-2-yl)benzenesulfonamide,

[0117] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-phenylthiazol-2-yl)benzenesulfonamide,

[0118] tert-Butyl 4-(3-(4-((2-hydroxy-3-methoxybenzyl)amino)phenylsulfonamido)phenyl)piperidine-1-carboxylate;

[0119] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-isopropylphenyl)benzenesulfonamide;

[0120] N-(6-Fluorobenzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide;

[0121] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(3-(piperazin-1-yl)phenyl)benzenesulfonamide;

[0122] 4-(2-hydroxy-3-methoxybenzylamino)-N-(4-(piperazin-1-yl)phenyl)benzenesulfonamide; and

[0123] 4-((2-hydroxy-3-methoxybenzyl)amino)-N-(4-(piperidin-4-yl)phenyl)benzenesulfonamide,

[0124] or a pharmaceutically acceptable salt thereof, an enantiomer thereof, a mixture of enantiomers thereof, or a diastereomer thereof.

[0125] In a preferred embodiment, the compound is ML-355, N-(benzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide.

[0126] In another embodiment, the compound is ML-355 glucuronide.

[0127] It should also be understood that the above compounds and salts may form solvates or exist in a substantially uncomplexed form, such as an anhydrous form. When the solvent contained in the solvate is water, the molecular complex is a hydrate. Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrile compounds, and the like. These compounds may also exist in polymorphic forms.

[0128] Formulation, administration and dosage

[0129] The present invention also relates to treating lupus or its symptoms, comprising administering to a patient in need thereof at least one compound of Formula (I)-(VII) as described herein. Also disclosed are routes of administration and effective dosages of pharmaceutical compositions comprising the compounds. The compounds of the present invention can be administered in combination with other agents in a variety of regimens to effectively treat the disease.

[0130] formulations

[0131] In addition to the compounds disclosed herein, the pharmaceutical compositions of the present invention may further comprise at least one 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, salts, and hydrates thereof may be prepared by any method known in the art of pharmacy. Generally, such preparation methods comprise mixing the 12-LOX inhibitor or a pharmaceutically acceptable salt thereof with a carrier or excipient and / or one or more other auxiliary ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single-dose or multi-dose units.

[0132] During any of the processes for preparing the compounds of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This may 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). Such protecting groups may be removed at a convenient subsequent stage using methods known in the art.

[0133] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any additional ingredients in the pharmaceutical compositions of the present invention will vary depending on the identity, size, and / or condition of the subject being treated, and will also depend on the route of administration of the composition. The compositions used in the methods of the present 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.

[0134] In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a diluent. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dibasic calcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0135] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a granulating agent and / or a 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 sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly (vinyl pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate, sodium lauryl sulfate, quaternary ammonium compounds and mixtures thereof.

[0136] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include 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., gum arabic, sodium alginate, Irish moss extract, panwar gum (panwar gum), ghattigum gum (ghattigum), plantago (isapol) husk mucus, carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, polyvinyl pyrrolidone, magnesium aluminum silicate, and larch arabogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, wax, water, alcohol, and / or mixtures thereof.

[0137] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may contain a preservative. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal 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.

[0138] In certain embodiments, the pharmaceutical composition used in the method of the present invention may comprise an antioxidant. Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0139] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a chelating agent. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salt and hydrate (for example, sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salt and hydrate (for example, citric acid monohydrate), fumaric acid and its salt and hydrate, malic acid and its salt and hydrate, phosphoric acid and its salt and hydrate, and tartaric acid and its salt and hydrate. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, disodium edetate, imidazole urea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol and thimerosal.

[0140] In certain embodiments, the pharmaceutical composition may comprise a buffering agent and a 12-LOX inhibitor or a salt thereof. Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glucuronate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0141] In certain embodiments, the pharmaceutical composition used in the method of the present invention may comprise a lubricant. Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0142] Parenteral Dosage Forms. In one embodiment, the novel compounds described herein may be administered in parenteral dosage forms. The term "parenteral" as used herein includes, but is not limited to, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, or infusion techniques.

[0143] In an embodiment, a parenteral pharmaceutical formulation described herein comprises a compound described herein and a pharmaceutically acceptable carrier.

[0144] In one embodiment, parenteral pharmaceutical formulations may contain liquid carriers including vegetable oils such as peanut oil, cottonseed oil, sesame oil, and organic solvents, PEG, propylene glycol, glycerol, and surfactants. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with a solubilizing agent such as Cremophor. TM , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and mixtures thereof.

[0145] 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.

[0146] In another embodiment, the pharmaceutical carrier comprises a solubilizing agent. In a specific embodiment, the solubilizing agent is a 2-hydroxyalkylated β-cyclodextrin, such as hydroxyethyl β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxybutyl β-cyclodextrin or sulfobutyl ether-β-cyclodextrin.

[0147] Pharmaceutically acceptable 2-hydroxyalkylated β-cyclodextrin can be present in any suitable amount in the aqueous parenteral pharmaceutical formulations described herein. Pharmaceutically acceptable 2-hydroxyalkylated β-cyclodextrin can be present in an amount of about 5% to 50% w / v. For example, the amount of a pharmaceutically acceptable solubilizer (optionally HP-β-cyclodextrin) can be about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% w / v. In specific embodiments, HP-β-cyclodextrin 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, 2-hydroxyalkylated β-cyclodextrin can be present in an amount of about 25% w / v of the total formulation.

[0148] For parenteral administration, sterile solutions and suspensions are required. When intravenous administration is required, isotonic preparations containing suitable preservatives are generally used. Pharmaceutical formulations can be administered parenterally by injection of a pharmaceutical formulation comprising a compound dissolved in an inert liquid carrier (e.g., sterile water or other pharmaceutically acceptable diluent).

[0149] Pharmaceutical compositions or formulations suitable for parenteral use include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The compositions may be present in unit dose or multi-dose containers, sealed ampoules, and vials, and may be stored in freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, saline, aqueous dextrose solution (D5W), lactated Ringer's solution, just before use. Prepare extemporaneously before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the types described previously.

[0150] Parenteral formulations may also include at least one any suitable adjuvant, including but not limited to diluents, crystal inhibitors, tension regulators, water structure forming agents or disruptors, polymers, ion pairing agents, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. Pharmaceutically acceptable adjuvants are preferred. Examples and methods for preparing such sterile solutions are well known in the art and can be found in well-known textbooks, such as but not limited to REMINGTON'S PHARMACEUTICAL SCIENCES (Adejare, 123rd edition, Academic Press. (2020); Handbook of Pharmaceutical Excipients, 9th edition, Pharmaceutical Press (2020)). A pharmaceutically acceptable carrier suitable for the mode of administration, solubility and / or stability of the compound can be conventionally selected.

[0151] Pharmaceutical excipients and additives that can be used in the parenteral drug formulations described herein may 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 sugar alcohols, aldonic acids, esterified sugars; and polysaccharides or sugar polymers), which may be present alone or in combination, alone or in combination, in the range of 1-99.99% by weight or volume. Exemplary protein excipients include serum albumins, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, and casein. Representative amino acid components that may also contribute to buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, and aspartame.

[0152] Suitable carbohydrate excipients for use in the parenteral pharmaceutical formulations described herein include, but are not limited to, monosaccharides such as glucose, fructose, maltose, galactose, dextrose, D-mannose, and sorbose; disaccharides such as lactose, sucrose, trehalose, and cellobiose; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, and starch; and sugar alcohols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), and inositol.

[0153] The pharmaceutical formulations comprising the compounds described herein may also include a pH adjuster. The pH adjuster may be a base, optionally sodium hydroxide. The pH adjuster may also be an acid, optionally hydrochloric acid.

[0154] In one embodiment, the present disclosure provides stable parenteral pharmaceutical formulations and preservative solutions and formulations containing preservatives, and multi-purpose preservative 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 include at least one known preservative. Preservatives include but are not limited to phenol, meta-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or a mixture thereof in an aqueous diluent. Any suitable concentration or mixture known in the art can be used, such as 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% alkyl parabens.

[0155] Other excipients, such as isotonic agents, buffers, antioxidants, preservatives and enhancers may optionally be added. When used, the dosage of the tension regulator is most often in the range of 0.1 to 1% (w / v). Non-limiting examples of suitable tension regulators include sodium chloride, glycerol, boric acid, calcium chloride, glucose and potassium chloride. The formulation may contain a local anesthetic to reduce the possibility of pain during injection. If necessary, a physiologically tolerated buffer may be added to provide better pH control. The pharmaceutical formulation can cover a wide range of pH, for example, from about pH 4 to about pH 10, specifically, from about pH 5 to about pH 9, and more specifically, from about 7.0 to about 9.0. In one aspect, the formulation described herein has a pH of about 8.4 to about 8.7.

[0156] The compositions of the present invention can be administered parenterally in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compounds of the present invention, the compositions of the present invention in liposome form may also contain stabilizers, preservatives, excipients, etc. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), including natural and synthetic ones. Methods for forming liposomes are known in the art (see Prescott, ed., METH. CELL BIOL. 14:33 (1976)). Liposomes, methods for their manufacture, and methods for their use are described in U.S. Pat. Nos. 4,089,8091 (Methods for preparing liposomes), 4,233,871 (Methods for encapsulating biologically active substances in lipid vesicles), 4,438,052 (Methods for producing mixed micelles), 4,485,054 (Large multilamellar vesicles), 4,532,089 (Giant liposomes and methods thereof), 4,897,269 (Liposomal drug delivery systems), 5,820,880 (Liposomal formulations), and the like.

[0157] Intravenous dosage can include bolus administration or slow administration. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It can be advantageous to formulate parenteral compositions in a unit dosage form for ease of administration and uniformity of dosage.

[0158] Oral Dosage Forms. Pharmaceutical compositions of the present invention suitable for oral administration can be presented as discrete units such as capsules, dragees, cachets, 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; or as an oil-in-water liquid emulsion or a water-in-oil emulsion, as boluses, and the like.

[0159] 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 carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin and bentonite, 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 include buffering agents.

[0160] Pharmaceutically acceptable excipients suitable for oral dosage forms include corn starch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose, and the like. Pharmaceutical compositions comprising the compound and / or its salt may 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, mixed with liquids to form a slurry, or poured directly into the mouth for rinsing.

[0161] For oral administration, the composition may also optionally contain a sweetener. Sweeteners include, but are not limited to, sucrose, fructose, saccharin sodium, sucralose, Sorbitol, mannitol, aspartame, cyclamate, etc. and combinations thereof.

[0162] Oral compositions of the present invention include sustained or controlled release formulations. For example, these may be diffusion-controlled products, dissolution-controlled products, erosion products, osmotic pump systems, or ionic resin systems. Diffusion-controlled products contain a water-insoluble polymer that controls the flow of water and the subsequent outflow of dissolved drug from the dosage form. Dissolution-controlled products control the dissolution rate of the drug by using a slowly dissolving polymer or by microencapsulating the drug (using different thicknesses to control release). Erosion products control the release of the drug by the erosion rate of the carrier matrix. Osmotic pump systems release the drug based on the continuous flow of water through a semipermeable membrane into a reservoir containing an osmotic agent. Ion exchange resins can be used to bind the drug so that when the drug is ingested, the release of the drug is determined by the ionic environment in the gastrointestinal tract.

[0163] Tablets can be prepared by compressing or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing a compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of a 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 slow or controlled release of the compound therein.

[0164] In other embodiments, the pharmaceutical composition containing the 12-LOX inhibitor or a salt thereof will be 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, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, 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 include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances. In certain embodiments for parenteral administration, the conjugate of the invention is mixed with a solubilizer such as Cremophor. TM , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and mixtures thereof.

[0165] The oral aqueous suspensions, emulsions and / or elixirs of the present invention may be combined with various sweeteners, flavorings (such as, but not limited to, orange or lemon flavor), and coloring agents (such as dyes, natural colorants, or pigments), in addition to the diluents described herein (e.g., water, glycerin, and various combinations).

[0166] Topical and transmucosal dosage forms. Topical and transmucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other dosage forms known to those skilled in the art. Dosage forms suitable for treating oral mucosal tissue can be formulated as mouthwashes or oral gels.

[0167] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide the topical and transmucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts and depend on the specific tissue to which a given pharmaceutical composition or dosage form will be applied. In one embodiment, excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form non-toxic and pharmaceutically acceptable solutions, emulsions, or gels. Moisturizers or humectants may also be added to pharmaceutical compositions and dosage forms.

[0168] The methods for preparing the pharmaceutical formulations described herein are manufactured in a known manner, including conventional mixing, dissolving or lyophilizing processes. Thus, aqueous pharmaceutical formulations can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture and, if desired or necessary, processing the granular mixture after adding excipients suitable for the solid dosage form.

[0169] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, in a single unit dose, and / or in a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject and / or a convenient fraction of such a dose, such as one-half or one-third of such a dose.

[0170] Administration. The pharmaceutical compositions of the present invention can be administered to any animal that can experience the beneficial effects of the compounds of the present invention. Such animals include humans and non-humans, such as livestock (e.g., dogs). In preferred embodiments, the patient is a human.

[0171] The present invention further contemplates administration of at least one compound disclosed herein by routes including, but not limited to, oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intracartilaginous, intracavitary, intracavitary, intracerebellar, intracerebroventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus injection, vaginal, rectal, buccal, sublingual, intranasal, iontophoresis, or transdermal administration.

[0172] The pharmaceutical compositions of the present invention are administered to subjects in a manner known in the art. The dosage administered will depend on the age, health, and weight of the recipient, kind of concurrent treatment (if any), frequency of treatment, and the nature of the desired effect.

[0173] Dosage. In general, the compounds disclosed herein can be used alone or in combination with other therapeutic agents at appropriate doses determined by routine testing to obtain optimal therapeutic effects while minimizing any potential toxicity. Pharmaceutical formulations useful in the present invention may contain an amount of a compound according to the present invention that is effective in treating or preventing the condition, illness, or disease of the subject being treated. As a non-limiting example, treatment of humans or animals can be provided at a one-time or regular dose of 0.0001 to about 50,000 mg of a compound of the present invention per patient per day. More specifically, for adults (about 60 kg), the range may be about 0.001 mg / kg to 500 mg / kg body weight / day, about 0.1 to 500 mg / kg; 0.1-100 mg / kg, about 1.0 to 100 mg / kg, about 1.0-75 mg / kg, about 1.0 to 50 mg / kg, about 1.0-25 mg / kg / day, or about 1.0 to 10 mg / kg. Additionally, dosages may 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 dosage as determined by a practitioner to achieve clinically relevant serum concentrations.

[0174] The dosage regimen for 12-LOX inhibitors can be selected based on 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 and hepatic function; and the specific compound being employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0175] Achieving optimal precision in drug concentration within the range that produces maximum efficacy and minimum toxicity may require a regimen tailored to the kinetics of compound availability to one or more target sites. Drug distribution, equilibrium, and elimination may be considered when determining optimal concentrations for a therapeutic regimen. The dosage of the compounds disclosed herein may be adjusted to achieve the desired effect when combined. Alternatively, the dosages of these different therapeutic agents may be independently optimized and combined to achieve a synergistic effect, wherein the degree of pathology reduction is greater than when either agent is used alone.

[0176] Specifically, the toxicity and therapeutic efficacy of the compounds disclosed herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD 50 (a dose lethal to 50% of the population) and ED 50 (The dose that has a therapeutic effect in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as LD 50 / ED 50Compounds that exhibit large therapeutic indices are preferred unless the cytotoxicity of the compound is the desired activity or therapeutic outcome. Although compounds that exhibit toxic side effects can be used, delivery systems can target such compounds to the site of the affected tissue to minimize potential 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.

[0177] The data obtained from cell culture assays and animal studies can be used in formulating a dosage range for use in humans. The dosage of such compounds preferably lies within the range that includes the ED 50 The range of circulating concentrations with minimal or no toxicity is within the range. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. For any compound used in the methods of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. Doses can be formulated in animal models to achieve IC values ​​as determined in cell culture. 50 The circulating plasma concentration range of the test compound (the concentration that achieves half-maximal inhibition of symptoms) can be used to accurately determine useful doses in humans. Levels in plasma can be measured by high performance liquid chromatography.

[0178] More specifically, the pharmaceutical composition can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three, or four times daily. Doses can 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 (e.g., during a disease flare) and determined to be clinically relevant. Because lupus is a chronic disease, patients may need to take 12-LOX inhibitors for life.

[0179] Combination therapy

[0180] In another embodiment of the present invention, the compounds of the present invention can be co-administered to patients in need thereof with another active ingredient having known side effects for treating lupus (including systemic lupus erythematosus). Such drugs include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, antibodies, antimalarials, and immunosuppressants. Such drugs include traditional 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, as well as 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.

[0181] Exemplary antibodies include, but are not limited to, anti-CD6 antibodies, anti-CD20 antibodies, anti-CD28 antibodies, anti-IL12 antibodies, anti-IL23 antibodies, anti-BDCA 2 antibodies, anti-CD52 antibodies, anti-CD74 antibodies, rituximab, anifrolumab, and belimumab, or a combination thereof.

[0182] The additional therapeutic agent can be dissolved or suspended in the preconcentrate (before dilution with the diluent), added to the preconcentrate prior to dilution, added to the diluted preconcentrate, or added to the diluent prior to mixing with the preconcentrate. The additional therapeutic agent can also be co-administered as part of a separate dosage form to achieve a therapeutic effect. Optionally, the additional therapeutic agent can be present in a first dissolved amount and a second non-dissolved (suspended) amount. Such additional therapeutic agent can be any agent that has therapeutic or other value when administered to an animal, particularly a mammal, such as a drug, nutrient, and diagnostic agent.

[0183] Treatment effect

[0184] The methods of the present invention can be used to treat patients with one or more lupus manifestations, including but not limited to systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, central nervous system (CNS) lupus, cardiovascular manifestations, pulmonary manifestations, hepatic manifestations, hematologic manifestations, gastrointestinal manifestations, musculoskeletal manifestations, neonatal lupus erythematosus, juvenile systemic lupus erythematosus, drug-induced lupus erythematosus, or complement deficiency syndromes leading to lupus manifestations.

[0185] Exemplary symptoms associated with lupus that can be prevented, alleviated, or ameliorated using 12-LOX inhibitors include, but are not limited to, joint pain and stiffness; muscle aches, pain, or weakness; fever; malaise; skin manifestations (e.g., rash, including a "butterfly" rash); abnormal weight loss or weight gain; anemia; neurological or neuropsychiatric manifestations (e.g., difficulty thinking, memory problems, confusion, depression, headache, seizures, stroke); kidney problems (e.g., nephritis, such as glomerulonephritis); chest pain; sunlight or photosensitivity; hair loss; Raynaud's phenomenon; vasculopathy or other vascular manifestations, as well as biological concomitants of lupus disclosed herein or known in the art (e.g., immune complexes, elevated cytokine levels (e.g., interferons (e.g., type I interferons, such as IFN-α and / or IFN-β); interleukins (e.g., IL-6, IL-8, IL-1, and IL-18), and TNF-α), elevated levels of antibodies associated with lupus (e.g., antinuclear antibodies (e.g., anti-Smith antibodies, anti-double-stranded DNA (dsDNA) antibodies, anti-U1 antibodies), and TNF-α). Overexpression of RNP, SS-a (or anti-Ro), SS-b (or anti-La), antiphospholipid antibodies, anti-ss DNA antibodies, anti-histone antibodies or anti-cardiolipin antibodies) and IFN-induced genes.

[0186] According to some embodiments, treatment of lupus with the disclosed 12-LOX inhibitory compounds produces at least one clinical outcome selected from the group consisting of: improved renal function, decreased serum anti-dsDNA antibody concentration, decreased serum anti-cardiolipin antibody concentration, increased serum complement factor C3 concentration, and increased serum complement factor C4 concentration. Each possibility represents a separate embodiment of the present invention.

[0187] Without being bound by any theory or mechanism, administration of the composition of the present invention to a subject suffering from lupus may result in the patient's CD19 + / CD27 + The expression of Toll-like receptor 9 and / or inflammatory cytokines (such as, but not limited to, IL-1, IL-6, IL-17, and interferon-γ) in B cells is reduced.

[0188] A reduction in the number of seizures or a decrease in the time between seizures compared to before treatment with the 12-LOX inhibitor is also considered a treatment outcome.

[0189] Although the preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the art that various modifications, additions, substitutions, etc. may be made without departing from the spirit of the invention, and such modifications, additions, substitutions, etc. are therefore deemed to be within the scope of the invention as defined by the following claims. In addition, to the extent not already indicated, it will be understood by those skilled in the art that any of the various embodiments described and illustrated herein may be further modified to incorporate features shown in any other embodiment disclosed herein.

[0190] All patents and other publications, including literature references, issued patents, published patent applications, and co-pending patent applications, cited in this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies that are described in such publications that might be used in conjunction with the techniques described herein.

[0191] 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. may 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 by the following claims. The following examples are not intended to limit the present invention in any way.

[0192] The technology described herein is further illustrated by the following examples, which should not be construed as further limiting.

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 method according to claim 1, wherein the 12-lipoxygenase inhibitor is a compound of formula (I): 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, 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; 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-piperidin-3-phenyl, oxazole, benzothiophene, p-thiazine, furan, pyran, chroman, benzofuran, pyrrole, pyrazole, pyrazine, pyrimidine, triazine, indole, purine, phthalazine; 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, 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. The method according to claim 2, wherein R3 is selected from the group consisting of 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-piperidinyl-phenyl, 4- Piperazine-3-pyridine, 6-methyl-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-morpholino-phenyl, 4N-boc-piperidin-3-phenyl, 3-piperidin-phenyl, 3-isopropyl-phenyl, 3-methoxy-phenyl, 5-methyl-3-isoxazole, 2-pyrimidine and 1,3-biphenyl.

4. The method of claim 1, wherein the 12-LOX inhibitor is selected from the group consisting of: 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. 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 of 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. The method of claim 7, wherein the 12-lipoxygenase inhibitor is dissolved in hydroxyalkylated β-cyclodextrin.

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

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

11. A method for treating or preventing lupus, comprising administering to a patient in need thereof 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. The method of claim 11, wherein the lupus is systemic lupus erythematosus.

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

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

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