Indoline Derivatives for the Treatment and / or Prevention of Fibrotic Diseases

Abstract

To provide a method for treatment and / or prevention of fibrosis diseases.SOLUTION: The invention provides the use of indoline derivatives, and their effective dose in the prevention and / or treatment of fibrosis diseases. Specifically, the compound of the structural formula in the figure is presented, for example. The compound allows effective prevention and / or treatment of a fibrosis disease without cytotoxicity or genotoxicity.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] The present invention relates to a method or use for treating and / or preventing fibrotic diseases. In particular, the method uses indoline derivatives to treat and / or prevent fibrotic diseases without cytotoxicity or genotoxicity. [Background technology]

[0002] Fibrosis is the formation of excess fibrous connective tissue in organs or tissues during repair or response processes, such as healing, usually following injury or prolonged inflammation. Fibrosis hardens and / or swells affected tissues, reducing fluid flow through these tissues. As a result, many tissues have fibrosis, and fibrotic tissues may be unable to function properly. For example, liver fibrosis is an overproliferative wound healing process in which excess connective tissue accumulates in the liver. Chronic liver disease, the underlying cause of chronic viral hepatitis B and alcoholic liver disease, can lead to liver fibrosis. Pulmonary fibrosis (literally "lung scarring") is a respiratory disease in which scarring forms in lung tissue, causing serious respiratory problems. Scarring and the accumulation of excess fibrous connective tissue (this process is called fibrosis) lead to thickening of the lung walls and reduced oxygen delivery in the blood. As a result, patients suffer from persistent shortness of breath. Renal fibrosis is an inevitable consequence of the excessive accumulation of extracellular matrix that occurs in virtually all types of chronic kidney disease. Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) and can occur in both ulcerative colitis (UC) and Crohn's disease (CD), but is more common in CD. Fibrosis can also occur in the heart; for example, cardiac fibrosis can manifest as thickening of the heart valves.

[0003] Histone deacetylases (HDACs) are classified into four categories: class I (HDAC1, 2, 3, and 8), class IIa (HDAC4, 5, 7, and 9), class IIb (HDAC6 and 10), class III (SIRT1-7), and class IV (HDAC11). They are involved in the post-translational modification of core histones and non-histone proteins. US 8,846,748 discloses certain indolyl and indolinyl hydroxamate compounds as HDAC inhibitors with potent anticancer activity. Masahiro Yoshikawa et al. showed that HDAC inhibitors prevent fibrosis in the liver, skin, and lungs, although the underlying mechanisms remain largely unknown. They suggested that the HDAC inhibitor TSA introduces several inhibitors of TGF-beta1 signaling (e.g., Id2 and BMP-7) into human RPTECs (Masahiro Yoshikawa et al., J Am Soc Nephrol 18:58-65, 2007). Maoyin Pang and Shougang Zhuang showed that the onset and progression of several chronic diseases are characterized by fibrosis, including chronic kidney disease, cardiac hypertrophy, and idiopathic pulmonary fibrosis (Maoyin Pang and Shougang Zhuang, The Journal of Pharmacology and Experimental Therapeutics, Vol. 355, No. 2, pp. 266-272, 2010).

[0004] However, very few HDAC inhibitors have been sufficiently developed to identify potential fibrotic candidates, and therefore there remains a need to develop anti-fibrotic drugs. Summary of the Invention

[0005] The present invention provides a method for preventing and / or treating a fibrotic disease in a subject. The method comprises administering to the subject an effective amount of a compound described herein as an active ingredient. Preferably, the effective amount is in the range of about 1.5 mg / kg / day to about 20 mg / kg / day to the subject. In some embodiments, the effective amount of the active ingredient is in the range of about 1.5 mg / kg / day to about 15 mg / kg / day, about 1.5 mg / kg / day to about 13 mg / kg / day, about 1.5 mg / kg / day to about 12 mg / kg / day, about 1.5 mg / kg / day to about 10 mg / kg / day, about 2.0 mg / kg / day to about 20 mg / kg / day, about 2.0 mg / kg / day to about 15 mg / kg / day, about 2.0 mg / kg / day to about 13 mg / kg / day, or about 2.0 mg / kg / day to about 12 mg / kg / day, about 5 mg / kg / day to about 20 mg / kg / day, about 5 mg / kg / day to about 15 mg / kg / day, or about 5 mg / kg / day to about 10 mg / kg / day. In some embodiments, the active ingredient of the methods of the invention is further co-administered with a second anti-fibrotic agent. Preferably, the second anti-fibrotic agent is ESBRIET (pirfenidone), OFEV (nintedanib), a LOXL2 antibody (such as simtuzumab), an IL-13 antibody (such as lebrikizumab), an αVβ6 antibody (such as STX-100), a CTGF antibody (such as FG-3019), tipelukast (such as MN-001), or aerosolized pirfenidone (such as GP-101). In some embodiments, the fibrotic disease is dermal fibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, intestinal fibrosis, cystic fibrosis, cardiac fibrosis, uterine leiomyoma, or adenomyosis. In further embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0006] The invention also provides a pharmaceutical composition comprising, as an active ingredient, 3-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a daily dose ranging from about 100 mg to about 1,400 mg in one or more unit dosage forms. [Brief explanation of the drawings]

[0007] [Figures 1A-1C] Figure 1 shows the antifibrotic effects of TMU-C-0012, dexamethasone, and pirfenidone on bleomycin-induced pulmonary fibrosis in mice. In a preventive model, the results show that TMU-C-0012 dose-dependently inhibits BLM-induced pulmonary fibrosis (A), and that TMU-C-0012 is more effective than dexamethasone at inhibiting pulmonary fibrosis (B). In a therapeutic model, the results show that TMU-C-0012 dose-dependently inhibits BLM-induced pulmonary fibrosis (A), and that TMU-C-0012 is more effective than pirfenidone at inhibiting pulmonary fibrosis (C).

[0008] [Figure 2] 1 shows the anti-fibrotic effects of TMU-C-0012 and SAHA on bleomydcin-induced pulmonary fibrosis in mice.

[0009] [Figure 3] 1 shows the antifibrotic effects of TMU-C-0012 and dexamethasone on OVA-induced pulmonary fibrosis in mice.

[0010] [Figure 4] 1 shows the antifibrotic effect of TMU-C-0012 on silica-induced pulmonary fibrosis in mice.

[0011] [Figure 5] 1 shows the anti-fibrotic effects of TMU-C-0012 and pirfenidone on CCl4-induced liver fibrosis in mice. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention is based, at least in part, on the discovery of the use of indoline derivatives and effective dosages thereof in the prevention and / or treatment of fibrotic diseases, which compounds can effectively prevent and / or treat fibrotic diseases without cytotoxicity or genotoxicity.

[0013] As used herein, unless the context otherwise requires, the terms "comprise" and variations such as "comprising," "comprises," "comprised," etc. are not intended to exclude other additives, components, integers or steps.

[0014] As used herein, unless the context indicates otherwise, the disclosed method steps are not intended to be limiting and are not intended to indicate that each step is essential to the method or that the steps must be performed in the order disclosed.

[0015] As used herein, unless stated otherwise, the use of "or" means "and / or." In the context of a multiple dependent claim, the use of "or" refers to more than one preceding independent or dependent claim in the alternative only.

[0016] As used herein, all numerical values are approximate and may vary to account for measurement error and rounding of significant figures. The use of "about" before a certain measured quantity includes variations due to sample impurities, measurement error, human error, statistical variation, and rounding of significant figures.

[0017] As used herein, the term "pharmaceutically acceptable salt" means a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of amino groups formed by methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate Salts derived from appropriate bases include alkali metal, alkaline earth metal, and ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.Where appropriate, further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0018] The term "solvate" refers to a form of a compound that is combined with a solvent, usually through solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0019] The term "prodrug" refers to a compound that is pharmaceutically active in vivo, including derivatives that have a cleavable group and become the compounds described herein by solvolysis or under physiological conditions. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Derivatives of the compounds of the present invention are active in both their acid and acid-derivative forms, but the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.

[0020] As used herein, the terms "administer," "administering," or "administration" mean implanting, absorbing, ingesting, injecting, inhaling, or introducing a compound of the invention or a pharmaceutical composition thereof into or onto a subject.

[0021] As used herein, the terms "condition," "disease," and "disorder" are used interchangeably.

[0022] An "effective amount" of a compound described herein means an amount sufficient to elicit a desired biological response, i.e., treat a condition. As will be appreciated by those skilled in the art, the effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatments.

[0023] A "therapeutically effective amount" of a compound described herein means an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent.

[0024] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0025] As used herein, the term "pharmaceutically acceptable carrier" means a solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation aid, or carrier conventional in the art for use with a therapeutic agent for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to a recipient at the dosage and concentration employed and is compatible with other ingredients of the formulation. Pharmaceutically acceptable carriers are determined, in part, by the particular composition being administered, as well as the particular method used to administer the composition.

[0026] As used herein, the term "subject" is defined herein to include mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In certain embodiments, the subject is a human. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as, for example, a human.

[0027] As used herein, the terms "treat," "treating," and "treatment" refer to the eradication or amelioration of a disease or disorder, or one or more symptoms associated with the disease or disorder. In certain embodiments, these terms refer to minimizing the spread or worsening of a disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder. In some embodiments, these terms refer to the administration of a compound or dosage form provided herein, with or without one or more additional active agents, after diagnosis or onset of a particular disease symptom.

[0028] As used herein, the terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of a disease or disorder, or one or more symptoms thereof. In certain embodiments, these terms refer to treatment or administration with a compound, antibody, or dosage form provided herein, with or without one or more other additional active agents, prior to the onset of symptoms, particularly to a patient at risk for a disease or disorder described herein. These terms encompass the suppression or alleviation of symptoms of a particular disease. However, the term "prevention" may be used interchangeably with the term "prophylactic treatment."

[0029] As used herein, the terms "co-administration" and "in combination with" include simultaneous, concurrent, separate, or sequential administration of two or more therapeutic agents, unless otherwise indicated, within an unlimited time period. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms.

[0030] In one aspect, the invention provides a method for the prevention and / or treatment of a fibrotic disease in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof as an active ingredient. JPEG0007723400000001.jpg5594 n is 0, 1, or 2; R1 is SO2R a and R a is alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; R2 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, cyano, nitro, OR b , S.R. b , S(O)R b , NHC(O)-CH=CH-C(O)Rb , NHC(O)-CH=CH-C(O)NR c R d , SO2NR c R d ,OC(O)R b , C(O)NR c R d , N.R. c R d , NHC(O)R b , NHC(O)NR c R d , or NHC(S)R c and R b , R c and R d are each independently H, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; R3, R4, R5 and R6 are each independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, cyano, nitro, OR b , S.R. b , S(O)R b , CH=CH-C(O)NR c R d , NHC(O)-CH=CH-C(O)R b , NHC(O)-CH=CH-C(O)NR c R d , SO2NR c R d ,OC(O)R b , C(O)NR c R d , N.R. c R d , NHC(O)R b , NHC(O)NR c R d , or NHC(S)R c and R b , R c and R dare each independently H, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl.

[0031] In some embodiments, R4 is CH=CH-C(O)NR c R d , NHC(O)-CH=CH-C(O)R b or NHC(O)-CH=CH-C(O)NR c R d Preferably, R4 is C(O)NHOH, CH=CH-C(O)NHOH, NHC(O)-CH=CH-C(O)OH, or NHC(O)-CH=CH-C(O)NHOH. More preferably, R4 is CH=CH-C(O)NHOH.

[0032] In some embodiments, R1 is SO2R a and R a is heteroaryl or phenyl optionally substituted with halogen, hydroxy, alkoxy, amino, cyano, or nitro.

[0033] In some embodiments, R2 is NHC(O)-CH=CH-C(O)R b or NHC(O)-CH=CH-C(O)NR c R d and R3, R5, and R6 are independently CH=CH-C(O)NR c R d , NHC(O)-CH=CH-C(O)R b or NHC(O)-CH=CH-C(O)NR c R d is.

[0034] In some further embodiments, R2 is NHC(O)-CH=CH-C(O)OH, or NHC(O)-CH=CH-C(O)NHOH; R3, R5, and R6 are independently CH=CH-C(O)NHOH, NHC(O)-CH=CH-C(O)OH, or NHC(O)-CH=CH-C(O)NHOH; and R1 is SO2R a and R a is heteroaryl or phenyl optionally substituted with halogen, hydroxy, alkoxy, amino, cyano, or nitro.

[0035] In a further embodiment, the compound of formula (I) is JPEG0007723400000002.jpg146162 Or, it is selected from the group consisting of a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0036] In a further embodiment, the compound of formula (I) is 3-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The structure of 3-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide is shown below. JPEG0007723400000003.jpg4489

[0037] In one embodiment, the effective amount is in the range of about 1.5 mg / kg / day to about 20 mg / kg / day. In another embodiment, the effective amount for humans is in the range of about 2.0 mg / kg / day to about 15 mg / kg / day. Meanwhile, the present invention also provides the use of an effective amount of a compound described herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof as an active ingredient in the manufacture of a medicament for preventing and / or treating a fibrotic disease.

[0038] The compounds of formula (I) described herein and their preparation are disclosed in US Pat. No. 8,846,748, which is incorporated herein by reference.

[0039] In some further embodiments, the effective amount of the active ingredient used in the present invention is in the range of about 1.5 mg / kg / day to about 15 mg / kg / day, about 1.5 mg / kg / day to about 13 mg / kg / day, about 1.5 mg / kg / day to about 12 mg / kg / day, about 1.5 mg / kg / day to about 10 mg / kg / day, about 2.0 mg / kg / day to about 20 mg / kg / day, about 2.0 mg / kg / day to about 15 mg / kg / day, about 2.0 mg / kg / day to about 13 mg / kg / day, or about 2.0 mg / kg / day to about 12 mg / kg / day, about 5 mg / kg / day to about 20 mg / kg / day, about 5 mg / kg / day to about 15 mg / kg / day, or about 5 mg / kg / day to about 10 mg / kg / day. In a further embodiment, the effective amount used in the present invention is from about 2.3 mg / kg / day to about 11 mg / kg / day.

[0040] For the treatment of fibrotic diseases, an effective amount of the active ingredient is in the range of about 5 mg / kg / day to about 20 mg / kg / day, about 5 mg / kg / day to about 18 mg / kg / day, about 5 mg / kg / day to about 15 mg / kg / day, about 5 mg / kg / day to about 13 mg / kg / day, about 5 mg / kg / day to about 11 mg / kg / day, or about 5 mg / kg / day to about 10 mg / kg / day.

[0041] For the prevention of fibrotic diseases, an effective amount of the active ingredient is in the range of about 1.5 mg / kg / day to about 10 mg / kg / day, about 1.5 mg / kg / day to about 8 mg / kg / day, about 2 mg / kg / day to about 10 mg / kg / day, about 4.0 mg / kg / day to about 8 mg / kg / day, or about 6.0 mg / kg / day to about 8.0 mg / kg / day.

[0042] In one embodiment, the active ingredient of the invention is further co-administered with a second anti-fibrotic agent. Preferably, the second anti-fibrotic agent is ESBRIET (pirfenidone), OFEV (nintedanib), a LOXL2 antibody (such as simtuzumab), an IL-13 antibody (such as lebrikizumab), an αVβ6 antibody (such as STX-100), a CTGF antibody (such as FG-3019), tipelukast (such as MN-001), or aerosolized pirfenidone (such as GP-101). In a further embodiment, the co-administration is simultaneous, separate, or sequential.

[0043] In some embodiments, the fibrotic disease is skin fibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, intestinal fibrosis, cystic fibrosis, cardiac fibrosis, uterine leiomyoma, or adenomyosis. In further embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis. In another further embodiment, the method for treating pulmonary fibrosis further comprises co-administered therapy with lung transplantation, hyperbaric oxygen therapy (HBOT), or pulmonary rehabilitation.

[0044] In another aspect, the invention provides pharmaceutical compositions comprising, as an active ingredient, a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in one or more unit dosage forms, in a daily dose ranging from about 100 mg to about 1,400 mg. In one embodiment, the pharmaceutical composition of the invention contains a daily dose ranging from about 140 mg to about 1,050 mg.

[0045] In some embodiments, the pharmaceutical compositions of the invention are in the form of one or more capsules or tablets. In further embodiments, the pharmaceutical compositions of the invention contain about 100 mg to about 300 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, about 200 mg to about 250 mg, about 220 mg to about 280 mg, about 220 mg to about 250 mg, or about 200 mg to about 220 mg of active ingredient in a single tablet, preferably about 200 mg or 220 mg in a single tablet. In another further embodiment, the pharmaceutical composition of the invention contains about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 180 mg to about 500 mg, about 200 mg to about 500 mg, about 150 mg to about 350 mg, about 150 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, about 250 mg to about 500 mg, about 250 mg to about 400 mg, about 250 mg to about 350 mg, or about 250 mg to about 300 mg of the active ingredient in a single capsule, preferably about 250 mg of the active ingredient in a single capsule.

[0046] In one embodiment, the pharmaceutical composition of the invention comprises a second antifibrotic agent. Preferably, the second antifibrotic agent is ESBRIET (pirfenidone), OFEV (nintedanib), a LOXL2 antibody (such as simtuzumab), an IL-13 antibody (lebrikizumab), an αVβ6 antibody (such as STX-100), a CTGF antibody (such as FG-3019), tipelukast (such as MN-001), or aerosolized pirfenidone (such as GP-101).

[0047] While the compounds of the invention can be administered as raw chemicals, they can also be provided as pharmaceutical formulations. Accordingly, the present invention provides pharmaceutical formulations or compositions comprising a compound or a pharmaceutically acceptable salt, prodrug, or solvate thereof, together with one or more pharmaceutically acceptable carriers and, optionally, one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Appropriate formulations depend on the chosen route of administration. The formulation can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other appropriate composition, comprising at least one compound of the invention in combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to those skilled in the art, and methods for formulating them and compositions thereof can be found in standard references such as Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa. Suitable liquid carriers include water, aqueous saline solution, aqueous dextrose solution, and glycols, particularly for injectable solutions. The pharmaceutical compositions of the present invention can be manufactured in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0048] Although the most suitable route will depend, for example, on the condition and disorder of the recipient, formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, buccal, sublingual, and ocular) administration. Oral administration is the preferred route. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound of the invention or a pharmaceutically acceptable salt, prodrug, or solvate thereof (the "active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0049] For oral administration, suitable pharmaceutical compositions of the present invention include powders, granules, pills, tablets, lozenges, chews, gels, and capsules, as well as liquids, syrups, suspensions, elixirs, and emulsions. These compositions may also contain antioxidants, flavorings, preservatives, suspending agents, thickening and emulsifying agents, colorants, flavorings, and other pharmaceutically acceptable additives. Formulations for oral administration can be formulated for immediate release or modified release. Modified release includes delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0050] For parenteral administration, the compounds of the present invention are administered directly into the blood stream, muscle, or internal organs via intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, or other injection or infusion. Parenteral formulations may be prepared in aqueous injection solutions which may contain, in addition to the compounds of the present invention, buffers, antioxidants, bacteriostats, salts, carbohydrates, and other additives commonly used in such solutions. Parenteral administration may be immediate release or modified release (such as by injection or implanted depot).

[0051] The compounds or compositions of the present invention can also be administered topically, intradermally, or transdermally to the skin or mucosa. Typical formulations include gels, hydrogels, lotions, solutions, creams, ointments, bandages, foams, skin patches, wafers, implants, and microemulsions. The compounds or compositions of the present invention can also be administered by inhalation or intranasal administration, for example, as a dry powder, aerosol spray, or drops. Additional routes of administration of the compounds of the present invention include vaginal and rectal (by suppository, pessary, or enema), eye, and ear.

[0052] Dosage regimens may be adjusted to provide the optimum therapeutic response, for example, several divided doses may be administered daily or the dosage may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

[0053] It is particularly advantageous to prepare compound in unit dosage form for ease of administration and uniformity of dosage.As used herein, unit dosage form refers to a physically separate unit suitable as a unit dosage for the subject to be treated, each containing a therapeutically effective amount of compound and at least one pharmaceutical excipient.Drug product includes unit dosage form in a container, which is labeled with a label indicating the intended treatment method or has a label attached thereto indicating the intended treatment method.

[0054] It is understood that the foregoing examples are merely illustrative of the present invention. Some modifications of the articles and / or methods employed may be made and still achieve the objectives of the present invention. Such modifications are considered to be within the scope of the claimed invention. Example

[0055] Example 1 Ames test for genotoxicity of 3-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide The compound 3-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide (hereafter referred to as "TMU-C-0012") was evaluated using the Ames test to assess its mutagenic potential. Two histidine-auxotrophic mutants of Salmonella typhimurium (TA98 and TA100) were used. The test strains were obtained from frozen working stock vials and thawed at room temperature. A 0.2 mL aliquot was inoculated into 25 mL of nutrient broth medium and then incubated at 35-37°C with shaking (120 rpm) for 16-18 hours. The test substance was dissolved in DMSO in 10-fold dilutions to obtain four stock concentrations: 30,000, 3,000, 300, and 30 μg / mL. A rat liver microsomal enzyme homogenate (S9) mixture was prepared containing 8 mM MgCl, 33 mM KCl, 4 mM NADP, 5 mM glucose-6-phosphate, 100 mM NaHPO (pH 7.4), and 4% (v / v) Acryl 1254-induced male rat liver microsomal enzyme homogenate (S9). A 0.2 mL aliquot of the test compound stock solution was combined with 0.1 mL of strain culture and 0.5 mL of rat liver enzyme homogenate (S9) mixture or 0.5 mL of PBS. The mixture was then incubated at 35–37°C with shaking (120 rpm) for 20 min. Molten top agar (2 mL, containing 0.05 mM histadine and 0.05 mM biotin) was added, and the mixture was poured onto the surface of minimal glucose agar plates (30 mL bottom agar per Petri plate) to give final test substance concentrations of 3000, 300, 30, and 3 μg / plate. Plates were incubated at 37°C for 72 hours, and then the number of His+ revertant colonies was counted. Treatments that resulted in a three-fold increase (3x) in revertant colonies compared to vehicle controls were considered mutagenic. Treatments that reduced colony numbers to ≤50% of vehicle controls were considered cytotoxic. Assays were performed in triplicate.

[0056] The table below shows the Ames test results, which indicate that compound TMU-C-0012 is negative for genotoxicity. JPEG0007723400000004.jpg89170 - No significant mutagenicity or cytotoxicity + Significant mutagenicity or cytotoxicity

[0057] Example 2 In vitro mammalian cell micronucleus assay The in vitro micronucleus (MNvit) assay provides a comprehensive basis for investigating the potential for chromosomal damage in vitro by detecting both aneugens and clastogens in cultured human cells. The assay was performed using the actin polymerization inhibitor cytochalasin B (Cyto B) according to OECD Chemicals Testing Guideline - TG487, In Vitro Mammalian Cell Micronucleus Assay (MNvit) (2014).

[0058] The table below shows the results of the assay, demonstrating that compound TMU-C-0012 is negative for genotoxicity. JPEG0007723400000005.jpg163170 PREC Precipitate visible under a microscope. CYTO High cytotoxicity (≥80% cytotoxicity) resulting in insufficient numbers of scored cells. Note: "+" p<0.05 by t-test, % of micronucleated cells is at least 3-fold higher than background levels. "+ / -" p<0.05 by t-test, % of micronucleated cells is at least 2-fold higher than background levels. JPEG0007723400000006.jpg99170 Example 3 In vivo efficacy: Bleomycin (BLM)-induced pulmonary fibrosis mouse model assay

[0059] In the preventive model, C57BL / 6JNarl mice (8 weeks old) were treated intratracheally with bleomycin (BLM, 0.05 U / 50 l) or PBS (50 l). From days 1 to 21 after BLM treatment, the bleomycin-treated mice were orally administered TMU-C-0012 (25, 50, 100 mg / kg / day, qd) and dexamethasone (0.5 mg / kg / day, qd). On day 21, the mice were sacrificed, and lung tissues were subjected to histological analysis by hematoxylin and eosin (H&E) staining (original magnification, ×100). In the therapeutic model, C57BL / 6JNarl mice (8 weeks old) were treated intratracheally with bleomycin (BLM, 0.05 U / 50 l) or PBS (50 l). From days 10 to 38 after BLM treatment, bleomycin-treated mice were orally administered TMU-C-0012 (25, 50, 100 mg / kg / day, qd) and pirfenidone (200 mg / kg / day, qd). On day 39, the mice were sacrificed, and lung tissues were subjected to histological analysis by hematoxylin and eosin (H&E) staining (original magnification, ×100).

[0060] Figure 1 shows the antifibrotic effects of TMU-C-0012, dexamethasone, and pirfenidone on bleomycin-induced pulmonary fibrosis in mice. In the preventive model, the results show that TMU-C-0012 dose-dependently suppresses BLM-induced pulmonary fibrosis (see Figure 1(A)), and that the efficacy of TMU-C-0012 in suppression is greater than that of dexamethasone (see Figure 1(B)). In the therapeutic model, the results show that TMU-C-0012 dose-dependently suppresses BLM-induced pulmonary fibrosis (see Figure 1(A)), and that the efficacy of TMU-C-0012 in suppression is greater than that of pirfenidone (see Figure 1(C)).

[0061] Additionally, C57BL / 6J Nar mice (8 weeks old) were treated intratracheally with bleomycin (BLM, 0.05 U / 50 l) or PBS (50 l). From days 10 to 38 after BLM treatment, the bleomycin-treated mice were orally administered TMU-C-0012 (25 mg / kg / day, qd) and SAHA (25 mg / kg / day, qd). On day 39, the mice were sacrificed, and histological analysis of lung tissue was performed by hematoxylin and eosin (H&E) staining (original magnification, ×100). Figure 2 shows the antifibrotic effects of TMU-C-0012 and SAHA on bleomycin-induced pulmonary fibrosis in mice. Example 4 In vivo efficacy: OVA pulmonary fibrosis mouse model assay

[0062] C57BL / 6J Narl mice (8 weeks old) were treated with OVA (50 g / 50 L / day) or PBS (50 L / day) via intraperitoneal injection for 4 weeks. The mice were then exposed to OVA (5% aerosol exposure) or PBS (aerosol exposure) for 8 weeks. The OVA-injected mice were orally administered TMU-C-0012 (25 mg / kg / day, qd) and dexamethasone (25 mg / kg / day, qd) for 4 to 12 weeks. At week 12, the mice were sacrificed, and histological analysis of lung tissue was performed by hematoxylin and eosin (H&E) staining (original magnification, ×100). Figure 3 shows the antifibrotic effects of TMU-C-0012 and dexamethasone on OVA-induced pulmonary fibrosis in mice. These results suggest that TMU-C-0012 inhibits OVA-induced pulmonary fibrosis in a dose-dependent manner and that the efficacy of TMU-C-0012 in inhibition is greater than that of dexamethasone. Example 5 Effect of TMU-C-0012 on silica-induced pulmonary fibrosis in mice

[0063] C57BL / 6J Nar mice (8 weeks old) were treated with silica (2.5 mg / 50 l) or PBS (50 l) via intratracheal administration. From days 1 to 21 after BLM treatment, silica-treated mice were orally administered TMU-C-0012 (100 mg / kg / day, qd). On day 21, mice were sacrificed, and lung tissue was subjected to histological analysis by hematoxylin and eosin (H&E) staining (original magnification, ×100). Figure 4 shows the antifibrotic effect of TMU-C-0012 on silica-induced pulmonary fibrosis in mice. Example 6 Effect of TMU-C-0012 on CCl4-induced liver fibrosis in mice

[0064] C57BL / 6J Nar mice (8 weeks old) were treated with CCl4 (1 L / g / BW, qw) or PBS (1 L / g / BW, qw) by intraperitoneal injection for 6 weeks. The CCl4-injected mice were orally administered TMU-C-0012 (25, 50, 100 mg / kg / day, qd) and pirfenidone (250 mg / kg / day, qd) for 2 to 6 weeks. On day 43, the mice were sacrificed, and α-SMA analysis of lung tissue was performed by IHC staining (original magnification, ×100). Figure 5 shows the antifibrotic effects of TMU-C-0012 and pirfenidone on CCl4-induced liver fibrosis in mice. As shown in Figure 5, the inhibition of CCl4-induced liver fibrosis by TMU-C-0012 was dose-dependent, and the efficacy of TMU-C-0012 in inhibition was greater than that of pirfenidone.

Claims

1. A medicament for treating renal fibrosis in a subject, comprising an effective amount for the subject of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient; n is 0, 1, or 2; R １ is SO ２ R ａ and R ａ is heteroaryl or phenyl optionally substituted with halogen, hydroxy, alkoxy, amino, cyano, or nitro; R ２ is alkyl, alkenyl, alkynyl, halogen, cyano, nitro, OR ｂ , S.R. ｂ , S(O)R ｂ ,NHC(O)-CH=CH-C(O)R ｂ ,NHC(O)-CH=CH-C(O)NR ｃ R ｄ , S.O. ２ NR ｃ R ｄ , O.C.(O.)R ｂ , C(O)NR ｃ R ｄ , N.R. ｃ R ｄ , NHC(O)R ｂ , NHC(O)NR ｃ R ｄ , or NHC(S)R ｃ and R ２ R in ｂ , R ｃ and R ｄ are each independently H, hydroxy, alkoxy, alkyl, alkenyl, or alkynyl; R ３ and R ５ are each independently H, alkyl, alkenyl, alkynyl, halogen, cyano, nitro, OR ｂ , S.R. ｂ , S(O)R ｂ , CH=CH-C(O)NR ｃ R ｄ ,NHC(O)-CH=CH-C(O)R ｂ ,NHC(O)-CH=CH-C(O)NR ｃ R ｄ , S.O. ２ NR ｃ R ｄ , O.C.(O.)R ｂ , C(O)NR ｃ R ｄ , N.R. ｃ R ｄ , NHC(O)R ｂ , NHC(O)NR ｃ R ｄ , or NHC(S)R ｃ and R ６ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, cyano, nitro, OR ｂ , S.R. ｂ , S(O)R ｂ , CH=CH-C(O)NR ｃ R ｄ ,NHC(O)-CH=CH-C(O)R ｂ ,NHC(O)-CH=CH-C(O)NR ｃ R ｄ , S.O. ２ NR ｃ R ｄ , O.C.(O.)R ｂ , C(O)NR ｃ R ｄ , N.R. ｃ R ｄ , NHC(O)R ｂ , NHC(O)NR ｃ R ｄ , or NHC(S)R ｃ and R ３ , R ５ and R ６ wherein Rb, Rc, and Rd are each independently H, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; R ４ is CH=CH-C(O)NR ｃ R ｄ or NHC(O)-CH=CH-C(O)NR ｃ R ｄ and R ４ R in ｃ and R ｄ wherein one of is H and the other is hydroxy.

2. R ４ The drug of claim 1, wherein is CH═CH—C(O)NHOH.

3. R ２ is NHC(O)-CH=CH-C(O)R ｂ or NHC(O)-CH=CH-C(O)NR ｃ R ｄ and R ３ , R ５ and R ６ are independently CH=CH-C(O)NR ｃ R ｄ ,NHC(O)-CH=CH-C(O)R ｂ or NHC(O)-CH=CH-C(O)NR ｃ R ｄ The drug product according to claim 1, characterized in that it is

4. R ２ is NHC(O)-CH=CH-C(O)OH or NHC(O)-CH=CH-C(O)NHOH, and R ３ , R ５ , and R ６ are independently CH=CH-C(O)NHOH, NHC(O)-CH=CH-C(O)OH, or NHC(O)-CH=CH-C(O)NHOH.

5. A medicament for treating renal fibrosis in a subject, comprising administering to the subject an effective amount of a compound of the following formula: or a pharmaceutically acceptable salt or solvate thereof.

6. 2. The drug product of claim 1, wherein the compound of formula (I) is 3-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide having the following structure:

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