Methods and compositions for treating hidradenitis suppurativa

Abstract

The present invention provides compositions and methods for treating hidradenitis suppurativa (HS) or apocrine gland infection. In one embodiment, the present invention provides a method for treating HS or an apocrine gland infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I): [Formula 1] JPEG2025533648000036.jpg5958 wherein R is halogen, amino, —NH(C1-C3-alkyl) or —N(C1-C3-alkyl)2, and n is 1 or 2. or a pharmaceutically acceptable salt thereof to a subject.

Description

[Background technology]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 413,883, filed October 6, 2022; U.S. Provisional Application No. 63 / 444,038, filed February 8, 2023; and U.S. Provisional Application No. 63 / 525,788, filed July 10, 2023, the entire teachings of which are incorporated herein by reference.

[0002] Hidradenitis suppurativa (HS) is a chronic condition affecting 1–2% of the population, often beginning in childhood or adolescence. HS manifests as skin lesions, including deep nodules and abscesses, fistulas, and fibrous scars, most frequently occurring in apocrine-rich intertriginous areas such as the axilla, groin, perianal area, perineum, and submammary region. Treatment failure in response to adalimumab, the only FDA-approved treatment for HS, is common (Saunte, DML & Jemec, GBE, J Am Med Assoc 318, 2019-2032 (2017)). Advances in understanding HS pathophysiology have highlighted resident and migratory cells of the innate immune system, as well as IL-1b, TNFa, and the NRLP3 inflammasome as drivers of inflammatory skin infiltration and destruction underlying the pathogenesis of HS (Sabat, R. et al., Nature Reviews Disease Primers 6, 18 (2020)). While adalimumab and other drugs currently in development for HS target specific inflammatory cytokines, no treatments exist that uniformly downregulate inflammatory mediators of HS, including IL-1b and the NRLP3 inflammasome (Saunte, DML & Jemec, GBE, ibid; Danby, FW & Margesson, LJ, Dermatol Clin 28, 779-793 (2010)). Therefore, new compositions and methods for treating HS are needed. Summary of the Invention

[0003] The present invention provides compositions and methods for treating hidradenitis suppurativa (HS).

[0004] In one embodiment, the present invention provides a method for treating HS in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I): [ka] wherein R is halogen, amino, —NH(C1-C3-alkyl) or —N(C1-C3-alkyl)2, and n is 1 or 2. or a pharmaceutically acceptable salt thereof to a subject.

[0005] In another embodiment, the present invention provides a method of treating an apocrine gland infection in a non-human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0006] The present invention further provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating HS or apocrine gland infection.

[0007] The foregoing and other objects, features and advantages of the present invention will become apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 is a graph showing the reduction in abscess / nodule (AN) counts at 16 weeks compared to baseline for the Compound 1 and control groups in the study described in Example 1. [Figure 2] FIG. 2 is a graph showing the reduction in HS Physician Global Assessment (HS-PGA) at week 16 compared to baseline for the Compound 1 and control groups in the study described in Example 1. [Figure 3]FIG. 3 is a graph showing HS Clinical Response 50 (HiSCR-50) at 16 weeks compared to baseline for the Compound 1 and control groups in the study described in Example 1. [Figure 4] FIG. 4 is a graph showing HS Clinical Response 75 (HiSCR-75) at 16 weeks compared to baseline for the Compound 1 and control groups in the study described in Example 1. [Figure 5] FIG. 5 is a graph showing HS Clinical Response 90 (HiSCR-90) at 16 weeks compared to baseline for the Compound 1 and control groups in the study described in Example 1. [Figure 6] FIG. 6 is a graph showing the concentrations of Compound 1 found in biopsied tissues of subjects grouped according to clinical response to Compound 1 therapy. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention relates to methods and compositions for treating HS. In one embodiment, the present invention provides a method for treating HS in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to methods and compositions for treating apocrine gland infection in a non-human subject.

[0010] The compounds of Formula I are potent inhibitors of heat shock protein 90 (HSP90), and the synthesis and HSP90 inhibitory activity of certain exemplary compounds of Formula I are described in WO 2008 / 115719, the contents of which are incorporated herein by reference in their entirety.

[0011] In preferred compounds of formula (I), R is chloro, bromo, iodo, amino, methylamino, or dimethylamino. In certain embodiments of compounds of formula I, n is 1. In other embodiments of compounds of formula I, n is 2. Suitable compounds of formula I include, but are not limited to, the compounds described below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0012] A particularly preferred compound of formula I is Compound 1, which is also known as CUDC-305, Debio-0932, and RGRN-305.

[0013] In the method for treating HS of the present invention, the subject is preferably a human subject.The subject may have HS with any severity of symptoms.For example, the subject may have HS at Hurley stage I, II or III.

[0014] In the methods of treating apocrine gland infections of the present invention, the non-human subject is preferably a mammal, preferably a domestic mammal. In certain embodiments, the subject is a companion or working animal, such as a domestic dog or cat, or a livestock animal, such as a bovine, ovine, equine, or porcine animal.

[0015] The compound of Formula I or a pharmaceutically acceptable salt thereof is preferably administered in the form of a pharmaceutical composition containing a therapeutic agent and a pharmaceutically acceptable carrier, excipient, or diluent. Suitable pharmaceutical compositions include solid, semi-solid, or liquid formulations (tablets, pellets, lozenges, capsules, suppositories, creams, ointments, aerosols, powders, solutions, emulsions, suspensions, syrups, injectable solutions, etc.). The pharmaceutical composition can be administered by any suitable means, including, but not limited to, parenteral administration, intravenous administration, intramuscular administration, subcutaneous administration, implantation administration, oral administration, sublingual administration, buccal administration, nasal administration, pulmonary administration, transdermal administration, topical administration, vaginal administration, rectal administration, and transmucosal administration. Topical administration can include the use of transdermal administration, such as a transdermal patch or iontophoresis device.

[0016] In a preferred embodiment, the pharmaceutical composition is orally administered, for example, as a solid or liquid formulation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets, effervescents, powders, etc. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, etc. In one embodiment of the present invention, the composition is formulated into a capsule. In another embodiment, the composition is formulated as a tablet.

[0017] Any inert excipient commonly used as a carrier or diluent, such as gum, starch, sugar, cellulose-based material, acrylate, or a mixture thereof, can be used in the pharmaceutical composition of the present invention.A preferred diluent is microcrystalline cellulose.The composition may further comprise a disintegrant (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and may further comprise one or more additives selected from binders, buffers, protease inhibitors, surfactants, solubilizers, plasticizers, emulsifiers, stabilizers, thickeners, sweeteners, film-forming agents, or any combination thereof.In addition, the composition of the present invention may be in the form of a controlled-release formulation or an immediate-release formulation.

[0018] For liquid formulations, pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, emulsions, or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Examples of oils include those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil. The solution or suspension can also contain the following components: a sterile diluent, such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, or phosphates, and agents for adjusting isotonicity, such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0019] Additionally, the compositions may contain binders (e.g., acacia, corn starch, gelatin, carbomer, ethylcellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone), disintegrants (e.g., corn starch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers of various pH and ionic strength (e.g., Tris-HCl, acetate, phosphate), additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizers (e.g., glycerol, polyethylene glycerol, polyethylene glycol), glidants (e.g., colloidal silicon dioxide), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose), thickeners (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavorings (e.g., peppermint, salicylic acid The formulation may further comprise additives such as methyl cellulose, methyl or orange flavoring, preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamer or poloxamine), coating and film formers (e.g., ethyl cellulose, acrylates, polymethacrylates) and / or adjuvants.

[0020] In some embodiments, the active compound is prepared with a carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be clear to those skilled in the art. These materials are also commercially available. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. They can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0021] For ease of administration and uniformity of dosage, it is particularly advantageous to prepare oral compositions in unit dosage form.As used herein, " unit dosage form " refers to a physically separate unit that is suitable as a unit dosage for the subject to be treated, and each unit contains a predetermined amount of active compound that is calculated to produce desired therapeutic effect together with required pharmaceutical carrier.The specification of unit dosage form of the present invention is determined by and directly depends on the inherent characteristics of active compound and the specific therapeutic effect that should be achieved, and the inherent limitation of the technology that combines these active compounds for individual treatment.

[0022] Formulations of the invention intended for oral administration may include one or more permeation enhancers, including long chain fatty acids or salts thereof, such as decanoic acid and sodium decanoate.

[0023] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0024] The pharmaceutical compositions of the present invention are preferably suitable for oral administration and are most preferably in the form of a tablet. In one embodiment, the pharmaceutical composition is a tablet comprising Compound 1. In certain embodiments, the tablet comprises Compound 1 in the form of the free base. In certain embodiments, the tablet comprises Compound 1 free base in an amount of 100 mg to 500 mg, 150 mg to 450 mg, 200 mg to 350 mg, 200 mg to 300 mg, 225 mg to 275 mg, 240 mg to 260 mg, or 250 mg.

[0025] In certain embodiments, the tablet comprises Compound 1 free base in an amount of 0.5 mg to 300 mg, 0.5 mg to 250 mg, 0.5 mg to 225 mg, 0.5 mg to 200 mg, 0.5 mg to 175 mg, 0.5 mg to 150 mg, 0.5 mg to 125 mg, 0.5 mg to 100 mg, 0.5 mg to 75 mg, 0.5 mg to 50 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 0.5 mg to 10 mg, or 0.5 mg to 5 mg.

[0026] In certain embodiments, the tablet comprises Compound 1 free base in an amount of 1 mg to 300 mg, 1 mg to 250 mg, 1 mg to 225 mg, 1 mg to 200 mg, 1 mg to 175 mg, 1 mg to 150 mg, 1 mg to 125 mg, 1 mg to 100 mg, 1 mg to 75 mg, 1 mg to 50 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, or 1 mg to 5 mg.

[0027] In certain embodiments, the tablet contains Compound 1 free base in an amount of 10 mg to 400 mg. In certain embodiments, the tablet contains Compound 1 free base in an amount of 10 mg to 300 mg, 10 mg to 250 mg, 10 mg to 225 mg, 10 mg to 200 mg, 10 mg to 175 mg, 10 mg to 150 mg, 10 mg to 125 mg, 10 mg to 100 mg, 10 mg to 75 mg, 10 mg to 50 mg, 10 mg to 20 mg, 10 mg to 15 mg per day, or 10 mg.

[0028] In certain embodiments, tablets contain Compound 1 free base in an amount of 20 mg to 300 mg, 25 mg to 275 mg, 30 mg to 260 mg, or 250 mg. In certain embodiments, tablets contain Compound 1 in an amount of 20 mg to 300 mg, 20 mg to 250 mg, 20 mg to 200 mg, 20 mg to 175 mg, 20 mg to 150 mg, 20 mg to 125 mg, 20 mg to 100 mg, 20 mg to 50 mg, 20 mg to 30 mg per day, 25 mg per day, or 20 mg per day. In certain embodiments, tablets contain Compound 1 in an amount of 50 mg to 150 mg, 60 mg to 140 mg, 70 mg to 130 mg, 75 mg to 125 mg, 80 mg to 120 mg, 90 mg to 110 mg, or 100 mg. In certain embodiments, the tablet comprises Compound 1 in an amount of 50 mg to 200 mg, 60 mg to 190 mg, 70 mg to 180 mg, 80 mg to 170 mg, 90 mg to 160 mg, 100 mg to 150 mg, 110 mg to 140 mg, 115 mg to 135 mg, or 125 mg.

[0029] Alternatively, the tablet contains a pharmaceutically acceptable salt of Compound 1 in the aforementioned amount, where the amount represents the free base equivalent. In certain embodiments, for example, the tablet contains 0.5 mg to 125 mg or 0.5 to 250 mg of the free base equivalent of a pharmaceutically acceptable salt of Compound 1.

[0030] The pharmaceutical composition can be administered daily or according to a suitable schedule.In one embodiment, daily administration is repeated continuously for a period of several days to several years.Oral treatment can be continued for one week to the patient's lifetime.Administration can be continuous or intermittent, for example, treatment for several consecutive days followed by a drug-free period.

[0031] The amount of the compound administered to a patient is preferably less than an amount that may cause toxicity in the patient. In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof administered to a patient is less than an amount that would cause the concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound.

[0032] The dosing schedules described herein describe the administration of Compound 1, which can be administered in free base form or as a pharmaceutically acceptable salt. The amount of Compound 1 administered in the dosing regimens described herein refers to the amount of the free base form of Compound 1, or, in the case of a pharmaceutically acceptable salt, the free base equivalent.

[0033] In certain embodiments, Compound 1 is administered to a human subject in the methods of the invention at a dose of 0.5 mg to 400 mg per day. Compound 1 is administered in an amount of 0.5 mg to 300 mg / day, 0.5 mg to 250 mg / day, 0.5 mg to 225 mg / day, 0.5 mg to 200 mg / day, 0.5 mg to 175 mg / day, 0.5 mg to 150 mg / day, 0.5 mg to 125 mg / day, 0.5 mg to 100 mg / day, 0.5 mg to 75 mg / day, 0.5 mg to 50 mg / day, 0.5 mg to 20 mg / day, 0.5 mg to 15 mg / day, 0.5 mg to 10 mg / day, 0.5 mg to 5 mg / day, or 0.5 mg to 2 mg / day.

[0034] In certain embodiments, Compound 1 is administered in an amount of 1 mg to 300 mg per day, 1 mg to 250 mg per day, 1 mg to 225 mg per day, 1 mg to 200 mg per day, 1 mg to 175 mg per day, 1 mg to 150 mg per day, 1 mg to 125 mg per day, 1 mg to 100 mg per day, 1 mg to 75 mg per day, 1 mg to 50 mg per day, 1 mg to 20 mg per day, 1 mg to 15 mg per day, 1 mg to 10 mg per day, or 1 mg to 5 mg per day, or 1 mg per day.

[0035] In certain embodiments, Compound 1 is administered at a dose of 10 mg to 400 mg per day. In certain embodiments, Compound 1 is administered at a dose of 10 mg to 300 mg per day, 10 mg to 250 mg per day, 10 mg to 225 mg per day, 10 mg to 200 mg per day, 10 mg to 175 mg per day, 10 mg to 150 mg per day, 10 mg to 125 mg per day, 10 mg to 100 mg per day, 10 mg to 75 mg per day, 10 mg to 50 mg per day, 10 mg to 20 mg per day, 10 mg to 15 mg per day, or 10 mg per day. In certain embodiments, Compound 1 is orally administered to a subject at a dose of 20 mg to 300 mg per day, 25 mg to 275 mg per day, 30 mg to 260 mg per day, or 250 mg per day. In certain embodiments, Compound 1 is orally administered to a subject at a dose of 20 mg to 300 mg / day, 20 mg to 250 mg / day, 20 mg to 200 mg / day, 20 mg to 175 mg / day, 20 mg to 150 mg / day, 20 mg to 125 mg / day, 20 mg to 100 mg / day, 20 mg to 50 mg / day, 20 mg to 30 mg / day, 25 mg / day, or 20 mg / day. In certain embodiments, Compound 1 is orally administered to a subject at a dose of 50 mg to 150 mg / day, 60 mg to 140 mg / day, 70 mg to 130 mg / day, 75 mg to 125 mg / day, 80 mg to 120 mg / day, 90 mg to 110 mg / day, or 100 mg / day. In certain embodiments, Compound 1 is orally administered to a subject at a dose of 50 mg to 200 mg per day, 60 mg to 190 mg per day, 70 mg to 180 mg per day, 80 mg to 170 mg per day, 90 mg to 160 mg per day, 100 mg to 150 mg per day, 110 mg to 140 mg per day, 115 mg to 135 mg per day, or 125 mg per day.

[0036] In certain embodiments, Compound 1 is orally administered to a human subject at a dose of 150 mg to 300 mg per day, 200 mg to 300 mg per day, 225 mg to 275 mg per day, 240 mg to 260 mg per day, or 250 mg per day.

[0037] As used herein, the term "day of administration" refers to the day on which Compound 1 is administered to a subject in the form of a free base or a pharmaceutically acceptable salt. In certain embodiments, Compound 1 is administered to a subject daily. In other embodiments, Compound 1 is administered every other day. In certain embodiments, Compound 1 is administered to a subject three days per week, preferably on non-consecutive days, for example, Monday, Wednesday, and Friday.

[0038] In certain embodiments, Compound 1 is initially administered to a human subject at a loading dose of 200-300 mg per day for an appropriate period of time, e.g., 1-12 weeks, 2-10 weeks, or 4-8 weeks. The loading dose is preferably administered daily. The loading dose may be followed by a reduced maintenance dose, e.g., a reduced dosing schedule and / or reduced dose per day, as described above. For example, Compound 1 may be administered at a loading dose of 200-250 mg per day for 4-8 weeks, followed by a maintenance dose of 0.5-200 mg per day, provided that the maintenance dose is a lower dose per day and / or is administered less frequently than the loading dose. In certain embodiments, the loading dose is 200 mg to 250 mg per day for 4 to 8 weeks, and the maintenance dose is 0.5 mg to 200 mg or 20 mg to 200 mg per day of administration, provided that the maintenance dose is lower and / or administered less frequently than the loading dose.

[0039] The administration of Compound 1 or its pharmaceutically acceptable salt can be continued for any period, preferably at least 16 weeks or more. Preferably, the administration is continued as long as the subject shows clinical improvement in the signs and symptoms of HS.

[0040] Administration of Compound 1 or a pharmaceutically acceptable salt thereof as described above may be interrupted by an occasional period of one or more days during which administration is suspended, after which administration may be continued as scheduled or upon recurrence or worsening of the signs and symptoms of HS.

[0041] A subject's response to the therapeutic methods of the present invention for treating HS can be determined as known in the art. For example, the subject may be evaluated using a Physician's Global Assessment (HS-PGA), a Dermatology Life Quality Index (DLQI), and / or an HS Clinical Response Score (HiSCR). 50 ,HiSCR 75 ,HiSCR 90 ) can be evaluated according to (see Ann Intern Med,.2012;157:846-855; J Eur Acad Dermatol Venereol 201;30:989-994; J Eur Acad Dermatol Venereol 2019;33:1633-1643).

[0042] definition Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0043] The compound of Formula I can be formulated and administered in the method of the present invention as a free base or a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compound of the present invention, or separately by reacting the free base functional group with a suitable organic or inorganic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts include, but are not limited to, salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, lactobionic acid, or malonic acid, or by using other methods used 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionic acid, and the like. These salts include, but are not limited to, phosphate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0044] As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., compatible with pharmaceutical administration, such as sterile pyrogen-free water. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference text in this field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils can also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the composition is contemplated.

[0045] The term "subject" as used herein refers to an animal. Preferably, the animal is a mammal. More preferably, the subject is a human. In certain embodiments, the subject is a companion animal or working animal, such as a domestic dog or cat, or a livestock animal, such as a horse, cow, sheep, or pig.

[0046] The terms "therapeutically effective amount" and "effective amount" of a therapeutic agent refer to an amount of such agent that confers a therapeutic effect on a treated subject at a reasonable benefit / risk ratio applicable to the treatment of HS or apocrine gland infection. The therapeutically effective amount of an agent may be different when used as a single agent than when used in combination with one or more other agents. Furthermore, the therapeutically effective amount of an agent may depend on the specific combination of agents administered. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows an indication of or feels an effect). The therapeutically effective dose also varies depending on the route of administration and the possibility of co-administration with other agents. However, it will be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; drugs used in combination or concomitantly with the particular compound used; and similar factors well known in the medical arts.

[0047] When the patient's condition improves, the maintenance dose of the compound or composition of the present invention can be administered as needed.Then, the dosage or the frequency of administration, or both, can be reduced according to the function of symptoms, until the symptom is alleviated to the desired level, and the improved condition is maintained.However, the patient may need to be treated intermittently on a long-term basis based on the recurrence of disease symptoms.

[0048] Preparation of Compounds of Formula (I) Compounds of Formula I, including compounds 1-9, can be prepared using the methods disclosed in published PCT application no. WO2008 / 115719. [Example]

[0049] Example 1 Clinical trial of Compound 1 in patients with hidradenitis suppurativa A placebo-controlled clinical trial was conducted to evaluate the efficacy of Compound 1 in patients with HS. The study design is summarized below.

[0050] Fifteen patients were enrolled in the study and randomly assigned to either the compound 1 group (10 patients) or the placebo group (5 patients). The study was open to male or female subjects aged 18 years or older with hidradenitis suppurativa and a minimum of five inflammatory nodules in at least two different anatomical regions. The study was conducted in Denmark.

[0051] The study duration was approximately 24 weeks, including a 4-week screening period, a 16-week treatment period, and a 4-week observational follow-up period to assess for recurrence and flares of hidradenitis suppurativa.

[0052] The primary objective of this study was to evaluate the efficacy of Compound 1 in subjects with moderate to severe hidradenitis suppurativa. Secondary objectives were (1) to evaluate the efficacy of Compound 1 on other clinical disease activity parameters in subjects with moderate to severe hidradenitis suppurativa, and (2) to evaluate the safety of Compound 1 in subjects with moderate to severe hidradenitis suppurativa.

[0053] The primary efficacy outcome of the study was the proportion of subjects achieving a Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) score at week 16. Secondary efficacy outcomes were: (1) The proportion of subjects with clear or minimal Hidradenitis Suppurativa Physician Global Assessment (HS-PGA) scores at weeks 2, 4, 8, 12, 14, 16, and 20; (2) the proportion of subjects achieving HiSCR-50, HiSCR-75, and HiSCR-90 at weeks 2, 4, 8, 12, 14, 16, and 20; (3) change from baseline in the Dermatological Disease Life Quality Index (DLQI) total score at weeks 4, 8, 12, 16, and 20; (4) Change from baseline in Pain Numerical Ranging score at weeks 4, 8, 12, 16, and 20; (5) change and percent change from baseline in lesion counts (abscess count, inflammatory nodule count, AN count, and drainage tunnel count); (6) Change from baseline in skin biomarkers at week 16; (7) Changes from baseline in blood biomarkers at weeks 4, 8, 12, and 16.

[0054] Secondary safety endpoints were the incidence of treatment-emergent adverse events (TEAEs) and the incidence of related TEAEs.

[0055] Overall test plan: This was a 16-week treatment-free, randomized, double-blind, proof-of-concept study designed to evaluate the safety and efficacy of Compound 1 compared with placebo for use in a future efficacy Phase 2 trial.

[0056] Eligible subjects will complete a screening phase of up to four weeks and then be sequentially randomized (2:1) to one of two cohorts: a treatment cohort (n=10) or a placebo-control cohort (n=5) for a 16-week treatment phase followed by a four-week observational follow-up phase. During the 16-week treatment phase, subjects randomized to the treatment group will receive 250 mg of Compound 1 free base in tablet form, administered orally once daily. The 250 mg dose was selected based on the results of earlier oncology studies conducted at doses exceeding 1000 mg / day as the minimum safe dose, allowing for dose escalation if necessary. Subjects randomized to the placebo-control group will receive a placebo treatment once daily (microcrystalline cellulose, mannitol, crospovidone, Opadry II red, magnesium stearate, colloidal silicon dioxide).

[0057] Efficacy was assessed by HiSCR, HS-PGA, pain NRS, and DLQI. Safety was assessed by vital signs, physical examination, laboratory tests, ECG, and AE collection.

[0058] result The results of this study are summarized in Figures 1-5. Figure 1 shows that patients in the Compound 1 group showed a substantially greater reduction in AN counts from baseline at week 16 compared to controls. Figure 2 shows the change in HS-PGA for patients in the Compound 1 and control groups. The active group showed a mean reduction in HS-PGA of 0.8 compared to baseline, while the control group showed no change. Figures 3-5 show the HiSCR for subjects in the Compound 1 and control groups, respectively. 50 ,HiSCR 75 and HiSCR 90 Starting at week 12 and continuing through week 16, subjects in the Compound 1 group had a HiSCR 50 By week 14, 50% of subjects in the Compound 1 group achieved HiSCR compared with none in the control group. 75 Similarly, 30% of subjects in the Compound 1 group achieved HiSCR by week 16 compared with none in the control group. 90 was achieved.

[0059] The following table shows the change from baseline in each subject's International Hidradentitis Suppurativa Severity Score System (IHS4) score at week 16. (See Zouboulis et al., Br J Dermatol 2017;177:1401-1409.) Nine of 10 subjects in the Compound 1 group showed a decrease in IHS4 score. In contrast, two of the control group subjects showed a moderate decrease in IHS4 score, one's IHS4 score remained unchanged, and two's score increased.

[0060] [Table 1]

[0061] Example 2 Pharmacokinetic study of compound 1 The accumulation of Compound 1 in the skin of human HS patients in the clinical trial described in Example 1 was determined. Snap-frozen skin punch biopsies obtained at the 16-week visit showed high concentrations of Compound 1, indicating that Compound 1 accumulates in tissues targeted by HS therapy. Figure 6 is a graph showing the concentrations of Compound 1 found in biopsied tissues of subjects grouped according to their clinical response to Compound 1 therapy. After 16 weeks of treatment with Compound 1, the mean skin concentration was 7130 ng / mg, which corresponds to 16.1 mM.

[0062] The skin accumulation observed in this study was compared with plasma levels of Compound 1 determined in a previous study in healthy human volunteers. Six healthy male subjects received a single oral dose of 250 mg of Compound 1, and plasma samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 72, and 96 hours post-dose. The results of this study are shown in the table below.

[0063] [Table 2]

[0064] C of Compound 1 determined for six subjects max ranged from 19.42 ng / mL to 24.92 ng / mL, with a median of 20.3 ng / mL or 46 nM.

[0065] The results show that accumulation of Compound 1 is approximately 100,000-fold higher in the skin than in the plasma after daily oral administration of 250 mg. Furthermore, the observed skin concentrations are within the IC50 of Compound 1 for inhibition of HSP-90. 50 (0.1 μM) to approximately 10 4 Those skilled in the art will appreciate that a daily oral dose of Compound 1 significantly less than 250 mg, for example as low as 1 mg per day, will result in sufficient dermal accumulation of Compound 1 to inhibit HSP-90 in the skin and thereby treat HS.

[0066] The patents and scientific literature referred to herein establish knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated herein by reference. All published foreign patents and foreign patent applications cited herein are incorporated herein by reference. All other published references, documents, manuscripts and scientific literature cited herein are incorporated herein by reference.

[0067] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. A method for treating hidradenitis suppurativa in a patient requiring treatment for hidradenitis suppurativa, comprising a therapeutically effective amount of a compound of formula (I), 【Chemistry 1】 (In the formula, R is halogen, amino, -NH(C) １ -C ３ -alkyl) or -N(C １ -C ３ -Alkyl) ２ And; n is either 1 or 2. A method comprising administering to the subject a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) is the compound shown below. 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 The method according to claim 1, selected from the following.

3. The compound of formula (I) above, 【Chemistry 11】 The method according to claim 2.

4. The method according to any one of claims 1 to 3, wherein the subject has hidradenitis suppurativa of stage I.

5. The method according to any one of claims 1 to 3, wherein the subject has hidradenitis suppurativa of stage II.

6. The method according to any one of claims 1 to 3, wherein the subject has hidradenitis suppurativa of stage III.

7. The method according to claim 3, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a rate of 1 to 7 days per week.

8. The method according to claim 7, wherein compound 1 is orally administered to the subject as a free base in a dose of 0.5 mg to 400 mg per day of administration.

9. The method according to claim 8, wherein compound 1 is orally administered to the subject as a free base in doses of 0.5 mg to 300 mg / day, 0.5 mg to 250 mg / day, 0.5 mg to 225 mg / day, 0.5 mg to 200 mg / day, 0.5 mg to 175 mg / day, 0.5 mg to 150 mg / day, 0.5 mg to 125 mg / day, 0.5 mg to 100 mg / day, 0.5 mg to 75 mg / day, 0.5 mg to 50 mg / day, 0.5 mg to 20 mg / day, 0.5 mg to 15 mg / day, 0.5 mg to 10 mg / day, 0.5 mg to 5 mg / day, 0.5 mg to 3 mg / day, or 0.5 mg to 2 mg / day.

10. The method according to claim 8, wherein compound 1 is orally administered to the subject as a free base in doses of 1 mg to 300 mg / day, 1 mg to 250 mg / day, 1 mg to 225 mg / day, 1 mg to 200 mg / day, 1 mg to 175 mg / day, 1 mg to 150 mg / day, 1 mg to 125 mg / day, 1 mg to 100 mg / day, 1 mg to 75 mg / day, 1 mg to 50 mg / day, 1 mg to 20 mg / day, 1 mg to 15 mg / day, 1 mg to 10 mg / day, or 1 mg to 5 mg / day, or 1 mg / day.

11. The method according to claim 8, wherein compound 1 is orally administered to the subject as a free base in doses of 10 mg to 400 mg / day, 10 mg to 300 mg / day, 10 mg to 250 mg / day, 10 mg to 225 mg / day, 10 mg to 200 mg / day, 10 mg to 175 mg / day, 10 mg to 150 mg / day, 10 mg to 125 mg / day, 10 mg to 100 mg / day, 10 mg to 75 mg / day, 10 mg to 50 mg / day, 10 mg to 20 mg / day, 10 mg to 15 mg / day, or 10 mg / day.

12. The method according to claim 8, wherein compound 1 is orally administered to the subject at doses of 225 mg to 275 mg / day, 240 mg to 260 mg / day, 245 mg to 255 mg / day, or 250 mg / day.

13. The method according to claim 7, wherein a pharmaceutically acceptable salt of compound 1 is orally administered to the subject in an amount of 0.5 mg to 400 mg of free base equivalent per day of administration.

14. The method according to claim 13, wherein the pharmaceutically acceptable salt of compound 1 is orally administered to the subject in the amount of free base equivalent of 0.5 mg to 300 mg / day, 0.5 mg to 250 mg / day, 0.5 mg to 225 mg / day, 0.5 mg to 200 mg / day, 0.5 mg to 175 mg / day, 0.5 mg to 150 mg / day, 0.5 mg to 125 mg / day, 0.5 mg to 100 mg / day, 0.5 mg to 75 mg / day, 0.5 mg to 50 mg / day, 0.5 mg to 20 mg / day, 0.5 mg to 15 mg / day, 0.5 mg to 10 mg / day, 0.5 mg to 5 mg / day, 0.5 mg to 3 mg / day, or 0.5 mg to 2 mg / day.

15. The method according to claim 13, wherein the pharmaceutically acceptable salt of compound 1 is orally administered to the subject in the free base equivalent of 1 mg to 300 mg / day, 1 mg to 250 mg / day, 1 mg to 225 mg / day, 1 mg to 200 mg / day, 1 mg to 175 mg / day, 1 mg to 150 mg / day, 1 mg to 125 mg / day, 1 mg to 100 mg / day, 1 mg to 75 mg / day, 1 mg to 50 mg / day, 1 mg to 20 mg / day, 1 mg to 15 mg / day, 1 mg to 10 mg / day, or 1 mg to 5 mg / day, or 1 mg / day.

16. The method according to claim 13, wherein the pharmaceutically acceptable salt of compound 1 is orally administered to the subject in the free base equivalent of 10 mg to 400 mg / day, 10 mg to 300 mg / day, 10 mg to 250 mg / day, 10 mg to 225 mg / day, 10 mg to 200 mg / day, 10 mg to 175 mg / day, 10 mg to 150 mg / day, 10 mg to 125 mg / day, 10 mg to 100 mg / day, 10 mg to 75 mg / day, 10 mg to 50 mg / day, 10 mg to 20 mg / day, 10 mg to 15 mg / day, or 10 mg / day.

17. The method according to claim 13, wherein the pharmaceutically acceptable salt of compound 1 is orally administered to the subject in a free base equivalent of 225 mg to 275 mg / day, 240 mg to 260 mg / day, 245 mg to 255 mg / day, or 250 mg / day.

18. The method according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally in the form of a tablet.

19. The method according to claim 12, wherein the compound of formula (I) is compound 1, and the tablet contains 0.5 mg to 300 mg of compound 1 or a pharmaceutically acceptable salt thereof in free base equivalent.

20. The method according to claim 13, wherein the free base equivalent of compound 1 or a pharmaceutically acceptable salt thereof is 1 to 275 mg, 10 to 150 mg, 50 to 150 mg, or 100 mg.

21. The method according to claim 14, wherein the free base equivalent of compound 1 or a pharmaceutically acceptable salt thereof is 125 or 250 mg.

22. The method according to claim 12, wherein the tablet contains compound 1 free base in an amount of 10, 50, 75, 100, 125, 150, 175, 200, 225, or 250 mg.

23. A method for treating apocrine gland infection in non-human subjects requiring treatment of apocrine gland infection, comprising a therapeutically effective amount of a compound of formula (I), 【Chemistry 12】 (wherein, R is halogen, amino, -NH(C １ -C ３ -alkyl) or -N(C １ -C ３ -alkyl) ２ is; n is either 1 or 2. A method comprising administering to the subject a pharmaceutically acceptable salt thereof.

24. The compound of formula (I) is the compound shown below. 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 The method according to claim 18, selected from the following.

25. The compound of formula (I) above, 【Chemistry 22】 The method according to claim 19.

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