Methods and compositions for treating hidradenitis suppurativa

Abstract

The present invention provides compositions and methods for the treatment of hidradenitis suppurativa (HS) or apocrine gland infection. In one embodiment, the present invention provides a method of treating HS or apocrine gland infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I): wherein R is halogen, amino,-NH (C1-C3-alkyl) or-N (C1-C3-alkyl) 2, n is 1 or 2, or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 413,883, filed Oct. 6, 2022; U.S. Provisional Application No. 63 / 444,038, filed Feb. 8, 2023; and U.S. Provisional Application No. 63 / 525,788, filed Jul. 10, 2023. The entire teachings of the above applications are incorporated herein by reference. Background of the Invention

[0003] Hidradenitis suppurativa (HS) is a chronic disease that affects 1% to 2% of the population and typically presents during childhood or adolescence. HS manifests as skin lesions including deep nodules and abscesses, sinus tracts, and fibrotic scars, which most commonly occur in apocrine-rich and intertriginous areas such as the axillae, groin, perianal, perineal, and sub-mammary regions. Adalimumab is the only FDA-approved treatment for HS, and treatment failure is common (Saunte, D.M.L. & Jemec, G.B.E., J Am Med Assoc 318, 2019-2032 (2017)). Advances in the understanding of the pathophysiology of HS have highlighted resident and migratory cells of the innate immune system and IL-1b, TNFa, and the NLRP3 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)). Although adalimumab and other drugs currently under development target specific inflammatory cytokines in HS, there is no therapy that uniformly downregulates the inflammatory mediators of HS, including IL-1b and the NLRP3 inflammasome (Saunte, D.M.L. & Jemec, G.B.E., ibid; Danby, F.W. & Margesson, L.J., Dermatol Clin 28, 779-793 (2010)). Thus, there is a need for new compositions and methods for treating HS. Summary of the Invention

[0004] The present invention provides compositions and methods for treating hidradenitis suppurativa (HS).

[0005] In one embodiment, the present invention provides a method of treating HS in a 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, wherein R is halogen, amino, -NH(C 1 -C 3 -alkyl) or -N(C1 -C 3 -alkyl) 2 , where n is 1 or 2.

[0006]

[0007] In another embodiment, the present invention provides a method for treating hidradenitis suppurativa 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.

[0008] The present invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for treating HS or hidradenitis suppurativa. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The foregoing and other objects, features and advantages of the present invention will become more apparent from the following more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings.

[0010] Figure 1 is a graph showing the reduction of abscess / nodule (AN) counts relative to baseline at week 16 for compound 1 and the control group in the study described in Example 1.

[0011] Figure 2 is a graph showing the reduction of HS physician's global assessment (HS-PGA) relative to baseline at week 16 for compound 1 and the control group in the study described in Example 1.

[0012] Figure 3 is a graph showing HS clinical response-50 (HiSCR-50) relative to baseline at week 16 for compound 1 and the control group in the study described in Example 1.

[0013] Figure 4 is a graph showing HS clinical response-75 (HiSCR-75) relative to baseline at week 16 for compound 1 and the control group in the study described in Example 1.

[0014] Figure 5 is a graph showing HS clinical response-90 (HiSCR-90) relative to baseline at week 16 for compound 1 and the control group in the study described in Example 1.

[0015] Figure 6A graph showing the concentration of Compound 1 found in biopsy tissues of subjects grouped according to their clinical response to treatment with Compound 1. Detailed Description

[0016] 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 infections in non-human subjects.

[0017] The compounds of formula I are potent inhibitors of heat shock protein 90 (HSP90). Examples of the synthesis and HSP90 inhibitory activity of specific compounds of formula I are described in WO2008 / 115719, the content of which is incorporated herein by reference in its entirety.

[0018] In preferred compounds of formula (I), R is chlorine, bromine, iodine, amino, methylamino or dimethylamino. In a specific embodiment of the compounds of formula I, n is 1. In other embodiments of the compounds of formula I, n is 2. Suitable compounds of formula I include, but are not limited to, the compounds listed below.

[0019]

[0020]

[0021]

[0022]

[0023] A particularly preferred compound of formula I is Compound 1, which is also known as CUDC-305, Debio-0932 and RGRN-305.

[0024] In the method of treating HS of the present invention, the subject is preferably a human subject. The subject can have HS symptoms of any severity. For example, the subject can have Hurley stage I HS, Hurley stage II HS or Hurley stage III HS.

[0025] In the method of treating apocrine gland infections of the present invention, the non-human subject is preferably a mammal, preferably a domesticated mammal. In a specific embodiment, the subject is a companion animal or a draft animal (such as a domesticated canine (dog) or feline (cat)) or a livestock animal (such as a cow, sheep, horse or pig).

[0026] The compound of formula I or a pharmaceutically acceptable salt thereof is preferably administered in the form of a pharmaceutical composition comprising a therapeutic agent and a pharmaceutically acceptable carrier, excipient or diluent. Suitable pharmaceutical compositions include solid preparations, semi-solid preparations or liquid preparations (tablets, pills, lozenges, capsules, suppositories, creams, ointments, aerosols, powders, liquids, emulsions, suspensions, syrups, injections, etc.). The pharmaceutical composition can be administered by any suitable means, including but not limited to parenteral, intravenous, intramuscular, subcutaneous, implant, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, rectal or transmucosal administration, etc. Topical administration can include the use of transdermal administration, such as transdermal patches or iontophoresis devices.

[0027] In a preferred embodiment, the pharmaceutical composition is administered orally, for example as a solid or liquid preparation. Suitable solid oral preparations include tablets, capsules, pills, granules, pellets, sachets and effervescent agents and powders, etc. Suitable liquid oral preparations include solutions, suspensions, dispersions, emulsions, oils, etc. In one embodiment of the present invention, the composition is formulated in a capsule. In another embodiment, the composition is formulated as a tablet.

[0028] Any inert excipient commonly used as a carrier or diluent can be used in the pharmaceutical composition of the present invention, for example, gums, starches, sugars, cellulosic materials, acrylates or mixtures thereof. A preferred diluent is microcrystalline cellulose. The composition may also contain a disintegrant (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and may additionally contain one or more additives selected from binders, buffers, protease inhibitors, surfactants, solubilizers, plasticizers, emulsifiers, stabilizers, thickeners, sweeteners, film formers or any combination thereof. In addition, the composition of the present invention can be in the form of a controlled release or immediate release preparation.

[0029] For liquid preparations, 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, alcohol / water solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are oils of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil and cod liver oil. Solutions or suspensions may also include the following ingredients: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetate, citrate or phosphate; and tonicity regulators such as sodium chloride or glucose. The pH value can be adjusted with an acid or a base such as hydrochloric acid or sodium hydroxide.

[0030] In addition, the composition may further comprise binders (e.g., gum arabic, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone), disintegrants (e.g., corn starch, potato starch, alginic acid, silica, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, sodium carboxymethyl starch (Primogel)), buffers of various pH and ionic strength (e.g., tris-HCl, acetate, phosphate), additives for preventing adsorption to surfaces (such as albumin or gelatin), detergents (such as Tween 20, Tween 80, Pluronic F68, bile salts), protease inhibitors, surfactants (such as sodium dodecyl sulfate), permeation enhancers, solubilizers (e.g., glycerol, polyglycerol, polyethylene glycol), glidants (e.g., colloidal silica), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose), thickeners (e.g., carbomer, colloidal silica, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., mint, methyl salicylate or orange flavor), preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium dodecyl sulfate), glidants (e.g., colloidal silica), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium dodecyl sulfate), polymer coatings (e.g., poloxamer or poloxamine), coating and film-forming agents (e.g., ethyl cellulose, acrylate, polymethacrylate) and / or adjuvants.

[0031] In some embodiments, the active compound is prepared with a carrier that will protect the compound from rapid elimination from the body, such as controlled release formulations including implants and microencapsulation 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 apparent to those skilled in the art. The materials are also available commercially. Liposome suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared by methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0032] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral compositions in unit dosage forms. As used herein, "unit dosage form" refers to physically discrete units suitable as a single dose for a subject to be treated; each unit contains a predetermined amount of the active compound which, together with the required pharmaceutical carrier, produces the desired therapeutic effect. The specifications of the unit dosage forms of the present invention are determined by the unique characteristics of the active compound and the particular therapeutic effect to be achieved, as well as the limitations inherent in the art of formulating such active compounds for individual therapy, and directly depend on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, as well as the limitations inherent in the art of formulating such active compounds for individual therapy.

[0033] The preparations of the present invention for oral administration may include one or more penetration enhancers, including long-chain fatty acids or their salts (such as capric acid and sodium caprate).

[0034] The pharmaceutical composition may be included in a container, package or dispenser together with instructions for administration.

[0035] The pharmaceutical composition of the present invention is preferably suitable for oral administration, most preferably in the form of tablets. In one embodiment, the pharmaceutical composition is a tablet comprising Compound 1. In a particular embodiment, the tablet comprises Compound 1 in free base form. In a particular embodiment, the tablet comprises an amount of Compound 1 free base 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 to 260 mg or 250 mg.

[0036] In a particular embodiment, the tablet comprises an amount of Compound 1 free base 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.

[0037] In a particular embodiment, the tablet comprises an amount of Compound 1 free base 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.

[0038] In certain embodiments, the tablet contains from 10 mg to 400 mg of Compound 1 free base. In certain embodiments, the tablet contains from 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, or 10 mg of Compound 1 free base per dosing day.

[0039] In certain embodiments, the tablet contains from 20 mg to 300 mg, 25 mg to 275 mg, 30 mg to 260 mg, or 250 mg of Compound 1 free base. In certain embodiments, the tablet contains from 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 dosing day, 25 mg per dosing day, or 20 mg per dosing day of Compound 1. In certain embodiments, the tablet contains from 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 of Compound 1. In certain embodiments, the tablet contains from 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 of Compound 1.

[0040] Alternatively, the tablet contains a pharmaceutically acceptable salt of Compound 1 in the foregoing amounts, where the amount represents the free base equivalent. In certain embodiments, for example, the tablet contains from 0.5 mg to 125 mg or from 0.5 mg to 250 mg of the free base equivalent of the pharmaceutically acceptable salt of Compound 1.

[0041] The pharmaceutical composition can be administered daily or according to a suitable schedule. In one embodiment, daily administration is repeated continuously for several days to several years. Oral treatment can continue for one week to the end of the patient's life. Administration can be continuous or intermittent, e.g., continuous treatment for several days followed by a period of rest.

[0042] The amount of the compound administered to the patient is preferably less than the amount that would be toxic to the patient. In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt administered to the patient is less than the amount that would cause the concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound.

[0043] The dosing regimens described herein describe the administration of Compound 1, which can be administered in the form of the free base or a pharmaceutically acceptable salt. Any amount of Compound 1 administered in the dosing regimens described herein refers to the amount of Compound 1 in the free base form, or, in the case of a pharmaceutically acceptable salt, the amount of the free base equivalent.

[0044] In certain embodiments, Compound 1 is administered to human subjects at a dose of 0.5 mg to 400 mg per dosing day in the methods of the present invention. Compound 1 is administered in an amount of 0.5 mg to 300 mg per dosing day, 0.5 mg to 250 mg per dosing day, 0.5 mg to 225 mg per dosing day, 0.5 mg to 200 mg per dosing day, 0.5 mg to 175 mg per dosing day, 0.5 mg to 150 mg per dosing day, 0.5 mg to 125 mg per dosing day, 0.5 mg to 100 mg per dosing day, 0.5 mg to 75 mg per dosing day, 0.5 mg to 50 mg per dosing day, 0.5 mg to 20 mg per dosing day, 0.5 mg to 15 mg per dosing day, 0.5 mg to 10 mg per dosing day, 0.5 mg to 5 mg per dosing day, or 0.5 mg to 2 mg per dosing day.

[0045] In certain embodiments, Compound 1 is administered in an amount of 1 mg to 300 mg per dosing day, 1 mg to 250 mg per dosing day, 1 mg to 225 mg per dosing day, 1 mg to 200 mg per dosing day, 1 mg to 175 mg per dosing day, 1 mg to 150 mg per dosing day, 1 mg to 125 mg per dosing day, 1 mg to 100 mg per dosing day, 1 mg to 75 mg per dosing day, 1 mg to 50 mg per dosing day, 1 mg to 20 mg per dosing day, 1 mg to 15 mg per dosing day, 1 mg to 10 mg per dosing day, 1 mg to 5 mg per dosing day, or 1 mg per dosing day.

[0046] In certain embodiments, Compound 1 is administered at a dose of 10 mg to 400 mg per dosing day. In certain embodiments, Compound 1 is administered in an amount of 10 mg to 300 mg per dosing day, 10 mg to 250 mg per dosing day, 10 mg to 225 mg per dosing day, 10 mg to 200 mg per dosing day, 10 mg to 175 mg per dosing day, 10 mg to 150 mg per dosing day, 10 mg to 125 mg per dosing day, 10 mg to 100 mg per dosing day, 10 mg to 75 mg per dosing day, 10 mg to 50 mg per dosing day, 10 mg to 20 mg per dosing day, 10 mg to 15 mg per dosing day, or 10 mg per dosing day. In certain embodiments, Compound 1 is orally administered to a subject at a dose of 20 mg to 300 mg per dosing day, 25 mg to 275 mg per dosing day, 30 mg to 260 mg per dosing day, or 250 mg per dosing day. In certain embodiments, Compound 1 is orally administered to a subject at a dose of 20 mg to 300 mg per dosing day, 20 mg to 250 mg per dosing day, 20 mg to 200 mg per dosing day, 20 mg to 175 mg per day, 20 mg to 150 mg per dosing day, 20 mg to 125 mg per dosing day, 20 mg to 100 mg per dosing day, 20 mg to 50 mg per dosing day, 20 mg to 30 mg per dosing day, or 25 mg per dosing day. In certain embodiments, Compound 1 is orally administered to a subject at a dose of 50 mg to 150 mg per dosing day, 60 mg to 140 mg per dosing day, 70 mg to 130 mg per dosing day, 75 mg to 125 mg per dosing day, 80 mg to 120 mg per dosing day, 90 mg to 110 mg per dosing day, or 100 mg per dosing day. In certain embodiments, Compound 1 is orally administered to a subject at a dose of 50 mg to 200 mg per dosing day, 60 mg to 190 mg per dosing day, 70 mg to 180 mg per dosing day, 80 mg to 170 mg per dosing day, 90 mg to 160 mg per dosing day, 100 mg to 150 mg per dosing day, 110 mg to 140 mg per dosing day, 115 mg to 135 mg per dosing day, or 125 mg per dosing day.

[0047] In certain embodiments, Compound 1 is orally administered to a human subject at a dose of 150 mg to 300 mg per dosing day, 200 mg to 300 mg per dosing day, 225 mg to 275 mg per dosing day, 240 mg to 260 mg per dosing day, or 250 mg per dosing day.

[0048] As used herein, the term "treatment day" refers to the day on which Compound 1 in the form of the free base or a pharmaceutically acceptable salt is administered to a subject. In certain embodiments, Compound 1 is administered to the subject daily. In other embodiments, Compound 1 is administered every other day. In certain embodiments, Compound 1 is administered to the subject three days a week, preferably on non-consecutive days, such as on Monday, Wednesday, and Friday.

[0049] In certain embodiments, Compound 1 is initially administered to a human subject at a loading dose of 200 mg to 300 mg per treatment day for a suitable period of time, such as 1 to 12 weeks, 2 to 10 weeks, or 4 to 8 weeks. The loading dose is preferably administered daily. After the loading dose may be a reduced maintenance dose, for example, any of the reduced dosing regimens and / or reduced per-treatment-day doses as described above. For example, Compound 1 may be administered at a loading dose of 200 mg to 250 mg per treatment day for 4 to 8 weeks, followed by a maintenance dose of 0.5 mg to 200 mg per treatment day, provided that the maintenance dose is a lower per-treatment-day dose and / or the dosing frequency is lower than the loading dose. In certain embodiments, the loading dose is 200 mg to 250 mg per treatment day for 4 to 8 weeks, and the maintenance dose is 0.5 mg to 200 mg or 20 mg to 200 mg per treatment day, provided that the maintenance dose is lower than the loading dose and / or the dosing frequency is lower than the loading dose.

[0050] Administration of Compound 1 or a pharmaceutically acceptable salt thereof as described above may continue for any length of time, and preferably for at least 16 weeks or longer. Preferably, administration continues as long as the subject shows a clinical improvement in HS signs and symptoms.

[0051] Administration of Compound 1 or a pharmaceutically acceptable salt thereof as described above may be interrupted occasionally for a day or several days during which dosing is suspended, and then administration may be continued according to a predetermined regimen or when HS signs and symptoms recur or worsen.

[0052] The response of a subject to the method of treating HS of the present invention can be determined as is known in the art. For example, it can be based on the Physician’s Global Assessment (HS-PGA), the Dermatology Life Quality Index (DLQI), and / or the HS Clinical Response Score (HiSCR 50 、HiSCR 75 、HiSCR 90) to evaluate the subject. (See Ann Intern Med,.2012; 157:846-855; J Eur AcadDermatol Venereol 201; 30:989-994; J Eur Acad Dermatol Venereol 2019; 33:1633-1643).

[0053] Definition

[0054] The definitions of various terms used to describe the present invention are set forth below. These definitions apply to the terms used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0055] The compounds of formula I can be formulated and administered in the methods of the present invention as the free base or a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and having a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S.M. Berge et al. in J. Pharmaceutical Sciences, 66:1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base moiety with a suitable organic or inorganic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts include, but are not limited to, amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or amino salts formed with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, lactobionic acid, or malonic acid, or amino salts formed by using other methods such as ion exchange commonly used in the art. Other pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valerates, etc.

[0056] 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 the administration of a drug, such as sterile pyrogen-free water. Suitable carriers are described in the latest edition of Remington’s Pharmaceutical Sciences, which is a standard reference in the art and is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, normal saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous carriers, such as fixed oils, may also be used. The use of such media and agents for active pharmaceutical substances is well known in the art. Their use in the compositions is contemplated, except for any conventional media or agents that are incompatible with the active compound.

[0057] The term "subject" as used herein refers to an animal. Preferably, the animal is a mammal. Most preferably, the subject is a human. In certain embodiments, the subject is a companion animal or a working animal, such as a domesticated canine (dog) or feline (cat)) or a livestock animal (such as a cow, sheep, horse, or pig).

[0058] The "therapeutically effective amount" and "effective amount" of a therapeutic agent refer to the amount of the therapeutic agent that confers a therapeutic effect on the subject being treated, with a reasonable benefit / risk ratio applicable to the treatment of HS or apocrine gland infections. When used as a single drug, the therapeutically effective amount of the drug may be different from when used in combination with one or more other drugs. In addition, the therapeutically effective amount of the drug may depend on the specific combination of drugs to be administered. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of the effect or feels the effect). The therapeutically effective dose will also vary depending on the route of administration and the likelihood of co-administration with other drugs. However, it will be understood that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of the treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical arts.

[0059] Once the patient's condition improves, maintenance doses of the compounds or compositions of the invention may be administered if needed. Subsequently, the dose or frequency of administration, or both, may be reduced to a certain level according to the symptoms, and when the symptoms have been alleviated to the desired level, the improved condition is maintained at that level. However, once the symptoms of the disease recur, the patient may require long-term intermittent treatment.

[0060] Preparation of the compounds of formula (I)

[0061] The compounds of formula I including Compound 1 to Compound 9 can be prepared using the methods disclosed in the published PCT application No. WO2008 / 115719.

[0062] Examples

[0063] Clinical Study of Compound 1 in the Treatment of Hidradenitis Suppurativa in Example 1

[0064] A placebo-controlled clinical study was conducted to evaluate the efficacy of Compound 1 in patients with HS. The study design is summarized as follows.

[0065] Fifteen patients entered the study and were randomly assigned to the Compound 1 group (10 patients) or the placebo group (5 patients). This study was open to male or female subjects with hidradenitis suppurativa aged 18 years or older who had at least 5 inflammatory nodules in at least two different anatomical regions. This study was conducted in Denmark.

[0066] The study duration was approximately 24 weeks, including a 4-week screening period, a 16-week treatment period, and a 4-week observation follow-up period to evaluate the recurrence and exacerbation of hidradenitis suppurativa.

[0067] The primary objective of the study was to evaluate the efficacy of Compound 1 in subjects with moderate to severe hidradenitis suppurativa. The 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.

[0068] The primary efficacy endpoint of the study was the percentage of subjects who achieved a Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) score at week 16. The secondary efficacy endpoints were:

[0069] (1) The percentage of subjects with a clear or minimal Hidradenitis Suppurativa Physician's Global Assessment (HS-PGA) score at weeks 2, 4, 8, 12, 14, 16, and 20;

[0070] (2) The percentages of subjects who achieved HiSCR-50, HiSCR-75, and HiSCR-90 at week 2, week 4, week 8, week 12, week 14, week 16, and week 20;

[0071] (3) The changes in the total scores of the Dermatology Life Quality Index (DLQI) relative to baseline at week 4, week 8, week 12, week 16, and week 20;

[0072] (4) The changes in the pain numerical rating scale scores relative to baseline at week 4, week 8, week 12, week 16, and week 20;

[0073] (5) The changes and percentage changes in the lesion counts (abscess count, inflammatory nodule count, AN count, and drain tube count) relative to baseline;

[0074] (6) The changes in skin biomarkers at week 16 relative to baseline;

[0075] (7) The changes in blood biomarkers relative to baseline at week 4, week 8, week 12, and week 16.

[0076] The secondary safety endpoints were the incidence of treatment-emergent adverse events (TEAE) and the incidence of related TEAEs.

[0077] Overall Study Design:

[0078] This was a 16-week, treatment, randomized, double-blind, proof-of-concept study designed to evaluate the safety and efficacy of Compound 1 compared to placebo in a future Phase 2 efficacy trial.

[0079] Eligible subjects completed a screening period of up to 4 weeks and were randomly assigned in a 2:1 ratio to one of two cohorts (treatment cohort (n = 10) or placebo control cohort (n = 5)) during a 16-week treatment period followed by a 4-week observation follow-up period. During the 16-week treatment phase, subjects randomly assigned to the treatment group received once-daily oral administration of Compound 1 free base in the form of 250 mg tablets. The 250 mg dose was selected based on the results of early oncology trials using a safety minimum dose of more than 1000 mg / day (with dose escalation if needed). Subjects randomly assigned to the placebo control group received once-daily placebo treatment (microcrystalline cellulose, mannitol, crospovidone, Opadry II red, magnesium stearate, colloidal silicon dioxide).

[0080] HiSCR, HS-PGA, pain NRS, and DLQI were performed to evaluate the efficacy. Safety was evaluated by vital signs, physical examination, clinical laboratory tests, ECG, and AE collection.

[0081] Results

[0082] The study results are summarized in Figures 1 to 5 . Figure 1 It is shown that, compared with the control group, the patients in the compound 1 group showed a significantly greater decrease in AN count at week 16 relative to the baseline. Figure 2 It shows the changes in HS-PGA of the patients in the compound 1 group and the control group. Compared with the baseline, the average HS-PGA of the treatment group decreased by 0.8, while there was no change in the control group. Figures 3 to 5 The HiSCR of the subjects in the compound 1 group and the control group was compared separately 50 , HiSCR 75 and HiSCR 90 . Starting from week 12 and continuing to week 16, the subjects in the compound 1 group were more likely to achieve HiSCR 50 . By week 14, compared with no subjects in the control group, 50% of the subjects in the compound 1 group achieved HiSCR 75 . Similarly, compared with no subjects in the control group, 30% of the subjects in the compound 1 group achieved HiSCR at week 16 90 .

[0083] The following table shows the change in the International Hidradenitis Suppurativa Severity Score System (IHS4) score of each subject at week 16 relative to the baseline. (See Zouboulis et al., Br J Dermatol 2017 177:1401-1409). Nine out of ten subjects in the compound 1 group showed a decrease in the IHS4 score. In contrast, two subjects in the control group showed a moderate decrease in the IHS4 score, one subject's IHS4 score remained unchanged, and two increased.

[0084]

[0085]

[0086] Pharmacokinetics Study of Compound 1 in Example 2

[0087] The accumulation of compound 1 in the skin of human HS patients in the clinical study described in Example 1 was determined. A rapidly frozen skin punch biopsy obtained at the week 16 visit showed a high concentration of compound 1, indicating that compound 1 accumulates in the target tissue for HS treatment. Figure 6It is a graph showing the concentration of Compound 1 found in biopsy tissues of subjects grouped according to their clinical response to treatment with Compound 1. The average skin concentration after 16 weeks of treatment with Compound 1 was 7130 ng / mg, which is equivalent to 16.1 mM.

[0088] The skin accumulation found in this study was compared with the plasma levels of Compound 1 measured in a previous study in healthy human volunteers. Six healthy male subjects were given a single oral dose of 250 mg of Compound 1, and plasma samples were collected before dosing and at 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, and 96 hours after dosing. The results of this study are shown in the following table.

[0089]

[0090]

[0091] The C of Compound 1 measured 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.

[0092] The results showed that after oral administration at 250 mg per day, the accumulation of Compound 1 in the skin was approximately 100,000 times higher than in the plasma. In addition, the observed skin concentration exceeded the IC of Compound 1 for inhibiting HSP-90 (0.1 μM) 50 by approximately 10 4 times. Those skilled in the art will understand that a daily oral dose of Compound 1 significantly lower than 250 mg, for example, as low as 1 mg / day, will result in sufficient accumulation of Compound 1 in the skin to inhibit HSP-90 in the skin, thereby treating HS.

[0093] The patents and scientific literature mentioned herein establish the knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are incorporated by reference. All other published references, documents, manuscripts, and scientific literature cited herein are incorporated by reference.

[0094] Although the present invention has been specifically shown and described with reference to preferred embodiments thereof, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the invention as defined by the appended claims.

Claims

1. A method for treating hidradenitis suppurativa in a 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, wherein or a pharmaceutically acceptable salt thereof, wherein, R is halogen, amino, -NH(C 1 -C 3 -alkyl) or -N(C 1 -C 3 -alkyl) 2 ; and n is 1 or 2.

2. The method according to claim 1, wherein, the compound of formula (I) is selected from the compounds listed below 3. The method according to claim 2, wherein, the compound of formula (I) is 4. The method according to any one of claims 1 to 3, wherein, the subject has hidradenitis suppurativa of Hurley stage I.

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

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

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

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

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

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

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

12. The method according to claim 8, wherein, Compound 1 is orally administered to the subject at a dose of 225 mg to 275 mg per dosing day, 240 mg to 260 mg per dosing day, 245 mg to 255 mg per dosing day, or 250 mg per dosing day.

13. The method according to claim 7, wherein, The pharmaceutically acceptable salt of Compound 1 is orally administered to the subject at a free base equivalent dose of 0.5 mg to 400 mg per dosing day.

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

15. The method according to claim 13, wherein, The pharmaceutically acceptable salt of Compound 1 is orally administered to the subject at an equivalent dose of 1 mg to 300 mg per dosing day, 1 mg to 250 mg per dosing day, 1 mg to 225 mg per dosing day, 1 mg to 200 mg per dosing day, 1 mg to 175 mg per dosing day, 1 mg to 150 mg per dosing day, 1 mg to 125 mg per dosing day, 1 mg to 100 mg per dosing day, 1 mg to 75 mg per dosing day, 1 mg to 50 mg per dosing day, 1 mg to 20 mg per dosing day, 1 mg to 15 mg per dosing day, 1 mg to 10 mg per dosing day, 1 mg to 5 mg per dosing day, or 1 mg per dosing day.

16. 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 dose of 10 mg to 400 mg per dosing day, 10 mg to 300 mg per dosing day, 10 mg to 250 mg per dosing day, 10 mg to 225 mg per dosing day, 10 mg to 200 mg per dosing day, 10 mg to 175 mg per dosing day, 10 mg to 150 mg per dosing day, 10 mg to 125 mg per dosing day, 10 mg to 100 mg per dosing day, 10 mg to 75 mg per dosing day, 10 mg to 50 mg per dosing day, 10 mg to 20 mg per dosing day, 10 mg to 15 mg per dosing day, or 10 mg per dosing 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 dose of 225 mg to 275 mg per dosing day, 240 mg to 260 mg per dosing day, 245 mg to 255 mg per dosing day, or 250 mg per dosing day.

18. The method according to any one of claims 1 to 17, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is orally administered in tablet form.

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 free base equivalent of Compound 1 or its pharmaceutically acceptable salt.

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

21. The method according to claim 14, wherein, The free base equivalent of Compound 1 or its pharmaceutically acceptable salt is 125 mg or 250 mg.

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

23. A method of treating apocrine gland infections in a non-human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt, wherein, R is halogen, amino, -NH(C 1 -C 3 -alkyl) or -N(C 1 -C 3 -alkyl) 2 ; and n is 1 or 2.

24. The method according to claim 18, wherein, The compound of formula (I) is selected from the compounds listed below 25. The method according to claim 19, wherein, The compound of formula (I) is

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