Methods and compositions for treating discoid lupus erythematosus, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus

Abstract

This invention provides a composition and method for treating discoid lupus erythematosus, subacute cutaneous lupus erythematosus, or systemic lupus erythematosus. In one embodiment, the invention provides a method or compound for treating discoid lupus erythematosus, subacute cutaneous lupus erythematosus, or systemic lupus erythematosus in a subject with this need. The method comprises administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof. (1)

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 543,357, filed October 10, 2023, and U.S. Provisional Application No. 63 / 631,730, filed April 9, 2024. The entire teachings of the above applications are incorporated herein by reference. Background Technology

[0002] Discoid lupus erythematosus and subacute cutaneous lupus erythematosus are characterized by lesions on the face and scalp. Discoid lupus erythematosus is characterized by the formation of circular skin lesions. Treatment is usually based on the administration of steroids, such as injections or topical corticosteroids. Anti-inflammatory drugs such as dapsone or low-dose methotrexate can reduce pain and swelling.

[0003] Systemic lupus erythematosus (SLE) is a disease in which the immune system attacks multiple organs, producing a variety of adverse effects depending on the organs involved. Typically, 70% to 85% of SLE patients present with some degree of cutaneous manifestations, resembling lesions associated with discoid lupus erythematosus and subacute cutaneous lupus erythematosus. Up to 25% of SLE patients present with cutaneous symptoms as the initial symptom of the disease. (Yell, JA et al., *British Journal of Dermatology*, 1996, 135:355-362; Shi, H. et al., *Current Opinion on Rheumatology*, 2020, 32:208-214). Tukaj et al. reviewed heat shock proteins as potential therapeutic targets in the treatment of autoimmune diseases in "Cell Stress and Chaperones" (2019) 24:475-479 and "Biomolecules" (2022) 12,1153.

[0004] The role of HSP90 inhibitors has been investigated by Liu et al. ("The HSP90 Inhibitor Ganetspib Alleviates Disease Progression and Augments Intermittent Cyclophosphamide Therapy in the MRI / lpr Mouse Model of Systemic Lupus Erythematosus", PLOS ONE|DOI:10.1371 / journal.pone.0127361, May 14, 2015) in systemic lupus erythematosus (SLE), a complex systemic autoimmune disease with diverse immunological and clinical manifestations.

[0005] However, new compositions and methods are still needed for the treatment of discoid lupus erythematosus and subacute cutaneous lupus erythematosus. Summary of the Invention

[0006] This invention provides compositions and methods for treating discoid lupus erythematosus and subacute cutaneous lupus erythematosus. In one embodiment, the invention provides a method for treating a subject with discoid lupus erythematosus, systemic lupus erythematosus, or subacute cutaneous lupus erythematosus in need, comprising administering to the subject a therapeutically effective amount of compound 1.

[0007] (1)

[0009] Or its pharmaceutically acceptable salt.

[0010] The present invention further provides compound 1 or a pharmaceutically acceptable salt thereof for the treatment of discoid lupus erythematosus, systemic lupus erythematosus or subacute cutaneous lupus erythematosus. Attached Figure Description

[0011] Figure 1 The figure shows IL1B qPCR data after in vitro treatment with DMSO solvent or compound 1, using non-lesion and lesion skin biopsies taken from three patients with discoid lupus erythematosus.

[0012] Figure 2 The figure shows IFNγ qPCR data of non-lesion and lesion skin biopsies taken from three patients with discoid lupus erythematosus, after in vitro treatment with DMSO solvent or compound 1.

[0013] Figure 3The figure shows CXCL10 qPCR data after in vitro treatment with DMSO solvent or compound 1, using non-lesion and lesion skin biopsies taken from three patients with discoid lupus erythematosus.

[0014] Figure 4 The figure shows IL6 qPCR data after in vitro treatment with DMSO solvent or compound 1, using non-lesion and lesion skin biopsies taken from three patients with discoid lupus erythematosus.

[0015] Figure 5 The figure shows IL18 qPCR data after in vitro treatment with DMSO solvent or compound 1, using non-lesion and lesion skin biopsies taken from three patients with discoid lupus erythematosus.

[0016] Figure 6 This is a graph showing the concentration of compound 1 found in the biopsy tissue of the subject as described in Example 2. Detailed Implementation

[0017] This invention relates to methods and compounds for treating discoid lupus erythematosus, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus. In one embodiment, the invention provides a method for treating systemic lupus erythematosus, discoid lupus erythematosus, and subacute cutaneous lupus erythematosus in a human subject with this need, comprising administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to compound 1 or a pharmaceutically acceptable salt thereof for treating discoid lupus erythematosus, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus.

[0018] Compound 1 is a potent inhibitor of HSP90. The synthesis and HSP90 inhibitory activity of compound 1 are described in WO2008 / 115719, the entire contents of which are incorporated herein by reference.

[0019] In the methods and compounds for treating systemic lupus erythematosus, discoid lupus erythematosus, and subacute cutaneous lupus erythematosus of the present invention, the subject is preferably a human subject. The subject may have systemic lupus erythematosus, discoid lupus erythematosus, and / or subacute cutaneous lupus erythematosus of any severity. For example, the subject may have systemic lupus erythematosus with manifestations, diffuse discoid lupus erythematosus, or subacute cutaneous lupus erythematosus.

[0020] In some embodiments, the subject has systemic lupus erythematosus with skin manifestations (e.g., skin lesions), and the subject is administered an amount of compound 1 or a pharmaceutically acceptable salt thereof that effectively reduces or alleviates the skin manifestations. In some embodiments, the systemic lupus erythematosus is bullous systemic lupus erythematosus.

[0021] Compound 1 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, semi-solid, or liquid formulations (tablets, pellets, lozenges, capsules, suppositories, creams, ointments, aerosols, powders, liquids, emulsions, suspensions, syrups, injections, etc.). The pharmaceutical composition may be administered by any suitable manner, including but not limited to parenteral, intravenous, intramuscular, subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, rectal, and mucosal administration. Topical administration may involve transdermal administration, such as transdermal patches or iontophoresis devices.

[0022] In a preferred embodiment, the pharmaceutical composition is administered orally, for example as a solid or liquid formulation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets, effervescent tablets, powders, etc. Suitable liquid oral formulations include solutions, suspensions, dispersants, emulsions, oils, etc. In one embodiment of the invention, the composition is formulated as a capsule. In another embodiment, the composition is formulated as a tablet. Compound 1 exhibits unexpectedly high accumulation in the skin after oral administration.

[0023] Any inert excipient commonly used as a carrier or diluent may be used in the pharmaceutical compositions of the present invention, such as gums, starches, sugars, cellulose materials, acrylates, or mixtures thereof. A preferred diluent is microcrystalline cellulose. The compositions may further comprise disintegrants (e.g., croscarmellose sodium) and lubricants (e.g., magnesium stearate), and may additionally 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. Furthermore, the compositions of the present invention may be in the form of controlled-release or immediate-release formulations.

[0024] 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 buffer media. Examples of oils are petroleum-derived, animal-derived, plant-derived, or synthetic oils, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and cod liver oil. Solutions or suspensions may also contain the following components: sterile diluents such as water for injection, physiological saline solutions, fixed oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antimicrobial 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 acetates, citrates, or phosphates; and reagents for adjusting pH such as sodium chloride or glucose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0025] Furthermore, the composition may further comprise binders (e.g., gum arabic, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrants (e.g., corn starch, potato starch, alginate, silica, croscarmellose sodium, croscarmellose, guar gum, carboxymethyl starch sodium, Primogel), buffers of different pH and ionic strengths (e.g., Tris-HCl, acetate, phosphate), additives to prevent adsorption to container surfaces (e.g., albumin or gelatin), and detergents (e.g., Tween 20, Tween 80, Pluronic). F68, bile salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), penetration enhancers, solubilizers (e.g., glycerol, polyvinylglycerol, 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., peppermint, methyl salicylate, or orange flavor). Flavors), preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow aids (e.g., colloidal silica), 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-forming agents (e.g., ethyl cellulose, acrylates, polymethyl methacrylate), and / or adjuvants.

[0026] In one embodiment, the active compound is prepared together with a carrier that protects it from rapid elimination in vivo, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be readily apparent to those skilled in the art. These materials are also commercially available. Liposome suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent No. 4,522,811.

[0027] Formulating oral compositions into unit dosage forms is particularly advantageous for ease of administration and dosage uniformity. As used herein, “unit dosage form” refers to a physically discrete unit suitable as a unitary dose for a subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in combination with the desired drug carrier. The specifications of the unit dosage forms of the present invention are determined by and directly dependent on the unique characteristics of the active compound and the specific therapeutic effect to be achieved, as well as the inherent limitations in the field of compounding such active compounds for individual treatment.

[0028] The present invention aims to provide formulations for oral administration that may contain one or more penetration enhancers, including long-chain fatty acids or salts thereof, such as decanoic acid and sodium decanoate.

[0029] The pharmaceutical composition may be included in a container, pack, or dispenser along with the instructions for use.

[0030] The pharmaceutical compositions of the present invention are preferably suitable for oral administration, such as tablets or capsules, and most preferably in tablet form. In one embodiment, the pharmaceutical composition is a tablet comprising compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises compound 1 in the form of a free base. In some embodiments, the tablet comprises 0.5 mg to 500 mg, 1 mg to 450 mg, 10 mg to 350 mg, 20 mg to 300 mg, 40 mg to 275 mg, 50 mg to 260 mg, or 250 mg of the free base of compound 1. Alternatively, the tablet comprises a pharmaceutically acceptable salt of compound 1 in the above amounts, wherein these amounts represent free base equivalents. Preferably, the tablet comprises 0.5 mg, 1 mg, 5 mg, 20 mg, 50 mg, 100 mg, 125 mg, or 250 mg of the free base of compound 1.

[0031] In some embodiments, the pharmaceutical compositions of the present invention are suitable for topical application, and are most preferably in the form of creams, lotions, gels, ointments, aerosols, powders, solutions, emulsions, suspensions, or administered via transdermal patches or iontophoresis devices. In one embodiment, the pharmaceutical composition is a cream comprising compound 1. In some embodiments, the cream comprises compound 1 in the form of a free base. In some embodiments, the amount of free base of compound 1 contained in the cream is 0.25 mg to 250 mg, 0.5 mg to 225 mg, 1 mg to 200 mg, 1.5 mg to 175 mg, 2 mg to 150 mg, 2.5 mg to 125 mg, 3 mg to 100 mg, 4 mg to 75 mg, 4.5 mg to 50 mg, 5 mg to about 25 mg. Preferably, the cream comprises 0.5 mg, 1 mg, 5 mg, 20 mg, 50 mg, 100 mg, 125 mg, or 250 mg of free base of compound 1. Alternatively, the cream may comprise a pharmaceutically acceptable salt of the aforementioned amount of compound 1, wherein these amounts represent free base equivalents.

[0032] The pharmaceutical composition can be administered daily or at a suitable schedule. In one embodiment, daily administration can be repeated continuously for periods ranging from several days to several years. Oral treatment can continue for a week or for the patient's entire life. The administration can be continuous or intermittent, for example, treatment for several consecutive days followed by a rest period.

[0033] The amount of compound administered to the patient is preferably below an amount that would be toxic to the patient. In some embodiments, the amount of compound 1 or a pharmaceutically acceptable salt thereof administered to the patient is below an amount that would cause the concentration of compound 1 in the patient's plasma to be equal to or exceed the toxic level of the compound.

[0034] The dosing regimens described herein describe the administration of compound 1, which may be administered in the form of a free base or a pharmaceutically acceptable salt. Any amount of compound 1 administered in the dosing regimens described herein refers to an amount in the form of a free base. The dosing regimens disclosed herein include the administration of a pharmaceutically acceptable salt of compound 1, and in these embodiments, the doses disclosed herein refer to free base equivalents.

[0035] In some embodiments, compound 1 is administered at a dose of 0.5 mg to 400 mg per dosing day. In some embodiments, compound 1 is administered at a dose of 10 mg to 50 mg, 100 mg, or 200 mg per dosing day. In some embodiments, compound 1 is administered orally to the subject at a dose of 0.5 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 some embodiments, compound 1 is administered orally to the subject at a dose of 0.5 mg to 200 mg per dosing day, 20 mg to 175 mg daily, 20 mg to 150 mg per dosing day, 20 mg to 125 mg per dosing day, 20 mg to 100 mg per dosing day, or 20 mg to 50 mg per dosing day. In some embodiments, compound 1 is administered orally to the subject at doses 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 per dosing day.

[0036] In some embodiments, compound 1 is administered orally to the subject at doses 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 daily, 245 mg to 255 mg daily, or 250 mg per dosing day.

[0037] As used herein, the term "dose day" refers to the day on which a subject is administered compound 1 in its free base form or a pharmaceutically acceptable salt form. In some embodiments, compound 1 is administered to the subject daily. In other embodiments, compound 1 is administered every other day. In some embodiments, compound 1 is administered to the subject three days a week, preferably on non-consecutive days, such as Monday, Wednesday, and Friday. The doses mentioned are daily amounts of the drug and will be related to the drug concentration in the particular dosage form and the amount / area of ​​administration.

[0038] In some embodiments, compound 1 is initially administered to the subject at a loading dose of 0.5-250 mg per dosing day for an appropriate duration, such as 1-12 weeks, 2-10 weeks, or 4-8 weeks. The loading dose is preferably administered daily. This loading dose may be followed by a reduced maintenance dose, such as any of the reduced dosing regimens described above and / or a reduced daily dose. For example, compound 1 may be administered at a loading dose of 25-250 mg per dosing day for 4-8 weeks, followed by a maintenance dose of 0.5-200 mg per dosing day, provided that the maintenance dose is a lower daily dose and / or a lower dosing frequency than the loading dose. In some embodiments, the loading dose is 200-250 mg daily for 4-8 weeks, followed by a maintenance dose of 25-200 mg daily, provided that the maintenance dose is lower than the loading dose.

[0039] As described above, administration of compound 1 or a pharmaceutically acceptable salt thereof may be continued for any period of time, and preferably for at least 16 weeks or longer. Preferably, administration continues as long as the subject demonstrates clinical improvement in the signs and symptoms of discoid lupus erythematosus and subacute cutaneous lupus erythematosus.

[0040] As described above, administration of compound 1 or a pharmaceutically acceptable salt thereof may be interrupted occasionally for a period of one or more days, after which administration may be resumed according to a predetermined schedule, or when signs and symptoms of discoid lupus erythematosus and subacute cutaneous lupus erythematosus recur or worsen.

[0041] The subject's response to the treatment method of the present invention can be determined according to methods known in the art. For example, the subject can be evaluated based on the Physician's Global Assessment (PGA) and / or the Dermatology Life Quality Index (DLQI).

[0042] definition

[0043] The following are definitions of the various terms used to describe the invention. Unless otherwise specified separately in a particular case or as part of a larger group, these definitions apply to the terminology used throughout this specification and the claims.

[0044] Compound 1 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" means that, within reasonable medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, anaphylactic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. described pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences 66:1-19 (1977). This salt can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by reacting a 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 formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, lactobionic acid, or malonic acid), or salts formed by other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-ethylhexanoate, glyceryl phosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0045] As used herein, “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents compatible with drug administration, such as sterile, pyrogen-free water. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference in the art, the entire contents of which are incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, physiological saline, Ringer's solution, glucose solution, and 5% human serum albumin. Liposomes and non-aqueous solvents such as fixed oils may also be used. The use of these media and reagents for the active pharmaceutical ingredient is well known in the art. The use of any conventional media or reagent in a composition should be considered unless it is incompatible with the active compound.

[0046] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. Most preferably, the subject is a human.

[0047] The terms "therapeutic effective amount" and "effective amount" for a therapeutic agent refer to the amount of the agent that produces a therapeutic effect on the treated subject, given a reasonable benefit / risk ratio for treating discoid lupus erythematosus, systemic lupus erythematosus, or subacute cutaneous lupus erythematosus. The therapeutic effective amount when the agent is used as a single agent may differ from its therapeutic effective amount when used in combination with one or more other agents. Furthermore, the therapeutic effective amount of the agent may depend on the specific combination of agents to be administered. The therapeutic effect can be objective (i.e., measurable by certain tests or markers) or subjective (i.e., the subject indicates or feels an effect). The therapeutic effective dose will also vary depending on the route of administration and the possibility of co-administration with other agents. However, it should 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 bounds of reasonable medical judgment. The specific effective dose level for any particular patient will depend on a number of factors, including: the disease being treated and its severity; the activity of the specific compound used; the specific combination used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; the drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0048] The dosage may need to be lower or higher than those listed above. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, rate of excretion, combination of drugs, severity and duration of the disease, condition or symptoms, the patient's susceptibility to the disease, condition or symptoms, and the judgment of the attending physician.

[0049] As the patient's condition improves, a maintenance dose of the compound or composition of the present invention may be administered if necessary. Subsequently, depending on the condition of the symptoms, the dosage or frequency of administration, or both, may be reduced to a level that maintains the improved condition when symptoms have been relieved to the desired level. However, if any recurrence of symptoms occurs, the patient may require long-term intermittent treatment.

[0050] Preparation of Compound 1

[0051] Compound 1 can be prepared using the method disclosed in published PCT application number WO2008 / 115719, the entire contents of which are incorporated herein by reference.

[0052] Example

[0053] Example 1: Effect of compound 1 on biopsy skin from patients with discoid lupus

[0054] To investigate the effects of compound 1 on inflammatory cytokines in the skin, 3mm trephine biopsies were obtained from volunteers with discoid lupus. Each patient's biopsy included one tissue sample taken from non-lesioned skin and two tissue samples taken from the lesioned skin area.

[0055] Each biopsy tissue was incubated separately in the device to create a gas-liquid interface on each tissue, mimicking skin orientation. The liquid used was cell culture medium supplemented with dimethyl sulfoxide (DMSO, solvent control) or Compound 1 (5 μM in DMSO). Cultures were incubated for 24 hours and then analyzed to compare relative gene expression. Reverse transcription was performed using TaqMan® reverse transcription reagent (Applied Biosystems, Foster City, California, USA). For qPCR, the master mix used was Platinum® qPCR Super-mix-UDG (Invitrogen, Life Technologies). Human primers / probes from Thermo Fisher Scientific: IFNgamma (Hs00989291_m1), IL-6 (Hs00174131_m1), IL-1beta (Hs01077958_s1), IL-18 (Hs01038788_m1), CXCL10 (Hs00171042_m1), and IL-1beta (Hs01555410_m1). Normalization was performed using human RPLP0 (Assay ID: Hs99999902) (TaqMan gene expression assay, Thermo Fisher Scientific) as a reference gene. Each gene was analyzed in triplicate on a real-time qPCR instrument, Rotor-gene Q (Qiagen). Relative gene expression levels were determined based on a standard curve prepared from 4-fold serial dilutions for each gene. Stable expression of the human RPLP0 gene was used as an internal reference to ensure experimental integrity and calibration.

[0056] Research results are as follows Figure 1-5 As shown. Figure 1-4 Individually, treatment of the lesion skin with compound 1 resulted in decreased expression of IL1B, IFNγ, and CXCL10 in each patient. The data consistently demonstrated a significant reduction in the mRNA levels of these key cytokines known to be associated with autoimmune inflammation in lupus-related diseases in lesion skin exposed to compound 1. In contrast, Figure 5 The results showed no clear trend in IL18 expression in the three patients, indicating that compound 1 did not inhibit too many biological pathways. Agents targeting single cytokine pathways have only shown limited clinical success. The complexity of lupus-related autoimmune biological pathways suggests that downregulation of multiple pathways induced by compound 1 would produce better therapeutic effects.

[0057] Example 2: Pharmacokinetic Study of Compound 1

[0058] A 16-week randomized, double-blind, proof-of-concept study was designed to evaluate the safety and efficacy of compound 1 compared to placebo in the treatment of hidradenitis suppurativa. Eligible participants completed a 4-week screening period and were then sequentially randomized in a 2:1 ratio to one of two cohorts: the treatment cohort (n=10) or the placebo control cohort (n=5) for the 16-week treatment period, followed by a 4-week observational follow-up period. During the 16-week treatment period, participants randomized to the treatment group received 250 mg of the free base of compound 1, in tablet form, orally once daily. Based on the results of an earlier oncology trial at doses exceeding 1000 mg / day, the 250 mg dose was selected as the safe minimum dose, from which dose escalation was performed as needed. Participants randomized to the placebo control group received placebo once daily (microcrystalline cellulose, mannitol, cropovidone, Opadry II red, magnesium stearate, colloidal silica).

[0059] The accumulation of compound 1 in the skin of patients with hidradenitis suppurativa in the treatment cohort was determined. Frozen skin trephine biopsies of non-lesioned skin obtained at the 16-week visit showed high concentrations of compound 1, indicating its accumulation in the skin. Figure 6 This 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 mean skin concentration of compound 1 after 16 weeks of treatment was 7130 ng / mg, equivalent to 16.1 mM.

[0060] The skin accumulation observed in this study was compared with plasma levels of compound 1 as determined in previous studies in healthy human volunteers. Six healthy male subjects received a single oral dose of 250 mg of compound 1, and plasma samples were collected before administration 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 after administration. The results of this study are shown in the table below.

[0061]

[0062] C of compound 1 was measured in 6 subjects max The range was 19.42 ng / mL to 24.92 ng / mL, with a median of 20.3 ng / mL or 46 nM.

[0063] The results showed that after daily oral administration of 250 mg, compound 1 accumulated in the skin at a rate approximately 100,000 times higher than in plasma. Furthermore, the observed skin concentrations exceeded the IC50 inhibitory concentration of compound 1 against HSP-90. 50 (0.1µM) Approximately 104 Those skilled in the art will understand that a daily oral dose of compound 1 significantly lower than 250 mg (e.g., as low as 1 mg daily) will result in sufficient accumulation of compound 1 in the skin to inhibit HSP-90 in the skin, thereby treating discoid lupus erythematosus, systemic lupus erythematosus, or subacute cutaneous lupus erythematosus.

[0064] The patents and scientific literature cited in this document establish knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited in this document are incorporated herein by reference. All published foreign patents and patent applications cited in this document are incorporated herein by reference. All other published references, documents, manuscripts, and scientific literature cited in this document are incorporated herein by reference.

[0065] While the invention has been specifically shown and described with reference to its preferred embodiments, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the scope of the invention as covered by the appended claims.

Claims

1. A method of treating a subject with discoid lupus erythematosus, subacute cutaneous lupus erythematosus, or systemic lupus erythematosus in need, comprising administering to the subject a therapeutically effective amount of compound 1, （1） Or its pharmaceutically acceptable salt.

2. The method according to claim 1, wherein the method is used to treat diffuse discoid lupus erythematosus.

3. The method according to claim 1, wherein the method is used to treat subacute cutaneous lupus.

4. The method of claim 1, wherein the method is used to treat systemic lupus erythematosus with cutaneous manifestations.

5. The method according to claim 1, wherein the method is used to treat bullous systemic lupus erythematosus.

6. The method according to any one of claims 1 to 5, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally to the subject.

7. The method of claim 6, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally to the subject at a free base equivalent dose of 0.5 mg to 400 mg daily.

8. The method according to claim 7, wherein the free base equivalent dose is 200 mg to 300 mg per day.

9. The method according to claim 7, wherein the free base equivalent dose is 25 mg to 275 mg daily, 30 mg to 260 mg daily, 50 mg to 255 mg daily, or 250 mg daily.

10. The method according to claim 8, wherein the free base equivalent dose is 225 mg to 275 mg daily, 240 mg to 260 mg daily, 245 mg to 255 mg daily, or 250 mg daily.

11. The method according to any one of claims 6 to 10, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in tablet form.

12. The method of claim 6, wherein the compound 1 or a pharmaceutically acceptable salt thereof is administered in tablet form, the tablet comprising 0.5 mg to 500 mg, 1 mg to 450 mg, 10 mg to 350 mg, 20 mg to 300 mg, 40 mg to 275 mg, 50 mg to 260 mg or 250 mg of free base equivalent of the compound 1 or a pharmaceutically acceptable salt thereof.

13. The method according to any one of claims 1 to 5, wherein compound 1 or a pharmaceutically acceptable salt thereof is applied topically.

14. The method of claim 13, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at a free base equivalent dose of 0.5 mg to 400 mg daily.

15. The method or compound according to claim 13 or 14, wherein compound 1 or a pharmaceutically acceptable salt thereof is applied topically as a cream, lotion, gel, ointment, aerosol, powder, liquid, emulsion, suspension, or via a transdermal patch or via an iontophoresis device.

16. The method according to claim 14 or 15, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered topically to the subject in the form of the free base at a dose of 25 mg to 275 mg daily, 30 mg to 260 mg daily, 50 mg to 255 mg daily, or 250 mg daily.

17. A compound or a pharmaceutically acceptable salt thereof, said compound being compound 1. （1） A method for treating discoid lupus erythematosus, subacute cutaneous lupus erythematosus, or systemic lupus erythematosus in a subject with this need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or a salt thereof.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the method is used to treat diffuse discoid lupus erythematosus.

19. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the method is used to treat subacute cutaneous lupus.

20. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the method is used to treat systemic lupus erythematosus with cutaneous manifestations.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein the method is used to treat bullous systemic lupus erythematosus.

22. The compound or a pharmaceutically acceptable salt thereof for the use according to any one of claims 17 to 21, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally or topically to the subject.

23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein the compound 1 or a pharmaceutically acceptable salt thereof is administered orally to the subject at a free base equivalent dose of 0.5 mg to 400 mg daily.

24. The compound or a pharmaceutically acceptable salt thereof for the use described in claim 23, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally to the subject at a free base equivalent dose of 25 mg to 275 mg daily, 30 mg to 260 mg daily, 50 mg to 255 mg daily, or 250 mg daily.

25. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein the compound 1 or a pharmaceutically acceptable salt thereof is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg daily.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the free base equivalent dose is 225 mg to 275 mg daily, 240 mg to 260 mg daily, 245 mg to 255 mg daily, or 250 mg daily.

27. The compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 23 to 26, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally in one or more tablet forms.

28. The compound or a pharmaceutically acceptable salt thereof for the use according to claim 23, wherein the compound or a pharmaceutically acceptable salt thereof is administered in one or more tablets, the tablets comprising 0.5 mg to 400 mg, 1 mg to 350 mg, 10 mg to 350 mg, 20 mg to 300 mg, 40 mg to 275 mg, 50 mg to 260 mg or 250 mg of the free base equivalent of compound 1 or a pharmaceutically acceptable salt thereof.

29. The compound or a pharmaceutically acceptable salt thereof for the use described in claim 22, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered topically.

30. The compound or a pharmaceutically acceptable salt thereof for the use described in claim 29, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of 0.5 mg to 400 mg of free base equivalent per day.

31. The compound or a pharmaceutically acceptable salt thereof for the use described in claim 29 or 30, wherein compound 1 or a pharmaceutically acceptable salt thereof is in the form of a cream, lotion, gel, ointment, aerosol, powder, liquid, emulsion, suspension, or administered via a transdermal patch or iontophoresis device.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein the compound 1 or a pharmaceutically acceptable salt thereof is administered topically to the subject at a free base equivalent dose of 25 mg to 275 mg daily, 30 mg to 260 mg daily, 50 mg to 255 mg daily, or 250 mg daily.

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