WO2025147657A1 - Méthodes de traitement de l'alopécie - Google Patents

Méthodes de traitement de l'alopécie Download PDF

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Publication number
WO2025147657A1
WO2025147657A1 PCT/US2025/010298 US2025010298W WO2025147657A1 WO 2025147657 A1 WO2025147657 A1 WO 2025147657A1 US 2025010298 W US2025010298 W US 2025010298W WO 2025147657 A1 WO2025147657 A1 WO 2025147657A1
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level
reduced level
polyamine
alkyl
subject
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Andre Bachmann
Caleb Bupp
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Michigan State University MSU
Corewell Health
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Michigan State University MSU
Corewell Health
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • alopecia results from increased dihydrotestosterone metabolism, and alopecia areata is an autoimmune disease.
  • Hair follicles are among the most highly proliferative tissues in the body.
  • Polyamines (putrescine, spermidine, spermine) are associated with cell proliferation, and polyamines also play anti-inflammatory roles.
  • the level of polyamines in hair cells and other cells and tissues can be determined and quantitated by high-performance liquid chromatography (HPLC) or mass spectrometry (MS).
  • the disclosure relates to, among other things, the recognition that the FDA- approved polyamine inhibitor difluoromethylornithine (DFMO or eflornithine) can be used to lower the elevated level of at least one polyamine (e.g., putrescine and/or N1 -acetylputrescine) in patients with alopecia areata, including its subtypes alopecia universalis, alopecia barbae, and alopecia totalis.
  • DFMO polyamine inhibitor difluoromethylornithine
  • eflornithine e.g., putrescine and/or N1 -acetylputrescine
  • DFMO also known Eflornithine
  • FIGS. 2A and 2B are photographs of wild type (WT) and K6ODC mutant mice (C57BL/6-Tg(K6ODCtr)55Tgo/J, Jackson Labs) with alopecia areata and alopecia totalis phenotype that were either exposed to water (controls) or the ODC inhibitor DFMO (1% w/v) in water.
  • FIG. 2C is a plot of ODC enzymatic activity.
  • FIG. 2D is a plot of polyamine levels where “Put” refers to putrescine, “Spd” refers to spermidine, and “Spm” refers to spermine.
  • R 6 is amino or alkoxy
  • the compound of the formula (I) can be eflornithine, wherein R 1 , R 2 , R 4 , and R 5 are each H, Q 1 is n-propyl (i.e., -CH2CH2CH2-), R 2 is -CHF 2 , and R 6 is OH: or a pharmaceutically acceptable salt thereof.
  • the disclosure is also directed to a method of treating alopecia areata, the method comprising administering to a subject with alopecia areata a therapeutically effective amount of eflornithine, or a pharmaceutically acceptable salt thereof.
  • the subject has reduced level of the at least one polyamine relative to preadministering level of the at least one polyamine in the subject.
  • post-administering the reduced level of the at least one polyamine is at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower or at least 90% lower relative to pre-administering level of the at least one polyamine in the subject.
  • post-administering the reduced level of the at least one polyamine can be from 50% to 90% lower; 50% to 80% lower, 60% to 90% lower; 65% to 85% lower; 70% to 90% lower; or 75% to 85% lower relative to pre-administering level of the at least one polyamine in the subject.
  • postadministering the subject in addition to reduced level of the at least one polyamine, exhibits reduced ornithine decarboxylase (ODC) activity, such as at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower, at least 90% lower or 100% lower ODC activity relative to a pre-administering ODC activity in the subject.
  • ODC ornithine decarboxylase
  • the ODC activity can be from 50% to 100% lower; 50% to 80% lower, 60% to 90% lower; 65% to 85% lower; 70% to 90% lower; or 75% to 85% lower ODC activity relative to a preadministering level ODC activity in the subject.
  • the polyamine level measured, pre-administering and/or postadministering can be the level of putrescine, cadaverine, spermidine, and/or spermine , and/or the level of mono- and diacetylated derivatives of the foregoing (e.g., N1 -acetylputrescine, N1 -acetylspermidine, N8-acetylspermidine, N1 - acetylspermine, and N1 ,N12-diacetylspermine).
  • putrescine e.g., putrescine, cadaverine, spermidine, and/or spermine
  • mono- and diacetylated derivatives of the foregoing e.g., N1 -acetylputrescine, N1 -acetylspermidine, N8-acetylspermidine, N1 - acetylspermine, and N1 ,N12-
  • the reduced level of putrescine and/or the reduced level of N1 -acetylputrescine, the reduced level of spermidine, and/or the reduced level of spermine are measured.
  • the level of the at least one polyamine measured pre-administering and/or post-administering is the level of putrescine and/or N1 -acetylputrescine.
  • the reduced level of putrescine and/or N1 -acetylputrescine is at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower or at least 90% lower relative to a preadministering level of putrescine and/or N1 -acetylputrescine in the subject.
  • the reduced level of putrescine and/or N1 -acetylputrescine can be from 50% to 90% lower; 50% to 80% lower, 60% to 90% lower; 65% to 85% lower; 70% to 90% lower; or 75% to 85% lower relative to pre-administering level of putrescine and/or N1 -acetylputrescine in the subject.
  • the disclosure also relates to a method of reducing the level of at least one polyamine in a subject with alopecia areata and elevated level of the at least one polyamine, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of at least one compound of the formula (I) e.g., eflornithine
  • Pre-administering level of the at least one polyamine in the subject with alopecia areata and elevated level of at least one polyamine can be at least 40% higher, at least 50% higher, at least 60% higher, at least 70% higher, at least 80% higher or at least 90% higher relative to pre-administering level of the at least one polyamine in the subject.
  • the elevated level of the at least one polyamine can be from 50% to 90% higher; 50% to 80% higher, 60% to 90% higher; 65% to 85% higher; 70% to 90% higher; or 75% to 85% higher relative to pre-administering level of the at least one polyamine in the subject.
  • the level (e.g., reduced level of the at least one polyamine) of the at least one polyamine in a subject with alopecia areata and elevated level of at least one polyamine can be at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower or at least 90% lower relative to pre-administering level of the at least one polyamine in the subject.
  • the reduced level of the at least one polyamine can be from 50% to 90% lower; 50% to 80% lower, 60% to 90% lower; 65% to 85% lower; 70% to 90% lower; or 75% to 85% lower relative to pre-administering level of the at least one polyamine in the subject with alopecia areata and elevated level of at least one polyamine.
  • the reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine are measured.
  • the reduced level of putrescine and/or the reduced level of N1 -acetylputrescine, the reduced level of spermidine, and/or the reduced level of spermine are measured.
  • the level of the at least one polyamine measured pre-administering and/or post-administering is the level of putrescine and/or N1 -acetylputrescine.
  • the reduced level of putrescine and/or N1 -acetylputrescine is at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower or at least 90% lower relative to a preadministering level of putrescine and/or N1 -acetylputrescine in the subject.
  • the reduced level of putrescine and/or N1 -acetylputrescine can be from 50% to 90% lower; 50% to 80% lower, 60% to 90% lower; 65% to 85% lower; 70% to 90% lower; or 75% to 85% lower relative to pre-administering level of putrescine and/or N1 -acetylputrescine in the subject.
  • the disclosure also relates to a method of regenerating hair follicles in a subject with elevated level of at least one polyamine, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of at least one compound of the formula (I) e.g., eflornithine
  • Pre-administering level of the at least one polyamine in the subject with alopecia areata and elevated level of at least one polyamine can be at least 40% higher, at least 50% higher, at least 60% higher, at least 70% higher, at least 80% higher or at least 90% higher relative to pre-administering level of the at least one polyamine in the subject.
  • the elevated level of the at least one polyamine can be from 50% to 90% higher; 50% to 80% higher, 60% to 90% higher; 65% to 85% higher; 70% to 90% higher; or 75% to 85% higher relative to pre-administering level of the at least one polyamine in the subject.
  • the level of the at least one polyamine in a subject with alopecia areata and elevated level of at least one polyamine can be at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower or at least 90% lower relative to pre-administering level of the at least one polyamine in the subject.
  • the reduced level of the at least one polyamine can be from 50% to 90% lower; 50% to 80% lower, 60% to 90% lower; 65% to 85% lower; 70% to 90% lower; or 75% to 85% lower relative to preadministering level of the at least one polyamine in the subject with alopecia areata and elevated level of at least one polyamine.
  • ODC ornithine decarboxylase
  • the administering the subject with alopecia areata and elevated level of at least one polyamine exhibits reduced ornithine decarboxylase (ODC) activity, such as at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower, at least 90% lower or 100% lower ODC activity relative to a pre-administering ODC activity in the subject with alopecia areata and elevated level of at least one polyamine.
  • ODC ornithine decarboxylase
  • the polyamine level measured, pre-administering and/or postadministering can be the level of putrescine, cadaverine, spermidine, and/or spermine, and/or the level of mono- and diacetylated derivatives of the foregoing (e.g., N1 -acetylputrescine, N1 -acetylspermidine, N8-acetylspermidine, N1 - acetylspermine, and N1 ,N12-diacetylspermine).
  • JAK inhibitors include but are not limited to the FDA-approved JAK inhibitors abrocitinib, baricitinib, fedratinib, momelotinib, pacritinib, ritlecitinib, ruxolitinib, tofacitinib, and upadacitinib.
  • Other JAK inhibitors include those described in https://pmc.ncbi.nlm.nih.gov/articles/PMC9146299/ including NVP- BBT594, NVP-CHZ868, deucravacitinib, LS104, ON044580,
  • compositions comprising one or more compounds of the disclosure (e.g., compounds of the formula (I), such as eflornithine) and one or more pharmaceutically acceptable excipients.
  • a “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a subject (e.g., mammal).
  • pharmaceutically acceptable carrier includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible.
  • the carrier is suitable for parenteral administration.
  • the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. 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, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions can be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the pharmaceutical compositions can include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the compounds described herein can be formulated in a time release formulation, for example in a composition that includes a slow release polymer.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • the compounds can be administered by a variety of dosage forms as known in the art. Any biologically-acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gum, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions,
  • Other compounds which can be included by admixture are, for example, medically inert ingredients (e.g., solid and liquid diluent), such as lactose, dextrosesaccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin,
  • a “dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.
  • the compounds of the present invention can be administered in an effective amount.
  • the dosages as suitable for this invention can be a composition, a pharmaceutical composition or any other compositions described herein.
  • compositions described herein can be administered in any of the following routes: buccal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal.
  • routes of administration are buccal and oral.
  • the administration can be local, where the composition is administered directly, close to, in the locality, near, at, about, or in the vicinity of, the site(s) of disease, e.g., inflammation, or systemic, wherein the composition is given to the patient and passes through the body widely, thereby reaching the site(s) of disease.
  • Local administration can be administration to, for example, tissue, organ, and/or organ system, which encompasses and/or is affected by the disease, and/or where the disease signs and/or symptoms are active or are likely to occur.
  • Administration can be topical with a local effect, composition is applied directly where its action is desired.
  • Administration can be enteral wherein the desired effect is systemic (non-local), composition is given via the digestive tract.
  • Administration can be parenteral, where the desired effect is systemic, composition is given by other routes than the digestive tract.
  • compositions can include the compounds described herein in a “therapeutically effective amount.”
  • a therapeutically effective amount is an amount sufficient to obtain the desired physiological effect, such as a reduction of at least one symptom.
  • the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, treatment that merely reduces symptoms, and/or delays disease progression is also contemplated.
  • the compounds and methods described herein can be used prophylactically or therapeutically.
  • prophylactic or therapeutic treatment refers to administration of a drug to a host before or after onset of a disease or condition. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate or maintain the existing unwanted condition or side effects therefrom).
  • Administering the compounds described herein (including enantiomers and salts thereof) is contemplated in both a prophylactic treatment and therapeutic treatment (e.g. to patients with symptoms of disease or to patients diagnosed with disease).
  • the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the condition being treated and the severity of the condition; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician. It is also appreciated that the therapeutically effective amount can be selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein.
  • Examples of straight chain bivalent (Ci-C 2 o)alkyl groups include those with from 1 to 6 carbon atoms such as - CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • Examples of branched bi-valent alkyl groups include -CH(CH 3 )CH 2 - and -CH 2 CH(CH 3 )CH 2 -.
  • alkyl includes a combination of substituted and unsubstituted alkyl.
  • alkyl, and also (Ci)alkyl includes methyl and substituted methyl.
  • (Ci )alkyl includes benzyl.
  • alkyl can include methyl and substituted (C 2 -C 8 )alkyl.
  • Alkyl can also include substituted methyl and unsubstituted (C 2 -C 8 )alkyl.
  • alkyl can be methyl and C 2 -C 8 linear alkyl.
  • alkyl can be methyl and C 2 -C 8 branched alkyl.
  • methyl is understood to be -CH 3 , which is not substituted.
  • methylene is understood to be -CH 2 -, which is not substituted.
  • (Ci )alkyl is understood to be a substituted or an unsubstituted -CH 3 or a substituted or an unsubstituted -CH 2 -.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, cycloalkyl, heterocyclyl, aryl, amino, haloalkyl, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • alkyl can be trifluoromethyl, difluoromethyl, or fluoromethyl, or alkyl can be substituted alkyl other than trifluoromethyl, difluoromethyl or fluoromethyl.
  • Alkyl can be haloalkyl or alkyl can be substituted alkyl other than haloalkyl.
  • alkyl also generally refers to alkyl groups that can comprise one or more heteroatoms in the carbon chain.
  • alkyl also encompasses groups such as -[(CH 2 ) p O] q H and the like.
  • alkenyl refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having at least one carbon-carbon double bond and from 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.
  • the double bonds can be trans or cis orientation.
  • the double bonds can be terminal or internal.
  • the alkenyl group can be attached via the portion of the alkenyl group containing the double bond, e.g., vinyl, propen-1 -yl and buten-1 -yl, or the alkenyl group can be attached via a portion of the alkenyl group that does not contain the double bond, e.g., penten-4-yl.
  • Examples of straight chain bi-valent (C2-C2o)alkenyl groups include those with from 2 to 6 carbon atoms such as -CHCH-, -CHCHCH2-, -CHCHCH2CH2-, and -CHCHCH2CH2CH2-.
  • Examples of branched bi-valent alkyl groups include -C(CH 3 )CH- and -CHC(CH 3 )CH 2 -.
  • Examples of cyclic alkenyl groups include cyclopentenyl, cyclohexenyl and cyclooctenyl. It is envisaged that alkenyl can also include masked alkenyl groups, precursors of alkenyl groups or other related groups.
  • Examples include, but are not limited to ethynyl, propynyl, propyn-1 -yl, propyn-2-yl, butynyl, butyn-1 -yl, butyn-2-yl, butyn-3-yl, butyn-4-yl, pentynyl, pentyn-1 -yl, hexynyl, Examples include, but are not limited to -C 2 CH, -C 2 C(CH 3 ), C 2 C(CH 2 CH 3 ), -CH 2 C 2 CH, -CH 2 C 2 C(CH 3 ), and -CH 2 C 2 C(CH 2 CH 3 ) among others.
  • Examples also include unsubstituted phenyl, unsubstituted napthalenyl, unsubstituted azulenyl, unsubstituted biphenylyl, unsubstituted indacenyl, unsubstituted fluorenyl, unsubstituted phenanthrenyl, unsubstituted triphenylenyl, unsubstituted pyrenyl, unsubstituted naphthacenyl, unsubstituted chrysenyl, and unsubstituted anthracenyl groups.
  • Aryl includes phenyl groups and also non-phenyl aryl groups.
  • heterocyclyl groups include heterocyclyl groups that include 2 to 5 carbon atoms (C2-C5), 3 to 8 carbon atoms (C 3 -C 8 ), 3 to 6 carbon atoms (C 3 -C 6 ) or 6 to 8 carbon atoms (C 6 -C 8 ).
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5- membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 - heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth.
  • alkoxycarbonyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyl group.
  • Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyenyl group.
  • Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkynyl group.
  • carboxy refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to a hydroxy group or oxygen anion so as to result in a carboxylic acid or carboxylate.
  • Carboxy also includes both the protonated form of the carboxylic acid and the salt form.
  • carboxy can be understood as COOH or CO 2 H.
  • amido refers to a group having the formula C(O)NRR, wherein R is defined herein and can each independently be, e.g., hydrogen, alkyl, aryl or each R, together with the nitrogen atom to which they are attached, form a heterocyclyl group.
  • alkylthio refers to a sulfur atom connected to an alkyl, alkenyl, or alkynyl group as defined herein.
  • substituted refers to a group that is substituted with one or more groups including, but not limited to, the following groups: halogen (e.g., F, Cl, Br, and I), R, OR, ROH (e.g., CH 2 OH), OC(O)N(R) 2 , CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , methylenedioxy, ethylenedioxy, (C 3 -C 2 o)heteroaryl, N(R) 2 , Si(R) 3 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, P(O)(OR) 2 , OP(O)(OR) 2 , C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)
  • Substituted also includes a group that is substituted with one or more groups including, but not limited to, the following groups: fluoro, chloro, bromo, iodo, amino, amido, alkyl, hydroxy, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido.
  • groups including, but not limited to, the following groups: fluoro, chloro, bromo,
  • the substituents can be linked to form a carbocyclic or heterocyclic ring.
  • Such adjacent groups can have a vicinal or germinal relationship, or they can be adjacent on a ring in, e.g., an ortho-arrangement.
  • Each instance of substituted is understood to be independent.
  • a substituted aryl can be substituted with bromo and a substituted heterocycle on the same compound can be substituted with alkyl.
  • a substituted group can be substituted with one or more non-fluoro groups.
  • a substituted group can be substituted with one or more non-cyano groups.
  • a substituted group can be substituted with one or more groups other than haloalkyl.
  • a substituted group can be substituted with one or more groups other than tert-butyl.
  • a substituted group can be substituted with one or more groups other than trifluoromethyl.
  • a substituted group can be substituted with one or more groups other than nitro, other than methyl, other than methoxymethyl, other than dialkylaminosulfonyl, other than bromo, other than chloro, other than amido, other than halo, other than benzodioxepinyl, other than polycyclic heterocyclyl, other than polycyclic substituted aryl, other than methoxycarbonyl, other than alkoxycarbonyl, other than thiophenyl, or other than nitrophenyl, or groups meeting a combination of such descriptions.
  • substituted is also understood to include fluoro, cyano, haloalkyl, tert-butyl, trifluoromethyl, nitro, methyl, methoxymethyl, dialkylaminosulfonyl, bromo, chloro, amido, halo, benzodioxepinyl, polycyclic heterocyclyl, polycyclic substituted aryl, methoxycarbonyl, alkoxycarbonyl, thiophenyl, and nitrophenyl groups.
  • the compounds described herein e.g., the compound of the formula (I), such as eflornithine
  • the compounds described herein can contain chiral centers. All diastereomers of the compounds described herein are contemplated herein, as well as race mates.
  • salts and “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
  • Pharmaceutically acceptable salts include the conventional nontoxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic,
  • salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric (or larger) amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference.
  • solvate means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention.
  • prodrugs include, but are not limited to, derivatives and metabolites of a compound of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
  • the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.
  • Prodrugs can typically be prepared using well-known methods, such as those
  • the term “subject” or “patient” refers to any organism to which a composition described herein can be administered, e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes.
  • Subject refers to a mammal receiving the compositions disclosed herein or subject to disclosed methods. It is understood and herein contemplated that “mammal” includes but is not limited to humans, non-human primates, cows, horses, dogs, cats, mice, rats, rabbits, and guinea pigs.
  • the steps can be carried out in any order without departing from the principles of the invention, except when a temporal or operational sequence is explicitly recited. Furthermore, specified steps can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed step of doing X and a claimed step of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.
  • substantially refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.
  • substantially no refers to less than about 30%, 25%, 20%, 15%, 10%, 5%, 3%, 2%, 1 %, 0.5%, 0.1%, 0.05%, 0.001 %, or at less than about 0.0005% or less or about 0% or 0%.
  • a method of treating alopecia areata comprising administering to a subject with alopecia areata a therapeutically effective amount of at least one compound of the formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 and R 2 are each independently H, alkyl or carboxy or, R 1 and R 2 , together with the nitrogen atom to which they are attached, form a heterocyclyl group;
  • R 3 is halo substituted alkyl
  • R 4 and R 5 are each independently H, alkyl or carboxy
  • R 6 is amino or alkoxy
  • the pre-administering level of the at least one polyamine is determined by HPLC or UPLC paired with mass spectrometry using the subject’s hair, hair follicle, urine and/or plasma sample.
  • the reduced level of the at least one polyamine is selected from reduced level of putrescine, reduced level of N1 - acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine.
  • a method of reducing the level of at least one polyamine in a subject with alopecia areata and elevated level of at least one polyamine, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 and R 2 are each independently H, alkyl or carboxy or, R 1 and R 2 , together with the nitrogen atom to which they are attached, form a heterocyclyl group;
  • R 3 is halo substituted alkyl
  • R 4 and R 5 are each independently H, alkyl or carboxy
  • R 6 is amino or alkoxy
  • Q 1 is alkyl
  • Embodiment 21 The method of Embodiment 20, wherein the pre-administering level of the at least one polyamine is determined by HPLC or UPLC paired with mass spectrometry using the subject’s hair, hair follicle, urine and/or plasma sample.
  • a method of regenerating hair follicles in a subject with elevated level of at least one polyamine comprising administering to the subject a therapeutically effective amount of at least one compound of the formula (I): or a pharmaceutically acceptable salt thereof, wherein:

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Abstract

La divulgation concerne, entre autres, une méthode de traitement de l'alopécie areata, la méthode comprenant l'administration à un sujet souffrant d'alopécie areata d'une quantité thérapeutiquement efficace d'au moins un composé de formule (I) (par exemple, l'éflornithine), ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2025/010298 2024-01-05 2025-01-03 Méthodes de traitement de l'alopécie Pending WO2025147657A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003059899A1 (fr) * 2002-01-14 2003-07-24 Boehringer Ingelheim Pharmaceuticals, Inc. Mimetiques de glucocorticoides, procedes de fabrication, preparations pharmaceutiques renfermant ces mimetiques et utilisations
US20040102483A1 (en) * 2001-02-19 2004-05-27 Stephen Brough Chemical compounds
WO2008057859A2 (fr) * 2006-11-01 2008-05-15 Bristol-Myers Squibb Company Modulateurs de récepteur de glucocorticoïde, de l'activité d'ap-1 et/ou du nf-kb et leur utilisation
WO2016172358A1 (fr) * 2015-04-21 2016-10-27 Gtx, Inc. Ligands de sard - composés de dégradation sélectifs des récepteurs aux androgènes - et méthodes d'utilisation
US20210137854A1 (en) * 2018-07-26 2021-05-13 Applied Biology, Inc. TAAR Receptor Agonists for the Treatment of Alopecia
WO2024220593A1 (fr) * 2023-04-17 2024-10-24 Olsen Elise A Compositions et procédés de prévention de la perte de cheveux liée à la chimiothérapie ou au rayonnement

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040102483A1 (en) * 2001-02-19 2004-05-27 Stephen Brough Chemical compounds
WO2003059899A1 (fr) * 2002-01-14 2003-07-24 Boehringer Ingelheim Pharmaceuticals, Inc. Mimetiques de glucocorticoides, procedes de fabrication, preparations pharmaceutiques renfermant ces mimetiques et utilisations
WO2008057859A2 (fr) * 2006-11-01 2008-05-15 Bristol-Myers Squibb Company Modulateurs de récepteur de glucocorticoïde, de l'activité d'ap-1 et/ou du nf-kb et leur utilisation
WO2016172358A1 (fr) * 2015-04-21 2016-10-27 Gtx, Inc. Ligands de sard - composés de dégradation sélectifs des récepteurs aux androgènes - et méthodes d'utilisation
US20210137854A1 (en) * 2018-07-26 2021-05-13 Applied Biology, Inc. TAAR Receptor Agonists for the Treatment of Alopecia
WO2024220593A1 (fr) * 2023-04-17 2024-10-24 Olsen Elise A Compositions et procédés de prévention de la perte de cheveux liée à la chimiothérapie ou au rayonnement

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