WO2025147657A1

WO2025147657A1 - Methods for treating alopecia

Info

Publication number: WO2025147657A1
Application number: PCT/US2025/010298
Authority: WO
Inventors: Andre Bachmann; Caleb Bupp
Original assignee: Michigan State University MSU; Corewell Health
Current assignee: Michigan State University MSU; Corewell Health
Priority date: 2024-01-05
Filing date: 2025-01-03
Publication date: 2025-07-10
Anticipated expiration: 2026-07-05

Abstract

The disclosure relates to, among other things, a method of treating alopecia areata, the method comprising administering to a subject with alopecia areata a therapeutically effective amount of at least one compound of the formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof.

Description

METHODS FOR TREATING ALOPECIA

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority from U.S. Appl. No. 63/617,904, filed January 5, 2024, which is incorporated by reference as if fully set forth herein.

BACKGROUND

[0002] Androgenic 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). In a recent study by Lee et al (Journal of Dermatology, 2019; 46:985-992, attached), certain polyamines displayed different concentrations between the androgenic alopecia and alopecia areata groups, suggesting that some polyamines, particularly N1 -acetylputrescine (P = 0.007) and N-acetyl cadaverine (P = 0.0021 ), are significantly different in androgenic alopecia. Furthermore, spermidine (P = 0.021 ) was significantly different in alopecia areata. The authors concluded that the non-invasive quantification of hair polyamines may help distinguish between androgenic alopecia and alopecia areata.

SUMMARY

[0003] 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. Patients with alopecia areata, but not patients with androgenic alopecia, could benefit from oral doses of DFMO, which will lower an elevated level of putrescine and/or N1 -acetylputrescine to physiologically normal levels, and consequently will regrow hair in patients. In examples, oral dosing of DFMO between 500 mg/m² BID-1500 mg/m² BID are proposed and based on previous clinical trial studies, including treatment of children with the pediatric cancer neuroblastoma and Bachmann-Bupp syndrome (BABS), causing minimal side effects (PLoSOne, 2015; 10:e0127246 and eLife, 2021 ; 10:e67097). DFMO (also known Eflornithine) was approved by the FDA in oral form (tablets) for the treatment of neuroblastoma, in December 2023. The new drug is called Iwilfin (https://www.iwilfin.com/).

DESCRIPTION OF THE DRAWINGS

[0004] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed herein.

[0005] FIG. 1 is a scheme showing the polyamine pathway. ODC gain-of-function mutations and elevated level of putrescine and N1 -acetylputrescine lead to Bachmann-Bupp Syndrome. Elevated N1 -acetylputrescine is also detected in hair samples of patients with alopecia areata, but not with androgenic alopecia.

[0006] 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.

[0007] FIG. 2C is a plot of ODC enzymatic activity.

[0008] FIG. 2D is a plot of polyamine levels where “Put” refers to putrescine, “Spd” refers to spermidine, and “Spm” refers to spermine.

[0009] FIG. 2E is a Western blot showing that the amount of ODC protein is significantly higher in the skin of K6ODC mice compared to WT mice.

[0010] FIG. 3A is a western blot analysis of JAK/STAT pathway protein analysis in skin tissues of heterozygous K6ODC mice or wild type (WT) mice, +/- DFMO. [0011] FIGS. 3B-3D are plots showing the level of Jak2, pStat3, and Stat3.

DESCRIPTION

[0012] Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0013] There is supporting evidence that lowering polyamines, and in particular putrescine and/or its derivative N1 -acetylputrescine, will lead to successful hair regrowth. An animal model developed in 1995 (J Invest Dermatol. 1996; 106:1 10S- 13) revealed that mice with elevated polyamine levels in skin cells (due to the overexpression of ornithine decarboxylase (ODC), the enzyme that produces putrescine) experience hair loss and DFMO stimulates re-growth of hair in this animal model. The inventors recently discovered BABS, a genetic condition caused by ODC gain-of-function mutation in human patients that produces high level of polyamines (putrescine and N1 -acetylputrescine) and patients present with alopecia. Treatment with oral DFMO of patients with complete baldness led to complete re-growth of full set of hair, eyebrows, eyelashes and body hair within several months of daily treatment (eLife, 2021 ; 10:e67097). Thus, although alopecia areata is not genetically related to the neurodevelopmental disorder BABS, they both share a common biological marker, N1 -acetylputrescine, which level is highly elevated in both patient groups. Knowing that reducing the polyamine N1 -acetylputrescine in BABS patients with DFMO triggers hair growth, lowering N1 -acetylputrescine in patients with alopecia areata will similarly stimulate hair growth. In the United States, there are an estimated 2.5 million individual affected by alopecia areata. It is likely that treatment with DFMO would need to be continued lifelong in order to support continuous hair growth. While DFMO is a safe drug, it suffers from high renal clearance (80% of drug is released in the urine), and therefore pharmacokinetically improved DFMO analogues or DFMO formulations may be optimized for further improved treatment of alopecia areata.

[0014] The disclosure relates to methods for treating alopecia areata, the method comprising administering to a subject with alopecia areata a therapeutically effective amount of at least one compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are each independently H, alkyl or carboxy or, R¹ and R², together with the nitrogen atom to which they are attached, form a heterocyclyl group (e.g., a piperdine or a piperazine group);

R³ is halo substituted alkyl;

R⁴ and R⁵ are each independently H, alkyl or carboxy;

R⁶ is amino or alkoxy; and

Q¹ is alkyl.

[0015] In the compounds of the formula (I), R¹ and R² can each independently be H. Alternatively, R¹ and R² can each independently be alkyl, such as C1-C3 alkyl, such as methyl, ethyl or propyl. Alternatively, one of R¹ and R² can be a carboxy group, such as a group of the formula R⁷OC(O)-, wherein R⁷ can be alkyl, such as Cs-Ce alkyl, including t-butyl and benzyl.

[0016] Alternatively or in addition to the options for R¹ and R², in the compounds of the formula (I), R⁴ and R⁵ can each independently be H. Alternatively, R⁴ and R⁵ can each independently be alkyl, such as C1-C3 alkyl, such as methyl, ethyl or propyl. Alternatively, one of R⁴ and R⁵ can be a carboxy group, such as a group of the formula R⁷OC(O)-, wherein R⁷ can be alkyl, such as C3-C6 alkyl, including t- butyl and benzyl.

[0017] Alternatively or in addition to the options for R¹ , R², R⁴, and R⁵, R³ can be C1-C3 halo substituted alkyl, such as fluoro substituted alkyl. Examples of fluoro substituted alkyl include CHF₂, CF₃, and the like.

[0018] Alternatively or in addition to the options for R¹ , R², R³, R⁴, and R⁵, Q¹ can be C1-C5 alkyl, such as C2-C4 alkyl. In one example, Q¹ can be C3 alkyl, such as n- propyl and the like.

[0019] Alternatively or in addition to the options for R¹ , R², R³, R⁴, R⁵, and Q¹ , R⁶ can be H, alkyl, hydroxy, amino or alkoxy. For example, R⁶ can be OH.

[0020] The compound of the formula (I) can be eflornithine, wherein R¹ , R², R⁴, and R⁵ are each H, Q¹ is n-propyl (i.e., -CH2CH2CH2-), R² is -CHF₂, and R⁶ is OH:

or a pharmaceutically acceptable salt thereof.

[0021] 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.

[0022] Following the administering (also referenced as “post-administering” herein), the subject has reduced level of the at least one polyamine relative to preadministering level of the at least one polyamine in the subject. Thus, for example, 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. Accordingly, 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. In one example, in addition to reduced level of the at least one polyamine, postadministering the subject 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. Accordingly, 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.

[0023] 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). In one example, the reduced level of the at least one polyamine is selected from a reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine. For example, the level of one, two, three or more polyamines can be measured. In one example, 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. For example, 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. In one example, the level of the at least one polyamine measured pre-administering and/or post-administering is the level of putrescine and/or N1 -acetylputrescine. In one example, 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. Accordingly, 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.

[0024] 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.

[0025] 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. Accordingly, 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.

[0026] Post-administering, 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. Accordingly, 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. In one example, in addition to reduced level of the at least one polyamine, after 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. Accordingly, 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 with alopecia areata and elevated level of at least one polyamine.

[0027] The polyamine level measured, pre-administering and/or postadministering (e.g., reduced level of the at least one polyamine) can be the level of putrescine, cadaverine, spermidine, and/or spermine. In one example, the reduced level of the at least one polyamine is selected from a reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine. For example, the level of one, two, three or more polyamines can be measured. In one example, 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. For example, 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. In one example, the level of the at least one polyamine measured pre-administering and/or post-administering is the level of putrescine and/or N1 -acetylputrescine. In one example, 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. Accordingly, 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.

[0028] 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.

[0029] 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. Accordingly, 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.

[0030] Post-administering, 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. Accordingly, 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. In one example, in addition to reduced level of the at least one polyamine, after 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. Accordingly, 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 pre-administering level ODC activity in the subject with alopecia areata and elevated level of at least one polyamine.

[0031] 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). In one example, the reduced level of the at least one polyamine is selected from a reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine. For example, the level of one, two, three or more polyamines can be measured. In one example, 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. For example, 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. In one example, the level of the at least one polyamine measured pre-administering and/or post-administering is the level of putrescine and/or N1 -acetylputrescine. In one example, 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. Accordingly, 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.

[0032] The level of the at least one polyamine in a subject can be determined by any suitable method, including HPLC or UPLC. In some instances, the HPLC or UPLC can be paired with mass spectrometry. The pre-administering level of the at least one polyamine in the subject and the post-administering level of the at least one polyamine in the subject can be determined using the subject’s hair sample from any place on the subject’s body including the head. In some examples, therefore, 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.

[0033] The compound of formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof, can be administered in any suitable fashion. For example, the compound of the formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof, is administered orally. Alternatively or in addition, the compound of the formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof, can be administered in any suitable frequency, such as twice daily. Alternatively or in addition, the compound of the formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof, can be administered in any suitable dose, such as a dose of between 500 mg/m² to 9.0 g/m², 500 mg/m² to 8 g/m², 750 mg/m² to 1 .2 g/m², 500 mg/m² to 1 .5 g/m², 1 g/m² to 3.0 g/m², 2.0 g/m² to 3.0 g/m², 500 mg/m² to 3.0 g/m² or 500 mg/m² to 5.0 g/m², 750 mg/m² to 2.0 g/m², 1 .5 g/m² to 5.0 g/m², 1 .0 g/m² to 6.0 g/m² or 2.0 g/m² to 6.0 g/m², such as 500 mg/m² to 8.0 g/m², 750 mg/m² to 1.2 g/m², 1.0 g/m² to 3.0 g/m², 2 g/m² to 3.0 g/m², 500 mg/m² to 3.0 g/m² or 500 mg/m² to 5.0 g/m², 750 mg/m² to 2.0 g/m², 1 .5 g/m² to 5.0 g/m², 1 .0 g/m² to 6.0 g/m² or 2.0 g/m² to 6.0 g/m² daily or a dose of between 500 mg/m² to about 1 .5 g/m², 500 mg/m² to 4.0 g/m², 750 mg/m² to 1 .2 g/m², 1 .0 g/m² to 3.0 g/m², 2.0 g/m² to 3.0 g/m², 500 mg/m² to 3.0 g/m² or 500 mg/m² to 5.0 g/m², 750 mg/m² to 2.0 g/m², 1 .5 g/m² to 5 g/m², 2.0 g/m² to 4.5 g/m² or 2.0 g/m² to 4.0 g/m² twice daily. Alternatively, or in addition, the compound of the formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof, can be administered in any suitable duration, such as for at least one, two, three, four, five, six, seven, eight or nine weeks or more. In one example, the compound of the formula (I) (e.g., eflornithine), or a pharmaceutically acceptable salt thereof, can be administered for 2-3 weeks, 2-5 weeks, or 3-8 weeks or longer, such as for 2-3 months, 3-8 months, 1 -2 years, 1 -5 years, 3-12 years, 5-20 years or for the life of the subject. [0034] This disclosure also contemplates the administration of at least one compound of the formula (I) (e.g., eflornithine) or a pharmaceutically acceptable salt thereof in combination with an amount (e.g., therapeutically effective amount) of at least one JAK inhibitor. In one embodiment, the combination of at least one compound of the formula (I) (e.g., eflornithine) or a pharmaceutically acceptable salt thereof with an amount (e.g., therapeutically effective amount) of at least one JAK inhibitor achieves a synergistic effect in the method of treating alopecia areata; the method of reducing the level of at least one polyamine in a subject with alopecia areata and elevated level of at least one polyamine; and/or the method of regenerating hair follicles in a subject with elevated level of at least one polyamine. Examples of 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,

[0035] This disclosure also contemplates pharmaceutical 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). Such compositions can be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, cutaneous, 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. In addition, administration can by means of capsule, drops, foams, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other suitable means of administration.

[0036] A “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” is a carrier, sometimes a liquid, in which an active therapeutic agent is formulated. The excipient generally does not provide any pharmacological activity to the formulation, though it can provide chemical and/or biological stability, and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated by reference in its entirety.

[0037] As used herein “pharmaceutically acceptable carrier” or “excipient” 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. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, 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.

[0038] Pharmaceutical 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.

[0039] In many cases, 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. Moreover, 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. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art.

[0040] Oral forms of administration are also contemplated herein. The pharmaceutical compositions of the present invention can be orally administered as a capsule (hard or soft), tablet (film coated, enteric coated or uncoated), powder or granules (coated or uncoated) or liquid (solution or suspension). The formulations can be conveniently prepared by any of the methods well-known in the art. The pharmaceutical compositions of the present invention can include one or more suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers.

[0041] For each of the recited embodiments, 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, and combinations thereof.

[0042] 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, polysorbates or laurylsulphates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.

[0043] Liquid dispersions for oral administration can be syrups, emulsions, solutions, or suspensions. The syrups can contain as a carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. The suspensions and the emulsions can contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0044] The amount of active compound in a therapeutic composition according to various embodiments of the present invention can vary according to factors such as the disease state, age, gender, weight, patient history, risk factors, predisposition to disease, administration route, pre-existing treatment regime (e.g., possible interactions with other medications), and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of therapeutic situation.

[0045] 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. In therapeutic use for treatment of conditions in mammals (e.g., humans) for which the compounds of the present invention or an appropriate pharmaceutical composition thereof are effective, 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.

[0046] It will be appreciated that the amount of compound(s) for use in treatment will vary not only with the particular carrier selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient. Ultimately the attendant health care provider may determine proper dosage.

[0047] The 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. The preferred 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.

[0048] The compositions can include the compounds described herein in a “therapeutically effective amount.” Such a therapeutically effective amount is an amount sufficient to obtain the desired physiological effect, such as a reduction of at least one symptom.

[0049] As used herein, 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.

[0050] The compounds and methods described herein can be used prophylactically or therapeutically. The term “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).

[0051] The term “therapeutically effective amount” as used herein, refers to that amount of one or more compounds of the various examples of the present invention that elicits a biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In some examples, the therapeutically effective amount is that which can treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein can be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the 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.

[0052] The term “alkyl” as used herein refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having from 1 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 1 to 10 carbons atoms, 1 to 8 carbon atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 1 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 1 to 5 carbon atoms, or 1 to 3 carbon atoms. Examples of straight chain mono-valent (Ci-C₂o)-alkyl groups include those with from 1 to 8 carbon atoms such as methyl (i.e., CH₃), ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl groups. Examples of branched mono-valent (Ci-C2o)-alkyl groups include isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, and isopentyl. Examples of straight chain bivalent (Ci-C₂o)alkyl groups include those with from 1 to 6 carbon atoms such as - CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, and -CH₂CH₂CH₂CH₂CH₂-. Examples of branched bi-valent alkyl groups include -CH(CH₃)CH₂- and -CH₂CH(CH₃)CH₂-. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopently, cyclohexyl, cyclooctyl, bicyclo[1 .1 .1 ]pentyl, bicyclo[2.1 ,1 ]hexyl, and bicyclo[2.2.1 ]heptyl. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. In some embodiments, alkyl includes a combination of substituted and unsubstituted alkyl. As an example, alkyl, and also (Ci)alkyl, includes methyl and substituted methyl. As a particular example, (Ci )alkyl includes benzyl. As a further example, alkyl can include methyl and substituted (C₂-C₈)alkyl. Alkyl can also include substituted methyl and unsubstituted (C₂-C₈)alkyl. In some embodiments, alkyl can be methyl and C₂-C₈ linear alkyl. In some embodiments, alkyl can be methyl and C₂-C₈ branched alkyl. The term methyl is understood to be -CH₃, which is not substituted. The term methylene is understood to be -CH₂-, which is not substituted. For comparison, the term (Ci )alkyl is understood to be a substituted or an unsubstituted -CH₃ or a substituted or an unsubstituted -CH₂-. 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. As further example, representative substituted alkyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, 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. In some embodiments, representative substituted alkyl groups can be substituted from a set of groups including amino, hydroxy, cyano, carboxy, nitro, thio and alkoxy, but not including halogen groups. Thus, in some embodiments alkyl can be substituted with a non-halogen group. For example, representative substituted alkyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro. In some embodiments, representative substituted alkyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups. For example, 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. The term “alkyl” also generally refers to alkyl groups that can comprise one or more heteroatoms in the carbon chain. Thus, for example, “alkyl” also encompasses groups such as -[(CH₂)_pO]_qH and the like.

[0053] The term “alkenyl” as used herein 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 mono-valent (C2-C2o)-alkenyl groups include those with from 1 to 8 carbon atoms such as vinyl, propenyl, propen-1 -yl, propen-2-yl, butenyl, buten-1 - yl, buten-2-yl, sec-buten-1 -yl, sec-buten-3-yl, pentenyl, hexenyl, heptenyl and octenyl groups. Examples of branched mono-valent (C2-C2o)-alkenyl groups include isopropenyl, iso-butenyl, sec-butenyl, t-butenyl, neopentenyl, and isopentenyl. 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(CH₃)CH- and -CHC(CH₃)CH₂-. 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. As such, where alkenyl groups are described it, compounds are also envisaged where a carbon-carbon double bond of an alkenyl is replaced by an epoxide or aziridine ring. Substituted alkenyl also includes alkenyl groups which are substantially tautomeric with a non-alkenyl group. For example, substituted alkenyl can be 2-aminoalkenyl, 2-alkylaminoalkenyl, 2-hydroxyalkenyl, 2-hydroxyvinyl, 2-hydroxypropenyl, but substituted alkenyl is also understood to include the group of substituted alkenyl groups other than alkenyl which are tautomeric with non-alkenyl containing groups. In some embodiments, alkenyl can be understood to include a combination of substituted and unsubstituted alkenyl. For example, alkenyl can be vinyl and substituted vinyl. For example, alkenyl can be vinyl and substituted (C₃-C₈)alkenyl. Alkenyl can also include substituted vinyl and unsubstituted (C₃-C₈)alkenyl. Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, for example, monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio, alkoxy, and halogen groups. As further example, representative substituted alkenyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, 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. In some embodiments, representative substituted alkenyl groups can be substituted from a set of groups including monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio and alkoxy, but not including halogen groups. Thus, in some embodiments alkenyl can be substituted with a non-halogen group. In some embodiments, representative substituted alkenyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro. For example, alkenyl can be 1 -fluorovinyl, 2-fluorovinyl, 1 ,2-difluorovinyl, 1 ,2,2- trifluorovinyl, 2,2-difluorovinyl, trifluoropropen-2-yl, 3,3,3-trifluoropropenyl, 1 - fluoropropenyl, 1 -chlorovinyl, 2-chlorovinyl, 1 ,2-dichlorovinyl, 1 ,2 ,2-trichlorovi nyl or 2,2-dichlorovinyl. In some embodiments, representative substituted alkenyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups.

[0054] The term “alkynyl” as used herein, refers to substituted or unsubstituted straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 50 carbon atoms, 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. 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 -C²CH, -C²C(CH₃), C²C(CH₂CH₃), -CH₂C²CH, -CH₂C²C(CH₃), and -CH₂C²C(CH₂CH₃) among others.

[0055] The term “aryl” as used herein refers to substituted or unsubstituted univalent groups that are derived by removing a hydrogen atom from an arene, which is a cyclic aromatic hydrocarbon, having from 6 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 20 carbon atoms, 6 to about 10 carbon atoms or 6 to 8 carbon atoms. Examples of C₆-C₂₀ aryl groups include phenyl, napthalenyl, azulenyl, biphenylyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, anthracenyl groups. Examples include substituted phenyl, substituted napthalenyl, substituted azulenyl, substituted biphenylyl, substituted indacenyl, substituted fluorenyl, substituted phenanthrenyl, substituted triphenylenyl, substituted pyrenyl, substituted naphthacenyl, substituted chrysenyl, and substituted anthracenyl groups. 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. From these examples, it is clear that the term C₆-C₂o aryl encompasses mono- and polycyclic C₆-C₂o aryl groups, including fused and non-fused polycyclic C₆-C₂o aryl groups such as fused and non-fused polycyclic Cs-C groups.

[0056] The term “heterocyclyl” as used herein refers to substituted aromatic, unsubstituted aromatic, substituted non-aromatic, and unsubstituted non-aromatic rings containing 3 or more atoms in the ring, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups that include 2 to 5 carbon atoms (C2-C5), 3 to 8 carbon atoms (C₃-C₈), 3 to 6 carbon atoms (C₃-C₆) or 6 to 8 carbon atoms (C₆-C₈). A heterocyclyl group designated as a C₂-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. Likewise a C₄- heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to piperidynyl, piperazinyl, morpholinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, and benzimidazolinyl groups. For example, heterocyclyl groups include, without limitation:

represents H, (Ci-C₂o)alkyl, (C₆-C₂o)aryl or an amine protecting group (e.g., a t- butyloxycarbonyl group) and wherein the heterocyclyl group can be substituted or unsubstituted. A nitrogen-containing heterocyclyl group is a heterocyclyl group containing a nitrogen atom as an atom in the ring. In some embodiments, the heterocyclyl is other than thiophene or substituted thiophene. In some embodiments, the heterocyclyl is other than furan or substituted furan.

[0057] The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. Thus, alkyoxy also includes an oxygen atom connected to an alkyenyl group and oxygen atom connected to an alkynyl group. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0058] The term “aryloxy” as used herein refers to an oxygen atom connected to an aryl group as are defined herein.

[0059] The term “aralkyl” and “arylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl, biphenylmethyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0060] The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0061] The term “amine” and “amino” as used herein refers to a substituent of the form -NH2, -NHR, -NR2, -NR₃ ⁺, wherein each R is independently selected, and protonated forms of each, except for -NR₃ ⁺, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. [0062] The term “acyl” as used herein 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 another carbon atom, which can be part of a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, group or the like. The carbonyl carbon atom can also be bonded to a nitrogen or an oxygen atom, for example to form an amide (e.g., amido as defined herein), a carboxylic acid (e.g., a carboxy group as defined herein) or an ester, such as an alkyl ester.

[0063] The term “formyl” as used herein 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 hydrogen atom.

[0064] The term “alkoxycarbonyl” as used herein 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. In a further case, which is included in the definition of alkoxycarbonyl as the term is defined herein, and is also included in the term “aryloxycarbonyl,” the carbonyl carbon atom is bonded to an oxygen atom which is bonded to an aryl group instead of an alkyl group.

[0065] The term “arylcarbonyl” as used herein 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 aryl group.

[0066] The term “alkylamido” as used herein 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 nitrogen group which is bonded to one or more alkyl groups. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more aryl group instead of, or in addition to, the one or more alkyl group. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to an nitrogen atom which is bonded to one or more alkenyl group instead of, or in addition to, the one or more alkyl and or/aryl group. In a further case, which is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more alkynyl group instead of, or in addition to, the one or more alkyl, alkenyl and/or aryl group.

[0067] The term “carboxy” as used herein 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. For example, carboxy can be understood as COOH or CO₂H.

[0068] The term “amido” as used herein 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.

[0069] The term “alkylthio” as used herein refers to a sulfur atom connected to an alkyl, alkenyl, or alkynyl group as defined herein.

[0070] The term “arylthio” as used herein refers to a sulfur atom connected to an aryl group as defined herein.

[0071] The term “alkylsulfonyl” as used herein refers to a sulfonyl group connected to an alkyl, alkenyl, or alkynyl group as defined herein.

[0072] The term “alkylsulfinyl” as used herein refers to a sulfinyl group connected to an alkyl, alkenyl, or alkynyl group as defined herein.

[0073] The term “dialkylaminosulfonyl” as used herein refers to a sulfonyl group connected to a nitrogen further connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups.

[0074] The term “dialkylamino” as used herein refers to an amino group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups.

[0075] The term “dialkylamido” as used herein refers to an amido group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups.

[0076] The term “substituted” as used herein 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., CH₂OH), OC(O)N(R)₂, CN, NO, NO₂, ONO₂, azido, CF₃, OCF₃, methylenedioxy, ethylenedioxy, (C₃-C₂o)heteroaryl, N(R)₂, Si(R)₃, SR, SOR, SO₂R, SO₂N(R)₂, SO₃R, P(O)(OR)₂, OP(O)(OR)₂, C(O)R, C(O)C(O)R, C(O)CH₂C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)₂, C(O)N(R)OH, OC(O)N(R)₂, C(S)N(R)₂, (CH₂)O-₂N(R)C(0)R, (CH₂)O-₂N(R)N(R)₂, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)₂, N(R)SO₂R, N(R)SO₂N(R)₂, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)₂, N(R)C(S)N(R)₂, N(COR)COR, N(OR)R, C(=NH)N(R)₂, C(O)N(OR)R, or C(=NOR)R wherein R can be hydrogen, (Cr C2o)alkyl, (Ce-C2o)aryl, heterocyclyl or polyalkylene oxide groups, such as polyalkylene oxide groups of the formula -(CH₂CH₂O)_f-R-OR, -(CH2CH₂CH₂O)g-R-OR, -(CH₂CH2O)f(CH2CH2CH₂O)g-R-OR each of which can, in turn, be substituted or unsubstituted and wherein f and g are each independently an integer from 1 to 50 (e.g., 1 to 10, 1 to 5, 1 to 3 or 2 to 5). 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. Where there are two or more adjacent substituents, 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. For example, a substituted aryl can be substituted with bromo and a substituted heterocycle on the same compound can be substituted with alkyl. It is envisaged that a substituted group can be substituted with one or more non-fluoro groups. As another example, a substituted group can be substituted with one or more non-cyano groups. As another example, a substituted group can be substituted with one or more groups other than haloalkyl. As yet another example, a substituted group can be substituted with one or more groups other than tert-butyl. As yet a further example, a substituted group can be substituted with one or more groups other than trifluoromethyl. As yet even further examples, 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. Further, 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.

[0077] In some instances, the compounds described herein (e.g., the compound of the formula (I), such as eflornithine) can contain chiral centers. All diastereomers of the compounds described herein are contemplated herein, as well as race mates.

[0078] As used herein, the term “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. Examples of 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. For example, 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.

[0079] Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In some instances, 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.

[0080] The term “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. [0081] The term “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. Examples of 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. 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 described by Burger’s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001 , Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0082] As used herein, 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.

[0083] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of “about 0.1 % to about 5%” or “about 0.1 % to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1 %, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1 % to 0.5%, 1 .1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0084] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading can occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0085] In the methods described herein, 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.

[0086] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1 % of a stated value or of a stated limit of a range.

[0087] The term “substantially” as used herein 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.

[0088] The term “substantially no” as used herein 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%.

[0089] Those skilled in the art will appreciate that many modifications to the embodiments described herein are possible without departing from the spirit and scope of the present disclosure. Thus, the description is not intended and should not be construed to be limited to the examples given but should be granted the full breadth of protection afforded by the appended claims and equivalents thereto. In addition, it is possible to use some of the features of the present disclosure without the corresponding use of other features. Accordingly, the foregoing description of or illustrative embodiments is provided for the purpose of illustrating the principles of the present disclosure and not in limitation thereof and can include modification thereto and permutations thereof.

[0090] The disclosure also relates to the following numbered Embodiments, which are presented in no particular order of importance: 1 . A method of treating alopecia areata, the method 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:

R¹ and R² are each independently H, alkyl or carboxy or, R¹ and R², together with the nitrogen atom to which they are attached, form a heterocyclyl group;

R³ is halo substituted alkyl;

R⁴ and R⁵ are each independently H, alkyl or carboxy;

R⁶ is amino or alkoxy; and

Q¹ is alkyl.

2. The method of Embodiment 1 , wherein R¹ and R² are each independently H.

3. The method of Embodiment 1 or 2, wherein R⁴ and R⁵ are each independently H.

4. The method of any preceding Embodiment, wherein R³ is C1-C3 halo substituted alkyl.

5. The method of any preceding Embodiment, wherein Q¹ is C1 -C5 alkyl.

6. The method of any preceding Embodiment, wherein R⁶ is hydroxy.

7. The method of any preceding Embodiment, wherein the compound of the formula (I) is eflornithine, wherein R¹, R², R⁴, and R⁵ are each H, Q¹ is n-propyl, R² is -CHF₂, and R⁶ is OH:

pharmaceutically acceptable salt thereof.

8. The method of any preceding Embodiment, wherein following said administering, the subject has reduced level of at least one polyamine, relative to pre-administering level of the at least one polyamine in the subject.

9. The method of Embodiment 8, 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. 10. The method of Embodiment 8 or 9, wherein 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.

1 1 . The method of Embodiment 10, wherein the reduced level of the at least one polyamine is selected from the reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine.

12. The method of Embodiment 11 , wherein the reduced level of putrescine and/or N1 -acetylputrescine is from 50% to 90% lower relative to a preadministering level of putrescine and/or N1 -acetylputrescine in the subject.

13. 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:

R³ is halo substituted alkyl;

R⁴ and R⁵ are each independently H, alkyl or carboxy;

R⁶ is amino or alkoxy; and

Q¹ is alkyl.

14. The method of Embodiment 13, wherein R¹ and R² are each independently H.

15. The method of Embodiment 13 or 14, wherein R⁴ and R⁵ are each independently H.

16. The method of any of Embodiments 13-15, wherein R³ is C1-C3 halo substituted alkyl.

17. The method of any of Embodiments 13-16, wherein Q¹ is C1-C5 alkyl.

18. The method of any of Embodiments 13-17, wherein R⁶ is hydroxy. 19. The method of any of Embodiments 13-18, wherein the compound of the formula (I) is eflornithine, wherein R¹, R², R⁴, and R⁵ are each H, Q¹ is n-propyl, R² is -CHF₂, and R⁶ is OH:

pharmaceutically acceptable salt thereof.

20. The method of any of Embodiments 13-19, wherein following said administering, the subject has reduced level of at least one polyamine, relative to pre-administering level of the at least one polyamine in the subject.

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.

22. The method of Embodiment 20 or 21 , wherein 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.

23. The method of Embodiment 22, wherein the reduced level of the at least one polyamine is selected from the reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine.

24. The method of Embodiment 23, wherein the reduced level of putrescine and/or N1 -acetylputrescine is from 50% to 90% lower relative to a preadministering level of putrescine and/or N1 -acetylputrescine in the subject.

25. 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):

or a pharmaceutically acceptable salt thereof, wherein:

R³ is halo substituted alkyl;

R⁴ and R⁵ are each independently H, alkyl or carboxy; R^s is amino or alkoxy; and

Q¹ is alkyl.

26. The method of Embodiment 25, wherein R¹ and R² are each independently H.

27. The method of Embodiment 25 or 26, wherein R⁴ and R⁵ are each independently H.

28. The method of any of Embodiments 25-27, wherein R³ is C1-C3 halo substituted alkyl.

29. The method of any of Embodiments 25-28, wherein Q¹ is C1-C5 alkyl.

30. The method of any of Embodiments 25-29, wherein R⁶ is hydroxy.

31 . The method of any of Embodiments 25-29, wherein the compound of the formula (I) is eflornithine, wherein R¹, R², R⁴, and R⁵ are each H, Q¹ is n-propyl, R² is -CHF₂, and R⁶ is OH:

pharmaceutically acceptable salt thereof..

32. The method of Embodiment 25, wherein the elevated level of the at least one polyamine is an elevated level of putrescine, elevated level of N1 - acetylputrescine, elevated level of cadaverine, elevated level of spermidine, and/or elevated level of spermine.

33. The method of Embodiment 32, wherein the elevated level of the at least one polyamine is the elevated level of putrescine.

34. The method of Embodiment 32, wherein the elevated level of the at least one polyamine is the elevated level of N1 -acetylputrescine.

35. The method of Embodiment 34, wherein the elevated level of putrescine and/or N1 -acetylputrescine is from 50% to 90% higher relative to a preadministering level.

36. The method of any of Embodiments 25-35, wherein following said administering, the subject has reduced level of at least one polyamine, relative to pre-administering level of the at least one polyamine in the subject.

37. The method of Embodiment 36, 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.

38. The method of Embodiment 36 or 37, wherein 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.

39. The method of Embodiment 38, wherein the reduced level of the at least one polyamine is selected from the reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine.

40. The method of Embodiment 39, wherein the reduced level of putrescine and/or N1 -acetylputrescine is from 50% to 90% lower relative to a preadministering level of putrescine and/or N1 -acetylputrescine in the subject.

41 . The method of any of preceding Embodiment, wherein the compound of the formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.

42. The method of any preceding Embodiment, wherein the compound of the formula (I), or a pharmaceutically acceptable salt thereof, is administered twice daily.

43. The method of any preceding Embodiment, wherein the compound of the formula (I), or a pharmaceutically acceptable salt thereof, is administered in a dose of between about 1 g/m² to about 6.0 g/m².

44. The method of Embodiment 43, wherein the compound of the formula (I), or a pharmaceutically acceptable salt thereof, is administered in a dose of between about 500 mg/m² to about 3 g/m² twice daily.

45. The method of any preceding Embodiment, wherein the compound of the formula (I), or a pharmaceutically acceptable salt thereof, is administered for at least two weeks; at least two months; or at least two years.

Examples

[0091] The disclosure can be better understood by reference to the following examples which are offered by way of illustration. The disclosure is not limited to the examples given herein.

Example 1

[0092] Wild type (WT) or K6ODC mutant mice (C57BL/6-Tg(K6ODCtr)55Tgo/J, Jackson Labs) with alopecia areata and alopecia totalis phenotype were either exposed to water (controls) or the ODC inhibitor DFMO (1 % w/v) in water. Drinking water (plus/minus DFMO) was replaced weekly. Mice were enrolled at eight weeks of age and treated for ten weeks. Hair growth was observed in DFMO treated K6ODC mice but not in K6ODC mice treated with water (FIG. 2A and FIG. 2B). ODC enzymatic activity and polyamine levels (putrescine, spermidine, spermine) were measured in skin biopsies from treated mice (FIG. 2C and FIG. 2D). ODC activity and putrescine were highly upregulated in K60DC mice with alopecia treated with water (control) compared to WT mice. K6ODC mice treated with DFMO had ODC activity and putrescine levels similar to WT, presumably allowing hair re-growth in hairless mice. FIG. 2E shows that the amount of ODC protein is significantly higher in the skin of K6ODC mice compared to WT mice, which confirms the result in FIG. 2C where ODC activity is also significantly increased in K6ODC mice. N = 2. Put, putrescine; Spd, spermidine; Spm, spermine.

Example 2

[0093] Making reference to FIGS. 3A-3D, FIG. 3A shows a JAK/STAT pathway protein analysis in skin tissues of heterozygous K6ODC mice or wild type (WT) mice, +/- DFMO, using western blotting method and specific antibodies for Jak2 and phospho Jak2 (pJak2), Stat3 and phosphor Stat3 (pStat3), and Stat5 and phospho Stat5 (pStat5). Actin served as a loading marker control. Jak2, pStat3 and Stat3 are slightly elevated in heterozygous K6ODC mice compared to WT mice. In heterozygous K6ODC mice treated with DFMO (1% w/v), the Jak2, pStat3 and Stat3 protein signals appear to decrease by varying degrees, via an unknown/indirect signaling mechanism. FIGS. 3B-3D show the quantification of western blot bands in (A) for Jak2 (B), pStat3 (C), and Stat3 (D).

Claims

What is claimed is:

1 . A method of treating alopecia areata, the method 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:

R³ is halo substituted alkyl;

R⁴ and R⁵ are each independently H, alkyl or carboxy;

R⁵ is amino or alkoxy; and

Q¹ is alkyl.

2. The method of claim 1 , wherein R¹ and R² are each independently H.

3. The method of claim 1 or 2, wherein R⁴ and R⁵ are each independently H.

4. The method of claim 3, wherein R³ is C1-C3 halo substituted alkyl.

5. The method of claim 4, wherein Q¹ is C1-C5 alkyl.

6. The method of claim 5, wherein R⁶ is hydroxy.

7. The method of claim 1 , wherein the compound of the formula (I) is eflornithine, wherein R¹, R², R⁴, and R⁵ are each H, Q¹ is n-propyl, R² is -CHF₂, and R⁶ is OH:

pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein following said administering, the subject has reduced level of at least one polyamine, relative to pre-administering level of the at least one polyamine in the subject.

9. The method of claim 8, 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.

10. The method of claim 8 or 9, wherein 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.

1 1 . The method of claim 10, wherein the reduced level of the at least one polyamine is selected from the reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine.

12. The method of claim 1 1 , wherein the reduced level of putrescine and/or N1 - acetylputrescine is from 50% to 90% lower relative to a pre-administering level of putrescine and/or N1 -acetylputrescine in the subject.

or a pharmaceutically acceptable salt thereof, wherein:

R³ is halo substituted alkyl;

R⁴ and R⁵ are each independently H, alkyl or carboxy;

R⁶ is amino or alkoxy; and

Q¹ is alkyl.

14. The method of claim 13, wherein R¹ and R² are each independently H.

15. The method of claim 13 or 14, wherein R⁴ and R⁵ are each independently H.

16. The method of claim 15, wherein R³ is C1-C3 halo substituted alkyl.

17. The method of claim 16, wherein Q¹ is C1-C5 alkyl.

18. The method of claim 17, wherein R⁶ is hydroxy.

19. The method of claim 13, wherein the compound of the formula (I) is eflornithine, wherein R¹, R², R⁴, and R⁵ are each H, Q¹ is n-propyl, R² is -CHF₂, and R⁶ is OH:

pharmaceutically acceptable salt thereof.

20. The method of claim 13, wherein following said administering, the subject has reduced level of at least one polyamine, relative to pre-administering level of the at least one polyamine in the subject.

21 . The method of claim 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.

22. The method of claim 20 or 21 , wherein 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.

23. The method of claim 22, wherein the reduced level of the at least one polyamine is selected from the reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine.

24. The method of claim 23, wherein the reduced level of putrescine and/or N1 - acetylputrescine is from 50% to 90% lower relative to a pre-administering level of putrescine and/or N1 -acetylputrescine in the subject.

or a pharmaceutically acceptable salt thereof, wherein:

R³ is halo substituted alkyl;

R⁴ and R⁵ are each independently H, alkyl or carboxy;

R⁶ is amino or alkoxy; and

Q¹ is alkyl.

26. The method of claim 25, wherein R¹ and R² are each independently H.

27. The method of claim 25 or 26, wherein R⁴ and R⁵ are each independently H.

28. The method of claim 27, wherein R³ is C1-C3 halo substituted alkyl.

29. The method of claim 28, wherein Q¹ is C1-C5 alkyl.

30. The method of claim 29, wherein R⁶ is hydroxy.

31 . The method of claim 25, wherein the compound of the formula (I) is eflornithine, wherein R¹, R², R⁴, and R⁵ are each H, Q¹ is n-propyl, R² is -CHF₂, and R⁶ is OH:

pharmaceutically acceptable salt thereof..

32. The method of claim 25, wherein the elevated level of the at least one polyamine is an elevated level of putrescine, elevated level of N1 -acetylputrescine, elevated level of cadaverine, elevated level of spermidine, and/or elevated level of spermine.

33. The method of claim 32, wherein the elevated level of the at least one polyamine is the elevated level of putrescine.

34. The method of claim 32, wherein the elevated level of the at least one polyamine is the elevated level of N1 -acetylputrescine.

35. The method of claim 34, wherein the elevated level of putrescine and/or N1 - acetylputrescine is from 50% to 90% higher relative to a pre-administering level.

36. The method of claim 35, wherein following said administering, the subject has reduced level of at least one polyamine, relative to pre-administering level of the at least one polyamine in the subject.

37. The method of claim 36, 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.

38. The method of claim 36 or 37, wherein 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.

39. The method of claim 38, wherein the reduced level of the at least one polyamine is selected from the reduced level of putrescine, reduced level of N1 -acetylputrescine, reduced level of cadaverine, reduced level of spermidine, and/or reduced level of spermine.

40. The method of claim 39, wherein the reduced level of putrescine and/or N1- acetylputrescine is from 50% to 90% lower relative to a pre-administering level of putrescine and/or N1 -acetylputrescine in the subject.

41 . The method of claim 1 , 13 or 25, wherein the compound of the formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.

42. The method of claim 1 , 13 or 25, wherein the compound of the formula (I), or a pharmaceutically acceptable salt thereof, is administered twice daily.

43. The method of claim 1 , 13 or 25, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in a dose of between about 1 g/m² to about 6.0 g/m².

44. The method of claim 43, wherein the eflornithine, or a pharmaceutically acceptable salt thereof, is administered in a dose of between about 500 mg/m² to about 3 g/m² twice daily.

45. The method of claim 1 , 13 or 25, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered for at least two weeks.