Treatment of alopecia disorders with deuterated jak inhibitors

Abstract

The present disclosure is a method of treating alopecia in a subject that is beneficially treated by administration of a JAK1 and / or JAK2 inhibitor. The method comprises administering to the subject an amount of Compound (I), or a pharmaceutically acceptable salt thereof, ranging from about 4 mg to about 50 mg. The present invention also provides compositions comprising Compound (I) and the use of such compositions in the method. Compound (I)

Description

[0001] This application is a divisional application of Chinese invention patent application filed on May 4, 2017, with application number 201780027427.2 and invention title "Treatment of hair loss disorder with deuterated JAK inhibitor". Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application Nos. 62 / 331,827, filed May 4, 2016; 62 / 338,869, filed May 19, 2016; 62 / 418,774, filed November 7, 2016; 62 / 419,237, filed November 8, 2016; 62 / 434,404, filed December 14, 2016; 62 / 466,358, filed March 2, 2017; and 62 / 492,758, filed May 1, 2017. The entire teachings of the above applications are incorporated herein by reference. Background Technology

[0003] Many drugs currently exhibit poor absorption, distribution, metabolism, and / or excretion (ADME) properties, limiting their widespread use or restricting their application to certain indications. Poor ADME properties are also a major cause of drug candidate failure in clinical trials. While formulation techniques and prodrug strategies can improve certain ADME properties in some cases, these approaches often fail to address the underlying ADME problems present in many drugs and drug candidates. One such problem is rapid metabolism, which results in the rapid elimination of many drugs from the body, even those that are otherwise highly effective in treating diseases. One possible solution to rapid drug clearance is frequent or high-dose administration to achieve sufficiently high plasma drug levels. However, this also introduces several potential treatment problems, such as poor patient adherence to dosage regimens, more severe side effects with increasing doses, and increased treatment costs. Rapidly metabolized drugs may also expose patients to unwanted toxic or active metabolites.

[0004] Another ADME limitation affecting many drugs is the formation of toxic or bioactive metabolites. Therefore, some patients receiving treatment with a drug may experience toxicity, or the safe dosage of the drug may be limited, resulting in patients receiving suboptimal doses of the active drug. In some cases, modifying the dosing interval or formulation method can help reduce clinical adverse reactions, but the formation of these undesirable metabolites is often inherent to the compound's metabolism.

[0005] In certain specific cases, metabolic inhibitors are co-administered with drugs that are cleared too quickly. This is the case with protease inhibitors used to treat HIV infection. The FDA recommends co-administering these drugs with ritonavir, an inhibitor of the cytochrome P450 enzyme 3A4 (CYP3A4), which is normally responsible for their metabolism (see Kempf, DJ, et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). However, ritonavir can cause adverse reactions and increase the drug burden on HIV patients because they must take a combination of different drugs. Similarly, to reduce the rapid CYP2D6 metabolism of dextromethorphan in the treatment of pseudobulbar affect, the CYP2D6 inhibitor quinidine is added to dextromethorphan. However, quinidine has adverse side effects that greatly limit its use in potential combination therapies (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and quinidine FDA labeling at www.accessdata.fda.gov).

[0006] Generally, combination therapy with cytochrome P450 inhibitors (CYPs) is not a satisfactory strategy for reducing drug clearance. Inhibition of CYP enzyme activity can affect the metabolism and clearance of other drugs by the same enzyme. CYP inhibition can lead to the accumulation of other drugs in the body to toxic levels.

[0007] One potentially attractive strategy for improving the metabolic properties of drugs is deuterium modification. In this approach, one or more hydrogen atoms are substituted with deuterium atoms to attempt to slow CYP-mediated drug metabolism or to reduce the formation of undesirable metabolites. Deuterium is a safe, stable, and non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In certain cases, the increased bond strength of deuterium can positively influence the ADME properties of drugs, potentially improving their efficacy, safety, and / or tolerability. Meanwhile, because deuterium is substantially the same size and shape as hydrogen, replacing hydrogen with deuterium is expected to not affect the biochemical potency and selectivity of drugs compared to the original hydrogen-only chemical entity.

[0008] Over the past 35 years, the effects of deuteration on metabolic rate have been reported for a very small percentage of approved drugs (see Blake, MI, et al., J Pharm Sci, 1975, 64: 367-91; Foster, AB, Adv Drug Res, 1985, 14: 1-40 (“Foster”); Kushner, DJ, et al., Can JPhysiol Pharmacol, 1999, 79-88; Fisher, MB, et al., Curr OpinDrug Discov Devel, 2006, 9: 101-09 (“Fisher”). The results are variable and unpredictable. For some compounds, deuteration leads to decreased metabolic clearance in vivo. For others, metabolism remains unchanged. Still others show increased metabolic clearance. The variability of the deuterium effect has also led experts to question or reject deuterium modification as a viable drug design strategy to inhibit adverse metabolism (see Foster on page 35 and Fisher on page 101).

[0009] The effects of deuterium modification on the metabolic properties of drugs are unpredictable, even if the deuterium atom is bound at a known metabolic site. Only by actually preparing and testing a deuterated drug can it be determined whether and how the metabolic rate differs from that of a non-deuterated drug. See, for example, Fukuto et al. (J. Med. Chem. [Journal of Medicinal Chemistry], 1991, 34, 2871-76). Many drugs have multiple possible metabolic sites. The number of sites requiring deuterium substitution, and the degree of deuteration (if any) required to observe its effect on metabolism, will vary for each drug.

[0010] Ruxolitinib phosphate is a heteroaryl-substituted pyrrolo[2,3-d]pyrimidine, also known as 3(R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile phosphate and (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate, which inhibits Janus-associated kinases (JAK) JAK1 and JAK2. These kinases mediate the signaling of many cytokines and growth factors that are essential for hematopoiesis and immune function. JAK signaling involves recruiting STATs (signal transduction and transcription activators) to cytokine receptors, activating and subsequently localizing STATs to the nucleus, thereby regulating gene expression.

[0011] Currently, ruxolitinib phosphate is approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Ruxolitinib phosphate is also currently in clinical trials for the treatment of other conditions.

[0012] Despite the beneficial activity of ruxolitinib, there remains a continued need for new compounds to treat the aforementioned diseases and conditions. Summary of the Invention

[0013] Currently, deuterated analogues of ruxolitinib (including compound (I), also known as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyclopentyl-2,2,3,3,4,4,5,5-d8)propionitrile, or D8-ruxolitinib) have been found to treat hair loss disorders, including alopecia areata. Compound (I) is represented by the following structural formula: Compound (I).

[0014] In some embodiments, compound (I) is administered as a pharmaceutically acceptable salt (e.g., a phosphate). The dosage of compound (I) may range from 4 mg to 50 mg daily (or based on an equivalent weight of a salt such as a phosphate of compound (I)), administered as a single daily dose or in separate doses (e.g., twice daily). Based on these findings, this document discloses a novel therapy for treating hair loss disorders in mammalian subjects using compound (I) or a pharmaceutically acceptable salt thereof.

[0015] One aspect of the invention is a method for treating hair loss disorder, which can be treated by a compound that modulates the activity of Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2). The method comprises administering to a subject (e.g., a mammalian subject) an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate), once or twice daily, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg / day to about 50 mg / day, for example about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg / day, 8 mg / day, 16 mg / day, 32 mg / day, or 48 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 4 mg, 8 mg, 12 mg, or 16 mg twice daily. In some embodiments, the hair loss disorder is alopecia areata. In some embodiments, the subject is a human. Preferably, compound (I) or a pharmaceutically acceptable salt thereof (e.g., phosphate) is administered orally at any of the above doses. Preferably, compound (I) or a pharmaceutically acceptable salt thereof is administered orally in a tablet form at any of the above doses.

[0016] In an alternative aspect, the present invention provides a method for treating hair loss disorders, the method comprising topically administering to a subject (e.g., a mammalian subject) an effective amount of a compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate). In some embodiments, the compound is administered as a pharmaceutical composition formulated for topical administration, such as a cream, ointment, lotion, foam, etc.

[0017] In another aspect, the present invention provides a method for inducing hair growth in a subject. The method comprises administering to a mammalian subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate), once or twice daily, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg / day to about 50 mg / day, for example about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg / day, 8 mg / day, 16 mg / day, 32 mg / day, or 48 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day. In some embodiments, the subject is suffering from alopecia areata; in other embodiments, the alopecia areata is alopecia areata. In some embodiments, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. Preferably, compound (I) or a pharmaceutically acceptable salt thereof (e.g., a phosphate) is administered orally at any of the above-described doses. Preferably, compound (I) or a pharmaceutically acceptable salt thereof is administered orally in a tablet form at any of the above-described doses.

[0018] Another aspect of the invention is a method for treating an autoimmune skin disorder, which can be treated by a compound that modulates the activity of Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2). The method comprises administering to a subject (e.g., a mammalian subject) an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate), once or twice daily, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg / day to about 50 mg / day, for example about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg / day, 8 mg / day, 16 mg / day, 32 mg / day, or 48 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 4 mg, 8 mg, 12 mg, or 16 mg twice daily. In some embodiments, the autoimmune skin disorder is alopecia areata, vitiligo, atopic dermatitis (eczema), or psoriasis. In some embodiments, the subject is a human. Preferably, compound (I) or a pharmaceutically acceptable salt thereof (e.g., phosphate) is administered orally at any of the above doses. Preferably, compound (I) or a pharmaceutically acceptable salt thereof is administered orally in a tablet form at any of the above doses.

[0019] Another aspect of the invention is a compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate), for treating alopecia areata, which can be treated by compounds that modulate the activity of Janus kinase 1 (JAK1) and / or Janus kinase 2 (JAK2). The compound may be administered in the dosage regimens disclosed herein. In some embodiments, the alopecia areata is patchy hair loss.

[0020] Another aspect of the invention is the use of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate) in a medicament for manufacturing a method of treating alopecia areata, said alopecia areata being treated by a compound that modulates the activity of Janus-associated kinase 1 (JAK1) and / or Janus-associated kinase 2 (JAK2). The compound may be administered in the dosage regimens disclosed in this invention. In some embodiments, the alopecia areata is alopecia areata.

[0021] Another aspect of the invention is a pharmaceutical composition comprising compound (I) in the range of about 4 mg to about 50 mg (e.g., about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg) or an equivalent amount of its pharmaceutically acceptable salt (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate), together with a pharmaceutically acceptable carrier or diluent. In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is about 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 4 mg, 8 mg, 12 mg, or 16 mg. In some embodiments, the pharmaceutical composition is a tablet. Attached Figure Description

[0022] Figure 1 shows the design and results obtained from a single escalation dose (SAD) trial in healthy volunteers. Figure 1A The SAD study design is described; Figure 1B A graph showing the plasma concentrations of CTP-543 (compound (I)) from 0 to 48 hours after administration; Figure 1C A table showing the average PK parameters of CTP-543 (compound (I)) in the SAD study.

[0023] Figure 2 shows the design and results obtained from the multiple escalation dose (MAD) trial in healthy volunteers. Figure 2A The MAD research design is described; Figure 2B A graph showing the plasma concentrations of CTP-543 (compound (I)) from 0 to 24 hours on day 1 and day 7 of the MAD study; Figure 2C A table showing the average PK parameters of CTP-543 (compound (I)) in the MAD study. Detailed description of the invention definition The term "treatment" means to reduce, inhibit, weaken, diminish, block, or stabilize the development or progression of a disease (e.g., the disease or disorder described herein), alleviate the severity of the disease, or improve symptoms associated with the disease. For example, treatment of hair loss disorders includes hair regrowth, preventing further hair loss, or slowing the rate of hair loss.

[0024] "Hair loss disorder" refers to any condition or disorder that causes hair loss in one or more parts of the body. Hair loss disorders include, but are not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia totalis, and alopecia universalis.

[0025] As used in this article, the term "mammal" includes humans as well as non-human mammals such as cats, dogs, sheep, cattle, pigs, goats, and non-human primates (including monkeys and apes).

[0026] It will be recognized that some variations in the abundance of natural isotopes in synthesized compounds depend on the source of the chemical materials used in the synthesis. Therefore, the preparation of ruxolitinib will inherently contain small amounts of deuterated isotopes. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol [Comparative Biochemistry and Physiology Molecular and Integrative Physiology], 1998, 119: 725.

[0027] In compound (I), any atom not explicitly designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position is understood to have an isotopic composition of hydrogen in its natural abundance. Furthermore, unless otherwise stated, when a position is specifically designated as “D” or “deuterium”, that position is understood to have a deuterium abundance of at least 3000 times that of the natural abundance of deuterium (i.e., 0.015%) (i.e., at least 45% deuterium doping).

[0028] As used in this article, the term "isotope enrichment factor" refers to the ratio of the isotopic abundance of a particular isotope to its natural abundance.

[0029] In other embodiments, the compounds of the present invention have an isotopic enrichment factor of at least 3500 (52.5% deuterium doped at each specified deuterium atom), at least 4000 (60% deuterium doped), at least 4500 (67.5% deuterium doped), at least 5000 (75% deuterium doped), at least 5500 (82.5% deuterium doped), at least 6000 (90% deuterium doped), at least 6333.3 (95% deuterium doped), at least 6466.7 (97% deuterium doped), at least 6600 (99% deuterium doped), or at least 6633.3 (99.5% deuterium doped) for each specified deuterium atom.

[0030] The term "isotope" refers to a substance whose chemical structure differs from compound (I) only in its isotopic composition.

[0031] When referring to the compounds of this invention, the term "compound" means a collection of molecules having the same chemical structure, except that there may be isotopic variations among the constituent atoms of the molecules. Therefore, those skilled in the art will understand that a compound represented by a specific chemical structure containing a designated deuterium atom will also contain a small number of isotopes with hydrogen atoms at one or more designated deuterium positions in that structure. The relative abundance of such isotopes in the compounds of this invention depends on many factors, including the isotopic purity of the deuterium reagent used to prepare the compound, and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.

[0032] The present invention also provides salts having the chemical formula (I). Salts of the compounds of the present invention are formed between an acid and a basic group (e.g., an amino functional group) of the compound, or between a base and an acidic group (e.g., a carboxyl functional group) of the compound. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt, such as a phosphate.

[0033] As used herein, the term "pharmaceutically acceptable" means, to the extent reasonably medically permissible, a component suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that, when administered to a recipient, can directly or indirectly provide the compound of the present invention. "Pharmaceutically acceptable counterion" is the ionic portion of a salt that is non-toxic when released from the salt after administration to a recipient.

[0034] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, pharmaceutically acceptable salts of this class include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, decanoates, heptanoates, propynylates, oxalates, malonates, succinates, caprylates, sebacic acid, fumarates, maleates, and butyn-1,4-dicarboxylic acid. Salts, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with inorganic acids (e.g., hydrochloric acid and hydrobromic acid), and especially those formed with organic acids (e.g., maleic acid).

[0035] As used herein, the term “stable compound” means a compound that has sufficient stability to allow its manufacture and to maintain the integrity of the compound for a sufficient period of time for the purposes detailed herein (e.g., formulation into therapeutic products, immediate use of therapeutic compounds, production of separable or storable intermediate compounds, treatment of diseases or conditions that respond to therapeutic agents).

[0036] Both "D" and "d" refer to deuterium. "Stereoisomer" means enantiomer and diastereomer. Both "Tert" and "t-" refer to tert-deuterium. "US" refers to the United States.

[0037] "Replaced by deuterium" means that one or more hydrogen atoms are replaced by a corresponding number of deuterium atoms.

[0038] In one aspect, the present invention provides a method for treating hair loss disorder, which can be treated by a compound that modulates (e.g., inhibits) the activity of JAK (JAK1, JAK2, and / or JAK3). The method comprises administering to a mammalian subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate), once or twice daily, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg / day to about 50 mg / day (e.g., 4 mg / day to 50 mg / day), for example about 5 mg / day (e.g., 5 mg / day), about 10 mg / day (e.g., 10 mg / day), about 20 mg / day (e.g., 20 mg / day), about 30 mg / day (e.g., 30 mg / day), about 40 mg / day (e.g., 40 mg / day), or about 50 mg / day (e.g., 50 mg / day).

[0039] In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate) administered in the method for treating hair loss disorder is about 4 mg / day (e.g., 4 mg / day), about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 32 mg / day (e.g., 32 mg / day), or about 48 mg / day (e.g., 48 mg / day).

[0040] In some embodiments, the method of treating hair loss disorder involves administering compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), or about 32 mg / day (e.g., 32 mg / day). In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 8 mg / day (e.g., 8 mg / day), about 12 mg / day (e.g., 12 mg / day), about 16 mg / day (e.g., 16 mg / day), or about 24 mg / day (e.g., 24 mg / day).

[0041] In some embodiments, the method for treating hair loss disorders involves administering compound (I) or a pharmaceutically acceptable salt thereof in an amount of 10.6 mg / day of phosphate, for example, at a dose of 5.3 mg twice daily. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of 21.1 mg / day of phosphate, for example, at a dose of 10.5 mg twice daily. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of 31.6 mg / day of phosphate, for example, at a dose of 15.8 mg twice daily. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of 42.2 mg / day of phosphate, for example, at a dose of 21.1 mg twice daily.

[0042] In some embodiments, the method for treating hair loss disorders administers compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 4 mg (e.g., 4 mg) twice daily. In one specific embodiment, compound (I) is administered as about 5.3 mg (e.g., 5.3 mg) of a phosphate of compound (I) twice daily. In some embodiments, the method for treating hair loss disorders administers compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 8 mg (e.g., 8 mg) twice daily. In one specific embodiment, compound (I) is administered as about 10.5 mg (e.g., 10.5 mg) of a phosphate of compound (I) twice daily.

[0043] In some embodiments, the method for treating alopecia areata administers compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 12 mg (e.g., 12 mg) twice daily. In one specific embodiment, compound (I) is administered as about 15.8 mg (e.g., 15.8 mg) of a phosphate of compound (I) twice daily. In some embodiments, the method for treating alopecia areata administers compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 16 mg (e.g., 16 mg) twice daily. In one specific embodiment, compound (I) is administered as about 21.1 mg (e.g., 21.1 mg) of a phosphate of compound (I) twice daily. In some embodiments, the alopecia areata is alopecia areata. In some embodiments, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. Preferably, compound (I) or a pharmaceutically acceptable salt thereof (e.g., phosphate) is administered orally at any of the doses described herein. Preferably, compound (I) or a pharmaceutically acceptable salt thereof is administered orally in a tablet form at any of the doses described herein.

[0044] In another aspect, the present invention provides a method for inducing hair growth in a subject. The method comprises administering to a mammalian subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate), once or twice daily, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg / day to about 50 mg / day (e.g., 4 mg / day to 50 mg / day), for example, about 5 mg / day (e.g., 5 mg / day), about 10 mg / day (e.g., 10 mg / day), about 20 mg / day (e.g., 20 mg / day), about 30 mg / day (e.g., 30 mg / day), about 40 mg / day (e.g., 40 mg / day), or about 50 mg / day (e.g., 50 mg / day).

[0045] In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth is about 4 mg / day (e.g., 4 mg / day), about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 32 mg / day (e.g., 32 mg / day), or about 48 mg / day (e.g., 48 mg / day).

[0046] In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth is about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), or about 32 mg / day (e.g., 32 mg / day). In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth is about 8 mg / day (e.g., 8 mg / day), about 12 mg / day (e.g., 12 mg / day), about 16 mg / day (e.g., 16 mg / day), or about 24 mg / day (e.g., 24 mg / day).

[0047] In some embodiments, the method for inducing hair growth involves administering compound (I) or a pharmaceutically acceptable salt thereof in an amount of 10.6 mg / day of phosphate, for example, at a dose of 5.3 mg twice daily. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg / day of phosphate, for example, at a dose of 10.5 mg twice daily. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 31.6 mg / day of phosphate, for example, at a dose of 15.8 mg twice daily. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 42.2 mg / day of phosphate, for example, at a dose of 21.1 mg twice daily.

[0048] In some embodiments, the method for inducing hair growth administers compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 4 mg (e.g., 4 mg) twice daily. In one specific embodiment, compound (I) is administered as about 5.3 mg (e.g., 5.3 mg) of a phosphate of compound (I) twice daily.

[0049] In some embodiments, the method for inducing hair growth administers compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 8 mg (e.g., 8 mg) twice daily. In one specific embodiment, compound (I) is administered as about 10.5 mg (e.g., 10.5 mg) of a phosphate of compound (I) twice daily.

[0050] In some embodiments, the method for inducing hair growth administers compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 12 mg (e.g., 12 mg) twice daily. In one specific embodiment, compound (I) is administered as about 15.8 mg (e.g., 15.8 mg) of a phosphate of compound (I) twice daily.

[0051] In some embodiments, the method for inducing hair growth administers compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 16 mg (e.g., 16 mg) twice daily. In one specific embodiment, compound (I) is administered as about 21.1 mg (e.g., 21.1 mg) of a phosphate of compound (I) twice daily.

[0052] In some embodiments, the subject is suffering from alopecia areata; in other embodiments, the alopecia areata is alopecia areata. In some embodiments, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. Preferably, compound (I) or a pharmaceutically acceptable salt thereof (e.g., a phosphate) is administered orally at any of the above-described doses. Preferably, compound (I) or a pharmaceutically acceptable salt thereof is administered orally in a tablet form at any of the above-described doses.

[0053] Hair loss disorders include, but are not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, total alopecia, and alopecia universalis.

[0054] Alopecia areata is an autoimmune disease that causes partial or complete loss of hair on the scalp and body, affecting up to 650,000 Americans at any given time. The scalp is the most common area affected, but any area of ​​hair growth can be affected, alone or in conjunction with the scalp. The disease can occur throughout a person's life and can affect both men and women. Alopecia areata can be associated with serious psychological consequences, including anxiety and depression. There are currently no medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of alopecia areata.

[0055] In one particular embodiment, the condition is alopecia areata in the subjects in need (e.g., mammalian (e.g., human) patients). In some embodiments, the alopecia areata is moderate to severe (e.g., hair loss of more than 30%, more than 40%, or more than 50% of the scalp).

[0056] In one embodiment of any aspect, the compound is administered orally once daily. In other embodiments of any aspect, the compound is administered orally twice daily.

[0057] Effective dosage can also vary, as is recognized by those skilled in the art, depending on the disease being treated, the severity of the disease, the route of administration, the patient’s sex, age and general health condition, the use of excipients, the possibility of synergistic use with other therapeutic treatments (e.g., the use of other drugs), and the judgment of the attending physician.

[0058] The administration of compound (I) or a pharmaceutically acceptable salt thereof (e.g., phosphate) may continue for, for example, one week, two weeks, one month, two months, three months, four months, six months, one year, two years, five years, ten years, or longer, as long as necessary for the treatment of hair loss disorder.

[0059] The effectiveness of treatments for hair loss disorders such as alopecia areata can be measured in a variety of ways, some of which are known in the field. For example, the “severity of alopecia tool,” also known as SALT, is a validated assessment scale—developed by the National Alopecia Areata Foundation working committee—to assess the extent of hair loss. See, for example, Olsen EA, Hordinsky MK, Price VH, et al., Alopecia areata investigational assessment guidelines—Part II. J Am Acad Dermatol [Journal of the American Academy of Dermatology] 2004:51: 440-447 (incorporated hereby by reference). A patient’s SALT score is calculated by measuring the percentage of hair loss in each of the four areas of the scalp and summing the results to obtain a composite score. Hair regrowth is reflected by a decrease in the SALT score. For example, a SALT score of 100 is for no hair on the scalp, while a SALT score of 0 is for complete hair regrowth. In some embodiments, the treatment methods described herein may provide an improvement of at least 10 points in SALT score after treatment (e.g., from a pre-treatment SALT score of 100 to a post-treatment SALT score of 90). In other embodiments, the treatment methods described herein may provide an improvement of at least 20, 30, 40, 50, 60, 70, 80, 90, or 100 points in SALT score. In some embodiments, the treatment methods described herein may provide a post-treatment improvement of at least 20% in a patient's SALT score from baseline, or at least 30% in a patient's SALT score from baseline, or at least 40% in a patient's SALT score from baseline, or at least 50% in a patient's SALT score from baseline, or at least 60% in a patient's SALT score from baseline, or at least 70% in a patient's SALT score from baseline.

[0060] In some embodiments, the treatment lasts for a period of time of at least four weeks, or at least eight weeks, or at least 12 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks.

[0061] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with a second therapeutic agent. Preferably, the second therapeutic agent is an agent for treating alopecia areata or autoimmune diseases, such as an inhibitor of JAK1, JAK2, or JAK3 and / or STAT1. Such inhibitors include ruxolitinib, tofacitinib, baricitinib, filgotinib, etc. Other orally administered second therapeutic agents include pharmaceutical agents for treating alopecia areata, such as oral corticosteroids.

[0062] For pharmaceutical compositions comprising a second therapeutic agent, the effective amount of the second therapeutic agent is about 20% to 100% of the dose normally used in a single treatment regimen using only the agent. Preferably, the effective amount is about 70% to 100% of the normal single treatment dose. The normal single treatment dose of these second therapeutic agents is well known in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2nd ed., Appleton and Lange, Stamford, Connecticut (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, hardcover, Tarascon Publishing, Loma Linda, California (2000); FDA approval label information for ruxolitinib and tofacitinib; and clinical trial information for baricitinib and filgotinib, each reference is combined here in whole by reference.

[0063] It is anticipated that some of the second therapeutic agents cited above will synergize with the compounds of the present invention. When this occurs, it will allow for a reduction in the effective dose of the second therapeutic agent and / or compound (I) or a pharmaceutically acceptable salt thereof from that required in monotherapy. This has the advantages of minimizing the toxic side effects of the second therapeutic agent or compound (I) or a pharmaceutically acceptable salt thereof, synergistic improvement in efficacy, improved convenience of administration or use, and / or reduced overall cost of compound preparation or formulation.

[0064] In another embodiment, any of the above treatment methods includes the additional step of co-administering one or more second therapeutic agents to a subject in need. The second therapeutic agent can be selected from any second therapeutic agent known to be useful for treating hair loss disorders (e.g., alopecia areata). The selection of the second therapeutic agent also depends on the specific disease or condition to be treated. Examples of second therapeutic agents that can be used in the methods of the present invention are those described above used in combined compositions comprising compound (I) or a pharmaceutically acceptable salt thereof, and the second therapeutic agent. Other therapeutic agents include medicines for treating alopecia areata, including, for example, topical minoxidil, injectable corticosteroids, and anthraquinone creams or ointments.

[0065] As used herein, the term "co-administration" means that the second therapeutic agent may be administered together with compound (I) or a pharmaceutically acceptable salt thereof, as part of a single dosage form (e.g., a composition of the present invention comprising the compound of the present invention and the second therapeutic agent as described above) or as a separate multi-dosage form. Alternatively, additional agents may be administered before, concurrently with, or after the administration of compound (I) or a pharmaceutically acceptable salt thereof. In such combination therapy treatments, both compound (I) or a pharmaceutically acceptable salt thereof and one or more second therapeutic agents are administered by conventional methods. Administration of a subject to a composition of the present invention comprising compound (I) or a pharmaceutically acceptable salt thereof and a second therapeutic agent does not preclude the separate administration of the same therapeutic agent, any other second therapeutic agent, or compound (I) or a pharmaceutically acceptable salt thereof to the subject at another time during treatment.

[0066] The effective doses of these secondary therapeutic agents are well known to those skilled in the art, and dosage guidelines can be found in the patents and published patent applications cited herein, along with Wells et al., Pharmacotherapy Handbook, 2nd edition, Appleton and Lange, Stamford, Connecticut (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, hardcover, Tarascon Publishing, Loma Linda, California (2000), and other medical texts. However, determining the optimal effective dose range for a secondary therapeutic agent is well within the scope of a person skilled in the art.

[0067] In one embodiment of the invention, when the second therapeutic agent is administered to a subject, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is less than the effective amount it would be without the second therapeutic agent. In another embodiment, the effective amount of the second therapeutic agent is less than the effective amount it would be without compound (I) or a pharmaceutically acceptable salt thereof. In this way, undesirable side effects associated with high doses of each agent can be minimized. Other potential advantages (including, but not limited to, improved dosing regimens and / or reduced drug costs) will be apparent to those skilled in the art.

[0068] In another aspect, the present invention provides the use of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equal amount of a pharmaceutically acceptable salt, such as a phosphate), alone or together with one or more of the aforementioned second therapeutic agents, in the manufacture of a medicament as a single composition or as separate dosage forms, for the treatment or prevention of the aforementioned disease, disorder, or symptoms in a subject. Another aspect of the invention is compound (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of a subject suffering from the disease, disorder, or symptoms described herein.

[0069] Another aspect of the invention is a pharmaceutical composition comprising compound (I) in the range of about 4 mg to about 50 mg (e.g., about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg), or an equivalent amount of its pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or diluent. In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is about 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 4 mg, 8 mg, 12 mg, or 16 mg. In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 5.3 mg of a phosphate of compound (I). In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 10.5 mg or 10.6 mg of a phosphate of compound (I). In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 15.8 mg of a phosphate of compound (I). In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg of a phosphate of compound (I). In some embodiments, the pharmaceutical composition is a tablet.

[0070] Another aspect of the invention is a unit dosage form comprising compound (I) in the range of about 4 mg to about 50 mg (e.g., about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg) or an equivalent amount of its pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or diluent. In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is about 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 4 mg, 8 mg, 12 mg, or 16 mg. In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 5.3 mg of phosphate of compound (I). In some embodiments, the amount of compound (I) or its pharmaceutically acceptable salt is 10.5 mg or 10.6 mg of phosphate of compound (I). In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 15.8 mg of a phosphate of compound (I). In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg of a phosphate of compound (I). In some embodiments, the unit dosage form is a tablet.

[0071] In one embodiment, any atom not designated as deuterium is present in the compound (I) or its pharmaceutically acceptable salt at its natural isotopic abundance.

[0072] The synthesis of compound (I) or a pharmaceutically acceptable salt (e.g., a phosphate) thereof can be readily performed by the methods described in U.S. Patent No. 9,249,149, the teachings of which are incorporated herein by reference and with appropriate modifications. For example, U.S. Patent No. 9,249,149 describes the production of D9-ruxolitinib products using D9-intermediate 15; The method described in U.S. Patent No. 9,249,149 uses intermediate A to provide compound (I). Additionally, intermediate B... Compound (I) can be prepared in place of intermediate 14 in U.S. Patent No. 9,249,149; removal of the amino protecting group can be accomplished by basic cleavage (e.g., with sodium hydroxide). Compound (I) (the free base) can be converted to its phosphate using phosphoric acid. An alternative method for preparing ruxolitinib (i.e., the non-deuterated compound (I)) is disclosed in U.S. Patent No. 9,000,161 and can be used in conjunction with a suitable deuterating agent to prepare compound (I).

[0073] This method can be used to synthesize the compounds described herein using appropriate deuterating agents and optionally other isotopic reagents and / or intermediates, or by invoking standard synthetic protocols known in the art for introducing isotopic atoms into chemical structures.

[0074] The present invention also provides a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate); and a pharmaceutically acceptable carrier. This or these carriers must be "acceptable" in the sense that they are compatible with other components of the formulation and, in the case of a pharmaceutically acceptable carrier, the amount used in the drug is harmless to its recipient. In some embodiments, the pharmaceutical composition is provided in unit dosage form.

[0075] This invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and 4 to 50 mg of a compound represented by the following structural formula: Compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate).

[0076] Pharmaceutically acceptable carriers, adjuvants, and delivery vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0077] If desired, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions can be improved by methods known in the art. One method includes using lipid excipients in the formulation. See “Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” edited by David J. Hauss, Informa Healthcare, 2007; and “Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples,” edited by Kishor M. Wasan, Wiley Publishing, 2006.

[0078] Another known method to improve bioavailability is by using, optionally, poloxamer (e.g., LUTROL). TM and PLURONIC TM The compounds of the present invention are formulated in amorphous form using BASF or block copolymers of ethylene oxide and propylene oxide. See U.S. Patent 7,014,866; and U.S. Patent Publications 20060094744 and 20060079502.

[0079] The pharmaceutical compositions of the present invention include those suitable for oral administration. Other formulations may be readily presented in unit dosage forms, such as tablets, sustained-release capsules, granules, and liposomes, and may be prepared by any method well known in the pharmaceutical field. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, MD (20th edition, 2000).

[0080] Such preparation methods involve the steps of associating the molecule to be administered with multiple components (e.g., a carrier constituting one or more auxiliary components). Generally, the composition is prepared by associating the active ingredient uniformly and closely with a liquid carrier, liposomes, or a subdivided solid carrier, or both, and then shaping the product if necessary.

[0081] In some embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration can be presented in discrete units, such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water emulsions; water-in-oil emulsions; encapsulated in liposomes; or as pellets, etc. Soft gel capsules can be useful for containing such suspensions, which can benefit from improved compound absorption. In one specific embodiment, the compound is administered orally as a tablet.

[0082] In the case of tablets for oral administration, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is administered orally, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners and / or flavoring agents and / or coloring agents may be added. In another embodiment, the composition is in tablet form. In some embodiments, exemplary formulations for tablets are disclosed in U.S. Patent No. 8,754,224, the teachings of which are incorporated herein by reference.

[0083] In one specific embodiment, the tablet formulation contains about 4 mg to about 50 mg of compound (I) or an equivalent amount of its pharmaceutically acceptable salt (e.g., phosphate), and the following active ingredients: colloidal silica, magnesium stearate, microcrystalline cellulose, and povidone. Wet granulation followed by tableting provides tablets containing compound (I) or its pharmaceutically acceptable salt. For example, to prepare 200 mg tablets, equal amounts of 16 mg of compound (I), 10.6 wt% of compound (I) phosphate, and 64.44 wt% of Avicel PH-101 microcrystalline cellulose were mixed in a high-shear granulator, along with an 8.5% w / w Kollidon 30 aqueous solution (containing Kollidon 30, polyvinylpyrrolidone (Povidone); 5% wt% (based on total formulation weight) was added during mixing to form granules. The granules were tray-dried in an oven at 60°C ± 10°C and ground using a Quadro Comil U5 grinder. A stainless steel scalpel was used to force the granules retained on the Comil sieve through a 20-mesh sieve. The resulting ground granules were mixed in a Turbula mixer with Avicel PH-200 microcrystalline cellulose (18.5 wt%) and Aerosil 200 colloidal silica (0.5 wt%). The final mixture was prepared by mixing (1 wt%) of compound (I) and 1 wt% of magnesium stearate. The final mixture was then compressed into 200 mg tablets using a Riva Piccola rotary tablet press with a 0.451” × 0.229” D-type modified capsule forming tool. Each tablet contains 21.1 mg of compound (I) (equivalent to 16 mg of compound (I) free base).

[0084] In one specific embodiment, the tablet contains about 10.5 mg or 10.6 mg of the phosphate of compound (I) (equivalent to 8 mg of the free base of compound (I)).

[0085] In one specific embodiment, the tablet comprises the following ingredients: 4 mg tablets

[0086] Equivalent to 4 mg of compound (I) free base In another specific embodiment, the tablet comprises the following ingredients: 8 mg tablets

[0087] Equivalent to 8 mg of compound (I) free base In an alternative embodiment, the tablet comprises the following ingredients: 8 mg tablets

[0088] Equivalent to 8 mg of compound (I) free base In yet another specific embodiment, the tablet comprises the following ingredients: 16 mg tablets

[0089] Equivalent to 16 mg of compound (I) free base In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent may be selected from any compound or therapeutic agent known to have or proven to have advantageous properties when administered together with a compound having the same mechanism of action as ruxolitinib.

[0090] Preferably, the second therapeutic agent is an agent used to treat hair loss disorders or autoimmune diseases, including inhibitors of JAK1, JAK2, or JAK3 and / or STAT1. Such inhibitors include ruxolitinib, tofacitinib, baricitinib, filgotinib, etc. Other second therapeutic agents include oral corticosteroids.

[0091] In another embodiment, the present invention provides a separate dosage form of compound (I) or a pharmaceutically acceptable salt thereof and one or more of the above-described second therapeutic agents, wherein compound (I) or a pharmaceutically acceptable salt thereof and the second therapeutic agent are associated with each other. As used herein, the term “associated with each other” means that the separate dosage forms are packaged together or otherwise attached to each other so that it is easy to see that the separate dosage forms are intended to be sold and administered together (within 24 hours between each other, consecutively or simultaneously).

[0092] In the pharmaceutical compositions of the present invention, compound (I) or a pharmaceutically acceptable salt thereof is present in an effective amount. As used herein, the term "effective amount" means an amount sufficient to treat the target disorder when administered in a suitable dosing regimen.

[0093] The dose relationships for animals and humans (based on milligrams per square meter of body surface area) are described in Freireich et al., Cancer Chemother Rep. 1966, 50: 219. Body surface area can be approximately determined by the subject's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, 1970, 537.

[0094] In one embodiment, the effective amount of compound (I) (as a free base or as an equivalent amount of its pharmaceutically acceptable salt, such as a phosphate) can range from about 4 mg to 50 mg / day (e.g., 4 mg to 50 mg / day), such as about 5 mg / day (e.g., 5 mg / day), about 10 mg / day (e.g., 10 mg / day), about 20 mg / day (e.g., 20 mg / day), about 30 mg / day (e.g., 30 mg / day), about 40 mg / day (e.g., 40 mg / day), or about 50 mg / day (e.g., 50 mg / day). In some embodiments, the amount is about 4 mg / day (e.g., 4 mg / day), about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), about 32 mg / day (e.g., 32 mg / day), or about 48 mg / day (e.g., 48 mg / day). In one embodiment, the dose is about 4 mg / day (e.g., 4 mg / day), about 8 mg / day (e.g., 8 mg / day), about 16 mg / day (e.g., 16 mg / day), about 24 mg / day (e.g., 24 mg / day), about 32 mg / day (e.g., 32 mg / day), or about 48 mg / day (e.g., 48 mg / day), administered once daily. In one specific example, a dose of 16 mg / day is given by administering two 8 mg tablets of compound (I) together (i.e., as a single dose) as a free base or as an equivalent amount of its pharmaceutically acceptable salt, such as phosphate. In another specific example, a dose of 16 mg / day is given by administering one 16 mg tablet of compound (I) (as a free base or as an equivalent amount of its pharmaceutically acceptable salt, such as phosphate). In another embodiment, the dosage of 4 mg / day, 8 mg / day, 16 mg / day, 24 mg / day, 32 mg / day, or 48 mg / day is administered twice daily in separate doses (e.g., a 48 mg / day dose is administered as 24 mg twice daily). In another embodiment, the dosage of 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day is administered twice daily in separate doses (e.g., a 32 mg / day dose is administered as 16 mg of compound (I) twice daily (as a free base or as an equivalent amount of its pharmaceutically acceptable salt, such as phosphate)) (i.e., as separate doses). In a specific embodiment, the 16 mg / day dose is administered as 8 mg of compound (I) twice daily (i.e., as separate doses).It should be understood that the amount of compound (I) mentioned or its pharmaceutically acceptable salt includes the amount of a pharmaceutically acceptable salt (e.g., phosphate) of compound (I), which is equivalent to the amount of compound (I) described as a free base (e.g., 10.5 mg of compound (I) phosphate is equivalent to 8 mg of compound (I) free base).

[0095] In some embodiments, an effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4 mg (e.g., 4 mg) twice daily. In one specific embodiment, an effective amount of compound (I) is administered as follows: about 5.3 mg (e.g., 5.3 mg) of compound (I) phosphate twice daily. In some embodiments, an effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 8 mg (e.g., 8 mg) twice daily. In one specific embodiment, compound (I) is administered as follows: about 10.5 mg (e.g., 10.5 mg) of compound (I) phosphate twice daily.

[0096] In some embodiments, an effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 12 mg (e.g., 12 mg) twice daily. In one specific embodiment, an effective amount of compound (I) is about 15.8 mg (e.g., 15.8 mg) of the phosphate of compound (I) administered twice daily. In some embodiments, an effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 16 mg (e.g., 16 mg) twice daily. In one specific embodiment, an effective amount of compound (I) is about 21.1 mg (e.g., 21.1 mg) of the phosphate of compound (I) administered twice daily.

[0097] Example Example 1. Determining the metabolic stability of D-ruxolitinib using CYP3A4 Supersomes Materials and Methods: Material: CYP3A4 supersomes TM Obtained from Corning (Gentest). β-Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl2), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich. The deuterated test compound was supplied by Concert Pharmaceuticals.

[0098] Determination of metabolic stability:Prepare a 10 mM stock solution of the test compound in DMSO. Dilute the 7.5 mM stock solution to 12.75 μM in acetonitrile (ACN). Dilute CYP3A4 supersomes in 0.1 M potassium phosphate buffer (pH 7.4, containing 3 mM MgCl2). Add the diluted supersomes in triplicate to the wells of a 96-well deep-well polypropylene plate. Add 10 μL aliquots of the 12.75 μM test compound to the supersomes and preheat the mixture for 10 min. The reaction is initiated by adding preheated NADPH solution. The final reaction volume is 0.5 mL, containing 50 pmol / mL CYP3A4 supersomes, 0.25 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer (pH 7.4, and 3 mM MgCl2). The reaction mixture was incubated at 37°C, and 50 μL aliquots were removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates (containing 50 μL of ice-cold ACN with internal standard) to stop the reaction. The plates were stored at 4°C for 20 minutes, after which 100 μL of water was added to the wells, followed by centrifugation to granulate the precipitated protein. The supernatant was transferred to another 96-well plate, and the amount of remaining parent protein was analyzed by LC-MS / MS using an Applied Biosystems mass spectrometer.

[0099] Data Analysis: The in vitro t-value of the test compound was calculated from the slope of the linear regression (ln) of the remaining parent percentage compared to the incubation time. ½ s.

[0100] In vitro t ½ = 0.693 / k k = -[the slope of the linear regression (ln) of the remaining parental percentage compared to the incubation time] Use Microsoft Excel software for data analysis.

[0101] The t½ of compound (I) was found to be approximately 80% longer than that of non-deuterated ruxolitinib. These results indicate that the metabolic stability of compound (I) is substantially superior to that of ruxolitinib in CYP3A4 supersome assays.

[0102] Example 2. Determining the metabolic stability of D-ruxolitinib using human liver microsomes Material:Human liver microsomes (20 mg / mL) were obtained from Xenotech, LLC (Naresa, Kansas). β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl2), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich. Deuterated test compounds were supplied by Concert Pharmaceuticals.

[0103] Determination of metabolic stability: Prepare a 7.5 mM stock solution of the test compound in DMSO. Dilute the 7.5 mM stock solution to 12.5 μM in acetonitrile (ACN). Dilute human liver microsomes in 0.1 M potassium phosphate buffer (pH 7.4, containing 3 mM MgCl2). Add the diluted microsomes to the wells of a 96-well deep-well polypropylene plate in triplicate. Add 10 μL aliquots of the 12.5 μM test compound to the microsomes and preheat the mixture for 10 min. The reaction is initiated by adding preheated NADPH solution. The final reaction volume is 0.5 mL and contains 5 mg / mL human liver microsomes, 0.25 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer (pH 7.4, and 3 mM MgCl2). The reaction mixture was incubated at 37°C, and 50 μL aliquots were removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates (containing 50 μL of ice-cold ACN with internal standard) to stop the reaction. The plates were stored at 4°C for 20 minutes, after which 100 μL of water was added to the wells, followed by centrifugation to granulate the precipitated protein. The supernatant was transferred to another 96-well plate, and the amount of remaining parent protein was analyzed by LC-MS / MS using an Applied Biosystems mass spectrometer.

[0104] Data Analysis: The in vitro t-value of the test compound was calculated from the slope of the linear regression (ln) of the remaining parent percentage compared to the incubation time. ½ s.

[0105] In vitro t ½ = 0.693 / k k = -[the slope of the linear regression (ln) of the remaining parental percentage compared to the incubation time] Use Microsoft Excel software for data analysis.

[0106] The t½ of compound (I) was found to be approximately 75% longer than that of non-deuterated ruxolitinib. These results indicate that the metabolic stability of compound (I) is substantially superior to that of ruxolitinib in HLM assays.

[0107] Example 3 - Human Studies Single-Augmentation-Dose (SAD) Study: Healthy volunteers were given either compound (I) or placebo under fasting conditions. The aim of this study was to evaluate the pharmacokinetics of a single dose of compound (I) at doses of 8 mg, 16 mg, 32 mg, or 48 mg as a phosphate (e.g., 10.5 mg of compound (I) phosphate is equivalent to 8 mg of the free base of compound (I)). For each dose group, 6 subjects received compound (I) and 2 subjects received placebo. The study design is shown in [details omitted]. Figure 1A The metabolites of compound (I) were analyzed. The dosage of compound (I) was determined by administering the phosphate form of compound (I) as a powder in capsules with water. Preliminary results are as follows: Figure 1B and 1C As shown.

[0108] Multiple escalation dose study: Under fasting conditions, healthy volunteers were given either compound (I) or placebo. The aim of this study was to evaluate the pharmacokinetics of compound (I) administered daily at doses of 8 mg, 16 mg, 24 mg, or 32 mg as a phosphate (e.g., 10.5 mg of compound (I) phosphate is equivalent to 8 mg of the free base of compound (I)). Compound (I) was administered once daily (QD) (8 mg, 24 mg, 32 mg dose) or twice daily (BID) (two 8 mg doses for a total of 16 mg / day, or two 16 mg doses for a total of 32 mg / day) for seven consecutive days. For each dose group, 8 subjects received compound (I) and 2 subjects received placebo. The study design is shown in Figure 1A The metabolites of compound (I) were analyzed. Compound (I) was administered as 8 mg tablets with water. Preliminary results are as follows: Figure 1B and 1C As shown.

[0109] The final results are shown in the table below:

[0110] Preliminary results from the SAD study are shown in Figure 1B and 1C Preliminary results from the MAD study are shown in... Figure 2B and 2C The final results from the MAD study are shown in the table below. In Figures 1 and 2, CTP-543 is compound (I), given as a phosphate.

[0111] In the combined SAD and MAD study, a total of 77 subjects were administered the drug (60 received CTP-543; 17 received placebo). CTP-543 was rapidly absorbed and did not accumulate with repeated dosing. No serious adverse events were reported; the most common adverse event reported was headache. No CTP-543-related discontinuation or dose adjustments occurred. Cases of mild neutropenia resolved or showed a trend toward recovery after completion of dosing. No severe neutropenia (grade 3 or 4) was observed.

[0112] In the Phase 1 study, compound (I) was well tolerated. Based on these studies, dosages of 8 mg BID (twice daily), 12 mg BID, 16 mg BID, and 32 mg BID were selected.

[0113] Further findings from the Phase 1 study showed that the mean systemic exposure of compound (I) at a BID of 16 mg (the highest dose assessed in the Phase 2a trial described below) appeared comparable to the published reported mean exposure for a BID of ruxolitinib (which indeed showed effective induction of hair regrowth in patients with moderate to severe alopecia). (See, for example, JCI Insight . [ JCI [Insight] 2016; 1(15): e89790. doi:10.1172 / jci.insight.89790. Pharmacodynamic analyses were performed during the Phase 1 MAD study clinical trial to assess the inhibition of IL-6- and IFN-γ-mediated JAK / STAT signaling. Consistent with the established pharmacological activity of CTP-543 (compound (I)), dose-related reductions in IL-6-stimulated phosphorylated STAT3 (pSTAT3) were observed. Generally, pSTAT3 inhibition returned to near baseline values ​​in all treatment groups within 24 hours post-dose. Meanwhile, IFN-γ-mediated STAT1 signaling, considered to play a key role in the pathogenesis of alopecia areata, was significantly inhibited across all evaluated doses in disease-associated immune cell types.

[0114] With a preliminary efficacy analysis planned at week 24, a phase 2a trial was designed to assess the safety and efficacy of compound (I) 12 months after administration. The phase 2a trial was a double-blind, randomized, placebo-controlled, parallel-dose trial to evaluate the safety and efficacy of compound (I) in adult patients with moderate to severe alopecia areata. Approximately 100 patients would be randomized to receive one of four doses of compound (I) as a phosphate (e.g., 10.5 mg of compound (I) phosphate is equivalent to 8 mg of compound (I) free base). The four doses of compound (I) were 4 mg, 8 mg (i.e., approximately 10.5 mg of compound (I) phosphate), 12 mg, and 16 mg twice daily, with an additional group receiving placebo. Preliminary outcome measurements would be taken using the Severity of Hair Removal Tool (SALT) after 24 weeks of administration. The trial would include an additional 28 weeks of administration, during which all study participants would receive compound (I).

[0115] Without further description, it is believed that those skilled in the art can use the foregoing description and illustrative examples to accomplish and utilize these compounds of the present invention and implement the claimed methods. It should be understood that the foregoing discussion and examples present only a detailed description of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention.

Claims

1. A method for treating alopecia in a mammalian subject, the method comprising administering to the subject daily an amount of a compound represented by the following structural formula, ranging from 4 mg to 50 mg: Compound (I), or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the hair loss obstacle is alopecia areata.

3. The method of any one of claims 1-2, wherein the method comprises administering the subject about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day of compound (I) or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-3, wherein the method comprises administering the subject about 8 mg / day, about 12 mg / day, about 16 mg / day, or about 24 mg / day of compound (I) or a pharmaceutically acceptable salt thereof.

5. The method according to any one of claims 1-4, wherein the compound is administered orally.

6. The method of any one of claims 1-5, wherein the compound is administered as a pharmaceutical formulation in the form of a tablet.

7. The method of any one of claims 1-6, wherein the compound is administered once a day.

8. The method of any one of claims 1-6, wherein the compound is administered twice a day.

9. The method according to any one of claims 1-8, wherein in compound (I), any atom not designated as deuterium is present at its natural isotopic abundance.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 4 mg to 50 mg of a compound represented by the following structural formula: Compound (I) Or its pharmaceutically acceptable salt.

11. The pharmaceutical composition of claim 10, comprising about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg of compound (I) or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of any one of claims 10 or 11, wherein the pharmaceutical composition is suitable for oral administration.

13. The pharmaceutical composition of any one of claims 10 or 11, wherein the composition is a tablet.

14. The pharmaceutical composition according to any one of claims 10-13, wherein the composition is administered once daily.

15. The pharmaceutical composition of claim 10, wherein the composition is a tablet comprising: (i) Approximately 5.2 wt% of compound (I) phosphate; (ii) Approximately 90.8 wt% microcrystalline cellulose; (iii) Approximately 2.5 wt% povidone; (iv) Approximately 0.5 wt% colloidal silica; and (v) Approximately 1.0 wt% magnesium stearate.

16. The pharmaceutical composition of claim 15, wherein the composition is a 200 mg tablet comprising about 10.5 mg of compound (I) phosphate.

17. The pharmaceutical composition of claim 10, wherein the composition is a tablet comprising: (i) Approximately 5.3 wt% of compound (I) phosphate; (ii) Approximately 88.2 wt% microcrystalline cellulose; (iii) Approximately 5.0 wt% povidone; (iv) Approximately 0.5 wt% colloidal silica; and (v) Approximately 1.0 wt% magnesium stearate.

18. The pharmaceutical composition of claim 17, wherein the composition is a 200 mg tablet comprising about 10.6 mg of compound (I) phosphate.

19. The pharmaceutical composition of claim 10, wherein the composition is a tablet comprising: (i) Approximately 10.6 wt% of compound (I) phosphate; (ii) Approximately 82.9 wt% microcrystalline cellulose; (iii) Approximately 5.0 wt% povidone; (iv) Approximately 0.5 wt% colloidal silica; and (v) Approximately 1.0 wt% magnesium stearate.

20. The pharmaceutical composition of claim 19, wherein the composition is a 200 mg tablet comprising about 21.1 mg of compound (I) phosphate.

21. A method for treating alopecia in a mammalian subject, the method comprising administering the subject approximately 4 mg of a compound represented by the following structural formula twice daily: Compound (I) or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein the compound (I) is administered twice daily as about 5.3 mg of phosphate.

23. A method for treating alopecia in a mammalian subject, the method comprising administering the subject approximately 8 mg of a compound represented by the following structural formula twice daily: Compound (I) or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the compound (I) is administered twice daily as about 10.5 mg of phosphate.

25. A method for treating alopecia in a mammalian subject, the method comprising administering the subject approximately 12 mg of a compound represented by the following structural formula twice daily: Compound (I) or a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein the compound (I) is administered twice daily as about 15.8 mg of phosphate.

27. A method for treating alopecia in a mammalian subject, the method comprising administering the subject approximately 16 mg of a compound represented by the following structural formula twice daily: Compound (I) or a pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein the compound (I) is administered twice daily as about 21.1 mg of phosphate.

29. The method of any one of claims 21-28, wherein the hair removal obstacle is alopecia areata.

30. The method of any one of claims 21-29, wherein the compound is administered orally.

31. The method of any one of claims 21-30, wherein the compound is administered as a pharmaceutical formulation in the form of a tablet.

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