Use of itaconate and derivatives / analogues thereof to induce hair growth

Abstract

Methods for inducing hair growth and treating inflammation or immune activation (adaptive or innate), skin conditions, or other conditions associated with hair loss are provided.SOLUTION: The method uses itaconic acid and prodrugs of 1 - and 4-methylitaconic acid.SELECTED DRAWING: None

Description

Federally sponsored research or development

[0001] This invention was made possible through grants AR068280 and AR064 awarded by the National Institutes of Health. This invention was made with government support under the Federal Trade Commission's 297 Act. The government has certain rights in this invention. do. [Background technology]

[0002] Alopecia areata (AA) is a widespread inflammatory cause of hair loss that affects a large proportion of the population over the course of a lifetime. Approximately 2% of people suffer from AA. A typical AA lesion is a non-scarring, hairless, round patch on the scalp. It may progress to multiple patches. Extensive forms of AA include alopecia totalis (alopecia Complete or generalized loss of scalp hair, called thoracocephaly (AT), Complete loss of body hair, called alopecia universalis (AU) AA can be associated with other skin and autoimmune diseases, especially atopic dermatitis. Allergic dermatitis (AD), as well as vitiligo, lupus erythematosus, psoriasis, autoimmune thyroid disease, and Allergic rhinitis is associated with AA. Although AA is not life-threatening, psychological comorbidities It is common among patients with AA and can have a significant impact on their lives. Current treatments for severe cases of AA include broad-spectrum immunosuppressants, but these are There may be serious side effects that prevent long-term use, including rapid hair loss after treatment. The pathogenesis of alopecia areata is not yet fully understood, and currently there are no treatments or methods to induce remission for alopecia areata. and no maintenance treatment exists. Summary of the Invention

[0003] The subject matter of the present disclosure is intended to induce hair growth and to treat inflammatory skin conditions or other conditions associated with hair loss, e.g. For example, itaconic acid and 1- and 4-methyl itaconic acid for treating alopecia areata. The use of prodrugs is provided.

[0004] More specifically, in some embodiments, the subject matter of the present disclosure is a method for treating a subject in need thereof. Inducing hair growth or reducing inflammatory skin conditions or immune activation (adaptive or apoptotic) in elephants 1. A method for treating hair loss (genetic or other hair loss-related condition), comprising administering to the subject a therapeutically effective amount of A compound of formula (I): [ka] [During the ceremony: R1 and R2 may be the same or different and may be one or more of the following and combinations thereof: Each combination is independently selected: (a) -OR3 (R3 is H or C1-C6 straight or branched unsubstituted or substituted alkyl); (b) [ka] wherein n is an integer selected from 1, 2, 3, and 4; R is a C1-C6 straight chain or branched unsubstituted or substituted alkyl or -OR5, where R5 is C1 -C6 straight or branched unsubstituted or substituted alkyl); (c) [ka] wherein m is an integer selected from 1, 2, 3, and 4; p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and and R6 is an integer selected from C1-C6 straight or branched unsubstituted or substituted alkyl); (d) [ka] wherein R7 is selected from: (i) -C(=O)-O-R8 (R8 is a C1-C6 straight or branched unsubstituted or is a substituted alkyl); (ii) [ka] (wherein R9 is H or C1-C4 linear or branched unsubstituted or substituted alkyl) Yes;R 10 is a C1-C6 straight or branched unsubstituted or substituted alkyl; R 11 and R 12 are each independently H or a protecting group; and R 13 is C1-C6 straight-chain or branched unsubstituted or substituted alkyl); (iii) [ka] wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. R 11 and R 12 are each independently H or a protecting group; R 14 H or is a C1-C4 straight or branched unsubstituted or substituted alkyl; and R 15 teeth, C1-C6 straight-chain or branched unsubstituted or substituted alkyl); and (iv) [ka] (In the formula, R 16 and R 17 are each H, C1-C4 straight or branched unsubstituted or R is independently selected from a substituted alkyl, and a protecting group; 18 is aryl); (e) [ka] (In the formula, R 19 is a C1-C4 straight or branched unsubstituted or substituted alkyl; (f) [ka] where u is an integer selected from 1, 2, 3, and 4; R 20 is H or C1 -C4 straight or branched unsubstituted or substituted alkyl; and R 21 Ha-OR2 2, where R 22 is a C1-C6 straight or branched unsubstituted or substituted alkyl or -NR 23 R 24 where R 23 and R 24 are each independently H or is a C1-C4 straight or branched unsubstituted or substituted alkyl. and a pharmaceutically acceptable salt thereof.

[0005] In yet other aspects, the presently disclosed subject matter provides a method for treating inflammation or immune system activation (adaptive or 1. A method for treating a disease, disorder or condition associated with a genetic disorder, comprising administering to a subject in need of such treatment, and administering to a subject a compound of formula (I) or a pharmaceutical composition thereof. Representative diseases and disorders associated with inflammation or immune system activation (adaptive or congenital) or conditions include, but are not limited to, androgenic alopecia lopecia), alopecia areata, other forms of alopecia, UV radiation, defective wound healing (wou nd healing defects), psoriasis, atopic dermatitis, contact dermatitis, alcohol These include eczema, acne, and autoimmune / autoinflammatory conditions.

[0006] Certain aspects addressed in whole or in part by the subject matter of the present disclosure are set forth herein. While the above has been described, other aspects are best described herein below in the accompanying drawings. This will become clear as the description proceeds when taken in conjunction with the examples and drawings. [Brief explanation of the drawings]

[0007] The patent or application file contains at least one drawing executed in color. Copies of color drawing(s) of the patent or patent application publication are available upon request and payment of the necessary fee. Provided by the Office. Having thus described the presently disclosed subject matter in general terms, Reference is made to the accompanying drawings, which are not drawn to scale. [Figure 1] FIG. 1 shows the release of itaconic acid (FIG. 1A) or monomethyl itaconate (FIG. 1B) prodrugs after 60 minutes of incubation in skin homogenate. [Figure 2] FIG. 1 shows the release of 4-methylitaconate from its prodrug after 60 minutes of incubation in mouse plasma. [Figure 3] FIG. 1 shows monomethyl itaconate release in mouse plasma after oral administration of 10 mg / kg equivalent in male CD1 mice. [Figure 4]Treatment of human keratinocytes with itaconate prodrugs perturbs the TLR3 / IL6 / STAT3 axis. IS-100-142 most effectively inhibits JAK-STAT signaling by mitigating poly(I:C) effects on downstream gene targets (TLR3, IL6, STAT3, WNT7B). [Figure 5] FIG. 1 shows that 20% dimethyl itaconate induces the transition from telogen, the resting phase of the hair cycle, to anagen, the growth phase of the hair cycle, in mice. [Figure 6] FIG. 1 shows the effect of dimethyl itaconate in blunting the effect of dsRNA (PIC; polyinosinic:polycytidylic acid) on increasing TLR3, IL-6, and STAT3 expression. [Figure 7] FIG. 1 shows that compound 5 induces hair growth in mice. [Figure 8] FIG. 1 shows further evidence that compound 5 induces hair growth in mice. [Figure 9] FIG. 1 shows that compound 5 induces hair growth in mice to a level comparable to that of ruxolitinib and tofacitinib. [Figure 10] FIG. 1 shows mouse skin homogenate stability of representative prodrugs. [Figure 11] FIG. 1 shows the release of active monomethyl itaconate (in skin homogenates) from representative prodrugs. [Figure 12] FIG. 1 shows mouse skin penetration in an alopecia model for IS-100-142 (compound 5) (left panel) and monomethyl itaconate (right panel). [Figure 13] Figure 1 shows ex vivo human skin penetration of IS-100-142 (compound 5). Monomethyl itaconate (MMI) levels in the medium and skin were higher than for intact IS-100-142; medium levels of both analytes were similar to those in the skin. Detailed Description of the Invention

[0008] The subject matter of this disclosure will now be described in detail with reference to certain preferred embodiments, some of which, but not all, of the present invention. DETAILED DESCRIPTION OF THE INVENTION Referring now more fully to the accompanying drawings, in which like numbers refer to like elements throughout: The subject matter of the present disclosure may be embodied in many different forms and is set forth herein. The invention should not be construed as being limited to the described embodiments; rather, these embodiments are intended to be illustrative and not restrictive of the invention. This information is provided to satisfy applicable legal requirements. Many modifications and other embodiments of the disclosed subject matter are illustrated in the foregoing description and associated drawings. It will occur to those skilled in the art to which the subject matter of this disclosure pertains having the benefit of the teachings thereof. The subject matter of this disclosure is not limited to the particular embodiments disclosed and modifications and other alternatives may be made. It is understood that all embodiments are intended to fall within the scope of the appended claims.

[0009] I. Use of Itaconate and Its Derivatives / Analogs to Induce Hair Growth

[0010] The compounds of formula (I) of the present disclosure may be used to induce hair growth and to treat one or more inflammatory skin conditions. or other conditions related to hair loss. In embodiments, the inflammatory skin condition or other condition associated with hair loss comprises alopecia areata.

[0011] Alopecia areata is a common inflammatory cause of hair loss, in which T lymphocytes attack hair follicles. It is thought to be an autoimmune disease that causes hair to stop growing and enter the telogen phase. At the end of the telogen phase, the hair falls out.

[0012] There are three subtypes of alopecia areata, named according to severity: (i) scalp (ii) alopecia areata, with mild patchy hair loss on the scalp; (iii) alopecia areata, with loss of all scalp hair; and (iii) alopecia universalis, which involves loss of scalp and whole body hair. Alopecia areata includes, but is not limited to, androgenic alopecia (androgenic alopecia). lopecia, anagen effluvium, self-induced Hair loss (self-induced hair loss), telogen effluvium en effluvium), and scarring alopecia a) is included.

[0013] Male pattern baldness includes male pattern baldness and female pattern baldness, accounting for 95% of all hair loss. Anagen effluvium is a type of hair loss that occurs during certain types of chemotherapy or radiation treatment. as a result of exposure to chemicals or radiation, or to toxic substances such as thallium and arsenic This is sudden hair loss that occurs as a result of exposure to chemicals. In most cases, the hair loss occurs after treatment is completed. Once the toxin exposure is eliminated, hair growth returns to normal. Self-induced hair loss can occur either consciously or can be caused unconsciously. The two main types of self-induced hair loss are trichotillomania and traction alopecia. Trichotillomania is This is self-induced hair loss caused by continuous pulling or plucking of hair. Trichotillomania is usually caused by constant and excessive pulling of hair due to various types of hair styling. This is caused by telogen effluvium, which gradually leads to hair loss that can become permanent. Sudden or severe stress-related hair loss that appears as a thinning of the entire scalp A sudden or stressful event can cause hair follicles to stop growing prematurely and enter the telogen phase. Other causes of telogen effluvium include thyroid dysfunction (thyroid-related Occurs when the thyroid gland produces too little or too much of the hormone thyroxine hypothyroidism or hyperthyroidism); diabetes; anemia; and autoimmune diseases Cicatricial alopecia occurs as a result of inflammation of the hair follicle due to infection. Cicatricial alopecia is a condition caused by discoid lupus erythematosus, a diffuse connective tissue disease that primarily affects the skin and mucous membranes. Lichen planus, an inflammatory disease; and atrophic alopecia, a rare cicatricial alopecia with no potential for regrowth. Pseudopelade of Brocq; usually located in the midline of the scalp, A rare congenital disorder that often presents as small, bullous atrophic areas present at birth It may be caused by cutaneous defects; or congenital atrichosis. Other types of hair loss include plum Syphilitic alopecia, which is a secondary symptom of the poison; scleroderma; and tinea capitis (ringworm) ) is included.

[0014] More specifically, the presently disclosed subject matter is a method for inducing hair growth in a subject in need of such treatment. or a method for treating an inflammatory skin condition or other condition associated with hair loss, comprising A subject is administered a therapeutically effective amount of a compound of formula (I): [ka] [During the ceremony: R1 and R2 may be the same or different and may be one or more of the following and combinations thereof: Each combination is independently selected: (a) -OR3 (R3 is H or C1-C6 straight or branched unsubstituted or substituted alkyl); (b) [ka] wherein n is an integer selected from 1, 2, 3, and 4; R is a C1-C6 straight chain or branched unsubstituted or substituted alkyl or -OR5, where R5 is C1 -C6 straight or branched unsubstituted or substituted alkyl); (c) [ka] wherein m is an integer selected from 1, 2, 3, and 4; p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and and R6 is an integer selected from C1-C6 straight or branched unsubstituted or substituted alkyl); (d) [ka] wherein R7 is selected from: (i) -C(=O)-O-R8 (R8 is a C1-C6 straight or branched unsubstituted or is a substituted alkyl); (ii) [ka] (wherein R9 is H or C1-C4 linear or branched unsubstituted or substituted alkyl) Yes;R 10 is a C1-C6 straight or branched unsubstituted or substituted alkyl; R 11 and R 12 are each independently H or a protecting group; and R 13 is C1-C6 straight-chain or branched unsubstituted or substituted alkyl); (iii) [ka] wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. R 11 and R 12 are each independently H or a protecting group; R 14 H or is a C1-C4 straight or branched unsubstituted or substituted alkyl; and R 15 teeth, C1-C6 straight-chain or branched unsubstituted or substituted alkyl); and (iv) [ka] (In the formula, R 16 and R 17 are each H, C1-C4 straight or branched unsubstituted or R is independently selected from a substituted alkyl, and a protecting group; 18 is aryl); (e) [ka] (In the formula, R 19 is a C1-C4 straight or branched unsubstituted or substituted alkyl; (f) [ka] where u is an integer selected from 1, 2, 3, and 4; R 20 is H or C1 -C4 straight or branched unsubstituted or substituted alkyl; and R 21 Ha-OR2 2, where R 22 is a C1-C6 straight or branched unsubstituted or substituted alkyl or -NR 23 R 24 where R 23and R 24 are each independently H or is a C1-C4 straight or branched unsubstituted or substituted alkyl) and a pharmaceutically acceptable salt thereof.

[0015] In certain embodiments of the disclosed methods, (a) R1 is -OR3 and R2 is [ka] wherein R7 is selected from [ka] Selected from; (b) R1 is [ka] and R2 is [ka] wherein R7 is selected from [ka] Selected from; (c) R1 is [ka] and R2 is [ka] wherein R7 is selected from [ka] Selected from; (d) R1 is [ka] and R2 is [ka] wherein R7 is selected from [ka] Selected from; (e) R1 is [ka] and R2 is [ka] wherein R7 is selected from [ka] Selected from; (f) R1 is [ka] wherein R7 is —C(═O)—O—R8 and R2 is [ka] wherein R7 is selected from [ka] Selected from; (g) R1 is [ka] wherein R7 is [ka] and R2 is [ka] wherein R7 is selected from [ka] Selected from; (h) R1 is [ka] wherein R7 is [ka] and R2 is [ka] wherein R7 is selected from [ka] selected from; and (i) R1 is [ka] wherein R7 is [ka] and R2 is [ka] wherein R7 is selected from [ka] Selected from; and pharmaceutically acceptable salts thereof.

[0016] In a more particular embodiment of the disclosed method, (ai) R1 is -OH and R2 is [ka] wherein R7 is —C(═O)—O—R8; (a-ii) R1 is -OR3 and R2 is [ka] wherein R7 is selected from [ka] Selected from; (b) R1 is [ka] and R2 is [ka] Selected from; (c) R1 is [ka] and R2 is -OR3; (d) R1 is [ka] and R2 is [ka] Selected from; (e) R1 is [ka] wherein R7 is -C(=O)-O-R8 and R2 is -OR3; (f) R1 is [ka] wherein R7 is [ka] and R2 is -OR3; (g) R1 is [ka] wherein R7 is [ka] and R2 is -OR3; (h) R1 is [ka] wherein R7 is [ka] and R2 is -OR3; and (i) R1 is [ka] and R2 is -OR3.

[0017] In some embodiments of the disclosed methods, R3, R4, R5, R6, R8, R9, R1 0, R 13 , R 15 and R 22 are each independently methyl, ethyl, or n-propyl. , isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl , isopentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane C1, C2 selected from 2,2-dimethylbutane and 2,3-dimethylbutane It can be a C3, C4, C5 or C6 straight or branched unsubstituted or substituted alkyl.

[0018] In some embodiments of the disclosed methods, R, R 14 , R16 , R 17 , R 19 , R 20 , R 23 and R 24 are each independently methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, sec-butyl, iso-butyl and t-butyl may be C1, C2, C3 or C4 straight or branched unsubstituted or substituted alkyl .

[0019] Representative substituents include, but are not limited to, alkyl, substituted alkyl, halogen , aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkyla amino, dialkylamino, sulfate, cyano, mercapto, and alkylthio. It can be enjoyed.

[0020] In certain embodiments of the disclosed methods, the protecting group is tert-butoxycarbonyl ( boc), carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), 9-fluorenylmethyloxycarbonyl (Fmoc) group, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM) , Tosyl (Ts), Troc (trichloroethyl chloroformate), (4-nitrophenyl (Nosyl), sulfonyl (Nosyl), and nitrophenylsulfenyl (Nps). In certain embodiments, the protecting group is tert-butoxycarbonyl (boc). is.

[0021] In some embodiments of the disclosed methods, R 18 is selected from phenyl.

[0022] In certain embodiments of the disclosed methods, (ai) R1 is -OH and R2 is [ka] Selected from; (a-ii) R1 is made up of -OCH3, -OCH(CH3)2 and -OC(CH3)3 is selected, and R2 is [ka] Selected from; (b) R1 is [ka] and R2 is [ka] is; (c) R1 is [ka] and R2 is -OCH3(12,13); (d) R1 is [ka] and R2 is [ka] Selected from; (e) R1 is [ka] and R2 is -OCH3(14); (f) R1 is [ka] and R2 is -OCH3(17,19); (g) R1 is [ka] and R2 is -OCH3(15,16); (h) R1 is [ka] and R2 is -OCH3(18,20); and (i) R1 is [ka] and R2 is -OCH3(3,4).

[0023] In certain embodiments of the disclosed methods, the compound of formula (I) is [ka] [ka] is selected from.

[0024] Active Agents Released by Representative Compounds of Formula (I) and Their Respective Prodrugs The agents are provided in Table 1.

[0025] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0026] In some embodiments, the methods of the present disclosure further comprise combining a compound of formula (I) with a pharmaceutically acceptable salt thereof. and an excipient as described above.

[0027] In certain embodiments of the disclosed methods, the inflammatory skin condition or other condition associated with hair loss is In certain embodiments, the condition comprises alopecia areata. In certain embodiments, the alopecia areata is patchy alopecia areata (pa In another embodiment, the alopecia areata is a form of alopecia areata. In yet another embodiment, the condition includes alopecia totalis. The alopecia areata includes alopecia universalis. .

[0028] In some embodiments, the method for inducing hair growth comprises inducing hair growth in the telogen activator of the hair growth cycle. In short, the three stages of hair growth are anagen, cytokinin, and cytokinin. Anagen, catagen, and telogen Anagen is the growth phase during which hair physically grows. The telogen phase is known as the resting phase during which the follicles are dormant. It is being done.

[0029] In certain embodiments, the method further comprises determining whether a protein present in the subject during the anagen phase is present in the subject. In certain embodiments, the subject receives a therapeutically effective amount of a formula Before administration of the compound (I), the hair follicles in the anagen phase were compared with the control subjects. The number of packets is decreasing.

[0030] In another embodiment, the subject has alopecia from an underlying health disorder or therapeutic treatment. In certain embodiments, the underlying Common health problems include Acquired Immune Deficiency (AID), Hypothyroidism, Hyperthyroidism, and Redness. Lupus, diabetes, anemia, syphilis, zinc deficiency, trichotillomania, Cushing's syndrome, systemic lupus erythematosus, infectious diseases, discoid lupus erythematosus, lichen planus, atrophic alopecia (Pseudope lade of Brocq), congenital skin defects, congenital atrichosis, scleroderma, and head Tinea (ringworm).

[0031] In a more particular embodiment, the underlying health disorder is a disorder or condition associated with hair loss. In certain embodiments, the hair loss-related disorder or condition is male pattern baldness (androgenetic alopecia). Androgenic alopecia, alopecia areata, anagen effluvium n effluvium), self-induced hair loss oss), telogen effluvium, and cicatricial alopecia scarring alopecia.

[0032] In some embodiments, the therapeutic treatment comprises chemotherapy or radiation therapy.

[0033] In yet other embodiments, the presently disclosed subject matter is directed to treating inflammation or immune system activation (adaptive or 1. A method for treating a disease, disorder or condition associated with a genetic disorder, comprising administering to a subject in need of such treatment, and administering to a subject a compound of formula (I) or a pharmaceutical composition thereof. Representative diseases and disorders associated with inflammation or immune system activation (adaptive or congenital) or conditions include, but are not limited to, androgenic alopecia lopecia), alopecia areata, other forms of alopecia, UV radiation, defective wound healing (wou nd healing defects), psoriasis, atopic dermatitis, contact dermatitis, alcohol These include eczema, acne, and autoimmune / autoinflammatory conditions.

[0034] Generally, as used herein, the term "treat" refers to any A disease, disorder, or condition for which the invention is intended, or one or more of such diseases, disorders, or conditions Reversing, alleviating, slowing down or preventing the onset of symptoms; Prevention may include reducing or preventing a disease, disorder, condition, or symptom thereof. Therefore, the present disclosure The compounds are used prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder or condition. can be administered to

[0035] The "subject" to be treated by the methods of the present disclosure, in many embodiments thereof, is preferably a human Although the subject matter is a subject matter, the methods described herein are not intended to be encompassed by the term "subject matter." It will be understood that the invention is effective with respect to all vertebrate species. is a prophylactic for treating an existing condition or disease or for preventing the onset of a condition or disease. including human subjects for medical purposes such as treatment, or animal subjects for medical, veterinary or developmental purposes Suitable animal subjects include, but are not limited to, primates (e.g., humans, monkeys, apes, etc.); bovines (e.g., cattle, bulls, etc.); ovines (e.g., sheep, etc.) Caprines (e.g., goats, etc.); Swine (e.g., pigs, boars, etc.); Equines (e.g., , horses, donkeys, zebras, etc.); felines (e.g., wild cats, domestic cats, etc.); canines (e.g., Lagomorphs (e.g., rabbits, hares, etc.); rodents (e.g., macaques, Animals may be transgenic. In embodiments, subjects include, but are not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Furthermore, a "subject" refers to a subject suffering from or suffering from a condition or disease. The term "subject" as used herein may include a patient suspected of being affected. The term "patient" is used interchangeably. The term "subject" refers to an organism, tissue, or tissue sample from a subject. , also refers to a cell or collection of cells.

[0036] Generally, an "effective amount" of an active agent or drug delivery device is an amount that elicits a desired biological response. As will be understood by those skilled in the art, the term "drug" refers to the amount of a drug or drug that is needed to The effective amount of a device depends on the desired biological endpoint, the agent being delivered, and the composition of the pharmaceutical composition. The dosage may vary depending on factors such as the target tissue, etc.

[0037] The term "combination" is used in its broadest sense and refers to at least two Drugs, more specifically compounds of formula (I) and at least one beta-lactam antibiotic The term "antimicrobial agent" refers to the administration of a substance containing an antimicrobial agent, and optionally one or more antimicrobial agents. The term "in combination" refers to the use of two (or more) of these compounds, e.g., for the treatment of a single disease state. As used herein, active agents refer to the simultaneous administration of a combination of active agents. They may be administered together in a single dosage form, or may be administered simultaneously in separate dosage forms, or may be administered simultaneously in the same dosage form. They may also be administered as separate dosage forms that are administered alternately or sequentially on the same or different days. In one embodiment of the presently disclosed subject matter, the active agents are combined and administered in a single dosage form. In some embodiments, the active agents are administered in separate dosage forms (e.g., varying the amount of one but (It is desirable to leave the amount of one drug and the other unchanged.) The single dosage form may contain additional The active agent may include:

[0038] Additionally, the compounds of formula (I) described herein may be used alone or in combination with one or more antibacterial agents. administration in combination with an adjuvant that enhances the stability of the compound of formula (I); and in certain embodiments, facilitate administration of pharmaceutical compositions containing them, dissolving or This can result in increased dispersion, enhanced inhibitory activity, and the provision of adjunctive therapy with other active ingredients. Advantageously, such combination therapy can be achieved with lower doses of conventional therapy. and therefore the potential consequences when these drugs are used as monotherapy. Avoid certain toxic and harmful side effects.

[0039] The timing of administration of the compound of formula (I) and at least one additional therapeutic agent may be adjusted accordingly. These drug combinations can be varied as long as they provide beneficial effects. Thus, the term "in combination" refers to a compound of formula (I) in combination with at least one additional therapeutic agent. This refers to the administration of therapeutic agents either simultaneously, sequentially, or in combination. Thus, administering a combination of a compound of formula (I) and at least one additional therapeutic agent The subject receiving the drug should be at least 18 years of age and at least 18 years of age, and should be at least 18 years of age or older, as long as the combined effects of both drugs are achieved in the subject. ) and at least one additional therapeutic agent simultaneously (i.e., simultaneously) or May be taken at different times (i.e., sequentially (in any order), on the same day, or on different days). This can be done.

[0040] When administered sequentially, the drugs should be administered 1, 5, 10, 30, 60, 120 minutes apart. It can be administered within a period of 180 minutes, 240 minutes or more. Sequentially administered drugs may be administered 1, 5, 10, 15, 20 or more days apart from each other. The compound of formula (I) and at least one additional treatment may be administered within a number of days. When the therapeutic agents are administered simultaneously, they each contain a compound of formula (I) or at least and one additional therapeutic agent. Alternatively, they may be administered to a subject as a single pharmaceutical composition containing both agents.

[0041] When administered in combination, the effective concentration of each agent to elicit a specific biological response may be lower than the effective concentration of each agent when administered alone, thereby allowing the agents to be administered alone A reduction in the dose of one or more drugs relative to the dose required if given alone The effects of multiple drugs may be, but do not have to be, additive or synergistic. No. The drug may be administered multiple times.

[0042] In some embodiments, two or more agents have a synergistic effect when administered in combination. As used herein, "synergistic effect" or "synergistic combination" or "Synergistic," "synergistically," and their derivatives in "synergistic composition," etc. The term refers to the biological activity of a combination of a compound of formula (I) and at least one additional therapeutic agent. A situation in which the activity is greater than the sum of the biological activities of each drug when administered individually Refers to...

[0043] The synergy can be expressed as a "synergy index (SI)", which is generally ll et al., Applied Microbiology 9,538 pages (1 961) from the ratio determined by the following formula: : Q a / Q A +Q b / Q B = Synergy Index (SI) During the ceremony: Q A is the concentration of component A acting alone, which produces the endpoint relative to component A. ru; Q a is the concentration of component A in the mixture, which produces the endpoint; Q B is the concentration of component B acting alone and relative to component B to produce the endpoint and Q b is the concentration of component B in the mixture, which produces the endpoint.

[0044] In general, Q a / Q A and Q b / Q B If the sum is greater than 1, antagonism is indicated. If the sum is equal to 1, additivity is indicated. If the sum is less than 1, synergy is indicated. The lower the SI, the greater the synergistic effect exhibited by that particular mixture. Therefore, a "synergistic combination" is defined based on the activity observed when the individual components are used alone. Furthermore, a "synergistically effective amount" of an ingredient is For example, the amount of the compound that is necessary to elicit a synergistic effect with another therapeutic agent present in the composition. Refers to the amount of an ingredient.

[0045] In another embodiment, the subject matter of the present disclosure comprises one compound of formula (I) alone or in combination with a pharmaceutical agent. in combination with one or more additional therapeutic agents admixed with a pharmaceutical acceptable excipient. Those skilled in the art will appreciate that pharmaceutical compositions are provided that are pharmaceutically acceptable in the presence of the compounds described above. It will be recognized that pharmaceutically acceptable salts include salts which are generally well known to those skilled in the art. and, depending on the particular substituent moieties found in the compounds described herein, are relatively non-toxic. Included are salts of the active compounds prepared with acids or bases. If the compound contains a neutral functional group, the base addition salt may be formed by combining the neutral form of such compound with a sufficient amount of the desired by contacting the base neat or in a suitable inert solvent or by ion exchange can be obtained, whereby one basic counterion (base) in an ionic complex is replaced by another Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or and similar salts thereof.

[0046] When compounds of the present disclosure contain relatively basic functional groups, acid addition salts of such compounds are readily available. The neutral form and a sufficient amount of the desired acid are combined, either neat or in a suitable inert solvent or by ion exchange. whereby one acid pair in the ionic complex Examples of pharmaceutically acceptable acid addition salts include hydrochloric acid, bromine, and methyl methyl ketone. Hydrogen fluoride, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrate those derived from inorganic acids such as hydroxysulphuric acid, hydroiodic acid, or phosphorous acid, and Acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid It is derived from relatively non-toxic organic acids such as acetic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine salts, and salts of glucuronic acid and galactose. Also included are salts of organic acids such as guar sulphonic acid (see, e.g., Berge et al., "Pha rmaceutical Salts”, Journal of Pharmaceu (See, Artificial Science, 1977, 66, pp. 1-19). The compounds contain both basic and acidic functional groups, and the compounds can be used as base addition salts or acid addition salts. It is possible to convert it into either a salt.

[0047] Thus, there are no limitations on the pharmaceutically acceptable salts suitable for use with the subject matter of the present disclosure. Examples include, but are not limited to, acetates, benzenesulfonates, benzoates, bicarbonates, etc. Acid salt, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, Edetate, edisylate, estolate, esylate, fumarate, gluceptate, Gluconate, glutamate, glycolylsanilate ilate, hexylresorcinate, hydra Hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate ( hydroxynaphthoate, iodide, isethionate ate), lactate, lactobionate, malate, maleate, mandelate, methylate phosphate, mucate, napsylate, nitrate, paclitaxel moate (embonate), pantothenate, Phosphate / diphosphate, polygalacturonate, salicylate, stearate, basic Acetate (subacetate), succinate, sulfate, tannate Other pharmaceutically acceptable salts include tartrate, tartrate, or teoclate. The salts are described, for example, in Remington: The Science and Practice CE of Pharmacy (20th Edition) Lippincott, Williams & Wilkins (2000).

[0048] In therapeutic and / or diagnostic applications, the compounds of the present disclosure may be administered systemically and topically or Topical or localized administration The techniques and formulations are generally: Remington:The Science and Practice of Ph. armacy (20th edition) Lippincott, Williams & Wilki ns (2000).

[0049] Depending on the particular condition being treated, such agents may be formulated into liquid or solid dosage forms. The agent may be administered systemically or locally, for example, as known to those skilled in the art. It may be delivered in a timed or sustained release form. Techniques for formulation and administration are described in Remin. gton:The Science and Practice of Pharmac Lippincott, Williams & Wilkins (20th Edition) Suitable routes include oral, buccal, inhalation spray, sublingual, rectal, and transdermal. , vaginal, transmucosal, nasal or intestinal administration; intramuscular, subcutaneous, intramedullary injection, as well as intrathecal, direct to the brain Intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intracerebral, intraperitoneal, intranasal or intraocular injections, etc. This may include parenteral administration of the compound or other modes of administration.

[0050] For injection, the agents of the present disclosure may be administered in aqueous solutions such as Hank's solution, Ringer's solution, or saline. The compound may be formulated and diluted in a physiologically compatible buffer, such as physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0051] To practice the present disclosure, the compounds disclosed herein are formulated in dosages suitable for systemic administration. The use of pharmaceutically acceptable inert carriers for the preparation of pharmaceutical compositions is within the scope of this disclosure. By selection and appropriate manufacturing methods, the compositions of the present disclosure, especially those formulated as solutions, can be administered intravenously. These compounds can be administered parenterally, such as by intravenous injection. The compound can be easily formulated into a dosage suitable for oral administration using a commercially available carrier. Such carriers may be used to administer the compounds of the present disclosure for oral ingestion by a subject (e.g., a patient) to be treated. The compound may be formulated as a tablet, pill, capsule, liquid, gel, syrup, slurry, suspension, etc. This allows it to be done.

[0052] For nasal or inhalation delivery, the agents of the present disclosure may also be formulated by methods known to those skilled in the art. The compound may be solubilized, diluted, or dispersed in, for example, but not limited to, saline. may contain preservatives such as benzyl alcohol; absorption enhancers; and fluorocarbons .

[0053] Pharmaceutical compositions suitable for use in the present disclosure include compositions in which the active ingredient achieves its intended purpose. The determination of an effective amount is particularly provided herein. It is within the ability of one skilled in the art in light of the detailed disclosure provided herein. is effective over a wide dosage range. For example, in the treatment of adult humans, 1-1000 mg, 0.5-100 mg, 1-50 mg / day, and 5-40 mg / day are examples of dosages that can be used. Non-limiting dosages are 10-30 mg / day. The exact dosage depends on the route of administration, the dosage form of the compound, the subject to be treated, the body weight of the subject to be treated, the bioavailability of the compound, and the dosage form of the compound. availability, absorption, distribution, metabolism and excretion (ADME) toxicity of the compound, and Depends on the preference and experience of the treating physician.

[0054] In addition to the active ingredient, these pharmaceutical compositions contain a compound that is capable of being formulated to produce a pharmaceutically acceptable formulation. The composition may include a suitable pharmaceutically acceptable carrier, including excipients and auxiliaries that facilitate processing. Preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or may be in the form of a solution.

[0055] Oral pharmaceutical formulations are prepared by combining an active compound with a solid excipient and optionally dissolving the resulting mixture. After grinding and, if desired, adding suitable auxiliaries, the granule mixture is processed into tablets or dragees. Suitable excipients include, inter alia, lactose, sucrose, sugars, including corn, mannitol, or sorbitol; cellulose preparations, e.g., corn Corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth Rubber, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose Carbohydrate sodium (CMC) and / or polyvinylpyrrolidone (PVP: povidone) Optionally, cross-linked polyvinylpyrrolidone, agar, alginic acid or Disintegrating agents, such as a salt thereof (eg, sodium alginate), may also be added.

[0056] The dragee cores are provided with a suitable coating. , talc, polyvinylpyrrolidone, carbopol gel, Concentrated cellulose, which may optionally contain polyethylene glycol (PEG), and / or titanium dioxide. Condensation solutions, lacquer solutions, as well as suitable organic solvents or solvent mixtures may be used. For different purposes, or to characterize different combinations of doses of active compounds, dyes or Pigments may be added to tablets or dragee coatings.

[0057] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as gelatin capsules. Soft, sealed capsule made of plaster, containing plasticizers such as glycerol and sorbitol. The capsules contain fillers such as lactose, binders such as starch, and / or Active ingredients mixed with lubricants such as talc and magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be contained in a mixture of fatty oils, liquid paraffin, and the like. Dissolve or suspend in a suitable liquid such as polyethylene glycol (PEG) or PEG-4. Furthermore, a stabilizer may be added.

[0058] In yet other embodiments, the compounds of formula (I) of the present disclosure can be used in viscous lotions, creams, and the like. Formulated into a cream, ointment, suspension, paste, gel, oil, spray, or aerosol Such viscous lotions, creams, or ointments may be administered topically. , can be water-based, and can also be based on liquid paraffin or vegetable oils (e.g., arachidonic acid). may contain oils (water-in-oil or oil-in-water), such as corn oil or castor oil, or solvents. The composition may contain one or more other ingredients, including but not limited to, permeation Accelerators (e.g., ethanol and propylene glycol), humectants (including but not limited to (but not including glycerin and / or glycerol), thickeners and / or gels Stabilizers (including but not limited to soft paraffin, aluminum stearate, ceteth- Stearyl alcohol, polyethylene glycol, wool fat, beeswax, carboxypolymer ethylene and cellulose derivatives, and / or glyceryl monostearate), and / or non-ionic emulsifying, stabilizing, dispersing and suspending agents. A typical liquid formulation is about 10% to 60% water, about 10% to 70% ethanol. propylene glycol, about 5% to about 10% propylene glycol, and about 2% to about 5% humectant. This can be done.

[0059] II. Definition

[0060] Although specific terms are employed herein, they are used in a generic and descriptive sense only. Unless otherwise defined, the terms used herein are used in their entirety and are not intended to be limiting. All technical and scientific terms used are within the scope of the art to which this currently described subject belongs. It has the same meaning as commonly understood by a person of ordinary skill in the art.

[0061] The following terms relating to compounds of formula (I) are believed to be well understood by those skilled in the art: However, to facilitate explanation of the presently disclosed subject matter, the following definitions are provided: These definitions are not intended to exclude definitions that would be apparent to one of skill in the art upon review of this disclosure. , is intended to supplement and explain.

[0062] As used herein, the term substituted ("optionally") The terms "substituted" and "substituted groups" (whether preceded by the term "" or not) will be understood by those skilled in the art. As will be understood, certain functional groups on a molecule may be added, provided that the valence of all atoms is maintained. This refers to the ability to change two or more positions in any given structure from a particular group to another functional group. When alkyl may be substituted with two or more substituents selected from the group consisting of aryl, aryl, arylsulfonyl ... The substituents may also be further substituted (e.g., aryl The substituents on a group may be externally connected to other substituents, e.g., other groups that are further substituted at one or more positions. It may have an aryl group.

[0063] When substituents or linking groups are designated by conventional chemical formulas written from left to right, they equally encompasses chemically identical substituents resulting from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-, and -C(=O)O- is equivalent to -OC(=O)-. and -OC(=O)NR- is equivalent to -NRC(=O)O-.

[0064] When the term "independently selected" is used, it refers to the fact that the referenced substituents (e.g., groups R groups such as R1, R2, or variables such as "m" and "n" may be the same or different. For example, R1 and R2 may both be substituted alkyl, or R1 may be hydrogen and R 2 may be a substituted alkyl, and so forth.

[0065] As used herein in reference to a group of substituents, "a," "an," "an The term "one" or "a(n)" means at least one. If the compound is substituted with "an" alkyl or aryl, the compound is , optionally substituted with at least one alkyl and / or at least one aryl Additionally, when a moiety is substituted with an R substituent, the group is referred to as "R-substituted." It is sometimes called "R-substituted." If the moiety is substituted with at least one R substituent, each R substituent is optionally varies.

[0066] A named "R" or group generally refers to that name unless otherwise specified herein. For illustrative purposes, the structures are recognized in the art as corresponding to groups having the formula: Certain representative "R" groups, as defined above, are defined below.

[0067] Description of compounds of the present disclosure is limited by principles of chemical bonding known to those skilled in the art. Thus, when a group may be substituted with one or more of multiple substituents, such substituents may be The conversion must be carried out in a manner that conforms to the principles of chemical bonding and is not inherently unstable. Likely unstable under ambient conditions, including aqueous, neutral, and some known physiological conditions For example, heterocyclohexane may be selected to provide compounds known to those skilled in the art to be The alkyl or heteroaryl may be substituted with a cyclic heteroaryl in accordance with principles of chemical bonding known to those skilled in the art. atoms to the rest of the molecule, thereby avoiding inherently unstable compounds. It is possible.

[0068] Unless expressly defined otherwise, a "substituent" as used herein means any of the following moieties: and a functional group selected from one or more of the following, as defined herein:

[0069] As used herein, the term hydrocarbon refers to any chemical group containing hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. In addition, all valences must be satisfied when substitutions are made. , saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Suitable hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, aryl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.

[0070] The term "alkyl," by itself or as part of another substituent, unless otherwise stated. and straight-chain (i.e., unbranched) or branched-chain, acyclic or cyclic hydrocarbon groups; is a combination thereof with a specified number of carbon atoms (i.e., C 1-10 is 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbons. may be fully saturated, monounsaturated or polyunsaturated, containing divalent and polyvalent groups In certain embodiments, the term "alkyl" refers to a group that can contain 1, 2, 3, or 4 alkyl groups. , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, C containing 19 and 20 carbons1-20 (C1 and C 20 linear (i.e., "straight") chain"), branched or cyclic, saturated or at least partially and possibly completely Unsaturated (i.e., alkenyl and alkynyl) hydrocarbon radicals containing one Derived from a hydrocarbon moiety containing 1 to 20 carbon atoms by the removal of a hydrogen atom means.

[0071] Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, Phenyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n -pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec- Hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl Cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and their homologues This includes isomers and isomers.

[0072] "Branched" means that a lower alkyl group such as methyl, ethyl, or propyl is bonded to a straight-chain alkyl group. "Lower alkyl" refers to an alkyl group having 1 to about 8 carbon atoms (e.g., 1, 2, , 3, 4, 5, 6, 7 or 8 carbon atoms) (i.e., C 1-8 "Higher alkyl" refers to a group having from about 10 to about 20 carbon atoms (e.g., 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms) In certain embodiments, "alkyl" refers to an alkyl group having, in particular, C 1-8 Straight chain In other embodiments, "alkyl" refers to, inter alia, C 1-8 Branched Chain Alkyl Refers to...

[0073] The alkyl group may be optionally substituted with one or more alkyl group substituents ("substituted alkyl group"). The one or more alkyl group substituents may be the same or different. The term "alkyl group substituent" includes, but is not limited to, alkyl, substituted alkyl, hydroxyl ... B, arylamino, acyl, hydroxyl, aryloxy, alkoxyl, alkyl Thio, arylthio, aralkyloxy, aralkylthio, carboxyl, alkoxy It includes carboxyl, oxo, and cycloalkyl. optionally inserted with a hydrogen, sulfur or substituted or unsubstituted nitrogen atom, Substituents include hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl" ), or aryl.

[0074] Thus, as used herein, the term "substituted alkyl" refers to The alkyl group described above, wherein one or more atoms or functional groups of the alkyl group are, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxy aryl, nitro, amino, alkylamino, dialkylamino, sulfate e) alkyl groups substituted with another atom or functional group, such as cyano and mercapto; Contains a methyl group.

[0075] The term "heteroalkyl", by itself or in combination with other terms, unless otherwise specified, as long as it has at least one carbon atom and is selected from the group consisting of O, N, P, Si and S and at least one heteroatom, and A stable straight or branched chain or a group having 3 to 10 carbon atoms or hetero atoms. or combinations thereof, wherein nitrogen, phosphorus, and sulfur atoms are present. The nitrogen heteroatom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. O, N, P, and S and Si may be at any interior position of a heteroalkyl group or an alkyl group. The group may be placed at the position where it is attached to the remainder of the molecule. Examples include, but are not limited to: However, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2- CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S (O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-C H3, O-CH3, -O-CH2-CH3, and -CN. For example, -CH2 Up to two or three, such as -NH-OCH3 and -CH2-O-Si(CH3)3 The heteroatoms may be consecutive.

[0076] As noted above, heteroalkyl groups as used herein include, but are not limited to, -C(O)NR', ​​- NR'R'', -OR', -SR, -S(O)R, and / or -S(O2)R', etc. "Heteroalkyl" includes groups that are attached to the remainder of the molecule through a heteroatom. " followed by a description of a particular heteroalkyl group such as NR'R, Heteroalkyl and NR'R'' are redundant but mutually exclusive. Rather, certain heteroalkyl groups may be omitted for added clarity. Thus, as used herein, the term "heteroalkyl" refers to an NR'R The term "heteroalkyl" should not be construed as excluding certain heteroalkyl groups such as ''.

[0077] "Cyclic" and "cycloalkyl" refer to groups having from about 3 to about 10 carbon atoms, e.g., 3, 4, Refers to a non-aromatic monocyclic or polycyclic ring system of 5, 6, 7, 8, 9 or 10 carbon atoms. Cycloalkyl groups can be optionally partially unsaturated. Cycloalkyl groups also include those described herein. Optionally substituted with alkyl group substituents, oxo, and / or alkylene as defined herein. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be present along the cyclic alkyl chain. Atoms can be inserted arbitrarily, where the nitrogen substituent can be hydrogen, unsubstituted alkyl, substituted alkyl The alkyl, aryl, or substituted aryl groups provide heterocyclic groups. Suitable monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decahydronaphthyl, and cycloalkyl. Quince, camphor, camphane, and nor Damantyl (noradamantyl), and dihydro- and tetrahydronaphthalene Included are fused ring systems such as benzophenone.

[0078] The terms "cycloalkyl" and "heterocycloalkyl" may be used by themselves or with each other. In combination with the terms "alkyl" and "heteroalkyl," respectively, unless otherwise specified. Furthermore, in the case of heterocycloalkyl, the heteroatom is A heterocycle can occupy the position at which it is attached to the remainder of the molecule. Examples include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexyl, Heterocycloalkyl includes cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuranyl tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-pipera The terms "cycloalkylene" and "heterocycloalkylene" are used. The terms refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0079] Unsaturated hydrocarbons have one or more double or triple bonds. Examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentyl, Thenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl) ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues Alkyl groups that are limited to hydrocarbon groups are called "homoalkyl." Be found out.

[0080] More specifically, the term "alkenyl" as used herein refers to an alkyl group containing one hydrogen atom. C having at least one carbon-carbon double bond by removal of 2-20 (C2 and C 20 An alkenyl group refers to a monovalent group derived from a straight-chain or branched hydrocarbon moiety (including For example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-butenyl, ten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl Includes:

[0081] As used herein, the term "cycloalkenyl" refers to at least one carbon-carbon Cycloalkenyl refers to a cyclic hydrocarbon containing a carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl and cyclopentyl. , cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3 -Cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctyl Tennille included.

[0082] As used herein, the term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond. Straight or branched chain of a designed number of carbon atoms including bonds 2-20 Monovalent derived from hydrocarbons Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1- These include propynyl, pentynyl, hexynyl, heptynyl groups and the like.

[0083] The term "alkylene" by itself or as part of another substituent means an alkylene group having from 1 to about 20 carbon atoms. Elementary atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , a straight chain derived from an alkyl group having 15, 16, 17, 18, 19 or 20 carbon atoms or branched divalent aliphatic hydrocarbon group. An alkylene group may be linear, branched, or cyclic. The alkylene group may also be optionally unsaturated and / or have one or more "alkyl" groups. The alkylene group may be optionally substituted with one or more oxygen, sulfur, or alkylene groups. or a substituted or unsubstituted nitrogen atom (also referred to herein as "alkylaminoalkyl"). wherein the nitrogen substituent is an alkyl as described above. The olefin group includes methylene (-CH2-); ethylene (-CH2-CH2-); propylene ( -(CH2)3-); cyclohexylene (-CH6H 10 -);-CH=CH-CH=CH -;-CH=CH-CH2-;-CH2CH2CH2CH2-, -CH2CH=CHCH 2-, -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r where each of q and r is independently and an integer from 0 to about 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20), and R is hydrogen or is lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxy The alkylene group is (-O-(CH2)2-O-). The alkylene group has about 2 to about 3 carbon atoms. and can have 6 to 20 carbon atoms. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, and groups having 10 or fewer carbon atoms. Those groups are some embodiments of the present disclosure. "Alkylene" refers to a shorter chain alkyl or alkylene group, generally eight or fewer carbon atoms. It has atoms.

[0084] The term "heteroalkylene" by itself or as part of another substituent means -CH 2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2 "-" means a divalent group derived from heteroalkyl, exemplified by, but not limited to, -. For heteroalkylene groups, heteroatoms may also occupy either or both of the chain termini. (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylene Additionally, for alkylene and heteroalkylene linking groups, No orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0085] The term "aryl" refers to any group of rings, whether fused or covalently joined, unless otherwise specified. means an aromatic hydrocarbon substituent which may be multiple rings (e.g., 1 to 3 rings) connected together The term "heteroaryl" refers to one to four heteroaryls selected from N, O and S. refers to an aryl group (or ring) containing an aryl atom (in each separate ring in the case of multiple rings). wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally tetrahydrofuran. A heteroaryl group is attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, Nyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2- Oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl , 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4 -Thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl. 5- Benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquino quinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and and 6-quinolyl. Each of the above substituents on the aryl and heteroaryl ring systems is included. Substituents are selected from the group of acceptable substituents described below: "arylene" and The term "heteroarylene" refers to the divalent forms of aryl and heteroaryl, respectively. Refers to the attitude.

[0086] For brevity, other terms (e.g., aryloxy, arylthioxy, arylalkoxy) may be used. The term "aryl" when used in combination with aryl refers to aryl rings and aryl groups as defined above. Thus, the terms "arylalkyl" and "heteroaryl" include both aryl and heteroaryl rings. "Heteroarylalkyl" refers to an aryl or heteroaryl group that is joined to an alkyl group, such as benzyl, phenethyl, pyridylmethyl, furylmethyl, etc.), e.g., carbon atoms (e.g. , methylene group) is substituted with an oxygen atom or the like (e.g., phenoxymethyl, 2 -pyridyloxymethyl, 3-(l-naphthyloxy)propyl, etc. However, as used herein, the term "haloalkyl" is meant to include: It is meant to cover only aryls substituted with one or more halogens.

[0087] When a heteroalkyl, heterocycloalkyl, or heteroaryl has a specific number of members (e.g., "3- to 7-membered" refers to a carbon or heteroatom.

[0088] Additionally, as used herein, the following formula: [ka] The structure generally represented by the formula: containing saturated, partially saturated and unsaturated ring structures, such as 3-carbon, 4-carbon, 5-carbon -carbon, 6-carbon, 7-carbon, etc. aliphatic and / or aromatic cyclic compounds, Substituent R groups may be present or absent, and if present, one or more R groups may be Each may be substituted on one or more available carbon atoms of the ring structure. The presence and number of R groups is determined by the value of the variable "n," which generally ranges from 0 to Each R group is an integer having a value ranging from 0 to the number of carbon atoms on the ring available for substitution. In some cases, substitution occurs on an available carbon atom of the ring structure rather than on another R group. For example, n The above structure in which is 0 to 2 includes, but is not limited to, the following: [ka] The compound group includes:

[0089] A dashed line representing a bond in a ring structure indicates that the bond may or may not be present within the ring. That is, the dashed lines representing bonds in a ring structure indicate whether the ring structure is a saturated ring structure, a partially saturated ring structure, or a It is indicated that the cyclic structure is selected from the group consisting of cyclic structures and unsaturated cyclic structures.

[0090] symbol: [ka] indicates the point of attachment of a moiety to the rest of the molecule.

[0091] If a named atom of an aromatic or heteroaromatic ring is defined as "absent," If so, the named atom is replaced by a direct bond.

[0092] As used herein, the term "acyl" refers to a group in which the -OH of a carboxyl group is substituted with another refers to an organic acid group substituted with a substituent and having the general formula RC(=O)-, where R is any of the groups defined herein. alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or is an aromatic heterocyclic group. Thus, the term "acyl" specifically refers to 2-( aryl acyl groups such as furan-2-ylacetyl and 2-phenylacetyl groups Examples of acyl groups include acetyl and benzoyl. Mido, -RC(=O)NR', ​​ester, -RC(=O)OR', ketone, -RC(=O )R', and aldehyde, -RC(=O)H.

[0093] The terms "alkoxyl" and "alkoxy" are used interchangeably herein. and saturated (i.e., alkyl-O-) or unsaturated alkyl groups attached to the parent molecular moiety through an oxygen atom. "Alkyl" refers to saturated (i.e., alkenyl-O- and alkynyl-O-) groups, where "alkynyl" refers to an alkyl group. The terms "alkenyl", "alkynyl" and "alkenyl" are as defined above, e.g. Methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec- Butoxyl, tert-butoxyl, n-pentoxyl, neopentoxyl, n-hexoxyl C, such as xyl 1-20 (C1 and C 20 straight-chain, branched or cyclic saturated or unsaturated It may contain saturated oxo-hydrocarbon chains.

[0094] As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkyl ethers, such as methoxyethyl or ethoxymethyl groups.

[0095] "Aryloxyl" refers to an aryl-O- group in which the aryl group is as previously described. and includes substituted aryl. As used herein, the term "aryloxyl" is phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxy-substituted phenyloxyl or hexyloxyl can.

[0096] "Aralkyl" refers to an aryl-alkyl- group, where the aryl and alkyl are As previously mentioned, including substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0097] "Aralkyloxyl" refers to an aralkyl-O- group, where the aralkyl group is as defined above. An exemplary aralkyloxyl group is benzyloxyl, i.e., CH 5-CH2-O-. The aralkyloxyl group may be optionally substituted.

[0098] "Alkoxycarbonyl" refers to an alkyl-OC(=O)- group. The oxycarbonyl group includes methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, nyl, and tert-butyloxycarbonyl.

[0099] "Aryloxycarbonyl" refers to an aryl-OC(=O)- group. Aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl .

[0100] "Aralkoxycarbonyl" refers to an aralkyl-OC(=O)- group. The alkoxycarbonyl group is benzyloxycarbonyl.

[0101] "Carbamoyl" refers to an amide group of the formula -C(=O)NH2. "R" refers to the group R'RN-C(=O)-, where one of R and R' is hydrogen and R and the other of R' is alkyl and / or substituted alkyl as described above. "Arylcarbamoyl" refers to the group R'RN-C(=O)-, where R and R' are Each is independently alkyl and / or substituted alkyl as described above.

[0102] As used herein, the term carbonyldioxyl refers to a group of the formula -OC(=O)-OR This refers to the carbonate group.

[0103] "Acyloxyl" refers to an acyl-O- group where acyl is as previously defined.

[0104] The term "amino" refers to the -NH2 group, which confers one or more hydrogen radicals to an organic radical It also refers to nitrogen-containing groups known in the art that are derived from ammonia by substitution with For example, the terms "acylamino" and "alkylamino" refer to acyl and alkylamino, respectively. and certain N-substituted organic radicals with alkyl substituents.

[0105] As used herein, an "aminoalkyl" refers to an amino group covalently attached to an alkylene linker. More specifically, alkylamino, dialkylamino, The term trialkylamino refers to the previously mentioned alkyl groups attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to one, two or three alkyl groups as defined above. refers to a group having the structure -NHR', where R' is an alkyl group as defined above; On the other hand, the term dialkylamino refers to a group having the structure -NR'R'', where R R′ and R″ are each independently selected from the group consisting of alkyl groups, trialkyl The term amino refers to a group having the structure -NR'R''R''', where R', R' R' and R''' are each independently selected from the group consisting of alkyl groups. R', R'' and / or R''', taken together, optionally represent -(CH2) k - and where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino , dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methyl Ethylamino, isopropylamino, piperidino, trimethylamino, and propylamino Mino included.

[0106] An amino group is -NR'R'', where R' and R'' are typically hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted silyl cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0107] The terms alkyl thioether and thioalkoxyl are linked to the parent molecule via the sulfur atom. Saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl) groups attached to the moiety Examples of thioalkoxyl moieties include, but are not limited to, alkynyl-S- and alkynyl-S- groups. However, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio This includes Lucio.

[0108] "Acylamino" refers to an acyl-NH- group, where acyl is as previously defined. "Aroylamino" means an aroyl-NH- group in which aroyl is as previously described. do.

[0109] The term "carbonyl" refers to the group -C(=O)- and is represented by the general formula RC(=O)H. The compound may contain an aldehyde group.

[0110] The term "carboxyl" refers to a -COOH group. Such a group is defined herein as Also referred to as the "carboxylic acid" moiety.

[0111] The term "cyano" refers to the group --C.ident.N.

[0112] As used herein, the terms "halo," "halide," or "halogen" refer to fluorocarbons. It refers to the chloro, bromo, and iodo groups. The term is meant to include monohaloalkyl and polyhaloalkyl. For example, "haloalkyl" refers to a group selected from the group consisting of aryl, ... (C 1-4 The term "alkyl" includes, but is not limited to, trifluoromethyl , 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. This means that...

[0113] The term "hydroxyl" refers to an --OH group.

[0114] The term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0115] The term "mercapto" refers to the group --SH.

[0116] As used herein, the term "oxo" refers to a group that is double-bonded to a carbon atom or another element. This refers to the oxygen atom.

[0117] The term "nitro" refers to the group --NO.sub.2.

[0118] The term "thio" is used herein to refer to a group in which a carbon or oxygen atom has been replaced with a sulfur atom. This refers to the aforementioned compound.

[0119] The term "sulfate" refers to the -SO4 group.

[0120] As used herein, the term thiohydroxyl or thiol refers to a group of formula -SH Point.

[0121] More specifically, the term "sulfide" refers to a compound having a group of formula -SR.

[0122] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R.

[0123] The term "sulfoxide" refers to a compound with a sulfinyl group -S(O)R.

[0124] The term ureido refers to a urea group of formula -NH-CO-NH2.

[0125] Throughout this specification and claims, a given chemical formula or name refers to all tautomers. isomers, homologs, optical isomers and stereoisomers, as well as racemic mixtures, Entities and mixtures thereof are included where present.

[0126] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical or chiral centers) or double bonds. enantiomers, racemates, diastereomers, tautomers, What isomers, in terms of absolute stereochemistry, can be (R)- or (S)- or for amino acids? The stereoisomeric forms, which may be defined as D- or L-, and the individual isomers are included in the present disclosure. The present disclosure includes compounds in racemic, scalaminic, and optically pure forms. Optically active (R)- and (S)-, or D- and The L-isomer may be prepared using chiral synthesis or chiral reagents, or may be prepared using conventional techniques. The compounds described herein may be decomposed by olefin bonds or geometric asymmetries. If the compound contains other centers, the compound may exist as both E and Z geometric isomers unless otherwise specified. It is intended to include both.

[0127] Unless otherwise specified, structures depicted herein represent all stereochemical forms of that structure, That is, it means that the R and S configurations of each asymmetric center are included. Single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds are It is within the scope of the disclosure.

[0128] It will be apparent to one skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, All such tautomeric forms of the compounds are within the scope of the present disclosure. The term "tautomer" refers to isomers that exist in equilibrium and can be easily transformed from one isomer to another. It refers to one of two or more structural isomers that are easily converted.

[0129] Unless otherwise stated, structures depicted herein are intended to be illustrative, not restrictive, and may be used in the presence of one or more isotopically enriched atoms. This also includes compounds that differ only in the amount of hydrogen. For example, replacing hydrogen with deuterium or tritium or carbon substituted with 13 C- or14 Compounds with this structure substituted with C-enriched carbons Combinations are within the scope of this disclosure.

[0130] The compounds of the present disclosure may also contain unnatural radicals at one or more of the atoms that constitute such compounds. For example, a compound may contain unnatural proportions of atomic isotopes. Tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 C) and other All isotopic variations of the compounds of the present disclosure may be radiolabeled with a radioisotope. All radioactive or non-radioactive compositions are within the scope of this disclosure.

[0131] Certain compounds of the present disclosure exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. All physical forms are equivalent for the uses contemplated by this disclosure and are within the scope of this disclosure. Something is intended to be.

[0132] The term "protecting group" refers to a group that blocks and protects some or all of the reactive moieties of a compound. Refers to a chemical moiety that prevents such moiety from participating in a chemical reaction until the group is removed, e.g. TWGreene, PGMWuts, Protective Gro ups in Organic Synthesis, 3rd Edition John Wiley & Sons (1999). When groups are employed, it is advantageous that each (different) protecting group be removable by a different means. Protecting groups that are cleaved under completely different reaction conditions may be used to distinguish between the removal of such protecting groups. For example, protecting groups can be used to protect against acid, base, and hydrogenolysis. It can be removed by genolysis. Trityl, dimethoxytrityl, acetone Groups such as silyl and tert-butyldimethylsilyl are acid-labile and can be removed by hydrogenolysis. In the presence of a removable Cbz group and a base-labile Fmoc-protected amino group, It can be used to protect carboxylic and hydroxy reactive moieties. The hydroxy-reactive moiety can be an acid-labile group such as tert-butyl carbamate or an acid and in the presence of base-stable but hydrolytically removable carbamate-blocked amines. and blocked with base-labile groups such as, but not limited to, methyl, ethyl, and acetyl It can be done.

[0133] Carboxylic acid and hydroxy reactive moieties also include hydrolytically removable groups such as benzyl groups. Amine groups that can be blocked with protecting groups and hydrogen bond with acids are base-labile, such as Fmoc. The carboxylic acid reactive moiety can be blocked with an acyl group such as 2,4-dimethoxybenzyl. The amino groups can be blocked with fluorine-labile silyl groups. Can be blocked with rubamate.

[0134] Allyl blocking groups are useful in the presence of acid and base protecting groups, since the former It is stable and can be subsequently removed by metal or π-acid catalysts. Allyl-blocked carboxylic acids are either acid-labile t-butyl carbamates or base-labile In the presence of suitable acetate amine protecting groups, the protection can be deprotected by palladium(O) catalysis. Yet another form of group is a resin to which a compound or intermediate can be attached. As long as the resin is attached to the resin, that functional group is blocked and cannot react. Once released, the functional group becomes available to react.

[0135] Typical blocking / protecting groups include, but are not limited to, the following moieties: p-Methoxybenzylcarbonyl (Moz or MeOZ), 3,4-dimethoxybenzyl (DMPM), Troc (trichloroethyl chloroformate), (4-nitrophenyl (Nosyl), and nitrophenylsulfenyl (Nps), and to [ka]

[0136] In accordance with long-standing patent law practice, when used in this application, including the claims, "a" The terms "an" and "the" refer to "one or more (one or more)." For example, a reference to "a subject" should be used when the context clearly indicates the opposite (e.g. , a plurality of subjects) except Includes of subjects.

[0137] Throughout this specification and claims, the terms "comprise" and "comprises" are used interchangeably. The terms "comprising" and "comprising" are used where the context so requires. Similarly, the term "includes" is used in a non-exclusive sense unless otherwise required. "Include" and its grammatical variants indicate that a citation of an item in a list is The terms are non-exclusive and should not be construed as excluding other similar items that may be substituted or added to the listed items. It is intended to

[0138] For purposes of this specification and the appended claims, unless otherwise indicated, The amounts, sizes, dimensions, ratios, shapes, compositions, parameters, proportions, All numerical values ​​expressing quantities, properties, and other values ​​are expressly limited to the value, quantity, or other numerical value even if the term "about" is used. In all instances, even if not expressly stated with a range or expression, the terms "about" and "about" are used to modify the present invention. Therefore, unless otherwise indicated, the following specifications The numerical parameters set forth in the specification and appended claims need not be precise. rather, tolerances may be applied depending on the desired properties sought to be obtained by the subject matter of the present disclosure. ces), conversion factors, rounding off, measurement errors, etc., and those skilled in the art may be approximate and / or larger or smaller as desired, reflecting other factors known to the art. For example, the term "about" when referring to a value may be used to denote the value of the disclosed Such variations are appropriate to practice the methods or employ the disclosed compositions. As such, in some embodiments, the range is ±100%, in some embodiments ±50%, or in some embodiments ±100% from the specified amount. In some embodiments, ±20%, in some embodiments, ±10%, in some embodiments, ±5%, In some embodiments, the morphology may vary by ±1%, in some embodiments by ±0.5%, and in some embodiments by ±0.1%. It can mean to include movement.

[0139] Additionally, when used in connection with one or more numerical values ​​or numerical ranges, the term "about" shall mean the range. It includes all numbers in the range and expands the range by extending the boundaries above and below the stated number. The term "numerical range" should be understood to refer to all relevant numerical values ​​modifying the range. The description includes all the numbers encompassed within the range, for example, whole integers including fractions thereof (e.g., The notation 1 to 5 means 1, 2, 3, 4, 5, and fractions thereof, for example, 1.5, 2.25, 3 .75, 4.1, etc.) and any range therein. [Example]

[0140] The following examples provide guidance to those of skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of this disclosure and the general state of the art, Therefore, one of ordinary skill in the art will recognize that the following examples are intended to be illustrative only and that numerous variations, modifications, and variations of the present invention may be possible. It will be understood that modifications and variations may be employed without departing from the scope of the subject matter of this disclosure. The synthetic descriptions and examples provided below are for illustrative purposes only and should not be construed as limiting the scope of the invention. Nothing in this document should be construed as limiting the ability to make the compounds of this disclosure by any method. do not have.

[0141] Example 1 Stability of the prodrug in mouse skin homogenate and plasma The stability of mouse skin homogenate was evaluated by diluting it 10-fold with 0.1M potassium phosphate buffer. Washed mouse skin homogenized using a woven homogenizer and CD1 mouse plasma were To assess the stability of the intact prodrug, skin homogenates were used. or to a 1 mL aliquot of plasma, add the prodrug to a final assay concentration of 20 μM. The spiked skin homogenate and plasma samples were then placed on an orbital shaker. After incubation in a car at 37°C for 1 hour, an internal standard (IS; losartan: 0 The reaction was quenched in three portions with three volumes of acetonitrile containing 0.5 μm of acetonitrile. The mixture was vortex mixed for 30 seconds and centrifuged at 10,000 xg and 4°C for 10 minutes. 50 μL of the supernatant was diluted with 50 μL of water and placed in a 250 μL polypropylene tube sealed with a Teflon cap. The released itaconic acid or methyl itaconate was transferred to a tandem The concentrations were measured by liquid chromatography with a mass spectrometer (LC-MS / MS).

[0142] Example 2 Pharmacokinetics in mice Male CD1 mice (25-30 g) were obtained from Harlan and maintained under a 12-hour light / dark cycle. The mice were kept in a cage and had free access to food and water. ), MK939 (compound 14) and MK941 (compound 16), at 10 mg / kg mol An equivalent amount of monomethyl itaconate was administered by oral gavage. Blood samples were taken 0.25 hours after administration. At the designated time points after drug administration, mice were resected and collected at 1 hour and 1 hour, respectively (n=3 per time point). Euthanize the animals with carbon monoxide and obtain a blood sample (approximately 0.8 mL) by cardiac puncture using heparinized myocardium. The blood samples were collected in a black tube and centrifuged at 3000 x g for 10 minutes at 4°C. Plasma samples (approximately 300 μL) were collected in polypropylene tubes and stored for bioanalysis. The samples were stored at -80°C. Monomethyl itaconate-added naive mouse plasma was used. Calibration standards were prepared. Monomethyl itaconate standards and samples were prepared using the internal standard One-stage incubation was performed using methanol (100% v / v) containing methyl succinate (5 μM) at 200 μM. Proteins were extracted from plasma by precipitation. An aliquot (100 μL) of the supernatant was diluted with water. (100 μL) and place in a 250 μL polypropylene vial sealed with a Teflon cap. The samples were transferred to a flask and analyzed by LC-MS / MS.

[0143] Example 3 Treatment of human keratinocytes with itaconate prodrugs Neonatal human epidermal keratinocytes (NHEK) isolated from neonatal foreskin were placed in one well. The cells were seeded at a density of 100,000 cells / well and grown in KGM supplemented with growth factors (KGM-GOLD). The prodrug was reconstituted in DMSO. NHEKs were pretreated with either vehicle (0.1% DMSO) or prodrug. Two days later, NHEKs were treated with 50 μg / μl of poly(I:C) for 24 hours.

[0144] Example 4 RNA isolation and quantitative real-time PCR RNeasy Mini Kit (Qiagen, Valencia, CA, #7 Total RNA was isolated and purified from cultured NHEKs using the Na RNA purity and concentration were assessed using a noDrop 2000 UV-Vis spectrophotometer. After evaluation, a reverse transcription kit and random hexamer primers (Applied Bios RNA was converted to cDNA using the genomic DNA library (Cat. No. 4368814). Expression of β-glucan was measured using gene-specific fluorophore-based TaqMan probes and universal TaqMan probes. Master mix (Applied Biosystems, #4366072) was used. The qRT-PCR reactions were performed for the target and reference genes ( The RLP0 probe was then multiplexed to determine the relative mRNA fragmentation. Fold changes were quantified using the ΔΔCt method.

[0145] Example 5 mouse All wild-type (C57BL6 / J) adult mice were approximately 8.5 weeks old and were cultured in the Jackson L abs (#00664). All animals were obtained from the AA at Johns Hopkins University. All experimental procedures were performed in an ALAC (Association for Accreditation of Laboratory Animal Care International)-accredited facility. The Johns Hopkins Institutional Animal Care and Use Committee Mal Care and Use Committee) under protocol #MO1 Approved under 7M298.

[0146] Example 6 Itaconate Prodrug Treatment Adult C57BL6 / J mice were treated during the refractory period of hair telogen to induce hair growth (anagen). To determine anagen re-entry, the mice were examined for thickening and blackening of the skin. The dorsum of the mice was shaved, and the left half of the skin was treated with either vehicle (DMSO) or The right side was treated with 20% IS-100-142 (compound 5) or a prodrug. The treatment regimen was administered once every other day for a total of two treatment cycles.

[0147] Example 7 Itaconate and derivatives / analogs for inducing hair growth In one aspect, the presently disclosed subject matter relates to compounds that may be capable of promoting hair growth. To this end, we investigated whether dimethyl itaconate inhibits hair growth cycle arrest in wild-type mice. We tested the ability of the enzyme to induce the transition from telogen, the resting phase of the hair cycle, to anagen, the growth phase of the hair cycle. As shown in Figure 5, 20% dimethyl itaconate strongly induced this transition. .

[0148] Next, we will examine whether itaconate derivatives, such as itaconate prodrugs, possess this same ability. To screen the compounds, we tested whether itacone We evaluated those that behave with similar properties to TLR3, IL-6, and STATs. Effect of dsRNA (PIC; polyinosinic acid:polycytidylic acid) on increasing expression of 3 The molecular effect of dimethyl itaconate (DI) in slowing the progression of leukemia was examined. Thus, DI strongly inhibits these markers.

[0149] Next, the synthesized itaconate prodrugs behaved similarly in in vitro assays. Referring now to Figure 4, compound 5 in Table 1 also exhibited the same dsRN activity as DI. The method was the same as above, except that the prodrug was substituted with dimethyl ether. It has been replaced by Louis Taconate.

[0150] Finally, compound 5 was also tested for its ability to induce hair growth, as observed with DI. This was indeed the case, as shown, where the left side is treated with compound 5 or DMSO. Mice were treated as above, except that one side was treated with DMSO and the right side was left untreated. The small amount of hair growth in treated mice was due to the initiation of the natural anagen cycle.

[0151] These results suggest that itaconate and its derivatives / analogs may play a role in hair growth, e.g., the hair cycle. This shows the ability to stimulate the telogen (resting phase) to anagen (growth phase) transition of cells. This approach should stimulate hair growth in many human settings. These include: This includes male-pattern or female-pattern hair loss in which the follicles are predominantly in the telogen phase, but also includes telogen phase hair loss. Similarly, the hair cycle synchronizes prematurely and enters telogen. This treatment should also be useful in treating alopecia areata, where the areas also enter telogen synchronously. As shown here, it is not only useful locally, but is also predicted to act systemically. can be.

[0152] Example 8 Compound (5) induces hair growth in mice All wild-type (C57BL6 / J) adult mice were approximately 8.5 weeks old and were cultured in the Jackson L The animals were obtained from abs. The animals were fed standard mouse chow. The results of the mouse model were Compound 5 promotes the transition from telogen (resting phase) to anagen (growth phase) in hair follicles. Adult C57BL6 / J mice were treated during the refractory period of hair telogen. This allowed hair growth (anagen) to resume. To determine anagen re-entry, the mouse skin The dorsal side of each mouse was shaved, and the right half of the skin was treated with a vehicle. (DMSO) or dimethyl itaconate (20%) or 1% Compound 5, 2% The left side was left untreated. A total of two or three treatments were given, one every other day, with similar results.

[0153] Example 9 Compound (5) exhibited similar activity to ruxolitinib and tofacitinib. Induces hair growth Referring now to Figure 9, compound 5 is known to be successful in treating alopecia areata. at levels comparable to two effective JAK inhibitors, ruxolitinib and tofacitinib Mice were treated as described in Example 8, and as shown in Figure 9, Ruxolitinib and tofacitinib were diluted in DMSO. They were also treated with 3% ruxolitinib, 3% tofacitinib, and 3% Compound 5.

[0154] Example 10 In Vitro Data - Mouse Skin Homogenate Stability The skin samples were diluted 10-fold with 0.1 M potassium phosphate buffer and analyzed using a Polytron and a Proton. The mixture was homogenized using a suction sonicator. Stability of the intact prodrug over time To assess the prodrug concentration, aliquots were prepared and the prodrug was added to a final assay concentration of 20 μM. The added sample was incubated in an orbital shaker at 37°C for 1 hour. After incubation, three volumes of acetate containing an internal standard (IS; losartan: 0.5 μM) were added. The reaction was quenched with dinitrile. The sample was vortex mixed and heated to 16000 g. The mixture was centrifuged at 4°C for 5 minutes. 50 μL of the supernatant was diluted with 50 μL of water and sealed with a Teflon cap. The solution was transferred to a sealed 250 μL polypropylene vial. The disappearance of the prodrug was monitored by liquid chromatography. Figure 10 shows the results of the reaction monitored over time by LC-MS. Figure 11 shows the mouse skin homogenate stability of representative prodrugs. Figure 1 shows the release of active monomethyl itaconate from the rag (into skin homogenate).

[0155] Example 11 In Vitro Data - Mouse Skin Penetration Referring now to Figure 12, IS-100-142 (compound 5) (left panel) and mono Methyl itaconate (right panel) penetration into mouse skin in a model of alopecia. After topical application in DMSO (dosage: 5% w / v), intact and monomethyl it Both conate levels are higher in skin than in plasma.

[0156] References

[0157] All publications, patent applications, patents, and other references mentioned herein are the property of their respective owners. All publications, patents, and related documents are intended to indicate the level of ordinary skill in the art to which the disclosed subject matter pertains. Applications, patents and other references are individual publications, patent applications, patents and other references. to the same extent as if the references were specifically and individually indicated to be incorporated by reference. Many patent applications, patents, and related publications are incorporated herein by reference. Although other documents are referenced, such references are not intended to be limiting unless expressly stated otherwise. It is understood that no admission is made that the information contained herein forms part of general knowledge in the field. There will be.

[0158] PCT Patent Application Publication No. WO2017142855 (Artyomov et al., Immunomodulatory Agents and Methods of Use Thereof, Published: August 24, 2017 PCT Patent Application Publication No. WO2019036509 (Artyomov et al., Methods and Compo positions for the Treatment of Diseases Associated with Cancer, Inflammation, or I mmune Response, Published: February 21, 2019) O'Neill, LAJ and Artyomov, MN, Itaconate: the poster child of metabolic reprogramming in macrophage function, Nature Reviews:Immunology, 19, pp. 273-281 ( 2019)

[0159] The foregoing subject matter has been described in some detail by way of illustration and example for clarity of understanding. However, it will be apparent to those skilled in the art that certain changes and modifications may be practiced within the scope of the appended claims. will be understood.

Claims

1. Inducing hair growth or treating an inflammatory skin condition or immune system condition in a subject in need thereof. In a method for treating an immune-activated condition (adaptive or congenital) or other condition associated with hair loss administering to said subject a therapeutically effective amount of a compound of formula (I): 【Chemistry 1】 [In the ceremony: R １ and R ２ may be the same or different and may be one or more of the following and combinations thereof: are independently selected from the set: (a) -OR ３ (R ３ is H or C １ -C ６ Straight or branched, unsubstituted or substituted alkyl); (b) 【Chemistry 2】 wherein n is an integer selected from 1, 2, 3, and 4; R ４ is C １ -C ６ Straight chain or branched unsubstituted or substituted alkyl or -OR ５ where R ５ is C １ -C ６ straight-chain or branched, unsubstituted or substituted alkyl); (c) 【Transformation 3】 wherein m is an integer selected from 1, 2, 3, and 4; p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and and 20; and R ６ is C １ -C ６ Linear or branched unsubstituted or substituted alkyl); (d) 【Chemistry 4】 In the formula, R ７ is selected from: (i)-C(=O)-OR ８ (R ８ is C １ -C ６ Straight or branched unsubstituted or substituted alkyl); (ii) 【Transformation 5】 (In the formula, R ９ is H or C １ -C ４ Straight-chain or branched unsubstituted or substituted alkyl be; R １０ is C １ -C ６ is a straight-chain or branched unsubstituted or substituted alkyl; R １１ and R １２ are each independently H or a protecting group; and R １３ is C １ -C ６ straight-chain or branched, unsubstituted or substituted alkyl); (iii) 【Transformation 6】 wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Ru;R １１ and R １２ are each independently H or a protecting group; R １４ H and is C １ -C ４ is a straight-chain or branched unsubstituted or substituted alkyl; and R １５ teeth, C １ -C ６ linear or branched, unsubstituted or substituted alkyl; and (iv) 【Transformation 7】 (In the formula, R １６ and R １７ are H and C, respectively. １ -C ４ Straight or branched unsubstituted or R is independently selected from a substituted alkyl, and a protecting group; １８ is aryl); (e) 【Transformation 8】 (In the formula, R １９ is C １ -C ４ straight-chain or branched, unsubstituted or substituted alkyl); (f) 【Chemistry 9】 wherein u is an integer selected from 1, 2, 3, and 4; R ２０ is H or C １ -C ４ is a straight-chain or branched unsubstituted or substituted alkyl; and R ２１ Ha-OR ２ ２ where R ２２ is C １ -C ６ Straight or branched unsubstituted or substituted alkyl or -NR ２３ R ２４ where R ２３ and R ２４ are each independently H or is C １ -C ４ straight-chain or branched, unsubstituted or substituted alkyl) and a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein: (a) R １ Ha-OR ３ and R ２ teeth 【Chemistry 10】 wherein R ７ teeth 【Chemistry 11】 Selected from: (b) R １ teeth 【Chemistry 12】 and R ２ teeth 【Chemistry 13】 wherein R ７ teeth 【Chemistry 14】 Selected from: (c) R １ teeth 【Chemistry 15】 and R ２ teeth 【Chemistry 16】 wherein R ７ teeth 【Chemistry 17】 Selected from: (d) R １ teeth [Chemistry 18] and R ２ teeth 【Chemistry 19】 wherein R ７ teeth 【Chemistry 20】 Selected from: (e) R １ teeth 【Chemistry 21】 and R ２ teeth 【Chemistry 22】 wherein R ７ teeth 【Chemistry 23】 Selected from: (f) R １ teeth 【Chemistry 24】 wherein R ７ is -C(=O)-O-R ８ and R ２ teeth 【Chemistry 25】 wherein R ７ teeth 【Chemistry 26】 Selected from: (g) R １ teeth 【Chemistry 27】 wherein R ７ teeth 【Chemistry 28】 and R ２ teeth 【Chemistry 29】 wherein R ７ teeth 【Transformation 30】 Selected from: (h) R １ teeth 【Chemistry 31】 wherein R ７ teeth 【Chemistry 32】 and R ２ teeth 【Transformation 33】 wherein R ７ teeth 【Transformation 34】 selected from; and (i) R １ teeth 【Chemistry 35】 wherein R ７ teeth 【Transformation 36】 and R ２ teeth 【Chemistry 37】 wherein R ７ teeth 【Transformation 38】 Selected from: and pharmaceutically acceptable salts thereof.

3. The method of claim 1, wherein: (a-i)R １ is —OH, and R ２ teeth 【Chemistry 39】 wherein R ７ is -C(=O)-O-R ８ is; (a-ii) R １ Ha-OR ３ and R ２ teeth 【Chemistry 40】 wherein R ７ teeth 【Chemistry 41】 Selected from: (b) R １ teeth 【Chemistry 42】 and R ２ teeth 【Chemistry 43】 Selected from: (c) R １ teeth 【Chemistry 44】 and R ２ Ha-OR ３ is; (d) R １ teeth 【Chemistry 45】 and R ２ teeth 【Chemistry 46】 Selected from: (e) R １ teeth 【Chemistry 47】 wherein R ７ is -C(=O)-O-R ８ and R ２ Ha-OR ３ is; (f) R １ teeth 【Chemistry 48】 wherein R ７ teeth 【Chemistry 49】 and R ２ Ha-OR ３ is; (g) R １ teeth [Transformation 50] wherein R ７ teeth 【Chemistry 51】 and R ２ Ha-OR ３ is; (h) R １ teeth 【Chemistry 52】 wherein R ７ teeth 【Chemistry 53】 and R ２ Ha-OR ３ and (i) R １ teeth 【Chemistry 54】 and R ２ Ha-OR ３ is.

4. R ３ , R ４ , R ５ , R ６ , R ８ , R ９ , R １０ , R １３ , R １５ and R ２２ Each methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isopropyl o-butyl, t-butyl, pentyl, isopentyl, neopentyl, n-hexyl, 2- Methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethyl The method according to any one of claims 1 to 3, wherein the swatches are independently selected from the group consisting of Louboutin.

5. R ９ , R １４ , R １６ , R １７ , R １９ , R ２０ , R ２３ and R ２４ are respectively ethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl 5. The method of claim 1, wherein the alkyl group is independently selected from the group consisting of butyl, methyl ...

6. The protecting groups include tert-butoxycarbonyl (boc), carbobenzyloxy (C bz), p-methoxybenzylcarbonyl (Moz or MeOZ), 9-fluorenyl Methyloxycarbonyl (Fmoc) group, benzyl (Bn), p-methoxybenzyl (P MB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), Troc (Tric) chloroethyl chloroformate), (4-nitrophenyl)sulfonyl (Nosyl), and and nitrophenylsulfenyl (Nps), How to post.

7. R １８ The method of any one of claims 1 to 6, wherein is selected from phenyl.

8. The method according to any one of claims 1 to 7, wherein (a-i)R １ is —OH, and R ２ teeth 【Transformation 55】 Selected from: (a-ii) R １ Ha-OCH ３ , -OCH(CH ３ ) ２ and -OC(CH ３ ) ３ from Selected, R ２ teeth 【Transformation 56】 Selected from: (b) R １ teeth 【Chemistry 57】 and R ２ teeth 【Chemistry 58】 is; (c) R １ teeth 【Chemistry 59】 and R ２ Ha-OCH ３ (12, 13); (d) R １ teeth 【Transformation 60】 and R ２ teeth 【Chemistry 61】 Selected from: (e) R １ teeth 【Transformation 62】 and R ２ Ha-OCH ３ (14); (f) R １ teeth 【Transformation 63】 and R ２ Ha-OCH ３ (17, 19); (g) R １ teeth 【Chemistry 64】 and R ２ Ha-OCH ３ (15, 16); (h) R １ teeth 【Transformation 65】 and R ２ Ha-OCH ３ (18, 20); and (i) R １ teeth 【Chemical Formula 66】 and R ２ Ha-OCH ３ (3, 4).

9. The compound of formula (I) is 【Chemistry 67-1】 【Chemistry 67-2】 【Chemistry 67-3】 The method according to any one of claims 1 to 8, wherein the method is selected from the group consisting of:

10. Further, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient. The method according to claim 1.

11. 10. The method of claim 1, wherein the inflammatory skin condition or other condition associated with hair loss includes alopecia areata. The method described.

12. The alopecia areata is called patchy alopecia areata. The method of claim 11 , comprising:

13. 10. The method of claim 1, wherein the alopecia areata includes alopecia totalis.

1. The method according to claim 1.

14. The alopecia areata includes alopecia universalis. The method according to claim 11 .

15. 10. The method of claim 1, wherein the method for inducing hair growth comprises: Inducing the transition from the anagen phase to the rhodamine phase.

16. and further comprising increasing the number of hair follicles present in the subject during the anagen phase. The method of claim 15.

17. The subject is compared to a control subject prior to administration of a therapeutically effective amount of a compound of formula (I).

17. The method of claim 16, wherein the number of hair follicles in the anagen phase is reduced.

18. The subject may be suffering from or have alopecia from an underlying health disorder or therapeutic treatment.

10. The method of claim 1, wherein the subject is at risk of developing alopecia.

19. The underlying health disorder may be acquired immune deficiency (AID), hypothyroidism, thyroid dysfunction, Hyperactivity, lupus erythematosus, diabetes, anemia, syphilis, zinc deficiency, trichotillomania, Cushing's disease syndrome, systemic lupus erythematosus, infectious disease, discoid lupus erythematosus, lichen planus, atrophic alopecia (Ps eudopelade of Brocq), congenital skin defects, congenital atrichia, scleroderma , and tinea capitis (ringworm), male pattern baldness, alopecia areata, and other forms alopecia, UV radiation, wound healing defects , psoriasis, atopic dermatitis, contact dermatitis, rosacea, acne, and autoimmune / autoinflammatory conditions 20. The method of claim 18, wherein the state is selected from the group consisting of:

20. 19. The method of claim 18, wherein the underlying health disorder comprises a disorder or condition associated with hair loss. Law.

21. The hair loss-related disorder or condition is androgenic alopecia (androgenic alopecia). alopecia), alopecia areata, anagen effluvium, Self-induced hair loss, telogen effluvium (TEE) alopecia effluvium, and scarring alopecia 21. The method of claim 20, wherein the plant is selected from the group consisting of:

22. 20. The method of claim 18, wherein the therapeutic treatment comprises chemotherapy or radiation therapy.

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