Use of itaconate and derivatives / analogs thereof for inducing hair growth

Abstract

The present application relates to the use of itaconates and derivatives / analogs thereof to induce hair growth. Disclosed herein are methods of using itaconic acid and prodrugs of 1-methylitaconic acid and 4-methylitaconic acid for inducing hair growth and treating inflammatory skin conditions or immune activation (adaptive or congenital), or other conditions associated with hair loss.

Description

[0001] This application is a divisional application of an application filed on October 29, 2020, with application number 202080087148.7, and invention name “Use of itaconates and their derivatives / analogs to induce hair growth”. background

[0003] Alopecia areata (AA) is a common inflammatory cause of hair loss, affecting approximately 2% of the population during their lifetime. Typical AA lesions are non-scarring, hairless, circular plaques on the scalp that can evolve into multiple plaques. Extensive forms of AA can progress to complete loss of scalp hair, known as alopecia totalis (AT); or complete loss of body hair, known as alopecia universalis (AU). AA is associated with other skin diseases and autoimmune diseases, particularly atopic dermatitis (AD), as well as vitiligo, lupus erythematosus, psoriasis, autoimmune thyroid disease, and allergic rhinitis. Although AA is not life-threatening, psychological complications are common in patients with AA and can have a significant impact on the patient's life. Current treatments for severe cases of AA include broad immunosuppressants, which can be associated with significant side effects, precluding long-term use, and with rapid hair loss after treatment termination. The pathogenesis of AA is not fully understood, and there is currently no cure for alopecia areata, nor any therapy to induce and maintain remission of alopecia areata. Overview

[0005] The presently disclosed subject matter provides the use of itaconic acid and prodrugs of 1-methylitaconic acid and 4-methylitaconic acid for inducing hair growth and treating inflammatory skin conditions or other conditions associated with hair loss, such as alopecia areata.

[0006] More particularly, in some aspects, the presently disclosed subject matter provides methods for inducing hair growth or treating inflammatory skin conditions, or immune activation (adaptive or innate), or other conditions associated with hair loss in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

[0007]

[0008] in:

[0009] R1 and R2 may be the same or different and are each independently selected from one or more of the following and combinations thereof:

[0010] (a) -OR3, wherein R3 is H or a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0011] (b) wherein n is an integer selected from 1, 2, 3 and 4; R4 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group or -OR5, wherein R5 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0012] (c) wherein m is an integer selected from 1, 2, 3 and 4; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; and R6 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0013] (d) Wherein R7 is selected from:

[0014] (i) -C(=O)-O-R8, wherein R8 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0015] (ii) Wherein R9 is H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; R 10 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; R 11 and R 12 are each independently H or a protecting group; and R 13 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0016] (iii) wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; R 11 and R 12 Each independently is H or a protecting group; R 14 is H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; and R 15 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; and

[0017] (iv) Where R 16 and R 17 R is independently selected from H, C1-C4 straight or branched unsubstituted or substituted hydrocarbon group and protecting group; 18 is an aromatic group;

[0018] (e) Where R 19 is a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group;

[0019] (f) wherein u is an integer selected from 1, 2, 3 and 4; R20 is H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; and R 21 Yes-OR 22 , where R 22 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group or -NR 23 R 24 , where R 23 and R 24 Each is independently H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group;

[0020] and pharmaceutically acceptable salts thereof.

[0021] In some embodiments:

[0022] (a) R1 is -OR3 and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0023]

[0024] (b) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0025] (c) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0026] (d) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0027] (e)R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0028]

[0029] (f) R1 is wherein R7 is -C(=O)-O-R8 and R2 is selected from -OR3,

[0030]

[0031] wherein R7 is selected from -C(=O)-O-R8,

[0032] (g) R1 is Where R7 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0033] (h) R1 is Where R7 is and R2 is selected from -OR3,

[0034]

[0035] wherein R7 is selected from -C(=O)-O-R8, and (i) R1 is Where R7 is and R2 is selected from -OR3,

[0036]

[0037] wherein R7 is selected from -C(=O)-O-R8,

[0038] and pharmaceutically acceptable salts thereof.

[0039] In some embodiments:

[0040] (ai) R1 is -OH and R2 is selected from:

[0041] -OH, wherein R7 is -C(=O)-O-R8;

[0042] (a-ii) R1 is -OR3 and R2 is selected from:

[0043] Wherein R7 is selected from

[0044] -C(=O)-O-R8,

[0045] (b) R1 is and R2 is selected from:

[0046] -OR3,

[0047] (c) R1 is and R2 is -OR3;

[0048] (d) R1 is and R2 is selected from: -OR3 and

[0049] (e)R1 is wherein R7 is -C(=O)-O-R8 and R2 is -OR3;

[0050] (f) R1 is Where R7 is and R2 is -OR3;

[0051] (g) R1 is Where R7 is and R2 is -OR3;

[0052] (h) R1 is Where R7 is and R2 is -OR3; and

[0053] (i) R1 is and R2 is -OR3.

[0054] In some embodiments, R3, R4, R5, R6, R8, R9, R 10 , R 13 , R 15 and R 22 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane.

[0055] In some embodiments, R9, R 14 , R 16 , R 17 , R 19 , R 20 , R 23 and R 24 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

[0056] In some embodiments, the protecting group is selected from tert-butyloxycarbonyl (boc), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), 9-fluorenylmethoxycarbonyl (Fmoc) group, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-toluenesulfonyl (Ts), Troc (trichloroethyl chloroformate), (4-nitrophenyl)sulfonyl (Nosyl) and nitrophenylsulfonyl (Nps).

[0057] In some embodiments, R 18 Selected from phenyl.

[0058] In some embodiments:

[0059] (ai) R1 is -OH and R2 is selected from:

[0060] -OH(1),

[0061] (a-ii) R1 is selected from -OCH3, -OCH(CH3)2, and -OC(CH3)3 and R2 is selected from:

[0062]

[0063] (b) R1 is and R2 is -OCH3(5,6) or

[0064]

[0065] (c) R1 is and R2 is -OCH3(12, 13);

[0066] (d) R1 is and R2 is selected from: -OCH3(11) and

[0067] (e)R1 is and R2 is -OCH3(14);

[0068] (f) R1 is and R2 is -OCH3(17, 19);

[0069] (g) R1 is and R2 is -OCH3(15, 16);

[0070] (h) R1 is and R2 is -OCH3(18, 20); and

[0071] (i) R1 is And R2 is -OCH3(3,4).

[0072] In some embodiments, the compound of formula (I) is selected from:

[0073]

[0074]

[0075] In some embodiments, the method as described above further comprises a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

[0076] In some embodiments, the inflammatory skin condition or other condition associated with hair loss comprises alopecia areata.

[0077] In some embodiments, the alopecia areata comprises patchy alopecia areata.

[0078] In some embodiments, the alopecia areata comprises alopecia totalis.

[0079] In some embodiments, the alopecia areata comprises alopecia universalis.

[0080] In some embodiments, the method for inducing hair growth induces a transition from the telogen phase to the anagen phase of the hair growth cycle.

[0081] In some embodiments, the above methods further comprise increasing the number of hair follicles present in said subject during said anagen phase.

[0082] In some embodiments, wherein prior to administration of a therapeutically effective amount of a compound of Formula (I), the subject has a decreased number of hair follicles in the anagen phase relative to a control subject.

[0083] In some embodiments, the subject suffers from or is at risk of developing hair loss due to an underlying health disorder or therapeutic treatment.

[0084] In some embodiments, the underlying health disorder is selected from acquired immune deficiency (AID), hypothyroidism, hyperthyroidism, lupus erythematosus, diabetes, anemia, syphilis, zinc deficiency, trichotillomannia, Cushing's syndrome, systemic lupus erythematosus, infection, discoid lupus erythematosus, lichen planus, pseudoalopecia of Broc, dysplasia cutis congenita, alopecia congenita, scleroderma and tinea capitis (ringworm), androgenic alopecia, alopecia areata, other forms of hair loss, UV radiation, wound healing defects, psoriasis, atopic dermatitis, contact dermatitis, rosacea, acne, and autoimmune / autoinflammatory conditions.

[0085] In some embodiments, the underlying health disorder comprises a disorder or condition associated with hair loss.

[0086] In some embodiments, the disease or condition associated with hair loss is selected from androgenetic alopecia, alopecia areata, anagen effluvium, self-induced hair loss, telogen effluvium, and cicatricial alopecia.

[0087] In some embodiments, the therapeutic treatment comprises chemotherapy or radiation therapy.

[0088] In yet other aspects, the disclosed subject of the present invention provides a method for treating a disease, disorder or condition related to inflammation or immune system activation (adaptive or congenital), the method comprising applying a compound of formula (I) or its pharmaceutical composition to a subject having corresponding treatment needs. Representative diseases, disorders or conditions related to inflammation or immune system activation (adaptive or congenital) include but are not limited to androgenetic alopecia, alopecia areata, other forms of alopecia, UV radiation, wound healing defects, psoriasis, atopic dermatitis, contact dermatitis, rosacea, acne and autoimmune / autoinflammatory conditions.

[0089] Certain aspects of the presently disclosed subject matter have been set forth above, which in whole or in part are presented by the presently disclosed subject matter, and other aspects will become apparent as the description proceeds when considered in conjunction with the accompanying examples and drawings which are described below as a detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Having thus generally described the presently disclosed subject matter, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and in which:

[0092] Figure 1A and Figure 1B Itaconic acid release from its corresponding prodrug after 60 min incubation in skin homogenate ( Figure 1A ) or monomethyl itaconate release ( Figure 1B );

[0093] Figure 2 Shown is the release of 4-methylitaconate from its prodrug after 60 min incubation in mouse plasma;

[0094] Figure 3 shows the release of monomethyl itaconate in mouse plasma following oral administration at a molar equivalent dose of 10 mg / kg in male CD1 mice; and

[0095] Figure 4It was shown that treatment of human keratinocytes with itaconate prodrugs interfered with the TLR3 / IL6 / STAT3 axis: IS-100-142 most effectively inhibited JAK-STAT signaling by mitigating the effects of poly(I:C) on downstream gene targets (TLR3, IL6, STAT3, WNT7B);

[0096] Figure 5 It was shown that, in mice, 20% dimethyl itaconate induces a shift from the resting phase of the hair cycle (telogen) to the growth phase of the hair cycle (anagen);

[0097] Figure 6 The effect of dimethyl itaconate in attenuating the effect of dsRNA (PIC; polyinosinic-polycytidylic acid) in increasing the expression of TLR3, IL-6, and STAT3 is shown;

[0098] Figure 7 It was shown that compound 5 induced hair growth in mice;

[0099] Figure 8 Further evidence showing that compound 5 induces hair growth in mice;

[0100] Fig. 9 The results showed that compound 5 induced hair growth in mice to levels comparable to those of Ruxolitinib and Tofacitinib;

[0101] Fig.10 Mouse skin homogenate stability of representative prodrugs is shown;

[0102] Fig.11 Shown is the release of active monomethyl itaconate (in skin homogenate) from a representative prodrug;

[0103] Fig.12 shows the mouse skin penetration of IS-100-142 (Compound 5) (left) and monomethyl itaconate (right) in the alopecia model; and

[0104] Fig.13 IS-100-142 (Compound 5) human skin ex vivo permeability is shown: monomethyl itaconate (MMI) levels in the media and skin are higher than intact IS-100-142; media levels of both analytes are similar to skin. Details

[0106] The subject matter disclosed in the present invention will now be described more fully below with reference to the accompanying drawings, in which some but not all embodiments of the present invention are shown. The same numbers refer to the same elements throughout the text. The subject matter disclosed in the present invention can be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein; on the contrary, these embodiments are provided so that the present disclosure will satisfy applicable legal requirements. In fact, a person skilled in the art to which the subject matter disclosed in the present invention belongs will think of many modifications and other embodiments of the subject matter disclosed in the present invention set forth herein, with the benefit of the teachings presented in the previous description and the related drawings. Therefore, it should be understood that the subject matter disclosed in the present invention is not limited to the specific embodiments disclosed and modifications and other embodiments are intended to be included within the scope of the appended claims.

[0107] I. Use of itaconate and its derivatives / analogs to induce hair growth

[0108] The compounds of formula (I) disclosed herein can be used to induce hair growth and treat one or more inflammatory skin conditions or other conditions associated with hair loss. In some embodiments, the inflammatory skin condition or other condition associated with hair loss includes alopecia areata.

[0109] Alopecia areata is a common inflammatory cause of hair loss and is considered an autoimmune disease in which T lymphocytes attack the hair follicles, causing the hair to stop growing and enter the telogen phase. At the end of the telogen phase, the hair falls out.

[0110] There are three subtypes of alopecia areata, named according to their severity: (i) alopecia areata, which involves mild patchy hair loss on the scalp; (ii) alopecia totalis, which involves loss of all scalp hair; and (iii) alopecia universalis, which involves loss of scalp hair and all body hair. Other types of hair loss include, but are not limited to, androgenic alopecia, effluvium, self-induced hair loss, telogen effluvium, and cicatricial alopecia.

[0111] Androgenetic alopecia includes male pattern baldness and female pattern baldness, and accounts for 95% of all hair loss. Anagen effluvium is the sudden hair loss that occurs due to exposure to chemicals or radiation, such as the hair loss caused during certain types of chemotherapy or radiation treatment, or the sudden hair loss that occurs due to exposure to toxic chemicals such as thallium and arsenic. In most cases, once treatment is completed or exposure to toxins is eliminated, hair growth will return to normal. Self-induced hair loss can be caused consciously or unconsciously. The two main types of self-induced hair loss are trichotillomania and traction alopecia. Trichotillomania is self-induced hair loss, which is caused by continuous pulling or pulling of hair. Traction alopecia is usually caused by continuous and excessive pulling of hair by various types of hairdressing, gradually leading to hair loss that may become permanent. Telogen effluvium is sudden or severe stress-related hair loss, which manifests as thinning of the entire scalp. Sudden or stressful events can cause hair follicles to stop growing prematurely and enter a resting phase. Other causes of telogen effluvium include thyroid dysfunction (hypothyroidism or hyperthyroidism, which occurs when the thyroid gland produces too little or too much thyroid hormone thyroxine, respectively), diabetes, anemia, and the autoimmune disease systemic lupus erythematosus. Scarring alopecia occurs due to inflammation of the hair follicles caused by infection. Scarring alopecia can be caused by: discoid lupus erythematosus, a diffuse connective tissue disease; lichen planus, an inflammatory disease that primarily attacks the skin and mucous membranes; Brock's pseudoalopecia, a rare scarring alopecia that does not have the potential for regrowth; congenital dermatophytosis, a rare disorder in which small, blistering atrophic areas usually appear in the midline of the scalp and are present from birth; or congenital alopecia. Other types of hair loss include syphilitic alopecia, a secondary manifestation of syphilis; scleroderma; and tinea capitis (ringworm).

[0112] More particularly, the presently disclosed subject matter provides methods for inducing hair growth or treating inflammatory skin conditions or other conditions associated with hair loss in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

[0113]

[0114] in:

[0115] R1 and R2 may be the same or different and are each independently selected from one or more of the following and combinations thereof:

[0116] (a) -OR3, wherein R3 is H or a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0117] (b) wherein n is an integer selected from 1, 2, 3 and 4; R4 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group or -OR5, wherein R5 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0118] (c) wherein m is an integer selected from 1, 2, 3 and 4; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; and R6 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0119] (d) Wherein R7 is selected from:

[0120] (i) -C(=O)-O-R8, wherein R8 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0121] (ii) Wherein R9 is H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; R 10 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; R 11 and R 12 are each independently H or a protecting group; and R 13 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group;

[0122] (iii) wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; R 11 and R 12 Each independently is H or a protecting group; R 14 is H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; and R 15 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; and

[0123] (iv) Where R 16 and R 17 R is independently selected from H, C1-C4 straight or branched unsubstituted or substituted hydrocarbon group and protecting group; 18 is an aromatic group;

[0124] (e) Where R 19 is a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group;

[0125] (f) wherein u is an integer selected from 1, 2, 3 and 4; R20 is H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; and R 21 Yes-OR 22 , where R 22 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group or -NR 23 R 24 , where R 23 and R 24 Each is independently H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group;

[0126] and pharmaceutically acceptable salts thereof.

[0127] In certain embodiments of the methods disclosed herein:

[0128] (a) R1 is -OR3 and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0129]

[0130] (b) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0131] (c) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0132] (d) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0133] (e)R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0134]

[0135] (f) R1 is wherein R7 is -C(=O)-O-R8 and R2 is selected from -OR3,

[0136]

[0137] wherein R7 is selected from -C(=O)-O-R8,

[0138] (g) R1 is Where R7 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8,

[0139] (h) R1 is Where R7 is and R2 is selected from -OR3,

[0140]

[0141] wherein R7 is selected from -C(=O)-O-R8, and (i) R1 is Where R7 is and R2 is selected from -OR3,

[0142] wherein R7 is selected from -C(=O)-O-R8,

[0143] and pharmaceutically acceptable salts thereof.

[0144] In certain other embodiments of the methods disclosed herein:

[0145] (ai) R1 is -OH and R2 is selected from:

[0146] -OH, wherein R7 is -C(=O)-O-R8;

[0147] (a-ii) R1 is -OR3 and R2 is selected from:

[0148] Wherein R7 is selected from

[0149] -C(=O)-O-R8,

[0150] (b) R1 is and R2 is selected from:

[0151] -OR3,

[0152] (c) R1 is and R2 is -OR3;

[0153] (d) R1 is and R2 is selected from: -OR3 and

[0154] (e)R1 is wherein R7 is -C(=O)-O-R8 and R2 is -OR3;

[0155] (f) R1 is Where R7 is and R2 is --OR3;

[0156] (g) R1 is Where R7 is and R2 is -OR3;

[0157] (h) R1 is Where R7 is and R2 is -OR3; and

[0158] (i) R1 is and R2 is -OR3.

[0159] In some embodiments of the methods disclosed herein, R3, R4, R5, R6, R8, R9, R 10 , R 13 , R 15 and R 22 Each may independently be a C1, C2, C3, C4, C5 or C6 straight or branched unsubstituted or substituted hydrocarbon group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane.

[0160] In some embodiments of the methods disclosed herein, R9, R 14 , R 16 , R 17 , R 19 , R 20 , R 23 and R 24Each may independently be a C1, C2, C3 or C4 straight or branched unsubstituted or substituted hydrocarbon group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

[0161] Representative substituent groups include, but are not limited to, hydrocarbyl, substituted hydrocarbyl, halogen, aryl, substituted aryl, hydrocarbyloxy, hydroxy, nitro, amino, hydrocarbylamino, dihydrocarbylamino, sulfate, cyano, mercapto, and hydrocarbylthio.

[0162] In certain embodiments of the methods disclosed herein, the protecting group is selected from tert-butyloxycarbonyl (boc), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), 9-fluorenylmethoxycarbonyl (Fmoc) group, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-toluenesulfonyl (Ts), Troc (trichloroethyl chloroformate), (4-nitrophenyl)sulfonyl (Nosyl) and nitrophenylsulfonyl (Nps). In a specific embodiment, the protecting group is tert-butyloxycarbonyl (boc).

[0163] In some embodiments of the methods disclosed herein, R 18 Selected from phenyl.

[0164] In certain embodiments of the methods disclosed herein:

[0165] (ai) R1 is -OH and R2 is selected from:

[0166] -OH(1),

[0167] (a-ii) R1 is selected from -OCH3, -OCH(CH3)2 and -OC(CH3)3, and R2 is selected from:

[0168]

[0169] (b) R1 is and R2 is -OCH3(5,6) or

[0170]

[0171] (c) R1 is and R2 is -OCH3(12, 13);

[0172] (d) R1 is and R2 is selected from: -OCH3(11) and

[0173] (e)R1 is and R2 is -OCH3(14);

[0174] (f) R1 is and R2 is -OCH3(17, 19);

[0175] (g) R1 is and R2 is -OCH3(15, 16);

[0176] (h) R1 is and R2 is -OCH3(18, 20); and

[0177] (i) R1 is And R2 is -OCH3(3,4).

[0178] In certain embodiments of the methods disclosed herein, the compound of formula (I) is selected from:

[0179]

[0180]

[0181]

[0182] Representative compounds of formula (I) and the active agent released by each corresponding prodrug are provided in Table 1.

[0183]

[0184]

[0185]

[0186]

[0187] 4-MI refers to 4-methylitaconate; 1-MI refers to 1-methylitaconate

[0188] In some embodiments, the methods disclosed herein also include a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

[0189] In certain embodiments of the methods disclosed herein, the inflammatory skin condition or other condition associated with hair loss comprises alopecia areata. In certain embodiments, alopecia areata comprises patchy alopecia areata. In other embodiments, alopecia areata comprises alopecia totalis. In yet other embodiments, alopecia areata comprises alopecia universalis.

[0190] In some embodiments, the method for inducing hair growth induces a transition from the telogen phase to the anagen phase of the hair growth cycle. In short, the three phases of hair growth are the anagen phase, the catagen phase, and the telogen phase. The anagen phase is known as the growth phase, during which hair grows naturally (physically). The catagen phase is known as the transition phase. The telogen phase is known as the resting phase, during which hair follicles remain dormant.

[0191] In certain embodiments, the method further comprises increasing the number of hair follicles present in the subject in the anagen phase.In certain embodiments, prior to administering a therapeutically effective amount of a compound of Formula (I), the subject has a decreased number of hair follicles in the anagen phase relative to a control subject.

[0192] In other embodiments, the subject suffers from or is at risk of developing hair loss caused by an underlying health disorder or therapeutic treatment. In certain embodiments, the underlying health disorder is selected from acquired immune deficiency (AID), hypothyroidism, hyperthyroidism, lupus erythematosus, diabetes, anemia, syphilis, zinc deficiency, trichotillomannia, Cushing syndrome, systemic lupus erythematosus, infection, discoid lupus erythematosus, lichen planus, pseudoalopecia of Broc, dysplasia cutis congenita, alopecia congenita, scleroderma, and tinea capitis (ringworm).

[0193] In yet other certain embodiments, the underlying health disorder comprises a disorder or condition associated with hair loss. In a particular embodiment, the disorder or condition associated with hair loss is selected from androgenetic alopecia, alopecia areata, anagen effluvium, self-induced hair loss, telogen effluvium, and cicatricial alopecia.

[0194] In some embodiments, therapeutic treatment comprises chemotherapy or radiation therapy.

[0195] In yet other embodiments, the disclosed subject matter provides a method for treating a disease, disorder or condition associated with inflammation or immune system activation (adaptive or congenital), the method comprising administering a compound of formula (I) or a pharmaceutical composition thereof to a subject in need of corresponding treatment. Representative diseases, disorders or conditions associated with inflammation or immune system activation (adaptive or congenital) include, but are not limited to, androgenetic alopecia, alopecia areata, other forms of alopecia, UV radiation, wound healing defects, psoriasis, atopic dermatitis, contact dermatitis, rosacea, acne and autoimmune / autoinflammatory conditions.

[0196] Generally, as used herein, the term "treating" can include reversing, alleviating, inhibiting the progression of, preventing or reducing the likelihood of the disease, disorder or condition to which such term is applied, or one or more symptoms or manifestations of such disease, disorder or condition. Prevention refers to preventing the disease, disorder, condition or its symptoms or manifestations from occurring, or preventing it from occurring with a worsening of severity. Thus, the compounds disclosed herein can be administered prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder or condition.

[0197] The "subject" treated by the methods disclosed herein in many of its embodiments is desirably a human subject, however it should be understood that the methods described herein are effective with respect to all vertebrate species, all of which are intended to be included in the term "subject". Thus, a "subject" may include a human subject for medical purposes, such as for treatment of an existing condition or disease or for prophylactic treatment to prevent the onset of a condition or disease, or an animal subject for medical purposes, veterinary purposes, or development purposes. Suitable animal subjects include mammals, including, but not limited to, primates, such as humans, monkeys, apes, etc.; bovines, such as cattle, bulls, etc.; ovines, such as sheep, etc.; caprines, such as goats, etc.; porcines, such as pigs, livestock pigs, etc.; equines, such as horses, donkeys, zebras, etc.; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, etc.; and rodents, including mice, rats, etc. The animal can be a transgenic animal. In certain embodiments, the subject is a human, including, but not limited to, a fetus, a newborn, an infant, a juvenile, and an adult subject. In addition, a "subject" can include a patient suffering from or suspected of suffering from a condition or disease. Therefore, the terms "subject" and "patient" are used interchangeably herein. The term "subject" also refers to an organism, tissue, cell, or cell collection from a subject.

[0198] Typically, an "effective amount" of an active agent or drug delivery device refers to the amount necessary to elicit a desired biological response. As will be appreciated by one of ordinary skill in the art, the effective amount of an agent or device may vary depending on factors such as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue, etc.

[0199] The term "combination" is used in its broadest sense, and means that the subject is administered at least two agents, more particularly, a compound of formula (I) and at least one β-lactam antibiotic, and optionally one or more antibacterial agents. More particularly, the term "combination" refers to the simultaneous administration of two (or more) active agents for the treatment of, for example, a single disease state. As used herein, the active agent can be combined and administered in a single dosage form, can be administered at the same time as a separate dosage form, or can be administered as a separate dosage form administered alternately or sequentially on the same or different days. In one embodiment of the subject matter disclosed in the present invention, the active agent is combined and administered in a single dosage form. In another embodiment, the active agent is administered in a separate dosage form (e.g., where it is desirable to vary the amount of one active agent, while the amount of another active agent does not vary). A single dosage form may include additional active agents for the treatment of a disease state.

[0200] In addition, the compounds of Formula (I) described herein can be administered alone or in combination with adjuvants that enhance the stability of the compounds of Formula (I), administered alone or in combination with one or more antibacterial agents, in certain embodiments facilitate administration of pharmaceutical compositions containing them (including other active ingredients), provide increased dissolution or dispersion, increase inhibitory activity, provide adjunctive therapy, etc. Advantageously, such combination therapies utilize lower doses of conventional therapeutic agents, thereby avoiding possible toxicity and adverse side effects when those agents are used as monotherapy.

[0201] The compound of formula (I) and at least one other therapeutic agent can be applied at different times (i.e., on the same day or on different days, in any order in sequence) to receive the compound of formula (I) and at least one other therapeutic agent, as long as the effect of the combination of two agents is achieved in the subject.

[0202] When administered sequentially, the doses can be administered within 1 minute, 5 minutes, 10 minutes, 30 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes or longer of each other. In other embodiments, the doses administered sequentially can be administered within 1 day, 5 days, 10 days, 15 days, 20 days or more of each other. When the compound of formula (I) and at least one other therapeutic agent are administered simultaneously, they can be administered to the subject as a separate pharmaceutical composition (each pharmaceutical composition comprises a compound of formula (I) or at least one other therapeutic agent), or they can be administered to the subject as a single pharmaceutical composition comprising two doses.

[0203] When administered in combination, the effective concentration of each of the agents that elicit a particular biological response can be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be required if the agent were administered as a single agent. The effects of multiple agents can, but need not be, additive or synergistic. An agent can be administered multiple times.

[0204] In some embodiments, when combined, two or more agents may have a synergistic effect. As used herein, the terms "synergy", "synergistic", "synergistically" and derivatives thereof, such as in "synergistic effect" or "synergistic combination" or "synergistic composition", refer to a situation where the biological activity of the combination of a compound of formula (I) and at least one other therapeutic agent is greater than the sum of the biological activities of the corresponding agents when administered alone.

[0205] Synergy can be expressed in terms of a "synergy index (SI)", which can generally be determined by the method described in FC Kull et al., Applied Microbiology 9, 538 (1961) from the ratio determined as follows:

[0206] Q a / Q A +Q b / Q B =Synergy Index (SI)

[0207] in:

[0208] Q A is the concentration of component A acting alone that produces an endpoint associated with component A;

[0209] Q a is the concentration of component A in the mixture that produces the endpoint;

[0210] Q B is the concentration of Component B, acting alone, which produces an endpoint associated with Component B; and

[0211] Q b is the concentration of component B in the mixture that produces the endpoint.

[0212] Usually, when Q a / Q A and Q b / Q BWhen the sum of the SI is greater than 1, antagonism is indicated. When the sum is equal to 1, an addition is indicated. When the sum is less than 1, a synergistic effect is indicated. The lower the SI, the greater the synergy shown by the particular mixture. Thus, a "synergistic combination" has an activity that is higher than what would be expected based on the activity observed for the individual components when used alone. In addition, a "synergistically effective amount" of a component refers to the amount of the component necessary to elicit a synergistic effect of, for example, another therapeutic agent present in the composition.

[0213] In another embodiment, the subject matter disclosed herein provides a pharmaceutical composition comprising a single compound of formula (I) or a combination of a compound of formula (I) and one or more additional therapeutic agents, mixed with a pharmaceutically acceptable excipient. Those skilled in the art will recognize that the pharmaceutical composition includes pharmaceutically acceptable salts of the compounds described above. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art and include salts of active compounds prepared from relatively nontoxic acids or bases, depending on the specific substituent moieties present on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in a neutral form with a sufficient amount of the desired base, either pure or in a suitable inert solvent, or by ion exchange, whereby one basic counterion (base) in the ionic complex is replaced by another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts.

[0214] When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent, or by ion exchange, whereby one acidic counterion (acid) in the ionic complex is replaced by another. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and the like, and salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid, and the like (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functional groups, which allow the compounds to be converted into either base addition salts or acid addition salts.

[0215] Thus, pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, by way of example, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, mucate, naphthylate, nitrate, pamoate (pamoate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or theoclate. Other pharmaceutically acceptable salts can be found, for example, in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

[0216] In therapeutic and / or diagnostic applications, the compounds of the present disclosure can be formulated for a variety of modes of administration, including systemic administration and topical or local administration. Techniques and formulations generally can be found in Remington: The Science and Practice of Pharmacy (20th Edition) Lippincott, Williams & Wilkins (2000).

[0217] Depending on the specific conditions being treated, such agents can be formulated into liquid or solid dosage forms and are administered systemically or topically. Agents can be delivered, for example, in a timed slow release form known to those skilled in the art or in a sustained slow release form. The technology used for preparation and administration can be found in Remington: The Science and Practice of Pharmacy (20th edition) Lippincott, Williams & Wilkins (2000). Suitable routes can include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular injection or other delivery modes.

[0218] For injection, the agents of the present disclosure can be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or saline buffer. For such transmucosal administration, penetrants suitable for the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art.

[0219] It is within the scope of the present disclosure to use a pharmaceutically acceptable inert carrier to prepare the compounds disclosed herein for practicing the present disclosure into a dosage suitable for systemic administration. In the case of appropriate selection of carriers and suitable manufacturing practices, the compositions of the present disclosure, particularly those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compound can be easily formulated into a dosage suitable for oral administration using pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present disclosure to be formulated into tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by a subject to be treated (e.g., a patient).

[0220] For nasal or inhaled delivery, the agents of the present disclosure may also be formulated by methods known to those skilled in the art, and may include, for example, but not limited to, examples of solubilizing, diluting or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption enhancers and fluorocarbons.

[0221] Pharmaceutical compositions suitable for use in the present disclosure include compositions in which the active ingredient is contained in an effective amount to achieve its intended purpose. The determination of the effective amount is fully within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein. Typically, compounds according to the present disclosure are effective over a wide dosage range. For example, in the treatment of adults, dosages from 0.01 mg to 1000 mg, from 0.5 mg to 100 mg, from 1 mg to 50 mg, and from 5 mg to 40 mg per day are examples of dosages that can be used. A non-limiting dose is 10 mg to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the bioavailability of the compound, the adsorption, distribution, metabolism and excretion (ADME) toxicity of the compound, and the preference and experience of the attending physician.

[0222] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Preparations formulated for oral administration may be in the form of tablets, dragees, capsules or solutions.

[0223] Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture and, if desired, processing the granulated mixture after adding suitable auxiliaries to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

[0224] The dragee core is provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talcum powder, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or characterization of the different combinations of active compound dosages.

[0225] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or a liquid polyethylene glycol (PEG). In addition, a stabilizer may be added.

[0226] In other embodiments, the compound of formula (I) disclosed in the present invention can be formulated into a viscous lotion, cream, ointment, suspension, paste, gel, oil, spray or aerosol and applied superficially. Such a viscous lotion, cream or ointment can be based on water, and can also contain oil (water-in-oil or oil-in-water), such as liquid paraffin or vegetable oil, such as peanut oil or castor oil, or solvent, and can contain one or more other components, including but not limited to penetration enhancers, such as ethanol and propylene glycol, wetting agents, including but not limited to glycerin and / or glycerol, thickeners and / or gelling agents, including but not limited to soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxypolyethylene and cellulose derivatives and / or glyceryl monostearate and / or nonionic emulsifiers, stabilizers, dispersants and suspending agents. By way of example only, a typical liquid formulation may contain between about 10% to about 60% water, between about 10% to about 70% ethanol, between about 5% to about 10% propylene glycol, and between about 2% to about 5% humectant.

[0227] II. Definitions

[0228] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described in this invention belongs.

[0229] Although it is believed that the following terms related to compounds of formula (I) are well understood by those of ordinary skill in the art, the following definitions are proposed to help explain the subject matter disclosed in the present invention. These definitions are intended to supplement and illustrate rather than exclude definitions that will be obvious to those of ordinary skill in the art after reviewing the present disclosure.

[0230] As used herein, the term substituted (whether or not preceded by the term "optionally"), and substituents, refers to the ability to change one functional group on a molecule to another functional group, as understood by those skilled in the art, provided that the valence of all atoms is maintained. When more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituents can be the same or different at each position. Substituents can also be further substituted (e.g., an aryl group substituent can have another substituent away from it, such as another aryl group, which is further substituted at one or more positions).

[0231] Where substituent groups or linking groups are specified by their conventional chemical formula written from left to right, they also encompass chemically identical substituents that would result from writing the structure from right to left, for example, -CH2O- is equivalent to -OCH2-; -C(=O)O- is equivalent to -OC(=O)-; -OC(=O)NR- is equivalent to -NRC(=O)O-, and so forth.

[0232] When the term "independently selected" is used, the substituents being referred to (e.g., R groups, such as groups R1, R2, and the like, or variables, such as "m" and "n") can be the same or different. For example, both R1 and R2 can be substituted hydrocarbyl, or R1 can be hydrogen and R2 can be substituted hydrocarbyl, etc.

[0233] When used with respect to a group of substituents herein, the term "a", "an" or "a(n)" means at least one. For example, in the case where a compound is substituted with "an" hydrocarbyl or aryl, the compound is optionally substituted with at least one hydrocarbyl and / or at least one aryl. In addition, in the case where a portion is substituted with an R substituent, the group may be referred to as "R-substituted". In the case where a portion is R-substituted, the portion is substituted with at least one R substituent and each R substituent is optionally different.

[0234] A named "R" or group will generally have a structure recognized in the art as corresponding to the group having that name, unless otherwise specified herein. For illustrative purposes, certain representative "R" groups as set forth above are defined below.

[0235] The description of the compounds of the present disclosure is subject to the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with the principles of chemical bonding and give compounds that are not inherently unstable and / or would be considered by one of ordinary skill in the art to be likely to be unstable under environmental conditions such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl group is attached to the remainder of the molecule via a ring heteroatom in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0236] Unless expressly defined otherwise, a "substituent group" as used herein includes a functional group selected from one or more of the following moieties defined herein:

[0237] As used herein, the term hydrocarbon refers to any chemical group comprising hydrogen and carbon. Hydrocarbons can be substituted or unsubstituted. As will be known to those skilled in the art, all valences must be satisfied when any substitution is made. Hydrocarbons can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl and similar hydrocarbons.

[0238] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight chain (i.e., unbranched) or branched, acyclic or cyclic hydrocarbon group, or combinations thereof, which may be fully saturated, monounsaturated or polyunsaturated and may include divalent and multivalent groups, having a specified number of carbon atoms (i.e., C 1-10 In certain embodiments, the term "hydrocarbyl" refers to a C alkyl group derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removing a single hydrogen atom. 1-20 and 20 inclusive, including linear (i.e., "straight chain"), branched or cyclic, saturated or at least partially unsaturated, and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon radicals of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbon atoms.

[0239] Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, 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)methyl, cyclopropylmethyl, and homologs and isomers thereof.

[0240] "Branched" refers to a hydrocarbyl group in which a lower hydrocarbyl group such as methyl, ethyl or propyl is attached to a linear hydrocarbyl chain. "Lower hydrocarbyl" refers to a hydrocarbyl 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 an alkyl group having from about 10 to about 20 carbon atoms, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. In certain embodiments, "alkyl" specifically refers to C 1-8 In other embodiments, "alkyl" refers specifically to C 1-8 Branched chain hydrocarbon.

[0241] The hydrocarbyl group may be optionally substituted with one or more hydrocarbyl substituents ("substituted hydrocarbyl") which may be the same or different. The term "hydrocarbyl substituent" includes, but is not limited to, hydrocarbyl, substituted hydrocarbyl, halogen, arylamino, acyl, hydroxyl, aryloxy, hydrocarbyloxy, hydrocarbylthio, arylthio, arylalkyloxy, arylalkylthio, carboxyl, hydrocarbyloxycarbonyl, oxo, and cycloalkyl. Along the hydrocarbyl chain there may be one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms optionally inserted, wherein the nitrogen substituent is hydrogen, a lower hydrocarbyl (also referred to herein as "hydrocarbylaminohydrocarbyl"), or an aryl.

[0242] Thus, as used herein, the term "substituted hydrocarbyl" includes hydrocarbyl groups as defined herein, wherein one or more atoms or functional groups in the hydrocarbyl group are replaced by additional atoms or functional groups, including, for example, hydrocarbyl, substituted hydrocarbyl, halogen, aryl, substituted aryl, hydrocarbyloxy, hydroxyl, nitro, amino, hydrocarbylamino, dihydrocarbylamino, sulfate, cyano, and mercapto.

[0243] Unless otherwise stated, the term "heteroalkyl" alone or in combination with another term means a stable straight or branched chain or cyclic hydrocarbon group having from 1 to 20 carbon atoms or heteroatoms, or having from 3 to 10 carbon atoms or heteroatoms, or a combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P and S and Si may be located at any interior position of the heteroalkyl group or at the position where the hydrocarbon group is attached to the remainder of the molecule. Examples include, but are not limited to, -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)-CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0244] As described above, heteroalkyl groups as used herein include those groups attached to the remainder of the molecule through a heteroatom, such as -C(O)NR', ​​-NR'R", -OR', -SR, -S(O)R and / or -S(O2)R'. Where the recitation of "heteroalkyl" is followed by a recitation of a specific heteroalkyl group (such as -NR'R" or the like), it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited for added clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, such as -NR'R" or the like.

[0245] "Cyclic" and "cycloalkyl" refer to non-aromatic monocyclic or polycyclic ring systems having from about 3 to about 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms). Cycloalkyl groups may optionally be partially unsaturated. Cycloalkyl groups may also optionally be substituted with alkyl group substituents, oxo and / or alkylene groups as defined herein. Along the cycloalkyl chain there may be one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms optionally inserted, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl or substituted aryl, thereby providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl and cycloheptyl. Polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl as well as fused ring systems such as dihydronaphthalene and tetrahydronaphthalene and the like.

[0246] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" alone or in combination with other terms represent the cyclic forms of "alkyl" and "heterocycloalkyl", respectively. In addition, for heterocycloalkyl, heteroatoms can occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and similar groups. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, and similar groups. The terms "cycloalkylene" and "heterocycloalkylene" refer to divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0247] Unsaturated hydrocarbons have one or more double bonds or triple bonds. Examples of unsaturated hydrocarbon groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl and higher homologues and isomers. Alkyl groups limited to hydrocarbon groups are referred to as "homoalkyl".

[0248] More specifically, the term "alkenyl" as used herein refers to a C-1-alkylene group having at least one carbon-carbon double bond. 2-20(2 and 20 inclusive) a monovalent group derived from a straight or branched hydrocarbon moiety by removing a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-butene-1-yl, pentenyl, hexenyl, octenyl, propadienyl and butadienyl.

[0249] As used herein, the term "cycloalkenyl" refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[0250] As used herein, the term "alkynyl" refers to a linear or branched C-chain radical having a designated number of carbon atoms and containing at least one carbon-carbon triple bond. 2-20 A hydrocarbon-derived monovalent group. Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl and heptynyl groups and the like.

[0251] The term "alkylene" alone or as part of another substituent refers to a straight or branched divalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms). The alkylene group can be straight chain, branched or cyclic. The alkylene group can also be optionally unsaturated and / or substituted with one or more "alkyl group substituents". Along the alkylene group there can be one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl"), optionally inserted, wherein the nitrogen substituent is an alkyl group as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-C6H 10 -); -CH=CH-CH=CH-; -CH=CH-CH2-; -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r-, wherein q and r are each independently 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 a lower hydrocarbon group; methylenedioxy (-O-CH2-O-); and ethylenedioxy (-O-(CH2) 2- O-). The alkylene group can have from about 2 to about 3 carbon atoms and can also have 6-20 carbons. Typically, the alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure. "Lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, typically having eight or fewer carbon atoms.

[0252] The term "heteroalkylene" alone or as part of another substituent means a divalent group derived from a heteroalkyl group (such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-). For heteroalkylene groups, heteroatoms may also occupy one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0253] Unless otherwise indicated, the term "aryl" means an aromatic hydrocarbon substituent which may be a single ring or multiple rings (such as from 1 to 3 rings) fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing from one to four heteroatoms (in each individual ring in the case of multiple rings) selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 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-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.

[0254] For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthio, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl" and "heteroarylalkyl" are intended to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furanylmethyl, and the like), including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced, for example, with an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like). However, the term "haloaryl" as used herein is intended to include only aryl groups substituted with one or more halogens.

[0255] In cases where the heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (eg, "3- to 7-membered"), the term "member" refers to a carbon or heteroatom.

[0256] Furthermore, as used herein, structures generally represented by the formula:

[0257]

[0258] Refers to a ring structure containing a substituent R group, such as, but not limited to, 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon, etc., aliphatic and / or aromatic cyclic compounds, including saturated ring structures, partially saturated ring structures and unsaturated ring structures, wherein the R group may be present or absent, and when present, one or more R groups may be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and the number of the R group are determined by the value of the variable "n", which is an integer generally having a value in the range of from 0 to the number of carbon atoms on the ring that can be used for substitution. Each R group, if more than one, is substituted on the available carbon of the ring structure rather than on another R group. For example, the above structure wherein n is 0 to 2 will include a compound group, which includes, but is not limited to:

[0259]

[0260] and the like.

[0261] A dotted line representing a bond in a cyclic ring structure indicates that the bond may or may not be present in the ring. That is, a dotted line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

[0262] symbol Represents the point of attachment of the moiety to the rest of the molecule.

[0263] When a named atom of an aromatic or heterocyclic aromatic ring is defined as being "absent," the named atom is replaced by a direct bond.

[0264] As used herein, the term "acyl" refers to an organic acid group in which the -OH of the carboxyl group has been replaced by another substituent and has the general formula RC(=O)-, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic or aromatic heterocyclic group as defined herein. Therefore, the term "acyl" specifically includes aryl acyl groups, such as 2-(furan-2-yl)acetyl groups and 2-phenylacetyl groups. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides, -RC(=O)NR', ​​esters, -RC(=O)OR', ketones, -RC(=O)R' and aldehydes, -RC(=O)H.

[0265] The terms "alkoxyl" or "alkoxy" are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms "alkyl," "alkenyl," and "alkynyl" are as previously described and may include C 1-20 (Inclusive of 1 and 20) linear, branched or cyclic, saturated or unsaturated oxyhydrocarbon chains including, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and n-pentoxy, neopentoxy, n-hexoxy and the like.

[0266] As used herein, the term "hydrocarbyloxyhydrocarbyl" refers to a hydrocarbyl-O-hydrocarbyl ether, for example, a methoxyethyl or ethoxymethyl group.

[0267] "Aryloxy" refers to an aryl-O-group, wherein the aryl group is as previously described, including substituted aryl. As used herein, the term "aryloxy" may refer to a phenoxy or hexyloxy group, and a phenoxy or hexyloxy group substituted with a hydrocarbyl, a substituted hydrocarbyl, a halogen, or a hydrocarbyloxy group.

[0268] "Arylalkyl" refers to an aryl-alkyl-group in which the aryl and alkyl are as previously described, and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0269] "Aryloxy" refers to an aryl-O- group, wherein the aryl group is as previously described. An exemplary aryloxy group is benzyloxy, i.e., C6H5-CH2-O-. The aryloxy group may be optionally substituted.

[0270] "Hydroxycarbonyl" refers to a hydrocarbyl-OC(=O)- group. Exemplary hydrocarbyloxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl.

[0271] "Aryloxycarbonyl" refers to an aryl-OC(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy-carbonyl and naphthoxy-carbonyl.

[0272] "Aryloxycarbonyl" refers to an arene-OC(=O)- group. An exemplary areneoxycarbonyl group is benzyloxycarbonyl.

[0273] "Carbamoyl" refers to an amide group of the formula -C(=O)NH2. "Alkylcarbamoyl" refers to an R'RN-C(=O)- group, wherein one of R and R' is hydrogen and the other of R and R' is a hydrocarbyl and / or substituted hydrocarbyl as previously described. "Dihydrocarbylcarbamoyl" refers to an R'RN-C(=O)- group, wherein each of R and R' is independently a hydrocarbyl and / or substituted hydrocarbyl as previously described.

[0274] The term carbonyldioxy, as used herein, refers to a carbonate group of the formula -OC(=O)-OR.

[0275] "Acyloxy" means an acyl-O- group in which the acyl group is as previously described.

[0276] The term "amino" refers to the -NH2 group and also refers to nitrogen-containing groups derived from ammonia by replacing one or more hydrogen groups with organic groups, as known in the art. For example, the terms "acylamino" and "hydrocarbylamino" refer to specific N-substituted organic groups having acyl and hydrocarbyl substituents, respectively.

[0277] As used herein, "aminoalkyl" refers to an amino group covalently bonded to an alkylene linker. More specifically, the terms alkylamino, dialkylamino and trialkylamino, as used herein, refer to one, two or three alkyl groups as previously defined, respectively, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', wherein R' is a alkyl group as previously defined; while the term dialkylamino refers to a group having the structure -NR'R", wherein R' and R" are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R"R"', wherein R', R" and R"' are each independently selected from the group consisting of alkyl groups. In addition, R', R" and / or R"' taken together may optionally be -(CH2) k -, wherein k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.

[0278] An amino group is -NR'R", wherein R' and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0279] The terms alkyl thioether and thioalkyloxy refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) groups attached to the parent molecular moiety through a sulfur atom. Examples of thioalkyloxy moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio and the like.

[0280] "Acylamino" refers to an acyl-NH- group in which the acyl group is as previously described. "Aroylamino" refers to an aroyl-NH- group in which the aroyl group is as previously described.

[0281] The term "carbonyl" refers to a -C(=O)- group, and may include an aldehyde group represented by the general formula RC(=O)H.

[0282] The term "carboxyl" refers to a -COOH group. Such groups are also referred to herein as "carboxylic acid" moieties.

[0283] The term "cyano" refers to a -C≡N group.

[0284] As used herein, the terms "halo", "halide" or "halogen" refer to fluorine, chlorine, bromine and iodine groups. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1-4 )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0285] The term "hydroxy" refers to an -OH group.

[0286] The term "hydroxyalkyl" refers to an alkyl group substituted with an -OH group.

[0287] The term "mercapto" refers to a -SH group.

[0288] The term "oxo" as used herein means an oxygen atom double-bonded to a carbon atom or another element.

[0289] The term "nitro" refers to the -NO2 group.

[0290] The term "thio" refers to compounds previously described herein wherein a carbon atom or an oxygen atom is replaced by a sulfur atom.

[0291] The term "sulfate" refers to the -SO4 group.

[0292] As used herein, the term thiol or thiol refers to a group of formula -SH.

[0293] More particularly, the term "sulfide" refers to a compound having a group of formula -SR.

[0294] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R.

[0295] The term "sulfoxide" refers to a compound having a sulfinyl group -S(O)R.

[0296] The term urea refers to a urea group of the formula -NH-CO-NH2.

[0297] Throughout the specification and claims, a given chemical formula or name will encompass all tautomers, congeners and optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0298] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or as D- or L- for amino acids are included within the scope of the present disclosure. The present disclosure is intended to include compounds in racemic, non-racemic (scalemic) and optically pure forms. Optically active (R)- and (S)-isomers or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0299] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the present disclosure.

[0300] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure. As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another isomeric form.

[0301] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacement of hydrogen by deuterium or tritium or by 13 C or 14 Compounds having the present structures in which C-enriched carbon replaces carbon are within the scope of this disclosure.

[0302] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. For example, the compounds may be treated with, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) is radiolabeled with a radioactive isotope. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0303] Some compounds of the present disclosure may exist in unsolvated forms as well as solvated forms (including hydrated forms). Typically, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present disclosure. Some compounds of the present disclosure may exist in multiple crystalline or amorphous forms. Typically, all physical forms are equivalent for the intended uses of the present disclosure and are intended to be within the scope of the present disclosure.

[0304] The term "blocking group" refers to some or all of the reactive parts of a blocking compound and prevents such part from participating in a chemical reaction until the chemical part of the blocking group is removed, for example, those parts listed and described below: TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, the 3rd edition John Wiley & Sons (1999). In the case where different blocking groups are used, it can be advantageous that each (different) blocking group is removable by different means. The blocking group cracked under completely different reaction conditions allows the removal of differences of such blocking groups. For example, blocking groups can be removed by acid, alkali and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid unstable, and can be used to protect carboxyl and hydroxyl reactive parts in the presence of amino groups protected with Cbz groups (which are removable by hydrogenolysis) and Fmoc groups (which are base unstable). Carboxylic acid and hydroxy reactive moieties can be blocked with base labile groups such as, but not limited to, methyl, ethyl and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are stable to both acid and base but removable by hydrolysis.

[0305] Carboxylic acid and hydroxyl reactive moieties may also be blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of acid hydrogen bonding may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride-labile silyl carbamates.

[0306] Allyl blocking groups are useful in the presence of acid and base protecting groups because the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, allyl blocked carboxylic acids can be deprotected by palladium (0)-catalyzed reactions in the presence of acid-labile tert-butyl carbamate or base-labile acetate amine protecting groups. Another form of protecting groups is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. After being released from the resin, the functional group can be used for reaction.

[0307] 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)sulfonyl (Nosyl), and nitrophenylsulfonyl (Nps), as well as

[0308]

[0309] Following long-standing patent law convention, the terms "a," "an," and "the" when used in this application, including the claims, mean "one or more." Thus, for example, reference to "a subject" includes more than one subject unless the context clearly indicates otherwise (e.g., more than one subject), etc.

[0310] Throughout the specification and claims, the terms "comprise," "comprises," and "comprising" are used in a non-exclusive sense, unless the context requires otherwise. Likewise, the term "include" and its grammatical variations are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

[0311] For the purpose of this specification and the appended claims, unless otherwise indicated, all numbers used in the specification and claims to indicate amounts, sizes, dimensions, ratios, shapes, formulas, parameters, percentages, quantities, characteristics and other numerical values ​​should be understood to be modified by the term "about" in all cases, even if the term "about" may not be explicitly presented with the value, amount or range. Therefore, unless otherwise indicated, the numerical parameters listed in the following specification and the appended claims are not and need not be precise, but may be close and / or larger or smaller as desired, reflecting tolerances, conversion factors, rounding, measurement errors, etc., and other factors known to those skilled in the art, depending on the desired properties sought to be obtained by the subject matter disclosed in the present invention. For example, when referring to a value, the term "about" may be intended to include differences of ±100% in some embodiments, ±50% in some embodiments, ±20% in some embodiments, ±10% in some embodiments, ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and ±0.1% in some embodiments from the specified amount, because such differences are appropriate for carrying out the disclosed method or employing the disclosed composition.

[0312] In addition, when used in conjunction with one or more numerical values ​​or numerical ranges, the term "about" should be understood to refer to all such values, including all values ​​within the range and to modify the range by extending the boundaries to above and below the listed values. Numerical ranges stated by endpoints include all values, such as all integers, included within the range, including fractions thereof (e.g., a statement of 1 to 5 includes 1, 2, 3, 4 and 5, and fractions thereof, such as 1.5, 2.25, 3.75, 4.1, etc.) and any range within the range. Example

[0313] The following examples have been included to provide guidance to those of ordinary skill in the art for practicing representative embodiments of the subject matter disclosed herein. Based on the present disclosure and the general level of skill in the art, it will be appreciated by the skilled person that the following examples are intended to be exemplary only, and that many variations, modifications, and changes may be employed without departing from the scope of the subject matter disclosed herein. The following descriptions and specific examples of the synthesis are intended only for illustrative purposes and are not to be construed as limiting in any way the compounds of the disclosure prepared by other methods.

[0314] Example 1

[0315] Stability of the prodrug in mouse skin homogenate and plasma

[0316] Mouse skin homogenate stability was performed using washed mouse skin or CD1 mouse plasma diluted 10-fold in 0.1M potassium phosphate buffer and homogenized using a tissue homogenizer. To evaluate the stability of the intact prodrug, 1 mL aliquots of skin homogenate or plasma were spiked with the prodrug to a final assay concentration of 20 μM. Spiked skin homogenate and plasma samples were incubated at 37°C in an orbital shaker for 1 h, and then the reaction was quenched in triplicate with three volumes of acetonitrile containing an internal standard (IS; losartan: 0.5 μM). The samples were vortexed for 30 s and centrifuged at 10,000 × g for 10 min at 4°C. 50 microliters of the supernatant were diluted with 50 μL of water and transferred to a 250 μL polypropylene vial sealed with a Teflon cap. The release of itaconic acid or methyl itaconate was measured by liquid chromatography tandem mass spectrometry (LC-MS / MS).

[0317] Example 2

[0318] Pharmacokinetics in mice

[0319] Male CD1 mice (25 g-30 g) were obtained from Harlan and maintained on a 12 h light-dark cycle with adlibitum access to food and water. IS-100-142 (Compound 5), MK939 (Compound 14) and MK941 (Compound 16) were administered via oral gavage at a molar equivalent dose of 10 mg / kg of monomethyl itaconate. Blood samples were collected at 0.25 h and 1 h after administration (n=3 for each time point). Mice were euthanized with carbon dioxide at designated time points after drug administration, and blood samples (~0.8 mL) were collected in heparinized microtubes by cardiac puncture. Blood samples were centrifuged at 3000×g for 10 min at a temperature of 4°C. Plasma samples (~300 μL) were collected in polypropylene tubes and stored at -80°C until bioanalysis. The naive experimentally tested samples were prepared using a 1:1 tdc-treated mouse model ... The calibration standards were prepared from the plasma of mice. Itaconate monomethyl ester standards and samples were extracted from the plasma by one-step protein precipitation using methanol (100% v / v) containing internal standard methyl succinate (5 μM). Aliquots of the supernatant (100 μL) were diluted with water (100 μL) and transferred to 250 μL polypropylene vials sealed with Teflon caps and analyzed via LC-MS / MS.

[0320] Example 3

[0321] Treatment of human keratinocytes with itaconate prodrugs

[0322] Neonatal human epidermal keratinocytes (NHEK) isolated from neonatal foreskin were seeded at a density of 100,000 cells per well and maintained in KGM supplemented with growth factors (KGM-GOLD Bullet Kit, #192060). Prodrugs were reconstituted in DMSO. NHEKs were pretreated with vehicle (0.1% DMSO) or prodrugs. After 2 days, NHEKs were treated with 50 μg / μL poly(I:C) for 24 h.

[0323] Example 4

[0324] RNA isolation and quantitative real-time PCR

[0325] Total RNA was isolated and purified from cultured NHEK using RNeasy Mini kit (Qiagen, Valencia, CA, #74106). After RNA purity and concentration were assessed using NanoDrop 2000UV-Vis spectrophotometer, RNA was converted to cDNA using reverse transcription kit and random hexamer primers (Applied Biosystems, #4368814). mRNA expression was determined by qRT-PCR using gene-specific, fluorophore-based TaqMan probes and universal master mix (Applied Biosystems, #4366072). qRT-PCR reactions were multiplexed using target probes and reference gene (RPLP0) probes. The relative mRNA change multiples were then quantified using the ΔΔCt method.

[0326] Example 5

[0327] Mouse

[0328] All adult wild-type (C57BL6 / J) mice were approximately 8.5 weeks old and obtained from Jackson Labs (#00664). All animals were maintained in facilities approved by AAALAC (Accreditation of Laboratory Animal Care International) at Johns Hopkins University. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Johns Hopkins under protocol #MO17M298.

[0329] Example 6

[0330] Itaconate prodrug treatment

[0331] Adult C57BL6 / J mice were treated during the refractory period (telogen) of hair dormancy to allow hair growth (anagen) to restart. To determine the reentry of the anagen phase, the mice were roughly observed for skin thickening and darkening. The mice were shaved on their dorsal sides, and the left half of the skin was surface treated with vehicle (DMSO) or prodrug (20% IS-100-142 (Compound 5)), with the right side untreated. The treatment regimen was once every other day for a total of 2 treatment cycles.

[0332] Example 7

[0333] Itaconate esters and derivatives / analogues for inducing hair growth

[0334] In one aspect, the presently disclosed subject matter relates to compounds that may be able to enhance hair growth. To this end, dimethyl itaconate was tested for its ability to induce a shift from the resting phase of the hair cycle (telogen) to the growth phase of the hair cycle (anagen) in wild-type mice. Figure 5 As shown in , 20% dimethyl itaconate effectively induced this transformation.

[0335] Next, it was tested whether itaconate derivatives, such as itaconate prodrugs, have this same ability. To screen compounds, compounds that behaved in vitro as itaconate were evaluated. First, the molecular role of dimethyl itaconate (DI) in attenuating the effects of dsRNA (PIC; polyinosinic-polycytidylic acid) in increasing TLR3, IL-6, and STAT3 expression was tested. Figure 6 As shown in , DI effectively inhibited those markers.

[0336] Next, the synthetic itaconate prodrugs were tested for their ability to perform similarly in an in vitro assay. Figure 4 , Compound 5 of Table 1 also effectively inhibited the same dsRNA response as DI. The method was the same as above, but dimethyl itaconate was used instead of the listed prodrug.

[0337] Finally, compound 5 was tested for its ability to induce hair growth as also observed for DI. Figure 7 This was indeed the case as shown in . Here, mice were treated as above except that the left side was treated with Compound 5 or DMSO and the right side was left untreated. The small amount of hair growth in the DMSO treated mice was due to the onset of the natural anagen cycle.

[0338] These results demonstrate the ability of itaconate and its derivatives / analogs to stimulate hair growth, such as the ability to transition from the telogen (resting phase) to the anagen (growth phase) of the hair cycle. The method should stimulate hair growth in many human use situations. These include male pattern hair loss or female pattern hair loss, where hair follicles predominate in the resting phase; and also include telogen effluvium, where similarly, the hair cycle enters the telogen phase prematurely and synchronously. In addition, the method should be useful for treating alopecia areata, where localized areas of the scalp also enter the telogen phase synchronously. As shown here, the therapy can be topically available, but it would also be predicted to be systemically effective.

[0339] Example 8

[0340] Compound (5) induces hair growth in mice

[0341] All adult wild-type (C57BL6 / J) mice were approximately 8.5 weeks old and obtained from Jackson Labs. Animals were fed a standard mouse diet. Results from the mouse model showed that compound 5 promoted the transition of hair follicles from the telogen (resting phase) to the anagen (growth phase) of the hair cycle ( Figure 8 ). Adult C57BL6 / J mice were treated during the refractory period (telogen) of hair dormancy to allow hair growth (anagen) to restart. To determine the reentry of the anagen phase, mice were grossly observed for skin thickening and darkening. Mice were shaved on their dorsal sides, and the right half of the skin was topically treated with vehicle (DMSO) or dimethyl itaconate (20%), or with 1% Compound 5, 2% Compound 5, or 5% Compound 5, with the left side untreated. The treatment regimen was once every other day for a total of 2 or 3 treatments with similar results.

[0342] Example 9

[0343] Compound (5) induces hair growth in mice to levels comparable to ruxolitinib and tofacitinib

[0344] Now mention Fig. 9 , Compound 5 induced hair growth in mice to levels comparable to ruxolitinib and tofacitinib, two potent JAK inhibitors known to successfully treat alopecia areata. Fig. 9 Mice were treated with ruxolitinib and tofacitinib as indicated, ie, 3% ruxolitinib, 3% tofacitinib, and 3% compound 5, each diluted in DMSO.

[0345] Example 10

[0346] In vitro data - mouse skin homogenate stability

[0347] Skin samples were diluted 10-fold in 0.1 M potassium phosphate buffer and homogenized using a polytron and a probe sonicator. To evaluate the stability of the intact prodrug over time, aliquots were prepared and the prodrug was spiked to a final assay concentration of 20 μM. The spiked samples were incubated at 37° C. in an orbital shaker for 1 h, and then the reaction was quenched with three volumes of acetonitrile containing an internal standard (IS; losartan: 0.5 μM). The samples were vortexed and centrifuged at 16,000 g for 5 min at 4° C. Fifty microliters of the supernatant were diluted with 50 μL of water and transferred to a 250 μL polypropylene vial sealed with a Teflon cap. The disappearance of the prodrug over time was monitored using liquid chromatography mass spectrometry (LC-MS). Fig.10 Mouse skin homogenate stability of representative prodrugs is shown; Fig.11 Shown is the release of active monomethyl itaconate (in skin homogenate) from a representative prodrug.

[0348] Embodiment 11

[0349] In vivo data - mouse skin penetration

[0350] Now mention Fig.12 , shows mouse skin penetration of IS-100-142 (Compound 5) (left) and monomethyl itaconate (right) in a hair loss model. After topical application in DMSO (dose: 5% w / v), levels of both intact itaconate and monomethyl itaconate were higher in the skin than in plasma.

[0351] References

[0352] All publications, patent applications, patents and other references mentioned in the specification are indicative of the level of those skilled in the art to which the subject matter disclosed herein belongs. All publications, patent applications, patents and other references are hereby incorporated by reference to the same extent as if each individual publication, patent application, patent and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that although many patent applications, patents and other references are referred to herein, such references do not constitute an admission that any of these documents form part of the common general knowledge in the art.

[0353] International PCT Patent Application Publication No. WO2017142855, Artyomov et al., Immunomodulatory Agents and Methods of Use Thereof, published on August 24, 2017;

[0354] International PCT Patent Application Publication No. WO2019036509, Artyomov et al., Methods and Compositions for the Treatment of Diseases Associated with Cancer, Inflammation, or Immune Response, published on February 21, 2019;

[0355] O'Neill, LAJ and Artyomov, MN, Itaconate: the poster child of metabolic reprogramming in macrophage function, Nature Reviews: Immunology, 19, 273-281 (2019).

[0356] Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. A method of inducing hair growth or treating an inflammatory skin condition, or an immune activation condition (adaptive or innate), or other condition associated with hair loss in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I): in: R1 and R2 may be the same or different and are each independently selected from one or more of the following and combinations thereof: (a) -OR3, wherein R3 is H or a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; (b) wherein n is an integer selected from 1, 2, 3 and 4; R4 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group or -OR5, wherein R5 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; (c) wherein m is an integer selected from 1, 2, 3 and 4; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; and R6 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; (d) Wherein R7 is selected from: (i) -C(=O)-O-R8, wherein R8 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; (ii) Wherein R9 is H or C1-C4 straight or branched chain unsubstituted or substituted hydrocarbon group; R 10 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; R 11 and R 12 are each independently H or a protecting group; and R 13 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; (iii) wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; R 11 and R 12 Each independently is H or a protecting group; R 14 is H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; and R 15 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group; and (iv) Where R 16 and R 17 R is independently selected from H, C1-C4 straight or branched unsubstituted or substituted hydrocarbon group and protecting group; 18 is an aromatic group; (e) Where R 19 is a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; (f) wherein u is an integer selected from 1, 2, 3 and 4; R 20 is H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; and R 21 Yes-OR 22 , where R 22 is a C1-C6 straight or branched unsubstituted or substituted hydrocarbon group or -NR 23 R 24 , where R 23 and R 24 Each is independently H or a C1-C4 straight or branched unsubstituted or substituted hydrocarbon group; and pharmaceutically acceptable salts thereof.

2. The method according to claim 1, wherein: (a) R1 is -OR3 and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, (b) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, (c) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, (d) R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, (e)R1 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, (f) R1 is wherein R7 is -C(=O)-O-R8 and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, (g) R1 is Where R7 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, (h) R1 is Where R7 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, as well as (i) R1 is Where R7 is and R2 is selected from -OR3, wherein R7 is selected from -C(=O)-O-R8, and pharmaceutically acceptable salts thereof.

3. The method according to claim 1, wherein: (ai) R1 is -OH and R2 is selected from: -OH, wherein R7 is -C(=O)-O-R8; (a-ii) R1 is -OR3 and R2 is selected from: Wherein R7 is selected from -C(=O)-O-R8、 (b) R1 is and R2 is selected from: <h2 style=";text-align:left;direction:ltr">-OR3、<h2 style=";text-align:left;direction:ltr"> (c) R1 is and R2 is -OR3; (d) R1 is and R2 is selected from: -OR3 and (e)R1 is wherein R7 is -C(=O)-O-R8 and R2 is -OR3; (f) R1 is Where R7 is and R2 is -OR3; (g) R1 is Where R7 is and R2 is -OR3; (h) R1 is Where R7 is and R2 is -OR3; and (i) R1 is and R2 is -OR3.

4. The method according to any one of claims 1 to 3, wherein R3, R4, R5, R6, R8, R9, R 10 , R 13 , R 15 and R 22 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane.

5. The method according to any one of claims 1 to 4, wherein R9, R 14 , R 16 , R 17 , R 19 , R 20 , R 23 and R 24 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

6. The method according to any one of claims 1 to 5, wherein the protecting group is selected from tert-butoxycarbonyl (boc), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), 9-fluorenylmethoxycarbonyl (Fmoc) group, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-toluenesulfonyl (Ts), Troc (trichloroethyl chloroformate), (4-nitrophenyl)sulfonyl (Nosyl) and nitrophenylsulfonyl (Nps).

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

8. The method according to any one of claims 1 to 7, wherein: (ai) R1 is -OH and R2 is selected from: -OH(1)、 (a-ii) R1 is selected from -OCH3, -OCH(CH3)2, and -OC(CH3)3 and R2 is selected from: (b) R1 is and R2 is -OCH3(5,6) or (c) R1 is and R2 is -OCH3(12, 13); (d) R1 is and R2 is selected from: -OCH3(11) and (e)R1 is and R2 is -OCH3(14); (f) R1 is and R2 is -OCH3(17, 19); (g) R1 is and R2 is -OCH3(15, 16); (h) R1 is and R2 is -OCH3(18, 20); as well as (i) R1 is And R2 is -OCH3(3,4).

9. The method according to any one of claims 1 to 8, wherein the compound of formula (I) is selected from:

10. The method according to claim 1, further comprising a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

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