Compounds for the treatment of hair loss

Abstract

Described in the present disclosure are compounds represented by the following formula: Also described herein are uses, methods, and medicaments relating to the treatment of conditions or diseases, such as mammalian hair growth. TIFF2025501324000062.tif4559

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 294,769, filed December 29, 2021, the entire contents of which are expressly incorporated by reference. [Background technology]

[0002] Hair follicle stem cells (HFSCs) undergo repeated periods of quiescence (telogen) punctuated by short periods of proliferation that correlate with the initiation of the hair cycle (the transition from telogen to anagen). It is well known that HFSC proliferation or activation is a prerequisite for the progression of the hair cycle. Despite advances in treatment options, baldness and alopecia remain unsuccessfully treatable conditions for many individuals. Some of the existing treatments are inconvenient for users, and others require surgical intervention or invasive procedures. Further therapies are needed. Summary of the Invention [Means for solving the problem]

[0003] Some embodiments are represented by Formula 1: [ka] or its E / Z isomer, wherein R is C 2-12 -Alkyl-, C 4-12 -alkyl-O-alkyl, or optionally substituted C 6-12 -aryl-; Ph is optionally substituted phenyl.

[0004] Some embodiments include pharmaceutical compositions comprising the compounds described herein, in some embodiments, the pharmaceutical compositions are for treating a disease or disorder, such as a disease or disorder that affects or is related to hair growth.

[0005] Some embodiments include pharmaceutical compositions for hair growth comprising a compound described herein.

[0006] Some embodiments include a method of growing hair comprising administering a compound described herein to an area of ​​mammalian skin where hair growth is intended.

[0007] Some embodiments include the use of a compound described herein in the manufacture of a medicament for hair growth.

[0008] Some embodiments include the use of a compound described herein in the manufacture of a medicament for treating a disease or disorder.

[0009] Some embodiments include a method of growing hair comprising administering a compound described herein to a mammal in need of hair growth.

[0010] Some embodiments include a method of treating a disease or disorder, such as a disorder affecting hair growth, comprising administering a compound described herein to a mammal in need of treatment. In some embodiments, the disorder is alopecia or baldness.

[0011] Some embodiments include kits that include a compound described herein and a label with instructions for administering the compound for a use described herein, such as for promoting hair growth. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Unless otherwise indicated, any reference herein to a compound by structure, name, or other means includes pharma- ceutically acceptable salts, such as sodium salts, potassium salts, ammonium salts, and the like; prodrugs, such as ester prodrugs; alternative solid forms, such as polymorphs, solvates, hydrates, and the like; deuterium-modified forms; Z and E olefin isomers; tautomers; or any other species that can be readily converted to the compounds described herein under the conditions in which the compounds are used as described herein. In some embodiments, the compounds contain more deuterium than naturally occurring. In some embodiments, one or more hydrogen atoms on the compounds are replaced with deuterium, and the replacement positions with deuterium are at least 50%, at least 80%, at least 90%, at least 95%, or at least 99% of the compounds. The E / Z isomers of the structures depicted herein are specifically contemplated.

[0013] Unless otherwise indicated, when a compound or chemical structure feature (such as alkyl or aryl) is referred to as being "optionally substituted," it includes the "substituted" feature, meaning a feature that has no substituents (i.e., is not substituted) or a feature that has one or more substituents. The term "substituent" has its broadest meaning known to those of skill in the art and includes a moiety that occupies a site normally occupied by one or more hydrogen atoms attached to the parent compound or structural feature. In some embodiments, the substituent can be a conventional organic moiety known in the art and can have a molecular weight (e.g., the sum of the atomic weights of the atoms of the substituent) of about 15 g / mol to about 50 g / mol, about 15 g / mol to about 100 g / mol, about 15 g / mol to about 150 g / mol, about 15 g / mol to about 200 g / mol, about 15 g / mol to about 300 g / mol, or about 15 g / mol to about 500 g / mol. In some embodiments, the substituents include or consist of 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, each of which may independently be N, O, S, P, Si, F, Cl, Br, or I; with the proviso that the substituents contain one C, N, O, S, P, Si, F, Cl, Br, or I atom. Examples of the substituents include, but are not limited to, those having the empirical formula:1-12 H 3-29 O 0-4 N 0-4 S 0-4 F 0-25 Cl 0-5 Si 0-3 P 0-3 、C 0-12 H 0-29 O 1-4 N 0-4 S 0-4 F 0-25 Cl 0-5 Si 0-3 P 0-3 、C 0-12 H 0-29 O 0-4 N 1-4 S 0-4 F 0-25 Cl 0-5 Si 0-3 P 0-3 、C 0-12 H 0-29 O 0-4 N 0-4 S 1-4 F 0-25 Cl 0-5 Si 0-3 P 0-3 、C 0-12 H 0-29 O 0-4 N 0-4 S 0-4 F 1-25 Cl 0-5 Si 0-3 P 0-3 、C 0-12 H 0-29 O 0-4 N 0-4 S 0-4 F 0-25 Cl 1-5 Si 0-3 P 0-3 、C 0-12 H 0-29 O 0-4 N 0-4 S 0-4 F 0-25 Cl 0-5 Si 1-3 P 0-3 、C 0-12 H 0-29 O 0-4 N 0-4 S 0-4 F 0-25 Cl 0-5 Si0-3 P 1-3 、C 1-6 H 3-16 O 0-4 N 0-4 S 0-4 F 0-13 Cl 0-3 Si 0-3 P 0-3 、C 0-6 H 0-16 O 1-4 N 0-4 S 0-4 F 0-13 Cl 0-3 Si 0-3 P 0-3 、C 0-6 H 0-17 O 0-4 N 1-4 S 0-4 F 0-13 Cl 0-3 Si 0-3 P 0-3 、C 0-6 H 0-17 O 0-4 N 0-4 S 1-4 F 0-13 Cl 0-3 Si 0-3 P 0-3 、C 0-6 H 0-17 O 0-4 N 0-4 S 0-4 F 1-13 Cl 0-3 Si 0-3 P 0-3 、C 0-6 H 0-17 O 0-4 N 0-4 S 0-4 F 0-13 Cl 1-3 Si 0-3 P 0-3 、C 0-6 H 0-17 O 0-4 N 0-4 S 0-4 F 0-13 Cl 0-3 Si 1-3 P 0-3 、C 0-6 H 0-17 O 0-4 N 0-4 S 0-4 F0-13 Cl 0-3 Si 0-3 P 1-3 、C 1-12 H 3-29 O 0-4 N 0-4 S 0-4 F 0-25 Cl 0-5 P 0-3 、C 1-12 H 3-27 O 0-4 N 0-2 S 0-2 F 0-25 Cl 0-5 P 0-1 、C 1-12 H 3-27 O 0-4 N 0-2 、C 1-12 H 3-25 O 0-4 、C 1-12 H 3-27 N 0-2 、C 1-9 H 3-21 O 0-4 N 0-2 S 0-2 F 0-19 Cl 0-5 P 0-1 、C 1-9 H 3-19 F 0-19 、C 1-9 H 3-21 O 0-4 N 0-2 、C 1-9 H 3-19 O 0-4 、C 1-9 H 3-21 N 0-2 、C 1-6 H 3-15 O 0-3 N 0-2 S 0-2 F 0-13 Cl 0-5 P 0-1 、C 1-6 H 3-13 F 0-13 、C 1-6 H 3-15 O 0-4 N 0-2 、C 1-6 H 3-13 O 0-4 、C 1-6 H3-15 N 0-2 , C 1-3 H 3-9 O 0-3 N 0-2 S 0-2 F 0-13 Cl 0-5 P 0-1 , C 1-3 H 3-7 F 0-7 , C 1-3 H 3-9 O 0-3 N 0-2 , C 1-3 H 3-7 O 0-3 , C 1-3 H 3-9 N 0-2 , F, Cl, Br, I, OH, OR A , S.H., S.R. A , NH2, NHR A , N.R. A R B , CF3, CN, carboxylic acid, optionally substituted carboxylic acid ester; or optionally substituted branched or linear C 1-3 Alkyl (e.g., -CH3, -C2H5, -C3H7), optionally substituted branched, straight chain or cyclic C 3-6 Alkyl (e.g., -C3H7, -C4H9, -C5H 11 , -CH 13 Optionally substituted branched C, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. 2-6 Alkyl or optionally substituted straight chain C 1-6 Optionally substituted C such as alkyl 1-6Compounds represented by the following formulae are included: alkyl; alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, carbocyclic ring, heterocyclic ring, hydroxyalkyl, hydroxyalkoxy, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamide, and the like.

[0014] For convenience, the term "molecular weight" is used in reference to a part or portion of a molecule, even if not a complete molecule, and refers to the sum of the atomic weights of the atoms in the part or portion of the molecule.

[0015] As used herein, the term "alkyl" has its broadest meaning as generally understood in the art and may include moieties consisting of carbon and hydrogen without double or triple bonds. Alkyl may be a straight chain alkyl, branched alkyl, cycloalkyl, or combinations thereof, and in some embodiments may contain 1 to 35 carbon atoms. In some embodiments, alkyl is any of the C alkyls such as methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), n-butyl (-CH2CH2CH2CH3), n-pentyl (-CH2CH2CH2CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), etc. 1-10 Straight chain alkyl; C3H7 (e.g., iso-propyl), C4H9 (e.g., branched butyl isomers), C5H 11 (e.g., branched pentyl isomers), C6H 13 (e.g., branched hexyl isomers), C7H 15 (e.g., branched heptyl isomers) etc. 3-10Branched alkyl; C3H5 (e.g., cyclopropyl), C4H7 (e.g., cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.), C5H9 (e.g., cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.), C6H 11 (e.g., cyclohexyl isomers), C7H 13 (e.g., cycloheptyl isomers) etc. 3-10 It may include cycloalkyl and the like.

[0016] With respect to formula 1, Ph is 0, 1, 2, 3, 4, or 5 of F, Cl, Br, I, OH, CN, CF3, C 1-6 Alkyl (-CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 etc.), or C 1-6 H 3-13 and optionally substituted phenyl, such as phenyl substituted with a substituent such as O(-C(=O)CH3 or -CH2OCH3, etc.).

[0017] In some embodiments, Ph is phenyl substituted with 1, 2, 3, 4, or 5 trifluoromethyl groups, such as 1 or 2 trifluoromethyl groups. In some embodiments, Ph is trifluoromethylphenyl. In some embodiments, Ph is di(trifluoromethyl)phenyl.

[0018] In some embodiments, Ph is [ka] It is.

[0019] In some embodiments, Ph is [ka] It is.

[0020] Some embodiments are represented by the formula 2 [ka] This includes compounds of the formula:

[0021] Some embodiments are represented by formula 3 [ka] This includes compounds of the formula:

[0022] With respect to formula 1, 2, or 3, R is -C2H4- (e.g., -CH2CH2-), -C3H6- (e.g., -CH2CH2CH2-), -C4H8- (e.g., -CH2CH2CH2CH2- or -CH2CH(CH3)CH2-), -C5H 10 - (e.g., -CH2CH2CH2CH2CH2- or -CH2C(CH3)2CH2-) 2-5 -Alkyl-, or -CH 12 -, -C7H 14 -, -C8H 16 -, -C9H 18 -, -C 10 H 20 -, -C 11 H 22 -, -C 12 H 24 -, etc. C 6-12 -Alkyl-containing C 2-12 -alkyl-; or C4-alkyl-O-alkyl- (e.g., -CH2CH2OCH2CH2-), C5-alkyl-O-alkyl- (e.g., -CH2CH2CH2OCH2CH2-), C6-alkyl-O-alkyl-, C7-alkyl-O-alkyl-, etc. 4-8 -Alkyl-O-alkyl-, or C8-Alkyl-O-alkyl-, C9-Alkyl-O-alkyl-, C 10 -alkyl-O-alkyl-, C 11 -alkyl-O-alkyl-, C 12 -alkyl-O-alkyl- etc. 8-12 -alkyl-O-alkyl- 4-12 -alkyl-O-alkyl-; or optionally substituted C, such as optionally substituted phenyl or optionally substituted naphthyl. 6-12 It is aryl.

[0023] With respect to Formula 1, in some embodiments, R is C 2-12 -alkyl-.

[0024] With respect to Formula 1, in some embodiments, R is C 2-5 -alkyl-.

[0025] With respect to Formula 1, in some embodiments, R is -C2H4-.

[0026] With respect to Formula 1, in some embodiments, R is -C3H6-.

[0027] With respect to Formula 1, in some embodiments, R is -C4H8-.

[0028] With reference to Formula 1, in some embodiments, R is -CH 10 -It is.

[0029] With reference to Formula 1, in some embodiments, R is -CH 12 -It is.

[0030] With reference to Formula 1, in some embodiments, R is -CH 14 -It is.

[0031] With reference to Formula 1, in some embodiments, R is -CH 16 -It is.

[0032] With reference to Formula 1, in some embodiments, R is -CH 18 -It is.

[0033] With respect to Formula 1, in some embodiments, R is -C 10 H 20 -It is.

[0034] With respect to Formula 1, in some embodiments, R is -C 11 H 22 -It is.

[0035] With respect to Formula 1, in some embodiments, R is -C 12 H 24 -It is.

[0036] With respect to Formula 1, in some embodiments, R is C 4-12 -alkyl-O-alkyl-.

[0037] With respect to Formula 1, in some embodiments, R is C 4-8 -alkyl-O-alkyl-.

[0038] With respect to formula 1, in some embodiments, R is C4-alkyl-O-alkyl-.

[0039] With respect to formula 1, in some embodiments, R is C5-alkyl-O-alkyl-.

[0040] With respect to Formula 1, in some embodiments, R is C-alkyl-O-alkyl-.

[0041] With respect to Formula 1, in some embodiments, R is C7-alkyl-O-alkyl-.

[0042] With respect to Formula 1, in some embodiments, R is C-alkyl-O-alkyl-.

[0043] With respect to Formula 1, in some embodiments, R is C9-alkyl-O-alkyl-.

[0044] With respect to Formula 1, in some embodiments, R is C 10 -alkyl-O-alkyl-.

[0045] With respect to Formula 1, in some embodiments, R is C 11 -alkyl-O-alkyl-.

[0046] With respect to Formula 1, in some embodiments, R is C 12-alkyl-O-alkyl-.

[0047] With respect to formula 1, in some embodiments, R is an optionally substituted phenyl.

[0048] With respect to formula 1, in some embodiments, R is an optionally substituted naphthyl.

[0049] With respect to Formula 2, in some embodiments, R is C 2-12 -alkyl-.

[0050] With respect to Formula 2, in some embodiments, R is C 2-5 -alkyl-.

[0051] With respect to formula 2, in some embodiments, R is -C2H4-.

[0052] With respect to formula 2, in some embodiments, R is -C3H6-.

[0053] With respect to formula 2, in some embodiments, R is -C4H8-.

[0054] With respect to Formula 2, in some embodiments, R is -CH 10 -It is.

[0055] With respect to Formula 2, in some embodiments, R is -CH 12 -It is.

[0056] With respect to Formula 2, in some embodiments, R is -CH 14 -It is.

[0057] With respect to Formula 2, in some embodiments, R is -CH 16 -It is.

[0058] With respect to Formula 2, in some embodiments, R is -CH 18 -It is.

[0059] With respect to Formula 2, in some embodiments, R is -C 10 H 20 -It is.

[0060] With respect to Formula 2, in some embodiments, R is -C 11 H 22 -It is.

[0061] With respect to Formula 2, in some embodiments, R is -C 12 H 24 -It is.

[0062] With respect to Formula 2, in some embodiments, R is C 4-12 -alkyl-O-alkyl-.

[0063] With respect to Formula 2, in some embodiments, R is C 4-8 -alkyl-O-alkyl-.

[0064] With respect to formula 2, in some embodiments, R is C4-alkyl-O-alkyl-.

[0065] With respect to formula 2, in some embodiments, R is C5-alkyl-O-alkyl-.

[0066] With respect to formula 2, in some embodiments, R is C-alkyl-O-alkyl-.

[0067] With respect to formula 2, in some embodiments, R is C7-alkyl-O-alkyl-.

[0068] With respect to formula 2, in some embodiments, R is C-alkyl-O-alkyl-.

[0069] With respect to formula 2, in some embodiments, R is C9-alkyl-O-alkyl-.

[0070] With respect to Formula 2, in some embodiments, R is C 10-alkyl-O-alkyl-.

[0071] With respect to Formula 2, in some embodiments, R is C 11 -alkyl-O-alkyl-.

[0072] With respect to Formula 2, in some embodiments, R is C 12 -alkyl-O-alkyl-.

[0073] With respect to formula 2, in some embodiments, R is an optionally substituted phenyl.

[0074] With respect to formula 2, in some embodiments, R is an optionally substituted naphthyl.

[0075] With respect to Formula 3, in some embodiments, R is C 2-12 -alkyl-.

[0076] With respect to Formula 3, in some embodiments, R is C 2-5 -alkyl-.

[0077] With respect to formula 3, in some embodiments, R is -C2H4-.

[0078] With respect to formula 3, in some embodiments, R is -C3H6-.

[0079] With respect to formula 3, in some embodiments, R is -C4H8-.

[0080] With respect to Formula 3, in some embodiments, R is -CH 10 -It is.

[0081] With respect to Formula 3, in some embodiments, R is -CH 12 -It is.

[0082] With respect to Formula 3, in some embodiments, R is -CH 14 -It is.

[0083] With respect to Formula 3, in some embodiments, R is -CH 16 -It is.

[0084] With respect to Formula 3, in some embodiments, R is -CH 18 -It is.

[0085] With respect to Formula 3, in some embodiments, R is -C 10 H 20 -It is.

[0086] With respect to Formula 3, in some embodiments, R is -C 11 H 22 -It is.

[0087] With respect to Formula 3, in some embodiments, R is -C 12 H 24 -It is.

[0088] With respect to Formula 3, in some embodiments, R is C 4-12 -alkyl-O-alkyl-.

[0089] With respect to Formula 3, in some embodiments, R is C 4-8 -alkyl-O-alkyl-.

[0090] With respect to formula 3, in some embodiments, R is C4-alkyl-O-alkyl-.

[0091] With respect to formula 3, in some embodiments, R is C5-alkyl-O-alkyl-.

[0092] With respect to formula 3, in some embodiments, R is C-alkyl-O-alkyl-.

[0093] With respect to formula 3, in some embodiments, R is C7-alkyl-O-alkyl-.

[0094] With respect to formula 3, in some embodiments, R is C-alkyl-O-alkyl-.

[0095] With respect to formula 3, in some embodiments, R is C9-alkyl-O-alkyl-.

[0096] With respect to Formula 3, in some embodiments, R is C 10 -alkyl-O-alkyl-.

[0097] With respect to Formula 3, in some embodiments, R is C 11 -alkyl-O-alkyl-.

[0098] With respect to Formula 3, in some embodiments, R is C 12 -alkyl-O-alkyl-.

[0099] With respect to formula 3, in some embodiments, R is an optionally substituted phenyl.

[0100] With respect to formula 3, in some embodiments, R is an optionally substituted naphthyl.

[0101] Some embodiments include the compound: [ka] Includes.

[0102] Some embodiments include the compound: [ka] Includes.

[0103] Some embodiments include the compound: [ka] Includes.

[0104] Some embodiments include the compound: [ka] Includes.

[0105] Some embodiments include the compound: [ka] Includes.

[0106] Some embodiments include the compound: [ka] Includes.

[0107] Some embodiments include the compound: [ka] Includes.

[0108] Some embodiments include the compound: [ka] Includes.

[0109] Some embodiments include the compound: [ka] Includes.

[0110] Some embodiments include the compound: [ka] Includes.

[0111] Some embodiments include the compound: [ka] Includes.

[0112] Some embodiments include the compound: [ka] Includes.

[0113] The compounds described herein are useful for hair growth. For example, certain compounds described herein can be administered to the skin of a mammal in areas where hair growth is intended.

[0114] In some aspects, the compounds of the present disclosure are mitochondrial pyruvate oxidation (MPO) inhibitors. In some embodiments, the compounds described herein may inhibit mitochondrial pyruvate carrier (MPC). In some embodiments, the MPO inhibitor is an MPC inhibitor. In some aspects, inhibition of MPO in cells enhances the production of lactic acid in cells and / or enhances the activity of lactate dehydrogenase (LDH) in cells, which has the effect of promoting hair growth. In some aspects, the present disclosure provides a method of promoting hair growth or treating a hair growth condition or disorder, such as baldness or alopecia, comprising administering to a patient (e.g., topically, such as in a pharmaceutical composition formulated for topical application) an MPO inhibitor, such as a compound of the present disclosure. In certain embodiments, the disclosure provides methods of promoting hair growth or treating a hair growth condition or disorder, such as baldness or alopecia, comprising administering to a patient an MPC inhibitor, such as a compound of the disclosure (e.g., topically, such as in a pharmaceutical composition formulated for topical application). In some embodiments, inhibition of MPO or MPC in cells enhances the production of lactic acid and / or enhances the activity of LDH in cells, which has the effect of promoting hair growth.

[0115] For purposes of this disclosure, the terms "treat," "treatment," or similar terms (such as "modulation") include the cure, mitigation, treatment, prevention of disease in humans or other animals, or other effects associated with a "drug" as defined in 21 USC 321(g).

[0116] In some embodiments, the compounds herein may exhibit higher hydrolysis rates (at least about 1.1-fold higher, at least about 1.5-fold higher, at least about 2-fold higher, at least about 5-fold higher, at least about 10-fold higher, at least about 50-fold higher, at least about 100-fold higher, at least about 500-fold higher, at least about 1,000-fold higher, at least about 10,000-fold higher, about 1.1-2-fold higher, about 2-4-fold higher, about 4-6-fold higher, about 6-8-fold higher, about 8-10-fold higher, about 1.1-10-fold higher, about 10-100-fold higher, about 100-1,000-fold higher, or about 1,000-10,000-fold higher rates, etc.) compared to conventional alkyl (ethyl or methyl) esters. In some embodiments, the compounds of the present disclosure may achieve high concentrations of hydrolyzed drug (carboxylic acid) in a skin homogenate assay.

[0117] It is understood that topical delivery of active pharmaceutical ingredients (API) for skin application is composed of a balance between lipophilicity and hydrophilicity. It is believed that a compound with lipophilicity as a prodrug and hydrophilicity as the corresponding free acid API can achieve the goal of reaching the desired skin layer target (e.g., hair follicle). The hydrolysis rate of the prodrug in the skin layer can be adjusted to achieve the desired result.

[0118] In some embodiments, the compounds of the present disclosure hydrolyze to release an active free carboxylic acid. In some aspects, the compounds of the present disclosure hydrolyze to release an active free carboxylic acid at an accelerated rate compared to conventional prodrugs (e.g., JXL082). In some embodiments, the rate of hydrolysis can be beneficial for delivery of active pharmaceutical ingredients to promote hair growth.

[0119] [ka]

[0120] In some aspects, the prodrug compounds of the present disclosure hydrolyze faster in human skin homogenates than known prodrugs, such as JXL082. In some embodiments, the concentration of carboxylic acid (API) released by the prodrugs of the present disclosure is at least about 150% to about 20,000% greater than the amount released by conventional prodrugs, such as JXL082. In some embodiments, the concentration of carboxylic acid (API) released by a prodrug of the present disclosure is at least about 150-300% greater, about 300-500% greater, about 500-1000% greater, about 1000-2000% greater, about 2000-4000% greater, about 4000-7000% greater, about 7000-10000% greater, about 10000-15000% greater, or about 15000-20000% greater, or any value within a range bounded by any of these ranges, than the amount released by a conventional prodrug, such as JXL082.

[0121] The following compounds were prepared by adapting the methods described in PCT / US21 / 39501, filed June 29, 2021, entitled "Compositions and Methods for Regulating Hair Growth," Attorney Docket No. UCH-22825 (32246.22825) (Examples 5-14, pages 73-88).

[0122] [ka]

[0123] 1 H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.48 (s, 1H), 8.46 (dd, J = 4.7, 1.5 Hz, 1H), 8.17 (dd, J = 8.0, 1.5 Hz, 1H), 7.81 (s, 1H), 7.78 (s, 2H), 7.31 (dd, J = 8.0, 4.7 Hz, 1H), 5.68 (s, 2H), 4.17 (s, 2H), 2.28 (s, 1H), 1.33 (s, 6H). 1313C NMR (125 MHz, CDCl3) δ 163.2, 147.6, 145.7, 145.5, 138.4, 133.1, 132.4 (q, 2 J C-F = 33.6 Hz, 2C), 127.9 (d, 3 J C-F = 4.3 Hz), 127.7, 122.9 (q, 1 J C-F = 273.0 Hz, 2C), 122.4 (p, 3 J C-F = 3.8 Hz, 2C), 120.3, 119.1, 117.4, 109.3, 96.2, 73.5, 69.9, 48.3, 26.1 (2C).

[0124]

Chem.

[0125] 1 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 8.46 - 8.45 (m, 2H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.60 (s, 1H), 7.56 - 7.55 (m, 1H), 7.45 - 7.44 (m, 2H), 7.29 (dd, J = 8.0, 4.7 Hz, 1H), 5.61 (s, 2H), 4.16 (s, 2H), 2.27 (br s, 1H), 1.33 (s, 6H). 13 13C NMR (125 MHz, CDCl3) δ 163.4, 147.7, 145.6, 145.5, 136.8, 133.5, 131.4 (q, 2 J C-F = 32.1 Hz), 131.0, 129.6, 127.5, 125.2 (q, 3 J C-F = 3.6 Hz), 124.6 (q, 3 J C-F = 3.8 Hz), 123.8 (q, 1 JC-F = 272.5 Hz), 120.3, 118.9, 117.5, 109.0, 95.6, 73.5, 69.9, 48.6, 26.1 (2C).

[0126]

Chem.

[0127] 1 1H NMR (500 MHz, CDCl3) δ 8.65 (s, 1H), 8.51 (d, J = 0.5 Hz, 1H), 8.48 (dd, J = 4.7, 1.5 Hz, 1H), 8.20 (dd, J = 7.9, 1.5 Hz, 1H), 7.82 (s, 1H), 7.77 (s, 2H), 7.34 (dd, J = 8.0, 4.7 Hz, 1H), 5.69 (s, 2H), 4.46 - 4.44 (m, 2H), 3.96 - 3.94 (m, 2H), 2.12 - 2.04 (m, 1H). 13 13C NMR (125 MHz, CDCl3) δ 163.5, 147.6, 145.8, 145.6, 138.4, 133.1, 132.4 (q, 2 J C-F = 33.4 Hz, 2C), 127.9 (d, 3 J C-F = 3.8 Hz), 127.7, 122.9 (q, 1 J C-F = 272.8 Hz, 2C), 122.5 (p, 3 J C-F = 3.7 Hz, 2C), 120.3, 119.1, 117.5, 109.3, 96.2, 67.7, 61.0, 48.4.

[0128]

Chem.

[0129] 11H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 8.50 (s, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 8.21 (dd, J = 8.1, 1.5 Hz, 1H), 7.82 (s, 1H), 7.77 (s, 2H), 7.33 (dd, J = 8.0, 4.7 Hz, 1H), 5.69 (s, 2H), 4.48 - 4.46 (m, 2H), 3.84 - 3.82 (m, 2H), 3.76 (t, J = 4.5 Hz, 2H), 3.67 (t, J = 4.4 Hz, 2H), 2.17 (br s, 1H). 13 13C NMR (125 MHz, CDCl3) δ 163.3, 147.6, 145.7, 145.4, 138.4, 133.0, 132.4 (q, 2 J C-F = 33.9 Hz, 2C), 127.9 (d, 3 J C-F = 2.8 Hz), 127.7, 122.9 (q, 1 J C-F = 273.2 Hz, 2C), 122.4 (p, 3 J C-F = 3.8 Hz, 2C), 120.3, 119.0, 117.5, 109.3, 96.5, 72.6, 68.8, 65.2, 61.8, 48.3.

[0130]

Chem.

[0131] 11H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.49 (s, 1H), 8.47 (d, J = 3.2 Hz, 1H), 8.19 (dd, J = 8.0, 1.4 Hz, 1H), 7.82 (s, 1H), 7.77 (s, 2H), 7.33 (dd, J = 7.9, 4.6 Hz, 1H), 5.69 (s, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.79 (t, J = 5.9 Hz, 2H), 2.00 (p, J = 6.0 Hz, 2H), 1.90 (br s, 1H). 13 13C NMR (125 MHz, CDCl3) δ 163.6, 147.6, 145.7, 145.3, 138.4, 133.0, 132.4 (q, 2 J C-F = 33.9 Hz, 2C), 127.9 (d, 3 J C-F = 2.8 Hz), 127.7, 122.9 (q, 1 J C-F = 273.0 Hz, 2C), 122.4 (p, 3 J C-F = 3.6 Hz, 2C), 120.3, 119.0, 117.5, 109.3, 96.5, 63.1, 59.0, 48.4, 31.6.

[0132]

Chem.

[0133] 11H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.49 (d, J = 0.5 Hz, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 8.19 (dd, J = 8.1, 1.5 Hz, 1H), 7.82 (s, 1H), 7.77 (s, 2H), 7.33 (dd, J = 8.0, 4.7 Hz, 1H), 5.69 (s, 2H), 4.16 (s, 2H), 3.43 (s, 2H), 2.08 (br s, 1H), 1.01 (s, 6H). 13 13C NMR (125 MHz, CDCl3) δ 163.7, 147.6, 145.7, 145.4, 138.4, 132.9, 132.4 (q, 2 J C-F = 33.9 Hz, 2C), 127.9 (d, 3 J C-F = 4.8 Hz), 127.7, 122.9 (q, 1 J C-F = 273.0 Hz, 2C), 122.4 (p, 3 J C-F = 3.8 Hz, 2C), 120.3, 119.1, 117.3, 109.3, 96.4, 71.0, 68.2, 48.3, 36.6, 21.4 (2C).

[0134]

Chem.

[0135] 11H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.48 (s, 1H), 8.46 (dd, J = 4.7, 1.5 Hz, 1H), 8.20 (dd, J = 8.0, 1.4 Hz, 1H), 7.81 (s, 1H), 7.77 (s, 2H), 7.32 (dd, J = 7.9, 4.7 Hz, 1H), 5.69 (s, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.68 (t, J = 6.5 Hz, 2H), 1.79 (p, J = 6.9 Hz, 2H), 1.67 - 1.48 (m, 5H) 13 13C NMR (125 MHz, CDCl3) δ 163.3, 147.6, 145.7, 145.0, 138.5, 132.8, 132.4 (q, 2 J C-F = 33.9 Hz, 2C), 127.9 (d, 3 J C-F = 3.5 Hz), 127.7, 122.9 (q, 1 J C-F = 272.8 Hz, 2C), 122.4 (p, 3 J C-F = 3.8 Hz, 2C), 120.3, 119.0, 117.6, 109.3, 96.9, 66.2, 62.6, 48.3, 32.3, 28.4, 22.2.

[0136]

Chem.

[0137] 11H NMR (500 MHz, CDCl3) δ 8.60 (s, 1H), 8.46 (s, 2H), 8.15 (d, J = 7.4 Hz, 1H), 7.60 (s, 1H), 7.56 - 7.55 (m, 1H), 7.47 - 7.45 (m, 2H), 7.30 (dd, J = 7.9, 4.6 Hz, 1H), 5.62 (s, 2H), 4.43 (t, J = 4.5 Hz, 2H), 3.94 (t, J = 4.5 Hz, 2H), 2.36 (br s, 1H). 13 13C NMR (125 MHz, CDCl3) δ 163.7, 147.7, 145.7, 145.6, 136.8, 133.6, 131.4 (q, 2 J C-F = 32.4 Hz), 131.0 (d, 4 J C-F = 0.8 Hz), 129.6, 127.5, 125.3 (q, 3 J C-F = 3.8 Hz), 124.6 (q, 3 J C-F = 3.8 Hz), 123.8 (q, 1 J C-F = 272.5 Hz), 120.3, 118.9, 117.6, 109.0, 95.6, 67.7, 61.0, 48.6.

[0138]

Chem.

[0139] 11H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H), 8.49 - 8.46 (m, 2H), 8.19 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.56 (d, J = 4.3 Hz, 1H), 7.47 - 7.44 (m, 2H), 7.31 (dd, J = 8.0, 4.7 Hz, 1H), 5.63 (s, 2H), 4.46 (t, J = 4.3 Hz, 2H), 3.82 (t, J = 4.4 Hz, 2H), 3.76 (s, 2H), 3.67 (d, J = 3.9 Hz, 2H), 2.19 (br s, 1H). 13 13C NMR (125 MHz, CDCl3) δ 163.4, 147.7, 145.6 (2C), 136.9, 133.5, 131.4 (q, 2 J C-F = 32.4 Hz), 130.9 (d, 4 J C-F = 1.0 Hz), 129.6, 127.5, 125.2 (q, 3 J C-F = 3.8 Hz), 124.6 (q, 3 J C-F = 3.6 Hz), 123.8 (q, 1 J C-F = 272.5 Hz), 120.3, 118.9, 117.6, 109.0, 95.8, 72.6, 68.9, 65.1, 61.8, 48.6.

[0140]

Chem.

[0141] 11H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H), 8.48 - 8.46 (m, 2H), 8.17 (dd, J = 7.9, 1.5 Hz, 1H), 7.59 (s, 1H), 7.57 - 7.55 (m, 1H), 7.47 - 7.44 (m, 2H), 7.30 (dd, J = 7.9, 4.7 Hz, 1H), 5.63 (s, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.79 (t, J = 5.4 Hz, 2H), 2.00 (t, J = 6.0 Hz, 3H). 13 13C NMR (125 MHz, CDCl3) δ 163.8, 147.7, 145.6, 145.5, 136.9, 133.4, 131.4 (q, 2 J C-F = 32.4 Hz), 131.0 (d, 4 J C-F = 1.2 Hz), 129.6, 127.5, 125.2 (q, 3 J C-F = 3.8 Hz), 124.6 (q, 3 J C-F = 3.8 Hz), 123.8 (q, 1 J C-F = 272.3 Hz), 120.3, 118.9, 117.6, 109.0, 95.8, 63.1, 59.0, 48.6, 31.7.

[0142]

Chem.

[0143] 11H NMR (500 MHz, CDCl3) δ 8.60 (s, 1H), 8.47 - 8.45 (m, 2H), 8.14 (dd, J = 7.9, 1.5 Hz, 1H), 7.60 (s, 1H), 7.57 - 7.55 (m, 1H), 7.45 (d, J = 5.2 Hz, 2H), 7.30 (dd, J = 7.9, 4.7 Hz, 1H), 5.63 (s, 2H), 4.14 (s, 2H), 3.42 (s, 2H), 2.22 (br s, 1H), 1.00 (s, 6H). 13 13C NMR (125 MHz, CDCl3) δ 163.9, 147.7, 145.5, 145.5, 136.8, 133.4, 131.4 (q, 2 J C-F = 32.9 Hz), 131.0 (d, 4 J C-F = 1.2 Hz), 129.6, 127.5, 125.2 (q, 3 J C-F = 3.6 Hz), 124.6 (q, 3 J C-F = 3.8 Hz), 123.8 (q, 1 J C-F = 272.5 Hz), 120.3, 118.9, 117.4, 109.0, 95.7, 70.9, 68.1, 48.6, 36.6, 21.5 (2C).

[0144]

Chem.

[0145] 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 1H), 8.47-8.46 (m, 2H), 8.18 (dd, J = 8.0, 1.4 Hz, 1H), 7.59 (s, 1H), 7.56-7.55 (m, 1H), 7.45-7.44 (m, 2H), 7.30 (dd, J = 7.9, 4.7 Hz, 1H), 5.62 (s, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.69 (s, 2H), 1.82-1.48 (m, 7H). 13 C NMR (125 MHz, CDCl3) δ 163.5, 147.7, 145.5, 145.2, 136.9, 133.3, 131.4 (q, 2 J C-F = 32.7 Hz), 130.9, 129.6, 127.5, 125.2 (q, 3 J C-F = 3.8 Hz), 124.5 (q, 3 J C-F = 3.8 Hz), 123.8 (q, 1 J C-F = 272.5 Hz), 120.3, 118.8, 117.7, 109.0, 96.2, 66.1, 62.6, 48.6, 32.3, 28.4, 22.2.

[0146] Following the procedures described in Example 17, page 46 of PCT / US2021 / 039502, Attorney Docket No. UCH-28325, filed on June 21, 2021, entitled "Compositions and Methods for Regulating Hair Growth," compounds were incubated in human skin homogenate at pH 7.4 and several compounds were found to be at least 50% hydrolyzed to the parent acid within about 1 hour. The parent acid has been shown to have hair growth properties in mammalian models.

[0147] An assay similar to that described in Example 16, pages 43-46 of PCT / US2021 / 039502, Attorney Docket No. UCH-28325, filed on June 21, 2021, entitled "Compositions and Methods for Regulating Hair Growth," was performed with some of the compounds described herein. The IC 50 The values ​​were below 1 μM and in some cases below 100 nM.

[0148] Unless otherwise indicated, all numbers expressing quantities of ingredients, molecular weights, reaction conditions, and the like used in the specification and claims are to be understood in all instances as modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, no attempt is made to limit the application of equivalents to the scope of the claims, and each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0149] The terms "a," "an," "the," and similar references used in the context of describing the present invention (particularly in the context of the claims below) should be construed to cover both the singular and the plural, unless otherwise specified or clearly contradicted by context. All methods described herein may be performed in any suitable order, unless otherwise specified herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better clarify the invention and does not limit the scope of the claims. Nothing in this specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0150] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. The members of each group may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience or patentability.

[0151] Several embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will be apparent to those of skill in the art upon reading the foregoing description. The inventors expect those of skill in the art to make appropriate use of such variations, and the inventors intend to practice the invention otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, combinations of the above-described elements in all possible variations are contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0152] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Thus, by way of example, and not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Thus, the scope of the claims should not be limited to the precise embodiments shown and described.

[0153] (Additional Note) (Appendix 1) formula: [ka] A compound represented by the formula: R is C 2-12 -Alkyl-, C 4-12 -alkyl-O-alkyl-, or optionally substituted C 6-12-aryl-; and Ph is an optionally substituted phenyl.

[0154] (Appendix 2) The compound according to claim 1, wherein Ph is di(trifluoromethyl)phenyl.

[0155] (Appendix 3) formula: [ka] The compound described in Appendix 1, further represented by:

[0156] (Appendix 4) The compound according to claim 1, wherein Ph is trifluoromethylphenyl.

[0157] (Appendix 5) formula: [ka] The compound described in Appendix 1, further represented by:

[0158] (Appendix 6) [ka] 2. The compound according to claim 1,

[0159] (Appendix 7) [ka] 2. The compound according to claim 1,

[0160] (Appendix 8) [ka] 2. The compound according to claim 1,

[0161] (Appendix 9) [ka] 2. The compound according to claim 1,

[0162] (Appendix 10) [ka] 2. The compound according to claim 1,

[0163] (Appendix 11) [ka] 2. The compound according to claim 1,

[0164] (Appendix 12) [ka] 2. The compound according to claim 1,

[0165] (Appendix 13) [ka] 2. The compound according to claim 1,

[0166] (Appendix 14) [ka] 2. The compound according to claim 1,

[0167] (Appendix 15) [ka] 2. The compound according to claim 1,

[0168] (Appendix 16) [ka] 2. The compound according to claim 1,

[0169] (Appendix 17) [ka] 2. The compound according to claim 1,

[0170] (Appendix 18) A pharmaceutical composition comprising a compound according to any one of claims 1 to 17.

[0171] (Appendix 19) A pharmaceutical composition for hair growth comprising a compound according to any one of claims 1 to 17.

[0172] (Appendix 20) 18. A method of promoting hair growth comprising administering to an area of ​​mammalian skin in which hair growth is intended a compound according to any one of claims 1 to 17.

[0173] (Appendix 21) 23. Use of a compound according to any one of claims 1 to 17 in the manufacture of a medicament for hair growth.

[0174] (Appendix 22) 18. A method for promoting hair growth, comprising administering to a mammal in need thereof a compound according to any one of claims 1 to 17.

[0175] (Appendix 23) 18. A method of treating a disorder affecting hair growth comprising administering to a mammal in need of such treatment a compound according to any one of claims 1-17.

[0176] (Appendix 24) 24. The method of claim 23, wherein the disorder is alopecia or baldness.

Claims

1. formula: 【Chemistry 1】 A compound represented by the formula: R is C ２－１２ -Alkyl-, C ４－１２ -alkyl-O-alkyl-, or optionally substituted C ６－１２ -aryl-; and Ph is an optionally substituted phenyl.

2. The compound of claim 1 , wherein Ph is di(trifluoromethyl)phenyl.

3. formula: 【Chemistry 2】 2. The compound of claim 1 further represented by:

4. The compound of claim 1 , wherein Ph is trifluoromethylphenyl.

5. formula: 【Chemistry 3】 2. The compound of claim 1 further represented by: 【Request 6】 【Chemical 4】 2. The compound of claim 1 , 【Request 7】 【Chemical 5】 2. The compound of claim 1 , 【Request 8】 【Chemical 6】 2. The compound of claim 1 ,

9. 【Chemical 7】 2. The compound of claim 1 ,

10. 【Chemical 8】 2. The compound of claim 1 ,

11. 【Chemical 9】 2. The compound of claim 1 ,

12. 【Catalog 10】 2. The compound of claim 1 ,

13. 【Chemical 11】 2. The compound of claim 1 ,

14. 【Chemical 12】 2. The compound of claim 1 ,

15. 【Chemical 13】 2. The compound of claim 1 ,

16.

14. 2. The compound of claim 1 ,

17. 【Catalogue 15】 2. The compound of claim 1 ,

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17.

19. A pharmaceutical composition for hair growth comprising a compound according to any one of claims 1 to 17.

20. 20. A method for promoting hair growth comprising administering to the area of ​​mammalian skin in which hair growth is intended a compound according to any one of claims 1 to 17.

21. 20. Use of a compound according to any one of claims 1 to 17 in the manufacture of a medicament for hair growth.

22. 20. A method of promoting hair growth comprising administering to a mammal in need thereof a compound according to any one of claims 1 to 17.

23. 23. A method of treating a disorder affecting hair growth comprising administering to a mammal in need of treatment a compound according to any one of claims 1 to 17.

24. 24. The method of claim 23, wherein the disorder is alopecia or baldness.

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