WO2023129854A1 - Compounds for treatment of hair loss - Google Patents

Abstract

Compounds represented by Formula 1, as depicted herein, are described in this disclosure. Use, methods, and medicaments related to treatment of conditions or diseases, such as for growing hair in a mammal, are also described herein.

Description

COMPOUNDS FOR TREATMENT OF HAIR LOSS

Inventors: Daniel Lui Sun and Daniel Walter Gil

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/294,775, filed December 29, 2021, which is incorporated by reference herein in its entirety.

BACKGROUND

Hair follicle stem cells (HFSCs) undergo successive rounds of quiescence (telogen) punctuated by brief periods of proliferation correlating with the start of the hair cycle (telogen-anagen transition). Proliferation or activation of HFSCs is well known to be a prerequisite for advancement of the hair cycle. Despite advances in treatment options, baldness and alopecia continue to be conditions that cannot be successfully treated in many individuals. Some of the existing treatments are inconvenient for users, others require surgical intervention or other invasive procedures. Additional therapies are needed.

SUMMARY

Some embodiments include a compound represented by Formula 1:

Formula 1 or an E/Z isomer thereof; wherein Ph is optionally substituted aryl, such as optionally substituted phenyl, or optionally substituted heteroaryl.

Some embodiments include a pharmaceutical composition comprising a compound described herein. In some embodiments, the pharmaceutical composition is for treating a disease or a disorder, such as a disease or disorder affecting or related to hair growth.

Some embodiments include a pharmaceutical composition for growing hair comprising a compound described herein.

Some embodiments include a method of growing hair, comprising: administering a compound described herein to the skin of a mammal in the area where hair growth is intended. Some embodiments include use of a compound described herein in the manufacture of a medicament for growing hair.

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

Some embodiments include a method of growing hair comprising administering a compound described herein to a mammal in need thereof.

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 thereof. In some embodiments, the disorder is alopecia or baldness.

Some embodiments include a kit comprising a compound described herein and a label with instructions to administer the compound for a use described herein, such as growing hair.

DETAILED DESCRIPTION

Unless otherwise indicated, any reference to a compound herein by structure, name, or any other means, includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; deuterium-modified forms; Z and E olefin isomers; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein. In some embodiments, the compound contains more than a natural abundance of deuterium. In some embodiments, one or more of the hydrogen atoms on the compound is replaced by deuterium so that the compound is at least 50%, at least 80%, at least 90%, at least 95%, or at least 99% deuterium in that position. The E/Z isomers of the structures depicted herein are specifically contemplated.

Unless otherwise indicated, when a compound or chemical structural feature (such as alkyl or aryl) is referred to as being "optionally substituted," it includes a feature that has no substituents (i.e., unsubstituted), or a feature that is "substituted," meaning that the feature has one or more substituents. The term "substituent" has the broadest meaning known to one of ordinary skill in the art, and includes a moiety that occupies a position normally occupied by one or more hydrogen atoms attached to a parent compound or structural feature. In some embodiments, a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g., the sum of the atomic masses 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, a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, P, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, P, Si, F, Cl, Br, or I atom. Examples of substituents include, but are not limited to, compounds represented by an empirical formula: C_1-12H_3-29O_0-4N_0-4S_{0- 4}F_0-25Cl_0-5Si_0-3P_0-3, C_0-12H_0-29O_1-4N_0-4S_{0- 4}F_0-25Cl_0-5Si_0-3P_0-3, C_0-12H_0-29O_0-4N_1-4S_0-4F_0-25Cl_0-5Si_0-3P_0-3, C_0-12H_0-29O_{0- 4}N_0-4S_1-4F_0-25Cl_0-5Si_0-3P_0-3, C_0-12H_0-290_0-4N_0-4S_0-4F_1-25Cl_0-5Si_0-3P_0-3, C_0-12H_0-290_0-4N_0-4S_0-4F_0-25Cl_1-5Si_0-3P_0-3, C_{0- 12}H_0-29O_0-4N_0-4S_0-4F_0-25Cl_0-5Si_1-3P_0-3, C_0-12H_0-29O_0-4N_0-4S_0-4F_0-25Cl_0-5Si_0-3P_1-3, C_1-6H_3-16O_0-4N_0-4S_0-4F_0-13Cl_0-3Si_0-3P_{0- 3}, C_0-6H_0-16O_1-4N_0-4S_0-4F_0-13Cl_0-3Si_0-3P_0-3, C_0-6H_0-17O_0-4N_1-4S_0-4F_0-13Cl_0-3Si_0-3P_0-3, C_0-6H_0-17O_0-4N_0-4S_1-4F_0-13CI_0-3Si_0- 3P_0-3, C_0-6H _0-170_0-4N_0-4S_0-4Fl-13Cl_0-3Si_0-3P_0-3, C_0-6H_0-170_0-4N_0-4S_0-4F_0-13Cl_1-3Si_0-3P_0-3, C_0-6H_0-17O_0-4N_0-4S_0-4F_0-13CI_{0- 3}Si_1-3P_0-3, C_0-6H_0-170_0-4N_0-4S_0-4F_0-13Cl_0-3Si_0-3P_1-3, C_1-12H_3-29O_0-4N_0-4S_0-4F_0-25CI_0-5P_0-3, C_1-12H_3-27O_0-4N_0-2S_0-2F_0-25CI_0- 5P_0-1, C_1-12H_3-27O_0-4N_0-2, C_1-12H_3-25O_0-4, C_1-12H_3-27N_0-2, C_1-9H_3-21O_0-4N_0-2S_0-2F_0-19CI_0-5P_0-1, C_1-9H_3-19F_0-19, C1-9H_{3- 21}O_0-4N_0-2, C_1-9H_3-19O_0-4, C_1-9H_3-21N_0-2, C_1-6H_3-15O_0-3N_0-2S_0-2F_0-13CI_0-5P_0-1, C_1-6H_3-13F_0-13, C_1-6H_3-15O_0-4N_0-2, C₁- ₆H_3-13O_0-4, C_1-6H_3-15N_0-2, C_1-3H_3-9O_0-3N_0-2S_0-2F_0-13CI_0-5P_0-1, C_1-3H_3-7F_0-7, C_1-3H_3-9O_0-3N_0-2, C_1-3H_3-7O_0-3, C_1-3H_{3- 9}N_0-2, F, Cl, Br, I, OH, OR^A, SH, SR^A, NH2, NHR^A, NR^AR^B, CF₃, CN, carboxylic acid, optionally substituted carboxylic ester, or optionally substituted C_1-6 alkyl, such as optionally substituted branched C2-6 alkyl or optionally substituted linear C_1-6 alkyl, including optionally substituted branched or linear C_1-3 alkyl (e.g., -CH₃, -C2H5, -C3H7), optionally substituted branched, linear, or cyclic C_3-6 alkyl (e.g., -C3H7, -C4H9, -C₅H₁₁, -C₆H₁₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, carbocycle, heterocycle, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, 0- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, etc.

For convenience, the term "molecular weight" is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.

With respect to Formula 1, Ph is optionally substituted aryl such as phenyl, such as phenyl substituted with 0, 1, 2, 3, 4, or 5 substituents, such as F, Cl, Br, I, OH, CN, CF₃, C_1-6 alkyl (such as -CH₃, -C₂H₅, -C₃H₇, -C₄H₉, -C₅H₁₁, -C₆H₁₃, etc.), or C_1-6H_3-13O (such as -C(=O)CH₃ or -CH2OCH₃), or optionally substituted heteraryl.

In some embodiments, Ph is phenyl with 1, 2, 3, 4, or 5 trifluoromethyl substituents. In some embodiments, Ph is trifluoromethylphenyl.

In some embodiments, Ph is:

In some embodiments, Ph is:

In some embodiments, Ph is:

In some embodiments, Ph is:

Some embodiments include the compound:

Some embodiments include t

he compound:

Some embodiments include the compound

Some embodiments include the compound

The compounds described herein are useful for growing hair. For example, a compound described herein may be administered to the skin of a mammal in the area where hair growth is intended.

In certain 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 certain embodiments, the MPO inhibitor is an MPC inhibitor.

In some aspects, inhibiting MPO in a cell has the effect of enhancing lactate production in a cell and/or enhancing the activity of lactic acid dehydrogenase (LDH) in a cell, and promoting hair growth. In certain aspects, the present 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 MPO inhibitor (e.g., topically, such as with a pharmaceutical composition formulated for topical application), such as a compound of the present disclosure. In certain embodiments, the present 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 (e.g., topically, such as with a pharmaceutical composition formulated for topical application), such as a compound of the present disclosure. In some embodiments, inhibiting the MPO or the MPC in a cell has the effect of enhancing lactate production and/or enhancing the activity of LDH in a cell, and promoting hair growth.

For the purposes of this disclosure, the term "treat," "treating," or a similar term (such as "modulating"), includes cure, mitigation, treatment, or prevention of disease in man or other animals, or any other effect that would be associated with a "drug" as defined under 21 USC 321(g).

Some embodiments include a pharmaceutical composition or a dosage form comprising an active pharmaceutical ingredient, such as a compound described herein, and polyethylene glycol 400 (PEG400) (such as about 50% PEG400), Transcutol® P (such as about 15% Transcutol® P), ethanol (such as about 25% ethanol), and/or dimethyl sulfoxide (DMSO) (such as about 10% DMSO).

Some embodiments include a pharmaceutical composition or a dosage form comprising an active pharmaceutical ingredient, such as a compound described herein, and PEG400 (such as about 10% PEG400), Transcutol® HP (such as about 20% Transcutol® HP), ethanol (such as about 45% ethanol), and/or water (such as about 25% water).

Some embodiments include a pharmaceutical composition or a dosage form comprising an active pharmaceutical ingredient, such as a compound described herein, and propylene glycol (such as about 10% propylene glycol), Transcutol® HP (such as about 20% Transcutol® HP), ethanol (such as about 45% ethanol), and/or water (such as about 25% water).

The compounds shown below were prepared by adapting the synthetic method described in WO 2019/006359 (e.g., Example 1: p. 45; and pp. 52-53).

Example 1

Several formulations were used to evaluate the solubility of the various compounds. Although any suitable pharmaceutical formulation may be used for the compounds, formulations such as those described below are suitable for administration of the compounds to the hair or scalp of a mammal such as a human being. The formulation may be sterilized before applying to a mammal such as a human being.

A Non-Aqueous Formulation, containing 50% PEG400, 15% Transcutol® P, 25% ethanol, and 10% DMSO was manufactured using the following general process: 10 g of PEG400, 3 g of Transcutol® P, 5 g of ethanol, and 2 g of DMSO were added to a clear vial. The mixture was then stirred using a stir bar until homogenous.

• Aqueous Formulation 1, containing 10% PEG400, 20% Transcutol® HP, 45% ethanol, and 25% water was manufactured using the following general process: in a large amber pyrex bottle, 1) 19.98 g of PEG400 was added; 2) 40.07 g of Transcutol® HP was added; 3) 90 g of ethanol was added; 4) 50.03 g of water was added; and 5) the mixture was stirred using a magnetic stir bar for 30 mins at 800 rpm.

• Aqueous Formulation 2, containing 10% propylene glycol, 20% Transcutol® HP, 45% ethanol, and 25% water was manufactured using the following process: in a large amber pyrex bottle, 1) 10.03 g propylene glycol was added; 2) 20.03 g Transcutol® HP was added; 3) 44.99 g ethanol was added; 4) 25.02 g water was added; and 5) the mixture was stirred using a magnetic stir bar for 30 mins at 800 rpm.

The solubilities of several compounds shown below in the described formulations are indicated below.

(E)-3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacrylic acid

(REFERENCE COMPOUND) results:

Aqueous Formulation 1: 0.5 mg Reference Compound and 9.9996 g Aqueous Formulation 1 (0.005% w/w) were stirred at 600 RPM for 1 hour. The Reference Compound remained undissolved in 1 hour;

Aqueous Formulation 2: 0.5 mg Reference Compound and 10.0006 g Aqueous Formulation 2 (0.005% w/w) were stirred at 600 RPM for 1 hour. The Reference Compound remained undissolved in 1 hour;

Aqueous Formulation 2: 0.5 mg Reference Compound and 2000.1 mg Aqueous Formulation 2 (0.025% w/w) were stirred at 600 RPM for 1 hour. The Reference Compound remained undissolved in 1 hour.

(E)-2-cyano-3-(1-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylic acid (Compound 1)

¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.60 (dd, J = 8.0, 1.5 Hz, 1H), 8.57 (d, J = 0.6 Hz, 1H), 8.44

(dd, J = 4.6, 1.5 Hz, 1H), 7.84-7.82 (m, 2H), 7.63-7.59 (m, 2H), 7.50-7.47 (m, 1H), 7.41 (dd, J = 8.0, 4.7 Hz, 1H).

¹³C NMR (125 MHz, DMSO-d₆) δ 164.5, 147.8, 146.0, 145.8, 137.0, 134.3, 130.0 (2C), 129.5, 128.5, 125.0 (2C), 120.4, 119.5, 118.4, 109.7, 98.1.

(E)-2-cyano-3-(1-(2-(trifluoromethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)acrylic acid (Compound 2)

¹H NMR (500 MHz, DMSO-d₆) 6 8.66 (s, 1H), 8.63-8.61 (m, 2H), 8.34 (dd, J = 4.6, 1.5 Hz, 1H), 8.02 (dd, J = 7.8, 1.2, 1H), 7.92 (td, J = 7.6, 0.9 Hz, 1H), 7.84 (t, J= 7.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.40 (dd, J = 8.0, 4.7 Hz, 1H).

¹³C NMR (125 MHz, DMSO-d₆) δ 164.4, 149.9, 146.1, 146.0, 136.0, 134.4, 134.4 (d, J = 1.9 Hz), 132.1, 131.1, 129.5, 127.8 (q, J = 4.8 Hz), 127.2 (q, J = 30.5 Hz), 123.5 (q, J = 273.5 Hz), 119.3, 119.1, 118.1, 109.6, 98.5.

Solubility results: Non-Aqueous Formulation: 0.75% w/w of Compound 2 dissolved in 1 hour, and 1% w/w of Compound 2 remained undissolved in 1 hour.

Aqueous Formulation 1:

• 1.1 mg Compound 2 and 1000 mg Aqueous Formulation 1 (0.1% w/w) were stirred at 600 RPM for 1 hour. Compound 2 dissolved in 1 hour.

• 2.1 mg Compound 2 and 997.8 mg Aqueous Formulation 1 (0.2% w/w) were stirred at 600 RPM for 1 hour. Compound 2 remained undissolved in 1 hour.

Aqueous Formulation 2:

• 1.0 mg Compound 2 and 1019.1 mg Aqueous Formulation 2 (0.1% w/w) were stirred at 600 RPM for 1 hour. Compound 2 dissolved in 1 hour.

2.0 mg Compound 2 and 1004.6 mg Aqueous Formulation 2 (0.2% w/w) were stirred at 600 RPM for 1 hour. Compound 2 remained undissolved in 1 hour.

(E)-2-cyano-3-(l-(3-(trifluoromethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)acrylic acid (Compound 3)

¹H NMR (500 MHz, DMSO-d₆) δ 13.67 (br s, 1H), 8.89 (s, 1H), 8.63 (dd, J = 7.9, 1.5 Hz, 1H), 8.57 (d, J = 0.8, 1H), 8.47 (dd, J = 4.7, 1.6 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H), 8.18-8.15 (m, 1H), 7.87-7.83 (m, 2H), 7.44 (dd, J = 8.0, 4.7 Hz, 1H).

¹³C NMR (125 MHz, DMSO-d₆) δ 164.4, 147.8, 146.0, 145.9, 137.6, 134.3, 131.3, 130.5 (q, J = 32.4 Hz), 129.8, 128.9, 124.9 (q, J = 3.8 Hz), 124.2 (q, J = 272.8 Hz), 121.7 (q, J = 4.1 Hz), 120.4, 119.7, 118.2, 110.2, 98.9. results:

Non-Aqueous Formulation: 0.1% w/w of Compound 3 dissolved in 1 hour and 0.2% w/w of Compound 3 remained undissolved in 24 hours.

(E)-2-cyano-3-(l-(4-(trifluoromethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)acrylic acid (Compound 4)

¹H NMR (500 MHz, DMSO-d₆) 6 8.89 (s, 1H), 8.62 (dd, J = 8.0, 1.6 Hz, 1H), 8.57 (d, J = 0.9 Hz, 1H), 8.47 (dd, J = 4.7, 1.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.5 Hz, 2H), 7.44 (dd, J = 8.0, 4.7 Hz, 1H).

¹³C NMR (125 MHz, DMSO-d₆) 6 164.3, 147.7, 145.9, 145.9, 140.3 (d, J = 1.1 Hz), 133.7, 129.8, 128.2 (q, J = 32.2 Hz), 127.2 (q, J = 3.6 Hz, 2C), 125.2 (2C), 124.5 (q, J = 272.3 Hz), 120.6, 119.8, 118.2, 110.4, 99.2.

Solubility results:

Non-Aqueous Formulation: 0.5% w/w of Compound 4 dissolved in 1 hour and 0.75% w/w of Compound 4 remained undissolved in 1 hour.

An assay similar to that described in Example 16, pp. 43-46, of PCT/US2021/039502, filed June 21, 2021 under the title "Composition and Methods for Modulating Hair Growth," (with the exception that the assay was performed with intact primary keratinocytes), was conducted on some of the compounds described herein. Primary neonatal Human Epidermal Keratinocytes (HEKn; Thermo Fisher, C0015C) were cultured in HEKn media containing EpiLife™ Medium (Thermo Fisher, MEPI500CA), Human Keratinocyte Growth Supplement (Thermo Fisher, S0015), and Primocin (Fisher Scientific, NC9392943). 8,000 cells were plated per well in XF96 microplates (Agilent) and the plates were humidified in a cell culture incubator at 37°C, 5% CO2, 95% air. The media was changed every day for 6-7 days before Seahorse analysis.

The IC₅₀ values at inhibiting mitochondrial oxidation for the tested compounds was less than 1 μM, and in some cases less than 100 nM.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

The terms "a," "an," "the" and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any nonclaimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to 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 and/or patentability.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than 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, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

1. A compound represented by a formula:

or a pharmaceutically acceptable salt thereof; wherein Ph is optionally substituted phenyl.

2. The compound of claim 1, wherein Ph is trifluoromethylphenyl. H

3. The compound of claim 1, which is:

, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, which is:

, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, which is , or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, which is , or a pharmaceutically

acceptable salt thereof.

7. A pharmaceutical composition comprising a compound of any preceding claim.

8. A pharmaceutical composition for growing hair comprising a compound according to any one of claims 1-6.

9. A method of growing hair, comprising: administering a compound of any one of claims 1-6 to the skin of a mammal in the area where hair growth is intended.

10. Use of a compound of according to any one of claims 1-6 in the manufacture of a medicament for growing hair.

11. A method of growing hair comprising administering a compound of any one of claims 1-6 to a mammal in need thereof.

12. A method of treating a disorder affecting hair growth comprising administering a compound according to any one of claims 1-6 to a mammal in need thereof.

13. The method of claim 12, where the disorder is alopecia or baldness.