# US 8,541,466 B2 · Compositions and methods for treating hair loss using non-naturally occurring prostaglandins

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,541,466 B2
- Document ID: US8541466B2
- Status: Granted
- Kind: B2
- Application number: 12/535,513
- Filed: 2009-08-04
- Published: 2009-11-19
- Granted: 2013-09-24
- Earliest claimed: 2000-03-31
- Assignees: Duke University
- Applicants: Mitchell Anthony DeLong; John McMillan McIver; Robert Scott Youngquist
- Inventors: Mitchell Anthony DeLong; John McMillan McIver; Robert Scott Youngquist
- Web page: https://patentgrep.com/patent/US8541466B2

## CPC

- A61K 8/49: containing heterocyclic compounds
- A61K 8/365: Hydroxycarboxylic acids; Ketocarboxylic acids
- A61K 8/37: Esters of carboxylic acids
- A61K 8/4986: {with sulfur as the only hetero atom}
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/381: having five-membered rings
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/5575: having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
- A61K 31/558: having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
- A61K 31/559: having heterocyclic rings containing hetero atoms other than oxygen
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 17/14: for baldness or alopecia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61Q 7/00: Preparations for affecting hair growth
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

A method for treating hair loss in mammals uses compositions containing prostaglandin F analogs. The compositions can be applied topically to the skin. The compositions can arrest hair loss, reverse hair loss, and promote hair growth.

## Claims

### Claim 1

A method of treating hair loss, wherein the method comprises topically applying to mammalian skin a safe and effective amount of a composition comprising:
A) an active ingredient selected from the group consisting of a prostaglandin F analog having a structure selected from the group consisting of
pharmaceutically acceptable salts of the structures above; biohydrolyzable amides, esters, and imides of the structures above; optical isomers, diastereomers, and enantiomers of the structures above; and combinations thereof;
wherein R1 is selected from the group consisting of C(O)OH, C(O)NHOH, C(O)OR3, CH2OH, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4, tetrazole, a cationic salt moiety, a pharmaceutically acceptable amine or ester comprising 2 to 13 carbon atoms, and a biometabolizable amine or ester comprising 2 to 13 atoms;
R2 is selected from the group consisting of a hydrogen atom, a lower heterogeneous group, and a lower monovalent hydrocarbon group;
R3 is selected from the group consisting of a monovalent hydrocarbon group, a heterogeneous group, a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted monovalent hydrocarbon group, a substituted heterogeneous group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group;
R4 is selected from the group consisting of a monovalent hydrocarbon group, a heterogeneous group, a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted monovalent hydrocarbon group, a substituted heterogeneous group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group;
X is selected from the group consisting of —C≡C—, a covalent bond, —CH═C═CH—, —CH═CH—, —CH═N—, —C(O)—, —C(O)Y—, —(CH2)n—, wherein n is 2 to 4, —CH2NH—, —CH2S—, and —CH2O—;
Y is selected from the group consisting of a sulfur atom, an oxygen atom, and NH; and
Z is selected from the group consisting of a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group,
with the proviso that when the bond at the C2-C3 position is a double bond, the bond at C5-C6 position is a double bond, R1 is C(O)OH or C(O)OR3, and R3 is a monovalent hydrocarbon group or substituted monovalent hydrocarbon group, then R2 is not hydrogen.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is selected from the group consisting of CO2H, C(O)NHOH, CO2R3, C(O)NHS(O)2R4, and tetrazole.

### Claim 3 (depends on 1)

The method of claim 1, wherein R2 is a hydrogen atom.

### Claim 4 (depends on 1)

The method of claim 1, wherein R3 is selected from the group consisting of methyl, ethyl, and isopropyl.

### Claim 5 (depends on 1)

The method of claim 1, wherein R4 is a phenyl group.

### Claim 6 (depends on 1)

The method of claim 1, wherein X is a covalent bond and Z is selected from the group consisting of an aromatic ring, a heteroaromatic ring, a substituted aromatic ring, and a substituted heteroaromatic ring.

### Claim 7 (depends on 1)

The method of claim 1, wherein X is —C≡C—, and Z is a monocyclic aromatic ring.

### Claim 8 (depends on 1)

The method of claim 1, wherein the composition is a topical composition in a form selected from the group consisting of solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, and skin patches.

### Claim 9 (depends on 1)

The method of claim 1, wherein the composition is a topical composition further comprising B) a carrier, wherein the carrier is selected from the group consisting of water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, dimethyl isosorbide, polypropylene glycol, 2 myristyl propionate, and combinations thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the composition further comprises C) an activity enhancer selected from the group consisting of i) a hair growth stimulant, ii) a penetration enhancer, and combinations thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein component i) is selected from the group vasodilator, an antiandrogen, a cyclosporin, a cyclosporin analog, an antimicrobial, an anti-inflammatory, a thyroid hormone, a thyroid hormone derivative, and a thyroid hormone analog, a non-selective prostaglandin agonist, a non-selective prostaglandin antagonist, a retinoid, a triterpene, and combinations thereof.

### Claim 12 (depends on 10)

The method of claim 10, wherein component ii) is selected from the group consisting of 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, polyoxyethylene(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, polyoxyethylene(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, polyoxyethylene ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, isopropyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, dimethyl sulphoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, and combinations thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein the composition is a topical composition locally administered on the skin once per day.

### Claim 14 (depends on 13)

The method of claim 13, wherein the composition is administered once per day for 6 to 12 weeks.

### Claim 15 (depends on 1)

The method of claim 1, wherein R1 is selected from the group consisting of C(O)NHOH, C(O)OR3, CH2OH, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4, tetrazole, a cationic salt moiety, a pharmaceutically acceptable amine or ester comprising 2 to 13 carbon atoms, and a biometabolizable amine or ester comprising 2 to 13 atoms; and
R3 is selected from the group consisting of a heterogeneous group, a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted monovalent hydrocarbon group, a substituted heterogeneous group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group.

### Claim 16 (depends on 15)

The method of claim 15, wherein R3 is selected from the group consisting of a heterogeneous group, a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted heterogeneous group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group.

### Claim 17 (depends on 1)

The method of claim 1, wherein the composition is topically applied directly to the locus of desired hair growth.

### Claim 18

A method of growing hair, wherein the method comprises topically applying to mammalian skin a safe and effective amount of a composition comprising:
A) an active ingredient selected from the group consisting of a prostaglandin F analog having a structure selected from the group consisting of
pharmaceutically acceptable salts of the structures above; biohydrolyzable amides, esters, and imides of the structures above; optical isomers, diastereomers, and enantiomers of the structures above; and combinations thereof;
wherein R1 is selected from the group consisting of C(O)OH, C(O)NHOH, C(O)OR3, CH2OH, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4, tetrazole, a cationic salt moiety, a pharmaceutically acceptable amine or ester comprising 2 to 13 carbon atoms, and a biometabolizable amine or ester comprising 2 to 13 atoms;
R2 is selected from the group consisting of a hydrogen atom, a lower heterogeneous group, and a lower monovalent hydrocarbon group;
R3 is selected from the group consisting of a monovalent hydrocarbon group, a heterogeneous group, a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted monovalent hydrocarbon group, a substituted heterogeneous group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group;
R4 is selected from the group consisting of a monovalent hydrocarbon group, a heterogeneous group, a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted monovalent hydrocarbon group, a substituted heterogeneous group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group;
X is selected from the group consisting of —C≡C—, a covalent bond, —CH═C═CH—, —CH═CH—, —CH═N—, —C(O)—, —C(O)Y—, —(CH2)n—, wherein n is 2 to 4, —CH2NH—, —CH2S—, and —CH2O—;
Y is selected from the group consisting of a sulfur atom, an oxygen atom, and NH; and
Z is selected from the group consisting of a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group,
with the proviso that when the bond at the C2-C3 position is a single bond, the bond at the C5-C6 position is a double bond, R1is C(O)OH or C(O)OR3, and R3 is a monovalent hydrocarbon group or substituted monovalent hydrocarbon group, then R2 is not hydrogen.

### Claim 19 (depends on 18)

The method of claim 18, wherein R1 is selected from the group consisting of CO2H, C(O)NHOH, CO2R3, C(O)NHS(O)2R4, and tetrazole.

### Claim 20 (depends on 18)

The method of claim 18, wherein R2 is a hydrogen atom.

### Claim 21 (depends on 18)

The method of claim 18, wherein R3 is selected from the group consisting of methyl, ethyl, and isopropyl.

### Claim 22 (depends on 18)

The method of claim 18, wherein R4 is a phenyl group.

### Claim 23 (depends on 18)

The method of claim 18, wherein X is a covalent bond and Z is selected from the group consisting of an aromatic ring, a heteroaromatic ring, a substituted aromatic ring, and a substituted heteroaromatic ring.

### Claim 24 (depends on 18)

The method of claim 18, wherein X is —C≡C—, and Z is a monocyclic aromatic ring.

### Claim 25 (depends on 18)

The method of claim 18, wherein the composition is a topical composition in a form selected from the group consisting of solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, and skin patches.

### Claim 26 (depends on 18)

The method of claim 18, wherein the composition is a topical composition further comprising B) a carrier, wherein the carrier is selected from the group consisting of water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, dimethyl isosorbide, polypropylene glycol, 2 myristyl propionate, and combinations thereof.

### Claim 27 (depends on 18)

The method of claim 18, wherein the composition further comprises C) an activity enhancer selected from the group consisting of i) a hair growth stimulant, ii) a penetration enhancer, and combinations thereof.

### Claim 28 (depends on 27)

The method of claim 27, wherein component i) is selected from the group vasodilator, an antiandrogen, a cyclosporin, a cyclosporin analog, an antimicrobial, an anti-inflammatory, a thyroid hormone, a thyroid hormone derivative, and a thyroid hormone analog, a non-selective prostaglandin agonist, a non-selective prostaglandin antagonist, a retinoid, a triterpene, and combinations thereof.

### Claim 29 (depends on 27)

The method of claim 27, wherein component ii) is selected from the group consisting of 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, polyoxyethylene(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, polyoxyethylene(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan1ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, polyoxyethylene ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, isopropyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, dimethyl sulphoxide, N,N—dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, and combinations thereof.

### Claim 30 (depends on 18)

The method of claim 18, wherein the composition is a topical composition locally administered on the skin once per day.

### Claim 31 (depends on 30)

The method of claim 30, wherein the composition is administered once per day for 6 to 12 weeks.

### Claim 32 (depends on 18)

The method of claim 18, wherein R1 is selected from the group consisting of C(O)NHOH, C(O)OR3, CH2OH, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4, tetrazole, a cationic salt moiety, a pharmaceutically acceptable amine or ester comprising 2 to 13 carbon atoms, and a biometabolizable amine or ester comprising 2 to 13 atoms; and
R3 is selected from the group consisting of a heterogeneous group, a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted monovalent hydrocarbon group, a substituted heterogeneous group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group.

### Claim 33 (depends on 32)

The method of claim 32, wherein R3 is selected from the group consisting of a heterogeneous group, a carbocyclic group, a heterocyclic group, an aromatic group, a heteroaromatic group, a substituted heterogeneous group, a substituted carbocyclic group, a substituted heterocyclic group, a substituted aromatic group, and a substituted heteroaromatic group.

### Claim 34 (depends on 18)

The method of claim 18, wherein the composition is topically applied directly to the locus of desired hair growth.