WO2001005364A1

WO2001005364A1 - Nitrogen-containing steroid compounds and their use to regulate hair growth

Info

Publication number: WO2001005364A1
Application number: PCT/US2000/018914
Authority: WO
Inventors: George C. Daher; Barton James Bradbury
Original assignee: The Procter & Gamble Company
Priority date: 1999-07-15
Filing date: 2000-07-11
Publication date: 2001-01-25
Also published as: AU6087700A

Abstract

Methods for regulating hair growth comprise administering to a mammal an effective amount of a compound according to formula (I), wherein a is 0 or 1 and each --- represents either a single bond or a double bond, provided that two adjacent --- are not both double bonds and that when O---C is O=C, a is 0, and further wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylacyl and arylacyl, and R' is selected from the group consisting of nitrogen-containing rings and C(CH3)=NOR', wherein R' is selected from the group consisting of alkyl and aryl.

Description

hmTRC)GEN-ODNTAlNING STEROID COMPOUNDS AND THEIR USE TO REGULATE HAIR GROWTH

TECHNICAL FIELD

The present invention relates to methods for regulating hair growth and to methods for stimulating the growth or regrowth of hair by administration of at least one novel steroidal compound which inhibits the enzymatic activity of Ci₇.₂o-lyase and 5α- reductase.

BACKGROUND

For men and women who suffer from hair loss, it is often desirable to "cure" their hair loss, and specifically to stimulate hair growth or regrowth. Many methods of "curing" hair loss have been disclosed in the literature and several products claiming to stimulate or regulate hair growth are currently marketed.

One approach for growing hair involves the much publicized use of minoxidil (Rogaine®)(6-(l-piperidinyl)-2,4-pyrimidinediamine 3-oxide), a potent antihypeπensive agent, as a hair growth promoting agent, as set forth in U.S. Patents Nos. 3,461 ,461 ; 3,973,061; 3,464,987; and 4,139,619. Unfortunately, not all people respond to minoxidil and the efficacy level is limited in those individuals who do exhibit a response.

Finasteride (Propecia®) is another currently marketed product for promoting hair growth, as set forth in U.S. Patent No. 5,670,643, EP 823436, WO 97/15564, and WO 97/15558. Unfortunately, as with minoxidil, not all people respond to finesteride and the efficacy is limited in those people who do exhibit a response. Moreover, the use of finesteride has been associated with reduced libido, teratogenic effects and other side effects in certain individuals.

Another approach for "curing" hair loss involves a procedure of weaving synthetic or natural hair strands into remaining hair strands of a subject. Such a procedure is time- consuming, expensive and requires follow-up re-weavings as the weaves loosen and/or the subject's existing hair strands grow. Furthermore, such a procedure does not cure hair loss, but merely masks the condition.

Another approach for treating hair loss is the use of hair plugs. This procedure involves the transplantation of terminal hair follicles from regions of normal hair growth on a subject's scalp to regions of thinning or no hair growth on the scalp. This procedure is time consuming, expensive and can be painful. Furthermore, the transplanted plugs, at least in the early stages following transplantation, produce an unnatural look to the scalp.

Thus, there is a need for an easily administered, effective agent for treating hair loss in a mammal, wherein the agent has little or no undesirable side effects.

SUMMARY OF THE INVENTION

Accordi ngly, it is an object of the present invention to provide methods for treating hair loss. It is a related object to provide methods for regulating hair growth. It is a further object to provide methods for stimulating hair growth or

regrowth.

I

These and additional objects are provided by the methods of the present invention, which relate to methods for regulating hair growth and for stimulating hair growth or regrowth. The methods comprise the administration to a mammal, preferably a human, of a compound of formula I:

wherein a is 0 or 1 and each — represents either a single bond or a double bond, provided that two adjacent — are not both double bonds and that when O — C is O=C, a is 0, and further wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylacyl and arylacyl, and R' is selected from the group consisting of nitrogen- containing rings and C(CH₃)=NOR", wherein R" is selected from the group consisting of alkyl and aryl.

These and other features, aspects and advantages of the present invention will become better understood in view of the following detailed description and appended claims. BRIEF DESCRIPTION OF THE DRAWING

The detailed description will be more fully understood in view of the drawing, in which:

Fig. 1 is a schematic reaction sequence showing a mechanism of the present method; and

Fig. 2 is a schematic diagram showing the mechanism in a hair follicle.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods for regulating hair growth or methods for stimulating hair growth or regrowth comprising the administration to a mammal, preferably a human, of at least one novel steroidal compound as described herein.

The following are definitions to be used throughout the specification:

As used herein, "salt" means ionic compounds consisting of a positive ion other than hydrogen and a negative ion other than hydroxyl ion characterized by their very low electrical conductivities as solids, high melting points and boiling points, and high degree of hardness while being quite brittle. Salts are often formed by the interaction of an acid and a base.

As used herein, "polar solvent" means solvents having a dipole moment sufficient to become aligned with the field gradient when placed in an electric field.

As used herein, "topical application" means directly laying on or spreading on outer skin.

As used herein, "effective amount" means a sufficient amount of a composition to provide a desired hair growth regulation, i.e., prevention of hair loss, or stimulation of hair growth or regrowth (whichever the case may be for the individual).

As used herein, "comprising" means that other steps and other ingredients. This term encompasses the terms "consisting of and "consisting essentially of.

As used herein, "pharmaceutically-acceptable" means that drugs, medicaments or inert ingredients which the term describes are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like.

As used herein, "cosmetically-acceptable" means that ingredients which the term describes are suitable for use in contact with the skin of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like.

As used herein, "regulating hair growth" means increasing the rate of hair growth and/or inducing the formation of a greater number of hair strands, and/or increasing the diameter of the hair strand, and/or lengthening the hair strand, and/or changing the hair follicle from vellus to terminal, and/or converting follicles from telogen to anagen phase (thereby increasing the overall ratio of anagen phase follicles relative to telogen phase follicles) and/or preventing, retarding, or arresting the process of hair loss, and/or treating alopecias. Thus, the term "regulating hair growth" includes and encompasses stimulating hair growth or regrowth and preventing hair loss.

As used herein, "anagen phase" refers to the period in the hair follicle growth cycle wherein the follicle is actively growing and producing new hair.

As used herein, "telogen phase' refers to the period in the hair growth cycle wherein the follicle is resting and not producing new hair.

As used herein, "vellus hair follicle" means a hair follicle which produces a soft, short, and often colorless hair fiber. The size of the vellus follicle is considerably smaller than the terminal hair follicle. In an adult, vellus follicles can be found on the forehead (i.e, receding hair line area) and bald scalp.

As used herein, "terminal follicle" means a hair follicle which produces a coarse, long and often pigmented hair shaft. The size of the terminal follicle is considerably larger, thicker in diameter and longer than the vellus follicle. In an adult, terminal follicles can be found on the scalp, axilla and pubic areas.

The methods according to the present invention comprise administering to a mammal an effective amount of a compound according to formula I:

wherein a is 0 or 1 and each — represents either a single bond or a double bond, provided that two adjacent — are not both double bonds and that when O— C is 0=C, a is 0, and further wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylacyl and arylacyl, and R' is selected from the group consisting of nitrogen- containing rings and C(CH₃)=NOR", wherein R" is selected from the group consisting of alkyl and aryl. The alkyl groups may be linear or branched, the aryl groups may comprise a single ring or multiple fused rings, with or without heteroatoms therein, the alkylacyl groups may comprise linear or branched alkyl portions and the arylacyl groups may comprise a single ring or multiple fused rings, with or without heteroatoms therein, Additionally, any or all of these groups maybe

substituted or R_aO- unsubstituted. The alkyl groups and the alkyl portion of the alkylacyl

I groups will typically comprise from 1 to about 24 carbon atoms, and preferably comprise from 1 to about 12, and more preferably from 1 to about 6 carbon atoms. These compounds are steroidal compounds and have been shown to inhibit Cι _, o-lyase and 5α-reductase in vitro and to inhibit androgen synthesis in normal male rats.

In a preferred embodiment, the compounds employed in the methods of the invention for regulating hair growth are of the formula II

wherein the numbers indicated within the ring structures identify the position of the respective carbon ring atoms according to standard chemical nomenclature numbering, and the — bonds between Cl (the carbon atom in position 1) and C2 (the carbon atom in position 2), between C5 (the carbon atom in position 5) and C6 (the carbon atom in position 6), and between C6 (the carbon atom in position 6) and C7 (the carbon atom in position 7) are all single bonds. In a further preferred embodiment, the — bonds between C4 (the carbon atom in position 4) and C5 (the carbon atom in position 5), and between C16 (the carbon atom in position 16) and C17 (the carbon atom in position 17) are double bonds.

As set forth above, the — bond in the R_aO — C moiety represents either a single bond or a double bond, provided that when the -

— bond is a double bond, a is 0. When the

— bond is a single bond, the bond can be either the α or β

stereochemical configuration, In preferred R_aO embodiments, the — bond in this moiety is a double bond, whereby a is 0, or the — bond in this moiety is a single bond, a is 1 and R is selected from the group consisting of hydrogen, unsubstituted, linear alkyl groups having from 1 to about 6 carbons, phenyl, alkylacyl groups in which the alkyl portion is unsubstituted and linear and comprises from 1 to about 6 carbon atoms, and benzoyl. In further preferred embodiments, the — bond in this moiety is a double bond, whereby a is 0, or the — bond is a single bond, wherein a is 1 and R is hydrogen. When the R' substitutent comprises a nitrogen-containing ring, the ring may include one or more additional heteroatoms and may comprise a single ring or multiple fused rings. The ring, or rings, may contain from 3 to about 12 or more ring atoms. Additionally, the nitrogen-containing ring may be substituted or unsubstituted, typically with an alkyl or aryl group. Additionally, in the embodiment wherein R' is the moiety - C(CH₃)=NOR", R" preferably comprises an alkyl group of from 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms, or an aryl group. In preferred embodiments, R' comprises a 5- or 6-membered nitrogen-containing ring with at least one additional hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, or R' is the moiety - C(CH₃)=NOH, commonly referred to as ethanone oxime, i.e., R" is H. In further preferred embodiments, R' comprises imidazoyl, pyrazoyl or

ethanone oxime.

Particularly III preferred compounds for use in the methods of the present invention comprise 20-hydroxyimino-4,16-pregnadien-3- one, of formula ϋl

17-(3'- pyrazolyl)androsta-4, 16-dien-3- one of formula IV IV 17-(3'- pyrazolyl)androsta-5 , 16-dien-3 β- ol of formula V

and 17β-(4'- imidazolyl) androsta-4-en-3- one of formula VI

VI

The compounds employed in methods of the present invention may be administered topically, orally, for example in solid tablet, semi-solid tablet or liquid form, or parenterally, for example in solution, to a mammal, preferably a human, to obtain the desired hair regulating effect. Preferably, the compounds are employed in combination with one or more additional components in the form of compositions. These compositions of the present invention can similarly be administered topically, orally or parenterally. In a preferred embodiment of the present invention, the compositions of the present invention are administered topically. Topical compositions of the present invention can be in any form, including but not limited to creams, gels, lotions, shampoos, rinses, tonics, sprays, ointments, mousses or pomade.

The compounds of formula I have been shown to inhibit Cι _j2o-lyase and 5α- reductase in vitro and also to inhibit androgen synthesis in normal male rats. Thus, the dual activity of these inhibitors account for diminished levels of circulating androgens in vivo.

Several commercially available products employ finasteride for the treatment of benign prostatic hyperplasia and male-pattern baldness, respectively. Finasteride is known to inhibit 5α-reductase, the enzyme responsible for converting testosterone into dihydrotestosterone (DHT), and therefore is effective in reducing the DHT levels in patients with either prostate cancer or male-pattern baldness. Unfortunately, finasteride also increases serum testosterone levels. Although DHT binds the androgen receptor with higher affinity than testosterone, in the absence of DHT, testosterone may also bind to the same androgen receptors and induce baldness or stimulate prostatic growth.

The compounds of formula I strongly inhibit Cι_{7> 0}-lyase, as well as 5α-reductase, thus reducing the formation of active metabolites upstream in the androgen pathway. Therefore, the compunds of formula I are particularly advantageous for treatment of male- pattern baldness and other hair growth irregularities. Enzymes that may be blocked by the compounds of formula I are illustrated in Fig. 1 using a crossed (X) reaction line. The result of the mechanisms is illustrated schematically in Fig. 2 which shows that the local presence of some of these enzymes permitting conversion to dehydroepiandrosterone (DHEA) to androstenedione (A), and then A to testosterone (T), and in turn, T to DHT in the skin. Thus, several androgenic hormones from circulation may illicit an androgenic effect. Thus, local inhibition of these enzymes in the skin may have a particularly advantageous effect in regulating hair growth, without, or with reduced, undesirable side effects. The methods of the present invention preferably employ compositions which contain from about 0.00001% to about 99.9%, preferably from about 0.001 to about 75%, more preferably from about 0.00 1% to about 50%, even more preferably from about 0.01%) to about 25%o, further preferably from about 0.1% to about 15%, and most preferably from about 1% to about 10%o by weight of the composition, of a compound of formula I as described above.

The compositions employed in the methods of the present invention can desirably contain a variety of optional ingredients in addition to the compound of formula I described above.

1. Vehicle

The compositions which are utilized in the method of the present invention preferably contain one or more solid, semi-solid or liquid cosmetically or pharmaceutically acceptable vehicles to act as a diluent, dispersant or carrier for the active components in the composition. As used herein, "pharmaceutically-acceptable" means that drugs, medications or inert ingredients which the term describes are suitable for use in humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like. As used herein, "cosmetically acceptable" means that ingredients which the term describes are suitable for use in contact with the skin or hair of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response and the like. The cosmetically or pharmaceutically acceptable vehicles comprise from about 0.1 % to about 99.999%), preferably from about 25% to about 99.99%o, more preferably from about 50%> to about 99.99%>, even more preferably from about 75% to about 99.9%, further preferably from about 85% to about 99.9%, and most preferably from about 90% to about 99%, by weight of the composition.

Acceptable vehicles include, for example, but are not limited to water, lipophilic or hydrophilic emollients, humectants, penetrants, surfactants, thickeners, powders, polymers, resins, plasticizers, fillers, lubricants, binders, disintegrants, solvents, co- solvents, buffer systems, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes and pigments. a. Water

Water can be employed in the compositions herein as a vehicle. When water is employed as the vehicle, the composition will be in the form of an emulsion, suspension or cream. b. Lipophilic or Hydrophilic Emollients/Humectants

Hydrophilic or lipophilic emollients and/or humectants can be incorporated into the compositions herein as the vehicle, for example, at levels ranging from about 0.5% to about 85%o, preferably from about 5% to about 50%, more preferably from about 10% to about 30% by weight of the composition, and are typically employed to form lotion or cream products. Suitable emollients and humectants are listed in CTFA Cosmetic Ingredient Handbook, Second Edition, 1992, pp. 572-575, which is herein incorporated by reference. Suitable emollients/humectants include esters, fatty acids and alcohols, polyols, hydrocarbons, silicones, waxes, triglycerides, cationic and nonionic polymers and mixtures thereof, examples of which include, but are not limited to, the following: i. Esters

C1-C30 alcohol esters of C1-C30 carboxylic acids and of C2-C30 dicarboxylic acids, including straight and branched chain materials, as well as aromatic derivatives, can be used herein. Also useful are esters such as monoglycerides of C1-C30 carboxylic acids, diglycerides of C1-C30 carboxylic acids, triglycerides of C1-C30 carboxylic acids, ethylene glycol monoesters of Cl -C30 carboxylic acids, ethylene glycol diesters of C1-C30 carboxylic acids, propylene glycol monoesters of C1-C30 carboxylic acids, and propylene glycol diesters of C1-C30 carboxylic acids. Straight chain, branched chain and aryl carboxylic acids are included herein. Also useful are propoxylated and ethoxylated derivatives of these materials. Nonlimiting examples include diisopropyl sebacate, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, myristyl propionate, ethylene glycol distearate, 2-ethylhexyl palmitate, isodecyl neopentanoate, di-2-ethylhexyl maleate, cetyl palmitate, myristyl myristate, stearyl stearate, cetyl stearate, behenyl behenrate, dioctyl maleate, dioctyl sebacate, diisopropyl adipate, cetyl octanoate, diisopropyl dilinoleate, caprilic/capric triglyceride, PEG-6 caprylic/capric triglyceride, PEG-8 caprylic/capric triglyceride, and mixtures thereof. Also useful are various C1-C30 monoesters and polyesters of sugars and related materials. These esters are derived from a sugar or polyol moiety and one or more carboxylic acid moieties. Depending on the constituent acid and sugar, these esters can be in either liquid or solid form at room temperature. Examples of liquid esters include glucose tetraoleate, the glucose tetraesters of soybean oil fatty acids (unsaturated), the mannose tetraesters of mixed soybean oil fatty acids, the galactose tetraesters of oleic acid, the arabinose tetraesters of linoleic acid, xylose tetralinoleate, galactose pentaolcate, sorbitol tetraoleate, the sorbitol hexaesters of unsaturated soybean oil fatty acids, xylitol pentaoleate, sucrose tetraoleate, sucrose pentaoletate, sucrose hexaoleate, sucrose hepatoleate, sucrose octaoleate, and mixtures thereof. Examples of solid esters include sorbitol hexaester in which the carboxylic acid ester moieties are palmitoleate and arachidate in a 1 :2 molar ratio; the octaester of raffrnose in which the carboxylic acid ester moieties are linoleate and behenate in a 1 :3 molar ratio; the heptaester of maltose wherein the esterifying carboxylic acid moieties are sunflower seed oil fatty acids and lignocerate in a 3:4 molar ratio; the octaester of sucrose wherein the esterifying carboxylic acid moieties are oleate and behenate in a 2:6 molar ratio; and the octaester of sucrose wherein the esterifying carboxylic acid moieties are laurate, linoleate and behenate in a 1 :3:4 molar ratio. A preferred solid material is sucrose polyester in which the degree of estenfication is 7-8, and in which the fatty acid moieties are C18 mono- and/or di- unsaturated and behenic, in a molar ratio of unsaturates:behenic of 1 :7 to 3:5. A particularly preferred solid sugar polyester is the octaester of sucrose in which there are about 7 behenic fatty acid moieties and about 1 oleic acid moiety in the molecule. Other materials include cottonseed oil or soybean oil fatty acid esters of sucrose. The ester materials are further described in U.S. Patent No. 2,831,854, U.S. Patent No. 4,005.196, to Jandacek, issued January 25, 1977; U.S. Patent No. 4,005,195, to Jandacek, issued January 25, 1977, U.S. Patent No. 5,306,516, to Letton et al, issued April 26, 1994: U.S. Patent No. 5,306,515, to Letton et al, issued April 26, 1994; U.S. Patent No. 5,305,514, to Letton et al, issued April 26, 1994; U.S. Patent No. 4,797,300, to Jandacek et al, issued January 10, 1989; U.S. Patent No. 3,963,699, to Rizzi et al, issued June 15, 1976; U.S. Patent No. 4,518,772, to Volpenhein, issued May 21, 1985; and U.S. Patent No. 4,517,360, to Volpenhein, issued May 21, 1985; all of which are incorporated by reference herein in their entirety. ii. Fatty Alcohols and Fatty Acids

Suitable fatty alcohols and acids include those compounds having from 10 to 20 carbon atoms. Especially preferred are such compounds as cetyl, myristyl, palmitic and stearyl alcohols and acids. iii. Polvols

Among the polyols which are useful as a vehicle herein are linear and branched chain alkyl polyhdyroxyl compounds. Preferred polyols include propylene glycol, sugars having up to about 12 carbons atoms, sugar alcohols having up to about 12 carbon atoms, and mixtures thereof, glycerin, polypropylene glycols, polyethylene glycols. ethyl hexane diol, hexylene glycols, ureas and mixtures thereof.

Specific examples of useful polyols include materials such as urea, guanidine, glycolic acid and glycolate salts (e.g. ammonium and quaternary alkyl ammonium); lactic acid and lactate salts (e.g. ammonium and quaternary alkyl ammonium); sucrose, fructose, glucose, eruthrose, erythritol, sorbitol, mannitol, glycerol, hexanetriol, propylene glycol, butylene glycol, hexylene glycol, and the like; polyethylene glycols such as PEG-2, PEG- 3, PEG-30, and PEG-50, polypropylene glycols such as PPG-9, PPG-12, PPG-15, PPG- 17, PPG-20, PPG-26, PPG-30, and PPG-34; alkoxylated glucose; hyaluronic acid; and mixtures thereof. Also useful are materials such as aloe vera in any of its variety of forms (e.g., aloe vera gel), chitin, starch-grafted sodium polyacrylates such as Sanwet® IM-1000, IM-1500, and IM-2500 (available from Celanese Superabsorbent Materials, Portsmouth, VA); lactamide; monoethanolamine; acetamide monoethanolamine; and mixtures thereof. Also useful are propoxylated glycerols as described in U.S. Patent No. 4,976,953, to Orr et al, issued December 11, 1990, which is incorporated by reference herein in its entirety. iv. Hydrocarbons

Suitable hydrocarbons are straight and branched chain hydrocarbons having anywhere from 7 to 40 carbon atoms. Nonlimiting examples include mineral oil, petrolatum, squalene, isoparaffins. dodecane, isododecane, cholesterol, hydrogenated polyisobutylene, docosane (i.e. a C hydrocarbon), hexadecane, isohexadecane (a commercially available hydrocarbon sold as Permethyl® 101A by Presperse, South Plainfield, NJ) Mineral oil, which is also known as petrolatum liquid, is a mixture of liquid hydrocarbons obtained from petroleum See, The Merck Index, Tenth Edition, Entry 7048, p 1033 (1983) and International Cosmetic Ingredient Dictionary, Fifth Edition, vol 1 , p 415-417 ( 1993), which are incorporated by reference herein in their entirety Petrolatum, which is also known as petroleum jelly, is a colloidal system of nonstraight - chain solid hydrocarbons and high-boiling liquid hydrocarbons, m which most of the liquid hydrocarbons are held inside the micelles See, The Merck Index, Tenth Edition, Entry 7047, p 1033 (1983), Schmdler, Drug Cosmet hid , 89, 36-37, 76, 78-80, 82 (1961), and International Cosmetic Ingredient Dictionary, Fifth Edition, Vol 1, p 537 (1993), which are incorporated by reference herein m their entirety v. Silicones

Nonvolatile silicones such as polydialkylsiloxanes, polydiarylsiloxanes, and polyalkarylsiloxanes are also useful herein These silicones are disclosed in U S Patent No 5,069,897, to Orr, issued December 3, 1991, which is incorporated by reference herein m its entirety The polyalkylsiloxanes correspond to the general chemical formula R₃SιO[R SιO]_xSιR₃ wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl) and x is an integer up to about 500, chosen to achieve the desired molecular weight Commercially available polyalkylsiloxanes include the polydimethylsiloxanes, which are also known as dimethicones, nonhmitmg examples of which include the Vicasil® seπes sold by General Electπc Company and the Dow Corning® 200 seπes sold by Dow Corning Corporation Specific examples of polydimethylsiloxanes useful herein include Dow Corning® 225 fluid having a viscosity of about 10 centistokes and a boiling point greater than 200°C, and Dow Coming® 200 fluids having viscosities of about 50, 350, and 12,500 centistokes, respectively, and boiling points greater than 200°C Also useful are mateπals such as tπmethylsiloxysihcate, which is a polymeπc mateπal corresponding to the general chemical formula [(CH₂)₃ SιOι_/ ]_x[SιO₂]_y, wherein x is an integer from about 1 to about 500 and y is an integer from about 1 to about 500 A commercially available tπmethylsiloxysihcate is sold as a mixture with dimethicone as Dow Coming® 593 fluid Also useful herein are dimethiconols, which are hydroxy terminated dimethyl silicones. These materials can be represented by the general chemical formulas R₃SiO[R₂SiO]_xSiR₂OH and HOR₂SiO[R₂SiO] SiR₂OH wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl) and x is an integer up to about 500, chosen to achieve the desired molecular weight. Commercially available dimethiconols are typically sold as mixtures with dimethicone or cyclomethicone (e.g. Dow Coming® 1401, 1402, and 1403 fluids). Also useful herein are polyalkylaryl siloxanes, with polymethylphenyl siloxanes having viscosities from about 15 to about 65 centistokes at 25 C being preferred. These materials are available, for example, as SF 1075 methylphenyl fluid (sold by General Electric Company) and 556 Cosmetic Grade phenyl trimethicone fluid (sold by Dow Corning Corporation). vi. Waxes Waxes which are potentially useful as the vehicle in the compositions herein include those set forth in CTFA Cosmetic Ingredient Handbook, Second Edition, 1992, pp. 535, which is herein incorporated by reference. Specific examples include beeswax, carnauba, candelilla wax, jojoba wax, lanolin wax, ozokerite, paraffin wax, and mixtures thereof. vii. Triglycerides Animal fats, vegetable oils and hydrogenated vegetable oils, and vegetable oil adducts are also potentially useful herein.

Examples of vegetable oils and hydrogenated vegetable oils include safflower oil, castor oil, coconut oil, cottonseed oil, menhaden oil, palm kernel oil, palm oil, peanut oil, soybean oil, rapeseed oil, linseed oil, rice bran oil, pine oil, sesame oil, sunflower seed oil, hydrogenated safflower oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated menhaden oil, hydrogenated palm kernel oil, hydrogenated palm oil, hydrogenated peanut oil, hydrogenated soybean oil, hydrogenated rapeseed oil, hydrogenated linseed oil, hydrogenated rice bran oil, hydrogenated sesame oil, hydrogenated sunflower seed oil, and mixtures thereof. c. Surfactants Surfactants can be desirably utilized as the vehicle in the compositions herein. Surfactants, if used, are typically employed at levels ranging from about 0.1 % to about 30%, preferably from about 1% to about \5%, and more preferably from about 0.1% to about 10%, by weight of the composition. Suitable surfactants for use herein include cationic, nonionic, anionic, amphoteric and combinations thereof.

Nonlimiting examples of anionic surfactants useful in the compositions of the present invention are disclosed in McCutcheon's, Detergents and Emulsifiers, North American Edition (1986), published by allured Publishing Corporation; McCutcheon^"s, Functional Materials, North American Edition (1992); and U.S. Patent No. 3,929,678, to Laughlin et al, issued December 30, 1975, all of which are incorporated by reference herein in their entirety.

A wide variety of anionic surfactants are useful herein. Nonlimiting examples of anionic surfactants include those selected from the group consisting of sarcosinates, sulfates, isethionates taurates, phosphates, and mixtures thereot. Amongst the sarcosinates and isethionates, the alkoyl sarcosinates and alkoyl isethionates are preferred, and amongst the sulfates, the alkyl and alkyl ether sulfates are preferred. Other anionic materials useful herein are soaps (i.e. alkali metal salts, e.g., sodium or potassium salts) of fatty acids, typically having from about 8 to about 24 carbon atoms, preferably from about 10 to about 20 carbon atoms. The fatty acids used in making the soaps can be obtained from natural sources such as, for instance, plant or animal-derived glycerides (e.g., palm oil, coconut oil, soybean oil, castor oil, tallow, lard, etc.) The fatty acids can also be synthetically prepared. Soaps are described in more detail in U.S. Patent No. 4,557,853, cited above. Other anionic materials include phosphates such as monoalkyl, dialkyl, and trialkylphosphate salts. Also useful are taurates which are based on taurine, which is also known as 2-aminoethanesulfonic acid. Examples of taurates include N-alkyltaurines such as the one prepared by reacting dodecylamine with sodium isethionate according to the teaching of U.S. Patent 2,658,072 which is incorporated herein by reference in its entirety. Nonlimiting examples of preferred anionic surfactants useful herein include those selected from the group consisting of sodium lauryl sulfate, ammonium lauryl sulfate. ammonium laureth sulfate, sodium laureth sulfate, sodium trideceth sulfate, ammonium cetyl sulfate, sodium cetyl sulfate, ammonium cocoyl isethionate, sodium lauroyl isethionate, sodium lauroyl sarcosinate, and mixtures thereof.

Nonlimiting examples of nonionic surfactants for use in the compositions of the present invention are also disclosed in McCutcheon's, Detergents and Emulsifiers, North American Edition (1986), and McCutcheon's, Functional Materials, North American Edition (1992), cited above. Nonionic surfactants useful herein include those selected from the group consisting of alkyl glucosides, alkyl polyglucosides, polyhydroxy fatty acid amides, alkoxylated fatty acid esters, sucrose esters, amine oxides, and mixtures thereof.

The term "amphoteric surfactant," as used herein, is also intended to encompass zwitterionic surfactants, which are well known to formulators skilled in the art as a subset of amphoteric surfactants. A wide variety of amphoteric surfactants can be used in the compositions of the present invention. Particularly useful are those which are broadly described as derivatives of aliphatic secondary and tertiary amines, preferably wherein the nitrogen is in a cationic state, in which the aliphatic radicals can be straight or branched chain and wherein one of the radicals contains an ionizable water solubilizing group, e.g., carboxy, sulfonate, sulfate, phosphate, or phosphonate. Nonlimiting examples of amphoteric surfactants useful in the compositions of the present invention are also disclosed in McCutcheon's, Detergents and Emulsifiers, North American Edition (1986), and McCutcheon's, Functional Materials, North American Edition (1992), cited above. Nonlimiting examples of amphoteric or zwitterionic surfactants are those selected from the group consisting of betaines, sultaines, hydroxysultaines, alkyliminoacetates, iminodialkanoates, aminoalkanoates, and mixtures thereof.

Nonlimiting examples of cationic surfactants useful herein are also disclosed in McCutcheon's, Detergents and Emulsifiers, North American Edition (1986), and McCutcheon's, Functional Materials, North American Edition (1992), cited above. Nonlimiting examples of cationic surfactants useful herein include cationic alkyl ammonium salts such as those having the formula R]R₂R₃R N X^" wherein Ri is selected from an alkyl group having from about 12 to about 18 carbon atoms, or aromatic, aryl or alkaryl groups having from about 12 to about 18 carbon atoms; R , R₃, and R-t are independently selected from hydrogen, an alkyl group having from about 1 to about 18 carbon atoms, or aromatic, aryl or alkaryl groups having from about 12 to about 18 carbon atoms; and X is an anion, for example chloride, bromide, iodide, acetate, phosphate, nitrate, sulfate, methyl sulfate, ethyl sulfate, tosylate, lactate, citrate, glycolate, or mixtures thereof. Additionally, the alkyl groups can also contain ether linkages, or hydroxy or amino group substituents (e.g., the alkyl groups can contain polyethylene glycol and polypropylene glycol moieties).

Alternatively, other useful cationic surfactants include amino-amides, wherein in the above structure Ri is alternatively R₅CO-(CH )_n- wherein R₅ is an alkyl group having from about 12 to about 22 carbon atoms, and n is an integer from about 2 to about 6, more preferably from about 2 to about 4, and most preferably from about 2 to about 3. Nonlimiting examples of these cationic emulsifiers include stearamidopropyl PG- dimonium chloride phosphate, stearamidopropyl ethyldimonium ethosulfate, stearamidopropyl dimethyl (myristyl acetate) ammonium chloride, stearamidopropoyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof. d. Thickeners/Binders

Another category of functional ingredients which can be employed in the vehicle of the compositions used in the method of the present invention are thickeners and binders. A thickener or binder will usually be present in amounts anywhere from about 0.01% to about 20%, by weight, preferably from about 0Λ% to about 10%, and more preferably from about 0.1% to about 5%, by weight of the composition. Suitable thickeners include cross-linked polyacrylate materials available under the trademark Carbopol from the B. F. Goodrich Company. Gums may be employed such as xanthan, carrageenan, gelatin, karaya, pectin and locust bean gum. Under certain circumstances, the thickening function may be accomplished by a material also serving as a silicone or emollient. For instance, silicone gums in excess of 10 centistokes and esters such as glycerol stearate have dual functionality.

Preferred binders include, but are not limited to me hycellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, carbomer, polyvinylpyrrolidone, acacia, guar gum, xanthan gum and tragacanth. Particularly preferred are methylcellulose, carbomer, xanthan gum, guar gum, polyvinylpyrrolidone and sodium carboxymethylcellulose.

Additional components may optionally be included in the vehicle carrier of the compositions employed in the inventive methods as follows: e. Flavoring/Coloring Agents

Flavoring agents among those useful herein include those described in Remington 's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, 1990, pp. 1288-1300, incorporated by reference herein. Dyes abd pigments useful herein include those described in Handbook of Pharmaceutical Excipients, Second Edition pp. 126-134, 1994 by the American Pharmaceutical Association & the Pharmaceutical Press, incorporated by reference herein. f. Buffering Systems

Preferred buffer systems include, but are not limited to potassium acetate, boric, carbonic, phosphoric, succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric and glutamic buffering systems, all of which are known in the art. Particularly preferred are phosphoric, tartaric, and citric systems, and potassium acetate. g. Preservatives

Preferred preservatives include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, benzoic acid and the salts thereof, boric acid and the salts thereof, sorbic acid and the salts thereof, chorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben. Particularly preferred are the salts of benzoic acid, benzalkonium chloride, methyl paraben and propyl paraben. h. Sweeteners

Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, and aspartame. Particularly preferred are sucrose and saccharin. i. Fillers

Preferred fillers include, but are not limited to lactose, sucrose, maltodextrin, mannitol, starch 1500, dicalcium phosphate and microcrystalline cellulose. j. Plasticizers

Preferred plasticizers include, but are not limited to polyethylene glycol, propylene glycol, dibutyl phthalate, and castor oil, acetylated monoglycerides, and triacetin. k. Lubricants

Preferred lubricants include, but are not limited to, magnesium stearate, stearic acid, and talc.

1. Disintegrants

Preferred disintegrants include, but are not limited to, crospovidone, sodium carboxymefhyl starch, sodium starch glycolate, sodium carboxymethyl cellulose, alginic acid, clays, and ion exchange resins. m. Polymers

Preferred polymers, include but are not limited to hydroxypropylmethylcellulose (HPMC) alone and/or in combination with hydroxypropylcellulose (HPC), carboxymethylcellulose, acrylic resins such as Eudragit® RL30D, manufactured by Rohm Pharma GmbH, Weiderstadt, West Germany, methylcellulose, ethylcellulose, and polyvinylpyrrolidone or other commercially available film-coating preparations such as Dri-Klear, manufactured by Crompton & Knowles Corp., Mahwah, NJ, or Opadry, manufactured by Colorcon, West Point, PA.

2. Activity Enhancers

The compositions herein may also optionally comprise an activity enhancer or enhancers, including additional hair growth agents. The activity enhancer or enhancers can be chosen from a wide variety of molecules which can function in different ways to enhance the hair growth effects of a compound of formula I according to the present invention. These optional activity enhancers, when present, are typically employed in the compositions herein at a level ranging from about 0.01% to about 15%>, preferably from about 0.1% to about 10%, most preferably from about 0.5%o to about 5%, by weight of the composition.

Vasodilators such as potassium channel agonists include, for example, minoxidil and minoxidil derivatives such as aminexil and those described in U.S. Patent 3,382.247, U.S. Patent 5,756,092, issued May 26, 1998, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,760,043, issued June 2, 1998, U.S. Patent 328,914, issued July 12, 1994, U.S. Patent 5,466,694, issued November 14, 1995, 5,438,058, issued August 1, 1995, and U.S. Patent 4,973,474, issued November 27, 1990, all of which are herein incorporated by reference. Cromakalin and diazoxide also can be used as optional activity enhancers in the compositions herein.

One suitable class of optional activity enhancer for use herein comprises other antiandrogens. Examples of suitable antiandrogens may include, but are not limited 5-α- reductase inhibitors such as finesteride and those described in U.S. Patent 5,516,779, issued May 14, 1996 (herein incorporated by reference), as well as cyproterone acetate, azelaic acid and its derivatives and those compounds described in U.S. Patent 5,480,913, issued January 2, 1996, flutamide, and those described in U.S. Patent 5,411,981, issued May 2, 1995, U.S. Patent 5,565,467, issued October 15, 1996 and U.S. Patent 4,910,226, issued March 20, 1990, all of which are herein incorporated by reference.

Another suitable class of optional activity enhancers comprises immunosuppressants such as 1) cyclosporin and cyclosporin analogs including those described in U.S. Provisional Patent Application No. 60/122,925, Fulmer et al., "Method of Treating Hair Loss Using Non-Immunosuppressive Compounds", filed March 5, 1999, herein incorporated by reference, and 2) FK506 analogs such as those described in U.S. Provisional Patent Application No. 60/102,449, Mclver et al, "Heterocyclic 2-Substituted Ketoamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,448, Mclver et al., "2-Substituted Ketoamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,539, Mclver et al., "2-Substituted Heterocyclic Sulfonamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,458, Tiesman et al., "Method of Treating Hair Loss Using Ketoamides", filed September 30, 1998, and U.S. Provisional Patent Application No. 60/102,437, Mclver et al., "Method of Treating Hair Loss Using Sulfonamides", filed September 30, 1998, all of which are herein incorporated by reference.

Another suitable class of optional activity enhancers comprises antimicrobials such as selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol, mipirocin and those described in EP 0,680,745A, herein incorporated by reference, clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin.

Anti-inflammatories can also be incorporated into the compositions herein as an optional activity enhancer. Examples of suitable anti-inflammatories may include glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone, nonsteroidal anti-inflammatories including cyclooxygenase or lipoxygenase inhibitors such as those described in U.S. Patent 5,756,092, and benzydamine, salicylic acid, and those compounds described in EP 0,770,399 A, published May 2, 1997, WO 94/06434, published March 31, 1994 and FR 2,268,523, published November 21, 1975, all of which are herein incorporated by reference.

Another suitable class of optional activity enhancers comprises thyroid hormones and derivatives and analogs thereof. Examples of suitable thyroid hormones for use herein may include triiodothyrionine. Examples of thyroid hormone analogs which may be suitable for use herein include those described in U.S. Provisional Patent Application No. 60/136,996, Zhang et al., "Method of Treating Hair Loss", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,024, Zhang et al., "Method of Treating Hair Loss Using Biphenyl Compounds", filed June 1 , 1999, U.S. Provisional Patent Application No. 60/137,022, Zhang et al., "Method of Treating Hair Loss Using Carboxyl Derivatives", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,023, Zhang et al., "Method of Treating Hair Loss Using Sulfonyl Thyromimetic Compounds", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,052, Youngquist et al, "Biaryl Compounds", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,063, Youngquist et al., "Sulfur-Bridged Compounds", filed June 1, 1999, and U.S. Provisional Patent Application No. 60/136,958, Youngquist et al., "Substituted Biaryl Ether Compounds", filed June 1, 1999.

Prostaglandin agonists or antagonists can also be used as optional activity enhancers in the compositions herein. Examples of suitable prostaglandins agonists or antagonists include latanoprost and those described in WO 98/33497, Johnstone, published August 6, 1998, WO 95/11003, Stjernschantz, published April 27, 1995, JP 97-100091, Ueno, and JP 96-134242, Nakamura. Another class of optional activity enhancers for use herein are retinoids. Suitable retinoids may include isotretinoin, acitretin, tazarotene.

Penetration enhancers may also be used as activity enhancers in compositions for use in the present methods. Non-limiting examples of penetration enhancers which may be used as optional activity enhancers herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, POE(2) ethyl ether, di(2- hydroxypropyl) ether, pentan-2,4-diol, acetone, POE(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1 ,4-dioxane, tetrahydrofuran, butan-l,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, diisopropyl 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, zsσ-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, z^'so-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hyroxyoctanoic acid, methylsulfoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1- methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, l,5-dimethyl-2-pyrrolidone, l-ethyl-2- pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diefhyl-w- toluamide,, l-dodecylazacyloheptan-2-one and those described in U.S. Patent 5,015,470, issued May 14, 1991 and U.S. Patent 5,496,827, issued July 15, 1994, both of which are herein incorporated in their entirety by reference.

Other classes of optional activity enhancers for use herein include flavinoids, ascomycin derivatives and analogs, histamine antagonists such as diphenhydramine hydrochloride, triterpenes such as oleanolic acid and ursolic acid and those described in U.S. Patent 5,529,769, JP 10017431, WO 95/35103, U.S. Patent 5,468,888, JP 09067253 , WO 92/09262, JP 62093215, U.S. Patent 5,631,282, U.S. Patent 5,679,705, JP 08193094, saponins such as those described in EP 0,558,509 to Bonte et al, published September 8, 1993 and WO 97/01346 to Bonte et al, published January 16, 1997, both of which are herein incorporated by reference in their entirety, proeoglycanase or glycosaminoglycanase inhibitors such as those described in U.S. Patents 5,015,470. issued May 14, 1991, U.S. Patent 5,300,284, issued April 5, 1994 and U.S. Patent 5,185,325, issued February 9, 1993, all of which are herein incorporated in their entirety by reference, estrogen agonists and antagonists, pseudoterins, cytokine and growth factor promotors, analogs or inhibitors such as interleukin- 1 inhibitors, interleukin-6 inhibitors, interleukin- 10 promotors, and tumor necrosis factor inhibitors, vitamins such as vitamin D analogs and parathyroid hormone antagonists, Vitamin B12 analogs and panthenol, interfuron agonists and antagonists, hydroxyacids such as those described in U.S. Patent 5,550,158, benzophenones and hydantoin anticonvulsants such as phenytoin.

Other hair growth agents are described in detail in, for example, JP 09-157139 to Tsuji et al, published June 17, 1997; EP 0277455 Al to Mirabeau, published August 10, 1988; WO 97/05887 to Cabo Soler et al, published February 20, 1997; WO 92/16186 to Bonte et al, published March 13, 1992; JP 62-93215 to Okazaki et al, published April 28, 1987; U.S. Patent 4,987,150 to Kurono et al, issued January 22, 1991 ; JP 290811 to Ohba et al, published October 15, 1992; JP 05-286835 to Tanaka et al, published November 2, 1993, FR 2,723,313 to Greff, published August 2, 1994; U. S. Patent 5,015,470 to Gibson, issued May 14, 1991 ; U.S. Patent 5,559,092, issued September 24, 1996; U.S. Patent 5,536,751, issued July 16, 1996; U.S. Patent 5,714,515, issued February 3, 1998; EP 0,319,991A, published June 14, 1989; EP 0,357,630A, published October 6, 1988; EP 0,573,253A, published December 8, 1993; JP 61-260010, published November 18, 1986; U.S. Patent 5,772,990, issued June 30, 1998; U.S. Patent 5,053, 410, issued October 1, 1991; and U.S. Patent 4,761,401, issued August 2, 1988; all of which are herein incorporated by reference.

These hair growth agents are typically employed in the compositions herein at a level ranging from about 0.01% to about 15%, preferably from about 0.1% to about 10%, most preferably from about 0.5% to about 5%, by weight of the composition.

3. Other Active Ingredients

In addition to other hair growth agents, other hair or skin active agents can be incorporated into the compositions herein in safe and effective amounts. The term "safe and effective amount" as used herein, means an amount of an active ingredient high enough to modify the condition to be treated or to deliver the desired skin or hair benefit, but low enough to avoid serious side effects, at a reasonable benefit to risk ratio within the scope of sound medical judgment. What is a safe and effective amount of the active ingredient will vary with the specific active, the ability of the active to penetrate through the skin/hair, the age, health condition, and skin/hair condition of the user, and other like factors.

The active ingredients useful herein can be categorized by their therapeutic benefit or their postulated mode of action. However, it is to be understood that the active ingredients useful herein can in some instances provide more than one therapeutic benefit or operate via more than one mode of action. Therefore, classifications herein are made for the sake of convenience and are not intended to limit the active ingredient to that particular application or applications listed. Also, pharmaceutically-acceptable salts of these active ingredients are useful herein. The following active ingredients can potentially be useful in the compositions of the present invention.

Non-Steroidal Anti-Inflammatory Actives (NSAIDS): Examples of NS AIDS include the following categories: propionic acid derivatives; acetic acid derivatives; fenamic acid derivatives; biphenylcarboxylic acid derivatives; and oxicams. All of these NSAIDS are fully described in U.S. Patent 4,985,459 to Sunshine et al., issued January 15, 1991, incorporated by reference herein in its entirety. Examples of useful NSAIDS include acetyl salicylic acid, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid. Also useful are the steroidal anti-inflammatory drugs including hydrocortisone and the like.

Topical Anesthetics: Examples of topical anesthetic drugs include beuzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine, phenol, and pharmaceutically acceptable salts thereof. Antimicrobial and Antifungal Actives: Examples of antimicrobial and antifungal actives include B-lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'- trichlorobanilide, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline, clindamycin, ethambutol, hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, lineomycin, methacycline, methenamine, minocycline, neomycin, netilmicin, paromomycin, streptomycin, tobramycin, miconazole, tetracycline hydrochloride, erythromycin, zinc erythromycin, erythromycin estolate, erythromycin stearate, amikacin sulfate, doxycycline hydrochloride, capreomycin sulfate, chlorhexidine gluconate, chlorhexidine hydrochloride, chlortetracycline hydrochloride, oxytetracycline hydrochloride, clindamycin hydrochloride, ethambutol hydrochloride, metronidazole hydrochloride, pentamidine hydrochloride, gentamicin sulfate, kanamycin sulfate, lineomycin hydrochloride, methacycline hydrochloride, methenamine hippurate, methenamine mandelate, minocycline hydrochloride, neomycin sulfate, netilmicin sulfate, paromomycin sulfate, streptomycin sulfate, tobramycin sulfate, miconazole hydrochloride, amanfadine hydrochloride, amanfadine sulfate, octopirox, parachlorometaxylenol, nystatin, tolnaftate, zinc pyrithione and clotrimazole.

Sunscreen Actives: Also useful herein are sunscreening actives. A wide variety of sunscreening agents are described in U.S. Patent No. 5,087,445, to Haffey et al, issued February 11, 1992; U.S. Patent No. 5,073,372, to Turner et al, issued December 17, 1991; U.S. Patent No. 5,073,371, to Turner et al issued December 17, 1991; and Segarin, et al, at Chapter VHI, pages 189 et seq., of Cosmetics Science and Technology, all of which are incorporated herein by reference in their entirety. Nonlimiting examples of sunscreens which are useful in the compositions of the present invention are those selected from the group consisting of 2-ethylhexyl p-methoxycinnamate, 2-ethylhexyl N,N-dimethyl-p- aminobenzoate, p-aminobenzoic acid, 2-phenylbenzimidazole-5-sulfonic acid, octocrylene, oxybenzone, homomenthyl salicylate, octyl salicylate, 4,4'-methoxy-t- butyldibenzoylmethane, 4-isopropyl dibenzoylmethane, 3-benzylidene camphor, 3-(4- methylbenzylidene) camphor, titanium dioxide, zinc oxide, silica, iron oxide, and mixtures thereof. Still other useful sunscreens are those disclosed in U.S. Patent No. 4,937,370, to Sabatelh, issued June 26, 1990; and U.S. Patent No. 4,999,186, to Sabatelh et al, issued March 12, 1991, both of which are incorporated by reference herein in their entirety. Especially preferred examples of these sunscreens include those selected from the group consisting of the 4-N,N-(2-ethylhexyl)methylaminobenzoic acid esters of 2,4-dihydroxybenzophenone, 4-hydroxydibenzoylmethane, 2-hydroxy-4-(2- hydroxyethoxy)benzophenone, and 4-(2-hydroxyethoxy)dibenzoylmethane, and mixtures thereof. Exact amounts of sunscreens which can be employed will vary depending upon the sunscreen chosen and the desired Sun Protection Factor (SPF) to be achieved. SPF is a commonly used measure of photoprotection of a sunscreen against erythema. See, Federal Register, Vol. 43, No. 166, pp. 38206-38269, August 25, 1978, which is incorporated herein by reference in its entirety.

4. Miscellaneous

The compositions of the present invention can comprise a wide range of other optional components. These additional components should be pharmaceutically acceptable. The CTFA Cosmetic Ingredient Handbook, Second Edition, 1992, which is incorporated by reference herein in its entirety, describes a wide variety of nonlimiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention. Examples of these and other functional classes include, but are not limited to, abrasives, absorbents, anticaking agents, antioxidants, vitamins, biological additives, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers, fragrance components, opacifying agents, pH adjusters, propellants, reducing agents, and skin bleaching agents.

The methods of the present invention comprise administration of the compounds of formula I, preferably in the form of the compositions described herein, for regulating hair growth in mammals (e.g., humans and domestic animals). In one embodiment, the present invention provides for the prevention of hair loss. In another embodiment, the present invention provides for the stimulation of new hair growth or hair regrowth. The compositions of the present invention can be administered topically, orally or parenterally. The preferred method of the present invention involves the topical application of the compositions described herein to the scalp, particularly where the scalp is already bald or balding. The amount of the composition and the frequency of application to the hair and or scalp/skin can vary widely, depending on the desired effect and/or personal needs. Typically the composition is applied from about 1 to about 10 times per day, more typically from about 1 to about 6 times per day and most typically from 1 to about 3 times per day. Suitably, the compositions may be applied in liquid form in amounts ranging from about 0.01 to about 100 ml per day, preferably about 0.1 to about 50 ml per day, and more preferably about 1 to about 5 ml per day, and preferably may contain from about 0.01 % to about 50%, more preferably from about 0.1 % to about 10%, and even more preferably from about 0.1 % to about 5%, of the compound of formula I. One skilled in the art will recognize that other dosing regimes and compositions may also be effective in the present methods.

The topical compositions can be delivered to the hair/scalp/skin from a variety of delivery devices. For example, the compositions can be incorporated into pads, for example of the type commonly employed as medicated cleansing pads, or a tissue wipe, or the like. Preferably pads for use in the present methods comprise from about 50% to about 75%o, by weight, of a substrate and from about 25% to about 50% of a liquid composition deliverable from the substrate. Suitable pads are described, for example, in U.S. Patents Nos. 4,891,228 and 4,891,227, issued January 2, 1990, both of which are incorporated by reference.

Alternatively, the compositions useful herein can be incorporated into and delivered from a controlled delivery dispensing device. These devices are useful for the controlled delivery of liquid or semi-liquid compositions to the skin surface and have the advantage that the treatment composition itself never need be directly handled by the user. Nonlimiting examples of these devices comprise a soft-tipped or flexible dispensing device, for example, a fluid container including a mouth, an applicator, means for holding the applicator in the mouth of the container and a normally closed pressure-responsive valve for permitting the flow of fluid from the container to the applicator upon the application of pressure to the valve. The liquid compositions suitable for use in this embodiment preferably comprise from about 0.01% to about 20%, by weight, of a compound of formula I, preferably from about 0.1% to about 10%, and more preferably from about 1% to about 5%, by weight, of a compound according to claim 1.

The valve can include a diaphragm formed from an elastically fluid impermeable material with a plurality of non-intersecting acruate slits therein, wherein each slit has a base which is intersected by at least one other slit, and each slit is out of intersecting relation with its own base, and wherein there is a means for disposing the valve in the container inside of the applicator. Examples of these applicator devices are described in U.S. Patents Nos. 4,693,623 to Schwartzman issued September 25, 1987; 3,669,323 to Harker et al issued June 13, 1972; 3,418,055 to Schwartzman issued December 24, 1968; and 3,410,645 to Schwartzman issued November 12, 1968, all of which are herein incorporated by reference. Examples of applicators useful herein are commercially available from Dab-O-Matic, Mount Vernon, N.Y.

Alternatively, the compositions can be administered with an applicator such as a roll-ball applicator, a controlled dropping applicator, a metered dosing applicator, a fined applicator, or a spray device such as an aerosol can containing propellant, or a container fitted with a pump to dispense the liquid product.

In a further embodiment, the compositions of the invention can be solid or semi- solid, for example, in the form of sticks, creams or gels. Such solid or semi-solid compositions may be formulated for use in conjunction with a suitable applicator or simply a tube, or bottle, or as a liquid-impregnated fabric, such as a tissue wipe.

Topical compositions of the present invention can also be delivered via conventional hair care products, including, but not limited to shampoos, conditioners, styling products, for example gels, mousses and sprays, or other leave-in or rinse off products.

The following examples demonstrate compositions suitable for use in the methods of the present invention. In the examples throughout the present specification, parts and percentages are by weight unless otherwise specified. EXAMPLE 1

This example is directed to a composition suitable for topical application. The composition is prepared by mixing about 15 weight percent of a compound according to formula I, about 30 weight percent water, about 35 weight percent ethanol and about 20 weight percent propylene glycol, according to conventional mixing techniques. The compositions are particularly suitable for topical application and the propylene glycol acts as a penetration aid for the compositions. EXAMPLE 2

This example is directed to compositions which are provided in solid, tablet-like form for oral administration of compounds according to the present invention. The components of the compositions are set forth in Table I:

TABLE 1

The specific embodiments set forth in the specification and examples are illustrative only and are not intended to limit the scope of the present invention. Additional embodiments and advantages provided by the methods of the present invention will be further understood by those skilled in the art and are encompassed by the following claims:

Claims

WHAT IS CLAIMED IS

1 A method for regulating hair growth, characterized m that it compπses administering to a mammal an effective amount of a compound according to formula I.

wherein a is 0 or 1 and each — represents either a single bond or a double bond, provided that two adjacent — are not both double bonds and that when O — C ιsO=C, a is 0, and further wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylacyl and arylacyl, and R is selected from the group consisting of nitrogen-contammg rings and C(CH))=NOR², wherein R² is selected from the group consisting of alkyl and aryl.

2. A method according to claim 1, wherein the mammal is a human and the compound is administered by topical application to the scalp of the human, preferably apphed to bald or balding areas of the scalp.

3. A method according to any preceding claim, wherein the compound is topically applied from 1 to 10 times per day, preferably from 1 to 3 times per day.

4. A method according to any preceding claim, wherein the compound is in a composition which further comprises at least one cosmetically-acceptable earner

5. A method according to any preceding claim, wherein the composition compπses from 0.001% to 50%, by weight, of the compound of formula I, preferably from 0.01% to 25%, more preferably from 0.1% to 15%, more preferably from 1% to 10%.

6. A method according to Claim 1 , wherein the compound is of formula II:

R_aO

wherein the — bonds between Cl and C2, C5 and C6, and C6 and C7 are single bonds, and preferably wherein the — bonds between C4 and C5, and C16 and C17 are double bonds.

7. The method according to claim 6, wherein the moιetyR_aO — C in formula II comprises 0=C or RO-C, wherein R is selected from the group consisting of hydrogen, unsubstituted linear alkyl of 1 to 6 carbon atoms, phenylalkylacyl wherein the alkyl moiety is unsubstituted, linear and of 1 to 6 carbon atoms, and benzoyl.

8. A method according to any of claims 6-7, wherein Rcompπses a 5- or 6-membered nitrogen-contammg ring, preferably wherein Rcompπses -C(CH₃)= NOR² wherein R² comprises hydrogen, alkyl or aryl, preferably wheremR² is hydrogen.

9. A method according to any preceding claim, wherein the compound is applied for a purpose selected from the group consisting of (a) preventing hair loss, (b) stimulating hair growth, (c) stimulating hairregrowth; and (d) combinations thereof.

10. A compound of the formula HI:

III

wherein a is 0 or 1 and each — represents either a single bond or a double bond, provided that two adjacent — are not both double bonds and that when O — C ι£)=C, a is 0, and further wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylacyl and arylacyl, andR is selected from the group consisting of m rogen-contaming πngs and C(CH₃)=NOR², wherein R² is selected from the group consisting of alkyl and aryl, provided that the compound is not 20-hydroxyιmmo-4, 16- pregnadιen-3-one, 17-(3'-pyrazolyl)androsta-4,16-dιen-3b-one, 17-(3'- pyrazolyl)androsta-5,16-dιen-3b-ol, or 17b-(4'-ιmιdazolyl) androsta-4-en-3-one.