NOVEL METHOD FOR REDUCING HAIR GROWTH

The invention relates to a method for reducing hair growth in humans, particularly for cosmetic purposes.

Hair is a characteristic feature of all mammals, including humans. It is primarily composed of proteins, in particular keratin, and is produced in hair follicles within the skin.

There are many reasons, including cultural, cosmetic, or medical reasons, why individuals wish to remove some or all hair from sites of their body. Thus, already for decades, various procedures have been employed to remove unwanted hair, most of them being based on depilation (removal of the part of the hair above the surface of the skin) or epilation (removal of the entire hair). All procedures, however, have significant drawbacks associated with them. Shaving, for example, may cause skin abrasion or cuts, and can lead to a perception of roughness caused by sharp, stubbly hairs as the hair reappears after shaving. Depilation e.g. by waxing or trimming on the other hand is an intrinsically painful and uncomfortable process. Depilatory creams, even though being highly effective, are often messy and difficult to apply and can cause severe skin irritations. Antiandrogens, which are used to treat female hirsutism, reportedly can have significant side effects, mainly due to their effect on the hormone balance in the body.

Thus, there is an ongoing need for efficient and safe compounds which inhibit, reduce or delay the (re-)growth of hair, which compounds can e.g. be used in adjunction with epilation or depilation to prolong the time interval between the mechanical or chemical treatment. Surprisingly, it has now been found that compounds of formula (I) as depicted below respectively a salt thereof are highly efficient in the inhibition of the growth of hair.

Thus, in a first aspect, the invention relates to a cosmetic or a therapeutic method (typically a cosmetic method) of reducing hair growth, said method comprising selecting an area of skin from which reduced hair growth is desired and applying to said area a topical composition comprising at least one compound of formula (I)

wherein

X is CH ₂ or NH and

R ¹ is are selected from the group consisting of a C ₁ -C ₁₀ alkylcarbonyl group, a C ₃ -C ₆ cycloalkylcarbonyl group, an arylcarbonyl group, an aryl C ₁ -C ₆ alkylcarbonyl group or an arylCi-C6 alkyl group.

R ² is an amino acid side chain of a basic amino acid or an amino acid side chain of a 2-amino C _2-8 alkanoic acid;

R ³ and R ^3’ are selected from the group consisting of H, an arylCi-C6 alkyl group or a heteroarylCi-C6 alkyl group, wherein the aryl respectively the heteroaryl can optionally be substituted,

R ⁴ and R ⁵ are, independently of each other, H, a C ₁ -C ₁₀ alkyl group or an arylCi-C6 alkyl group; and

with the proviso that only one of R ³ or R ^3’ is H and the respective other one of R ³ and R ^3’ is not H

or a salt thereof in an amount effective to reduce hair growth.

The unwanted hair growth may be normal but undesirable from a cosmetic perspective or may result, for example, from the symptoms of a disease or an abnormal condition such as hirsutism or hypertrichosis. Individuals who have hair bearing naevi or pseudofolliculitis barbae may also wish to achieve a reduction of hair growth according to the present invention.

In a second aspect, the invention relates to the use of a compound of formula (I) or a salt thereof for the inhibition of hair growth in an individual in need thereof.

In further aspect, the invention provides a method (typically a cosmetic (non-therapeutic) method) of reducing unwanted hair growth by applying to the skin a compound of formula (I) or a salt thereof in an amount effective to reduce hair growth.

In addition, the present invention relates to a compound of formula (I) or a salt thereof respectively a topical composition comprising said compound or the salt thereof for reducing hair growth in individuals suffering from a disorder resulting in excessive hair growth such as hirsutism or hypertrichosis.

The term‘C _x -C _y alkylcarbonyl group’ as used herein refers to a‘C _x -C _y alkyl group’ linked via a carbonyl (C=0) residue to X, the term‘C _x -C _y alkyl group’ referring to unbranched C _x -C _y alkyl or branched C3-C _y alkyl groups. Exemplary unbranched C _x -C _y alkyl or branched C3-C _y alkyl groups encompass methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1 , 1 -dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1- ethylpropyl, n-hexyl, 1 , 1 -dimethyl propyl, 1 ,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 , 1 -dimethyl butyl, 1 ,2-dimethylbutyl, 1 ,3-dimethyl butyl, 2,2- dimethyl butyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 -methylpropyl, 1-ethyl-2-methylpropyl and 3,5,5-trimethylhexyl groups.

The term‘C3-C6cycloalkylcarbonyl group’ as used herein refers to a C3-C6cycloalkyl group linked via a carbonyl (C=0) residue to X, the term C3-C6cycloalkyl group referring to saturated, 3 to 6 membered hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl Preferably in all embodiments of the present invention the C3-C6cycloalkyl group is cyclopropyl, cyclopentyl or cyclohexyl, most preferably cyclohexyl.

The term‘arylcarbonyl’ as used herein refers to an aryl group linked via a carbonyl (C=0) residue to X, the term‘aryl’ referring to an aromatic substituent containing 5 to 15 carbon atoms and containing a single aromatic ring or multiple aromatic rings which are fused together, directly linked or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene group). A particularly preferred‘arylcarbonyl’ when X is NH is benzoyl.

The term aryl groups as used herein refers to unsubstituted as well as substituted aryl groups. Particularly advantageous aryl groups in all embodiments according to the present invention contain 6 to 12 carbon atoms containing a single aromatic ring or multiple aromatic rings which are fused together or directly linked. Said aryl groups may furthermore optionally be substituted, preferably with one residue selected from halogen or an alkoxy group, such as with F or (m)ethoxy, even more preferably in para-position. Most preferred aryl residues in all embodiments of the present invention are, optionally substituted phenyl, naphtyl and biphenyl. Particularly advantageous aryl groups according to the present invention contain 6 to 12 carbon atoms containing a single aromatic ring or multiple aromatic rings which are fused together or directly linked. Preferably, in all embodiments of the present invention, if the aryl group is phenyl, it is unsubstituted or substituted with one alkoxy group such as preferably a methoxy group. Most preferred aryl residues in all embodiments of the present invention are phenyl, 4-methoxyphenyl, naphtyl and biphenyl.

The term‘arylCi-C ₆ alkyl group’ as used herein refers to a -C1-C6 alkyl-aryl group (i.e. linked via the alkyl group), wherein the term‘aryl’ is as defined above. Advantageous arylCi-C ₆ alkyl groups are arylCi-C2 alkyl groups such as in particular phenyl(m)ethyl, 4-methoxyphenyl(m)ethyl, or naphthyl(m)ethyl.

The term‘aryl C1-C6 alkylcarbonyl group’ as used herein refers to a -C1-C6 alkyl-aryl group as defined above linked via a carbonyl (C=0) residue to X, such as e.g. a benzoyl group.

The term‘side chain’ of an amino acid as used herein refers to that portion of the amino acid attached to the common NFh-kl-l-COOH backbone of the respective amino acids. For instance, the side chain of serine is -CH ₂ -OH and the side chain of alanine is -CH ₃ .

The term‘basic amino acid’ as used herein refers to any natural or unnatural amino acid that have basic side chains at neutral pH such as the natural occurring amino acids arginine (Arg), lysine (Lys), and histidine (His) as well as the unnatural amino acids 2,4-diaminobutyric acid, homolysine and ornithine without being limited thereto. Advantageous amino acid side in all embodiments of the present invention are the side chains of arginine, lysine, 2,4-diaminobutyric acid, homolysine and ornithine such as in particular the side chains of arginine and 2,4-diaminobutyaric acid and most preferably the one of arginine.

The term‘2-amino C2-8 alkanoic acid’ as used herein refers to amino acids having a C2-8 alkyl side chain, preferably a linear C4-7 alkyl side chain. Most preferred 2-amino C^ alkanoic acids in all embodiments of the present invention are 2-amino butanoic acid, 2-amino pentanoic acid, 2- amino hexanoic acid or 2-amino heptanoic acid such as in particular 2-amino hexanoic acid.

The term‘heteroarylCi-C ₆ alkyl group’ as used herein refers to a -C1-C6 alkyl-heteroaryl wherein the term ‘heteroaryl’ refers to a 5- or 6-membered aromatic ring containing one or more heteroatoms, viz., N, O or S; these heteroaromatic rings may be fused to other aromatic systems. Particularly preferred heteroaromatic rings encompass indole, pyridine and quinoline. In all embodiments of the present invention preferred heteroarylCi-C ₆ alkyl group are heteroarylCi-C2 alkyl groups such as (1 H-indol-3-yl)(m)ethyl, (pyridin-2-yl)(m)ethyl, (pyridin-3-yl)(m)ethyl, (quinolin-2-yl)(m)ethyl and (quinolin-3-yl)(m)ethyl groups.

The aromatic aryl respectively heteroaryl residues may, independently of each other, be unsubstituted or substituted with one or more substituents. In all embodiments of the present invention, such substituents are preferably selected from halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkanoyloxy. More preferably in all embodiments of the present invention the aryl respectively heteroaryl residues are, independently of each other, unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, hydroxy, cyano, C1 -C3 alkyl, C1 -C3 alkoxy and C1 -C3 alkanoyloxy such as in particular unsubstituted or substituted with one substituent selected from the group consisting of F or hydroxy. Most preferably, in all embodiments of the present invention, the aryl and the heteroaryl residues are unsubstituted.

In all embodiments of the present invention particular preferred heteroarylCi-C2 alkyl groups are (1 H-indol-3-yl)(m)ethyl, 5-fluoro(1 H-indol-3-yl)(m)ethyl, 6-fluoro(1 H-indol-3-yl)(m)ethyl, 5- hydroxy(1 H-indol-3-yl)(m)ethyl, (pyridin-2-yl)(m)ethyl, (pyridin-3-yl)(m)ethyl, (quinolin-2- yl)(m)ethyl and (quinolin-3-yl)(m)ethyl. Most preferred in all embodiments of the present invention are the heteroarylCi alkyl groups (1 H-indol-3-yl)methyl, 5-fluoro(1 H-indol-3-yl)methyl, 6- fluoro(1 H-indol-3-yl)8m)ethyl, 5-hydroxy(1 H-indol-3-yl)methyl, (pyridin-2-yl)methyl, (pyridin-3- yl)methyl, (quinolin-2-yl)methyl and (quinolin-3-yl)methyl and the heteroarylC2 alkyl groups (1 H- indol-3-yl)ethyl such as in particular (1 H-indol-3-yl)methyl and (1 H-indol-3-yl)ethyl.

Particularly suitable amino acid side chain of 2-amino C2-8 alkanoic acid are the ones of 2-aminopentanoic acid, 2-aminohexanoic acid and 2-aminohexanoic acid. The most preferred amino acid side chain of a 2-amino C2-8 alkanoic acid in all embodiments of the present invention is the amino acid side chain of 2-aminohexanoic acid.

The term‘or a salt thereof refers to all conventional non-toxic salts of compounds of formula (I), such as those formed from organic or mineral acids, such as for example the respective acetates, trifluoro acetates, mesylates, citrates, oleates, oxalates or gluconates as well as chlorides, sulfates, borates or carbonates. The nature of the salt is not critical, provided that it is cosmetically, dermatologically and/ or pharmaceutically acceptable. Such salts are well known to a person skilled in the art. The cosmetically, dermatologically or pharmaceutically acceptable salts of the compounds of formula (I) can be obtained by conventional methods that are well known in the state of the art.

Most preferred in all embodiments of the present invention are the compounds of formula (I) as such or in the form of their acetates, trifluoroacetates (i.e. as 2,2,2-trifluoroacetates) or mesylates. Such salts are easily prepared by a person skilled in the art.

It is well understood, that the present invention encompasses the compounds of formula (I) as optically pure isomers such as e.g. as pure enantiomers or stereoisomers as well as mixtures of different isomers such as e.g. as racemates, or mixtures of diastereoisomers.

In all embodiments according to the present invention it is preferred that

• R ³ and R ^3’ are selected from the group consisting of H, an unsubstituted aryl(m)ethyl group and an unsubstituted heteroaryl(m)ethyl group, most preferably R ³ is selected from the group consisting of H, phenylmethyl, naphthylmethyl and (1 H-indol-3-yl)methyl and R ^3’ is H or (1 H-indol-3-yl)ethyl;

• R ⁴ and R ⁵ are, independently of each other, H, a C3-C8 alkyl group or an arylCi-C3 alkyl group, most preferably H, propyl, octyl or benzyl; and with the proviso that only one of R ³ or R ^3’ is H and the respective other one of R ³ and R ^3’ is not H (but the respective arylCi-C ₆ alkyl group or heteroarylCi-C ₆ alkyl group, with all the definitions and preferences as given herein for R ³ and R ^3’ ).

It is furthermore preferred that if one of R ⁴ and R ⁵ is benzyl the other one is H.

In all embodiments of the present invention it is furthermore preferred that the side chain of the amino acid is selected from the side chain of arginine, 2,4 diaminobutyric acid or 2-aminohexanoic acid.

Particularly preferred compounds of formula (I) respectively a salt thereof such as in particular the acetate, trifluoroacetate or mesylate salt thereof in all embodiments of the present invention, are compounds of formula (I) wherein

X is NH or CH ₂

R ¹ is a Ci-C ₂ alkylcarbonyl group or a C ₆ -C ₁₂ arylcarbonyl group or an arylCi-C ₃ alkyl group;

R ² is an amino acid side chain of a basic amino acid such as preferably of arginine or 2,4-diaminobutyric acid or the amino acid side chain of 2-aminohexanoic acid;

R ³ and R ^3’ are selected from the group consisting of H, an unsubstituted aryl(m)ethyl group or an unsubstituted heteroaryl(m)ethyl group; and

R ⁴ and R ⁵ are, independently of each other H, a Ci-Cioalkyl group or an arylCi-C ₃ alkyl group; and with the proviso that only one of R ³ or R ^3’ is H and the respective other one of R ³ and R ^3’ is not H.

Particularly advantageous compounds of formula (I) respectively a salt thereof such as in particular the acetate, trifluoroacetate or mesylate salt thereof in all embodiments of the present invention, are compounds of formula (I) wherein

X is NH or CH ₂

R ¹ is a Ci-C ₂ alkylcarbonyl group or a C ₆ -C ₁₂ arylcarbonyl group, a phenylCi-C ₂ alkyl group or a methoxyphenylCi-C2 alkyl group;

R ² is an amino acid side chain of a basic amino acid such as preferably of arginine or 2,4-diaminobutyric acid or the amino acid side chain of 2-aminohexanoic acid;

R ³ and R ^3’ are selected from the group consisting of H, an unsubstituted aryl(m)ethyl group or an unsubstituted heteroaryl(m)ethyl group; and R ⁴ and R ⁵ are, independently of each other H, a Ci-Cioalkyl group or an arylCi-C3 alkyl group; and with the proviso that only one of R ³ or R ^3’ is H and the respective other one of R ³ and R ^3’ is not H.

Even more preferred compounds of formula (I) or salts thereof such as in particular the trifluoroacetate or mesylate salt thereof in all embodiments of the present invention are the ones, wherein

X is NH or CH ₂ ,

R ¹ is phenylcarbonyl, benzyl or 4-methoxybenzyl;

R ² is the amino acid side chain of arginine, 2-aminohexanoic acid, or 2,4-diaminobutyric acid, preferably of arginine or 2-aminohexanoic acid;

R ³ is H, phenylmethyl, naphthylmethyl or (1 H-indol-3-yl)methyl and R ^3’ is H or (1 H-indol-3- yl)ethyl;

R ⁴ and R ⁵ are, independently of each other H, propyl, octyl or benzyl;

with the proviso that only one of R ³ or R ^3’ is H and the respective other one of R ³ and R ^3’ is not H.

Even more advantageous compounds of formula (I) or salts thereof such as in particular the trifluoroacetate or mesylate salt thereof in all embodiments of the present invention are the ones, wherein

X is NH or CH ₂ ,

R ¹ is phenylcarbonyl, benzyl or methoxybenzyl;

R ² is the amino acid side chain of arginine or of 2-aminohexanoic acid;

R ³ is (1 H-indol-3-yl)methyl and R ^3’ is H;

R ⁴ and R ⁵ are propyl or benzyl.

Particularly advantageous compounds of formula (I) according to the present invention are compounds of formula (II)

wherein

R ^1a is are selected from the group consisting of a C ₁ -C ₁₀ alkyl group, a C ₃ -C ₆ cycloalkyl group, an aryl group or an aryl C ₁ -C ₆ alkyl group;

R ^2a is an amino acid side chain of a basic amino acid or an amino acid side chain of a 2-amino C _2-8 alkanoic acid;

R ^3a and R ^3a’ are selected from the group consisting of H, an arylCi-C ₆ alkyl group or a heteroarylCi-C ₆ alkyl group, wherein the aryl respectively the heteroaryl can optionally be substituted,

R ^4a and R ^5a are, independently of each other, H or a C ₁ -C ₁₀ alkyl group; and with the proviso that only one of R ^3a or R ^3a’ is H and the respective other one of R ^3a and R ^3a’ is not H

Preferred are compounds of formula (II) wherein

• R ^3a and R ^3a’ are selected from the group consisting of H, an unsubstituted aryl(m)ethyl group and an unsubstituted heteroaryl(m)ethyl group, most preferably R ^3a is selected from the group consisting of H, phenylmethyl, naphthylmethyl and (1 H-indol-3-yl)methyl and R ^3a is H or (1 H-indol-3-yl)ethyl;

• R ^4a and R ^5a are, independently of each other, H or a C ₃ -C ₈ alkyl group, most preferably H, propyl or octyl; and

with the proviso that only one of R ^3a or R ^3a’ is H and the respective other one of R ^3a and R ^3a’ is not H (but the respective arylCi-C ₆ alkyl group or heteroarylCi-C ₆ alkyl group, with all the definitions and preferences as given herein for R ^3a and R ^3a ). Particularly preferred compounds of formula (II) respectively a salt thereof such as in particular the acetate, trifluoroacetate or mesylate salt thereof in all embodiments of the present invention, are compounds of formula (I) wherein

R ^1a is a C1-C2 alkyl group or a C6-C12 aryl group;

R ^2a is an amino acid side chain of a basic amino acid;

R ^3a and R ^3a’ are selected from the group consisting of H, an unsubstituted aryl(m)ethyl group or an unsubstituted heteroaryl(m)ethyl group; and

R ^4a and R ^5a are, independently of each other H or a CrCioalkyl group; and

with the proviso that only one of R ^3a or R ^3a’ is H and the respective other one of R ^3a and R ^3a’ is not H.

Even more preferred compounds of formula (II) or salts thereof such as in particular the trifluoroacetate or mesylate salt thereof in all embodiments of the present invention are the ones, wherein

R ^1a is phenyl;

R ^2a is the amino acid side chain of arginine or 2,4-diaminobutyric acid, preferably of arginine; R ^3a is H, phenylmethyl, naphthylmethyl or (1 H-indol-3-yl)methyl and R ^3a’ is H or (1 H-indol-3- yl)ethyl;

R ^4a and R ^5a are, independently of each other H, propyl or octyl;

with the proviso that only one of R ^3a or R ^3a’ is H and the respective other one of R ^3a and R ^3a’ is not H.

In another preferred embodiment, the compounds of formula (I) according to the present invention are compounds of formula (III)

wherein

R ^{1 b} is are selected from the group consisting of a aryl group or an aryl C1 -C3 alkyl group, wherein the aryl group is optionally substituted with one residue selected from halogen or a (m)ethoxygroup, preferably with F or methoxy, most preferably in para-position;

R ^2b is the amino acid side chain of arginine or 2-amino hexanoic acid;

R ^3b is selected from the group consisting of selected from the group consisting of an unsubstituted aryl(m)ethyl group or an unsubstituted heteroaryl(m)ethyl group, and R ^4b and R ^5b are, independently of each other, H, a C1-C10 alkyl group or an arylCi-C ₆ alkyl group.

Particularly preferred compounds of formula (III) respectively a salt thereof such as in particular the acetate, trifluoroacetate or mesylate salt thereof in all embodiments of the present invention, are compounds of formula (I) wherein

R ^{1 b} is benzyl or a 4-methoxybenzyl;

R ^2a is the an amino acid side chain of arginine or 2-amino hexanoic acid;

R ^3b is selected from the group consisting of an unsubstituted aryl(m)ethyl group or an unsubstituted heteroaryl(m)ethyl group; and

R ^4b and R ^5b are, independently of each other H, a CrCsalkyl group or an arylCi-C3 alkyl group.

Even more preferred compounds of formula (III) or salts thereof such as in particular the trifluoroacetate or mesylate salt thereof in all embodiments of the present invention are the ones, wherein

R ^{1 b} is benzyl or 4-methoxybenzyl;

R ^2b is the amino acid side chain of arginine or 2-aminohexanoic acid;

R ^3b is phenylmethyl, naphthylmethyl or (1 H-indol-3-yl)methyl;

R ^4b and R ^5b are, independently of each other H, propyl or benzyl, with the proviso that it is even more preferred that when R ^4b is benzyl, R ^5b is H. Particularly advantageous compound of formula (I) in all embodiments of the present invention are the compounds as listed in table 1 , respectively the respective trifluoroacetate or mesylate salts thereof:

Table 1

The compounds according to the present invention may be prepared by methods standard in peptide chemistry as e.g. illustrated in WO-2018065345. Most preferred in all embodiments is Bz-Gly-His-D-Phe-Arg-D-Trp-N(Pr)2 ^* 2MSA [CAS No. 2210277-15-7], which preferably is used in the form of a solution in glycerin/ water, most preferably in a concentration of about 1000 ppm (w/w).

The compounds of formula (I) respectively a salt thereof are preferably applied to the affected skin area in the form of a topical composition. Preferred topical compositions in all embodiments of the present invention are cosmetic or pharmaceutical compositions further comprising a cosmetically or pharmaceutically acceptable carrier.

The term‘cosmetic composition’ as used herein refers to compositions which are used to treat, care for or improve the appearance of the affected skin area. Particular advantageous cosmetic compositions according to the present invention are skin care compositions.

The term‘pharmaceutical composition’ as used herein refers to compositions which are used to treat a disorder.

The term ‘cosmetically or pharmaceutically acceptable carrier’ as used herein refers to a physiologically acceptable medium which is compatible with keratinous substances such as the skin. Suitable carriers are well known in the art and are selected based on the end-use application.

Preferably, the carriers of the present invention are particularly suitable for application to skin (e.g., sunscreens, creams, milks, lotions, masks, serums (e.g. in ethanol or acetone), hydrodispersions, foundations, creams, creamgels, or gels etc.). Such carriers are well-known to one of ordinary skill in the art and can include one or more compatible liquid or solid filler diluent, excipient, additive or vehicle which are suitable for application to skin. The exact amount of carrier will depend upon the level of the compound of formula (I) and any other optional ingredients that one of ordinary skill in the art would classify as distinct from the carrier (e.g., other active components). The compositions of the present invention preferably comprise from about 75% to about 99.999%, more preferably from about 85% to about 99.99%, still more preferably from 90% to about 99%, and most preferably, from about 93% to about 98%, by weight of the composition, of a carrier.

The term ‘effective amount’ as used herein refers to an amount necessary to obtain the physiological effect. The physiological effect may be achieved by one single dose or by repeated doses. The dosage administered may, of course, vary depending upon known factors, such as the physiological characteristics of the particular composition and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired and can be adjusted by a person skilled in the art.

Preferably, the amount of the compound of formula (I) or a salt thereof in the topical compositions according to the present invention is at least 1 ppm based on the total weight of the topical composition. In all embodiments of the present invention the amount of the compound of formula (I) or a salt thereof is preferably selected in the range of about 0.00001 to 0.5 wt.-%, more preferably in the range of 0.0001 to 0.25 wt.-%, most preferably in the range of 0.0001 to 0.1 wt.-%, based on the total weight of the topical composition.

The topical compositions of the present invention can be formulated into a wide variety of product types, including creams, waxes, pastes, lotions, milks, mousses, gels, oils, tonics, and sprays. Preferably the compounds of formula (I) are formulated into lotions, creams, gels, and tonics. These product forms may be used for a number of applications, including, but not limited to, hand and body lotions, facial moisturizers, anti-ageing preparations, make-ups including foundations, and the like. Any additional components required to formulate such products vary with product type and can be routinely chosen by one skilled in the art. The composition may also be in the form of a shaving preparation or an aftershave product intended for application to the skin after shaving.

If compositions of the present invention are formulated as an aerosol and applied to the skin as a spray-on product, a propellant is added to the composition.

The topical compositions according to the present invention may be in the form of a suspension or dispersion in solvents or fatty substances, or alternatively in the form of an emulsion or micro emulsion (in particular of oil-in-water (O/W) or water-in-oil (W/O) type, silicone-in-water (Si/W) or water-in-silicone (W/Si) type, PIT-emulsion, multiple emulsion (e.g. oil-in-water-in oil (O/W/O) or water-in-oil-in-water (W/O/W) type), pickering emulsion, hydrogel, alcoholic gel, lipogel, one- or multiphase solution or vesicular dispersion or other usual forms, which can also be applied by pens, as masks or as sprays. If the cosmetic composition is an emulsion, such as in particular an O/W, W/O, Si/W, W/Si, O/W/O, W/O/W multiple or a pickering emulsion, then the amount of the oily phase present in such cosmetic emulsions is preferably at least 10 wt.-%, such as in the range of 10 to 60 wt.-%, preferably in the range of 15 to 50 wt.-%, most preferably in the range of 15 to 40 wt.-%, based on the total weight of the cosmetic composition.

In one embodiment, the topical compositions according to the present invention are advantageously in the form of an oil-in-water (O/W) emulsion comprising an oily phase dispersed in an aqueous phase in the presence of an O/W emulsifier. The preparation of such O/W emulsions is well known to a person skilled in the art.

In a particular advantageous embodiment, the topical compositions according to the present invention are in the form of O/W emulsions comprising an oily phase dispersed in an aqueous phase in the presence of an O/W emulsifier, preferably in the presence of potassium cetyl phosphate. The amount of oily phase in such O/W emulsions is preferably at least 10 wt.-%, more preferably in the range of 10 to 60 wt.-%, most preferably in the range of 15 to 50 wt.-%, such as in the range of 15 to 40 wt.-%.

In another particular advantageous embodiment, the topical compositions according to the present invention are after-shaves or toners in the form of aqueous solution or aqueous gels further containing at least one gelling and/ or thickening agent such as e.g. selected from the group of acrylate copolymers of sodium/lecithin, copolymer of hydroxyethyl acrylate/sodium acryloyldimethyl taurate, isohexadecane, polysorbate 60, xanthan gum, carrageenan and mixtures thereof.

The topical compositions according to the invention in general have a pH in the range of 3 to 14. Generally topical compositions for skin care preferably exhibit a pH in the range of 4 to 8 and most preferably a pH in the range of 4 to 7.5. The pH of depilatory creams, however, generally is selected in the range of > 12. The pH can easily be adjusted as desired with suitable acids, such as e.g. citric acid, or bases, such as sodium hydroxide (e.g. as aqueous solution), triethanolamine (TEA Care), Tromethamine (Trizma Base) and Aminomethyl Propanol (AMP-Ultra PC 2000), according to standard methods in the art. The topical compositions according to the present invention can be prepared by conventional methods in the art such as e.g. by admixing a compound of formula (I) or a salt thereof with all the definitions and preferences given herein with an appropriate carrier such as a cosmetically or pharmaceutically acceptable carrier. The cosmetic compositions of the invention (including the carrier) may comprise further conventional cosmetic adjuvants and additives, such as preservatives/antioxidants, fatty substances/oils, water, organic solvents, silicones, thickeners, softeners, emulsifiers, antifoaming agents, aesthetic components such as fragrances, surfactants, fillers, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or basifying agents, dyes, colorings/colorants, abrasives, absorbents, chelating agents and/ or sequestering agents, essential oils, skin sensates, astringents, pigments or any other ingredients usually formulated into such compositions.

The topical compositions according to the present invention should be topically applied to a selected area of the body from which it is desired to reduce hair growth. For example, the composition can be applied to the face, particularly to the beard area of the face, i.e., the cheek, neck, upper lip, and chin.

The topical composition according to the present invention can also be applied to the legs, groin region (bikini area), arms, torso or armpits. The topical compositions according to the present invention are furthermore particularly suitable for reducing the growth of unwanted hair in women having hirsutism or other conditions. In humans, the composition should be suitably applied once a day, preferably at least twice a day, to achieve a perceivable reduction in hair growth. Perception of reduced hair growth could occur as early as 24 hours or 48 hours (for instance, between normal shaving intervals) following use, but may require several months. Reduction in hair growth is demonstrated when, for example, the rate of hair growth is slowed, the need for removal is reduced, the subject perceives less hair on the treated site, or quantitatively, when the weight of hair removed is reduced.

The amount of the topical composition to be applied to the skin is not critical and can easily be adjusted by a person skilled in the art. Preferably the amount is selected in the range of 0.1 to 3 mg/cm ² skin, such as preferably in the range of 0.1 to 2 mg/cm ² skin and most preferably in the range of 0.5 to 2 mg/cm ² skin. Preferably, the compound of formula (I) or a salt thereof is applied to the skin in an amount of from 0.001 to 10 micrograms of the compound of formula (I) per square centimeter of skin.

In an advantageous embodiment, the present invention is directed to the use of a topical compositions according to the present invention for delaying hair growth in combination with a short-term or instantaneous method of hair removal. By "in combination with" it is meant that the application of the composition of the invention to the surface of the skin within one hour or less of the hair removal by the other method.

The short-term or instantaneous method of hair removal can be performed by any method well known in the art, including, but not limited to chemical or mechanical depilation such as, shaving (whether using razors, electrical shavers, or clippers or the like), wax depilation, chemical depilation (i.e. dissolution of hair by a depilation agent such as an alkaline thioglycolate), mechanical plucking with an epilator and combinations thereof. Other methods by which hair may be removed include electrology (in which electrical current is applied to hair follicles), and laser hair removal. By short-term or instantaneous it is meant that the hair removal method removes the hair by cutting, dissolution or plucking, but does not prevent or inhibit regrowth of the hair.

The time at which the topically active or the topical composition is applied to the skin, as well as the amount of time for which the composition remains on the skin, may vary, but is suitably within one hour of instantaneous hair removal. Preferably the topical composition is applied to the skin surface either immediately before, immediately after or simultaneously with instantaneous hair removal. More preferably, the topical composition is applied either simultaneously with or immediately following hair removal, most preferably immediately following instantaneous hair removal, and is left on the skin for a period sufficient to obtain an effect to delay hair growth, preferably at least five minutes and more preferably at least fifteen minutes. Most preferably, the composition is allowed to remain on the skin indefinitely to permit absorption into the skin. An advantage of this aspect of the invention is that the compounds of formula (I) or a salt thereof combines a skin tanning effect with the inhibition, delay or reduction in hair growth.

Except where the context requires otherwise, the uses and methods of the invention may be used in the inhibition of hair growth in both human and non-human subjects. For example, the invention may be used in animals which suffer from in-growing hairs or hypertrichosis, especially domestic animals such as cats and dogs. Preferably, however, the uses and methods of the invention are used in the inhibition of hair growth in human subjects.

Inhibition of hair growth may be assessed with reference to the elongation of the hair shaft. It will be appreciated that an agent that reduces elongation of a hair shaft as compared to a suitable control demonstrates the ability to inhibit hair growth.

Suitably the agents, methods, or compositions of the invention may be able to bring at least a 5 % inhibition of hair growth, i.e. a 5 % reduction in the elongation of the hair when compared to a respective control (i.e. non-treated/ vehicle treated area). In a suitable embodiment, an agent, method, or composition of the invention may be able to bring about a 10%, 15% or 20% inhibition of hair growth. The requisite extent of inhibition may be demonstrated in any of the experimental models of hair growth elongation as illustrated in the example.

In a suitable embodiment, the hair growth to be inhibited is regrowth of hair after hair removal. The uses, methods, and compositions of the invention may thus be used to prolong the effects of hair removal. This may allow greater time to elapse between incidences of hair removal. In a suitable embodiment, an agent, method, or composition of the invention may be able to increase the time elapsing between incidences of hair removal by 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or more. The increase in the time between incidences of hair removal achieved may be determined with reference to suitable controls.

In a suitable embodiment the topical composition according to the present invention may be formulated for use in combination with a device which enhances transdermal penetration of the composition. The composition may thus be applied to the area requiring hair growth inhibition prior to use of the device, or concurrently with use of the device. Merely by way of example such devices may include devices which produce electrical current such as galvanic devices, lasers, devices which produce vibrations such as ultrasound, and massage devices which enhance blood circulation around the hair follicles.

The invention is further illustrated with reference to the following, non-limiting examples, in which all percentages are by weight based on total weight unless otherwise specified.

Experimental part 1. Growth inhibition of hair follicle dermal papilla cells

Human hair follicle dermal papilla cells used at the 6 ^th passage, were seeded in 96-well plates and cultured for 24 hours in culture medium at 37°C, 5% CO2. The medium was then replaced with assay medium and the cells were incubated overnight. The medium was then replaced with assay medium containing or not (control) the test compounds and the cells were incubated for 72 hours. BrdU was added for the last 24 hours of incubation. At the end of incubation, the cell proliferation was evaluated using an ELISA kit (ROCHE, ref. 11647229001) measuring BrdU incorporation according to the supplier’s instructions.

*[cell growth sample -cell growth control set to 100%]

2. Hair growth inhibition

Microdissection of human hair follicles: Human scalp skin samples containing mainly anagen VI hair follicles were obtained from elective face-lift plastic surgery. Informed consent was obtained. Hair follicles were truncated below the dermis, while the remaining hair bulb was separated from the dermal/subcutaneous tissue and placed in appropriate culture medium. Before the experiment, each hair follicle underwent a stringent selection, that is operated by controlling the hair shaft elongation following 18 hrs of organ culture, as well as the general organ morphology. Only the hair follicles that grew at least 0.19 ± 0.02 mm/18 hrs were used for the experiment. Treatment: The hair growth inhibition of Bz-Gly-His-D-Phe-Arg-D-Trp-N(Pr)2 ^* 2MSA in the concentrations as indicated in table 2 was assessed versus control, i.e. versus a treatment with the vehicle (i.e. DMSO) alone.

Evaluation of hair growth inhibition : pictures of the hair follicles in culture were taken at baseline and after 4 days and the hair shaft elongation was measured to determine the hair growth.

Table 2: Results

As can be retrieved from the results depicted in table 2, the compounds according to the present invention significantly reduced the hair growth.

3. Topical anti-hair growth compositions

Generally, the ingredients are listed by their I NCI names, with the exception of the compound of formula (I) which is labeled as Bz-Gly-His-D-Phe-Arg-D-Trp-N(Pr)2 ^* 2MSA (compound of formula (Id) in table I in the form of its mesylate salt).