HK1022140A - Method for treatment of dermatological disorders - Google Patents

Description

Method for treating skin diseases

Priority of U.S.S.n60/030,512 entitled "method of treating skin disorders" filed 11/12/1996, according to 35 U.S.C. § 119(e), the entire disclosure of which is incorporated herein by reference.

Technical Field

The present invention relates to cosmetic or pharmaceutical compositions comprising as active ingredient a novel ester of an alpha, omega-carboxylic acid (6-14C atom) covalently linked to a keratolytically active alcohol. The invention also relates to methods of administering such compositions in the treatment of skin disorders.

Background

A number of skin disorders can lead to hypertrophy of the stratum corneum, a condition which is also described as hyperkeratosis. The thickened epidermis results in scaly plaques on the skin surface. These scale plaques are, due to their similarity to fish scales, the appearance of a class of diseases known as ichthyosis. Plaque may be a symptom of skin disease, and thus may interfere with treatment of diseases originating from the inner layers of the skin. The hypertrophic skin layer itself also has infections concentrated within it.

Typical examples of ichthyosis for which the etiology has not been known to date include psoriasis, pityriasis, rosacea and seborrheic dermatitis. These diseases can be treated symptomatically with keratolytic agents to remove plaque; or symptomatic treatment with glucocorticoids to reduce inflammation. The skin disease is ichthyosis caused by fungal infection. Hyphae and spores confine the non-viable parts of the tissue and therefore proliferate in hyperkeratotic tissues of the skin, hair and nails. Typical examples of skin diseases include tinea capitis (cradle cap), dermatophytosis (tinea pedis), and onychomycosis. These conditions can be treated with antifungal agents, typically with keratolytic agents, to remove the confined and infected skin layers.

Skin diseases can also be caused by hormonal dyssecretion. This imbalance can cause increased testosterone levels, particularly at the beginning of puberty. Testosterone is reduced to Dihydrotestosterone (DHT) in targeted tissues, including sebaceous glands. In common acne skin diseases, DHT binds to receptors in the pilosebaceous glands, stimulating excessive sebum secretion. Sebum can be used as a nutrient for bacteria, including Propionibacterium acnes, which infect sebaceous glands, causing inflammation and abnormal keratinization of the skin. Acne is typically treated with antiseptics and disinfectants, and also with keratolytics, such as salicylic acid or retinoic acid, to remove hyperkeratotic tissue.

Skin disorders such as those described above are cosmetically disturbing and are often considered to include cosmetic methods. They can be treated by using well-known drugs, however, it is generally known that cosmetic preparations such as soaps, lotions and shampoos can also be used to alleviate conditions such as acne, dandruff, seborrhea and androgenic alopecia.

Azelaic acid (AZA) is a naturally occurring nine carbon linear molecule with two carboxyl end groups. AZA is an anti-keratinizing agent, has an anti-proliferative effect on keratinocytes isolated from the stratum corneum, and modulates the early and late stages of epidermal differentiation (Passi et al, G.Ital. Dermatol. Venerol.1989,124(10): 455-463). AZA is a competitive inhibitor of the reduction of testosterone to dihydrotestosterone and also reduces sebum production in the sebaceous glands. Further, recent studies have shown that AZA and sebacic acid also have antibacterial and antifungal properties. Structure-activity relationship studies have shown that alpha, omega-dicarboxylic acids can maintain this effect when they have a backbone of about 6 to 14 carbon atoms.

It follows that azelaic acid and other α, ω -dicarboxylic acids can be used as therapeutic agents in the treatment of skin diseases, however the treatment of such diseases is affected by the low bioavailability of such therapeutic agents. Due to the presence of two carboxyl groups, dicarboxylic acids such as azelaic acid are therefore very polar; due to this polarity, skin permeability is low. In addition, the presence of acid functionality lowers the pH, which can irritate the skin. In topical formulations (20%), only high concentrations of azelaic acid will work in the treatment of acne. To illustrate how weak the therapeutic effect of the AZA lotion is, for twice daily administration, 20% of the formulation will only have an effect after 3-6 months of topical application. See A.Fitton and K.L.Goa, Drugs41:780-798 (1991). Further, in additional studies, topical application of AZA did not induce specific changes in sebum composition, sebum secretion rate and sebaceous gland size (see, e.g., Mayer-da-Silva et al, 1989, Acta derm. Venoreol. Suppl. (Stockholm)143: 20-23). Other dermatological agents also include polar functional groups, such as carboxyl or hydroxyl groups, which make them relatively low in skin permeability. There is thus a need to improve the efficacy of these drugs in the treatment of skin disorders, and the bioavailability of the drugs by topical administration should be improved.

Alpha, omega-dicarboxylic acids and their mercapto, ester and salt derivatives have been used to treat various skin disorders. For a relevant discussion of its use, reference may be made to the following references.

U.S. patent 4,034,077 to Hill et al uses compositions containing sebacic acid to treat skin irritation and prevent diaper rash, wherein the dicarboxylic acid serves as a barrier between urine and skin and also neutralizes ammonia. This patent does not use sebacic acid for the treatment of any intrinsic disease, including any form of ichthyosis, nor for the treatment of any hormonal dyssecretion.

Nazzaro-Porro (U.S. Pat. No. 4,292,326) discloses a method of treating hyperpigmented skin disorders using dicarboxylic acids such as azelaic acid. These acids and their mono-and dimercapto derivatives are capable of normalizing skin color by inhibiting melanogenesis. Nazzaro-Porro (U.S. Pat. No. 4,386,104) used the same compound to treat acne and also disclosed that small amounts of keratolytic agents could be added to the composition. Nazzaro-Porro (U.S. Pat. No. 5,385,943) also discloses the use of topically applied formulations containing dicarboxylic acid esters, particularly glycerides, cleavable by skin enzymes to treat aged skin conditions. However, the patent recognizes that, in general, any ester can be cleaved by skin non-specific enzymes, including those disclosed in the prior art.

Thornfeldt (us patent 4,885,282) discloses the treatment of hyperhydrolysis, ichthyosis and wrinkles of the skin by using mono-or di-carboxylic acids (4-18C) and their mercapto derivatives, salts and esters; the use of alkyl, polyol, oligosaccharide and polysaccharide esters of mono-or di-carboxylic acids, particularly glycerol, polyethylene glycol, polypropylene glycol and sucrose esters of mono-or di-carboxylic acids, is disclosed. British patent application GB2,285,805 uses dicarboxylic acid esters containing vitamins A, E and D as antineoplastic agents. Chanmess (us patent 5,547,989) discloses compositions comprising dicarboxylic acids (7-13C, especially AZA) and their salts and esters, which are useful for the treatment of corns and calluses; but no specific ester is claimed or illustrated by the examples.

Sugibayashi et al (chem. pharm. Bull.,36(4):1519-1528(1988)) used permeation enhancers in the exemplary compound indomethacin. This document uses salicylate as a reinforcing agent, since salicylate softens and dissolves the stratum corneum. They use salicylates as keratolytic agents, thereby removing the outer layer of the cell, and then allowing easier penetration of the desired compound.

Lueders (U.S. Pat. No. 4,299,826) discloses physical mixtures of erythromycin antibacterial agents with diisopropyl sebacate permeation enhancers. Lueders teaches that such additives enhance the permeability of erythromycin.

The known literature discloses complex esters of linear dicarboxylic acids. In U.S. patent 5,494,924, Cavazza et al disclose the use of complex esters of alpha, omega dicarboxylic acids and carnitine for the treatment of ichthyosis. Bilibin et al (USSR patent 711,452) disclose the synthesis of straight carbon chain alpha, omega-dicarboxylic acids by esterification with p-hydroxybenzoate, which are then used as monomers for the preparation of liquid crystalline polymers. In us patent 3,660,467 Gould discloses phenoxyphenyl alpha, omega-dicarboxylates for use as synthetic lubricants and heat exchange fluids. Portnory et al (Chemical engineering Data Series,1958,3:287-293) disclose the use of phenyl alpha, omega-dicarboxylates in the development of non-atomizing lubricants. Although compounds comprising esterified α, ω -dicarboxylic acids are described in this document, there is no discussion of the use of these compounds in the treatment of skin disorders.

Thus, there is a need to provide a therapeutic agent for the treatment of skin disorders, which should have an increased efficacy and reduced irritation compared to prior art therapeutic agents.

Summary of The Invention

The present invention aims to provide a novel compound comprising an α, ω -dicarboxylate derivative, which is effective for treating skin diseases and improving skin appearance.

It is a further object of the present invention to provide cosmetic or pharmaceutical compositions comprising novel ester derivatives, useful for treating skin disorders and improving the appearance of skin.

The object of the present invention is to provide a new composition for increasing the permeability of the skin.

The present invention aims to provide novel compositions capable of treating various skin disorders.

It is a further object of the present invention to provide novel dual acting prodrugs capable of delivering a variety of therapeutically active agents to a skin site of a patient.

It is a further object of the present invention to provide a method of treatment which is effective in alleviating the symptoms of hyperkeratosis, excess sebum secretion, microbial infections, skin disorders and excessive conversion of testosterone to dihydrotestosterone.

It is a further object of the present invention to provide a method of treatment which is effective in alleviating the symptoms of acne, psoriasis, seborrheic dermatoses, ichthyosis, rosacea, dandruff, hirsutism and androgenic alopecia.

These and other objects are achieved by the embodiments of the invention described herein.

In one aspect, the present invention provides novel ester derivatives of α, ω -dicarboxylic acids. The compounds comprise an alpha, omega-dicarboxylic acid moiety covalently linked to at least one keratolytically active alcohol moiety. The compound may have the formula:

wherein n is 6 to 12; m is 0 to 8; r 'is selected from H, alkyl, aryl, alkenyl, benzyl, OH, NHR', COOR 'and CONHR'; r' is selected from H, alkyl, aryl, alkenyl or benzyl; and Y is selected from H, alkyl, aryl, alkenyl, benzyl or X.

The compounds of the invention are useful for alleviating the symptoms of hyperkeratosis, excessive sebum secretion, microbial infections, skin disorders and excessive testosterone conversion to testosterone, and for alleviating the symptoms of acne, psoriasis, seborrheic dermatoses, ichthyosis, rosacea, dandruff, hirsutism, hypertrichosis and androgenic alopecia.

The compounds of the invention can also be used in cosmetic methods carried out by non-medical specialists, i.e. for conditioning conditions in humans, such as acne, dandruff, seborrhea and androgenic alopecia. Detailed Description

The present invention provides a novel compound useful for effectively treating skin diseases. Such compounds may be incorporated into pharmaceutical preparations, prescribed by a physician; can also be used in cosmetic preparation for direct application.

According to the invention, the compounds comprise an α, ω -dicarboxylic acid moiety covalently linked to a keratolytically active alcohol via an ester bond. The compounds may comprise one or two alcohols, thereby providing the corresponding mono-or diesters. Likewise, the compounds comprise two moieties, an α, ω -dicarboxylic acid moiety and a keratolytic agent, each capable of treating various skin disorders or improving the appearance of skin. The compound additionally has the advantage of being able to provide two parts, which are able to penetrate the skin rapidly.

As used herein, "α, ω -dicarboxylic acid moiety" refers to a straight carbon chain having two carboxylic acid functional group termini. The length of the α, ω -dicarboxylic acid moiety is about 6 to 14 carbon atoms. In a preferred embodiment, the α, ω -dicarboxylic acid moiety comprises 8 to 10 carbon atoms. The carbon chain backbone may be saturated or unsaturated. In a preferred embodiment, the unsaturated backbone contains 1-3 double bonds. The straight carbon chain may also be substituted, for example, with a hydrocarbyl group attached to the carbon skeleton. Suitable α, ω -dicarboxylic acid moieties include, but are not limited to: adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1, 11-undecanedioic acid, 1, 12-dodecanedioic acid, 1, 13-tridecanedioic acid and 1, 14-tetradecanedioic acid. In a preferred embodiment, the α, ω -dicarboxylic acid is azelaic acid. Suitable substituents on the carbon chain backbone include, but are not limited to: alkyl, aryl, alkenyl and benzyl. By way of example only, suitable hydrocarbyl substituents (e.g., aryl and alkyl) include: methyl, ethyl, propyl, phenyl, benzyl, and the like.

As used herein, "keratolytically active alcohol moiety" refers to a compound that is capable of loosening and removing the stratum corneum of the skin or has an anti-keratinizing effect by modulating keratinocyte differentiation and growth. Suitable keratolytic agent moieties include phenols and substituted phenol compounds. Suitable substituents include, but are not limited to: hydroxy, - (CH)₂)_m-COOH and- (CH)₂)_m-COOR ', wherein m =0-8 and R' is aryl, alkyl, alkenyl and benzyl. By way of example only, suitable aryl and alkyl substituents include: methyl, ethyl, propyl, phenyl, benzyl, and the like. R' and R "are generally selected to give the compound hydrophobicity, or to improve skin permeability, targeting of the compound to the site of action should be enhanced. In addition, the substituents on the benzene ring can impart keratolytic phenol therapeutic properties. For example, in addition toThe hydroxyl groups of (a) can enhance keratolytic properties and the presence of carboxylic acid and alkyl carboxylate substituents can impart anti-inflammatory properties. The remaining substituents may increase the partial hydrophobicity. Keratolytic agents include, but are not limited to: hydroxybenzoic acid and its ester, anhydride and amine derivatives, alkylhydroxybenzoate esters, dihydroxybenzene and its ester, anhydride and amide derivatives, cresol and its ester, anhydride and amide derivatives or alcohol derivatives of vitamin a.

Many suitable keratolytic agents are effective for treating various skin conditions. Salicylic acid (o-hydroxybenzoic acid) and its ester derivatives have anti-inflammatory properties and keratolytic activity. It is known to lyse and loosen the intracellular matrix of hyperkeratotic tissue. Also, they are used to treat skin disorders. Dihydroxybenzene and its derivatives are considered effective keratolytic agents. Resorcinol (m-dihydroxybenzene) and its derivatives are used as anti-acne agents.

Hydroquinone (p-dihydroxybenzene) has keratolytic effect in addition to anti-pigmentation properties. These compounds also have antibacterial properties. Cresol also has antibacterial and keratolytic properties. When used alone, all of these compounds are limited to pharmaceutical use due to their poor skin permeability and relatively weak efficacy. However, when covalently linked to the α, ω -dicarboxylic acid moieties of the present invention, the permeability and/or delivery properties of these compounds to the region of action are enhanced. It can be seen that the efficacy of these compounds is significantly increased compared to the prior art.

A particularly preferred keratolytic agent is o-hydroxybenzoic acid. In other preferred embodiments, it is desirable to use alkyl or aryl ortho-hydroxybenzoate as keratolytic alcohol. By way of example only, suitable aryl and alkyl substituents include: methyl, ethyl, propyl, phenyl, benzyl, and the like. Alkyl and aryl hydroxybenzoates have the additional advantage of increased hydrophobicity compared to the acid counterpart, which increases skin permeability. Further, aryl and alkyl ester derivatives of alpha, omega-dicarboxylic acids form low melting compoundsA solid that is a liquid at physiological temperatures. This property is very useful in enhancing skin penetration. Particularly preferred compounds of the invention have the following formula:

wherein n is 6 to 12; r is OH, COOH and COOR'; r' is alkyl, aryl, alkenyl or benzyl. Y is H, alkyl, aryl, alkenyl, benzyl or X. Most preferred are compounds wherein n =7, R is ortho-COOR 'and R' is alkyl. By way of example only, suitable aryl and alkyl substituents include: methyl, ethyl, propyl, phenyl, benzyl, and the like.

Chemical binding of the alpha, omega-dicarboxylic acid with the above alcohol results in compounds with enhanced therapeutic effect which are useful in the treatment of skin disorders. Some exemplary compounds have a melting point of about 30-40 ℃. These compounds are liquids at physiological temperatures and the compounds of the present invention increase the ease of skin penetration compared to compounds that are solids at physiological temperatures.

Skin permeability is directly related to hydrophobicity. In the present invention, the polarity of the carboxylic acid and hydroxyl functional groups is masked by reaction with another functional group to form a complex monoester or diester. As complex esters, the novel derivatives of the invention are more hydrophobic than their corresponding free alpha, omega-dicarboxylic acids and free alcohols, which allows for increased skin penetration. As the permeability increases, the compound then has a therapeutic effect on the inner layers of the skin. These effects include, but are not limited to: the above properties of the α, ω -dicarboxylic acid moiety, the keratolytic properties of the specific alcohol and the anti-inflammatory effect.

The compounds of the invention may be used as dual-acting "prodrugs," i.e., once delivered to a target site, the compound undergoes a chemical or enzymatic process that produces the two corresponding chemical forms of the active agent, i.e., the pharmaceutical chemical form of the α, ω -dicarboxylic acid and the alcohol moiety. The Skin naturally contains non-specific esterases that can affect the necessary cleavage, see Montagna, w.the Structure and function of Skin,1962, second edition; and Stevens, C.S. and C-Villez, R.L.int.J.Dermatol,19:295 (1980). In particular, high concentrations of non-specific esterases are located to target the interior of sebaceous glands, see Holt, r.j.br., j.dermatol.85:18 (197). After penetrating the outer layers of the skin, the compounds of the invention interact with these esterases. Since the enzymes are non-specific enzymes, they can hydrolyze the ester bonds to the α, ω -dicarboxylic acid moiety and the alcohol, thus releasing the two therapeutically effective agents in their pharmaceutically active form.

The prodrug is allowed to penetrate the outer layers of naturally occurring skin and can penetrate abnormal plaques of hyperkeratotic cells. These plaques are often symptoms of the targeted disease and the barriers of the affected area. These hydrolysis reactions thus occur in the inner layers of the skin. Two pharmaceutically active agents capable of treating two or more separate conditions, where the pharmaceutically active agent has its own therapeutic properties, can reach the target tissue through these barriers. It can thus be seen that two therapeutic agents can be delivered to a targeted site using the novel compounds of the present invention.

The compounds of the present invention have increased permeability, thereby improving the delivery of pharmaceutically active agents to targeted tissues, resulting in more effective dermatological treatment than the prior art. Due to the increased delivery efficacy, less active ingredient than disclosed in the prior art is required to alleviate the symptoms of skin disorders. In addition, the acidity of the agent is reduced due to the esterification reaction, thereby reducing inflammation and irritation at the application area.

Another aspect of the present invention relates to a pharmaceutical or cosmetic composition capable of solving both the problems of skin disorders. The alpha, omega-dicarboxylic acids may have a therapeutic effect on sebum secretion, skin keratinization, bacterial and fungal infections associated with keratolysis and/or an anti-inflammatory effect, wherein the anti-inflammatory effect is given by the phenolic moiety.

In one embodiment of the invention, a composition comprising 10% by weight (200mmol/ml) of bis (ethyl salicylate) azelate has an effective effect on the reduction of blackheads in an rabbit ear model. The acne decomposition effect of bis (ethyl salicylate) azelate was comparable to that of 0.025% Retin A cream. This comedolytic effect is superior to the 20% (1,060mmol/ml) azelaic acid formulation disclosed in the prior art. See Lee et al, Kor.J.Dermatol.28(5):543-549 (1990).

In addition, unlike the inflammatory effects observed with 0.025% RetinA treatment, treatment with this composition did not elicit any inflammatory response in the treated area. Comparative skin irritation tests in volunteers showed that di (ethyl salicylate) azelate (20%, 400mmol/ml) did not irritate the skin. In contrast, an equimolar mixture of its components (7.5%, 400mmol/ml azelaic acid and 11%, 800mmol/ml salicylic acid) caused inflammatory reactions including moderate erythema, mild edema and local pruritus. The in vivo skin irritation test in rabbits also showed no signs of irritation after 24 hours of application of bis (ethyl salicylate) azelate (10% and 20%). These results highlight the clear difference between bis (ethyl salicylate) azelate and its parent composition.

The sebaceous lytic effect of bis (ethyl salicylate) azelate was also demonstrated in human trials. The forehead skin oil of the volunteers decreased from 223 units (similar to "oily skin") to 205 units (normal skin value) after 14 days of topical treatment using a photometer. This finding demonstrates the superiority of the compounds of the invention over azelaic acid, which, according to the published literature, is not capable of altering skin oils.

The direct effect of the compounds of the invention on the proliferation of human stratum corneum cells can be determined by using stratum corneum cell lines in vitro. The results indicate that the compounds of the present invention are potent inhibitors of stratum corneum cell proliferation. At a concentration of 0.3mM, bis (ethyl salicylate) azelate inhibited cell proliferation; whereas retinyl azelate has an inhibitory effect at a concentration of 15. mu.M. The respective cytotoxic concentrations of the same reagents were 3mM and 100. mu.M with a basic therapeutic safety factor of 6.6-10. In contrast, the inhibitory concentration of azelaic acid can be as high as 1mM, with cytotoxic concentrations of only 2.6-fold more. Thus, the use of the compounds of the present invention is advantageous over the use of free azelaic acid for the treatment of skin diseases involving hyperkeratosis.

A preferred embodiment relates to pharmaceutical or cosmetic compositions comprising a therapeutically effective amount of the novel compounds of the present invention and a pharmaceutically or cosmetically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to any liquid, gel, emulsion, cream, ointment, liquid oil base, solvent, diluent, or the like suitable for use in contact with living mammalian tissue, which carrier must be capable of dissolving the therapeutically active agent of the present invention and not interact in a deleterious manner with any of the other components of the composition. Alcohols are particularly preferred carriers. Additives to such compositions may include, but are not limited to, preservatives, moisturizers, petroleum, thickeners, alpha-hydroxy carboxylic acids, mineral oils, pigments, and other components described in the CTFA handbook of cosmetic ingredients. It will be readily apparent to those of ordinary skill in the dermatological arts that the resulting compositions may exist in many forms, which may include, but are not limited to: a solution, lotion, cream, paste, emulsion, gel, soap bar, spray or aerosol. These compositions may be applied manually or by various means.

One aspect of the present invention relates to a pharmaceutical or cosmetic composition for the treatment of hyperkeratosis. Another aspect of the invention relates to effective compositions and methods for treating skin disorders caused by hormonal imbalance in targeted tissues. Alpha, omega-dicarboxylic acids are known to inhibit the reduction of testosterone to Dihydrotestosterone (DHT). By inhibiting this transformation, the α, ω -dicarboxylic acid can be used as a therapeutic agent for treating diseases caused by an increase in the amount of dihydrotestosterone. DHT is an androgen with second characteristics in developing males. An increased level of DHT may cause excessive hair growth, so-called hirsutism. Both men and women can suffer from hirsutism, in which hair growth is increased anywhere in the body. Another disease that may affect women and is caused by increased DHT levels is hirsutism. In this disease, increased levels of androgens lead to hair growth characteristic of males. Since the above-mentioned diseases are caused by an increase in the level of DHT in the hair follicle, they are associated with an increased possibility of acne. The increased permeability of the compounds of the present invention may provide a means for delivering alpha, omega-dicarboxylic acids to the inner layers of the skin. The compositions of the invention are therefore useful in the treatment of secondary effects of hormonal imbalance.

Androgenic alopecia, also known as male pattern baldness, is primarily a genetic disorder that is the most common cause of male pattern baldness. The hair follicles are very sensitive to DHT and its breakdown products and they are thought to inhibit hair growth in the scalp. Thus, an increase in the amount of DHT in the hair follicle must increase the inhibitory effect, resulting in hair loss. Women may also suffer from androgenic alopecia. Increased levels of circulating androgens in women may result from endocrine disorders, including ovarian or adrenal dysfunction. In these women, excessive androgens in the targeted tissues, particularly hair follicles, inhibit hair growth, eventually leading to hair loss. The compositions of the present invention are effective in reducing the amount of DHT in the hair follicle, which reduces the inhibition and thereby promotes hair growth.

Another aspect of the invention relates to a method of treating a particular skin condition comprising applying to the affected area an effective amount of a compound in admixture with a pharmaceutically or cosmetically acceptable carrier. The compositions comprise a therapeutically effective amount of the novel mono-or diesters of the present invention. The actual effective amount may vary depending on the particular skin condition being treated, but the present invention generally employs the composition at a concentration of 0.1% to 30% by weight by volume. The composition may be applied topically to the affected area. The term "topical" as used herein means sprayed or placed directly onto the epidermal tissue. Application may be by rubbing, using a hospital pad, or any other convenient means. Because of the low toxicity of the compounds of the present invention, administration can be by oral, nasal or parenteral means.

The novel compounds of the present invention can be prepared by methods known in the art. Methods for synthesizing esters from carboxylic acids and derivatives thereof are well known to those skilled in the art. Combining a carboxylic acid and an alcohol in the presence of an acid catalyst yields an ester and water. Acid halides or other suitable derivatives of carboxylic acids (e.g., tosyl, 2,4, 6-trimethylphenyl, etc.) may also be effective in forming the desired ester. For a review of the synthesis of esters, the reader is directed to Vollhardt, Organic Chemistry, Chapter 17.

The following examples illustrate the invention without limiting it.

Example 1 synthesis of azelaic acid, di- [ (2' -ethoxycarbonyl) phenyl ] ester (also known as "bis (ethyl salicylate) azelate"). In a three-necked flask equipped with a nitrogen inlet and outlet, 80mmol of ethyl salicylate was dissolved in 50ml of pyridine. The solution was cooled to 0 ℃ and azelaic acid chloride (40mmol) was added over 1 hour with magnetic stirring. The reaction mixture was stirred at room temperature for 2 hours, then 200ml of 5% HCl was injected. The mixture was extracted 3 times with dichloromethane, the organic phase was worked up with sodium bicarbonate and water and evaporated to give a viscous beige product. The product was purified on a silica gel column eluting with 3: 5 ethyl acetate: hexane. Then evaporated and mixed with 50ml hexane overnight to give 11.6g (24mmol, yield 60%) of white powder (mp =34-35 ℃, MW = 485). Compound identity was confirmed by NMR and IR. NMR 1.25-2.04, m, 10H; 2.63, t, 4H; 4.32, dd, 4H; 7.08, d, 2H; 7.30, t, 2H; 7.52, t, 2H; 7.99, d, 2H; and IR:1769,1757,1713,1606,1365,1255,1198,1140,1088,770,715. Elemental analysis: c =67.25 (calculation 66.94); h =6.68 (calculation 6.61).

EXAMPLE 2 Synthesis of o, o-bis- (7-methoxycarbonyl-1-octanoyl-1, 4-dihydroxybenzene). 20g (100mmol) of monoethyl azelate are added dropwise to 24g (14.7mmol) of SOCl in a water bath at 40-50 ℃ over a period of 5 h₂In (1). Distilling off SOCl₂The acid chloride obtained was slowly added dropwise to 12g (110mmol) of hydroquinone at room temperature under magnetic stirring. The reaction mixture was stirred at room temperature for a further 16 hours and then poured into 5% HCl. Extraction with dichloromethane, washing with water, drying and evaporation. Crystallization from toluene gave 17g (58mmol, yield = 58%) of a light brown solid (mp =53-56 ℃). Compound identity was confirmed by NMR. NMR 1.31-1.77, m, 20H; 2.3, t, 4H; 2.54, t, 4H; 3.67, s, 6H; 7.07, s, 4H.

EXAMPLE 3 Synthesis of o- (7-methoxycarbonyl-1-octanoyl-1, 4-dihydrobenzene). 20g (100mmol) of monoethyl azelate are added dropwise to 24g (14.7mmol) of SOCl in a water bath at 40-50 ℃ over a period of 5 h₂In (1). Distilling off SOCl₂The resulting acid chloride was slowly added dropwise to 5 at room temperature under magnetic stirring.5g (50mmol) of hydroquinone. The reaction mixture was stirred at room temperature for a further 16 hours and then poured into 5% HCl. Extraction with dichloromethane, washing with water, drying, evaporation and mixing with 50ml hexane overnight gave 9.5g (20mmol, yield = 40%) of a white powder. Compound identity was confirmed by NMR and IR. NMR 1.31-1.77, m, 10H; 2.32, t, 2H; 2.53, t, 2H; 3.67, s, 3H; 5.60, width s, 1H; 6.82, dd, 4H; 3458,2943,1740,1510,1444,1267,1223,1149.

EXAMPLE 4 Synthesis of retinyl azelate. In a 25ml flask fitted with a calcium chloride outlet, vitamin a (retinol, 0.86g,3mmol) was dissolved in 2ml pyridine and 7.5ml dichloromethane. The solution was cooled on an ice bath. Azelaic acid chloride (0.3ml,0.345g,1.5mmol) was added with magnetic stirring. The reaction mixture was stirred at room temperature for 2 hours and then poured into 10ml of 5% HCl/ice. The mixture was extracted 3 times with dichloromethane, the organic phase was worked up with sodium bicarbonate and water, dried over magnesium sulfate and evaporated. The product was purified on a silica gel column to give 0.5g (0.7mmol, yield = 46%). Compound identity was confirmed by NMR. NMR 1.0, s, 12H; 1.3-1.6, m, 18H; 1.70, s, 6H; 1.88, s, 6H; 1.95, s, 6H; 2.0, t, 4H; 2.30, t, 4H; 4.72, d, 4H; 5.6, t,2H,6.0-6.2, m, 6H; 6.27, d, 2H; 6.63, t, 2H.

Example 5. an anti-acne/anti-seborrhea lotion was prepared. 10g of bis (ethyl salicylate) azelate were dissolved in 10ml of ethanol and 90ml of PEG400 to give a clear, colorless solution with a viscosity < 100 cps.

Example 6 efficacy of bis (ethyl salicylate) azelate (10%) in rabbit ear acne model. Three mature male rabbits with white-flowered disease were treated according to the following method. The external auditory meatus of both ears was treated with 1% raw coal tar in hydrophilic ointment USP for five working days, once daily for 3 weeks. One of the rabbit ears was then treated with the anti-acne lotion of example 4 for five working days, once a day, for a total of 3 weeks; and the other as an untreated control. It was fixed in formalin, cut into half-series (semiserial) and stained in H and E forms. The untreated ear showed tight hyperkeratosis of the sebum dust. These are considered examples of moderate comedones with malformations of the saccular arterial cone represented by tight keratosis. Acne was significantly reduced in all three treated ears. Only a small amount of keratosis remained in some of the vesicles, and these keratoses were loose and not tight. The acne separation effect of bis (ethyl salicylate) azelate was comparable to that of 0.025% Retin A cream. No inflammatory response was elicited by this treatment.

Example 7 human skin irritation test. The following lotion (0.1ml) was applied to human skin for 48 hours using a standard skin irritation test chamber (0.64 sq.cm.):

(1) 20% bis (ethyl salicylate) azelate (400mmol/ml) dissolved in PEG-400/ethanol 1: 1;

(2) a mixture of 7.5% azelaic acid (400mmol/ml) and 11% salicylic acid (800mmol/ml) was dissolved in PEG-400/ethanol 1: 1; and

(3) PEG-400/ethanol 1: 1 (control).

The chamber was removed and after 1, 24 and 48 hours, neither the control nor the bis (ethyl salicylate) azelate applied showed any skin reaction signal. Equimolar prodrug-component (2) mixtures caused inflammatory responses including moderate erythema, mild edema and local pruritus.

Example 8. acute epidermal toxicity/irritation test. The aim of this study was to evaluate the acute potential epidermal irritation following topical application of bis (ethyl salicylate) azelate on the skin of rabbits. As described in the OECD guide, this test is a modified version of the original Draise method. 0.5ml of bis (ethyl salicylate) azelate (10% or 20%, dissolved in PEG-400/ethanol 1: 1) and a separate vehicle were applied to three rabbits for 24 hours. After 1, 24 and 72 hours of removal of the test solution, the skin irritation signal was tested with rabbits. No skin irritation signal was observed by this study. Based on current test records, a conclusion can be drawn that bis (ethyl salicylate) azelate is a non-irritating agent.

Example 9. acute subcutaneous toxicity limit test. Five female and five male ICR mice were subcutaneously administered 2000mg/kg di (ethyl salicylate) azelate and then waited for 14 days. There were no toxic effects throughout the treatment and observation periods, indicating that bis (ethyl salicylate) azelate can be considered non-toxic.

Example 10 sebum solubilization of bis (ethyl salicylate) azelate. The anti-acne/anti-seborrhea lotion of example 5 was topically administered twice daily to the forehead of women with oily skin prior to treatment. Before and after 14 days of treatment, the skin oiliness was determined using a "skin tester model STC 20" (IMS ltd., Haifa, Israel). Before treatment, the sebum value was 223 units, typical of oily skin. The sebum value after two weeks of treatment was 205 units, relative to normal skin.

Example 11 anti-psoriasis gel. 20g of bis (ethyl salicylate) azelate were dissolved in 50ml of ethanol and 50ml of water. The solution was warmed to 60 ℃ with stirring, and 1g of PEG-4000 was added. The mixture was cooled to room temperature and slowly stirred magnetically for 2 hours.

Example 12 control of keratinocyte proliferation. The effect of bis (ethyl salicylate) azelate and retinyl azelate on cell proliferation and cell viability was tested in vitro using a human keratin cell culture system.

And (4) measuring cell proliferation. 50,000 individuals of keratinocytes in subcultures were seeded in 24-well plates in 1ml DMEM-F12 medium (Green H. (1978) Cell15:801-805) with growth factors and 10% fetal bovine serum. Cells in CO₂Incubate under atmosphere at 37 ℃ until 30-40% confluence is reached, then add the various test substances dissolved in ethanol in a volume of 0.1-20. mu.l, with a final volume of 0.5 ml. The same volume of ethanol was added to the control medium to compare the ethanol cytotoxicity values. No significant cytotoxicity was found up to 40. mu.l/ml ethanol. The medium was replaced with fresh medium before the test substance was added. At 37 ℃ and 5% CO₂Incubation under conditions was continued for 3 hours and then utilizedPhosphate Buffered Saline (PBS) wash. Cell numbers were determined using two methods: 1) trypsinization followed by cell counting; and 2) 2% p-formaldehyde in PBS was used in combination with the medium and stained with methylene blue, followed by color extraction and optical density measurement at 650 nm. Both methods have good correlation, with 1OD unit corresponding to 1,000,000 cells. IC50 (i.e., the concentration that results in 50% inhibition of cell proliferation for each test substance) is shown in table 1.

And (4) carrying out cytotoxicity test. In the absence of test substances, the above keratolytic cells were proliferated in the medium to 100% confluence and subjected to one medium exchange during growth. At 37 ℃ and 5% CO₂The fusion cultures were incubated for 3 days under conditions in which the ethanol concentration of the test substances was increased. At the end of the incubation period, the cultures were washed with PBS and residual adherent cells were determined using the method described above. LC50 (i.e. the concentration that caused 50% cytotoxicity) is also shown in table 1.

Table 1 indicates; the efficacy of di-retinyl azelate and di (ethyl salicylate) azelate was significantly higher than that of azelaic acid and salicylic acid in inhibiting cell proliferation; but also their cytotoxic concentrations are 6.6-10 times higher than their inhibitory concentrations, indicating that they are safer than free azelaic acid.

Table 1: IC50 of Compounds of the invention, Melaric acid and salicylic acid

(inhibitory concentration) and LC50 (cytotoxic concentration)

Test substance	IC50	LC50	Factor of safety (CD50/ID50)
				Diretinyl azelate	15μM	100μM	6.6
Bis (ethyl salicylate) azelate	0.3mM	3mM	10
				Azelaic acid	1.5mM	4mM	2.6
Salicylic acid	1.5mM	ND	NA

Claims (33)

1. A compound comprising an alpha, omega-dicarboxylic acid covalently linked through an ester linkage to at least one keratolytically active alcohol moiety, of the formula

Wherein n is 6 to 12; m is 0 to 8; r 'is selected from H, alkyl, aryl, alkenyl, benzyl, OH, NHR', CONHR 'and COOR'; r' is selected from H, alkyl, aryl, alkenyl or benzyl; and Y is selected from H, alkyl, aryl, alkenyl, benzyl or X.

2. A compound, comprising:

alpha, omega-dicarboxylic acid mono-or diesters, wherein the ester portion of the dicarboxylic acid comprises a keratolytically active alcohol.

3. A compound according to claim 1 or 2, wherein the α, ω -dicarboxylic acid moiety comprises about 6 to 14 carbon atoms.

4. A compound according to claim 1 or 2, wherein the α, ω -dicarboxylic acid moiety comprises 8 to 10 carbon atoms.

5. A compound according to claim 1 or 2, wherein the α, ω -dicarboxylic acid carbon chain backbone is unsaturated.

6. The compound according to claim 5, wherein the backbone comprises about 1 to 3 double bonds.

7. A compound according to claim 1 or 2 wherein the carbon chain of the α, ω -dicarboxylic acid moiety is linked to a hydrocarbyl substituent.

8. A compound according to claim 1 or 2, wherein the carbon chain of the α, ω -dicarboxylic acid moiety is substituted with an alkyl, aryl, alkenyl or benzyl group.

9. The compound according to claim 1 or 2, wherein the α, ω -dicarboxylic acid is adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1, 11-undecanedioic acid, 1, 12-dodecanedioic acid, 1, 13-tridecanedioic acid and 1, 14-tetradecanedioic acid.

10. A compound according to claim 1 or 2, wherein the α, ω -dicarboxylic acid is azelaic acid.

11. A compound according to claim 1 or 2, wherein the keratolytically active alcohol comprises salicylic acid or a derivative thereof.

A pharmaceutical or cosmetic composition according to claim 13 or 14, wherein the keratolytic alcohol is selected from the group consisting of o-, m-and p-hydroxybenzoic acid, o-, m-and p-hydroxyalkylbenzoate, o-, m-and p-dihydroxybenzene, o-, m-and p-hydroxytoluene and derivatives thereof.

12. The compound according to claim 9, wherein the keratolytically active alcohol comprises salicylic acid or a derivative thereof.

13. A pharmaceutical or cosmetic composition comprising:

a therapeutically effective amount of a compound comprising an alpha, omega-dicarboxylic acid mono-or diester, said ester comprising a keratolytically active alcohol; and

a pharmaceutically acceptable carrier.

14. The pharmaceutical or cosmetic composition according to claim 13, wherein the α, ω -dicarboxylic acid is selected from adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1, 11-undecanedioic acid, 1, 12-dodecanedioic acid, 1, 13-tridecanedioic acid and 1, 14-tetradecanedioic acid.

15. The pharmaceutical or cosmetic composition according to claim 13 or 14, wherein the α, ω -dicarboxylic acid is azelaic acid.

16. The pharmaceutical or cosmetic composition according to claim 13 or 14, wherein the keratolytic alcohol is selected from the group consisting of o-, m-and p-hydroxybenzoic acid, o-, m-and p-hydroxyalkylbenzoate, o-, m-and p-dihydroxybenzene, o-, m-and p-hydroxytoluene and derivatives thereof.

17. The pharmaceutical or cosmetic composition according to claim 13 or 14, wherein the keratolytic alcohol comprises an alkyl derivative of ortho-, meta-, and para-hydroxybenzoate.

18. A composition according to claim 13 or 14, wherein said compound comprises two keratolytically active alcohol moieties.

19. The pharmaceutical or cosmetic composition of claim 13 or 14, wherein the therapeutically effective amount of the compound comprises an amount effective to treat a dermatological condition comprising: hyperkeratosis, hypertrophy of the stratum corneum, excessive sebum secretion, microbial infections, skin diseases and increased conversion of testosterone to dihydrotestosterone.

20. A method of treating a skin disorder, the method comprising:

topically administering a therapeutically effective amount of a compound comprising a therapeutically effective amount of a mono-or diester of an alpha, omega-dicarboxylic acid via the nose, mouth, or parenteral route to a site having said skin disorder, wherein at least one alcohol of said ester comprises a keratolytically active alcohol.

21. A method of treating a skin disorder, the method comprising:

topically applying to the affected area a therapeutically effective amount of a compound comprising a therapeutically effective amount of an alpha, omega-dicarboxylic acid mono-or diester, wherein at least one alcohol of the ester comprises a keratolytically active alcohol.

22. The method according to claim 20 or 21, wherein said skin disorders comprise hyperkeratosis, stratum corneum hypertrophy, excessive sebum secretion, microbial infections, skin disorders and increased conversion of testosterone to dihydrotestosterone.

23. The method according to claim 20 or 21, wherein the skin disease is selected from the group consisting of: acne, seborrheic skin disorders, dandruff, psoriasis, ichthyosis, rosacea, hirsutism, and androgenic alopecia.

24. A method of increasing the penetration of an α, ω -dicarboxylic acid through a skin layer, the method comprising:

applying to the skin layer an alpha, omega-dicarboxylic acid mono-or diester derivative, said ester moiety comprising a keratolytically active alcohol.

25. A compound according to claim 1 or 2, wherein the compound is capable of releasing a substantial amount of the dermatologically active compound when delivered to a target site on the skin.

26. A composition according to claims 13 to 19, wherein the composition is capable of releasing a substantial amount of the dermatologically active compound when delivered to a target site on the skin.

27. A compound according to any one of claims 1 to 12 for use in the treatment of a skin disorder.

28. Use of a compound comprising an alpha, omega-dicarboxylic acid mono-or diester, wherein the ester moiety of the dicarboxylic acid comprises a keratolytically active alcohol, for the preparation of a pharmaceutical composition for topical, oral or parenteral administration for the treatment of a skin disorder.

29. The use according to claim 28, wherein the skin disorders include hyperkeratosis, stratum corneum hypertrophy, excessive sebum secretion, microbial infections, skin disorders and increased conversion of testosterone to dihydrotestosterone.

30. Use according to claim 28, wherein the disease is selected from: acne, seborrheic skin disorders, dandruff, psoriasis, ichthyosis, rosacea, hirsutism, and androgenic alopecia.

31. Use of a mono-or diester derivative of an alpha, omega-dicarboxylic acid, wherein the ester moiety of said dicarboxylic acid comprises a keratolytically active alcohol, for the preparation of a composition for increasing the penetration of the alpha, omega-dicarboxylic acid into the skin layers.

32. Use according to any one of claims 28 to 31 wherein the compound or derivative is a compound according to any one of claims 1 to 12.