MXPA99004350A - Method for treatment of dermatological disorders - Google Patents

Abstract

A compound effect for the treatment of dermatological disorders comprises a mono- or diester of an alpha , omega -dicarboxylic acid, wherein the alcohol moiety of the said ester comprises a keratolytically active alcohol. The compound may have formula (I), where n is in the range of 6 and 12;m is in the range of 0 and 8;R'is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl, OH, NHR'', CONHR''and COOR'';R''is selected from the group consisting of H, alkyl, aryl, alkenyl, and benzyl;and Y is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl and X.

Description

METHOD FOR THE TREATMENT OF DERMATOLOGICAL DISORDERS FIELD OF THE INVENTION The invention relates to cosmetic or pharmaceutical compositions containing, as an active ingredient, one of the novel ester derivatives of o, β-dicarboxylic acid (from 6 to 14 carbon atoms), covalently linked to a keratolytically active alcohol. The invention also relates to the administration of these compositions, for the purpose of treating dermatological disorders. BACKGROUND OF THE INVENTION Numerous skin disorders result in hypertrophy of the stratum corneum, which is also described as hyperkeratinization. The thickened surface layer of the epidermis results in flake-like plaques on the surface of the skin. These scaly plaques are the manifestation of a group of disorders called ichthyosis, because they resemble the scales of fish. The plaques can be symptoms of a skin disorder, and in accordance with the above, prohibit the treatment of these disorders that originate in the underlying layers of the skin. The hypertrophic skin layer can also harbor infections inside of itself.

Typical examples of ichthyosis that do not have known etiologies include psoriasis, pityriasis, rosacea, and seborrhoeic dermatitis. These disorders are treated symptomatically with keratolytic agents to remove plaques, and with glucocorticoids to relieve inflammation. Dermaphytosis is ichthyosis caused by fungal infections Z Hyphae and spores are confined to the non-viable portions of the tissue, and therefore, proliferate in the hyperkeratinized tissues of the skin, hair, and nails. Examples of typical dermaphytoses include tinea capitis (crib hat), tinea pedis (athlete's foot), and tinea unguium. These disorders are treated with anti-fungal agents, and locally with keratolytic agents to remove the cornified and infected layer. Skin disorders can also be caused by a hormonal imbalance. This imbalance can cause higher levels of testosterone, such as at the beginning of puberty. Testosterone is reduced to dihydrotestosterone (DHT) in target tissues, including the sebaceous glands. In the common dermatological acne disorder, dihydrotestosterone binds to the pilosebaceous complex receptors, and stimulates excessive secretion of sebum. Sebum acts as a nutrient for bacteria, such as Propionibacterium acnes, which infect the sebaceous gland, and lead to an inflammatory response and abnormal cornification of the skin. Acne is usually treated with antibacterial and antiseptic agents, and also with keratolytic agents, such as salicylic acid or retinoic acid, to remove hyperkeratinized tissue. Skin disorders, such as those described above, create aesthetic discomfort, and are often considered to be cosmetically included processes. They can be treated using known medications; however, it is common knowledge that cosmetic products are also being used, for example soaps, lotions, and shampoos, to combat conditions such as acne, dandruff, seborrhea, and androgenic alopecia. Azelaic acid (AZA) is a straight chain molecule of 9 carbon atoms that occurs "naturally, with two terminal carboxyl groups.Azelaic acid is an antiqueratinizing agent, which exhibits antiproliferative effects on keratinocytes, and which modulates the phases early and terminal epidermal differentiation (Passi et al, G. Ital, Derma Tol, Venerol, 1989, 124 (10): 455-463) .Azelaic acid is a competitive inhibitor of the reduction of testosterone to dihydrotestosterone, and as such, it is supposed to reduce the production of sebum in the sebaceous gland.In addition, recent research has shown that azeotic acid and sebacic acid also have antibacterial and antifungal properties.Structure-activity relationship studies have revealed that these effects are retained when the α, β-dicarboxylic acid has a base structure of about 6 to about 14. carbon atoms. Accordingly, azelaic acid, and other a, co-dicarboxylic acids, can be used as therapeutic agents in the treatment of skin disorders; however, the treatment of the above disorders is impeded by the low bioavailability of these therapeutic agents. Dicarboxylic acids, such as azelaic acid, are very polar, due to the two carboxyl groups. Due to this polarity, the penetration in the skin is very low. In addition, the presence of the acid functional group lowers the pH, which can cause skin irritation. Only the high concentrations of azelaic acid in the local preparations (20 percent) are effective in the treatment of acne, to show how weak the therapeutic effect of the azelaic acid lotion is, a 2Q percent preparation was effective only after 3 to 6 months of local application, twice a day. See A. Fitton and K.L. Goa, Drugs 41: 780-798 (1991). In addition, in additional studies, local administration of azelaic acid failed to induce specific changes in sebum composition, in the rate of sebum excretion, and in the size of sebaceous glands (see, for example Mayer-da-Silva and collaborators, 1989, Derm. Venereol Act. (Stockholm) 143: 20-30). Other dermatological agents also comprise a polar functional group, such as a carboxy or hydroxy group, which makes penetration into the skin relatively low. Therefore, There remains a need to increase the efficacy of these drugs in the treatment of skin disorders, where the availability of drugs is improved through local application. The a, β-dicarboxylic acids, and their mercapto, ester, and salt derivatives have been used in the treatment of a variety of disorders and / or skin conditions. The pertinent discussions about its uses can be found in the following references. Hill et al., In U.S. Patent No. 4,034,077, teach the use of a composition comprising sebacic acid for the treatment of skin irritation, and for the prevention of diaper rash, wherein the dicarboxylic acid It acts as a barrier between urine and skin, and also neutralizes ammonia. They do not teach the use of sebacic acid in the treatment of any endogenous disorder, including any form of ichthyosis, or any hormonal imbalance. Nazzaro-Porro (U.S. Patent No. 4,292,326), discloses a method for treating hyperpigmentary desma-tosis with dicarboxylic acids, such as azelaic acid. These acids, together with their mono- and di-mercapto derivatives, are used for their ability to normalize skin color by inhibiting melanogenesis. Nazzaro-Porro (U.S. Patent No. 4,386,104), teaches the use of the same compounds for the treatment of acne. It also teaches the addition of a small amount of keratolytic agent to the composition. Nazzaro-Porro (U.S. Patent No. 5,385,943) also discloses the use of locally applied preparations, comprising an ester of a dicarboxylic acid which can be cleaved by skin enzymes, particularly a glycerol ester, to the treatment of presbyderma of aging skin. However, it is noted that in general, any ester can be dissociated by the non-specific esterases of the skin, including those esters described in the anteriox technique. Thornfeldt (U.S. Patent 4,885,282), discloses a treatment of hyperhidrosis, ichthyosis, and wrinkling of the skin, by means of mono- or dicarboxylic acids (of 4 to 18 carbon atoms), together with its derivatives of mercapto, salts and esters. The use of esters of alkyl, polyol, oligosaccharide and polysaccharide, and specifically of esters of glycerol, polyethylene glycol is described, polypropylene glycol, and sucrose, of the respective mono- or di-carboxylic acids. U.S. Patent Application No. GB 2,285,805 teaches the use of dicarboxylic acid esters with vitamins A, E, and D as antitumor agents. Chamness (U.S. Patent No. 5,547,989) teaches a local composition comprising dicarboxylic acids (of 7 to 13 carbon atoms, and specifically azelaic acid), salts and esters thereof, for the treatment of grains and calluses. However, there is no claim specific ester, nor is shown in an example. Sugibayashi et al. (Chem. Pharm. Bull, 36 (4): 1519-1528 (1988)) teach the use of penetration enhancers for the indomethacin model compound. They make known the use of salicylates as enhancers, due to their ability to soften and dissolve the stratum corneum. They teach the use of salicylates as keratolytic agents to remove the outer layer of cells, which then allows an easier penetration of the desired compound. Luedders (U.S. Patent No. 4,299,826), teaches a physical mixture of the antibacterial agent erythromycin, with the penetration enhancer of diisopropyl sebacate. Luedders teaches that this additive increases the penetration of erythromycin. The known references disclose complex esters of straight chain dicarboxylic acids. In U.S. Patent No. 5,494,924, Cavazza et al. Teach the treatment of ichthyosis, using complex esters of α-α-dicarboxylic acids and carnitine. Bilibin et al. (USSR Patent No. 761,452) teach the synthesis of straight-chain, carbon-acid-dicarboxylic acids esterified by their reaction with p-hydroxybenzoates, which are used as monomers for the formation of liquid crystalline polymers. In U.S. Patent No. 3,660,467, Gould teaches phenoxyphenyl esters of O O, β-dicarboxylic acids for use as synthetic lubricants and as heat transfer fluids. Portnoy et al. (Chemical Engineering Data Series, 1958, 3: 287-293) teach the use of phenyl α, β-dicarboxylates in the development of oil lubricants that do not spread. Although the aforementioned technique discloses compounds comprising esterified acids or β-dicarboxylic acids, there is no discussion about the use of these compounds in the treatment of skin disorders. Accordingly, there remains a need to provide therapeutic agents for the treatment of skin disorders, which demonstrate improved efficacy and reduced irritation over the agents available in the prior art. SUMMARY OF THE INVENTION It is an object of this invention to provide novel compounds comprising ester derivatives of α, β-dicarboxylic acids, effective in the treatment of skin disorders, and to improve the appearance of the skin. It is a further object of this invention to provide cosmetic or pharmaceutical compositions comprising these novel ester derivatives, for the treatment of skin disorders and for improving the appearance of the skin. It is an object of this invention to provide a novel composition with increased penetration through the skin. It is an object of this invention to provide a Novel composition that can treat multiple aspects of a skin disorder. It is a further object of the present invention to provide a novel dual-action pro-drug that can deliver multiple therapeutically active agents to a site on the skin of a patient. It is still a further object of the invention to provide an effective therapeutic treatment to mitigate the symptoms of hyperkeratinization, excessive secretion of sebum, microbial infection, dermaphytosis, and excessive conversion of testosterone to dihydrotestosterone. It is still an additional objective of the invention to provide an effective therapeutic treatment to mitigate the symptoms of acne, psoriasis, seborrheic dermatitis, ichthyosis, rosacea, dandruff, hirsutism, hypertrichosis, and androgenic alopecia. These and other objects are realized by the practice of the invention described herein. In one aspect of the present invention, novel ester derivatives of α, β-dicarboxylic acids are provided. The compound includes a fraction of OI, -dicarboxylic acid covalently linked with at least one fraction of keratolytically active alcohol. The compound can have the formula: where n is on the scale of 6 to 12; m is on the scale of 0 to 8; R 'is H, alkyl, aryl, alkenyl, benzyl, OH, HR ", COOR", or CONHR "; R" is H, alkyl, aryl, alkenyl, or benzyl; and Y is H, alkyl, aryl, alkenyl, benzyl, or X. The compounds of the invention are useful in pharmaceutical treatment for mitigating the symptoms of hyperkeratinization, excessive secretion of sebum, microbial infection, derma-phytosis, and conversion. excessive testosterone to dihydrotes-tosterone, or to mitigate the symptoms of acne, psoriasis, seborrheic dermatitis, ichthyosis, rosacea, dandruff, hirsutism, hypertrichosis, and androgenic alopecia. The compounds of the invention are also useful in cosmetic methods performed by non-medical specialists, ie, lay people, to combat conditions such as acne, dandruff, seborrhea, and androgenic alopecia. Detailed Description of the Invention The present invention provides novel compounds effective in the treatment of skin disorders. These compounds can be incorporated into pharmaceutical products, to be prescribed by medical professionals, or in preparations Cosmetics offered directly to customers for their own use. In accordance with the invention, the compounds include an O.sup.-α-dicarboxylic acid moiety, which is covalently linked through an ester linkage, with a keratolytically active alcohol. The compound may contain one or two alcohols to provide the respective mono- or di-ester. As such, the compound comprises two fractions, a?,? - dicarboxylic acid and a keratolytic agent, each capable of treating the symptoms of a variety of skin disorders, or of improving the appearance of the skin. The compound has the additional advantage of providing the two fractions in a form that rapidly penetrates a dermal site. An "a, β-dicarboxylic acid moiety" is used herein to mean a straight carbon chain terminating at both ends with a carboxylic acid functional group. The length of the α, β -dicarboxylic acid fraction is from about 6 to 14 carbon atoms. In a preferred embodiment, the a, β-dicarboxylic acid fraction comprises between 8 and 10 carbon atoms. The base structure of the carbon chain may be saturated or unsaturated. In preferred embodiments, the unsaturated base structure may contain from 1 to 3 double bonds. The straight carbon chain may also be substituted, for example, it may be linked with hydrocarbon groups along the base structure of carbon atoms.

Suitable α, β-dicarboxylic acid moieties include, but are not limited to, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1,1-undecano-dioic acid, 1,2-dodecanedioic acid, acid 1, 13-tridecanodioic, and 1,4-tetradecanedioic acid. In a preferred embodiment, the α -dicarboxylic acid is azelaic acid. Suitable substitutions along the base structure of the carbon chain include, but are not limited to, alkyl, aryl, alkenyl, and benzyl groups. By way of example only, suitable hydrocarbon substituents, for example aryl and alkyl, include methyl, ethyl, propyl, phenyl, benzyl, and the like. A "keratolytically active alcohol fraction" is used herein to mean a compound that loosens and removes the stratum corneum of the skin, or that has an anti-aging effect by modulating the differentiation and growth of keratinocytes. Suitable fractions of the keratolytic agent include phenol and substituted phenolic compounds. Suitable substituents include, but are not limited to, hydroxy groups, (CH2) m -COOH and - (CH2) m-COOR ', wherein m = 0 to 8, and R' is an 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 impart hydrophobicity to the compound, or to improve the direction of the compound towards the site of action, in order to improve the penetration into the skin. The substituents on the phenyl ring can additionally impart therapeutic properties to the keratolytic phenol. For example, additional hydroxy groups can increase keratolytic performance, and the presence of carboxylic acid or alkyl carboxylate substituents, can impart anti-inflammatory properties. Other substitutes can increase the hydrophobicity of the fraction. Keratolytic agents include, but are not limited to, hydroxybenzoic acid and its ester, anhydride, and amine derivatives, alkyl hydroxybenzoate, dihydroxybenzene and its ester, anhydride, and amide derivatives, cresols and their ester, anhydride derivatives, and amide, or alcohol derivatives of vitamin A. Many of the suitable keratolytic agents are effective for the treatment of different skin disorders. Salicylic acid (o-hydroxybenzoic acid) and its ester derivatives have anti-inflammatory as well as keratolytic activity. It is known that they dissolve and loosen the intracellular matrix of hyperkeratinized tissue. As such, they are used in the treatment of dermatological disorders. Dihydroxybenzene and its derivatives have been recognized as potent keratolytic agents. Resorcinol (m-dihydroxybenzene) and its derivatives are used in anti-acne preparations. Hydroquinone (p-dihydroxybenzene), in addition to its anti-pigmentation properties, is also keratolytic.

These compounds also exhibit antiseptic properties. The cresols also have bactericidal and keratolytic properties. All these compounds, when used alone, have a limited pharmaceutical use, due to their poor penetration into the skin and their relatively weak potency. However, when they are covalently linked to a fraction of OI, β -dicarboxylic acid according to the invention, these compounds experience a greater penetration into the skin, and / or a greater supply to the affected site. Accordingly, the potency of these agents increases in a significant way over those of the prior art. A particularly preferred keratolytic agent is o-hydroxybenzoic acid. In other preferred embodiments, it may be desirable to use alkyl o-hydroxybenzoates or aryl o-hydroxybenzoates such as keratolytic alcohols. By way of example only, suitable aryl and alkyl substituents include methyl, ethyl, propyl, phenyl, benzyl, and the like. The alkyl and aryl hydroxybenzoates have the additional benefit of increased hydrophobicity over the acidic counterpart, which increases skin penetration. In addition, the aryl hydroxybenzoate and alkyl derivatives of the α-dicarboxylic acids form low melting point solids that are liquid at physiological temperatures. This property is useful to improve skin penetration. The particularly preferred compound of the present invention has the general formula: COOY where n is from 6 to 12; R is OH, COOH and COOR '; and R 'can be alkyl, aryl, alkenyl, or benzyl. Y is H, alkyl, aryl, alkenyl, benzyl, or X. More preferred is a compound wherein n = 7; R is ortho-COOR '; and R 'is an alkyl group. By way of example only, suitable aryl and alkyl substituents include methyl, ethyl, propyl, phenyl, benzyl, and the like. The chemical combination of the α, β-dicarboxylic acid moieties with the aforementioned alcohols results in compounds having better therapeutic effects for the treatment of skin disorders. Some modalities have melting points of around 30 ° C to 40 ° C. These compounds are liquid at physiological temperatures, which increases the ease of penetration into the skin, comparing with compounds that are solid at physiological temperatures. Penetration into the skin is directly correlated with hydrophobicity. In the present invention, the polarity of the functional groups of carboxylic acid and hydroxy is masked by the reaction of one with the other to form a complex monoester or diester. As a complex ester, the novel derivatives of the present invention are more hydrophobic than the free ce, β-dicarboxylic acids and the corresponding free alcohols, and this allows a greater penetration through the skin. With the greatest penetration, then the compound can exert its therapeutic effects on the underlying layers of the skin. These effects include, but are not limited to, the aforementioned properties of the a, β-dicarboxylic acid moieties, the keratolytic properties, and the anti-inflammatory effects of the specific alcohols thereof. The compounds of the present invention can function as double-acting "pro-drugs", ie, compounds that once supplied to the target site undergo chemical or enzymatic dissociation to produce the active form of the two corresponding active agents, i.e. , the OI,? -dicarboxílico acid and the alcohol fraction, in their pharmacologically active forms. The skin naturally contains nonspecific esterases that can effect the necessary dissociation. See Montagna, W. The Structure and Function of Skin, 1962, 2nd edition; and Stevens, C.S. and C-Villez R.L. In t. J. Derma tol. 19: 295 (1980). In particular, high concentrations of non-specific esterases are located within the targeted sebaceous glands. See Holt, R.J. Br. J. Derma tol. 85:18 (197). After the penetration Through the outer layers of the skin, the compounds of the present invention interact with these esterases. Since the enzymes are non-specific, they hydrolyse the ester bond that binds to the α, β-dicarboxylic acid fraction and the alcohol fraction. Accordingly, two therapeutically effective agents are released in their pharmacologically active forms. The hydrophobicity of the pro-drug allows penetration through the external layers that occur naturally of the skin, as well as through the abnormal plaques of the hyperkeratinized cells. These plaques are often symptoms of the targeted disorder and barriers to the affected area. Accordingly, the hydrolysis reaction occurs in the underlying layers of the skin. The two pharmacologically active agents, capable of treating two or more separate symptoms of a disorder, derive these barriers to reach the target tissue. There, they can then exert their respective therapeutic properties. Accordingly, it is possible to deliver two therapeutic agents to a target site using the novel compound of the invention. The greater penetration of the present invention, and therefore, the better delivery of the pharmacologically active agents towards the target tissue, makes it possible to have a more effective treatment of skin disorders than is known in the prior art. Because the efficiency of the supply is improved, the amounts of active ingredients less than which is previously disclosed in the prior art, will alleviate a skin disorder. In addition because the acidity of the agent is reduced by esterification, there is reduced inflammation and irritation at the site of application. Another aspect of the invention is a pharmaceutical or cosmetic composition that can treat two aspects of a skin disorder. The acid, β -dicarboxylic acid can exert its therapeutic effects on the secretion of sebum, keratinization of the skin, microbial and fungal infections with concomitant keratolysis of the stratum corneum, and / or an anti-inflammatory effect, exerted by the phenolic fraction. In one embodiment of the invention, a composition comprising 10 percent by weight (200 millimoles / milliliter) of di (ethyl salicylate) azelate was effective in reducing comedones in a rabbit ear model. The comedolytic effect of di (ethyl salicylate) azelate was comparable to the effect of 0.025% Retin A Cream. This comedolytic effect is superior to a 20 percent azelaic acid preparation (1, 060 millimoles / milliliter) disclosed in the prior art. See Lee et al., Kor J. Derma tol 28 (5): 543-549 (1990). Additionally, treatment with this composition did not induce any inflammatory response in the treated area, as opposed to the inflammatory effect observed when treated with 0.025% Retin A. Moreover, an irritation test of comparative skin in human volunteers has shown that the di (ethyl salicylate) azelate (at 20 percent, 400 millimoles / milliliter) did not irritate the skin. In contrast, an equimolar mixture of its components (7.5 percent azelaic acid, 400 millimoles / milliliter, and 11 percent salicylic acid, 800 millimoles / milliliter), induced an inflammatory reaction, including moderate erythema, mild edema, and pruritus. local. A live skin irritation test in rabbits also showed no signs of irritation 24 hours after the application of di (ethyl salicylate) azelate (10 percent and 20 percent). These findings emphasize a distinct advantage of di (ethyl salicylate) azelate over its original components. The sebolitic effects of di (ethyl salicylate) azelate were revealed in a test with humans. 14 days after the local treatment, the oiliness of the skin of the forehead of a human volunteer was reduced, tested using a photometric instrument, from 223 units (similar to "oily skin") to 205 units (normal skin value) ). This discovery demonstrates the superiority of the compounds of the invention over azelaic acid, which, according to published literature, can not alter the oiliness of the skin. The direct effect of the compounds of the invention on the proliferation of human keratinocytes was evaluated in vitro, using a keratinocyte cell line. HE found that the compounds of the invention are strong inhibitors of keratinocyte proliferation. Di (ethyl salicylate) azelate inhibited cell proliferation at a concentration of 0.13 mM, and di-retinyl azelate was inhibitory at a concentration of 15 μM. The respective cytotoxic concentrations of the same agents were 3 mM and 100 μM, allowing a substantial therapeutic safety margin of 6.6-10. In contrast, the inhibitory concentration of azelaic acid was as high as 1 mM, and its cytotoxic concentration was only 2.6 times higher. Accordingly, the use of the compounds of the invention in the treatment of skin disorders involving hyperkeratinization is convenient over the use of free azelaic acid. A preferred embodiment is a pharmaceutical or cosmetic composition comprising a therapeutically effective amount of the novel compound described herein, and a pharmaceutically or cosmetically acceptable carrier. With respect to a "pharmaceutically acceptable carrier", as used herein, it means any liquid, gel, emulsion, cream, ointment, ointment fluid base, solvent, diluent, and the like, which is suitable for use in contact with the mammalian living tissue, which is desirably capable of dissolving the therapeutically active agents of the invention, and which does not interact with the other components of the composition in a detrimental manner. Alcohols are vehicles particularly preferred. The additives to these compositions may include, but are limited to, preservatives, humectants, petroleum jelly, thickening agents, alpha-hydroxycarboxylic acids, mineral oil, pigments and other components described in the CTFA cosmetic ingredients manual. Ordinary experts in the field of dermatology could see the resulting compositions can be in many forms, including, but not limited to, solutions, lotions, creams, pastes, emulsions, gels, soap bars, sprays, or aerosols. These compositions can be applied manually, or using different application devices. One aspect of the invention is a pharmaceutical or cosmetic composition for the treatment of hyperkeratinization. Another aspect of the invention is an effective composition and method for the treatment of dermatological disorders resulting from a hormonal imbalance in target tissues. It has been suggested that acids,? -dicarboxílicos inhibit the reduction of testosterone to dihydrotestosterone (DHT). By inhibiting this conversion, c., Β-dicarboxylic acids act as therapeutic agents in the treatment of disorders caused by an increase in the amount of dihydrotestosterone. Dihydrotestosterone is an androgen responsible for the development of secondary sexual characteristics. Higher levels of dihydrotestosterone can cause excessive hair growth, a disorder known as hypertrichosis. Both the Men like women can be afflicted by hypertrichosis, where there is an increase in hair growth in any part of the body. Another disorder that impacts women, and that is caused by higher levels of dihydrotestosterone, is hirsutism. In this disorder, the higher levels of androgens cause the subject to develop male patterns of hair growth. Since the aforementioned disorders are caused by a higher level of dihydrotestosterone in the hair follicle, they are often accompanied by a greater presentation of acne. The greater penetration of the composition of the invention provides a method for delivering fractions of o-, β-dicarboxylic acid to the underlying layers of the skin. Accordingly, the composition of the invention is expected to be effective in the treatment of the "secondary effects of hormonal imbalance." Androgenic alopecia, also called male pattern baldness, is a predominantly hereditary disease that is the most common cause of loss. The hair follicles are more sensitive to dihydrotestosterone and its subsequent breakdown products, which are thought to inhibit hair growth on the scalp, consequently, an increase in the amount of hydrotestosterone in the hair follicle. would increase this inhibition, and lead to hair loss.Androgenic alopecia can also afflict women.

Increased levels of circulating androgens in women can be caused by endocrine disorders, such as ovarian or adrenal dysfunction. In these women, excessive amounts of androgen in the target tissue, specifically the hair follicles, inhibit hair growth, and ultimately result in hair loss. It is expected that the composition of the invention will effectively reduce the amount of dihydrotestosterone in the hair follicles. This reduction will decrease inhibition and promote hair growth. Another aspect of the invention is a method for the treatment of a particular disorder of the skin by applying a composition comprising an effective amount of the compound mixed with a pharmaceutically or cosmetically acceptable vehicle to the affected area. The composition contains a therapeutically effective amount of the novel mono- or di-ester of the invention. The actual effective amount may vary depending on the particular skin disorder treated; however, it is generally contemplated that the composition having from 0.1 percent to 30 percent (by weight by volume) according to the invention can be used. The composition can be applied locally to the affected area. "Local" application, as that term is used herein, means to be extended or placed directly on the epidermal tissue. The application can be done by rubbing, using medicated cushions, or by any other convenient means. Due to the very low toxicity of Composition of the invention, oral, nasal, or parenteral administration of the agent is also applicable. The novel compound of the invention can be prepared according to methods known in the art. The synthesis of ester from carboxylic acids and their derivatives is well known to those of ordinary skill in the art. A carboxylic acid and an alcohol can be combined in the presence of an acid catalyst to obtain the desired ester and water. The acyl halide derivative, or other suitable derivative (eg, tosyl, mesityl, etc.) of the carboxylic acid, will also effectively produce the desired ester. For a review of the ester synthesis, the reader is directed to Voll-hardt, Orcranic Chemistrv, chapter 17. The following examples are illustrative of the present invention, without constituting limitations thereon. Example 1 Synthesis of di- [(2'-ethoxycarbonyl) phenyl] ester of nonanodioic acid (also referred to herein as "di (ethyl salicylate) azelate"). Dissolve 80 millimoles of ethyl salicylate in 50 milliliters of pyridine, in a three-necked flask equipped with a nitrogen inlet and outlet. The solution is cooled to 0 ° C. Azelaoyl chloride (40 millimoles) is added dropwise for 1 hour with magnetic stirring. The reaction mixture is stirred for 2 hours at room temperature, and then poured into 200 milliliters of 5% HCl. hundred. The mixture is extracted three times with methylene chloride, and the organic phase is worked with sodium bicarbonate and water, and evaporated to give a viscous white product. The product is purified on a column of silica gel using 3: 5 ethyl acetate: hexane as an eluent. It is then evaporated and mixed overnight with 50 milliliters of hexane, to give 11.6 grams (24 millimoles, 60 percent yield) of a white powder (m.p. = 34-35 ° C, molecular weight = 485). The compound was characterized by nuclear and infrared magnetic resonance. 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 (calculated 66.94); H = 6.68 (calculated 6.61). Example 2 Synthesis of o, o-di- (7-methoxycarbonyl-l-octanoyl-l, 4-dihydroxybenzene). 20 grams (100 millimoles) of azelaic monoethyl ester are added dropwise over a period of 5 hours, to 24 grams (14.7 millimoles) of S0C12 over a water bath at 40-50 ° C. S0C12 was distilled, and the resulting acyl chloride was slowly dripped in 12 grams (110 mmol) of hydroquinone at room temperature with magnetic stirring. The reaction mixture was further stirred at room temperature for 16 hours, then poured into 5 percent HCl. It was extracted with methylene chloride, washed with water, dried, and evaporated. Crystallization from toluene gave 17 grams (58 mmol, yield = 58 percent) of a pale chestnut solid (m.p. = 53-56 ° C). The compound was characterized by nuclear magnetic resonance. 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-l-octanoyl-1,4-dihydro-xybenzene). 20 grams (100 millimoles) of azelaic monomethyl ester are added dropwise over the course of 5 hours to 24 grams (14.7 millimoles) of S0C12 over a water bath at 40-50 ° C. S0C12 was distilled, and the resulting acyl chloride was slowly dripped into 5.5 grams (50 mmol) of hydroquinone at room temperature with magnetic stirring. The reaction mixture was further stirred at room temperature for 16 hours, then poured into 5 percent HCl. It was extracted with methylene chloride, washed with water, dried, evaporated, and mixed overnight with 50 milliliters of hexane, to give 9.5 grams (20 millimoles, yield = 40 percent) of a white powder. The compound was characterized by nuclear and infrared magnetic resonance. NMR: 1.31-1.77, m, 10H; 2.32, t, 2H; 2.53, t, 2H; 3.67, s, 3H; 5.60, broad s, ÍH; 6.82, dd, 4H; and IR: 3458, 2943, 1740, 1510, 1444, 1267, 1223, 1149. Example 4 Synthesis of di-retinyl-azelate. Vitamin was dissolved A (retinol, 0.86 grams, 3 mmol) in 2 milliliters of pyridine and 7.5 milliliters of methylene chloride in a 25 milliliter flask equipped with a calcium chloride vent. The solution was cooled on an ice bath. Azelaoyl chloride (0.3 milliliter, 0.345 gram, 1.5 millimole) was added with magnetic stirring. The reaction mixture was stirred for 2 hours at room temperature, and then poured into 10 milliliters of 5 percent HCl / ice. The mixture was extracted three times with methylene chloride, and the organic phase was washed with sodium bicarbonate and water, dried with magnesium sulfate, and evaporated. The product was purified on a column of silica gel, to give 0.5 grams (0.7 mmol, yield = 46 percent). The compound was characterized by nuclear magnetic resonance: 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 Preparation of an anti-acne / anti-seborrheic lotion. 10 grams of di (ethyl salicylate) azelate are dissolved in 10 milliliters of ethanol and 90 milliliters of PEG400, to give a clear colorless solution with a viscosity of < 100 cps. Example 6 Efficacy of di (ethyl salicylate) azelate (10 percent) in the rabbit ear acne model. Mature male albino rabbits were treated as follows. The external channels of the ear, in both ears, once a day for five days a week for three weeks, with 1 percent crude coal tar in USP Hydrophilic Ointment. An ear with anti-acne lotion of Example 4 was then treated once a day for five days a week for three weeks, while the opposite ear served as an untreated control. Cutting biopsies were taken from both sides at the end of the three weeks of treatment. These were fixed in formalin, sectioned in semi-series, and stained with H and E. The untreated ears showed compact hyperkeratosis of the sebaceous ducts. These were judged to be moderate examples of comedones with distortion of the follicular infundibulum by dense horn. The three ears treated showed a marked reduction of the comedones. A few follicles showed a small amount of residual horn, but it was loose and not compact. The comedolytic effect of di (ethyl salicylate) azelate was comparable to the effect of 0.025% Retin A Cream. There was no inflammatory reaction resulting from the treatment. Example 7 Irritation test of human skin. The following lotions (0.1 milliliters) were applied to the skin of a human subject for 48 hours, using standard skin irritation test chambers (0.64 square centimeters): (1) di (ethyl salicylate) 20% azelate (400 millimoles / milliliter), dissolved in PEG 400 / ethanol 1: 1; (2) mixture of azelaic acid at 7.5 percent (400 millimoles / milliliter), and 11 percent salicylic acid (800 millimoles / milliliter), dissolved in PEG 400 / ethanol, 1: 1; and (3) PEG 400 / ethanol, 1: 1 (placebo). When removed from the chambers, and 1, 24, and 48 hours later, there were no signs of skin reaction resulting from the application of either placebo or di (ethyl salicylate) azelate. The equimolar mixture of the pro-drug components (2) induced an inflammatory response, including moderate erythema, mild edema, and local pruritus. Example 8 Acute dermal toxicity / irritation test. The purpose of this study was to evaluate the effect of acute skin dermal irritation on the skin following the local application of di (ethyl salicylate) azelate, in rabbits. This test is a modified version of Draise's original method, as described in the OECD guidelines. 0.5 milliliters of di (ethyl salicylate) azelate (10 percent or 20 percent, dissolved in PEG 400 / ethanol 1: 1), or vehicle alone, was applied to the skin of three rabbits for 24 hours. The rabbits were examined to determine the signs of skin irritation at 1, 24, and 72 hours after removing the test solutions. Throughout the entire study, no signs of skin irritation were observed. Based on the current protocol, it was concluded that di (ethyl salicylate) azelate is a non-active agent irritating. Example 9 Acute subcutaneous toxicity limit test. Five male ICR mice and five females were administered subcutaneously 2,000 milligrams / kilogram of di (ethyl salicylate) azelate, and then followed for 14 days. No toxic effects were observed throughout the treatment and the observation period, indicating that di (ethyl salicylate) azelate can be considered as non-toxic. Example 10 Sebolytic effect of di (ethyl salicylate) azelate. The anti-acne / anti-seborrhoeic lotion of Example 5 was applied twice daily to the forehead of a woman who had oily skin, before treatment. The oiliness of the skin was tested using the "Skin Tester, Model STC20" (IMS Ltd., Haifa, Israel) before the treatment and 14 days later. Before treatment, the sebum value was 223 units, typical of oily skin. The sebum value after two weeks of treatment was 205 units, corresponding to normal skin. Example 11 Anti-psoriatic gel. Dissolve 20 grams of di (ethyl salicylate) azelate in 50 milliliters of ethanol and 50 milliliters of water. The solution is heated to 60 ° C with stirring, and 1 gram of PEG 4000 is added. The mixture is cooled to room temperature, and a gentle magnetic stirring is applied for 2 hours. hours . Example 12 Modulation of keratinocyte proliferation. The effect of di (ethyl salicylate) azelate and di-retinyl-azelate on cell proliferation and viability of in vitro cells was tested using the human keratinocyte culture system. Cell Proliferation Assay 50,000 human keratinocytes were seeded from a secondary culture, in 24-well plates, in 1 milliliter of DMEM-F12 medium (Green H. (1978) Cell 15: 801-805) with growth factors and serum fetal calf at 10 percent. The cells were incubated at 37 ° C in 5 percent C02, until a confluence of 30 to 40 percent was reached, and then the different test materials, dissolved in ethanol, were added in volumes of 0.1 to 20 microliters, up to a final volume of 0.5 milliliters. The same volumes of ethanol were added to the control cultures to determine the comparative values of ethanol cytotoxicity. No apparent cytotoxicity was found up to four microliters / milliliter of ethanol. The medium was replaced with a fresh medium before the addition of the test materials. The cultures were further incubated for three days at 37 ° C and with 5 percent C02, and then washed with phosphate buffered saline (PBS). The cell numbers were determined using two methods: 1) trypsinization, followed by cell counting; and 2) fixation of the culture with 2 percent p-formaldehyde in serum regulated with phosphate, and stained with methylene blue, followed by extraction of color and measurement of optical density at 650 nanometers. Both methods were found in good correlation, such that an OD unit corresponded to 1,000,000 cells. The IC50, that is, the concentration that caused a 50 percent inhibition of cell proliferation for each of the test materials, is presented in Table 1. Cytotoxicity Test The keratinocyte cells were allowed, as before, they will proliferate in the medium, without the test materials, until a confluence of 100 percent, with an exchange of medium during growth. The confluent cultures were incubated with increasing concentrations of the test materials in ethanol for 3 days at 37 ° C and with 5% C02. At the end of the incubation period, the cultures were washed with phosphate-regulated serum, and were measured to determine remaining adhered cells, using the methods described above. The LC50, that is, the concentration that caused 50 percent cytotoxicity, is also presented in Table 1. Table 1 shows that di-retinyl-azelate and di (ethyl salicylate) azelate are significantly more potent that azelaic acid and salicylic acid to inhibit cell proliferation. Moreover, their cytotoxic concentrations were 6.6 to 10 times higher than their inhibitory concentrations, making them safer than free azelaic acid. Table: IC50 (inhibitory concentration) and I.C50 (cytotoxic concentration) of the compounds of the invention, azelaic acid and salicylic acid

Claims (49)

1. CLAIMS 1. A compound, comprising: an O 1, β -dicarboxylic acid covalently linked through an ester linkage with at least one keratolically active alcohol moiety, having the formula: where n is in the range of 4 to 12; m is in the range of 0 to 8; R 'is selected from the group consisting of II, alkyl, aryl, alkenyl, benzyl, OH, NHR ", CONHR" and COOR "; R" is selected from the group consisting of alkyl, aryl, alkenyl and benzyl; and Y is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl and X. The compound of claim 1, characterized in that the compound is a liquid at 40 ° C. 3. The compound of claim 1, wherein the α, β-dicarboxylic acid moiety comprises about 6 to 14 carbon atoms. 4. The compound of claim 1, wherein the acid, α -dicarboxylic fraction comprises 8 to 10 carbon atoms. 5. The compound of claim 1, wherein the backbone of the carbon chain of the acid, β -dicarboxylic acid is unsaturated. 6. The compound of claim 5, wherein the spinal column comprises about one to three double bonds. 7. The compound of claim 1, wherein the carbon chain of the o, β-dicarboxylic acid moiety is linked to a hydrocarbon substituent. 8. The compound of claim 1, wherein the carbon chain of the OI, β -dicarboxylic acid moiety is substituted by alkyl, aryl, alkenyl or benzyl groups. The compound of claim 1, wherein said α, β -dicarboxylic acid is selected from the group consisting of adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1,1-undecanedioic acid, acid 1, 12 -dodecane-dioic acid, 1,3-tridecanedioic acid, and 1,4-tetradecanedioic acid. 10. The compound of claim 1, wherein said c¿, β -dicarboxylic acid comprises azelaic acid. The compound of claim 1, wherein said keratolytically active alcohol moiety comprises an ester, anhydride or amide derivative of salicylic acid or a derivative thereof. 12. A pharmaceutical or cosmetic composition, which comprises: a therapeutically effective amount of a compound comprising a mono- or diester of a α, β-dicarboxylic acid, wherein the ester comprises a keratolytically active alcohol moiety, having the formula: where n is in the range of 4 to 12; ¡I is in the range of 0 to 8; R 'is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl, OH, NHR ", CONHR" and COOR "; R" is selected from the group consisting of alkyl, aryl, alkenyl and benzyl; and Y is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl and X; and a pharmaceutically acceptable carrier. The pharmaceutical or cosmetic composition of claim 12, wherein said α, β -dicarboxylic acid is selected from the group consisting of adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1,11-undecanedioic acid, acid 1,2-dodecanedioic acid, 1,3-tridecane-dioic acid, and 1,4-tetradecanedioic acid. 14. The pharmaceutical or cosmetic composition of the Claim 12, wherein the α-dicarboxylic acid comprises azelaic acid. 15. The composition of claim 12, wherein the compound is a liquid at body temperature. 16. The composition of claim 12, wherein the backbone of the carbon chain of c¿, β-dicarboxylic acid is unsaturated. The composition of claim 16, wherein the spine comprises about one or three double bonds. The composition of claim 12, wherein the backbone of the α, β -dicarboxylic acid moiety is linked to a hydrocarbon substituent. 19. The composition of claim 12, wherein the backbone of the α, β-dicarboxylic acid moiety is substituted by alkyl, aryl, alkenyl or benzyl groups. 20. The pharmaceutical or cosmetic composition of claim 12, wherein said keratolytic alcohol is selected from a group consisting of ortho, meta, and para-hydroxyalkylbenzoate, ortho, meta and para-dihydroxybenzene, ortho, meta and para-hydroxytoluene, and their derivatives. The pharmaceutical or cosmetic composition of claim 12, wherein said keratolytically active alcohol comprises an ortho, meta and para-hydroxyalkylbenzoate. 22. A pharmaceutical or cosmetic composition, which comprising: a therapeutically effective amount of a compound comprising a mono- or diester of a β-dicarboxylic acid, wherein the ester comprises a retinol moiety or its derivatives; and a pharmaceutically acceptable carrier. The composition of claim 12 or 22, wherein said therapeutically effective amount of said compound comprises an amount effective to treat skin disorders. The pharmaceutical or cosmetic composition of claim 12 or 22, wherein said therapeutically effective amount of said compound comprises an amount effective to treat dermatological disorders selected from the group consisting of hyperkeratinization, hypertrophy of the stratum corneum, excessive sebaceous secretion, microbial infection, dermatophytosis, or increased conversion of testosterone to dihydrotestosterone. 25. A method of treating dermatological disorders, comprising: administering topically, nasally, orally or parenterally to a subject having said dermatological disorder a therapeutically effective amount of a compound comprising a mono- or diester of an acid, β -dicarboxylic acid , wherein at least one ester moiety of said compound comprises a keratolytically active alcohol, the compound having the formula: where n is in the range of 4 to 12; m is in the range of 0 to 8; R 'is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl, OH, NHR ", CONHR" and COOR "; R" is selected from the group consisting of alkyl, aryl, alkenyl and benzyl; and Y is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl and X. 26. The method of claim 25, wherein said compound is applied topically to an affected area. 27. The method of claim 25 or 26, wherein the compound is a liquid at body temperature. The method of claim 25 or 26, wherein said dermatological disorder is linked with hyperkeratinization, hypertrophy of the stratum corneum, excessive sebaceous secretion, microbial infection, dermatophytosis, or increased conversion of testosterone to dihydrotestosterone. 29. The method of claim 25 or 26, wherein said dermatological disorder is selected from a group consisting of acne, seborrheic dermatitis, dandruff, psoriasis, ichthyosis, rosacea, hirsutism, hypertrichosis and androgenic alopecia. 30. The method of claim 25 or 26, wherein said dermatological disorder comprises dermatosis. 31. The method of claim 25 or 26, wherein said OI, β -dicarboxylic acid is selected from the group consisting of adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1,1-undecanedioic acid, acid 1. , 12-dodecanedioic acid, 1,3-tridecanedioic acid, and 1,4-tetrade-canodioic acid. 32. The method of claim 25 or 26, wherein the OI, β -dicarboxylic acid comprises azelaic acid. 33. The method of claim 25 or 26, wherein the backbone of the carbon chain of the acid, β -dicarboxylic acid is unsaturated. 34. The method of claim 25 or 26, wherein the spine comprises about one to three double bonds. 35. The method of claim 25 or 26, wherein the carbon backbone of the OI, β -dicarboxylic acid moiety is replaced by a hydrocarbon substituent. 36. The method of claim 25 or 26, wherein the carbon backbone of the OI, β-dicarboxylic acid moiety is substituted by alkyl, aryl, alkenyl or benzyl groups. 37. The method of claim 25 or 26, wherein said keratolytic alcohol fraction is selected from the group which consists of ortho, meta and para-hydroxyalkylbenzoates, ortho, meta and para-dihydroxybenzene, ortho, meta and para-hydroxytoluene, and their derivatives. 38. The method of claim 25 or 26, wherein said keratolytically active alcohol moiety comprises an alkyl derivative of ortho, meta and para-hydroxyalkylbenzoate. 39. A method of treating dermatological disorders, comprising: administering topically, nasally, orally or parenterally to a subject having said dermatological disorder a therapeutically effective amount of a compound comprising a mono or diester of an OI, β -dicarboxylic acid, wherein at least one of said esters comprises a keratolytically active alcohol moiety, comprising a retinol moiety, or their derivatives. 40. A method of increasing the penetration of a α, β -dicarboxylic acid through the dermal layer, comprising: applying a mono- or diester derivative of α, α -dicarboxylic acid to the dermal layer, said ester fraction comprising an alcohol keratolytically active 41. A method of increasing the penetration of a salicylic acid derivative through the dermal layer, comprising: applying a mono- or disalicylate ester derivative of a β-α-dicarboxylic acid to the dermal layer. 42. Compounds of claims 1 to 11, which are functional to release a plurality of dermatologically active compounds when delivered to a target site of the skin. 43. Compositions of claims 12 to 24, which are functional to release a plurality of dermatologically active compounds when delivered to an objective site of the skin. 44. The compounds of any of claims 1 to 11, for use in the treatment of dermatological disorders. 45. Use of a compound comprising a mono- or diester of a β -dicarboxylic acid, wherein the ester moiety of the dicarboxylic acid comprises a keratolytically active alcohol, for the manufacture of a pharmaceutical composition in a topically, orally administrable form parenteral, to treat dermatological disorders, said compound having the formula: where n is in the range of 4 to 12; P is in the range of 0 to 8; R 'is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl, OH, NHR ", CONHR" and COOR "; R" is selected from the group consisting of alkyl, aryl, alkenyl and benzyl; and Y is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl and X. 46. The use of claim 45, wherein the dermatological disorder is linked with hyperkeratinization, hypertrophy of the stratum corneum, excessive sebaceous secretion, microbial infection. , dermatophytosis, or increased conversion of testosterone to dihydrotestosterone. 47. The use of claim 45, wherein the dermatological disorder is selected from acne, seborrheic dermatitis, dandruff, psoriasis, ichthyosis, rosacea, hirsutism, hypertrichosis and androgenic alopecia. 48. The use of a mono- or diester derivative of a α, β -dicarboxylic acid, wherein the ester fraction comprises a keratolytically active alcohol, for the manufacture of a composition for increasing the penetration of O O, β -dicarboxylic acid through a dermal layer. 49. The use according to any of claims 45 to 48, wherein the compound or derivative is a compound according to any of claims 1 to 11.