MX2008004946A - Treatment and prevention of benign pigmented moles (naevi) using artemisinine and the derivatives thereof - Google Patents

Abstract

Benign pigmented moles or athlete's foot or ringworm of the nails can be treated with locally applicable, especially topically formulated active ingredients of formula (I) wherein X represents CO, CHOZ or CHNRZ, Z is selected from hydrogen, linear or branched (C1-C6) alkyl, linear or branched (C2-C6) alkenyl, linear or branched (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C6-C24) aryl, (C7-C24) aralkyl, m- und p- represent CH2(C6H4)COOM;COR3;CSR3;C (NR6) R3;SOR4;SO2OM;SO2NR7R8;SO2O- artemisinyl;SO2NH-artemisinyl;POR4R5and PSR4R5;R3represents a linear or branched (C1-C6) alkyl, a linear or branched (C1-C6) alkoxy;a linear or branched (C2-C6) alkenyl;a linear or branched (C2-C6) alkynyl;(C3-C8) cycloalkyl;(C6-C24) aryl;(C6-C10) aryloxy;(C7-C24) aralkyl;-(CH2)n-COOM, where n represents a whole number between 1 and 6;or 10a-dihydroartemisinyl;R4and R5are independently selected from linear or branched (C1-C6) alkyl;linear or branched (C2-C6) alkenyl;linear or branched (C2-C6) alkynyl;(C3-C8) cycloalkyl;(C6-C24) aryl;(C7-C24) aralkyl;OM;linear or branched (C1-C6) alkoxy;(C6-C10) aryloxy and NR7R8;R6is selected from linear or branched (C1-C6) alkyl;linear or branched (C2-C6) alkenyl;linear or branched (C2-C6) alkynyl;(C3-C8) cycloalkyl;(C6-C24) aryl and (C7-C24) aralkyl;M represents hydrogen or a pharmaceutically acceptable cation;and R7and R8independnetly represent hydrogen or a linear or branched (C1-C6) alkyl, or R7and R8together form am alkylene bridge (C4-C6);and R is selected from hydrogen and the groups cited for R6. Said compounds are also effective in the prevention of acquired Naevus cell naevi.

Description

TREATMENT AND PREVENTION OF BENIGN PIGMENTED MOLES (NAEVI) USING ARTEMISINE AND DERIVATIVES THEREOF The present invention relates to the treatment of benign pigmented moles (naevi) of the skin and mucous membranes; in particular with nevus cell nevi, of lentigos with pigmented nevi of mucous membranes with locally applied formulations, but in particular topical ones. In addition, it is related to topical formulations that are appropriate for this purpose. The term nevus cell nevi means benign skin changes, pigmented moles (birthmark, liver spot) that are composed in cellular terms of so-called nevus cells. Nevo cells are a defective development of normal pigment formation cells, the melanocytes. Melanocytic nevi occur in different numbers, sizes and intensity of color in virtually all human beings. The external appearance of the nevi can be very different. They can be pigmented moles that are level with the skin or raised above the level of the skin (rounded, pedunculated or flat) punctate but also on a large scale, wart-like, uneven or uniform, and the color changes from skin color to coffee or black The number of acquired melanocytic nevi increases during the course of life. Nevus cell nevi with conspicuous structure have an increased risk of degeneration and are called nevus dysplastic or atypical cell nevi. A malignant melanoma, which is black skin cancer, can develop from a nevus of a nevus cell. In more than 60 percent of all cases it develops from a nevus of nevus cell. In recent years, a clear increase in the incidence of melanoma has been recorded. While in the USA in 1960 the lifetime risk of approximately 1: 600 was assumed, currently one of 1: 100 is observed. In this way, in accordance with Dr. Matthias Volkenandt (Clinic for Dermatology and Allergiology of Lud ig-Maximilian University, Munich, Frauenlobstrasse 9, 80337 Munich), for example, melanoma has an incidence in the Bavarian region of approximately 14 (ie 14 new cases) per 100,000 inhabitants per year. This corresponds to a lifetime risk of approximately 1% (each 100th person will be diagnosed with melanoma in the course of their life). Given this number, melanoma is not the most frequent tumor in humans, but the incidence increase according to Volkenandt is higher than any other tumor. In accordance with the current level of knowledge, there is no preventive treatment or therapy to combat the degeneration of nevus cell nevi. Nevi with increased risk of degeneration are mainly removed surgically. Laser treatment plays more than one role in cosmetic aspects. Both methods are invasive, associated with certain risks (formation of wounds, discoloration of the skin, etc.) and high costs. The development of an acquired nevus is always preceded by a small red spot, sometimes microscopically small (a bleeding or hemangioma). From this precursor of nevo a greater red, somewhat elevated mole develops frequently. From the nevus precursors then the nevo brown cell nevi, of different size, color and structure, are developed. Artemisinin (also called qinghaosu) is a sisquiterpene lactone with a peroxide group, which until now has been examined and used primarily as a systematically active antimalarial drug. Artemisinin is difficult to dissolve; however, artemisinin-water-soluble derivatives have been developed. The use of sitic or topical artemisinin and derivatives thereof for the treatment of psoriasis, diseases of viral origin (warts, molluscum contagiosum and ovinia), diseases induced by ultraviolet radiation (light polymorphous desosis, "vascular collagen disease" , premalignant keratosis, Bowen syndrome, lentigo maligna, basal cell carcinoma, squamous cell carcinoma and malignant melanoma), vesicular skin diseases and hemorrhoids is described in EP-A-0 428 773. The object of the present invention is to provide formulations that act locally, but preferably topical, which are effective against benign pigmented moles, in particular against melanocytic nevi and thus can also be used in the prevention of skin cancer. The object is achieved according to the invention that the active ingredients of a class of compounds of the formula (I): (I) in which formula (I) X represents CO, CHOZ or CHNRZ, wherein Z is selected from: hydrogen, straight and branched chain (C? -C6) alkyl, straight or branched chain (C2-C6) alkenyl, alkynyl C2-Cß) of straight or branched chain; cycloalkyl (C3-C8), aryl (C6-C24); aralkyl (C7-C2); m- and -CH2 (C5h4) COOM; COR3; C (NR6) R3; SOR4; S02OM; S02NR7R8, S02NH-arteminisil; POR4R6; wherein R3 is a straight or branched chain straight or branched alkoxy (Ci-Ce), straight or branched chain C2-C2 alkenyl, straight or branched chain alkynyl (Ci-C6), straight or branched chain; cycloalkyl (C3-C8); aryl (Cs-C24); aryloxy (C6-C? 0); aralkyl (C7-C24); - (CH2) n "COOM, with n as an integer from 1 to 6, or lOa-di-hydroartemisinyl, R4 and R5 are independently selected from each other straight chain or branched alkyl (Ci-Ce), alkenyl (C2) -Cß) of straight or branched chain; straight or branched chain (C2-Cs) alkynyl, (C3-C8) cycloalkyl, (C5-C2) aryl, (C7-C24) aralkyl, OM; (C6-alkoxy) straight or branched chain, aryloxy (C6-C? o = and NR7R8.) R6 is selected from straight or branched chain alkyl (Ci-Cß) or straight or branched chain alkenyl (C2-Ce), alkynyl (C2-C6) ) straight or branched chain, (C3-C8) cycloalkyl, (C6-C24) aryl and (C7-C24) aralkyl, M is hydrogen a pharmaceutically acceptable cation, and R7 and R8 independently of each other are hydrogen or alkyl (Ci -Cß) of straight or branched chain, or R7 and R8 together form an alkylene bridge (C4-Ce), and R is selected from hydrogen and the group listed for R6 are used to produce the locally applied formulation, in particular t pica, against benign pigmented moles. Surprisingly, it was found that pigmented moles of the skin, in particular those of melanocytic origin, can be successfully treated locally very early with the active agents mentioned above, in particular with topical (cutaneous) preparations. It was also found that the prevention of skin cancer (in particular carcinoma or basal cell melanoma) is possible through the treatment of nevo cell nevi with compounds of the formula (I). In addition, it was found that these active agents are also effective with local application in the prevention of benign pigmented moles, in particular acquired nevi cells. Within the scope of the present application, "benign pigmented moles" are understood to be in particular: nevi, in particular nevi cell nevi (banal or dysplastic; nevi cell nevi are also often called melanocytic nevi); including its three subtypes that can be differentiated by place of origin, nevi cell nevi (epidermis / dermis boundary zone), nevi cell nevi compounds (desmis connector tissue) and nevo dermal cell nevi (deep layers) of the dermis), and its subtypes that can be differentiated according to the time of occurrence, congenital nevus cell nevi (= birthmark) and acquired nevus cell nevi. A subgroup of acquired nevi cell nevi are recurrent nevi, which develop after the surgical removal of another benign birthmark. An example of congenital joint nevus cell nevi are the Naevus Spidlus, an example of nevus cell nevi of acquired joint or nevus of nevus compound cell is the nevus halo (Naevus Sutton); and examples of acquired melanocytic nevus nevi cell nevi, nevo cell compounds or nevo dematerial cell nevi are the Naevus Spitz and the Naevus Reed. An example of a composite nevi dermal cell nevus is the Mongolian spot (= Naevus Blue) and an example of a nevus of nevus congenital compound cell or nevo devemo nevo cell is the congenital giant pigment nevus (Naevus gigantus); - lentigo (such as liver spots - lentigo simple, freckles = lentigo Solaris, age spots - lentigo seniles, PUVA lentigos); or disorders of melanin pigmentations (such as freckles = effelids); and o pigmented moles of the mucous membranes (such as nevus of connective tissue in the eye, nevus in the lips and oral mucosa and in reproductive organs). The compounds of the formula (I) are effective in the treatment of all the benign pigmented moles mentioned above, in particular the acquired or congenital nevi cells. Among the above-mentioned nevi, nevus dysplastic (atypical) cell nevi have a higher probability of degeneration to skin cancer and therefore are nevi that are preferably treated with compounds of formula (I) to prevent skin cancer . For the alkyl (C? ~ C6), methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, sec-pentyl, neo-pentyl, n-hexyl, sec-hexyl and neo-hexyl are preferred. More preferably it is a straight chain (C? -C3) alkyl, and methyl or ethyl is particularly preferred. For straight or branched chain (C2-Cß) alkenyl, alkenyls (C2-C4), such as vinyl, allyl, 1-methylvinyl, 2-methylvinyl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, but-l-en-2-yl, but-2-en-2-yl, but-3-en-2-yl, 2,2-dimethylvinyl and 1,2-dimethylvinyl are preferred. For straight or branched chain (C2-C6) acinyl, eg, ethinyl, propargyl, proa-1-yn-l-yl, but-1-yn-l-yl, but-2-in-l -yl, but-3-in-l-yl, but-3-yn-2-yl, 3-methylbutyl-l-yn-l-yl, 3,3-dimethylbutyl-1-yn-l-yl, 1 , l-dimethylbuty-2-yn-l-yl and 1,1-dimethylprop-2-yn-l-yl are preferred. For cycloalkyl (C3-C8), cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferred. For aryl (C6-C2), aryls (C6-C? O), such as phenyl, naphth-1-yl, and naphth-2-yl, are preferred. For the aralkyl (C-C24), aralkyls (C7-C2), such as benzyl, phenethyl, (kart-1-yl) methyl and (naphth-2-yl) methyl, are preferred. For the alkyl in (C? -C6) alkoxy, the same radicals as exemplified above for alkyl (Ci-Cß) are preferred. Preferably it is a (C? -C3) alkoxy, and more preferred is methoxy, ethoxy or n-propoxy. For the aryl in aryloxy (C6-C? O) the same radicals are exemplified above for the aryl (C6-C2). More preferably it is phenoxy or α- or β-nafrtoxy. Within the scope of the present application, the term "artemisinyl" denotes a group of the formula (I) wherein X = CH-, so that this group can be bound to oxygen or nitrogen through the free valency of the carbon . Within the scope of the present application, the term "10-a-dihydroartemisinyl" denotes -O-artemisinyl, wherein artemisinyl has the above meaning. In the formula (I), for Z hydrogen; straight chain or branched alkyl (C? -C6) m- and p-CH2 (C6h5) COOM; COR3; SOR4; S02OM; S02NRR8; S02NH-artemisinyl and PORR5 are preferred. For the pharmaceutically acceptable cation as M, for example, alkali metal cations, e.g., lithium, sodium or potassium, or alkaline earth metals, e.g., magnesium and calcium, ammonium, and H + N ( RXRYRZ) can be mentioned by way of example, wherein R2, R ?, R1 independently of one another can be methyl or ethyl. For Z as S02OM it is preferred if M is an alkali metal, an alkaline earth metal or ammonium. For Z as PORR5 it is preferred if R4 and R5 are selected from OM or straight or branched chain alkoxy (Ci-Cß). More preferably, one of R 4 and R 5 is OM, wherein M is in particular sodium, potassium or ammonium, and the other straight or branched chain alkoxy (Ci-Ce) or OH. The compounds of the formula (I) are known or can be produced analogously to known compounds of the formula (I). The compound in count X = CO is artemisinin, and the compound in which X = CHOH is dihydroartemisin. Compounds where X = CHOZ, with Z different from hydrogen, or where X = CHNRZ, are referred to below as "dihydroartemisin derivatives". The compounds of the formula (I) can be obtained as follows: Artemisin (X = CO) can, as is known, be isolated from the Artemisia Annua plant. Dihydroartemisin (X = CHOH) is known and can be produced, for example, by the reduction of artemisinin with sodium borohydride in methanol at about 0 ° C. or The dihydroartemisin derivatives, wherein X = CHOZ, wherein Z is a straight or branched chain alkyl (Ci-Cß), straight or branched chain (C2-C6) alkenyl, straight chain (C2-C6) alkynyl or branched, (C3-C8) cycloalkyl, (C6-C24) aryl or (C-C24) aralkyl; can be produced from dihydroartemisin, in which it is first converted with trimethylsilyl chloride into its trimethylsilyl ether, the trimethylsilyloxy group is exchanged with trimethylsilyl bromide by bromine (according to Example 1 of US-A-2005/0119232), and then the bromine atom in turn is replaced in the presence of a base with HOZ which if desired is used in an excess, where Z has the indicated meaning. Among these derivatives artemether (Z = Me) and arteether (Z = Et) are known compounds. The dihydroartemisin derivatives, wherein X = CHNRZ, in R has the meaning indicated for formula (I) and Z = hydrogen, straight or branched chain (C? -C6) alkyl, (C2-C6) alkenyl chain straight or branched, cycloalkyl (C3-C8), aryl (C6-C24) or aralkyl (C7-C24); can be produced dihydroartemisinin, in which it is first converted with trimjetilsilyl chloride to its trimethylsilyl ether, the trimethylsilyloxy group is exchanged by bromine with trimethylsilyl bromide (according to example 1 of US-A-2005/0119232) and then the bromine atom, in turn, is replaced in the presence of a base with an amine HNRZ which if desired is used in an excess, where R and Z have the indicated meaning. The dihydroartemisinin derivatives, wherein X = CHOZ or CHNRZ, wherein R has the meaning indicated with the formula (I) and Z = m- or p-CH2 (C6H4) COOM (the definition of M as given for the formula (I)), k are available from dihydroartemisin or the dihydroartemisin derivative wherein X = CHNRH, in which they are alkylated with methyl ester of m- or p-bromomethylbenzoic acid in the presence of a base, followed by hydrolysis of the methyl ester and formation of appropriate salts, if M is not going to be hydrogen. Among these derivatives, the derivative wherein X = CHOZ and Z = p-CH2 (C6H4) COOH is known as "artelinic acid".

The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ, R having the meaning indicated with the formula (I), Z = COR3 or means CSR3 and R3 is straight or branched chain or C2-C6 alkoxy or aryloxy (C2) -Cio) can be produced by reacting dihydroartemisinin or the dihydroartemisinin derivative wherein X = CHNRH with the appropriate alkyl chlorocarbonic acid ester (Ci-Cß) or aryl ester (Cß-Cio) of chlorocarbon acid or alkyl ester ( C? -C6) of clortiocarbonic acid or Cs-Cryl aryl ester) of clortiocarbonic acid and a base. The dihydroartemisinin derivatives, where X = CHOZ or is CHNRZ, where R has the meaning indicated by the formula (I) Z = COR3 and R3 is alkyl (C? -C6) straight or branched chain, straight or branched chain (C2-C6) alkenyl, straight or branched chain (C2-C6) alkynyl, cycloalkyl (C3-C (), aryl (C6-C24)) or aralkyl (C7-C24) can be produced by reacting dihydroartemisinin or the dihydroartemisinin derivative wherein X = CHNRH with an acyl chloride and a base, wherein the acyl chloride is substituted with the appropriate R3, or the derivatives of dihydroartemisinin, wherein X = CHOZ or is CHNRZ, R having the meaning indicated with the formula (I), Z = CSR3 and R3 is a straight or branched chain (C2-C6) alkyl, (C2-C6) alkenyl chain straight or branched, straight or branched chain C2-C6 alkynyl, (C3-C8) cycloalkyl, (C6-C24) aryl or (C7-C24) aralkyl can be obtained by reacting the corresponding derivative described above wherein Z = COR3 with Lawesson's reagent o The dihydroartemisinin derivatives, where X = CHOZ or is CHNRZ, R having the meaning indicated with the formula (I), Z-COR3 and R3 is - (CH2) n-COOM (M having the meaning indicated with the formula (I)), can be prepared by reacting dihydroartemisinin or the dihydroartemisinin derivative wherein X = CHNRH with a cyclic acid anhydride (if n = 2 or is 3) or with MeOOC- (CH2) n-COOMe. In the latter case where X = CHOZ, a basic catalyst such as Net3 can also be used, and the methyl alcohol released during transesterification can be removed from equilibrium, such as by evaporation under reduced pressure. If M is not hydrogen, a corresponding salt formation may follow, in which the remaining methyl ester group is divided, e.g., with M-cyanide. Among these derivatives, that where X = CHOZ, n = 2 and M = hydrogen is known as "artsunato". or The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ, R having the meaning indicated with the formula (I), Z = CSR3 and R3 is - (CH2) n-COOM (M having the meaning indicated with the formula ( I)), can be produced in that in MeOOC- (CH2) nCOOMe one of the two carbonyl oxygens is replaced by sulfur with Lawesson's reagent and this semitodioster is reacted with dihydroartemisinin or the dihydroartemisinin derivative where X = CHNRN, followed by hydrolysis of the -COOMe group still free to COOH and corresponding salt formation, if M is not hydrogen. or The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ, R having the meaning indicated with the formula (I), Z = C (NR6) R3 (R6 having the meaning indicated with the formula (I) and R3 is a straight or branched chain alkoxy (Ci-Cß) or aryloxy (C6-C? o), it can be obtained, in which an isocyanate R6-NCO, in which R6 has the indicated meaning, is reacted with an alcohol (Ci -Ce) or aryl alcohol (C6-C? O), and the urethane obtained in this way is reacted with P0C13 and then with dihydroartemisinin or the dihydroartemisinin derivative wherein X = CHNRH in the presence of a base. of dihydroartemisinin, wherein X = CHOZ or is CHNRZ, R having the meaning in the formula (I), Z = C (NR6) R3 (R6 having the meaning indicated with the formula (I)) and R3 is alkyl (C? -C6) of straight or branched chain, straight or branched chain alkenyl (C2-Cd), straight or branched chain alkynyl (C2-Ce); cycloalkyl (C3-C8), aryl (C6-C24), aryl (C-C24) or aralkyl (C7-C2), can be obtained in which an isocyanate R6-NCO, wherein R6 has the indicated meaning, is reacted with a corresponding Girgnard reagent R3MgBr, where R3 has the indicated meaning, and the amide obtained in this way is reacted with P0C13 and then with dihydroartemisinin or the dihydroartemisinin derivative, where X = CHNRH in the presence of a base. The dihydroartemisinin derivatives, where X = CHOZ or is CHNRZ, R having the meaning indicated with the formula (I), Z = C (NR6) R3 and R3 is - (CH2) N-COOM (M and R6 having the meaning indicated with the formula (I)) is they can obtain in that a compound MeOOC- (CH2) n-CONHR6, where n and R6 have the indicated meaning, are reacted with P0C13 and then with dihydroartemisinin or the dihydroartemisinin derivative wherein X = CHNRH in the presence of a base, and the methyl ester is hydrolyzed and, if M is not hydrogen, formation of an appropriate salt is carried out. The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ (R having the meaning indicated with the formula (I)), wherein Z = SOR4 and R4 = OMe, can be obtained by reacting dihydroartemisinin with excess dimethyl sulphite DRP 487253), optionally in the presence of a basic catalyst, and distillation of the released methanol and finally the excess of dimethyl sulfite under reduced pressure. The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ, R having the meaning indicated with the formula (I), and Z = SOR4 (R4 being an alkoxy (Cx-Cβ) Straight or branched chain or aryloxy (C 1 -Cy)) i can be obtained through the reaction of the corresponding derivative wherein X = CHOH or CHNRH with excess thionyl chloride and an appropriate base, such as pyridine, removal of excess thionyl chloride and subsequent reaction of the sulphurous acid derivative obtained with alcohol (C? -C6) straight or branched chain or aryl alcohol (C6-C? O) in the presence of an appropriate base, such as pyridine. The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ, R having the meaning indicated with the formula (I) and Z = SOR4 (R4 being straight (C6-6) alkyl, straight-chain (C2-C6) alkenyl or branched, straight or branched chain (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C6-C24) aryl or (C7-C24) aralkyl), can be obtained by reacting a Girgnard reagent R4MgBr, wherein R4 it has the indicated meaning, with excess of thionyl chloride, removal of the excess of thionyl chloride and subsequent reaction of the obtained R4S0C1 with the corresponding dihydroartemisinin derivative wherein X = CHOH or CHNRH in the presence of an appropriate base, such as pyridine. or The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ, r having the meaning with the formula (I) and Z = SOR4 (R4 being NR7R8, and R7 and R8 having the meaning indicated with the formula (I)) can be obtained by reacting an amine HNR7R8 with excess thionyl chloride, removal of excess thionyl chloride, and subsequent reaction of the obtained RR7R8NS0C1 with the corresponding dihydroartemisinin derivative wherein X = CHOH or CHNRH in the presence of an appropriate base, such as pyridine. The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ, with Z = S02OM (M having the meaning indicated with the formula (I)) can be obtained by reacting the corresponding derivative wherein X = CHOH or CHNRH with complex of pyridine-sulfur trioxide and exchange of the pyridinium counterion of the sulfonate obtained for M. The dihydroartemisinin derivatives, wherein X = CHOZ or is CHNRZ, wherein Z = S02NRR8 and R, R7 and R8 have the meaning indicated with the formula ( I), can be obtained by reacting the dihydroartemisinin derivative wherein X = CHOZ or CHYNRH with 1 equivalent of sulfuryl chloride in the presence of a base, such as, e.g., pyridine and subsequent reaction with 1 equivalent of an amine HNR7R8, wherein R7 and R8 have the indicated meaning, in the presence of base such as pyridine. The dihydroartemisin derivative, wherein X = CHOZ, wherein Z = S020-artemisinyl, can be obtained by reaction of 2 equivalents of dihydroartemisinin with 1 equivalent of sulfuryl chloride in the presence of base such as pyridine. The dihydroartemisinin derivative, wherein X = CHOZ, wherein Z = S02NH-artemisinyl, can be obtained by reacting dihydroartemisinin with 1 equivalent of sulfuryl chloride in the presence of base such as pyridine and subsequent reaction with 1 equivalent of the artemisinin derivative in where X = CHNH2 in the presence of base such as pyridine. The derivative obtained in this way is identical to the derivative wherein X = CHNHZ and Z = S020-artemisinyl. From the derivative obtained in this way, subsequently the dihydroartemisinin derivatives wherein X = CHNRZ, R having the meaning indicated with the formula (I) except for hydrogen, can be obtained by deprotonation of the sulfamido nitrogen and alkylation with alkyl bromide RBr, where R has the indicated meaning . The dihydroartemisinin derivative, where X = CHNHZ, wherein Z = S02NH-artemisinyl, can be produced in accordance with Example 2 of US-A-20O5 / 0119232. Of this, in turn, the dihydroartemisinin derivatives can be produced, wherein X = CHNRZ, R having the meaning indicated with the formula (I) except for hydrogen, by deprotonation in one of the sulfonamide nitrogens and alkylation with bromide of alkyl RBr, where R has the meaning given. The dihydroartemisinin derivatives, where X = CHOZ or CHNHZ, where Z = POR4R5 or PSRR5, and R, R4 and R5 have the meaning indicated with the formula (I), it can be obtained in that first dihydroartemisinin or the dihydroartemisinin derivative wherein X = CHNRH is reacted with excess of P0C13 (or PSC13) and the excess of P0C13 (or PSC13) is removed by distillation.

To the obtained crude product, where X = CH0P0C12 or (CH0PSC12) or CHNRP0C12 (or CHNRPSC12), depending on the type of radicals R4 and R5 to be introduced, these are introduced as Grignard reagent RMgBr / R5MgBr 8 if R4 and / or R6 are going to be alkyl (C? -C6) straight or branched chain alkenyl (C2-C6), straight or branched chain (C2-C2) alkynyl, (C3-C8) cycloalkyl, (C6-C24) aryl or (C7-C24) aralkyl) in the form of an alcoholate R40 ~ / R50"(if R4 or R5 are to be straight or branched chain or C2-C2 alkoxy) or in the form of amines HNR7R8 or in the form of water or hydroxide, with the conditions that these reagents are preferably added in the order of their increasing nucleophilicity and, if at least one is going to be R4 and / or R5OM, the MOH necessary for this or Purpose is added as the last reagent. where X = CHOZ or CHNRZ, the configuration of this C atom (ie, the C 0 atom of the sesquiterpene structure) can be (R) or (S) The compound of the formula (I) also It can be used in the form of a Cio-epimer mixture, where the reaction of the two epimers can be caused by the preceding artemisinin reduction and / or by exchange of the C? o ~ hydroxyl group for a different hydroxyl derivative of water or for one of the nucleophiles used in the synthesis. Those active agents of the above formula (I) which are selected from artemisinin, dihydroartemisinin, derivatives containing carboxyl groups (in particular artesunate), artemether, arteether, dihydroartemisinin propylcarbonate and artelinic acid are preferred. Artemisinin, dihydroartemisinin and artesunate are particularly preferred. The compounds of the formula (I) can be used individually or as a combination of two or more of these compounds. The compounds of the formula (I), in particular artesunate, are also effective in the prevention of acquired nevi cell nevi. For the prevention of nevus of nevus cells, the compounds of formula (I), in particular artesunate, and applied extensively on the whole skin, to areas of skin with increased probability of the formation of nevi, or to nevus precursors already visible . Skin areas with increased likelihood of nevi formation, on the one hand, are areas that are more frequently exposed to UV radiation. On the other hand, these skin areas frequently occur in the vicinity of an already formed nevus cell nevus (e.g., within a radius of typically up to 5 cm around the nevus already present). The compounds of formula (I), in particular artesunate, thus have the additional advantageous property of making visible the existing nevus progenitors which are so weak that they are hardly visible to the naked eye. Under the action of the compounds of the formula (I), the still invisible nevus precursors first form small red spots, which will become dark to black after a few days and are partly seen as dark crystals seated in the pores. In favorable cases, a microscope examination of light reflected from the regions of skin in trouble, therefore it is no longer necessary. For application, the active agents of the formula (I) can be formulated in an appropriate formulation for local application, in particular for topical (cutaneous) application. The concentration of the active agents in the formulations (preparations) produced is not particularly critical. Formulations with a concentration of about 0.1 to about 40% by weight, based on the formulation, can be produced. For the treatment of nevus cell nevi (congenital = birthmarks or acquired), the formulations preferably contain about 5 to about 20% by weight of the active agent, and particularly preferably contain about 10% by weight, based on the formulation . For the prevention of acquired nevi cell nevi, the formulations preferably contain up to about 5% by weight of the compound of the formula (I) based on the formulation; more preferably, they contain about 1 about 5% by weight. The precise, therapeutically required quantity of active agent depends on the active agent itself, the base used, the prepared galenic form (such as ointment, suspension, paste, poultice, cream, gel, solution) and on the additives used and can be determined by one expert in the field through simple effectiveness tests. The duration of treatment of existing nevi cells (congenital = birthmarks or acquired) depends on the type, size, structure, pigmentation and age of the nevus. Preferably, the treatments are carried out cyclically with high concentrations of the compound of the formula (I). Initial reactions are often visible after the first few days of treatment. It may take up to several months before a clear improvement or change, which is shown by a fading or a disappearance of the nevus of nevus cell. This period may be longer in the case of older patients, since the removal of the epidermis takes much longer with the increase in age. For the prevention of nevi cell nevi acquired an application two or three times is suffient. Preferred older precursor nevi are treated longer until the fading or disappearance of the nevus precursors. The active agent of the formula (I) must penetrate the skin at different depths depending on the therapeutic approach: For the treatment of nevus cell novae (congenios = birthmark or acquired), the active agent preferably penetrates to the upper dermis , depending on the type and age of the nevus. For the prevention of acquired nevi cell nevi, the active agent preferably penetrates through the epidermis to the joint area, the border between the epidermis and dermis. As the formulation basis for the active agents of the formula (I) all the bases which are usual for local formulations and are inert toward these agents are appropriate. In particular, these bases for topical formulations can be petrolatum, fats, waxes, fatty acid esters, pa5rafines, oils, silicones and polymers thereof. Preferably the active agents are formulated with from about 60 to about 99.9% by weight, more preferably from about 80 to about 95% by weight of the formulation base, based on the finished formulation. If hydrophilic / aqueous topical formulation bases are used, such as, e.g., hydrogels, creams, the active ingredients can be protected from degradation by nano-encapsulation, envelope in loposomes or complex formation with, e.g. , cyclodextrins. Regarding the formation of artemisinin complex and derivatives thereof with cyclodextrins, reference is made by way of example to US-A-2005/187189. Topical formulations with a single-phase, anhydrous base, e.g., anaphase of pure fat that is anhydrous, are referred to as ointments in accordance with Germán Pharcopeia. The ointments in which the active agents of the formula (I) are used in accordance with the invention, thus consist of an ointment base of this type. Which may contain the active agents finally distributed for application to the skin. If the topical formulation is to be an ointment, the formulation base of preference may consist of lipophilic constituents with a division coefficient of N-octanol / water at room temperature of from about 1 to about 105, more preferably about 10 to about 105 and particularly preferably from about 50 to about 104. Examples of the formulation base herein are, for example, petrolatum, fats, eras, fatty acid esters, paraffins, oils, silicones and polymers thereof (e.g., polydialkylsiloxanes). , silicone elastomers, silicone waxes, silicone emulsifiers). In the application of an ointment the active agent of the formula (I) leaves the topical base that surrounds it and penetrates towards the skin. The lipophilic base adheres very well to the skin and forms a water-repellent coating on the outside. This layer also prevents water from leaving the skin outside (occlusion effect). Through this effect, the skin stays moist and heats up because less water can evaporate. Through increased moisture, the skin also becomes more elastic, which promotes the absorption of active agent. In contrast to ointment, two-phase systems (aqueous and fat phase) are called creams. The compounds of the formula (I) can also be formulated as a cream. The same substances are possible for the fat phase as explained above for the ointment base. In addition to water, the aqueous phase may also optionally contain buffering agents which can cause a pH of the aqueous phase well tolerated by the skin, or may also contain known gel-forming polymers, such as eg, hydroxypropylmethylcellulose, carboxymethylcellulose , polyvinyl alcohol with crosslinkers (such as borax or multivalent metal cations such as Mg2 + or Ca2 +) and the like. For emulsification, conventional surface-active substances well tolerated by the skin, such as, eg, mono or diglycerides of fatty acid, castor oil hydrogenated with PEG-40 (Cremophor®) or lecithin can be used. I use auxiliary agents for topical formulations, conventional penetration accelerators (such as dimethylacetamide, dimethylformamide, propylene glycol, fatty alcohols, triethanolamine, dimethyl sulfoxide, azones and the like) keratolytics to improve effectiveness (such as salicylic acid, urea, retinoids) and Conservatives are possible. The additives generally serve to improve the effectiveness, stability, durability and consistency of a galenic form of administration. The compounds of the formula (I) are preferably formulated in topical formulations essentially free of substances which improve penetration. The compounds of the formula (I) are also preferably formulated essentially free of monocarboxylic acids (C5-C19), esters thereof and amides of the same. Within the scope of the present application, "essentially free" means that the topical formulation is less than 1% by weight, preferably less than 0.1% by weight of substances that improve penetration, based on the formulation. All derivatives with a carboxyl group, in particular artesunate, are preferred as compounds of the formula (I) for pastes, ointments, creams, solutions, gels, sprays or suspensions. The carboxyl group in this manner can optionally be present in the form of alkali metal, alkaline earth metal or ammonium salt. The active agents of the formula (I) for application on or to the skin are preferably applied as a plaster in the form of a topical formulation, in particular in the form of a paste, ointment, suspension, solution, gel, spray or cream, particularly preferably in the form of an ointment. This plaster may optionally have a material that receives or absorbs the topical formulation. However, the active agent can also be directly suspended or dissolved in an inert adhesive of the plaster; known plaster analogs, such as for scopolamine (e.g., "Scoopoderm TTS") OR FOR ESTRADIOL (V.GR., "Estraderm TTS"). In this way, the active agents can be in contact with the location to be treated directly and for a longer period. In addition, an occlusion effect occurs, which improves the penetration of the active agent. Additional forms of application of the active agents of the formula (I) would be pastes, solutions, suspensions, gels and chromas and sprays. Semi-solid or liquid formulations of the above-mentioned active agents may also be present in the form of a stick (e.g., as a felt tip for precise dosing) or a roll(with the active agent in a base, solution, suspension, ointment, appropriate cream). Further examples of local application forms that can be used according to the invention for the compounds of the formula (I) are applicators that effect the penetration of the compounds of the formula (I) into the skin or mucous membrane by means of ultrasound , by means of electric fields or by means of microneedles. Known applicators that use ultrasound and can be used in accordance with the invention are described, e.g., in US-B-6,908,448, which is hereby incorporated by reference. Applicators that use electric fields for the application of active agents (which, therefore, use the principle of iontophoresis) have been known for a long time. They are suitable according to the invention for those active agents of formula (I) which are saline, ie, those wherein X is CHOZ or CHNRZ, Z being selected from m- and p-CH2 (C6H) COOM, S02OM and POR4R5, wherein one of R4 and R5 is OM and the other is a straight or branched chain alkoxy (Ci-Cß) or OH, and M represents a pharmaceutically acceptable cation. For known applicators with microneedles for the local application according to the invention of active agents to the skin, reference can be made to the invention of active agents to the skin, reference can be made by way of example to US-A-2005 / 065463, which is also incorporated by reference herein. Another example of a local form of application that can be used according to the invention is a technique in which the skin is lifted by means of a suction cup at the location to be treated and at the raised portion of the skin. a part of the skin thickness of the dermis is removed mechanically, such as with a blade. This portion of the skin with partially removed dermis is more permeable for the compounds of the formula (I) and allows the local treatment of deeper layers of the dermis in this location. The equipment necessary for this is described in WO-A-95715783, incorporated by reference herein. A low-risk, non-invasive preventive or therapeutic treatment of acquired nevi cells or acquired or congenital nevi cells (= birthmarks) with artemisinin and derivatives thereof (dihydroartemisinin, arteether, artemether, semisynthetic artesunate derivatives) of them and synthetically analog compounds) represents a huge progress in the treatment of nevi cells and could drastically reduce the risk of skin cancer. The invention in this way is of great significance not only medically, but also socioeconomically. No allergic skin reactions to the compounds were observed with the topical treatments described with the compounds of the formula (I), in particular artesunate. It is also notorious that healthy tissue is not damaged and the treatment is painless and simple. In view of the results obtained so far, it can be assumed that local therapy, in particular topical with artemisinin and derivatives thereof, is very effective and, in a long term, is considered as prevention and treatment of nevi is more effective in cost and Low risk than traditional and invasive treatment methods. The invention is now further illustrated by the following examples. Example 1: Topical formulation Different amounts of artesunate (see Table 1) were incorporated in various bases. In part, surface active substances were also added to the formulations.

Table 1: Examples 9a-9i: topical (cutaneous) applications in the treatment or prevention of pigmented moles. a) A 13-year-old boy with raised dark brown birthmark (nevus of dysplastic nevus9 on his chest, with an uneven structure of approximately 1.2 cm in diameter was treated 2-3 times a week with artesunate vaseline ointment at 10% of example 2a After 2 weeks the birthmark was light brown with a few dark punctate spots that looked like "crystallized" coloring material.The birthmark is dry and scaly and looks as if it is being removed from inside". b) A woman with 3 black birthmarks raised on the surface of the skin (joint nevi on the trunk) with a diameter of 0.5 to 12.0 cm applied to the artesunate vaseline ointment at 105 of Examples 2a 3 times per week under Occlusion (like a poultice) during the night. After one week a dark spot was discernible on each birthmark. After 3 weeks a skin was desescamó along with its formations similar to dark glass.

Three pale birthmarks remained, with free places of birth, which are no longer raised above the surface of the skin. A continuation of the treatment leads to an additional fade and flaking of the skin in the treated sites. c) Treatment of 2 nevus cell nevus precursors, which is raised areas extravasated from the skin with a diameter of 0.3-0.4 cm: A three-fold application of the plaster with the artesunate ointment to 105 of Example 2a overnight after Two weeks led to a change in color, light red formation with dark spots. The changed, raised area of the skin could be separated. Two small wounds remained, due to too early separation, which healed. d) A female test subject with a nevus of approximately 3-4 cm in diameter (basiloma) was applied the artesunate ointment to 10% of Example 1 for 3 months (cyclically in the afternoon, every third week). Initially the nevus exhibited a reddish (similar to the inflammation process). After 3 months a recession (in terms of color and structure) could be seen of approximately 90%. After around 5 months, the nevus was no longer visible. e) A female test subject with a nevus in her arm (joint nevus) also applied with the 10% artesunate ointment of Example 1. Since the test subject was not monitored, precise data can not be provided here on the frequency of application; however, the application of the ointment was extended for several weeks. The nevus is hardly visible today. f) A male subject of 13 years of age with a congenital nevus in the root of the nose / eye area applied with artesunate ointment at 105 of example 1 two to three times in a week under occlusion (poultice) for two months. At first the nevus exhibited many small dark spots. Reacts more slowly However, initial successes were already indicated, especially it has become much paler and exhibits several areas of skin color. g) A female patient of 13 years of age with a dermal nevus applied with the artesunate ointment at 105 of example 1 for 3 days. An immediate concentration with the formation of 3 dark spots in the nevus occurred and the remaining area is virtually colorless. h) A female test subject applied with the 10% artesunate ointment of Example 1 twice (once every 2 consecutive days) over a large area in the abdomen, where she had already had numerous nevi cell nevi (nevi of meeting) .

In addition to the existing nevi, red, partly precursor nevi of the type described in the beginning, were already visible on the 2nd day of treatment in the form of small spots that were unevenly distributed through the treated areas. These nevus precursors were already in existence, but became visible only by treatment with the ointment. After 2-3 days they became dark to black. In part they looked like dark crystals sitting in pores. They were descaled within 2 - 3 weeks with the upper layer corneal layer or separated if scratched a little with a fingernail. i) A female test subject treated in the posterior parts of her hands, in which she had numerous pigmented millets (nevi) of different sizes, with the ointment of example 1. The existing nevi and nevus precursors quickly vanished and regressed with Increasing duration of application (7 or 10 days). The color of the pigmented moles became clearer after the treatment was discontinued. After four weeks they were hardly to not visible. Example 10: Topical application in the treatment of nail fungal infections. The fungal infections of the nail on the middle fingers and thumb of the foot: half of the nail on the thumb of the infected foot. Treatment with conventional agents such as Lamisil had little success. The 10% artesunate petrolatum ointment of Example 2a was applied 3-4 times a week. The ointment was applied on the entire nail bed and under the nail. Already after 2 weeks a distinctive improvement could be observed. After 4 weeks the discoloration on the middle toe had completely disappeared or had grown out. The portion of the necrotic nail on the thumb of the foot collapsed. The treatment of the remaining nail was easier and more effective. The active agent reached the edge region to the healthy portion of the unimpeded nail. The growth of nail in its end, did not have pale discoloration. In the case of fungal infections particularly of the nails, it can be expected that no additional systemic treatment with antifungals will be necessary and thus not only the cost but also the risk of side effects of the antifungal treatment will be reduced.

Claims (21)

1. CLAIMS 1.- The use of a compound that has the formula
2. : D
3. (I) in which formula (I) X represents CO, CHOZ or CHNRZ, z being selected from: hydrogen; straight or branched chain alkyl (Ci-Cß), straight or branched chain (C2-C6) alkenyl, straight or branched chain (C2-C6) alkynyl, (C3-C8) cycloalkyl; aryl (C6-C24); aralkyl (C7-C24), m- and p-CH2 (C6H4) COOM; COOR3; CSR3; C (NR6) R3; SORm S02OM; S02NR7R8, S020-artemisinyl; S02NH-artemísinílo; PORR6; wherein R3 is straight or branched chain alkyl (C? -C6); straight or branched chain alkoxy (C? -C6), straight or branched chain (C2-C6) alkenyl; straight or branched chain alkynyl (C2-Ce); cycloalkyl (C3-C8); aryl (C6 ~ C24); aryloxy (C6-C? 0); aralkyl (C7-C24); - (CH2) n-COOM, with n as an integer from 1 to 6; or lOa-dihydroartemisinyl; R4 and R5 are independently selected from each other straight or branched chain alkyl (C? -C6); straight or branched chain (C2-C6) alkenyl, straight or branched chain (C2-C6) alkynyl; cycloalkyl (C3-C8); aryl (C6-C24); aralkyl (C-C2); OM, straight or branched chain alkoxy (C? -C6); aryloxy (C6-C? 0) and NR7R8; R6 is selected from straight or branched chain alkyl (C? -C6); straight or branched chain (C2-C6) alkenyl; straight or branched chain alkynyl (C2-Ce); cycloalkyl (C3-C8); aryl (C6-C2) and aralkyl (C7-C24); M is hydrogen or a pharmaceutically acceptable cation; and R7 and R8 independently of one another are hydrogen or straight or branched chain (Ci-Cß) alkyl, or R7 and R8 together form an alkylene bridge (C4-Cß); and R is selected from hydrogen and the groups listed for R6; for the production of a locally applicable formulation, preferably topical against benign pigmented moles. 2. The use according to claim 1, characterized in that the benign pigmented moles are selected from acquired nevi cell nevi, congenital nevus cell nevi, ie, birthmarks; lentigines, in particular liver spots, freckles or age spots, melanin pigmentation disorders, such as spots, and pigmented moles of mucous membranes. 3. The use according to claim 2, characterized in that the pigmented moles are acquired nevi cell nevi, congenital nevus cell nevi (ie, birthmarks) or liver spots. 4. The use according to claim 3, characterized in that the formulation is also used to prevent skin cancer. 5. The use of a compound of the formula (I) according to claim 1 to produce a local formulation, in particular topical, for the prevention of acquired nevi cell nevi. 6. The use according to one of the preceding claims, characterized in that the compound of the formula (I) is selected from artemisinin; dihydroartemisinin; the carboxyl group containing derivatives of the formula (I) (in particular artesunate); artemether; Arteter; dihydroartemisin propyl carbonate, and artelinic acid. 1 . - The use according to claim 6, characterized in that the compound of the formula (I) is artemisinin, dihydroartemisinin or artesunate. 8.- Plaster with a topical formulation containing an active agent of the formula (I):
4. (I) wherein formula (I) X represents CHOZ or CHNRZ, Z being selected from: hydrogen, straight or branched chain (C? -C6) alkyl, straight or branched chain (C2-C) alkenyl; straight or branched chain (C2-C4) alkynyl, cycloalkyl
5. (C3-C8); aryl (C6-C24); aralkyl (C7-C24), aralkyl (C7-C24), m- and p-CH2 (C6H4) -COOM, COR3, CSR3; C (NR7) R3; SOR4; S02OM;
6. S02NR7R8; S02o-artemisinyl; S02NH-artemísinílo; POR4R6; wherein R3 is straight or branched chain alkyl (C? -C6); straight or branched chain alkoxy (C? -C6); straight or branched chain alkenyl (C2-Ce), straight or branched chain alkynyl (C2-Cd); cycloalkyl (C3-C8); aryl (C6-C24); aryloxy (C6-C? 0); aralkyl (C-C24; - (CH2) n -COOM, with n as an integer of 1 to 6; or l-O-hydroartemisinyl; R4 and R5 are independently selected from each other straight or branched chain alkyl (C? -C6); straight or branched chain (C2-Cß) alkenyl, straight or branched chain (C2-C6) alkynyl, (C3-C8) cycloalkyl, aryl
7. (C6-C24); aryloxy (C6-C? 0; aralkyl (C7-C24); OM, straight or branched chain alkoxy (Ci-Cd); aryloxy (C6-C? 0) and NR7R8; R6 is selected from alkyl (Ci-Cß) straight or branched chain; straight or branched chain (C2-C6) alkenyl;
8. Straight or branched chain alkynyl (C2-C6); cycloalkyl
9. (C3-C8); aryl (C6-C24) and aralkyl (C7-C24); M is hydrogen or a pharmaceutically acceptable cation; and R7 and R8 independently of one another are hydrogen or straight or branched chain alkyl (Ci-Cß), or R7 and R8 together form an alkylene bridge (C4-Cß); and R is selected from hydrogen and the groups listed for R6; and wherein the topical formation is essentially free of substances that improve penetration. 9. A poultice according to claim 8, characterized in that X is CHOZ and wherein Z is selected from m- and p-CH2 (C6H4) CP, or CPR3; R being - (CH2j) n-COOM.
10. 10. The poultice according to claim 9, characterized in that the compound of the formula (I) is artesunate.
11. 11. The poultice according to claim 10, characterized in that the topical formulation is a paste, ointment, suspension, solution, gel, spray or cream, in particular an ointment.
12. 12. Method for treating benign pigmented moles in a human patient in need of such treatment, characterized in that a compound of the formula (I): in which formula (I) X represents CO, CHOZ or CHNRZ, Z being selected from hydrogen, straight and branched chain alkyl (C? -C6); straight or branched chain (C2-C6) alkenyl; straight or branched chain (C2-C6) alkynyl; cycloalkyl (C3-C6); aryl (C6-C24), aralkyl (C7-C24); m- and p-CH2 (C6H) -COOM; COR3, CSR3; C (NR6) R3; SOR4; S02OM; S02NR7R8; S020-artemisinyl; S02NH-artemisinyl; PORR5 and PSR4R5, wherein R3 is straight or branched chain (C1-C5) alkyl, straight or branched chain alkoxy (Ci-Cß), straight or branched chain (C2-C6) alkenyl; alkynyl (straight or branched chain C2-Cß; cycloalkyl (C3-C8); aryl (C6-C24); aryloxy (C6-C? 0); aralkyl (C7-C24); - (CH2) n-COOM, with n as an integer from 1 to 6; or lOa-dihydroartemisinyl; R4 and R5 are independently selected from each other straight or branched chain alkyl (C? -C6), straight or branched chain (C2-C6) alkenyl; straight or branched chain (C2-C6) alkynyl; cycloalkyl (C3-C8), aryl (C6-C24); aralkyl (C-C24); OM, straight or branched chain alkoxy (C? -C6); aryloxy (C6-C? 0) and NR7R8; R6 is selected from straight or branched chain (C? -C6) alkyl, straight or branched chain (C2-C6) alkenyl; straight or branched chain (C2-C6) alkynyl, (C6-C8) cycloalkyl; aryl (C6-C24) and aralkyl (C7-C24); M is hydrogen or a pharmaceutically acceptable cation and R7 and R8 independently of one another are hydrogen or straight or branched chain (C? -C6) alkyl, or R7 and R8 together form an aldylene bridge of (C4-C6); and R is selected from hydrogen and the groups listed for R6; it is applied locally, particularly topically in an amount that is effective against pigmented moles.
13. 13. The method according to claim 12, characterized in that the benign pigmented moles are selected from acquired nevi cells; nevus cell nevi congeniuses, that is to say, nesting marks; lentigines, in particular liver spots, freckles or age spots, melanin pigmentation disorders, such as freckles; and moles pigmented from mucous membranes.
14. 14. Method according to claim 13, characterized in that the pigmented moles are acquired nevi cell nevi, congenital nevi cell nevi, ie, birthmarks, or liver spots.
15. 15. Method for the prevention of acquired cell nevi, characterized in that a compound of the formula (I) according to claim 1 is applied locally, preferably topically, in an amount that is effective in preventing nevi from acquired nevus cell.
16. 16. Method of compliance with one of claims 12 to 15, characterized in that the compound of the formula (I) is applied to a paste, ointment, suspension, solution, gel, spray or a cream, in particular formulated in an ointment.
17. 17. Method according to claim 16, characterized in that the compound of the formula (I) is formulated in an ointment and the loss of moisture from the skin is prevented by the application of the ointment.
18. 18. Method according to one of claims 12 to 17, characterized in that the formulation is applied with a plaster.
19. 19. Method according to one of claims 12 to 18, characterized in that the compound of the formula (I) is selected from artemisinin; dihydroartemisinin; the carbgoxyl group containing derivatives of the formula (I), in particular artesunate, artemether; arteether, dihydroartemisinin propyl carbonate, and artelinic acid.
20. 20. Method according to claim 19, characterized in that the compound of the formula (I) is artemisinin, dihydroartemisinin or artesunate.
21. 21. Method according to claim 14, characterized in that it is also used to prevent skin cancer.SUMMARY OF THE INVENTION Benign pigmented moles, or athlete's foot or nail tub can be treated with locally applicable, especially topically formulated, active ingredients of the formula (I) wherein X represents CO, CHOZ or CHNRZ, Z is selected from hydrogen , linear or branched (C! -C6) alkyl, straight or branched (C2-C6) alkenyl, linear or branched (C2-Ce) alkynyl, (C3-C8) cycloalkyl, aryl (C? -24), aralkyl (C7) -C24), m- and p- represent CH2 (C6H4) COOM; COR3; CSR3; C (NR6) R3; SOR4; S02OM; S02NR7R8; R3 represents a linear or branched Ci-Cβ alkyl, a linear or branched alkoxy (Ci-Cβ), a linear or branched (C2-C6) alkenyl, a linear or branched (C2-C6) alkynyl, (C3-C8 cycloalkyl) ), aryl (C6-C24), aryl (C6-C24), aryloxy (C6-C? 0), aralkulo (C7-C24); - (CH2) n-COOM, where n represents an integer between 1 and 6 or 10a-dihydroartemisinyl, R4 and R5 are independently selected from linear or branched (C6-6) alkyl, linear or branched (C2-C6) alkenyl, linear or branched alkynyl (C2-Ce), cycloalkyl (C3-C8) ), aryl (C6-C24), aralkyl (C2-C2), OM, linear or branched (C6-6) alkoxy, aryloxy (C6-C6) and NR7R8; R6 is selected from alkyl (C6-C6) ) linear or branched, linear or branched (C2-C2) alkenyl, straight or branched (C2-C6) alkynyl, linear or branched (C2-C) alkynyl, (C3-C8) cycloalkyl, aryl (C6 ~ C24) and aralkylol (C7-C24); M represents hydrogen or a pharmaceutically acceptable cation, and R7 and R8 independently represent so hydrogen or a straight or branched alkyl (Ci-Cß), or R7 and R8 together form an alkylene bridge (C4-Ce); and R is selected from hydrogen and the groups mentioned for R6. Said compounds are also effective in the prevention of acquired Naevus cell nevi. (I)