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US 20080171729A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0171729 A1 Meingassner (43) Pub. Date: Jul. 17, 2008

(54) USE OF A FOR ENHANCEMENT (30) Foreign Application Priority Data OFSKN PERMEABILITY Aug. 2, 2004 (GB) ...... O417205.2 (75) Inventor: Josef Gottfried Meingassner, Aug. 27, 2004 (GB) ...... 60605328 Perchtoldsdorf (AT) Sep. 16, 2004 (GB) ...... O415994.3 Correspondence Address: PublicationDCOSSO Classificati MONTGOMERY, MCCRACKEN, WALKER & (51) Int. Cl. RHOADS, LLP A 6LX 3/573 (2006.01) 123 SOUTH BROAD STREET, AVENUE OF THE A6IP 7/06 (2006.01) ARTS A6IP35/00 (2006.01) PHILADELPHIA, PA 19109 A63L/407 (2006.01) A63L/4375 (2006.01) (73) Assignee: Novartis AG A 6LX 3L/395 (2006.01) A6IP37/02 (2006.01) (21) Appl. No.: 11/571,895 (52) U.S. Cl...... 514/171; 514/183: 514/411; 514/291; 514f182 (22) PCT Filed: Jul. 15, 2005 (57) ABSTRACT (86). PCT No.: PCT/EP05/07740 A method for enhancing skin permeability by administration of a tetracyclic compound and improved methods for treat S371 (c)(1), ment of disorders by administration of a tetracyclic com (2), (4) Date: Sep. 20, 2007 pound and a pharmaceutically active compound. US 2008/0171729 A1 Jul. 17, 2008

USE OF A STEROID FOR ENHANCEMENT practically independent of the pharmaceutical, e.g. therapeu OFSKN PERMEABILITY tical, activity (potency) of the CS used because of comparable permeation rates in case of the weakly potent with the high potent . Wetherefore estimate that the 0001. The present invention relates to the use of tetracyclic chemical structure of a tetracyclic compound, e.g. as defined compounds. Such as , for the enhancement of skin below, may be responsible for high skin permeation. High permeability, e.g. for use in the enhancement of skin perme skin permeation may result in efficacious concentrations of ability for a pharmaceutically active compound. Such as a the active compound in affected epidermal and dermal layers. compound for therapeutic use. 0011. The present invention will facilitate skin permeabil 0002 Tetracyclic compounds, such as steroids, e.g. ity of e.g. T cell modulators to be effective against pathogenic including corticoids, may exhibit numerous pharmaceutical T cells in skin layers, e.g. dermal layers, infiltrated with activities. We have now found Surprisingly an unknown use of pathogenic T cells. In other words, a tetracyclic compound Such tetracyclic compounds. when administered before or simultaneously, preferably 0003. In one aspect the present invention provides a tetra before, administering a pharmaceutically active compound, cyclic compound for use in the enhancement, e.g. improve may enhance the skin permeability for Such pharmaceutically ment, of skin permeability. active compound compared with the skin permeability of 0004. According to the present invention, for enhancing untreated skin and, if the pharmaceutically active compound skin permeability a tetracyclic compound is administered is of formula I, such as of formula I, also skin penetration by preferably topically (epicutanously). Such compound may be enhanced. According to the present 0005. In another aspect the present invention provides a invention a pharmaceutically active compound is other than a tetracyclic compound for topical (epicutanous) use in the tetracyclic compound of the present invention. If adminis enhancement, e.g. improvement, of skin permeability. tered topically (epicutanously) a tetracyclic compound is 0006 Enhanced skin permeability as used herein means administered to that part of the skin to which a pharmaceuti that the infiltration of a pharmaceutically active compound cally active compound is intended to be administered. other than a tetracyclic compound according to the present 0012. The consequence of such (pre-)treatment with a tet invention, e.g. when administered topically (epicutanously), racyclic compound may be that into the skin and Subcutaneous tissue is enhanced, e.g. 0013 the infiltration into the skin of a pharmaceutically improved, Such as accelerated, if the skin is treated with a active compound is enhanced, e.g. accelerated, and tetracyclic compound, compared with the permeability for a 0.014 the pharmaceutically active compound may infil pharmaceutically compound of untreated skin (e.g. skin trate deeper into the skin, e.g. deeper into the dermal which is not treated with a tetracyclic compound according to layers. the present invention). Treatment includes simultaneous compared with administration of said pharmaceutically treatment and pre-treatment, preferably pre-treatment. active compound to untreated skin, i.e. administration to skin 0007. In another aspect the present invention provides a which is not treated with a tetracyclic compound according to tetracyclic compound for, e.g. topical (epicutanous), use for the present invention. the enhancement, e.g. improvement, such as acceleration, of 0015. In another aspect the present invention provides a the skin permeability for a pharmaceutically active com method of enhancing the skin permeability for a pharmaceu pound, which pharmaceutically active compound is other tically active compound comprising treating the skin with a than a tetracyclic compound according to the present inven tetracyclic compound and administering a pharmaceutically tion. active compound. 0008 We also have found, that the skin permeability for e.g. treating that part of the skin, where a pharmaceutically pimecrolimus when administered topically (epicutanously) active compound is intended to be administered, may be enhanced if the skin is treated, e.g. pre-treated, with a e.g. using an effective amount of a tetracyclic compound and tetracyclic compound. an effective amount of a pharmaceutically active compound, 0009. In another aspect the present invention provides a e.g. by topical (epicutanous), administration of the tetracyclic tetracyclic compound for, e.g. topical (epicutanous), use in compound and of the pharmaceutically active compound, and the enhancement, e.g. improvement, such as acceleration, of administering a pharmaceutically active compound, e.g. a the skin permeability for a compound of formula I. Such as of compound of formula I, such as of formula I. formulas I. 0016 A pharmaceutically active compound according to 0010. The barrier function of the skin plays a pivotal role the present invention includes pharmaceutically active com in the percutaneous absorption of epicutaneously applied pounds which effectively may be administered topically (epi drugs. In a side-by-side comparison we have evaluated the cutaneously) and which are permeating the skin for action in penetration (infiltration into the epidermal and Superficial vivo. Such compounds e.g. include T-cell modulators, other dermal layers) and permeation (infiltration across Superficial than tetracyclic compounds according to the present inven layer into deep dermal layers) of pimecrolimus and tacroli tion, e.g. other than steroidal T-cell modulators. mus in untreated and (CS) treated (pre-treated) 0017. In another aspect the present invention provides a porcine skin, wherein pimecrolimus and tacrolimus are tetracyclic compound applied epicutaneously as the marketed formulations (Elidel 0018 for use, or 1% cream, Protopic 0.1% ointment). We have found that the 0019 in a method skin permeability for pimecrolimus and tacrolimus are according to the present invention, wherein a pharmaceuti enhanced when skin is pre-treated with CS; e.g. we have cally active compound is a non-steroidal T-cell modulator. found the skin permeability to be increased by factors of 3.6 0020. In a preferred aspect of the present invention a phar (pimecrolimus) and 1.7 (tacrolimus) as compared with nor maceutically active T-cell modulator is a calcineurin inhibi mal untreated skin. These factors have been found to be tOr. US 2008/0171729 A1 Jul. 17, 2008

0021. In another aspect the present invention provides a 0029. In another aspect the present invention provides a tetracyclic compound tetracyclic compound 0022 for use, or 0.030 for use, or 0023 in a method in a method according to the present invention, wherein a pharmaceuti 0.031 cally active compound is a calcineurin inhibitor. according to the present invention, wherein a pharmaceuti 0024 Calcineurin is a /calmodulin-regulated pro cally active compound is a cyclosporin, e.g. including a com tein phosphatase involved in intracellular signalling. For pound of formula

III CH3

CH2CH(CH3)2 CH3 HO CH, O O CH 3 NN N1 CH 3 O CH, O R (CH3)CHCH CH2CH(CH3)2 O O CH2CH(CH3)2 CH3 O O N CH3 H H -N N N CH N N CH2CH(CH3)2 O CH, O CH3 O

reviews on calcineurin see e.g. Rusnak and Mertz, Physiol. wherein R is methyl, ethyl, propyl, isopropyl or —CH(OH) Rev. 80, 1483-1521 (2000) and Feske et al., Biochem. Bio CH preferably R is ethyl (Cyclosporin A). phys. Commun. 311, 1117-1132 (2003). 0032 Examples of macrophilin-binding calcineurin 0.025 Calcineurin inhibitors are substances which block inhibitors include ascomycin and ascomycin derivatives calcineurin dephosphorylation of appropriate Substrates. (hereinafter ascomycins), see e.g. Liu et al., Cell 66,807-815 0026. A calcineurin inhibitor of the present invention is preferably an immunophilin binding compound having cal (1991) and Dumont et al., J. Exp. Med., 176, 751-780 (1992), cineurin inhibitory activity. as well as tacrolimus (FK506). 0027. Immunophilin binding calcineurin inhibitors are 0033 Ascomycins and their preparation are known. Asco compounds forming calcineurin inhibiting complexes with mycin (FR520) is a macrollide antibiotic disclosed e.g. in U.S. immunophilins, e.g. cyclophilin and macrophilin. Pat. No. 3,244,592 and in EP349061, wherein in a compound of formula I preferred substituents are indicated, which pre 0028. Examples of cyclophilin-binding calcineurin ferred substituents are also preferred substituents in the inhibitors include e.g. cyclosporins orcyclosporin derivatives present application; e.g. in a compound of formula I each (hereinafter cyclosporins). Cyclosporins and their prepara single defined Substituent may be a preferred Substituent, e.g. tion are e.g. disclosed in U.S. Pat. No. 4,117,118, wherein in independently of each other substituent defined. A wide range a compound of formula I preferred Substituents are indicated, of ascomycin derivatives are known, which are either natu which preferred substituents are also preferred substituents in rally occurring amongst fungal species or are obtainable by the present application; e.g. in a compound of formula I each manipulation of fermentation procedures or by chemical single defined substituent may be a preferred Substituent, e.g. independently of each other substituent defined. Cyclosporin, derivatization. originally extracted from the soil fungus Potypaciadium infi 0034. In another aspect the present invention provides a latum, has a cyclic 11-amino acid structure and includes e.g. tetracyclic compound Cyclosporins A through 1. Such as Cyclosporin A, B, C, D and 0035 for use, or G, preferably Cyclosporin A. 0.036 in a method US 2008/0171729 A1 Jul. 17, 2008 3 according to the present invention, wherein a pharmaceuti- 0038. In another aspect the present invention provides a cally active compound is a compound of formula tetracyclic compound 0039 for use, or 0040 in a method II according to the present invention, wherein a pharmaceuti cally active compound is a compound of formula

CHO I

OCH, OCH wherein R is hydroxy or protected hydroxy, wherein either R is hydrogen, hydroxyl or protected hydroxyl, R is a group (a) of formula R is methyl, ethyl, propyl or allyl, n is an integer of 1 or 2, and the dotted line is a bond, or is no bond, preferably a compound of formula (a)

HO

CHO 0041 wherein 0042 R is chloro, bromo, iodo or azido, O 0.043 R is hydroxy or methoxy, and 0044 R is hydroxy and there is a single bond in 10, 11 position; or absent, and there is a double bond in 10,11 position '',1st, O R is a group (b) or (c) of formula

(b)

5CH, 6CH, (c) (tacrolimus, FK506). 0037. If the dotted line is a bond, there is a double bond, if the dotted line is no bond there is a single bond in a compound of formula II, where a bond together with a dotted line is indicated. US 2008/0171729 A1 Jul. 17, 2008

0045 wherein 0051 Compounds of formula TETR preferably comprise 0046 R is as defined above, and compounds having as a part of its chemical structure 0047 R is hydroxy and there is a single bond in 10,11 a. a group of formula position, R is oxo and there is a single bond in 23.24 position; hydroxy and there is a single or double 0048 bond in 23.24 position; or absent and there is a double bond in 23.24 position; and R is methyl, ethyl, propyl or allyl, e.g. a compound of formula

C co STERA

0.052 wherein rings A, B and D each have 6 ring mem bers and E has five ring members, b. a group of formula cGO STERE

5CH, 6CH, 0.053 wherein rings A, B, D and E each have 6 ring members (pimecrolimus, ASM981). c. a group of formula 0049 Compounds of formula I are e.g. disclosed in EP-B- 0427680, wherein in a compound of formula I preferred substituents are indicated, which preferred substituents are also preferred Substituents in the present application; e.g. in a compound of formula I each single defined substituent may be a preferred substituent, e.g. independently of each other Substituent defined; e.g. including a compound of formula I, such as disclosed in EP-B-0427680 in Example 66a as “33 cC epi-33-chloro-FR 520', also known as “ASM981. STERC 0050. A tetracyclic compound as used herein includes a steroid, Such as a compound having as a part of its chemical structure a group of formula 0.054 wherein rings A, B and E each have 6 ring mem bers and D has five ring members, and d. a group of formula

TETR wherein each of the rings A, B, C and D have from 5 to 7 ring cit members, STERD e.g. ring A has 5 or 6 ring members, e.g. ring B has 6 or 7 ring members, e.g. ring D has 5 or 6 ring members, 0.055 wherein rings A and D each have 6 ring members, e.g. ring E has 5 or 6 ring members. B has 7 ring members and E has five ring members; US 2008/0171729 A1 Jul. 17, 2008

more preferably of formula STER, STER or STER, and 0.066 5-membered rings, e.g. including heterocyclic even more preferably of formula rings, such as 2 7 0067 5-membered rings comprising carbonatoms as ring members, such as cyclopentane, e.g. spiro-anel lated with a further ring, e.g. of formula

STERA 0056 Ring members comprise carbon atoms and, prefer ably in rings A, B and E additionally hetero atoms selected TETR TETR from N, O, S, preferably from N or O. E.g. in ring. A ring members include carbon atoms and heteroatoms selected from N or O, e.g. see dutasterin, Samandarine. E.g. in ring B ring members include carbonatoms and heteroatoms selected from O, e.g. see brassinolide. E.g. in ring E ring members include carbon atoms and heteroatoms selected from 0, e.g. N see cimigenol. E.g. in ring D all ring members are carbon TETR atOmS. 0057 Preferably the ring members in rings A, B, D and E all are carbon atoms. 0068 5-membered heterocyclic rings comprising one 0058 Rings A, B, D and E comprise saturated and par or more, e.g. two nitrogen atoms as heteroatoms, which tially or completely unsaturated. Such as aromatic, rings. ring may be anellated with a further ring, such as pyrro 0059 Preferably lidines, pyrazoles, including dihydropyrazoles, indoliz rings A and B comprise Saturated and partially or completely ines, such as octahydroindolizines, e.g. of formulae unsaturated. Such as aromatic rings, preferably 0060 (C-7)cycloalkyl, (C-7)cycloalkylene, (C-7)cy cloalkyldiene, wherein cycloalkyl preferably is hexyl; or CH phenyl; and N= rings D and E comprise saturated and partially unsaturated HN N rings, preferably N CH3 N ()- A 0061 (C-7)cycloalkyl, (C-7)cycloalkylene, (C-7)cy cloalkyldiene, wherein cycloalkyl preferably is cyclo TETR TETR TETR pentyl or cyclohexyl. 0062 Each of the rings A, B, D and E in a compound of formula TETR may be anellated with further rings, including N= M rings having 3 to 8, preferably 3 to 6 ring members, which F N CH further rings may be anellated further with rings having 3 to 8, H3C preferably 3 to 6 ring members, to form a ring system. Anel N lated rings (ring systems) include spiro-anellated rings. Anel lated ring also include bridged rings, e.g. Such as appropriate, TETR e.g. Such as conventional, e.g. including as a bridge TETR O—, CH2—O—, CH-NH CH-CH O (e.g. see batrachotoxin). 0069 5-membered heterocyclic rings comprising one 0063. Such anellated ring (systems) include saturated and partially and completely unsaturated ring (systems), option or two oxygenatoms, e.g. furanes, such as di- or tetrahy ally comprising heteroatoms selected from N, O and S, e.g. drofuranes, or 1,3-dioxolanes, e.g. of formulae rings (ring systems) as described above. 0064 Rings anellated with a ring system of formula TETR include for example CH 0065 3-membered rings, e.g. including heterocyclic CH rings, such as cyclopropanes, oxiranes, thiranes, e.g. of formulae H3C CH3 O HN H3C O

O O O O A A A HC TETR TETR TETR TETR TETR TETR TETR US 2008/0171729 A1 Jul. 17, 2008

-continued CH CH H3C OR

O-CO-CH O O O O O O

TETR R is tiglic or angelic acid TETR TET R TETR TETR 0.073 pyranes, such as tetrahydropyranes, e.g. bridged pyranes Such as 6,8-dioxabicyclo3.2.1]octane, and pyr anes anellated with a further ring, such as octahydro pyrano.3.2.bpyridine, e.g. of formulae O O O O

CH3

TETR TETR CH OH HN 0070 5-membered heterocyclic rings comprising oxy CH3 OH gen atom and nitrogen atoms as hetero atoms, e.g. oxazoles, e.g. including dihydrooxazoles, isoxazoles, including dihydroisoxazoles, or furazanes, e.g. of for mulae TETR TETR

0074 1,4-dioxanes, such as 1,4-dioxanesanellated with CH another ring, e.g. of formula o1'N, N1,No. N1 NN o ' / W f TETR TETR TETR O OH 0071 6-membered rings, e.g. including 6-membered OH rings comprising carbon atoms as the ring members and O O heterocyclic rings, e.g. comprising cyclohexanes and 6-membered heterocyclic rings comprising one or more heteroatoms selected from N, O or S. preferably Nor O, TETR Such as 0072 cyclohexanes, e.g. of formula 0075 piperidines, such as piperidines anellated with another ring, e.g. quinolizines, such as octahydroquino lizines, e.g. of formula CH CH3 H3C CH3 H3C OH. H.C. COOH HC

HC

TETR TETR TETR TETR CH HC OH

HC TETR

TETR wherein TETR together with the two carbon atoms to which TETR is attached is a tetracyclic compound of formula TETR as defined above. US 2008/0171729 A1 Jul. 17, 2008

0076 Each of the rings A, B, D and E comprises unsub 0110 (Cl)alkenyloxycarbonyloxy, e.g. including stituted rings and Substituted rings, e.g. unsubstitute or one or phenyl(C)alkenyloxycarbonyloxy, e.g. wherein phe more fold substituted. Anellated rings may be substituted or nyl is Substituted by hydroxy and (Cl)alkoxy, unsubstituted. 0111 (C.)alkylthiocarbonyl, e.g. including fluoro 0077 Ring substituents include appropriate substituents, (C)alkylthiocarbonyl, e.g. Such as conventional in Steroids, e.g. including one or 0112 (Cl)alkylcarbonyl, e.g. including halo(C) O alkylcarbonyl, hydroxy(C)alkylcarbonyl, (C)alky 0078 halogen, such as fluoro, chloro, bromo, lcarbonyl(C)alkylcarbonyl, (C)alkylcarbonyloxy 0079 amino, including unsubstituted amino and substi (C)alkylcarbonyl, di(C)alkylamino(C) tuted amino, Such as amino, di(Ce)alkylamino, e.g. alkylcarbonyloxy(C)alkylcarbonyl, including di(Ce)alkylamino-di(C)alkylamino, hydroxycarbonyl(C)alkylcarbonyloxy(C)alkyl 0080 hydroxyimino, carbonyl, mercapto(C)alkylcarbonyl, heterocyclyl I0081 hydroxy, (C)alkylcarbonyl, wherein heterocyclyl has 1 to 4 I0082 a keto group, heteroatoms selected from N, O, S and 5 to 6 ring mem I0083 formyl, bers, e.g. piperazinyl, I0084 (Cl)alkyl, including unsubstituted alkyl, and 0113 (Cs)alkylcarbonyloxy, substituted alkyl, e.g. alkyl substituted by 0114 (Cl)alkylcarbonylthio. I0085 sulfonyl, 0115 (Cs)alkenylcarbonyloxy, 0086 amino, e.g. including (di(C)alkylamino, 0116 heterocyclylcarbonyloxy, wherein heterocyclyl has 1 to 4 heteroatoms selected from N, O, 5 and 5 to 6 amino(C)alkylamino(C)alkylamino, ring members, e.g. including furane, I0087 hydroxy, 0117 aminocarbonyloxy, e.g. including di(C)alky 0088 (C)alkenylcarbonyl, e.g. including (C) laminocarbonyloxy, Such as dichloroethylaminocarbo alkylcarbonyloxy(C)alkenylcarbonyl, nyloxy, I0089 cyano, 0118 cyano, 0090 heterocyclyl having 5 to 6 ring members and 0119 heterocyclyl having 5 or 6 ring members and 1 to one to 4 heteroatoms selected from N, O and S, such 4 heteroatoms selected from N, O and S, including as dihydrofurane, dihydropyrane, piperidinyl, e.g. unsubstituted heterocyclyl and substituted heterocyclyl, Substituted by (Cl)alkyl, a keto group, e.g. Substituted by (Cl)alkyl, hydroxy or keto groups, 0091 (C.)alkylcarbonyloxy, C.2. including e.g. piperidinyl, morpholino, hydroxycarbonyl(C)alkylcarbonyloxy, 0120 heterocyclyloxy, wherein heterocyclyl has 5 or 6 0092 heterocyclylcarbonyloxy, wherein heterocy ring members and 1 to 4 heteroatoms selected from N. C clyl has 5 or 6 ring members and 1 to 4 heteroatoms and S, including unsubstituted heterocyclyl and Substi selected from N, O and S, including unsubstituted tuted heterocyclyl, e.g. Substituted by hydroxy, (C) heterocyclyl and Substituted heterocyclyl, e.g. Substi alkyl, or (C1-)alkoxy, e.g. including a Sugar residue, tuted one or morefold by (Cl)alkyl, bound to a compound of formula TETR via an oxygen I0093 (C.)alkylaminocarbonyl, e.g. including atom, which sugar residue itself may be further substi hydroxycarbonyl(C)alkylaminocarbonyl. Sulfonyl tuted one or morefold via an oxygen atom by further (C)alkyl-di(C)alkylammonium(C)alkylami Sugar residues, nocarbonyl, I0121 Substituents in the meaning of substituted heterocy 0094 (Ces.)arylaminocarbonyl, such as phenylami clyl and Substituents in rings anellated to a ring in a compound nocarbonyl, e.g. including di-trifluoromethylphenyl of formula TETR include such as described above for a com aminocarbonyl, pound of formula TETR. (0095 hydroxycarbonyl, 0.122 Compounds of formula TETR are steroids. Steroids I0096 halo(C.)alkyl, such as trifluoromethyl, include natural and chemically modified corticoids, Such as (0097 a group —CH, or=CH-OH, pharmaceutically active corticoids and derivatives thereof, 0.098 (C)alkenyl, e.g. including unsubstituted and e.g. including , such as (i.e. Substituted (C-)alkenyl, e.g. substituted by hydroxy having -like activity), e.g. which show phar carbonyl, maceutical activity, e.g. including steroids in free form and in the form of (0099 (C.)alkynyl, 0123 esters, e.g. including mono- and diesters, e.g. in 0100 (Ces.)aryl, such as phenyl, e.g. di(C)alky the form of salts, e.g. sodium, laminophenyl, 0.124 acetals and ketals, such as acetonides, 0101 (C.)alkoxy, e.g. including unsubstituted alkoxy e.g. in the form of salts and Solvates, where applicable. and Substituted alkoxy, e.g. alkoxy Substituted by 0.125 Examples of compounds of formula TETR include 0102 hydroxy, halogen, (C)haloalkyl, Such as such as described in The Merck Index, 12th and 13th edition, CCls, e.g. see , e.g. including 21-acetoxypregnenolone, adonitoxin, adrenos (0103) (C)alkylthio. terone, alclomethasone, (e.g. diproprionate), aldosterone, 0104 (Cs)cycloalkyloxy, e.g. cyclopentyloxy, alfadolone , alfaxalone, (e.g. acetophenide), allocholesterol, allopregnane (e.g. and -ols and ones thereof), 0105 (Cs)cycloalkenyloxy, e.g. cyclopentenyloxy, allotetrahydrocortisone, allylesterenol, , amcino 0106 hydroxycarbonyl, nide, , , (e.g. ols and 01.07 (Cl)alkoxycarbonyl, ones), (e.g. acetate, diacetate, benzoate, 0.108 (C)alkylthiocarbonyl, diproprionate), , androst-16-en-3-ol, andros 0109 (Cl)alkoxycarbonyloxy, terone, antheridiol, alphaantiarin, azacosterol, batrachotoxin, US 2008/0171729 A1 Jul. 17, 2008 beclomethasone () (e.g. -dipropionate), yltestosterone 3-cyclopentyl enol ether, methyltrienolone, (e.g. -acetate, -benzoate, -dipropionate, , (e.g. fluorate), moxestrol, Sodium phosphate, -Valerate), , , bold mytatrienediol, , neoergosterol, neriifolin, niva enone, , bufalin, bufogenin B, bufotalin, bufo Zol, norbolethone, norcholanic acid, , nore toxin, calotropin, , campesterol, , thindrone, norethynodrel, , , norg cephalosporin P. CHAPS, chenodiol, (e.g. estrel, , , , acetate), chlorogenin, chinoprednisone, cholane, cholanic oleandrin, , gamma-oryZanol, , oua acid,5alpha-cholestane, cholestanol, cholesterol, cholic acid, bagenin, ouabain, , , , chondrillasterol, , cimigenol, cinobufotalin, clo , , pancuronium halogenide betasol (e.g. propionate), (e.g. butyrate), clocor (bromide), (e.g. -acetate), pavoninin-5, pent tolone (e.g. -acetate, -pivalate), clomestrone, , agestrone, periplogenin, peruvoside, phenesterine, pipecu , cloXotestosterone, colpornon, conessine, conval riomhalogenide (bromide), ponasterone A, , pred lamarogenine, convallatoxin, coproergostane, coprostane, nicarbate, , (e.g. including coprosterol, , (hydrocortisone), corti -acetate, -hemisuccinate, -sodium phosphate, -sodium Succi Sone (e.g. -acetate), , cortol, cortolone, cucurbit nate, -tebutate, 21-diethylaminoacetate), , predni acins (e.g. A, B, C, D, F. P. R), cyclobuxine D., cynanchogenin, val, , , pregnanediol. 3.20-pregnanedi , , , 3-beta-7-dehydrocholes one, pregnan-3alpha-ol-20-one, 4-pregnene-20,21-diol-3, terol, dehydrocholic acid, 11-dehydrocorticosterone, dehy 11-dione, 4-pregnene-11beta, 17alpha,20beta,21-tetrol-3- droergosterol, 7-dehydrositosterol, (e.g. One, 4-pregnene-17alpha,20beta,21-triol-3,11-dione, acetate), , deoxycholic acid, deoxycorticoster 4-pregnene-17alpha,20beta,21-triol-3-one, , one (e.g. -acetate), (e.g. -acetonide), deslano , , proscillaridin, pyrocalciferol, side, desmoSterol, desogestrol, , , , quinestradiol, quinestrol, rapacuronium halo 11-desoxy-17-hydroxycorticosterone, (e.g. genide (bromide), resibufogenin, , rocuronium Sodium phosphate, -acetate, -isomicotinate), dichiorisone, halogenide (bromide), rofileponide (e.g. palmitate), rubijerv , (e.g. diacetate), difluocortolone (e.g. ine, Samanderine, sarmentogenin, Sarsasapogenin, Sarvero -pivalate, Valerate), , digalogenin, diginatige genin, Scillaren (A and B), Scillarenin, Scilliroside, alpha-, nin, diginin, digitalin, digitogenin, digitoxigenin, digoxige beta- and gamma-sitosterol, Solanidine, Solanocapsine, nin, dihydroequiline, , dinosterol, , Solasodine, alpha-spinasterol, , squalamine dromostanolone (masterone), , dutasteride, halogenide (trihydrochloride), stanolone, , Sten , ecdysteroids (ecdysone, 20-hydroxyecdys bolone, Stigmastanol, Stigmasterol, stophanthidin, tanghini one), , epicholestanol, epicholesterol, genin, taurocholic acid, , tetrahydrocortisone, 16-epiestriol, epinestrol, , epostane, epristeride, thevetin A, , (e.g. -propionate), tigogenin, equilenin, equilin, ergostane, ergostanol, alpha-, beta- and , , tirilazad, , tomatidine, tral gamma-ergostenol, ergosterol, (alpha-), estramus onide, , , (e.g. -ac tine, estriol, estrone, ethinyl estradiol, , ethylestre etonide, -acetonide Sodium phosphate, -diacetate, bene nol, ethynodiol, etiocholane, etiocholanic acid, , tonide, hexacetonide), , ursodiol, uscharidin, , finasteride, , flucloronide, fludrocorti uZarigenin, uZarin, Vercuronium halogenide (bromide), Ver Sone, acetate, flumethasone (e.g. -pivalate), alkamine, withaferin A, e.g., and pharmacodynamic equiva , (e.g. -acetonide), , fluo lents thereof, preferably acilomethasone, beclomethasone, cortin butyl, (e.g. -caproate), , betamethasone, clobetasole, hydrocortisone, dexametha (halotestin), (e.g. -acetate), flu Sone, difluocortolene, , halobetasol, halometha prednidene (e.g. -21-acetal, -acetate), (e.g. Sone and mometaSone, Such as e.g. hydrocortisone, -Valerate), flurandrenolide, fluorogestone (e.g. acetate), fluti betamethasone, e.g. betamethasone 17-Valerate, dexametha casone (e.g. -propionate, Valerate), , , Sone, mometaSone, e.g. mometasone furoate, or clobetasol, , fucosterol, fungisterol, funtumine, , e.g. clobetasol-17-butyrate, more preferably hydrocortisone, fusidic acid, fusidic acid, gamabufotaline, ganaxolone, gen mometasone, clobetasol and triamcinolone. trogenin, , gestonorone (e.g. caproate), I0126. In another aspect the present invention provides a (including ), gitogenin, F-gitonin, tetracyclic compound gitoxigenin, gitoxin, alpha- and beta-acetylgitoxin, glyco cholic acid, gratiogenin, , halobetasol (e.g. -pro O127 for use, or pionate), halomethasone (e.g. monohydrate), 0128 in a method (e.g. acetate), hecogenin, hellebrin, helvolic acid, holarrhe according to the present invention wherein a tetracyclic com nine, hydralloStane, , hydrocortisone (e.g. pound is a steroid, such as a compound of formula TETR, e.g. -acetate, -buteprat, -butyrate, cypionate, -sodium phosphate, a corticoid, such as a corticoid, e.g. selected from the group -Sodium Succinate, -hemisuccinate, -Valerate), 24- and 25-hy consisting of hydrocortisone, betamethasone, e.g. betametha droxycholesterol, hydroxydione (sodium), 17-hydroxy-16 Sone 17-Valerate, dexamethasone, mometasone, e.g. methylene-A-progesterone, 17alpha-hydroxyprogesterone, mometasone furoate, and clobetasol, e.g. clobetasol-17-bu hyodeoxycholic acid, isoestradiol, 8-isoestrone, isoflupre tyrate, more preferably hydrocortisone, mometaSone, triam done, isopyrocalciferol, isorubijervine, 11-ketoprogesterone, cinolone and clobetasol. kurchessine, kurcholessine, lanosterol, lithocholic acid, (e.g. etabonate), lumisterol, , I0129. Pharmacodynamic equivalents are meant to include maZiprednone, , , corticoids, showing pharmaceutical activity similar with spe , (acetate), , , cific corticoids listed herein. , , , mestranol, meth 0.130. A method according to the present invention may be andriol, methandrostenolone (dianabol), methenolone, meth used for improved treatment of disorders, such as diseases, ylprednisolone (e.g. -acetate, -sodium phosphate, -sodium e.g. including skin disorders, e.g. wherein the disorder is a Succinate, aceponate), 17-, 17alpha-meth disorder in which T lymphocytes (T cells) are involved in the US 2008/0171729 A1 Jul. 17, 2008 pathophysiology of the disorder, such as T-cell mediated tions, vasculitides or pyoderma gangrenoSum; preferably acute or chronic inflammatory disorders or autoimmune dis psoriasis, atopic eczema, Seborrheic dermatitis, irritant or orders. allergic contact dermatitis, lichen planus, lichen rubber, 0131. In another aspect the present invention provides a alopecia greata, pyoderma gangrenosum. Inflammatory dis method of treatment, e.g. topical (epicutaneous) treatment, of orders which may be treated by a method according to the disorders in which T cells (i.e. T lymphocytes) are involved in present invention include such which are mediated by a T-cell the pathophysiology of the disorder, comprising administer modulator, e.g. a calcineurin inhibitor. ing, e.g. topically (epicutanously), to a Subject in need of such 0.161. In another aspect the present invention provides a treatment an effective amount of a tetracyclic compound, and method for topical (epicutanous) treatment, of inflammatory administering, e.g. simultaneously or in consequence, e.g. in disorders, e.g. skin disorders, selected from the group con consequence, an effective amount of a T-cell modulator, pref sisting of psoriasis, atopic eczema, seborrheic dermatitis, erably a calcineurin inhibitor, more preferably a compound of intertrigo, nummular eczema, irritant or allergic contact der formula I, II or III. matitis, urticaria, parapsoriasis, lichen simplex chronicus, 0132) The principle of topical (epicutanous) treatment acute/chronic dyshidrotic eczema, lupus erythematosus, with a tetracyclic compound and a pharmaceutically active pemphigus, lichen planus, granuloma annulare, acne, alope compound according to the present invention may be applied cia greata, cutaneous Graft VS Host reactions, vasculitides, e.g. for and pyoderma gangrenosum, Such as psoriasis, atopic 0.133 anti-inflammatory, e.g. including acne, treatment, eczema, Seborrheic dermatitis, irritant or allergic contact der 0.134 treatment of hyperproliferative disorders, matitis, lichen planus, lichen rubber, alopecia greata, pyo 0.135 treatment of phototoxic conditions (solar derma derma gangrenosum, comprising topically (epicutaneously) toses), administering an effective amount of a tetracyclic compound, 0.136 anti aging treatment, and an effective amount of a topically (epicutaneously) effec 0.137 topical analgetic treatment, tive, anti-inflammatory agent, e.g. a T-cell modulator, 0.138 anti-hairloss treatment, Such as a calcineurin inhibitor, 0.139 antiperspirant treatment, e.g. a compound of formula I, II or III, preferably 0140 anti-pruritic treatment, and 0162 a compound of formula I (pimecrolimus), 0141 astringent agent. 0163 a compound of formula II (tacrolimus), 0142 Treatment includes prophylaxis, prevention, medi 0.164 a compound of formula III wherein R is ethyl cation and/or therapy. (cyclosporin A), 0143. In another aspect the present invention provides a more preferably a compound of formula I or of formula II; method for topical (epicutanous) treatment of to a subject in need of Such treatment. 0144 inflammatory disorders, e.g. including acne, 0.165 Hyperproliferative disorders, e.g. including skin (0145 microbial disorders, disorders, which may be treated by topical administration by 0146 hyperproliferative disorders, a method of the present invention, e.g. include psoriasis, T 0147 phototoxic conditions, e.g. including Solar der cell lymphoma, pseudolymphoma, actinic keratosis, warts, matoses, hairloss, or precancerous lesions, benign epithelial tumors, keratoacan 0.148 conditions wherein an analgetic, anti-aging, anti thomas, squamous cell carcinoma, basel cell carcinoma. perspirant, anti-pruritic agent or astringentagentis help 0166 Hyperproliferative disorders which may be treated ful, by a method according to the present invention include Such comprising topically (epicutaneously) administering an which are mediated by a T-cell modulator, e.g. a calcineurin effective amount of inhibitor. 0149 a tetracyclic compound, and 0167. In another aspect the present invention provides a 0150 a pharmaceutically active compound selected method for topical (epicutanous) treatment of hyperprolifera from the group consisting of tive disorders, e.g. skin disorders, selected from the group 0151 an anti-inflammatory agent, e.g. including an consisting of psoriasis, actinic keratosis, warts, precancerous anti-acne agent, lesions, benign epithelial tumors, keratoacanthomas, squa 0152 antimicrobial, mous cell carcinoma, basel cell carcinoma, such as actinic 0153 anti-hyperproliferative agent, keratosis, warts, precancerous lesions, benign epithelial 0154 anti-phototoxic agent, tumors, keratoacanthomas, squamous cell carcinoma, basel 0155 anti-hairloss agent, cell carcinoma, comprising topically (epicutaneously) 0156 analgetic agent, administering an effective amount of a tetracyclic compound, O157 anti-aging agent, and an effective amount of a topically (epicutaneously) effec 0158 antiperspirant, and tive anti-hyperproliferative agent, 0159 anti-pruritic agent e.g. a T-cell modulator, to a Subject in need of Such treatment; Such as a calcineurin inhibitor, e.g. wherein a tetracyclic compound is administered before or e.g. a compound of formula I, II or III, preferably simultaneously, preferably before the pharmaceutically (0168 a compound of formula I (pimecrolimus), active compound. 0.169 a compound of formula II (tacrolimus), 0160 Inflammatory disorders, e.g. including skin disor 0170 a compound of formula III wherein R is ethyl ders, which may be treated by topical administration by a (cyclosporin A), method of the present invention, e.g. include psoriasis, atopic more preferably a compound of formula I or of formula II; eczema, Seborrheic dermatitis, intertrigo, nummular eczema, to a subject in need of Such treatment. irritant or allergic contact dermatitis, urticaria, parapsoriasis, 0171 In another aspect the present invention provides a lichen simplex chronicus, acute/chronic dyshidrotic eczema, method for the preparation of a medicament for the treatment lupus erythematosus, pemphigus, lichen planus, granuloma of disorders, e.g. for topical (epicutaneous treatment, in annulare, acne, alopecia greata, cutaneous Graft VS Host reac which T lymphocytes are involved in the pathophysiology of US 2008/0171729 A1 Jul. 17, 2008 the disorder, comprising combining an effective amount of a e.g. together with an indication for administering topically tetracyclic compound and an effective amount of a T-cell (epicutanously), an effective amount of said agent, e.g. simul modulator, preferably a calcineurin inhibitor, more prefer taneously or Subsequently, preferably Subsequently to a tet ably a compound of formula I, II or III, e.g. together with an racyclic compound. indication for administering topically (epicutanously), an 0177. In a method for treating disorders according to the effective amount of said agent, e.g. simultaneously or Subse present invention a tetracyclic compound is administered quently, preferably Subsequently to a tetracyclic compound. before or simultaneously, preferably before the pharmaceu tically active compound, e.g. the pharmaceutically active 0172. In another aspect the present invention provides a compound is administered Subsequently to a tetracyclic com method for the preparation of a medicament for treating topi pound, e.g. the disorder is topically (epicutanously) pre cally (epicutanously) inflammatory disorders, e.g. including treated with a tetracyclic compound and Subsequently topi acne, microbial disorders, hyperproliferative disorders, pho cally (epicutanously) treated with a pharmaceutically active totoxic conditions (Solar dermatoses), hairloss, or conditions compound. wherein an analgetic, anti-aging, antiperspirant, anti-pruritic 0.178 A tetracyclic compound and/or a pharmaceutically agent or astringent agent is helpful, comprising combining an active compound for use or in a method according to the effective amount of present invention independently of each other may be in free 0173 a tetracyclic compound, and form, in the form of a salt, in solvate form or in the form of a 0.174 a pharmaceutically active compound selected salt and a Solvate, where salts and/or Solvates exist. from the group consisting of an anti-inflammatory 0179. In another aspect the present invention provides a agent, e.g. including an anti-acne agent, antimicrobial, tetracyclic compound anti-hyperproliferative agent, anti-phototoxic agent, 0180 for use, or 0181 in a method anti-hairloss agent, analgetic, anti-aging agent, antiper according to the present invention, wherein a pharmaceuti spirant, and anti-pruritic and astringent, cally active compound is in the form of a salt. e.g. together with an indication for administering topically 0182. In another aspect the present invention provides a (epicutanously), an effective amount of said agent, e.g. simul tetracyclic compound in the form of a salt; taneously or Subsequently, preferably Subsequently to a tet 0183 for use, or racyclic compound. 0.184 in a method (0175. In another aspect the present invention provides a according to the present invention, wherein a pharmaceuti method for the preparation of a medicament for topical (epi cally active compound is in free form. cutaneous) treatment of inflammatory disorders, e.g. skin 0185. In another aspect the present invention provides a disorders, selected from the group consisting of psoriasis, tetracyclic compound in the form of a salt; atopic eczema, seborrheic dermatitis, intertrigo, nummular 0186 for use, or eczema, irritant or allergic contact dermatitis, urticaria, 0187 in a method parapsoriasis, lichen simplex chronicus, acute/chronic according to the present invention, wherein a pharmaceuti dyshidrotic eczema, lupus erythematosus, pemphigus, lichen cally active compound is in the form of a salt. planus, granuloma annulare, acne, alopecia greata, cutaneous 0188 Treatment includes treatment, e.g. therapy, and pre Graft VS Host reactions, and pyoderma gangrenosum, vention, e.g. prophylaxis. For such treatment, the appropriate Such as psoriasis, atopic eczema, seborrheic dermatitis, irri dosage will, of course, vary depending upon, for example, the tant or allergic contact dermatitis, lichen planus, alopecia chemical nature and the pharmacokinetic data of a compound greata, pyoderma gangrenosum, of the present invention employed, the individual host, the comprising combining an effective amount of a tetracyclic mode of administration and the nature and severity of the compound, and an effective amount of an antiinflammatory conditions being treated. However, in general, for satisfactory agent, e.g. a T-cell modulator, Such as a calcineurin inhibitor, results in larger for example humans, a pharmaceu e.g. a compound of formula I, II or III, tically active compound may be used in similar dosage ranges e.g. together with an indication for administering topically as conventionally used in therapies, e.g. in dosage ranges as (epicutanously), an effective amount of said agent, e.g. simul known for a therapy with Such pharmaceutically active com taneously or Subsequently, preferably Subsequently to a tet pound, e.g. a calcineurin inhibitor, e.g. pimecrolimus or tac racyclic compound. rolimus, may be provided as a solution or cream (gel) in the range from about 0.1% to 5% w/v or w/w when administered 0176). In another aspect the present invention provides a locally, wherein the dosage will depend on the kind and method for the preparation of a medicament for topical (epi severity of the disease to be treated e.g. a tetracyclic com cutaneous) treatment of hyperproliferative disorders, e.g. pound, such as a steroid, e.g. a corticoid, is given in dosages skin disorders, selected from the group consisting of psoria as known for standard therapies, such as e.g. in a range of 0.5 sis, actinic keratosis, warts, precancerous lesions, benign epi to 5% in case of topical application (or in a range of 0.25 to thelial tumors, keratoacanthomas, squamous cell carcinoma, 2500 mg, preferably 1 to 500 mg, such as 1 to 50 mg, when basel cell carcinoma; administered systemically, e.g. orally). The ratio of a phar Such as actinic keratosis, warts, precancerous lesions, benign maceutically active compound to a tetracyclic compound epithelial tumors, keratoacanthomas, squamous cell carci according to the present invention is not critical. A tetracyclic noma, basel cell carcinoma, compound is used in an amount which is effective to enhance comprising combining an effective amount of a tetracyclic penetration/permeability of the (inflamed) skin by a pharma compound, and an effective amount of an antihyperpolifera ceutically active compound, and a pharmaceutically active tive agent, e.g. a T-cell-modulator, such as a calcineurin compound is used in an amount effective for treating a cor inhibitor, e.g. a compound of formula I, II or III, responding disease for which the pharmaceutically active US 2008/0171729 A1 Jul. 17, 2008 compound is useful. According to a method of the present (0198 ESI electrospray source invention the amount of the pharmaceutically active com (0199 HC hydrocortisone pound may be even lower compared with administration to 0200 HPLC high pressure liquid chromatography untreated skin, e.g. because of better and deeper skin perme ation/penetration. 0201 MOM mometasone furoate 0189 According to the use and in a method of the present 0202 MS mass spectroscopy invention (0203 PBS phosphate buffered saline 0.190 one or more tetracyclic compounds may be used, (0204 RP reverse phase preferably one single tetracyclic compound is used; 0205 RPLC reverse phase liquid chromatography 0191 one or more pharmaceutically active compounds may be used, preferably one single pharmaceutically Methods active compound is used. 0.192 A tetracyclic compound and a pharmaceutically EXAMPLEA active compound of the present invention may be used, e.g. administered, in free form or in the form of a pharmaceuti Pre-Treatment of Porcine Skin. In Vivo, Collection of cally acceptable salt, e.g. an acid addition salt or metal salt; Skin Samples optionally in the form of a solvate. Tetracyclic compounds may additionally be in the form of esters, acetonides, e.g. and 0206 Three young, male castrated domestic pigs with additionally in the form of salts. The tetracyclic and pharma body weights of approximately 15 kg are used as skin donors. ceutically active compounds of the present invention in the The animals are obtained from a local breeder and maintained form of a saltfesterfacetonide? solvate/exhibit the same order under standardized conditions (22+1, 55+5% relative of activity as the compounds used in the present invention in humidity, 10 changes of fresh air/hour, 12 hours day/12 hours free form; optionally in the form of a solvate. Pharmaceuti night cycle). After a settling-in period of 7 days the pigs are cally active compounds of the present invention, such as treated topically on test areas on the dorsolateral back T-cell modulators, e.g. calcineurin inhibitors, e.g. including 0207 with CS solutions in EtOH/propylene glycol compounds of formulae I, II and III, and tetracyclic com (3+7, V/v) as a solvent, and pounds according to the present invention are known or may 0208 contra-laterally with solvent alone, be obtained according, e.g. analogously, to a method as con twice daily for 5 days. ventional. 0209 HC (Sigma) at 1.0%, MOM (Sequoia Research 0193 In the following examples temperatures are given in Products) at 0.1% and CLO (Sigma) at 0.05% are used as CS. degrees Celsius (°C.) and are uncorrected. The CS-samples and solvent alone are applied in volumes of 0194 ASD732 used as a reference compound is a com 50 ul to skin areas of 3.5x6.5 cm each. All three CS and pound of formula solvent alone are applied to all animals. 16 hours after the last application the animals are killed and the treated skin Samples are dissected. Full-thickness skin samples are dissected from vehicle- and CS-treated sites and cut into 0.4 mm split-thick ness skin Samples with a dermatome (AesculapR). The samples include the epidermal layers and the Superficial part of the dermis but no deep dermal layers and no subcutaneous fat. Tissue from the same animals are used for testing pen etration and permeation rate of 2 different pharmaceutically active test compounds, namely a compound of formula I (pimecrolimus) and a compound of formula II (tacroli mus), in the skin penetration/permeation assay, see Example B below.

EXAMPLEB Skin Penetration/Permeation Assay 0210 Percutaneous penetration is studied in static Franz type diffusion cells with 2.54 cm exposed skin areas and receptor chamber volumes from 5.30 to 6.05 ml, see e.g. Schmook FB, StitZA, Reinhardt J, Skin Pharmacol 1993: 6: 116-124. PBS/EtOH3:1 is used as receptor phase. All experi ments are performed at 32° in triplicates for 48 hours. Test compounds are applied to the epidermal side of the skin samples in their marketed formulations, i.e. Elidel(R) 1% cream (pimecrolimus) and Protopic(R) 0.1% ointment (tacroli mus), each in amounts of 300 mg. Samples of 100 ulare taken from the receptor phase at 5 time points during the 48-hours (0195 The following abbreviations are used: experiment and replaced by fresh receptor fluid. After addi 0196. CS corticosteroids tion of an internal standard (ASD732, see e.g. EP569337) the (0197) CLO clobetasol-17-propionate samples are directly analyzed by RPLC using MS-based US 2008/0171729 A1 Jul. 17, 2008

detection. After termination of the experiment, the skin is 0219 the differences are less pronounced with tacroli removed from the diffusion cells and the stratum corneum is mus (factors 1.3-1.9) peeled off with 20 strippings with a transparent adhesive tape 0220 the permeation rate of tacrolimus in comparison (Kores(R). Specimens from the stripped skin are taken with a with pimecrolimus, is 11.2 times higher in untreated biopsy punch, weighed and then homogenized in 0.1 M skin, 5.9 times higher in HC-pre-treated skin, 7.1 times sodium phosphate buffer, pH 7. Following addition of an higher in MOM-pre-treated skin and 3.5 times higher in internal standard (ASD732) and buffer of pH 10 to the homo genates, extraction is performed with tert-butyl methylether. CLO-pretreated skin Solvent from each extract obtained is evaporated, each resi 0221 the skin penetration (skin concentration) is due obtained is redissolved and subjected to analysis by enhanced for pimecrolimus (at least about 10%) but not RPLC using MS-based detection. significantly for tacrolimus, in pre-treated skin com pared with untreated skin. EXAMPLE C Analytical Methods for Receptor Fluid and Skin Samples 1. A tetracyclic compound for use in the enhancement of skin permeability. 0211 Receptor fluid samples are analyzed by RP-HPLC with MS detection in ESI positive mode (LC-MS/MS analy 2. A tetracyclic compound for use in the enhancement of sis). The MS/MS mode is used to increase selectivity. LC skin permeability for a pharmaceutically active compound, MS/MS analysis is carried out with an Agilent 1100 Series which pharmaceutically active compound is other than a tet Capillary L.C System coupled to a Finnigan LCQ mass spec racyclic compound according to the present invention. trometer. A Phenomenex Luna C18(2) column (3 um, 100x2 3. A tetracyclic compound for use according to claim 1, mm) equipped with a precolumn is used and eluted isocrati wherein the use is a topical use. cally with a flow rate of 100 ul/minute at 60°. The effluent is 4. A method of enhancing the skin permeability for a phar delivered unsplit to the ESI ion-source. Under the chromato maceutically active compound comprising treating the skin graphic conditions used, all compounds tested yield a strong with a tetracyclic compound and administering a pharmaceu sodium adduct. For MS/MS parent are selected. The quantification of the parent ions is based on the area ratio of tically active compound. the fragmentions to the fragmention of the internal standard. 5. The method of claim 4, wherein the tetracyclic com pound and the pharmaceutically active compound both are EXAMPLED administered topically. 6. A method for treatment of disorders in which T cells are Penetration/Permeation Profiles involved in the pathophysiology of the disease comprising Results administering to a Subject in need of such treatment an effec 0212. The concentrations of pimecrolimus and tacrolimus tive amount of a tetracyclic compound and an effective in the various skin Samples (indicating skin penetration) as amount of a T-cell modulator. well as the data on the permeation rate (a measure of com 7. A method for the preparation of a medicament for the pound passing the skin barrier) are Summarized in TABLE 1 treatment of disorders in which T cells are involved in the below. pathophysiology of the disorder comprising combining an effective amount of a tetracyclic compound and an effective TABLE 1. amount of a T-cell modulator. 8. A method according to claim 6, wherein the treatment is Pre-Treatment Formulation Skin concentration Permeation rate topical treatment. None Elidel cream, 1% 2.49 0.36 O.13 - 0.04 9. A method according to claim 8, wherein disorders are HC Elidel cream, 1% 3.95 - 0.76 O49, O.OS inflammatory disorders selected from the group consisting of MOM Elidel cream, 1% 4.33 - 1.18 O38, O.OO CLO Elidel cream, 1% 3.46 - 0.31 O.S3 O.OS psoriasis, atopic eczema, seborrheic dermatitis, intertrigo, None Protopic 0.1% 3.55 - 0.34 145 - 0.53 nummular eczema, irritant orallergic contact dermatitis, urti HC Protopic 0.1% 6.47 1.76 2.87 0.17 caria, parapsoriasis, lichen simplex chronicus, acute/chronic MOM Protopic 0.1% 4.31 O.95 2.70 - 0.56 dyshidrotic eczema, lupus erythematosus, pemphigus, lichen CLO Protopic 0.1% 3.02 0.26 1860.53 planus, lichen rubber, granuloma annulare, acne, alopecia greata, cutaneous Graft VS Host reactions, vasculitides and 0213. In TABLE I pyoderma gangrenosum and wherein a T-cell-modulator is an 0214 Skin concentration is indicated in ug/g antiinflammatory agent. 0215 Permeation rate is indicated in ng/ml/hour. 10. A method according to claim 8, wherein disorders are 0216. From TABLE 1 it is evident that hyperproliferative disorders selected from the group consist 0217 the concentrations of active compounds in ing of psoriasis, T cell lymphoma, pseudolymphoma, actinic untreated and pre-treated skin samples are in a compa keratosis, warts, precancerous lesions, benign epithelial rable range, despite of the different drug concentration tumors, keratoacanthomas, squamous cell carcinoma, basel in Elidel cream 1% and Protopic ointment 0.1% cell carcinoma, comprising topically and wherein a T-cell 0218 in corticosteroid pretreated samples permeation modulator is an antihyperproliferative agent. rates of pimecrolimus are increased by factors 3.8 (HC 11. A method according to claim 6, wherein a T-cell modu pre-treatment), 2.9 (MOM pre-treatment) and 4.1 (CLO lator, an antiinflammatory agent, or an antihyperproliferative pre-treatment) compared with untreated skin agent is a calcineurin inhibitor. US 2008/0171729 A1 Jul. 17, 2008 13

12. A method according to claim 11, wherein a calcineurin inhibitor is a compound of formula

III CH3

CH2CH(CH3)2 CH3 HO CH, O O

3a 1 3 CH N N --- N CH O O R (CH3)CHCH O

CH, O O N CH3 H H -N N N CH N N CH2CH(CH3)2 O CH, O CH3 O

wherein R is methyl, ethyl, propyl, isopropylor—CH(OH) R is methyl, ethyl, propyl or allyl, CH preferably R is ethyl (Cyclosporin A). n is an integer of 1 or 2, and the dotted line is a bond, or is 13. A method according to claim 11, wherein a calcineurin no bond, preferably a compound of formula inhibitor is a compound of formula

II IIFK

OCH, OCH

wherein R is hydroxy or protected hydroxy, R is hydrogen, hydroxyl or protected hydroxyl, (tacrolimus, FK506). US 2008/0171729 A1 Jul. 17, 2008

14. A method according to claim 11, wherein a calcineurin R is oxo and there is a single bond in 23.24 position; inhibitor is a compound of formula hydroxy and there is a single or double bond in 23.24 position; or absent and there is a double bond in 23.24 position; and R is methyl, ethyl, propyl or allyl. 15. A method of topical treatment of inflammatory disor ders, acne, microbial disorders, hyperproliferative disorders, phototoxic conditions (Solar dermatoses), hairloss, or condi tions wherein an analgetic, anti-aging, antiperspirant, anti pruritic or astringent is helpful, comprising topically admin istering an effective amount of a tetracyclic compound, and a pharmaceutically active compound selected from the group consisting of an anti-inflammatory agent, anti-acne agent, antimicrobial, anti-hyperproliferative agent, anti-phototoxic agent, anti-hairloss agent, analgetic, anti-aging agent, anti perspirant, anti-pruritic and astringent to a Subject in need of Such treatment. 16. A method for the preparation of a medicament for treating topically inflammatory disorders, acne, microbial disorders, hyperproliferative disorders, phototoxic condi tions (Solar dermatoses), hairloss, or conditions wherein an analgetic, anti-aging antiperspirant, anti-pruritic or astringent agent is helpful, comprising combining an effective amount of a tetracyclic compound, and a pharmaceutically active compound selected from the group consisting of an anti inflammatory agent, anti-acne agent, antimicrobial, anti-hy wherein either perproliferative agent, anti-phototoxic agent, anti-hairloss R is a group (a) of formula agent, analgetic, anti-aging agent, antiperspirant, anti-pru ritic and astringent. 17. A tetracyclic compound for use in the enhancement of (a) skin permeability for a compound of formula I or I as defined in claim 14. 18. A tetracyclic compound for use or in a method accord ing to claim 1, wherein the tetracyclic compound is a steroid. 19. A tetracyclic compound for use according to claim 18, wherein a tetracyclic compound is a compound having as a part of its chemical structure a group of formula wherein Rs is chloro, bromo, iodo or azido, R is hydroxy or methoxy, and R is hydroxy and there is a single bond in 10, 11 position; or absent, and there is a double bond in 10.11 position, O R is a group (b) or (c) of formula TETR

(b) wherein each of the rings A, B, C and D have from 5 to 7 and ring members. 20. A tetracyclic compound for use according to claim 19, wherein a tetracyclic compound is a corticoid. 21. A tetracyclic compound for use according to claim 18, (c) wherein a tetracyclic compound is selected from the group consisting of acilomethasone, beclomethasone, betametha Sone, clobetasole, hydrocortisone, dexamethasone, difluo OHC cortolene, fluticaSone, halobetasol, halomethasone, mometa Sone and triamcinolone. 22. A method or use according to claim 4, wherein in a first wherein step a tetracyclic compound and in a second step a pharma R is as defined above, and ceutically active compound is administered. R is hydroxy and there is a single bond in 10, 11 posi tion, c c c c c