GB2420281A

GB2420281A - Topical formulations for use in the treatment or prevention of dermatological conditions

Info

Publication number: GB2420281A
Application number: GB0425633A
Authority: GB
Inventors: Gerald Curtis; David Bar-Or; George Margetts
Original assignee: Stegram Pharmaceuticals Ltd
Current assignee: Stegram Pharmaceuticals Ltd
Priority date: 2004-11-22
Filing date: 2004-11-22
Publication date: 2006-05-24
Also published as: WO2006054119A1; EP1865964A1; GB0425633D0

Abstract

Topical compositions comprising a steroid selected from the group consisting of ethisterone and derivatives thereof and trilostane and derivatives thereof and the use of these steroids in the manufacture of a medicament for the prevention or treatment of a dermatological treatment that may be so treated by modifying the growth and interaction of one or more blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis. Conditions include cellulite, solar elastosis, senile elastosis, lipoma, naevi, telangiectasis, keloids, ainhum, Peyronie's Disease, keratosis, solar chelitis, angioma and dermatofibroma. Preferred steroids are ethisterone, stanozolol, danazol, trilostane, keto-trilostane, trilostane II and trilostane III.

Description

Topical Formulations for Use in the Treatment or Prevention of

DermatologicaJ Conditions

Field of the Invention

The present invention relates to topical formulations for use in the treatment or prevention of dei-matological conditions that can be so prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes arid fibroblasts and/or by modifying fibrosis, particularly cellulite. It also relates to the use in the treatment or prevention of dermatological conditions of certain antiandrogens and compounds that lower the blood concentrations of glucocorticoids such as cortisol.

Background to the Invention

Cellulite is the lumpy fat found (mostly in women) in the thighs, hips, buttocks, abdomens and breasts, giving rise to a dimpled appearance of the skin in these areas.

Many people consider that the appearance of cellulite is unappealing and there is therefore considerable interest in seeking ways of reducing its occurrence. It is estimated that the US market alone for products and clinical treatments of cellulite is approximately $3 billion per year, with a similar market in Europe.

Some things are known about the structure and causes of cellulite. Ultrasound examination has shown a diffuse pattern of extrusion of underlying fat (adipose) tissue into the reticular dermis in individuals with cellulite which is absent from unaffected individuals. No significant differences have been found in the way the fat tissue looks under the microscope, how it responds to fat deposition and resorption or even in the regional blood flow between affected and unaffected sites within individuals. There are, however, structural characteristics of the connective tissue below the skin that predispose individuals to develop the irregular extrusion of adipose tissue into the dermis, which characterizes cellulite, Thus, it can be said that cellulite represents areas of a "break in the fence" where fat cells come into the skin area and the dimpling represents where the support structure of the skin (the original "fence") is still intact, The two main factors that affect the amount of cellulite present under the skin appear to be the number of fat cells (adipocytes) and the amount of fat inside the V:tflifldrcwsIEflhlaflcc/0Dp790738s doc GBP290238/GI3 spcciIicfltion/tsi/22. I I 04 adipocytes. Current evidence suggests that the original number of fat cells in any area of the body is controlled by the original genetic make up of the individual concerned. There are no factors or substances that increase the number of cells in a body region, but rather they do not multiply unless the other fat cells get filled to capacity.

Adipose tissue is specialized in storing lipids. The majority of lipids are triglycerides formed from free fatty acids and glycerol. The overall mass of adipose tissue is determined by the adipocyte number and size. Increase can be caused by hyperplastic growth (an increase of adipocytes). This comes from the result of mitotic activity of precursor cells. Also, an increase can be caused by hypertrophic growth which is an increase in the size of existing adipocytes. A connection exists between these two growth factors. Once an adipoctye reaches a critical size through hypertrophic growth, the precursor cells are stimulated to form additional adipocytes resulting in hyperplastic growth. The key therefore appears to be to limit the expansion of existing adipocytes by limiting lipid buildup.

The market is saturated with products that claim that they have the cure for cellulite. However, none of the products that have so far been placed on the market have been shown to be anything other than transiently effective. Any temporary benefit from such products is simply due to water loss; the adipose tissue is still there. Up until now, diet and exercise have been the best means to attack cellulite. As fat cells reduce in size, fat deposits shrink, resulting in minimisation of the dimpling effect.

A topical formulation that can be applied to areas of skin affected by cellulite and which actually reduces the number and size of the adipose cells as a result would clearly be of huge interest to what is a large market. The present inventors have discovered that the administration of certain antiandrogens and compounds that lower the blood concentrations of glucocorticoids such as cortisol leads to a remarkable reduction in the maturation of preadipocytes into adipocytes, thus preventing the formation of adipose tissue and reducing cellulite formation. These compounds also appear to be able to modify the growth and interaction of blood vessels and/or fibroblasts and/or modify fibrosis. This also makes them suitable for reducing cellulite formation. In addition, there are many other dermatological conditions which can also be prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and V:/Tandrcws/Enhancc/GBP29O238s.dOC G13P290238/GB spcciflcationitsa/22.1 I.04 fibroblasts and/or by modifying fibrosis (e.g. naevi, senile elastosis, sun exposure-related conditions and superficial benign neoplastic conditions such as lipoma and angioma), so these topical formulations are also suitable for preventing or treating these other conditions as well.

Summary of the Invention

In a first aspect of the present invention there is provided the use of a steroid selected from the group consisting of ethisterone and derivatives thereof and trilostane and derivatives thereof in the manufacture of a topical medicament for the prevention or treatment of a dermatological condition that can be so prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and f'ibroblasts and/or by modifying fibrosis.

In a second aspect of the present invention, there is provided a topical formulation comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a steroid selected from the group consisting of ethisterone and derivatives thereof and tillostane and derivatives thereof.

In a third aspect of the present invention, there is provided a method for the treatment or prevention of a dermatological condition that can be so prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis, said method comprising the topical administration to a patient in need thereof of an effective amount of a steroid selected from the group consisting of ethisterone and derivatives thereof and trilostane and derivatives thereof.

As is explained and exemplified in greater detail below, the topical formulations of the present invention demonstrate a remarkable and unique combination of effects that make them suitable for the treatment or prevention of a wide variety of dermatological conditions. Specifically, the topical formulations of the present invention have been found to demonstrate one, some and often all of the following activities: (a) the ability to reduce the maturation of preadipocytes into adipocytes; (b) the ability to modify the growth and interaction of blood vessels (angiogenesis); (c) the ability to modify the growth and interaction of fibroblasts; and V/Tandrcws/EnhancciGBP29O23Es doe GBP29023B/G13 spccilicalion/tsaI22.1.04 (d) the ability to modify fibrosis.

The fact that the formulations of the present invention have these activities makes them uniquely suited to the prevention or treatment of derrnatological conditions which can be prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis. It is also possible that the known hormonal effect of the steroids of the present invention may also contribute to their particular effectiveness.

Dermatological conditions which can be prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis by the topical administration to a patient in need thereof of an effective amount of a steroid selected from the group consisting of ethisterone and derivatives thereof and trilostane and derivatives thereof in accordance with the present invention include, but are not limited to cellulite, naevi (e.g. port wine naevi and strawberry naevi), telangiectasia, senile elastosis, keloids, ainhum, Peyronie's disease, sun exposure related dermatological conditions (e.g. solar elastosis, keratosis and solar chelitis), dermatological treatment of the sinus and superficial benign neoplastic conditions (e.g. lipoma, angioma and dermatofibroma). Preferred dermatological conditions which can be prevented or treated according to the present invention include cellulite, port wine naevi, strawberry naevi, senile elastosis, solar elastosis, keratosis, solar chelitis, lipoma, angioma and dermatofibroma. More preferred dermatological conditions which can be prevented or treated according to the present invention include cellulite, senile elastosis, solar elastosis and lipoma. The most preferred dermatological condition which can be prevented or treated according to the present invention is cellulite.

The steroids that can be used in the topical formulations and in the method of treatment or prevention of dermatological conditions according to the present invention are selected from a group consisting of ethisterone and derivatives thereof and trilostane and derivatives thereof. Preferred examples of ethisterone and derivatives thereof include compounds of the following formula (I) and pharmacologically acceptable salts and esters thereof: V:fTandrcws/EnhanCCJGBP29O238SdOC 013P2902381GB speciflcationhtsa/22. I I.04 R2 A1 (I) wherein: R' is an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms or an aikynyl group having from 2 to 6 carbon atoms; R2 is hydroxyl, an alkoxy group having from 1 to 6 carbon atoms, an alkanoyloxy group having from 1 to 7 carbon atoms, a group of formula (II) or a group of formula (III): A12 -(CH2) (CH2)mN "Rla (Ii) (III) wherein R' is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, each of R'2 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, and m and n are the same or different and each is 0 or an integer of from 1 to 4; each of R3 and R4 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms; V:ITandrcws/Enhancc/0BP2902385dOC GBP29O38/Of3 spccificition/tsa/22. I I. 04 each of R5 and R6 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R5 and R6 together represent a single bond; each of R7, R8, R9 and R' is the same or different and is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -NCR15)2 wherein each group R is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or R7 and R8 and/or R9 and R1 together with the carbon atom to which they are attached represent a carbonyl group, or R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5to 9-membered heterocyclyl group, said 5- to 9-membered heterocyclyl group optionally being substituted with from 1 to? substituents (said substituents are the same or different and are selected from substituent group a defined below) ; substituent group a represents a group consisting of a halogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkylsulfinyl group having from 1 to 6 carbon atoms, an alkylsulfonyl group having from I to 6 carbon atoms, a phenyl group and a group of formula -N(R'6)2 wherein each group R16 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms.

Preferred examples of trilostane and derivatives thereof include compounds of the following formula (IV) and pharmacologically acceptable salts and esters thereof: 18 22 A17 (IV) V:(Tandrcws/EnhanceIGBP29O23BS. dOC 013 I'29D238100 spcciflcation/Lsa122.l 1.04 wherein: R'8, R'9 and R2' are the same or different and each is hydrogen or an alkyl group having from 1 to 6 carbon atoms; R'7 is hydrogen, an alkyl group having from 1 to 6 carbon atoms or an alkenyl group having from 2 to 6 carbon atoms, R22 is hydroxyl, an alkoxy group having from I to 6 carbon atoms, an alkanoyloxy group having from 1 to 7 carbon atoms, a group of formula (II) as defined above for formula (I) or a group of formula (II!) as defined above for formula (I), or R7 and R22 together represent an oxo group, an ethylenedioxy group or a propylenedioxy group; each of R2 and R24 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R2 and R24 together represent a single bond; each of R23 and R29 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R23 and R29 together represent an epoxy linkage; each of R25, R26, R21 and R28 is the same or different and is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a cyano group, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R30)2 wherein each group R is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or R and R26 and/or R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and R28 together with the carbon atoms to which they are attached represent a 5- to 9-membered heterocyclyl group, said 5- to 9-membered heterocyclyl group optionally being substituted with from I to 7 substituents (said substituents are the same or different and are selected from substituent group a defined above).

Where R7, R8, R9 and R' together with the carbon atoms to which they are attached represent an optionally subsitituted 5- to 9-membered heterocyclyl group or R25, R26 R27 and R28 together with the carbon atoms to which they are attached represent an optionally substituted 5- to 9membered heterocyclyl group, said heterocyclyl group is a V:IFandrews/EntianccIOBP29O238S.dOC GBP290238/GB specficaIion/Isa/22.1 104 5- to 9-membered heterocyclic group containing from 1 to 4 atoms selected from a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and may be, for example, an unsaturated heterocyclic group such as a furyl group, a thienyl group, a pyrrolyl group, an azepinyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a 1,2,3-oxadiazolyl group, a triazolyl group, a tetrazolyl group, a thiadiazolyl group, a pyranyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, an azepinyl group, an azocinyl group or an azoninyl group; or a group wherein the unsaturated heterocyclic groups described above are partially or completely reduced, such as a morpholinyl group, a thiomorpholinyl group, a pyrrolidinyl group, a pyrrolinyl group, a imidazolidinyl group, a imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a pipendyl group, a piperazinyl group, a perhydroazepinyl group, a perhydroazocinyl group or a perhydroazoninyl group; preferably it is a 5- to 7-membered heterocyclic group containing one or more nitrogen atom and optionally containing an oxygen atom and/or a sulfur atom, which is, for example, an unsaturated heterocyclic group such as a pyrrolyl group, an azepinyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a 1,2,3-oxadiazolyl group, a triazolyl group, a tetrazolyl group, a thiadiazolyl group, a pyridyl group, a pyidazinyl group, a pyrimidinyl group or a pyrazinyl group; or a group wherein this unsaturated heterocyclic group is partially or completely reduced, such as a morpholinyl group, a thiomorpholinyl group, a pyrrolidinyl group, a pyrrolinyl group, a imidazolidinyl group, a imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a piperidyl group or a piperazinyl group; and more preferably it is an isoxazolyl group or a pyrazolyl group for R1, R8, R9 and R' together with the carbon atoms to which they are attached and an isoxazolyl group for R25, R26, R27 and R28 together with the carbon atoms to which they are attached.

The alkyl group having from Ito 6 carbon atoms in the definitions of R', R3, R4, R5, R6, R7, R8, R9, R' , R'', R'2, R3, R'4, R'5, R'6, R'7, R'8, R'9, R20, R21, R23, R24, R, R26, R21, R28, R29, R3 and substituent group c is a straight or branched chain alkyl group having from 1 to 6 carbon atoms and may be, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl V:)Tandrcws/EnhanccIOBP29O238s.doc 013P290238/OB specifica(ion/1a/22, 11. 04 group, a t-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a t-pentyl group, a 1-methylbutyl group, a hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1-ethylbutyl group or a 2-ethylbutyl group; preferably it is an alkyl group having from I to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group or a t-butyl group; more preferably it is a methyl group, an ethyl group, a propyl group or an isopropyl group; and most preferably it is a methyl group.

The alkenyl group having from 2 to 6 carbon atoms in the definition of R' and R'7 is a straight or branched chain alkenyl group having from 2 to 6 carbon atoms and may be, for example, vinyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2- propenyl, 2-butenyl, 1 -methyl-2-butenyl, 2-methyl-2-butenyl, 1 -ethyl-2- butenyl, 3- butenyl, 1 -methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2- pentenyl, 1- methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1 -methyl-3-pentenyl, 2-methyl-3- pentenyl, 4-pentenyl, 1 -methyl-4-penten yl, 2-methyl-4-pentenyl, 2- hexeny), 3-hexenyl, 4- hexenyl and 5-hexenyl groups. Alkenyl groups having from 2 to 4 carbon atoms are preferred, and alkenyl groups having 2 or 3 carbon atoms are most preferred.

The alkynyl group having from 2 to 6 carbon atoms in the definition of R' and R'1 is a straight or branched chain alkyny) group having from 2 to 6 carbon atoms and may be, for example, ethynyl, 2-propynyl, 1 -methyl-2propynyl, 2-butynyl, 1 -methyl-2-butynyl, 1-ethyl -2-butynyl, 3-butynyl, 1 -methyl-3-butynyl, 2-methyl-3-butynyl, 1 -ethyl-3-butyn yl, 2-pentynyl, 1 -methyl-2-pentynyl, 3-pentynyl, 1 -methyl-3-pentynyl, 2methyl-3-pentynyl, 4-pentynyl, 1 -methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl groups. Alkynyl groups having from 2 to 4 carbon atoms are preferred, and alkynyl groups having 2 or 3 carbon atoms are most preferred.

The alkanoyloxy group having from I to 7 carbon atoms in the definitions of R2 and R22 is a carbonyloxy group (-COO-) the carbon atom of which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms as described above and may be, for example, a formyloxy group, an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a pentanoyloxy group or a hexanoyloxy group; it is preferably an alkanoyloxy group having from 2 to 5 carbon atoms such as an VTandrews/Enhance/GBP2D0238s.doC 0BP290238/GB spcciflcation/tsa/22. I 1.04 acetyloxy group, a propionyloxy group, a butyryloxy group or an isobutyryloxy group; and more preferably it is an acetyloxy group.

The alkoxy group having from 1 to 6 carbon atoms in the definitions of R2, R1, R8, R9, R' , R", R22 and substituent group a is a hydroxy group in which the hydrogen atom is substituted with an alkyl group having from 1 to 6 carbon atoms as described above and may be, for example, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, an s-butoxy group, a tert- butoxy group, an n-pentyloxy group, an isopentyloxy group, a 2- methylbutoxy group, a neopentyloxy group, an n-hexyloxy group, a 4-methylpentyloxy group, a 3methylpentyloxy group, a 2-methylpentyloxy group, a 3,3-dimethylbutoxy group, a 2,2- dirnethylbutoxy group, a 1,1-dimethylbutoxy group, a 1,2-dimethylbutoxy group, a 1,3- dimethylbutoxy group or a 2,3-dimethylbutoxy group; it is preferably an alkoxy group having from 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, an n- propoxy group or an n-butoxy group; and more preferably it is a methoxy group.

The alkylthio group having from 1 to 6 carbon atoms in the definition of substituent group a is a mercapto group substituted with an alkyl group having from 1 to 6 carbon atoms as described above and may be, for example, a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, an sbutylthio group, a tert-butylthio group, an n-pentylthio group, an isopentylthio group, a 2-methylbutylthio group, a neopentylthio group, a 1- ethylpropylthio group, an n-hexylthio group, an isohexylthio group, a 4- methylpentylthio group, a 3-methylpentylthio group, a 2-methylpentylthio group, a 1-methylpentylthio group, a 3,3-dimethylbutylthio group, a 2,2-dimethylbutylthio group, a 1, 1dimethylbutylthio group, a 1,2-dimethylbutylthio group, a 1,3dimethylbutylthio group, a 2,3-dimethylbutylthio group or a 2-ethylbutylthio group; it is preferably an alkylthio group having from 1 to 4 carbon atoms such as a methylthio group, an ethylthio group, an n-propylthio group or an n-butylthio group; and more preferably it is a methylthio group.

The alkylsulfinyl group having from 1 to 6 carbon atoms in the definition of substituent group a is a sulfinyl group (-SO-) which is substituted with an alkyl group having from 1 to 6 carbon atoms as described above and may be, for example, a methanesulfinyl group, an ethanesulfinyl group, an n-propanesulfinyl group, an V,Tandrcws/anhancc/GBP290238s.doc 0BP290238/GB spccification/isa/22.1 1.04 isopropanesulfinyl group, an n-butanesulfinyl group, an isobutanesulfinyl group, an s- butanesulfinyl group, a tert-butanesulfinyl group, an n-pentanesulfinyl group, an isopentanesulfinyl group, a 2-methylbutanesulfinyl group, a neopentanesulfinyl group, an n-hexanesulfinyl group, a 4-methylpentanesul finyl group, a 3-methylpentanesulfinyl group, a 2-methylpentanesulfinyl group, a 3,3-dimethylbutanesulfinyl group, a 2,2- dimethylbutanesulfinyl group, a 1,1-dimethylbutanesulfinyl group, a 1,2- dimethylbutanesulfinyl group, a 1,3-dimethylbutanesulfinyl group or a 2,3- dimethylbutanesulfinyl group; preferably it is an alkylsulfinyl group having from 1 to 4 carbon atoms such as a methanesulfinyl group, an ethanesulfinyl group, an npropanesulfinyl group, an isopropanesulfinyl group or an n-butanesulfinyl group; and more preferably it is a methanesulfiny! group.

The alkylsulfonyl group having from 1 to 6 carbon atoms in the definition of substituent group cx is a sulfonyl group (-SO2-) substituted with an alkyl group having from 1 to 6 carbon atoms as described above and may be, for example, a methanesulfonyl group, an ethanesulfonyl group, an npropanesulfonyl group, an isopropanesulfonyl group, an n-butanesulfonyl group, an isobutanesulfonyl group, an s-butanesulfonyl group, a tertbutanesulfonyl group, an n-pentanesulfonyl group, an isopentanesulfonyl group, a 2-methylbutanesulfonyl group, a neopentanesulfonyl group, an nhexanesulfonyl group, a 4-methylpentanesulfonyl group, a 3-methylpentanesulfonyl group, a 2- methylpentanesulfon yl group, a 3,3-dimethylbutanesulfonyl group, a 2,2- di methylbutanesulfonyl group, a 1,1 -dimethylbutanesulfonyl group, a 1,2- dimethylbutanesulfonyl group, a 1,3-dimethylbutanesulfonyl group or a 2,3- dimethylbutanesulfonyl group; preferably it is an alkylsulfonyl group having from 1 to 4 carbon atoms such as a methanesulfonyl group, an ethanesulfonyl group, an npropanesulfonyl group or an n-butanesulfonyl group; and more preferably it is a methanesulfonyl group.

Where the compound of formula (I) or (IV) of the present invention or a pharmacologically acceptable ester thereof has a basic group, the compound can be converted to a salt by reacting it with an acid, and in the case where the compound of formula (I) or (IV) of the present invention or a pharmacologically acceptable ester thereof has an acidic group, the compound can be converted to a salt by reacting it with a V:rrandrcws/Enhancc/GBP2902385.doc GBP290238/GB spccification/tsa'22.I I 04 base. The compounds of the present invention encompass such salts. Where said salts are to be used for a therapeutic use, they must be pharmacologically acceptable.

Preferred examples of the salts formed with a basic group present in the compound of formula (I) or (IV) of the present invention include inorganic acid salts such as hydrohalogenated acid salts (e.g. hydrochlorides, hydrobromides and hydroiodides), nitrates, perchlorates, sulfates and phosphates; organic acid salts such as lower alkanesulfonates in which the lower alkyl moiety thereof is an alkyl group having from 1 to 6 carbon atoms as defined above (e.g. methanesulfonates, trifluoromethanesulfonates and ethanesulfonates), arylsulfonates in which the aryl moiety thereof is an aryl group having from 6 to 14 carbon atoms (e.g. benzenesulfonate or p-toluenesulfonate), acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates and rnaleates; and amino acid salts such as glycine salts, lysine salts, arginine salts, omithine salts, glutamates and aspartates. Hydrohalogenated acid salts are particularly preferred.

Preferred example of the salts formed with an acidic group present in the compound of formula (I) or (IV) of the present invention include metal salts such as alkali metal salts (e.g. sodium salts, potassium salts and lithium salts), alkali earth metal salts (e.g. calcium salts and magnesium salts), aluminium salts and iron salts; amine salts such as inorganic amine salts (e.g. ammonium salts) and organic amine salts (e.g. toctylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylgl yci nealkyl ester salts, ethylenediamine salts, N-methyl glucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'- dibenzylethylenedi amine salts, chloroprocai ne salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminomethane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates and aspartates. Alkali metal salts are particularly preferred.

The compounds of formulae (I) and (IV) of the present invention and pharmacologically acceptable salts and esters thereof of the present invention can sometimes take up water upon exposure to the atmosphere or when recrystallized to absorb water or to form a hydrate and such hydrates are also included within the scope of the present invention. Additionally, certain other solvents may be taken up by the V!FandrcwslEnhancelGBP29O238s.doc GBP290238/GB spccilication/tsa/22. II. 04 compounds of the present invention to produce solvates, which also form a part of the present invention.

The compounds of formulae (I) and (IV) of the present invention sometimes contain one or more asymmetric centres, and can therefore form optical isomers (including diastereoisomers). For the compounds of the present invention, each of said isomers and mixture of said isomers are depicted by a single formula, i.e. the formula (I) and (IV) respectively. Accordingly, the present invention covers both the individual isomers and mixtures thereof in any proportion, including racemic mixtures.

The present invention encompasses esters of the compounds of formulae (I)and (IV). These esters are compounds of formulae (I) and (IV) in which a hydroxyl group or a carboxy group of said compound of formula (I) or (IV) is modified by the addition of a protecting group using conventional techniques well-known in the art (see, for example, "Protective Groups in Organic Synthesis, Second Edition, Theodora W. Greene and Peter G.M. Wuts, 1991, John Wiley & Sons, Inc.).

There is no particular restriction on the nature of this protecting group, provided that, where the ester is intended for therapeutic purposes, it must be pharmacologically acceptable, i.e. the protecting group must be capable of being removed by a metabolic process (e.g. hydrolysis) on administration of said compound to the body of a live mammal to give a compound of formula (I) or (IV) or a salt thereof. In other words, the pharmacologically acceptable esters are pro-drugs of the compounds of formula (I) or (IV) of the present invention.

Whether an ester of a compound of formula (I) or (IV) of the present invention is pharmacologically acceptable can be easily determined. The compound under investigation is intravenously administered to an experimental animal such as a rat or mouse and the body fluids of the animal are thereafter studied. If a compound of formula (I) or (IV) or a pharmacologically acceptable salt thereof can be detected in the body fluids, the compound under investigation is judged to be a phmmacologically acceptable ester.

The compounds of formula (I) or (IV) of the present invention can be converted to an ester, examples of which include a compound of formula (I) or (IV) in which a hydroxyl group present therein is esterified. The ester residue must be capable of being V/Tandrcws/EnhanccIGBP29O238S.dOC GBP2902381G8 spccificationflsa/22. I I.04 removed by a metabolic process (e.g. hydrolysis) in vivo in order for the esterified compound to be one which is pharmacologically acceptable. Preferred examples of such a protecting group include the following: (i) 1-(acyloxy)lower alkyl groups, examples of which include 1-(aliphatic acyloxy)Iower aflcyl groups which comprise an alkyl group having from 1 to 6 carbon atoms as defined above which is substituted with an alkylcarbonyloxy group having from 1 to 6 carbon atoms, examples of which include formyloxymethyl, acetoxymethyl, propi onyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymeth yl, isovaleryloxymethyl, hexanoyloxymethyl, 1 - formyloxyethyl, 1acetoxyethyl, 1 propionyloxyethyl, 1 -butyryloxyethyl, 1 pivaloyloxyethyl, 1- valeryloxyethyl, 1-isovaleryloxyethyl, 1 -hexanoyloxyethyl, 1 - formyloxypropyl, 1- acetoxypropyl, I -propionyloxypropyl, 1 -butyryloxypropyl, 1 - pivaloyloxypropyl, 1valeryloxypropyl, 1 -isovaleryloxypropyl, 1 -hexanoyloxy-propyl, 1 acetoxybutyl, 1- propionyloxybutyl, 1 -butyryloxybutyl, 1 -pi valoyloxybutyl, 1 - acetoxypentyl, 1- propionyloxypentyl, 1 -butyryloxypentyl, 1-p1 valoyloxypentyl and 1- pivaloyloxyhexyl groups, 1-(cycloalkylcarbonyloxy)Iower alkyl groups which comprise an alkyl group having from 1 to 6 carbon atoms as defined above which is substituted with a cycloalkylcarbonyloxy group in which a carbonyloxy group is substituted with a cycloalkyl group having from 1 to 6 carbon atoms, examples of which include cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxy-meth yl, 1cyclopentylcarbonyloxYethY), 1 -cyclohexylcarbonyloxyethyl, 1 -cyclopentylcarbonyloxypropYl, 1 -cyclohexylcarbonyloxypropyl, 1 cyclopentyl- carbonyloxybutyl and I -cyclohexylcarbonyl oxybutyl groups, and 1-(aromatic acyloxy)lower alkyl groups which comprise an alkyl group having from 1 to 6 carbon atoms as defined above which is substituted with an arylcarbonyloxy group which comprises an oxygen atom which is substituted with an arylcarbonyl group, examples of which include benzoyloxymethyl groups; (ii) substituted carbonyloxyalkyl groups, examples of which include (lower alkoxycarbonyloxy)alkyl groups which comprise an alkyl group having from 1 to 6 carbon atoms as defined above or a cycloalkyl group having from 1 to 6 V:/Tandrews/Enhancc/G8P290238S.dOC 013P290238/GB spcciflcation/1sa122.l 1.04 carbon atoms which is substituted with a lower alkoxycarbonyloxy group which comprises a carbonyloxy group substituted with an alkoxy group having from I to 6 carbon atoms as defined above or a cycloalkoxy group having from 1 to 6 carbon atoms, examples of which include methoxycarbonYloxYmethYl, ethoxycarbonyloXYmethYl propoxy-carbonyloxymethYl, isopropoxycarbonyloxymethYl7 butoxycarbony]OXYmethYl isobutoxycarboflYlOXYmethYl, pentyloxycarbonyloxymethYl, hexyloxycarbonYlOXY- methyl, cyclohexyloxycarbOflYlOXYmethYli cyclohexyloxycarbonYlOXY(CYCJ0heXYDmethyl, 1 (methoxycarbonYlOXY)ethYl, 1 (ethoxycarbonYlOXY)ethYI, 1 (propoxy- carbonyloxy)ethy], 1 (isopropoxycarbonYlOXY)ethYl 1 (butoxycarbonylOXy) ethYl1 I -(i sobutoxycarbonYloXY)ethYl, 1 -(t-butoxycarbonylOXY)ethYl 1 - (pentyloxy- carbonyloxy)ethyl, 1 (hexyloxycarbonYlOXY)ethYl, 1 (cyclopentyloXycarbOflYlOXY)-ethYl 1 (cyciopentyIoxycarbonyloxY)pro1)Yl 1 (cyclohexyloxycarbOflYlOXY)Pr0PYl 1 -(cyclopentyl oxycarbonyloxy)butYl, 1 -(cyclohexylox ycarbonyloxy)butyl, 1 (cyclohexyloxycarbOflYlOXY)ethYl, 1 (ethoxycarbonylOXY)PrOPYl, 1 (methoxy- carbonyloxy)propyl, 1 -(ethoxycarbonyloXY)PrOPYl, 1 (propoxycarbOnYlOXY) PrOPYl 1 (isopropoxycarbonYloXY)PrOPYl 1 (butoxycarbonyIOXY)PrOPYl 1 -(isobutoxy- carbonyloxy)propyl, 1 (pentyIoxycarbOflylOXY)PrOPYl 1 (hexyloxycarbonylOXY)-PrOPYJ, 1(methoxycarbonYlOXY)bUtYl, 1 (ethoxycarbonylOXY)bUtYl, 1 -(propoxycarbonyloxy)butyl, 1(isopropoxycarbonY1OXY)bUtYl1 1-(butoxycarboflYlOXY) bUtY1, 1 -(isobutoxycarbon yloxy)butyl, 1 (methoxycarbO11YIOXY)PeT1tYl, 1 - (ethoxy- carbonyloxy)pentyl, I (methoxycarbOnylOXY)heXYl and 1 -(ethoxycarbonyloxy) heXYl groups, and oxodioxolenylmethYl groups, which comprise a methyl group which is substituted with an oxodioxolenyl group which itself may optionally be substituted with a group selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms as defined above and aryl groups having from 6 to 14 carbon atoms as defined above which may optionally be substituted with at least one alkyl group having from 1 to 6 carbon atoms as defined above, alkoxy group having from 1 to 6 carbon atoms as defined above or a halogen atom, examples of which include (5-phenyl-2-oxo-1,3- dioXOlefl-4- yl)methyl, [5-(4-methylphenyl)-2-OXo- 1,3-dioxolen-4-yl]methYl, [5-(4methoxyphenyl)- 2-oxo- 1,3-dioxolen-4-yl]methyl, [5-(4-fluoropheflyl)-2-OXO- 1,3-dioxolen- 4-yl]methyl, [5(4-chlorophenyl)-2-oxo- 1,3-dioxolen-4-ylJmethy), (2-oxo- 1,3-di oxolen-4yl)-methyl, (5- V:TFandrcwsIanhanCeIGBP29O238S.d0C 0BP290238103 spccification/tsa/22. I I. 04 methyl-2-oxo- 1,3-dioxolen-4-yl)methyl, (5-ethyl -2-oxo- 1,3-dioxolen-4- yl)methyl, (5- propyl-2-oxo1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo- 1,3-dioxolen- 4-yl)methyl and (5-butyl-2-oxo- 1,3-dioxolen-4-yl)meth yl groups; (iii) phthalidyl groups which comprise a phthalidyl group which may optionally be substituted with a substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms as defined above and alkoxy groups having from 1 to 6 carbon atoms as defined above, examples of which include phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl groups; (iv) aliphatic acyl groups, examples of which include alkylcarbonyl groups having from 1 to 25 carbon atoms, examples of which include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, i sovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1 -methylpentadecanoyl, 14- methyl- pentadecanoyl, 13,1 3-dimethyltetradecanoyl, heptadecanoyl, 1 5- methylhexadecanoyl, octadecanoyl, 1.mothylheptadecanoyl, nonadecanoyl, eicosanoyl and heneicosanoyl groups, ester forming residues of a saturated or unsaturated C2-C0 aliphatic di-carboxylic acids such as a fumarate, a maleate, oxalate, malonate or succinate, halogenated alkylcarbonyl groups having from 1 to 25 carbons in which the alkyl moiety thereof is substituted by at least one halogen atom, examples of which include chloroacetyl, dichioroacetyl, trichioroacetyl and trifluoroacetyl groups, lower alkoxyalkylcarbonyl groups which comprise an alkylcarbonyl group having from 1 to 25 carbon atoms in which the alkyl moiety thereof is substituted with at least one C1-C6 alkoxy group as defined above, examples of said lower alkoxyalkylcarbonyl groups including methoxyacetyl groups, and unsaturated alkylcarbonyl groups having from 1 to 25 carbon atoms, examples of which include acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl and (E)-2- methyl-2-butenoyl groups; of these, alkylcarbonyl groups having from 1 to 6 carbon atoms are preferred; (v) aromatic acyl groups, examples of which include V:/Taridrews/Enhancc/0BP290238S.dOC GB P290238/GB spccification/tsa/22. 11.04 arylcarbonyl groups which comprise a carbonyl group which is substituted with an aryl group having from 6 to 14 carbon atoms as defined above, examples of which include benzoyi, cz-naphthoyl and - naphthoyl groups, halogenated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one halogen atom, examples of which include 2-bromobenzoyl, 4chlorobenzoyl and 2,4,6-tnfluorobenzoyl groups, lower alkylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one alkyl group having from 1 to 6 carbon atoms as defined above, examples of which include 2,4,6-trimethylbenzoyl and 4-toluoyl groups, lower alkoxylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one alkoxy group having from 1 to 6 carbon atoms as defined above, examples of which include 4-anisoyl groups, nitrated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one nitro group, examples of which include 4nitrobenzoyl and 2-nitrobenzoyl groups, lower alkoxycarbonylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with a carbonyl group which is itself substituted with an alkoxy group having from I to 6 carbon atoms as defined above, examples of which include 2-(methoxycarbonyl)benzoyl groups, and arylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one aryl group having from 6 to 14 carbon atoms as defined above, examples of which include 4-phenylbenzoyl groups; (vi) half-ester salt residues of succinic acid; (vii) phosphate ester salt residues; (viii) ester-forming residues of an amino acid such as glutamate and aspartate; (ix) carbamoyl groups which may optionally be substituted with 1 or 2 alkyl groups having from 1 to 6 carbon atoms as defined above; and (x) 1-(acyloxy)alkoxycarbonyl groups which comprise a lower alkoxycarbonyl group as defined above in which the lower alkoxy moiety is substituted with an aliphatic acyloxy group as defined above or an aromatic acyloxy group as defined above, examples of V:/Tandrcws/Enhancc/GBP290238s.dOc GBP290238/G13 spccilication/tsa122. Ii. 04 which include p1 valoyloxymethylOxYcarboflYl groups.

Of the above protecting groups which are capable of being removed by a metabolic process (e.g. hydrolysis) in vivo which are used to synthesise a compound of formula (I) or (IV) in which a hydroxyl residue therein is modified, the C1-C25 alkylcarbonyl groups and substituted carbonyloxyalkYl groups are preferred.

Preferred compounds of formula (I) are compounds of formula (Ta) and phannacologiCally acceptable salts and esters thereof: (Ta) wherein R', R2, R3, R4, R5, R6, R7, R8, R9 and R1 are as defined and exemplified above.

Of these compounds of formula (Ia) and pharmacologically acceptable salts and esters thereof, preferred are those wherein: (i) R' is an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms or an alkynyl group having from 2 to 4 carbon atoms; (ii) R is a methyl group or an ethynyl group; (iii) R2 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R" is an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (111) wherein m is 0, 1 or 2, and each of R12 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; v:rrandrcwsanhanc&0BP2902385.d0c GBP290238/GB specificaion/tsa/22.1 1.04 (iv) R2 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R" is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, or a group of formula (III) wherein m is 0 or 1, and each of R'2 and R3 is the same or different and is hydrogen, a methyl group or an ethyl group; (v) R2 is hydroxyl; (vi) R3 is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (vii) R3 is a methyl group; (viii) R4 is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (ix) R4 is a methyl group; (x) each of R1 and R8 is a hydrogen atom and R9 and R' together with the carbon atom to which they are attached represent a carbonyl group, or R7, RB, R9 and R' together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined below), and substituent group a' represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula -N(R'6 wherein each group Rboa is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (xi) R7, R8, R9 and R' together with the carbon atoms to which they are attached represent an isoxazolyl group; and (xia) each of R5 and R6 is a hydrogen atom or R5 and R6 together represent a single bond.

In each group of (i) to (ii), (iii) to (v), (vi) to (vii), (viii) to (ix) and (x) to (xi) compounds of formula (Ia) and pharmacologically acceptable salts and esters thereof having substituents falling within the larger numbered group are more preferred.

The compounds of formula (Ia) and pharmacologically acceptable salts and esters thereof which are given by an optional combination of R' selected from (i) to (ii), R2 selected from (iii) to (v), R3 selected from (vi) to (vii), R4 selected from (viii) to (ix), R7, V:/TandcwsIEnhancc/GBP290238S. dOC G0P290238/GB spcciflcation/tsa/22.I 1.04 R8, R9 and R' selected from (x) to (xi) and R5 and R6 selected from (xia) are also preferred.

Compounds of formula (Ia) and pharmacologically acceptable salts and esters thereof having the following combinations are particularly preferred: (a) R' = (I), R2 = (iii), R3 = (vi), R4= (viii), R5 and R6 = (xia), R7, R8, R9 and R' = (x); (b) R' = (ii), R2 = (iv), R3 (vii), R4= (ix), R5 and R6 = (xia), R7, R8, R9 and R' = and (c) R1 = (ii), R2 = (v), R3 = (vii), R4 = (ix), R5 and R6 = (xia), R7, R8, R9 and R1 = (xi).

The most preferred compounds of formula (Ia) and pharmacologically acceptable salts and esters thereof are ethisterone, danazol and stanozolol and pharmacologically acceptable salts and esters thereof: HO /H HO H N(TJJc1 athsierone Danazol HN(1IIIIIII1IIIIIIIIII Stanozolol V:(FandrcwslEnhancc/GBP29O238s.doc G13P2902381G9 spccification/tsa/22. II. 04 Ethisterone, danazol and stanozolol are known synthetic steroid hormones having antiandrogen activity. Ethisterone (1 7ahydroxypregn-4-en2O-yn-3-Ofle) is a progestogen that has been used in the past to treat menstrual disorders and as a component of combined oral contraceptives. Danazol (17a-pregna-2,4-dien- 20-yflO[2,3- d]-isoxazol-1713-ol) is a derivative of ethisterone that is a weak androgen that binds to numerous steroid hormone receptors and blocks the synthesis of estradiol, progesterone, testosterone and glucocorticoids; it is known for use as an oral agent employed in the treatment of endometriosi s. Stanozolol (17-methyl-5a -androstano[3,2-c]pyrazol- 173- ol) is a synthetic testosterone analogue.

Preferred compounds of formula (IV) are compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof: A22 A17 ::7.R23R24 (IV a) wherein R'7, R'8, R'9, R20, R21, R2, R23, R24, R, R26, R27, R28 and R29 are as defined and exemplified above.

Of these compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof, preferred are those wherein: (xii) each of R18 and R is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (xiii) each of R'8 and R'9 is a methyl group; (xiv) each of R20, R1 and R24 is the same or different and is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms or R21 is a hydrogen atom and R2 and R24 together represent a single bond; V:iThnclrcws/Enhancc/G13P2902385 doc 0BP290238/GB specificationhL5a/22. 11.04 (xv) each of R20, R2' and R24 is a hydrogen atom or R2' is a hydrogen atom and R2 and R24 together represent a single bond; (xvi) R'7 is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (xvii) R'7 is hydrogen; (xviii) R22 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R" is an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R'4)z wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (ill) wherein m is 0, 1 or 2, and each of R'2 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (xix) R22 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (H) wherein n is 0 and R" is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a 1' dimethylamino group, or a group of formula (III) wherein m is 0 or 1, and each of R - and R'3 is the same or different and is hydrogen, a methyl group or an ethyl group; (xx) R17 and R22 together represent an oxo group; (xxi) each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; (xxii) R25 is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and R together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituerits are the same or different and are selected from substituent group & defined above); and (xxiii) R25 is hydrogen, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and R28 together with the carbon atoms to which they are attached represent an isoxazolyl group.

ViTandrcws/Enhaflcc/GBP290238S doc 0BP290238/GB specificaiion/tsa(22. I I. 04 In each group of (xii) to (xiii), (xiv) to (xv), (xvi) to (xvii), (Xviii) to (xix) and (xxii) to (xxiii), compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof having substituents falling within the larger numbered group are more preferred.

The compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof which are given by an optional combination of R'8 and R'9 selected from (xii) to (xiii), R20, R2' and R24 selected from (xiv) to (xv), R'1 selected from (xvi), (xvii) and (xx), R22 selected from (xviii) to (xx), R and R29 selected from (xxi) and R25, R26, R27 and R28 selected from (xxii) to (xxiii) are also preferred.

Compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof having the following combinations are particularly preferred: (d) R'8 and R'9 = (xii), R20, R2' and R24 = (xiv), R7 = (xvi) and R22= (xviii), R and R29 = (xxi), and R25, R26, R27 and R28 = (xxii); (e) R and R19 = (xiii), R20, R2' and R24 = (xv), R'7 = (xvii) and R22 = (xix), R23 and R29 = (xxi), and R25, R26, R27 and R28 = (xxiii); (t) R'8 and R'9 = (xii), R20, R2' and R24 = (xiv), R'7 and R22 together= (xx), R23 and R29 = (xxi), and R25, R26, R27 and R28 = (xxii); and (g) R'8 and R'9 = (xiii), R20, R2' and R24 = (xv), R'7 and R22 together = (xx), R23 and R29 = (xxi), and R25, R26, R27 and R28 = (xxiii).

The most preferred compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof are trilostane, trilostane IT, trliostane Ill, keto-trilostane and pharmacologically acceptable salts and esters thereof: V:ITandrews/Enhance/00P290238s.doc GBP2902381GB spccification/tsaf22. II.04 N(5 Trilostanc Triloslorte 11 Keto-Trilostane Trilostane III Trilostane (2a-cyano-4a,5a-epoxyandroStafl- 1 7J3-ol-3-one) and derivatives thereof are synthetic steroid hormones having activity in lowering the blood concentrations of glucocorticoids such as cortisol. Trilostane is known as an oral medication for the treatment of Cushing's Syndrome and advanced breast cancer and is described in UK Patent Nos. 1,123,770, 2,130,588 and 2,345,851, US Patent No. 3,296,295 and WO-A02/080930, the contents of which are incorporated herein by reference thereto.

The topical formulations of the present invention comprise a pharmaceutically acceptable carrier or diluent and an effective amount of a steroid selected from the group consisting of ethisterone and derivatives thereof and trilostane and derivatives thereof.

These topical formulations can be in any suitable form known to the person skilled in this field and can, for example, take the form of an ethanol solution, cleansing foam, cleansing cream, skin gel, skin lotion, shampoo gel, cream shampoo or the like.

Topical formulations are prepared by adding an exemplified compound to a base well known to those skilled in the art; for example, suspending agents (examples include gum arabic, tragacanth, methyl cellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium alginate and bentonite), emulsifying agents V:/TandrcwsIEnhanccIOI3P29O23Ss,dOC GBP290238/OB spccificationltsal22. 11. 04 (examples include tnethanolamine, sodium lauryl sulfate, sorbitan sesquioleate, polysorbate 80 and stearic acid polyoxyl 40), moistening agents (examples include sorbitol, ethylene glycol, propylene glycol, butylene glycol and glycerin), preservatives (examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and butyl paraoxybenzoate) or solvents (examples include water; alcohols such as ethanol, isopropyl alcohol, propylene glycol, cetanol and isostearyl alcohol; hydrocarbons such as natural fats and oils, waxes and liquid paraffin; aliphatic acids such as stearic acid, isostearic acid, oleic acid and linoleic acid; and esters such as isopropyl myristate) or a mixture thereof.

The amount of the ethisterone or derivative thereof or trilostane or derivative thereof locally administered will vary depending on the condition, age or the like of the patient. It is desirably administered at a concentration of 0.01 mg/mI formulation (preferably 0.1 mg/mI formulation, most preferably 1 mg/mI formulation) as a lower limit and 100 mg/mI formulation (preferably 25 mg/mI formulation, most preferably 10 mg/mI formulation) as an upper limit and administered in a single dose or in several divided doses a day.

V:/Tandrcws/EnhaflCcIGBP29O285.dOC G5P290238/GB spcciiication/tsa/22. II. 04

The Best Mode for Carrying Out the Invention

Additional objects, advantages and novel features of the present invention will become apparent to those skilled in the art by consideration of the following non-limiting examples. Reference is made to accompanying Figures 1 to 6 in which: Figure 1 shows the fluorescence measured due to the presence of triglycerides inside adipocytes differentiated in the presence of danazol; Figure 2 shows the fluorescence measured due to the presence of triglycerides inside adipocytes differentiated in the presence of danazol and trilostane ifi; Figure 3 shows the concentration of glycerol measured after treatment of adipocytes treated with danazol and trilostane III; Figure 4 shows the fluorescence measured after treatment of HUVEC cells with danazo) and trilostane III as a measure of their ability to prevent endothelial cell invasion; Figure 5 shows the OD levels measured after incubation of HUVEC cells with trilostane Ill as a measure of its ability to prevent initial proliferation of endothelial cells; Figure 6 shows photograps of HUVEC cells taken after incubation with trilostane III as a measure of its ability to prevent tube formation of endothelial cells.

V:Trandrcws/Enhancc/0BP290238S.dOC GBP290238/613 spccificationltsa/22I 1. 04

Example I

Danazol Effect on Adipocyte Differentiation Purpose: To determine if danazol has an effect on the maturation of primary subcutaneous fibroblasts into adipocytes induced by insulin, glucocorticoids, and phosphodiesterase inhibitors (inactivation leads to elevated intracellular cAMP).

Materials: * Primary subcutaneous preadipocytes, Cambrex, Walkersville, IvID * Preadipocyte medium and Differentiation medium, Cambrex.

* AdipoRed Assay reagent, Cambrex.

* 96 well tissue culture plates, Corning, Corning, NY.

* Mifepristone, Sigma, St. Louis, MO * Recombinant Human TNFu, Pierce Biotechnologies, Rockford, IL.

* Phosphate buffered saline solution (PBS), Pierce Biotechnologies.

* Fluorescent Microplate reader * Danazol at varying concentrations in ethanol, Sigma, St. Louis, MO Protocol: 1. Preadipocytes were plated on 96 well tissue culture plates and incubated at 37 C and 5% CO2.

2. Once confluence was achieved, preadiopocyte medium was removed and replaced with differentiation medium containing danazol (0.1.tM - 50 i.tM) or controls (Preadipocytes medium, Nil wells, and TNFa or Mifepristone as positive controls).

3. Cells were then placed back in the incubator and maintained for 10 days in culture.

4. Wells were then washed two times with room temperature PBS and AdipoRed solution diluted 1:40 in PBS was added to determine lipid content in the cells.

V:(FandrcwslEnhance/0BP2902385.dDC 0BP2902381GB specilication/tsa#22. 11. 04 5. After 15 minute incubation at room temperature, fluorescence was obtained at 485 nm excitation and 530 nm emission.

The results obtained are as shown in Table 1 below and in graphic form in Figure 1.

Table I

OD OD pvalue vs Sample Mean OD std OD 1 2 OD 3 nil Undifferentiated -21. 24.04163 -4 -38 Nil 782.3333 81.59248 707 869 771 0.luMDanazol 709 133.5178 832 728 567 0.462481428 luMDanazol 795.6667 106. 3689 918 725 744 0.871591451 SuMDanazol 745 61.61169 811 735 689 0. 561438044 lOuMDanazol 279 61.04916 210 326 301 0.001024909 50uMDanazol -55 35.76311 -93 -50 -22 8.33123E-05 1 uM Mifepristone 87. 66667 8.504901 78 94 91 0.000125733 lOuM Mifepristone 35.66667 17.24336 51 39 17 0.000100928 0.5 ng/ml TNFa 473 73.36893 411 454 554 0.008144216 5ng/mlTNFa 55 13.52775 42 54 69 0.000108331

Results and Conclusion:

Adipocytes play a fundamental role as a fat depot and control homeostatic release of free long-chain fatty acids, Preadiopocytes obtained from subcutaneous fat can be differentiated into mature adipocytes. The hallmark of preadipocyte differentiation is the accumulation of lipid droplets that become detectable after about 4 days. AdipoRed is a solution of the stain Nile Red that will fluoresce when partitioned in a hydrophobic environment. AdipoRed was used to determine the triglyceridelevels inside adipocytes differentiated in the presence of danazol. The fluorescence detected by the microplate reader is directly proportional to the amount of lipid found inside the cells. In this V:fT'andrcws/Enhicincc/GBP29O28S.dDC G0P2902381013 spccificaiionflsa/22.1 I.04 experiment, maturing the adipocytes in the presence of 10 tM danazol or higher led to significant reduction in intracellular lipid. No lipid was detected in the wells dosed with i.tM danazol. Two known strong inhibitors of adipocyte differentiation, mifepristone arid TNFa, were run in concert with danazol as positive controls and for comparative purposes. The data suggests that danazol could prevent the formation of adipose tissue by inhibiting adipocyte maturation.

Example 2

Trilostane III and Danazol Effect on Adipocyte Differentiation Purpose: To determine if trilostane III and danazol can prevent the maturation of primary subcutaneous fibroblasts into adipocytes as induced by insulin, glucocorticoids, and phosphodiesterase inhibitors (inactivation leads to elevated intracellular cAMP).

Materials: * 50 mM danazol in ethanol, Sigma, St. Louis, MO * 50 mM trilostane Ill in ethanol, Bowman Research, Newport, South Wales, UK (prepared as, for example, described in GB 1,123,770) * Primary subcutaneous preadipocytes, Cambrex, Walkersvifle, MD * Preadipocyte medium and Differentiation medium, Cambrex.

* AdipoRed Assay reagent, Cambrex.

* 96 well tissue culture plates, Corning, Corning, NY.

* Mifepristone, Sigma * Recombinant Human TNFa, Pierce Biotechnologies, Rockford, IL.

* Phosphate buffered saline solution (PBS), Pierce Biotechnologies.

* Fluorescent Microplate reader Protocol: 1. Preadipocytes were plated on 96 well tissue culture plates and incubated at 37 C and 5% CO2.

V.fl'andrcwsIEnhancJG8P29O238S.dOC GBI'2902381G5 spccificationhlsa/22.I 1. 04 2. Once confluence was achieved, preadiopocyte medium was removed and replaced with differentiation medium containing danazol or trilostane III (5 1.tM - 25 tM) as well as control reactions of preadipocytes medium only, Ni] wells, and TNFc& or mifepnstone as positive.

5. After 15 minute incubation at room temperature, fluorescence was obtained at 485 nm excitation and 530 nm emission.

Results and Observations: The results obtained are as shown in Table 2 and depicted graphically in Figure 2.

V:/Tandrcws/EnhancCiGBP29O238Sd0C 013P290238/Gli spccificaton/tsa/22. I I. 04

Table 2

Adipored results for danazol and trilostane III

Plate Background blank

Mean blank 1 blank 2 436.11 407.02 465.2 P value Mean Adj Adj Sample FU Std FU FU 1 FU 2 FU 1 FU 2 vs Diff Undifferentiated 50.39 104.5104 -23.51 124.29 412.6 560.4 0. 016456 Differentiated 723.09 142.8356 622.09 824.09 1058.2 1260.2 Danazol 5 uM 663.89 24.32447 646.69 681.09 1082.8 1117.2 0.310886 Danazol 10 uM 611.59 17.67767 624.09 599.09 1060.2 1035.2 0.193786 Danazol 25 uM 268.79 12.86934 277.89 259.69 714 695.8 0.023 194 Trilostane 5 aM 460.19 7. 495332 465.49 454.89 901.6 891 0.008437 Trilostane 10 uM 390.39 10.6066 382.89 397.89 819 834 0.04075 Trilostane25uM 156.19 9.192388 162.69 149. 69 598.8 585.8 0,015213 Mifepristone 0.1 uM 641.49 41.86072 671.09 611.89 1107.2 1048 0.259637 Mifepristone 1 aM 245.09 35.35534 220.09 270.09 656. 2 706.2 0.02213 MifepristonelOuM 73.89 3.11127 71.69 76.09 507.8 512.2 0. 011685 TNF alpha 0.05 ng/ml 832.79 10.32376 825.49 840.09 1261.6 1276.2 0. 195946 TNFalpha0.5 nglml 731.39 10.6066 723.89 738.89 1160 1175 0.471074 TNF alpha 5 ng/ml 45.09 26.30437 63.69 26.49 499.8 462.6 0.011092

Results and Conclusion:

AdipoRed is a dye used to detect intracellular lipid levels in cells. When the dye enters the cell and gets compartmentalized in triglyceride containing vacuoles, it will ViFandrewsIEnhancciGI3P29O238s.doc GBP90238/OB speciIicalioWtsa/22.I 1.04 fluoresce. Dose-response curves of both trilostane Ill and danazol were incubated on preadipocytes while they were differentiated by insulin, dexamethasone, indomethacin, and isobutyl-methylxanthine. Both compounds showed an ability to reduce the amount of detectable lipid in a dose dependent fashion. Trilostane III was more effective exhibiting a 36%, 46%, and 78% decrease in Adipored fluorescence at 5 M, 10 j.tM, and l.LM doses respectively (compared to 8%, 15%, and 63% decreases observed in danazol treated wells). Both compounds show the ability to prevent adipocyte differentiation but tnlostane Ill appears to be more potent.

Example 3

Danazol and Trilostane III Induction of Lipolysis Purpose: To determine if danazol and trilostane Ill can induce the release of triglycerides, in the form of glycerol, from mature adipocytes in culture.

Materials: * Primary subcutaneous preadipocytes, Cambrex, Walkersville, MD * Preadipocyte medium and Differentiation medium, Cambrex.

* Lipolysis Assay Kit, Zen-Bio, Chapel Hill, NC * 96 well tissue culture plates, Coming, Corning, NY.

* Danazol, Sigma, St. Louis, MO * Trilostane III, Bowman Research, Newport, South Wales, UK (prepared as, for example, described in GB 1,123,770) * Microplate reader Protocol: 1. Preadipocytes were differentiated with insulin, dexamethasone, indomethacin, and isobutyl-methylxanthine for two weeks.

2. Medium was then removed and cells were washed with Zen-Bio wash solution.

V:IThndrcwS/EnhancCIGBP29D238S.dOC 013 P290238/GB spccificaLion/sa/22. 11. 04 3. 50 mM stocks of danazol and tnlostane in ethanol were diluted in supplied assay buffer to 25 iM and added to the cells.

4. Control reaction of ethanol and a known inducer of lipolysis, isoproternol, were included on the plate as well.

5. The solutions were then incubated on the cells for 24 hours at 37 C and 5%C02.

6. 100 j.tl of the assay buffer was then removed and added to 100 p1 ZenBio glycerol reagent and incubated at room temperature for 15 minutes.

7. OD was then determined at 530 nm in microplate reader The results obtained are as shown in Table 3 below and depicted graphically in Figure 3.

Table 3

Results and Observations: Lipolysis induction p value vs mean std glycerol glycerol glycerol ethanol control Sample glycerol glycerol [1] [2] [3] Undifferentiated cells 2.87815 2.519916 1.0963 4.66 0.223576 Ethanol control 4.861433 2.475045 7.6357 4.0688 2.8798 1 uMisoproterenol 12.39167 2.591251 10.608 15.364 11.203 0.010984 uM Danazol 5.257767 2.724287 4.6633 8.2302 2.8798 0.430563 uM Trilostane 8. 5274 1.949069 6.744 10.608 8.2302 0.057038

Discussion and Conclusion:

The release of stored lipid by adipocytes can be detected by the concentration of glycerol in the media after stimulation. 25 tM danazol and trilostane III did not induce V:rrandrcws!EflhLInCCiGRP29O23810c G8P290238/GB spccificatioWtsa/22.I I.04 adipocytes to release glycerol after 24 hours in culture. This data would indicate that the effect of danazol and trilostane on adipose tissue is not the result of a breakdown of stored lipids.

Example 4

Trilostane III and Danzol Effect on H'UVEC Angiogenesis: Invasion Chamber Purpose: To examine the effect of trilostane UI and clanazol on fetal calf serum induced endothelial cells invasion through matrigel treated inserts.

Materials: * Passage 5 Human umbilical vein endothelial cells 7016 (HUVEC), Cambrex * EGM-2 medium, Cambrex: supplemented to include 0.1% or 5% fetal calf serum * 10 mM LY294002 and LY30351 1 in DMSO, CalBiochem mM trilostane III in ethanol, Bowman Research, Newport, South Wales, UK (prepared as, for example, described in GB 1,123,770) * 50 mM danazol in ethanol, Sigma * 4 mM Calcein AM in DMSO, Sigma * Hepes buffered saline solution (HBSS), Cambrex * BD Biocoat Marigel Invasion Chamber, BD Biosciences * microplate fluorescence reader Protocol: in short 1. Trypsinized HUVEC cells from flasks grown in Cambrex EGM-2 media to 7080% confluence were washed two times with 37 C EGM-2 with 0.1% FCS.

2. Cell suspensions containing 30,000 cells and compounds in EGM-2 0.1% FCS were added to the upper chamber of inserts.

3. EGM-2 containing 5% FCS was added to the bottom chamber and then incubated for 24 hours at 37 C and 5% Co2.

V:TFandrews/Enhance/0BP29O238S doc GBP290238/613 spcciftcation/ta/22. 1104 4. Non-invading cells were removed from the upper chamber with cotton swab and the inserts were washed two times with 37 O C HBSS.

5. Inserts were then placed in wells containing 10.tM Calcein AM in HBSS.

6. Following four hours at 37 C and 5% CO2. fluorescence was measured at 485 nm excitation and 595 nm emission.

Results and Observations: Results presented as mean fluorescent units (FU) in triplicate (n=3) with background fluorescence subtracted. HUVEC 7016 cells were used for this experiment exhibiting 95% viability by trypan blue exclusion at time of seeding. To determine background invasion, nil inserts were included in triplicate that had EGM-2 with 0.1% FCS added to the bottom chamber. Without a chemotactic signal, these inserts will give a background invasion to compare the FCS and FCS plus compound wells. The results are as shown in Table 4 below and depicted graphically in Figure 4.

Table 4

Mean std SEM p values Sample FU FU FU vs 5% FCS Nil 9034 1688.2 974.687 0. 024186 5%FCS 12039.7 764.86 441.591 uM Danazol 8867.67 743.84 429.454 0.003373 25uMDanazol 10067 552.21 318.818 0.01116 uMTrilostane 9101.33 540.28 311. 928 0.002781 25uMTrilostane 11212.3 2748.7 1586.94 0.320938 SOuMLY 303511 12795.3 609. 45 351.867 0.125899 50uMLY294002 9454.33 1877.9 1084.18 0.045893

Discussion and Conclusion:

Treatment with 25 i.tM dariazol lead to a significant decrease in endothelial cell invasion into the lower chamber. At 50 iM danazol, the invasion was reduced to V'uTflndtcvsIEfll ncc/GBP29O238S.dOC 03P290238/GB spccificalion/tsaI22 11.04 background levels similar to wells without fetal calf serum added to initiate invasion.

Tnlostane III may have been less effective then danazol, but the high dose did drop the levels back to background. LY294002, a known inhibitor of invasion, was included as a control and exhibited similar inhibition as 50 ItM danazol and trilostane. LY303511 is an inactive variant of the LY294002 and had no effect on invasion as expected. After examining the data from this experiment and our previous invasion results, danazol and trilostane III may have an effect on endothelial cell invasion in certain individuals or at the appropriate time in the cell cycle.

Example 5

Trilostane Ill Effect on HUVEC Cell Proliferation Purpose: To determine the effect trilostane III has on HTJVEC cell proliferation.

Materials: * Passage 2 Human umbilical vein endothelial cells (HUVEC), Cambrex * EGM-2 medium supplemented to include 0.1% and 5% fetal calf serum, Cambrex * 50 mM trilostane UT in ethanol, Bowmai Research, Newport, South Wales, UK (prepared as, for example, described in GB 1,123,770) * Hepes buffered saline solution (HBSS), Cambrex * Celltiter 96 Aqueous One reagent, Promega * Falcon 96 well tissue culture plates * Microplate fluorescence reader Protocol: 1. 1-I1JVEC cells were plated in 96 well plates at 5,000 cells/cm2 and incubated for 24 hours at 37 C and 5% CO2 in EGM-2 media.

2. Medium was aspirated and the cells were then washed two time with 37 C HBSS.

V:(FandrewsIEnhflflCCIGBPZ9D23SS.dOC GBP290238/GB speciflcition/tsa/22. I 1.04 3. EGM-2 containing 5% FCS with and without the compound (0.01.tM j.tM trilostane ifi) was added to the wells and incubated for 24, 48, or 72 hours.

4. Cells were again washed to times with warm HBSS and then Celltiter reagent in EGM-2 with 0.1% FCS was added.

5. After 4 hours in culture the OD of each well was determine at 470 nm.

6. Repeat steps 4 and 5 for each time point.

Results and Observations: Results are presented as mean OD of samples performed in triplicate (n=3) with mean blank OD subtracted. HIJVEC 8750 cells were used for this experiment with 98% viability by trypan blue exclusion at time of seeding. Extra fetal calf serum (2% increased to 5%) was added to keep trilostane Ill in solution. The raw data are shown in Table 5 below and depicted graphically in Figure 5,

Table 5

Tn lostane Ill Sample 24 hour 48 hour 72 hour Nil 0.414 0.629333 1.1135 0.1 uM 0.387333 0.656 0.918667 1 uM 0.311 0.434667 0.387667 lOuM 0.246667 0.203 0.072 uM 0.278667 0. 214667 0.108 Trilostane III 24 hour results pvalue vs Sample OD 1 OD 2 OD 3 std Nil Nil 0.345 0.457 0.44 0.060357 0.1 uM 0.362 0.368 0.432 0.038799 0.277404 1 uM 0.284 0.328 0.321 0.023643 0.025631 lOuM 0.18 0.267 0.293 0.059181 0. 013283 V:ITandrcws/EnhanccJGI3P29O238S.dOC G8P290238/GB specigication/LSa/22.I I.04 uM 0.235 0.334 0.267 0.050521 0.020409 Trilostane m 48 hour results pvalue vs Sample OD 1 OD 2 OD 3 std Nil Nil 0.521 0.666 0.701 0.095438 0.1 uM 0.575 0.698 0.695 0.070164 0.358232 1 uM 0.358 0.489 0.457 0.068296 0.022665 lOuM 0.159 0.208 0.242 0.041725 0.001045 uM 0.17 0.23 0.244 0.039311 0.001121 Trilostane III 72 hour results pvalue vs Sample OD 1 OD 2 OD 3 std Nil Nil 1.075 1.152 0.054447 0.1 uM 0.733 0.962 1.061 0.168239 0.113558 1 uM 0.387 0.437 0.339 0.049003 0.000285 uM 0.03 1 0.095 0.09 0.035595 5. 8E-05 uM 0,092 0.119 0.113 0.014177 3.09E-05

Discussion and Conclusion:

Trilostane Ill proved effective at inhibiting endothelial cell proliferation.

Concentrations as low as 1 j.tM (at 24 hours), exhibited statistically relevant decreases in cell proliferation. Increasing the dose to 100 tM, inhibited cultures by 33, 67, and 90 % at 24, 48, and 72 hours respectively. The initial seeding of 1,500 cells per well is not detectable by the ceiltiter assay. Cells must expand to detectable levels so 100% inhibition can be expected and would not infer cell toxicity. Viable cells were visible in all wells examined under the inverted microscope, even at the highest doses after 72 V:IFandrews/EnhanceiGBl'2902385.dOC 013P290238/GB spcciflcMion/Isaf22. II. 04 hours in culture. These results indicate that trilostane UI may be an effective antiangiogenic compound, by interfering with the initial proliferation of endothelial cells.

Example 6

Trilostane III Effect on HUVEC Angiogenesis Tube formation Purpose: To examine the effect of trilostane III on the formation of tube-like structures by HUVEC cells in an extracellular matrix gel.

Materials: * Passage 3 Human umbilical vein endothelial cells (HUVEC), Cambrex * EGM-2 medium, Cambrex: supplemented to include 0.1% or 5% fetal calf serum * 10 mM LY294002 and LY30351 1 in DMSO, CalBiochem * 50 mM trilostane UI in ethanol, Bowman Research, Newport, South Wales, UK (prepared as, for example, described in GB 1,123,770) * BD Biocoat Angiogenesis system: tube formation assay, BD Biosciences * Microscope with camera Protocol: in short 1. Trypsinized HUVEC cells from flasks grown in Cambrex EGM-2 media to 70- 80% confluence were washed two times with 37 C EGM-2 with 0.1% FCS.

2. Cell suspensions containing 10,000 cells and compounds in both EGM-2 0.1% and 5% FCS were added per well then incubated for 18 hours at 37 C and 5% CO2.

3. Following incubation, tube formations were photographed under microscope.

Results and Observations: Passage 3 HIJVEC 8750 cells were used for this experiment at 98 % viability by trypan blue exclusion at time of seeding. Few cells were obtained for this experiment but V:ffandrcws/Enhancc/GBP20238S.dOC 013P290238/GB speciIication/tsaI22 11. 04 f did not seem to interfere with the development of tubes. Pictures of representative wells for the compound and controls are shown in Figure 6.

Discussion and Conclusion:

The final step of angiogenesis is the formation of new vascular structures.

HUVEC cells when grown in gels consisting of extracelluler matrix proteins, will exhibit a "latticework" of vacuoles that mimic the inner lumen of the capillary. Addition of fetal calf serum, or other angiogenic substances, will enhance the length and definition of these structures. Dosing with 50.tM trilostane III led to a decrease in branching, vacuole formation, and increase in satellite cells. 50 jiM LY294002, a P13 kinase inhibitor known to interfere with tube formation, completely inhibited the development seen in the nil wells while the inactive form exhibited comparable tube formations to untreated cells.

The inclusion of 5% fetal calf serum to the wells increased tube definition and vacuole formation. 50 p.M trilostane HI and 50 p.m LY294002 treatment greatly reduced tube formation in the presence of fetal calf serum. The untreated cells are far more susceptible to the effects of the control compounds and trilostane ifi. In conclusion, trilostane Ill appears to prohibit tube formation of HUVEC cells.

Viflindrcws/Rnhancc/GBP290238s.doc GB P290238/GB spcciflcaLionflsa/22. 11. 04

Claims

Claims 1. Use of a steroid selected from the group consisting of

ethisterone and derivatives thereof and trilostane and derivatives thereof in the manufacture of a topical medicament for the prevention or treatment of a dermatological condition that can be so prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis.
2. Use according to claim 1, wherein said steroid has one or more of the following activities: (a) the ability to reduce the maturation of preadipocytes into adipocytes; (b) the ability to modify the growth and interaction of blood vessels (angiogenesis); (c) the ability to modify the growth and interaction of fibroblasts; and (d) the ability to modify fibrosis.
3. Use according to claim 1 or claim 2, wherein said dermatological condition that can be prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis is selected from the group consisting of cellulite, naevi, telangiectasia, senile elastosis, keloids, ainhum, Peyronie's disease, sun exposure related dermatological conditions, dermatological treatment of the sinus and superficial benign neoplastic conditions.
4. Use according to claim 1 or claim 2, wherein said dermatological condition that can be prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis is selected from the group consisting of cellulite, port wine naevi, strawberry naevi, senile elastosis, solar elastosis, keratosis, solar chelitis, lipoma, angioma and dermatofibroma.
5. Use according to claim 1 or claim 2, wherein said dermatological condition that can be prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis is selected from the group consisting of cellulite, senile elastosis, solar elastosis and lipoma.
6. Use according to claim 1 or claim 2, wherein said dermatological condition that can be prevented or treated by modifying the growth and interaction of one or more of blood vessels, adipocytes and fibroblasts and/or by modifying fibrosis is cellulite.

V:(TandrewsIEnIurnccIGI3P29O238s.dOC GBP290238/GIl spcciflcotionltsa/22. 11.04
7. Use according to any one of claims 1 to 6, wherein said ethisterone or derivative thereof is a compound of' the following formula (I) or a pharmacologically acceptable salt or ester thereof: R2 R' (I) wherein: R1 is an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms or an alkyny) group having from 2 to 6 carbon atoms; R2 is hydroxyl, an alkoxy group having from 1 to 6 carbon atoms, an alkanoyloxy group having from 1 to 7 carbon atoms, a group of formula (II) or a group of formula (111): R11 (CH2)mN \R13 (H) (III) wherein R' is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, V:iTandrcws/anhanCcJGBP29O238S.dOC GBP290238/GB specilicationflsat22. II. 04 each of R'2 and R13 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, and m and n are the same or different and each is 0 or an integer of from 1 to 4; each of R3 and R4 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms; each of R5 and R6 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R5 and R6 together represent a single bond; each of R7, R8, R9 and R' is the same or different and is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R'5)2 wherein each group R'5 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or R7 and R8 and/or R9 and R' together with the carbon atom to which they are attached represent a carbonyl group, or R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5- to 9-membered heterocyclyl group, said 5- to 9-membered heterocyclyl group optiona'ly being substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group a defined below); substituent group a represents a group consisting of a halogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkylsulfinyl group having from 1 to 6 carbon atoms, an alkylsulfonyl group having from 1 to 6 carbon atoms, a phenyl group and a group of formula -N(R'6)2 wherein each group R" is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms.
8. Use according to claim 7, wherein said compound of formula (I) is a compound of formula (Ta) or a pharmacologically acceptable salt or ester thereof: VlTandrcwslEnhancc/0BP2902385.d0C GBP290238/GB spcciiicatlonltsa/22. I I.04 (Ia) wherein R', R2, R3, R4, R5, R6, R7, R8, i? and R are as defined in claim 7.
9. Use according to claim 7 or claim 8, wherein R' is an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms or an alkynyl group having from 2 to 4 carbon atoms.
10. Use according to claim 7 or claim 8, wherein R' is a methyl group or an ethynyl group.
11. Use according to any one of claims 7 to 10, wherein R2 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R" is an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (III) wherein m is 0, 1 or 2, and each of R'2 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
12. Use according to any one of claims 7 to 10, wherein R2 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, or a group of formula (III) wherein m is 0 or 1, and each of R12 and R'3 is the same or different and is hydrogen, a methyl group or an ethyl group.
13. Use according to any one of claims 7 to 10, wherein R2 is hydroxyl.

V:fl'ancirews/EnhanccIGDP29O238S.dOC GBP2902381GB spcdflcationltsa/22.I 1. 03
14. Use according to any one of claims 7 to 13, wherein R3 is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
15. Use according to any one of claims 7 to 13, wherein R3 is a methyl group.
16. Use according to any one of claims 7 to 15, wherein R4 is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
17. Use according to any one of claims 7 to 15, wherein R4 is a methyl group.
18. Use according to any one of claims 7 to 17, wherein each of R7 and R8 is a hydrogen atom and R9 and R' together with the carbon atom to which they are attached represent a carbonyl group, or R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group c' defined below), and substituent group & represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula -N(R'6)2 wherein each group RI6a is the same or different and is hydrogen or an alkyl group having from I to 4 carbon atoms.
19. Use according to any one of claims 7 to 17, wherein R7, R8, R9 and R' together with the carbon atoms to which they are attached represent an isoxazolyl group.
20. Use according to any one of claims 7 to 19, wherein each of R5 and R6 is a hydrogen atom or R5 and R6 together represent a single bond.
21. Use of a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof according to claim 8, wherein: R' is an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms or an alkynyl group having from 2 to 4 carbon atoms; R2 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R" is an alkyl group having from ito 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R14)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (III) wherein m is 0, 1 V/Tandrcws/EnbanCc/GBP290238S.dOC G8P29023810R spccification/tsaI22. II. 04 or 2, and each of R'2 and R13 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; R3 is hydrogen or an alkyl group having from 1 to 4 carbon atoms; R4 is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R5 and R is a hydrogen atom, or R5 and R6 together represent a single bond; and each of R7 and R8 is a hydrogen atom and R9 and R' together with the carbon atom to which they are attached represent a carbonyl group, or R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined below), and substituent group & represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula N(R'6')2 wherein each group R16a is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
22. Use of a compound of formula (Ta) or a pharmacologically acceptable salt or ester thereof according to claim 8, wherein: R' is a methyl group or an ethynyl group; R2 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methyl amino group or a dimethylamino group, or a group of formula (Ill) wherein m is 0 or 1, and each of R'2 and R'3 is the same or different and is hydrogen, a methyl group or an ethyl group; R3 is a methyl group; R4 is a methyl group; each of R5 and R6 is a hydrogen atom, or R5 and R6 together represent a single bond; and each of R7 and R8 is a hydrogen atom and R9 and R' together with the carbon atom to which they are attached represent a carbonyl group, or V(l'andrcws/EflhaflCCJGBP29O23SS doc 08P2902381013 spccificationhtsa/22.l 1.04 R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined below), and substituent group & represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula _.N(R16a)2 wherein each group R'6 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
23. Use of a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof according to claim 8, wherein: R' is a methyl group or an ethynyl group; R2 is hydroxyl; R3 is a methyl group; R4 is a methyl group; each of R5 and R6 is a hydrogen atom, or R5 and R6 together represent a single bond; and R7, R8, R' and R' together with the carbon atoms to which they are attached represent an isoxazolyl group.
24. Use according to claim 8, wherein said compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof is selected from ethisterone, danazol and stanozolol and pharmacologically acceptable salts and esters thereof:

H H

Ethisteronc Danazol V:ITandrews/EnhanCc/013P2902385.doc GBP290238/GB spccilication!tsa/22.1 1.04 HNjiiiIIIifIi5 Stanozolol
25. Use according to any one of claims 1 to 6, wherein said trilostane or derivative thereof is a compound of the following formula (IV) or a pharmacologically acceptable salt or ester thereof: R22 R17 (IV) wherein: R'8, R'9 and R2' are the same or different and each is hydrogen or an alkyl group having from 1 to 6 carbon atoms; R'7 is hydrogen, an alkyl group having from I to 6 carbon atoms or an alkertyl group having from 2 to 6 carbon atoms, R22 is hydroxyl, an alkoxy group having from 1 to 6 carbon atoms, an alkanoyloxy group having from 1 to 7 carbon atoms, a group of formula (II) as defined in claim 7 or a group of formula (III) as defined in claim 7, or V;/Tandrews/Enhance/GBP290238S.dOC 0BP290238/GB spccilicationhisa/22 I I 04 R'7 and E.22 together represent an oxo group, an ethylenedioxy group or a propylenedioxy group; each of R and R is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R2 and R24 together represent a single bond; each of R23 and R29 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R23 and R29 together represent an epoxy linkage; each of R25, R26, R27 and R28 is the same or different and is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a cyano group, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R30)2 wherein each group R3 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or R25 and R26 andIor R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R, R26, R21 and R28 together with the carbon atoms to which they are attached represent a 5- to 9- membered heterocyclyl group, said 5- to 9-membered heterocyclyl group optionally being substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group a as defined in claim 7).
26. Use according to claim 25, wherein said compound of formula (IV) is a compound of formula (IVa) or a pharmacologically acceptable salt or ester thereof: R22 17 (iVa) wherein R'7, R'8, R'9, R20, R21, R22, R23, R24, R25, R26, R27, R28 and R29 are as defined in claim 25.

VtTandrcwnhanccIGI3P29O238S.dOC 013P290238108 spcciflcaton/Lsa/22. 1104
27. Use according to claim 25 or claim 26, wherein each of R18 and R19 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
28. Use according to claim 25 or claim 26, wherein each of R'8 and R' is a methyl group.
29. Use according to any one of claims 25 to 28, wherein each of R20, R2' and R24 is the same or different and is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms or R2' is a hydrogen atom and R2 and R24 together represent a single bond.
30. Use according to any one of claims 25 to 28, wherein each of R20, R2' and R24 is a hydrogen atom or R2' is a hydrogen atom and R2 and R24 together represent a single bond.
31. Use according to any one of claims 25 to 30, wherein R'7 is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
32. Use according to any one of claims 25 to 30, wherein R'7 is hydrogen.
33. Use according to any one of claims 25 to 32, wherein R22 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a gwp of formula (II) wherein n is 0, 1 or 2, and R"is an alkyl group having from I to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R'4)2 wherein each group R14 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (III) wherein m is 0, 1 or 2, and each of R'2 and R13 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
34. Use according to any one of claims 25 to 32, wherein R22 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R" is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, or a group of formula (ifi) wherein m is 0 or 1, and each of R'2 and R'3 is the same or different and is hydrogen, a methyl group or an ethyl group.
35. Use according to any one of claims 25 to 32, wherein R'7 and R22 together represent an oxo group.
36. Use according to any one of claims 25 to 35, wherein each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage.

v.rrandrcws/Enhancc/GBP29O238s.dOC 0BP290238/GB spccification!tsa/22.1 04
37. Use according to any one of claims 25 to 36, wherein R is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R, R26, R27 and R28 together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituentS are the same or different and are selected from substituent group & defined in claim 18).
38. Use according to any one of claims 25 to 36, wherein R25 is hydrogen, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R, R26, R27 and R28 together with the carbon atoms to which they are attached represent an isoxazolyl group.
39. Use according to claim 26 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R'8 and R'9 is the same or different and is hydrogen or an alkyl group having from I to 4 carbon atoms; each of R20, R2' and R24 is the same or different and is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R2' is a hydrogen atom and R2 and R24 together represent a single bond; R'7 is a hydrogen atom or an alkyl group having from I to 4 carbon atoms; R22 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R" is an alkyl group having from ito 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula - N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (III) wherein m is 0, 1 or 2, and each of R'2 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; and V./Tandrcws/EflhIflCC/GDP29O23BS doc 013P290238/GB speciflcutionItsii22. 11.04 R is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and E.28 together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined in claim 18).
40. Use according to claim 26 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R'8 and R'9 is a methyl group; each of R20, R2' and R24 is a hydrogen atom, or R2' is a hydrogen atom and R2 and R24 together represent a single bond; R'7 is a hydrogen atom; R22 is hyclroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R'1 is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, or a group of formula (III) wherein m is 0 or 1, and each of R'2 and R'3 is the same or different and is hydrogen, a methyl group or an ethyl group; each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; and R25 is hydrogen, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and R28 together with the carbon atoms to which they are attached represent an isoxazolyl group.
41. Use according to claim 26 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R'8 and R'9 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R20, R2' and R24 is the same or different and is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R is a hydrogen atom and R2 and R together represent a single bond; V:lrandrcws/Enhance/G0P290238540C 0BP290238105 speci1icationits/22 II 04 R'7 and R22 together represent an oxo group; each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; and R25 is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R, R26, R27 and R26 together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituentS are the same or different and are selected from substituent group & defined in claim 18),
42. Use according to claim 26 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R'8 and R is a methyl group; each of R20, R2' and R24 is a hydrogen atom, or R2' is a hydrogen atom and R2 and R24 together represent a single bond; R'7 and R22 together represent an oxo group; each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; and R25 is hydrogen, R26 is a cyano group and R27 and R2B together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and R28 together with the carbon atoms to which they are attached represent an isoxazolyl group.
43. Use according to claim 26, wherein said compound of formula (IVa) or a pharmacologically acceptable salt or ester thereof is trilostane, trilostane II, trliostane Ill, keto-trilostane or a pharmacologically acceptable salt or ester thereof: Virandrcws/I5flhanccIOBP29O23SS.d0C G0P290238/GB spcciflcationflsa/22. Ii 04 N;c9t o H Trilostone Trilostane II o H Keto-Trilostanc Triloslanc III
44. A topical formulation comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a steroid selected from the group consisting of ethisterone and derivatives thereof and trilostane and derivatives thereof.
45. A topical formulation according claim 44, wherein said ethisterone or derivative thereof is a compound of the following formula (I) or a pharmacologically acceptable salt or ester thereof: R53 R5 (1) V:, Tandrcws/anhancc/GBP2902385dOC GI329O23B/GB spccitication/tsa/22.I.04 wherein: R' is an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms or an alkynyl group having from 2 to 6 carbon atoms; R2 is hydroxyl, an alkoxy group having from 1 to 6 carbon atoms, an alkanoyloxy group having from 1 to 7 carbon atoms, a group of formula (II) or a group of formula (HI): R12 / -(CH2) CH2)mN. "R13

(II) (III) wherein R" is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, each of R'2 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, and m and n are the same or different and each is 0 or an integer of from 1 to 4; each of R3 and R4 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms; each of R5 and R6 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R5 and R6 together represent a single bond; each of R7, R8, R9 and R' is the same or different and is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R'5)2 wherein each group R'5 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or R7 and R8 and/or R9 and R' together with the carbon atom to which they are attached represent a carbony] group, or Vfrandrcw5/EflhaflCCGBP29O23BL0C 013P290238/G13 spccilicaiion/tsa/22, I I.04 R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5- to 9-membered heterocyclyl group, said 5- to 9-membered heterocyclyl group optionally being substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group a defined below); substituent group a represents a group consisting of a halogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkylsulfinyl group having from 1 to 6 carbon atoms, an alkylsulfonyl group having from 1 to 6 carbon atoms, a phenyl group and a group of formula -N(R'6)2 wherein each group R'6 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms.
46. A topical formulation according to claim 45, wherein said compound of formula (I) is a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof: (Ia) wherein R', R2, R3, R4, R5, R6, R7, RS, R9 and R1 are as defined in claim 45.
47. A topical formulation according to claim 45 or claim 46, wherein R' is an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms or an alkynyl group having from 2 to 4 carbon atoms.
48. A topical formulation according to claim 45 or claim 46, wherein R' is a methyl group or an ethynyl group.
49. A topical formulation according to any one of claims 45 to 48, wherein R2 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R is an alkyl group having from 1 to 4 carbon atoms, a V:Fandrc%vsEnIlaflcC/0BP290238Sd0C GBP290238/GB specificotonhtsa/22. II. 04 hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (III) wherein m is 0, 1 or 2, and each of R'2 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
50. A topical formulation according to any one of claims 45 to 48, wherein R2 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (Ii) wherein n is 0 and R" is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, or a group of formula (Ill) wherein m is 0 or 1, and each of R'2 and R'3 is the same or different and is hydrogen, a methyl group or an ethyl group.
51. A topical formulation according to any one of claims 45 to 48, wherein

R2 is hydroxyl.
52. A topical formulation according to any one of claims 45 to 51, wherein R3 is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
53. A topical formulation according to any one of claims 45 to 51, wherein R3 is a methyl group.
54. A topical formulation according to any one of claims 45 to 53, wherein R4 is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
55. A topical formulation according to any one of claims 45 to 53, wherein R4 is a methyl group.
56. A topical formulation according to any one of claims 45 to 55, wherein each of R7 and R8 is a hydrogen atom and R9 and R' together with the carbon atom to which they are attached represent a carbonyl group, or R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7- membered heterocyclyl group optionally being substituted with from I to 3 substituents (said substituents are the same or different and are selected from substituent group & defined below), and substituent group & represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula _N(R16a)2 V:/TandrcwsiEflhaflcc/G0P290238Sd0C 08P290238/GB spcificadoWtsa/22. II.04 wherein each group R'6' is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
57. A topical formulation according to any one of claims 45 to 55, wherein R7, R8, R9 and R' together with the carbon atoms to which they are attached represent an isoxazolyl group.
58. A topical formulation according to any one of claims 45 to 57, wherein each of R5 and R6 is a hydrogen atom or R5 and R6 together represent a single bond.
59. A topical formulation of a compound of formula (Ta) or a pharmacologically acceptable salt or ester thereof according to claim 46, wherein: R' is an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms or an alkynyl group having from 2 to 4 carbon atoms; R2 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R" is an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy having from 1 to 4 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (ifi) wherein m is 0, 1 or 2, and each of R'2 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; R3 is hydrogen or an alkyl group having from 1 to 4 carbon atoms; R4 is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R5 and R6 is a hydrogen atom, or R5 and R6 together represent a single bond; and each of R7 and R8 is a hydrogen atom and R9 and R' together with the carbon atom to which they are attached represent a carbonyl group, or R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyc]yl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined below), and substituent group ct' represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula _N(R16a)2 V frandrcws/EflhaflCc/6BP290238Sd0C 0BP290238/GB spcciiication/tsa/22.I 1.04 wherein each group Rboa is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
60. A topical formulation of a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof according to claim 46, wherein: R' is a methyl group or an ethynyl group; R2 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R" is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, or a group of formula (III) wherein m is 0 or 1, and each of R'2 and R'3 is the same or different and is hydrogen, a methyl group or an ethyl group; R3 is a methyl group; R4 is a methyl group; each of R5 and R6 is a hydrogen atom, or R5 and R6 together represent a single bond; and each of R7 and R8 is a hydrogen atom and R9 and R' together with the carbon atom to which they are attached represent a carbonyl group, or R7, R8, R9 and R' together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocycl yl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined below), and substituent group & represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula _N(R16a)2 wherein each group R'6' is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
61. A topical formulation of a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof according to claim 46, wherein: R' is a methyl group or an ethynyl group; R2 is hydroxyl; R3 is a methyl group; R4 is a methyl group; vilandrc%vs/Enhancc/0BP29O238S doi 08 P2902381GB spccificationhtsa/22.1 1.04 each of R5 and R6 is a hydrogen atom, or R5 and R6 together represent a single bond; and R', R8, R9 and R' together with the carbon atoms to which they are attached represent an isoxazolyl group.
62. A topical formulation according to claim 46, wherein said compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof is selected from ethisterone, danazol and stanozolol and pharmacologically acceptable salts and esters thereof:

HO HO H NG9

Ethisteronc Danazol Stanozolol
63. A topical formulation according to claim 44, wherein said trilostane or derivative thereof is a compound of the following formula (IV) or a pharmacologically acceptable salt or ester thereof: V. /Tandrcws/EnhanCCJGBP29O23SS.dOC 0BP290238/GB spccificationhtsa/22.1 1.04 A22 H17 R24 (IV) wherein: R'8, R'9 and R2' are the same or different and each is hydrogen or an alkyl group having from 1 to 6 carbon atoms; R" is hydrogen, an alkyl group having from 1 to 6 carbon atoms or an alkenyl group having from 2 to 6 carbon atoms, R22 is hydroxyl, an alkoxy group having from 1 to 6 carbon atoms, an alkanoyloxy group having from 1 to 7 carbon atoms, a group of formula (II) as defined in claim 45 or a group of formula (Ill) as defined in claim 45, or R17 and R22 together represent an oxo group, an ethylenedioxy group or a propylenedioxy group; each of R2 and R24 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R and R24 together represent a single bond; each of R23 and R29 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R23 and R29 together represent an epoxy linkage; each of R, R26, R27 and R28 is the same or different and is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a cyano group, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R30)2 wherein each group R3 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or R and R26 and/or R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or Vfrundrcws/Enhancc)GBP2902385.d0C 013P290238/GS spccificationltsnl22. II. 04 R25, R2, R27 and R28 together with the carbon atoms to which they are attached represent a 5- to 9-membered heterocyclyl group, said 5- to 9- membered heterocyclyl group optionally being substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group cc as defined in claim 45).
64. A topical formulation according to claim 63, wherein said compound of formula (IV) is a compound of formula (IVa) or a pharmacologically acceptable salt or ester thereof: A22 17 :::25.23R1 (IVa) wherein R'7, R'8, R9, R20, R21, R22, R23, R24, R25, R26, R27, R28 and R29 are as defined in claim 63.
65. A topical formulation according to claim 63 or claim 64, wherein each of R'8 and R'9 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
66. A topical formulation according to claim 63 or claim 64, wherein each of R'8 and R'9 is a methyl group.
67. A topical formulation according to any one of claims 63 to 66, wherein each of R20, R2' and R24 is the same or different and is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms or R2' is a hydrogen atom and R2 and R24 together represent a single bond.
68. A topical formulation according to any one of claims 63 to 66, wherein each of R20, R2' and R24 is a hydrogen atom or R2' is a hydrogen atom and R2 and R24 together represent a single bond.

ViTandrcws/Enhancc/GBP290738S,d0C G8P290238/GB spcciflcation/tti/22.I I. 04
69. A topical formulation according to any one of claims 63 to 68, wherein R17 is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
70. A topical formulation according to any one of claims 63 to 68, wherein R'7 is hydrogen.
71. A topical formulation according to any one of claims 63 to 70, wherein R22 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (11) wherein n is 0, 1 or 2, and R" is an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from I to 4 carbon atoms or a group of formula (Ill) wherein m is 0, 1 or 2, and each of R'2 and R'3 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.
72. A topical formulation according to any one of claims 63 to 70, wherein R22 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R1' is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, or a group of formula (Ill) wherein m is 0 or 1, and each of R12 and R13 is the same or different and is hydrogen, a methyl group or an ethyl group.
73. A topical formulation according to any one of claims 63 to 70, wherein R'7 and R22 together represent an oxo group.
74. A topical formulation according to any one of claims 63 to 73, wherein each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage.
75. A topical formulation according to any one of claims 63 to 74, wherein Ri" is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R2 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R, R26, R27 and R28 together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined in claim 60).

V:(rnndrcwS/EnhaflCC/GL3P2DO23S0c 0BP290238/G13 spccificationhlsa/22. I. 04
76. A topical formulation according to any one of claims 63 to 74, wherein R is hydrogen, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R, R26, R27 and R28 together with the carbon atoms to which they are attached represent an isoxazolyl group.
77. A topical formulation according to claim 64 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R'8 and R'9 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R20, R21 and R24 is the same or different and is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R2' is a hydrogen atom and R2 and R24 together represent a single bond; R'7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; R22 is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R1' is an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R'4)2 wherein each group R'4 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms or a group of formula (Iii) wherein m is 0, 1 or 2, and each of R'2 and R3 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; and R25 is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and R28 together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined in claim 60).
78. A topical formulation according to claim 64 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: V:rrandrcwsEflhaflCdGBP29O23SS0c 013P290238/OB spccilication/tsal22. 11. 04 each of R'8 and R'9 is a methyl group; each of R20, R2' and R24 is a hydrogen atom, or R2 is a hydrogen atom and R2 and R24 together represent a single bond; R17 is a hydrogen atom; R22 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R'1 is a methyl group, an ethyl group, a hydroxyl group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylaminO group, or a group of formula (111) wherein m isO or 1, and each of R'2 and R13 is the same or different and is hydrogen, a methyl group or an ethyl group; each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; and R25 is hydrogen, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and R28 together with the carbon atoms to which they are attached represent an isoxazolyl group.
79. A topical formulation according to claim 64 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R'8 and R'9 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R20, R2' and R24 is the same or different and is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R2' is a hydrogen atom and R2 and R24 together represent a single bond; R'7 and R22 together represent an oxo group; each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; and R25 is hydrogen or an alky) group having from 1 to 4 carbon atoms, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R, R26, R27 and R28 together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered heterocyclyl V.flandrcwsEnhtrnCCGBP29O23B5d0c GBP290238/GB spcciflcation/(si/22.l I.04 group optionally being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group & defined in claim 60).
80. A topical formulation according to claim 64 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R'8 and R'9 is a methyl group; each of R20, R2' and R24 is a hydrogen atom, or R21 is a hydrogen atom and R2 and R24 together represent a single bond; R'7 and R22 together represent an oxo group; each of R23 and R29 represents a hydrogen atom or R23 and R29 together represent an epoxy linkage; and R25 is hydrogen, R26 is a cyano group and R27 and R28 together with the carbon atom to which they are attached represent a carbonyl group, or R25, R26, R27 and R28 together with the carbon atoms to which they are attached represent an isoxazolyl group.
81. A topical formulation according to claim 64, wherein said compound of formula (IVa) or a pharmacologically acceptable salt or ester thereof is trilostane, trilostane II, trliostane III, keto-trilostane or a pharmacologically acceptable salt or ester thereof: Tnlostanc TnIosWflc II Kern-Triloslafle Trilostanc UI Vi1'andrc%vS/EnhaflCCfGBP29O23BS doc 08P29023810B specification./tsa/22.I 1.04