WO2006054119A1

WO2006054119A1 - Topical formulations for use in the treatment or prevention of dermatological conditions

Info

Publication number: WO2006054119A1
Application number: PCT/GB2005/050209
Authority: WO
Inventors: Gerald Curtis; David Bar-Or; George Margetts
Original assignee: Stegram Pharmaceuticals Ltd
Priority date: 2004-11-22
Filing date: 2005-11-22
Publication date: 2006-05-26
Also published as: GB2420281A; 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 said steroids in the manufacture of a topical medicament for the prevention or treatment of a dermato logical 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.

Description

Topical Formulations for Use in the Treatment or Prevention of Dermatological

Conditions

Field of the Invention The present invention relates to topical formulations for use in the treatment or prevention of dermatological conditions 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, particularly cellulite and fibrocystic breast condition. 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 celis (adipocytes) and the amount of fat inside the 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 states.

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, ϊn addition, there are many other derrnatological conditions which can also 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 (e.g. fibrocystic breast condition, 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 fibroblasts 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 trilostane 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

(d) the ability to modify fibrosis. The fact thai the formulations of the present invention have these activities makes them uniquely suited to the prevention or treatment of 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. It is aiso 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, fibrocystic breast condition (also known as breast fibrosis or fibrocystic breast disease), naevi (e.g. port wine naevi and strawberry naevi), telangiectasia, senile elastosis, keloids, ainhurn, Peyronie's disease, sun exposure related dermatological conditions (e.g. solar elastosis, keratosis and solar chelitis), dermatological treatment of the sinus, superficial benign neoplastic conditions (e.g. lipoma, angioma and dermatofibroma) and dermatological conditions that have an immunological component [e.g. endometriosis (deficient cell mediated immunity has been observed in women with this condition), idiopathic thrombocytopaenic purpura (ITP) and systemic lupus erythematosus (SLE)]. Preferred dermatological conditions which can be prevented or treated according to the present invention include cellulite, fibrocystic breast condition, 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 celluHte, fibrocystic breast condition, senile elastosis, solar elastosis and lipoma. The most preferred dermatological conditions which can be prevented or treated according to the present invention are cellulite and fibrocystic breast condition.

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 triiostane and derivatives thereof. Preferred examples of ethisterone and derivatives thereof include compounds of the following formula (I) and pharmacologically acceptable salts and esters thereof:

(3)

wherein:

R¹ is an alky] 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 hydroxy!, an alkoxy group having from 1 to 6 carbon atoms, an alkanoyloxy group having from 1 to 7 carbon atoms, a group of formula (11) or a group of formula (111):

(II) (III)

wherein R¹¹ is hydrogen, an alky] group having from 1 to 6 carbon atoms, a hydroxy! group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R^M)₂ wherein each group R^M is the same or different and is hydrogen or an alky! group having from 1 to 6 carbon atoms, each of R¹² 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 alky! group having from 1 to 6 carbon atoms; each of R³ and R⁶ is the same or different and is hydrogen or an alky! group having from 1 to 6 carbon atoms or R³ and R⁶ together represent a single bond; each of R⁷, R⁸, R⁹ and R¹⁰ 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(R¹^)₂ wherein each group R^b 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 R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or

R⁷, R⁸, R⁹ and R¹⁰ 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 α defined below); substituent group α 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 aikoxy 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(R¹⁶)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 triloslane and derivatives thereof include compounds of the following formula (IV) and pharmacologically acceptable salts and esters thereof:

(IV)

wherein:

R^{1 S}, R¹⁹ and R²¹ 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,

R" is hydroxy], 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 above for formula (I) or a group of formula (111) as defined above for formula (1), or

R¹⁷ and R²² together represent an oxo group, an ethylenedioxy group or a propyienedioxy group; each of R²⁰ and R²⁴ is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R²⁰ 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 R , 2"3 and R 2"9 . together represent an epoxy linkage; each of R^2s, 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 3 to 6 carbon atoms or a group of formula -N(R³⁰J₂ wherein each group R³⁰ is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or R R²²⁵⁵ a anndd I R²⁶ and/or R²⁷ and R^2S 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 heterocycly! group, said 5- to 9-membered heterocyclyl group optionally being substituted with from 1 to 7 substituents (said sυbstituents are the same or different and are selected from substituent group α defined above).

Where R⁷, R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached represent an optionally subsitituted 5- to 9-membered heterocyclyl group or R^2D, R²⁶, R²⁷ and R²⁸ together with the carbon atoms to which they are attached represent an optionally substituted 5- to 9-membered heterocyclyl group, said heterocyclyl group is a 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 thienyi 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 pyrroϋdinyl group, a pyrroliny! group, a imidazolidinyl group, a tmidazoliny] group, a pyrazolidinyl group, a pyrazolinyl group, a piperidyl 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 pyridazinyl 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 pyrroliny] group, a imidazolidinyl group, a imidazolinyi 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 R⁷. R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached and an isoxazolyl group for R²³, R²⁶, R²⁷ and R²⁸ together with the carbon atoms to which they are attached. The alky! group having from 1 to 6 carbon atoms in the definitions of R¹, R³, R⁴,

R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^M, R¹⁵, R¹⁶, R^!7, R¹⁸, R¹⁹, R²⁰, R²¹, R³³, R²\ R²⁵, R²⁶, R²⁷, R^2S, R²⁹, R³⁰ and substituent group α 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 isobuty! group, an s-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a neopenty! group, a t-pentyl group, a 1-methylbutyl group, a hexyl group, a 1-methylpentyl group, a 2-methylpenty] group, a 3-methy!pentyl group, a 1-ethySbutyl group or a 2-ethyIbutyl group; preferabiy it is an alkyl group having from 1 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 R¹ and R¹⁷ is a straight or branched chain alkenyl group having from 2 to 6 carbon atoms and may be, for example, vinyl, 2-propenyl, l-methyl-2-propenyI, 2-me£hyl-2-propenyl, 2-ethyl-2- propenyl. 2-butenyl, 1 -methyl -2-butenyI, 2-methyl-2-butenyI, l-ethyl-2-butenyl, 3- butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, l-ethyl-3-butenyl, 2-pentenyl, 1- methyl-2-pentenyl, 2-methyl-2-pentenyI, 3-pentenyl, l-melhyI-3-pentenyl, 2-methyl-3- pentenyl, 4-pentenyl, l-methyl-4-penlenyl, 2-methyl-4-pentenyl, 2-hexeπyl, 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 allcyny] group having from 2 to 6 carbon atoms in the definition of R¹ and R¹⁷ is a straight or branched chain alkynyl group having from 2 to 6 carbon atoms and may be, for example, ethynyl, 2-propynyl, l-methyl-2-propynyl, 2-butynyl, l-methyl-2-butynyl, 1 -ethyl -2-butynyl, 3-butynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, l-ethyl-3-butyπyl, 2-pentynyl, l-methyl-2-pentynyl, 3-pentynyl, l-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, l-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 1 to 7 carbon atoms in the definitions of R^" and R^"" 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 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, R⁷, R⁸, R⁹, R¹⁰, R^{1 1}, R" and substituent group α 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 π-hexyloxy group, a 4-methylpentyloxy group, a 3- methylpentyloxy group, a 2-methylpentyloxy group, a 3,3-dimethylbutoxy group, a 2,2- dimethylbutoxy 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 α 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 melhylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, an s-butylthio group, a tert-butylthio group, an n-penlylthio 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-meth yip enty ItMo group, a 1-methylpentylthio group, a 3,3-dimethylbutykhio group, a 2,2-dimethylbutylthio group, a 1,1- I I

dimethyibutylthio group, a 1,2-dimethylbutyIthio group, a 1,3-dimethylbutylthio group, a 2,3-dimethylbutyllhio group or a 2-ethylbutylthio group; it is preferably an afkylthio 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 α is a sulfϊny! group (-SO-) which is substituted with an alky! group having from 1 to 6 carbon atoms as described above and may be, for example, a methanesulfiny! group, an ethanesulfinyl group, an n-propanesulfmyl group, an isopropanesulfjnyl group, an n- butanesulfinyl group, an isobutanesulfinyl group, an s-butanesulfϊnyl group, a tert- butanesulfinyl group, an n-pentanesulfinyl group, an isopentanesulfinyl group, a 2- methylbutanesulfinyl group, a neopentanesulfinyl group, an n-hexanesulfjny! group, a A- methylpentanesulfiny! group, a 3-methylpentanesulfinyl group, a 2- methylpentanesulfinyl group, a 3,3-dimethylbutanesulfinyl group, a 2,2- dimethylbutanesulfmyl group, a I,l-dimethylbutanesulfinyl group, a 1 ,2- dimethylbutanesulfinyl group, a 1 ,3-dimethylbutanesuifinyl 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 n- propanesulfiπy! group, an isopropanesulfinyl group or an n-butanesulfinyl group; and more preferably it is a methanesulfinyl group. The aikylsulfonyl group having from 1 to 6 carbon atoms in the definition of substituent group α 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 n-propanesulfonyl group, an isopropanesulfonyl group, an n- butanesulfoπyl group, an isobutanesulfonyl group, an s-butanesulfonyl group, a tert- butanesulfoπyl group, an n-pentanesulfonyl group, an isopentanesulfonyl group, a 2- methylbutanesulfonyl group, a neopentanesulfonyl group, an n-hexanesulfonyl group, a 4-methylpentanesulfony] group, a 3-methylpentanesulfonyl group, a 2- methylpentanesulfonyl group, a 3,3-dimethylbutanesulfonyl group, a 2,2- dimethylbutanesulfonyl group, a 1 ,1-dimethylbutanesuIfonyl group, a 1,2- dimethylbutanesulfonyl group, a 1,3-dimethyibutanesulfonyl group or a 2,3- dimethylbutanesulfonyl group; preferably it is an aikylsulfonyl group having from 1 to 4 carbon atoms such as a methanesulfonyl group, an ethanesulfoπyl group, an n- propanesulfonyl group or an n-butanesulfonyl group; and more preferably it is a methanesulfonyl group.

Where the compound of formula (1) 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 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. rnethanesulfonates, trifluoromethanesulfonates and ethanesulfonates), arylsulfonates in which the aryl rnoiety thereof is an aryl group having from 6 to 14 carbon atoms (e.g. benzenesulfonate or p-toluenesulfonate), acetates, rnalates, fumarates, succinates, citrates, ascorbates. tartrates, oxalates and maleates; and amino acid salts such as glycine salts, lysine saits, arginine salts, ornithine 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. t- octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycinealkyl ester salts, ethyienediamine salts, N-methy]glucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'- dibenzylethylenediamine salts, chloroprocaine 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 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 hydroxy! 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 pharmacologically acceptable ester.

The compounds of formula (3) 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 hydroxy! group present therein is esterifted. The ester residue must be capable of being 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) l-(acyloxy)lower alkyl groups, examples of which include l-(aliphatic acy!oxy)lower alkyl 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, propionyloxymethyl, bulyryloxymethyi, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, I-foiτnyloxyethyl, 1- acetoxyethyl, 1-propionyloxyethyl, l-butyry!oxyethyl, l -pivaloyloxyethyl, 1- valerybxyethyl, 1 -isovaleryloxyethyl, 1 -hexanoyloxyethyl, 1-formyloxypropyl, 1- acetoxypropyl, 1 -propionyloxypropyl, l-butyry!oxypropyl, 1-pivaloyloxypropyl, 1- valeryioxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxy-propyl, 1-acetoxybutyl, 1- propionySoxybuty], 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1- propionyloxypentyl, 1-bιιtyryloxypentyl, 1-pivaloyloxypentyl and l-pivaloyloxyhexyl groups, l-(cycloalkylcarbonyloxy)lower 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 cyciopentyScarbonyloxymethy], cyclohexylcarbonyloxy-methyl, 1 - cyclopentylcarbonyloxyethyl, 1 -cyclohexylcarbonyloxyethyl,

1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentyl- carbonyloxybuty] and l-cyclohexylcarbonyloxybuty! 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;

(ϋ) 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 carbon atoms which is substituted with a lower alkoxycarbonyloxy group which comprises a carbonyloxy group substituted with an alkoxy group having from 1 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, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxy- methyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy(cyclohexyl)- methyl, l-(methoxycarbonyloxy)ethyl, l-(ethoxycarbonyloxy)ethyl, l-(propoxy- carbonyloxy)ethyl, 1 -(isopropoxycarbonyloxy)ethyl, 1 -(butoxycarbonyloxy)ethyl, 1 -(isobutoxycarbonyloxy)ethyl, 1 -(t-butoxycarbonyloxy)ethyl, 1 -(pentyloxy- carbonyloxy)ethyl, 1 -(hexyloxycarboπyloxy)ethyl, 1 -(cyclopentyloxycarbonyloxy)-ethyl, l-(cyclopentyloxycarbonyloxy)propyl, 1 -(cyclohexyloxycarbonyloxy)propyl, 1 -(cyclopenty ioxycarbonyloxy)bulyl, 1 -(cyclohexyloxycarbonyloxy)butyl, l-(cyclohexyloxycarbonyloxy)ethyl, l-(ethoxycarbonyloxy)propyl, l-(methoxy- carbonyloxy)propyl, l-(ethoxycarbonyloxy)propyl, l-(propoxycarbonyloxy)propyi, 1 -(isopropoxycarbonyloxy)propyl, 1 -(butoxycarbonyloxy)propyl, 1 -(isobutoxy- carbonyloxy)propyl, l-(pentyloxycarbonyloxy)propyl, l-(hexyfoxycarbonyloxy)-propyl, 1 -(methoxycarbonyloxy)butyl, 1 -(ethoxycarbonyloxy)butyl, 1 -(propoxy- carbony!oxy)butyl, 1 -(isopropoxycarbonyloxy)buty 1, I -(butoxycarbonyloxy)butyl, 1 -(isobutoxycarbonyloxy)butyl, 1 -(methoxycarbonyloxy)pentyl, 1 -(ethoxy- carbonyloxy)ρentyl, l-(methoxycarboπyloxy)hexyl and l-(ethoxycarbonyloxy)hexyl groups, and oxodioxolenylmethyl groups, which comprise a methyl group which is substituted with an oxodioxoleπyl group which itself may optionally be substituted with a group selected from the group consisting of alky! 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-phenyI-2~oxo~l ,3-dioxolen-4- yl)methyl, [5-(4-methylphenyl)-2-oxo-l,3-dioxolen-4~yl]methyi, [5-(4~methoxyphenyl)- 2-oxo-l ,3-dioxolen-4-yI]methyl, [5-(4-fϊuoropheny!)-2-oxo-l ,3-dioxolen-4-yl]methyl, [5- (4-chlorophenyl)-2-oxo~I,3-dioxolen-4-yl]rnethyl, (2-oxo-l,3-dioxolen-4-y!)-methyϊ, (5- methyl~2-oxo~l,3-dioxoleπ-4-yl)methyl, (5-ethyl-2-oxo-l,3-dioxolen-4-yl)methyl, (5- propyl-2-oxo-l ,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-l ,3-dioxolen-4-yl)methyl and (5-butyl-2-oxo-l ,3~dioxoIen-4-yl)methyl 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, dimethylphlhalidyl and dimethoxyphthalidyl groups; (ϊv) aliphatic acyl groups, examples of which include alkylcarbonyl groups having from 1 to 25 carbon atoms, examples of which include formyl, acetyl, propionyl, butyryi, isobutyryl. pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methy!nonanoyl, 8-methylnonanoyl,

3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methyl- pentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl and heneicosanoyl groups, ester forming residues of a saturated or unsaturated C₂-Ci₀ 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 alky! moiety thereof is substituted by at least one halogen atom, examples of which include chioroacetyl, dichloroacetyl, trichloroacety! and trifiuoroacetyl groups, lower aikoxyallcylcarbonyl groups which comprise an alkylcarbonyl group having from 1 to 25 carbon atoms in which the alky] moiety thereof is substituted with at least one C]-C₆ aikoxy 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, crotonoy!, isocrotonoyl and (E)-2- methy!-2-butenoyl groups; of these, alkylcarbonyl groups having from 1 to 6 carbon atoms are preferred; (v) aromatic acyl groups, examples of which include 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 benzoyl, α-naphthoy! and β-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, 4-chlorobenzoyl and 2,4,6-trifluorobenzoyl 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 2₅4,6-trimethy]-benzoyl and 4-toiuoyI groups, lower alkoxylated arylcarbonyl groups which comprise an arylcarbonyl group as defined above which is substituted with at least one aikoxy 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 4- nitrobenzoyl 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 aikoxy group having from 1 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 ary! group having from 6 to 14 carbon atoms as defined above, examples of which include 4-pheny!benzoyl groups; (vi) half-ester salt residues of succinic acid; (vii) phosphate ester salt residues ;

(viϋ) 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) l-(acyloxy)alkoxycarbony! 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 which include pivaloyloxymethyloxycarbonyl 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 (ϊ) 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 (Ia) and pharmacologically acceptable salts and esters thereof:

(Ia) wherein R\ R², R³, R⁴, R^S, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined and exemplified above.

Of these compounds of formula (Ia) and pharmacologically acceptable salts and esters thereof, preferred are those wherein: (i) R¹ 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; (ϋ) R¹ 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^{1 !} is an alkyl group having from 1 to 4 carbon atoms, a hydroxy! group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R^M)₂ wherein each group R¹⁴ is the same or different and is hydrogen or an alkyl group having from I to 4 carbon atoms or a group of formula (III) wherein m is 0, 1 or 2, and each of R¹² and R¹³ is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms;

(iv) R² is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R^{1 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 R¹² and R¹³ 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 R⁷ and R⁸ is a hydrogen atom and R and R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or

R⁷, R⁸, R⁹ and R^t0 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 optionaily being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group α¹ defined below), and substituent group α¹ 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 I to 4 carbon atoms, a phenyl group and a group of formula -N(R¹⁶³J₂ wherein each group R^16a is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (xi) R⁷, R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached represent an isoxazoly! 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), (in) 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), R^" selected from (iii) to (v), R³ selected from (vi) to (vii), R⁴ selected from (viii) to (ix), R⁷,

R⁸, R⁹ and R¹⁰ selected from (x) to (xi) and R³ and R⁶ selected from (xia) are also preferred. Compounds of formula (3a) and pharmacologically acceptable salts and esters thereof having the following combinations are particularly preferred: (a) R¹ = (i), R² - (iii), R³ = (vi), R⁴ = (viii), R⁵ and R⁶ = (xia), R⁷, R⁸, R⁹ and R¹⁰ - (x);

(b) R¹ - (ϋ), R² - (iv), R³ = (vii), R⁴ = (ix), R⁵ and R⁶ = (xia), R⁷, R⁸, R⁹ and R^!0 = (x); and

(c) R¹ = (ii), R² - (V), R³ = (vii), R⁴ = (ix), R⁵ and R⁶ = (xia), R⁷, R⁸, R⁹ and R¹⁰ = (xi).

The most preferred compounds of formula (Ia) and pharmacologically acceptable salts and esters thereof are ethisterone, danazo! and stanozolol and pharmacological iy acceptable salts and esters thereof:

Ethisterone Danazol

Stanozolol

Ethisterone, danazol and stanozolol are known synthetic steroid hormones having antiandrogen activity. Ethisterone (17α-hydroxypregn-4-en-20-yπ-3-oπe) is a progestogen that has been used in the past to treat menstrual disorders and as a component of combined oral contraceptives. Danazo! (17α-pregna-2,4-dien-20-yno[2,3~ d]-isoxazol-17β-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 endometriosis. Stanozolol (17-methyl-5α -aπdrostano[3,2-c]pyrazo!~17β-o!) is a synthetic testosterone analogue.

Preferred compounds of formula (IV) are compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof:

<^1Va> wherein R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R^", R²³, R²⁴, R²⁵, 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:

(xϋ) each of R¹⁸ and R¹⁹ is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (xiϋ) each of R¹⁸ and R¹⁹ is a methyl group;

(xiv) 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 R²¹ is a hydrogen atom and R² and R^" together represent a single bond; (xv) each of R²⁰, R²¹ and R^2A is a hydrogen atom or R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond;

(xvi) R¹⁷ is hydrogen or an alkyl group having from 1 to 4 carbon atoms;

(xvii) R¹⁷ is hydrogen;

(xviii) R²² is hydroxyl, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (H) wherein n is 0, 1 or 2, and R¹¹ is an alkyl group having from 1 to 4 carbon atoms, a hydroxy] group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R¹⁴Ji 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 R¹² and R¹³ 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 (II) wherein n is 0 and Rⁿ 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 I , and each of R¹² and R¹³ 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 R²³, 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 α¹ 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

R²ⁱ, R²⁶, R²⁷ and R²⁸ together with the carbon atoms to which they are attached represent an isoxazolyl group.

In each group of (xii) to (xiii), (xiv) to (xv), (xvi) to (xvii), (xviii) to (xix) and (xxϋ) 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^iS and Rⁱ⁹ selected from (xii) to (xiii), R²⁰, R²¹ and R²⁴ selected from (xiv) to (xv), R¹⁷ selected from (xvi), (xvii) and (xx), R²² selected from (xviii) to (xx), R²³ and R²⁹ selected from (xxi) and R²\ R²⁶, R²⁷ and R²⁸ selected from (xxϋ) to (xxiii) are also preferred.

Compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof having the following combinations are particularly preferred:

(d) R¹⁸ and R¹⁹ = (xii), R²⁰, R²¹ and R²⁴ - (xiv), R^!7 = (xvi) and R²² = (xviii), R²³ and R²⁹ = (xxi), and R²⁵, R²⁶, R²⁷ and R²⁸ = (xxπ);

(e) Rⁱ⁸ and R¹⁹ = (xiii), R²⁰, R²¹ and R²⁴ = (xv), R¹⁷ - (xvii) and R²² = (xix), R²³ and R²⁹ = (xxi), and R²⁵, R²⁶, R²⁷ and R²⁸ - (xxiii);

(f) R¹⁸ and R¹⁹ - (xii), R²⁰, R²¹ and R²⁴ = (xiv), R¹⁷ and R²² together - (xx), R²³ and R²⁹ = (xxi), and R²⁵, R²⁶, R²⁷ and R²⁸ = (xxii); and (g) R¹⁸ and R¹⁹ = (xiii), R²⁰, R²¹ and R²⁴ - (xv), R¹⁷ and R²² together = (xx), R²³ and R²⁹ = (xxi), and R²⁵, R²⁶, R²⁷ and R^2S = (xxiii).

The most preferred compounds of formula (IVa) and pharmacologically acceptable salts and esters thereof are trilostane, trilostane II, trliostane III, keto-trilostane and pharmacologically acceptable salts and esters thereof:

Triloslanc Trilostnne 11

H

Keso-Tπlostane Triloslaπe HI

Trϋostane (2α-cyano-4α,5α-epoxyandrostan-I7β-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 orai 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-A- 02/080930, 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 ethaπol 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 carboxymethylceliulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium alginate and bentonite), emulsifying agents (examples include triethanolamine, sodium lauryl sulfate, sorbitaπ 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 myri stale) 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/ml formulation (preferably 0.1 mg/ml formulation, most preferably 1 mg/ml formulation) as a lower limit and 100 mg/ml formulation (preferably 25 mg/ml formulation, most preferably 10 mg/ml formulation) as an upper limit and administered in a single dose or in several divided doses a day.

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 III;

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 danazol 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 III 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.

Example 1

Danazoϊ 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, MD

• Preadipocyte medium and Differentiation medium, Cambrex.

* AdipoRed Assay reagent, Cambrex. e 96 well tissue culture plates, Coming, Corning, NY, β Mifepristone, Sigma, St. Louis, MO β Recombinant Human TNFα, Pierce Biotechnologies, Roclcford, IL.

« Phosphate buffered saline solution (PBS), Pierce Biotechnologies, β Fluorescent Microplate reader β 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 ⁰C and 5% CO₂.

2. Once confluence was achieved, preadiopocyte medium was removed and replaced with differentiation medium containing danazol (0.1 μM - 50 μM) or controls (Preadipocytes medium, Nil wells, and TNFα 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. 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 1

OD OD pvalue vs

Sample Mean OD std OD 1 2 OD 3 nil

Undifferentiated -21 24.04163 -4 -38

Nil 7823333 81.59248 707 869 771

0.1 uM Danazol 709 133.5178 832 728 567 0.462481428

1 uM Danazol 795.6667 106.3689 918 725 744 0.871591451

5 uM Danazol 745 61.61169 81 1 735 689 0.561438044

10 uM Danazol 279 61.04916 210 326 301 0.001024909

50 uM Danazo) -55 35.7631 1 -93 -50 -22 8.33123E-05

1 uM

Mifepristone 87.66667 8.504901 78 94 91 0.000125733

10 uM

Mifepristone 35.66667 17.24336 51 39 17 0.000100928

0.5 ng/ml TNFa 473 73.36893 41 1 454 554 0.008144216

5 ng/ml TNFa 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 triglyceride levels 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 experiment, maturing the adipocytes in the presence of 10 μM danazo! or higher led to significant reduction in intracellular lipid. No lipid was delected in the wells dosed with 50 μM danazol. Two known strong inhibitors of adipocyte differentiation, mifepristone and TNFα, 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 111 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: ^β 50 mM danazol in ethanol, Sigma, St. Louis, MO

» 50 mM trilostane III in ethanol, Bowman Research, Newport, South Wales, UK

(prepared as, for example, described in GB 1 ,123.770) • Primary subcutaneous preadipocytes, Cambrex, Waikersvϋle, MD

• Preadipocyte medium and Differentiation medium, Cambrex. « AdipoRed Assay reagent, Cambrex. β 96 well tissue culture plates, Corning, Coming, NY.

• Mifepristone, Sigma • Recombinant Human TNFα, 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 ⁰C and 5% CO,. 2. Once confluence was achieved, preadiopocyte medium was removed and replaced with differentiation medium containing danazol or trilostane III (5 μM - 25 μM) as well as control reactions of preadipocytes medium only, Nil wells, and TNFα or mifepristone as positive. 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.

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

Results and Observations:

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

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 l FU 2 FU l FU 2 vs Diff

Undifferentiated 50.39 104.5104 -23.51 124.29 432.6 560.4 0.016456

Differentiated 723.09 342.8356 622.09 824.09 1058.2 1260.2

Danazol 5 uM 663.89 24.32447 646.69 681.09 1082.8 1 1 17.2 0.310886

Danazol 10 uM 61 1.59 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 0.023194

Trilostane 5 uM 460.19 7.495332 465.49 454.89 901.6 891 0.008437

Trilostane lO uM 390.39 10.6066 382.89 397.89 819 834 0.04075

Trilostane 25 uM 156.19 9.392388 162.69 149.69 598.8 585.8 0.015213

Mifepristone 0.1 uM 641.49 41.86072 671.09 61 1.89 1 107.2 1048 0.259637

Mifepristone 1 uM 245.09 35.35534 220.09 270.09 656.2 706.2 0.02213

Mifepristone 10 uM 73.89 3.1 1 127 71.69 76.09 507.8 512.2 0.03 1685

TNF alpha 0.05 ng/ml 832.79 10.32376 825.49 840.09 1261.6 1276.2 0.195946

TNF alpha 0.5 ng/ml 731.39 10.6066 723.89 738.89 1 160 1175 0.471074

TNF alpha 5 ng/ml 45.09 26.30437 63.69 26.49 499.8 462.6 0.01 1092

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 fluoresce. Dose-response curves of both trilostane III and danazo! were incubated on preadipocyles while they were differentiated by insulin, dexamethasone, indomethacin, and isobutyi-methylxanthine. Both compounds showed an ability to reduce the amount of detectable lipid in a dose dependent fashion. Trilostane IH was more effective exhibiting a 36%, 46%, and 78% decrease in Adipored fluorescence at 5 μM, 10 μM, and 25 μM doses respectively (compared to 8%, 15%, and 63% decreases observed in danazol treated wells). Both compounds show the ability to prevent adipocyte differentiation but trilostane ID appears to be more potent.

Example 3

Danazol and Trilostane III Induction of Lipolysis

Purpose:

To determine if danazol and trilostane 111 can induce the release of triglycerides, in the form of glycerol, from mature adipocytes in culture.

Materials:

• Primary subcutaneous preadipocytes, Cambrex. Walkersville, MD β Preadipocyte medium and Differentiation medium, Cambrex. « Lipolysis Assay Kit, Zen-Bio, Chapel Hill, NC

• 96 well tissue culture plates, Corning, 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 isobutyi-methylxanthine for two weeks. 2. Medium was then removed and cells were washed with Zen-Bio wash solution. 3. 50 niM stocks of danazol and trilostane in ethanol were diluted in supplied assay buffer to 25 μM and added to the ceils.

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% CO2.

6. 100 μl of the assay buffer was then removed and added to 100 μl Zen-Bio 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 LiM Isoproterenol 32.39167 2.591251 10.608 15.364 1 1.203 0.010984 25 uM Danazol 5.257767 2.724287 4.6633 8.2302 2 .8798 0.430563

25 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 μM danazol and trilostane III did not induce 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 HUVEC Angiogenesis: Invasion Chamber

Purpose:

To examine the effect of trilostane III and danazol 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

» 50 mM trilostane 111 in ethanol, Bowman Research, Newport, South Wales, UK

(prepared as, for example, described in GB 1,123,770) ^β 50 mM danazo! in ethanol, Sigma

• 4 mM Caiceiπ 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 70-80% confluence were washed two times with 37 ⁰C 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 ⁰C and 5% CO₂. 4. Non-invading cells were removed from the upper chamber with cotton swab and the inserts were washed two times with 37 ° C HBSS.

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

6. Following four hours at 37 ⁰C and 5% CO^, 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

50 uM Danazo! 8867.67 743.84 429.454 0.003373

25 u M Danazol 10067 552.21 318.818 0.01 1 36

50 uM Trilostane 9101.33 540.28 31 1.928 0.002781

25 uM Trilostane 11212.3 2748.7 1586.94 0.320938

5O uM LY 303511 12795.3 609.45 351.867 0.125899

50 uM LY 294002 9454.33 1877.9 1084.18 0.045893

Discussion and Conclusion: Treatment with 25 μM danazol lead to a significant decrease in endothelial cell invasion into the lower chamber. At 50 μM danazol, the invasion was reduced to background levels similar to wells without fetal calf serum added to initiate invasion. Triiostane 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 μM danazol and triiostane. LY30351 1 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 triiostane III may have an effect on endothelial cell invasion in certain individuals or at the appropriate time in the cell cycle.

Example s

Triiostane III Effect on HUVEC Cell Proliferation

Purpose:

To determine the effect triiostane III has on HUVEC cell proliferation.

Materials: β 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 triiostane UI in ethanol, Bowman Research, Newport, South Wales, UK (prepared as, for example, described in GB 3 ,323,770)

• Hepes buffered saline solution (HBSS), Cambrex

• Celltiter 96 Aqueous One reagent, Promega

• Falcon 96 well tissue culture plates

• Microplate fluorescence reader

Protocol:

1. HUVEC 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 ⁰C HBSS. 3. EGM-2 containing 5% FCS with and without the compound (0.01 μM - 200 μM trϋostane III) 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 Ceϋtiter 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. IfUVEC 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 III in solution. The raw data are shown in

Table 5 below and depicted graphically in Figure 5.

Table 5

Trilostane 111

Sample 24 hour 48 hour 72 hour

Nil 0.414 0.629333 1.1 135

0.1 uM 0.387333 0.656 0.918667

I uM 0.31 1 0.434667 0.387667

10 uM 0.246667 0.203 0.072

100 uM 0.278667 0.214667 0.108

Trilostane III 24 hour results pvalue vs

Sample OD l 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 l O uM 0.18 0.267 0.293 0.059181 0.013283 100 uM 0.235 0.334 0.267 0.050521 0.020409

Trilostane III 48 hour results pvalue vs

Sample OD l 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

10 uM 0.159 0.208 0.242 0.041725 0.001045

100 uM 0.17 0.23 0.244 0.039311 0.001 121

Trilostane 111 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 0.1 13558

I uM 0.387 0.437 0.339 0.049003 0.000285

10 uM 0.031 0.095 0.09 0.035595 5.8E-05

100 uM 0.092 0.1 19 0.113 0.014177 3.09E-05

Discussion and Conclusion:

Trilostane III proved effective at inhibiting endothelial cell proliferation. Concentrations as low as 1 μM (at 24 hours), exhibited statistically relevant decreases in cell proliferation. Increasing the dose to 100 μM, 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 hours in culture. These results indicate that trilostane III may be an effective antiaπgiogenic compound, by interfering with the initial proliferation of endothelial cells.

Example 6 Trilostane III Effect on HUVEC Angiogeπesis: 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: β Passage 3 Human umbilical vein endothelial cells (HUVEC), Cambrex

* EGM-2 medium, Cambrex: supplemented to include 0.1 % or 5% fetal calf serum

* 1O mM LY294002 and LY303511 in DMSO, CalBiochem * 50 niM trilostane III in ethanol, Bowman Research, Newport, South Wales. UK (prepared as, for example, described in GB 1 ,323,770)

* 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 ⁰C 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 38 hours at 37 ⁰C and 5% CO₂. 3. Following incubation, tube formations were photographed under microscope.

Results and Observations:

Passage 3 HUVEC 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 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 celis 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 μM trilostane III led to a decrease in branching, vacuole formation, and increase in satellite cells. 50 μM LY294002, a PΪ3 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 μM trilostane III and 50 μm 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 III. In conclusion, trilostane III appears to prohibit tube formation of HUVEC cells.

Claims

1. Use of a steroid selected from the group consisting of ethisterone and derivatives thereof and triiostane 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 derm alo logical 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, fibrocystic breast condition, 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, fibrocystic breast condition, 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 fibrocystic breast condition. 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.

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:

(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 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 (111):

(II) (III)

wherein R¹¹ 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(R¹⁴)₂ wherein each group R^M is the same or different and is hydrogen or an alky] group having from 1 to 6 carbon atoms, each of R¹² and R¹³ is the same or different and is hydrogen or an alky! 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 I 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 R^a and R⁶ together represent a single bond; each of R⁷, R^s, R⁹ and R¹⁰ is the same or different and is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxy! group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R¹⁵)i wherein each group R¹⁵ 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 R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or

R⁷, R⁸, R⁹ and R¹⁰ 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 α defined below); substituent group α 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 alkylsulfiny! group having from 1 to 6 carbon atoms, an alkylsυlfony! group having from 1 to 6 carbon atoms, a phenyl group and a group of formula -N(Rⁱ⁶)2 wherein each group R¹⁶ 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 (ϊ) is a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof:

(Ia) wherein R¹, R², κ\ R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined in claim 7.

9. Use according to claim 7 or claim 8, wherein R¹ 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.

1 1. Use according to any one of claims 7 to 10, wherein R^* is hydroxy], 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 hydroxy] group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R^μ)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 ~ and R¹³ 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 hydroxy!, 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 (III) 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.

13. Use according to any one of claims 7 to 10, wherein R² is hydroxy]. 14. Use according to any one of claims 7 to 13, wherein R³ is hydrogen or an alky] 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 R¹⁰ together with the carbon atom to which they are attached represent a carbony! group, or R⁷, R⁸, R⁹ and R¹⁰ 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 α¹ defined below), and substituent group α^s 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(R¹⁶³)? wherein each group R^16a is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.

19. Use according to any one of claims 7 to 17. wherein R⁷, R⁸, R⁹ and R¹⁰ 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 R³ and R⁶ is a hydrogen atom or R²¹ 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^s 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 R¹¹ 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(R¹⁴)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 R¹² and R¹³ is the same or different and is hydrogen or an alScyl group having from 1 to 4 carbon atoms;

R³ is hydrogen or an alkyl group having from 1 to 4 carbon atoms;

R^ 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 R^ώ together represent a single bond; and each of R⁷ and R⁸ is a hydrogen atom and R⁹ and R¹⁰ together with the carbon atom to which they are attached represent a carbonyi group, or

R⁷, R⁸, R⁹ and R¹⁰ 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 α¹ defined below), and substituent group α¹ represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alkyj 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^16a)2 wherein each group R^16a 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 (Ia) or a pharmacologically acceptable salt or ester thereof according to claim 8, wherein: R¹ is a methyl group or an ethynyl group;

R² is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (11) wherein π is 0 and Rⁿ 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 I, and each of Kⁿ and R¹³ 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 R¹ together with the carbon atom to which they are attached represent a carbonyi group, or R⁷, R⁸, R⁹ and R¹⁰ 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 α¹ defined below), and substituent group α¹ represents a group consisting of a halogen atom, a hydroxy! group, an amino group, an alkyl group having from I to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula -N(R^s6a)₂ wherein each group R^i6a 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:

R¹ is a methyl group or an ethynyl group;

R^" is hydroxyl;

R³ is a methyl group; R⁴ is a methyl group; each of R⁵ and R⁶ is a hydrogen atom, or R⁵ and R together represent a single bond; and

R⁷, R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached represent an isoxazoly! 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:

Ethisieroπe Danazol

SSanozolol

25. Use according to any one of claims 1 to 6, wherein said triiostane or derivative thereof is a compound of the following formula (IV) or a pharmacologically acceptable salt or ester thereof:

wherein:

R¹⁸, R¹⁹ and R^2! are the same or different and each is hydrogen or an alky! group having from 1 to 6 carbon atoms;

R¹⁷ 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 7 or a group of formula (III) as defined in claim 7, or R¹⁷ and R²² together represent an oxo group, an ethylenedioxy group or a propylenedioxy group; each of R²⁰ and R²⁴ is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R²⁰ and R²⁴ together represent a single bond; each of R²³ and R²⁹ is the same or different and is hydrogen or an aikyl 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 3 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 R³⁰ is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or

R²⁵ and R²⁶ and/or R²⁷ and R²⁸ together with the carbon atom to which tiiey are attached represent a carbonyl group, or

R²³, 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 1 to 7 substϊtuents (said substituents are the same or different and are selected from substituent group α 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:

(IVa) wherein R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R", R²³,

R²⁵, R²⁶, R²⁷, R²⁸ and R²⁵ are as defined in claim 25. 27. Use according to claim 25 or claim 26, 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.

28. Use according to claim 25 or claim 26, wherein each of R¹⁸ and R¹⁹ is a methyl group. 29. Use according to any one of claims 25 to 28, wherein 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 R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond.

30. Use according to any one of claims 25 to 28, wherein each of R²⁰, R²¹ and R²⁴ is a hydrogen atom or R^2! 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 R¹⁷ is hydrogen or an alkyl group having from 3 to 4 carbon atoms.

32. Use according to any one of claims 25 to 30, wherein R¹⁷ 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 group of formula (II) wherein n is 0, 1 or 2, and R^! ' is an alkyl group having from 3 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from I to 4 carbon atoms or a group of formula -N(R¹⁴)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 O₅ 1 or 2, and each of R¹" 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 R" is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R¹¹ 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 R¹³ 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 R¹⁷ 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. 37. Use according to any one of claims 25 to 36, wherein R² is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R²⁶ is a cyano group and R²⁷ and R² together with the carbon atom to which they are attached represent a carbony! group, or

R²³, R²⁶, R²⁷ and R²⁸ together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocycly! 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 substihient group α¹ defined in claim 38).

38. Use according to any one of claims 25 to 36, wherein R^2:π 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

R²³, R²⁶, R²⁷ and R^2S 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 R¹⁸ and R¹⁹ is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R²⁰, R^2! and R² 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 R²⁰ and R²⁴ together represent a single bond; R¹⁷ 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 R^{1 1} 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 ^l% 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 rn is 0, 1 or 2, and each of R¹² and R¹³ is the same or different and is hydrogen or an alkyl group having from I to 4 carbon atoms; each of R²³ and R²⁹ represents a hydrogen atom or R²³ and R²⁹ together represent an epoxy linkage; and R²³ is hydrogen or an alkyl group having from ] 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

R²⁵, R²⁶, R²⁷ and R²⁸ together with the carbon atoms to which they are attached represent a 5- to 7-rnembered heterocyclyl group, said 5- to 7-membered heterocyclyl group optionaliy being substituted with from 1 to 3 substituents (said substituents are the same or different and are selected from substituent group α¹ 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 R¹⁸ and R¹⁹ is a methyl group; each of R²⁰, R²¹ and R²⁴ is a hydrogen atom, or R²¹ is a hydrogen atom and R²⁰ 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 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 (III) wherein m is 0 or 1 , and each of R " 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 R^"3 and R² together represent an epoxy linkage; and

R is hydrogen, R" is a cyano group and R" and R^~ 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 isoxazolyi 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^iS and R¹⁹ is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; each of R² , R" and R^" is the same or different and is a hydrogen atom or an alkyl g rroouupp h haavviinngg f frroomm 11 t too 44 c caarbon atoms, or K'¹ is a hydrogen atom and R^"0 and R² together represent a single bond; R¹⁷ and R" together represent an oxo group; each of R and R^" represents a hydrogen atom or R and R^~ together represent an epoxy linkage; and

R²³ is hydrogen or an alky] group having from I 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 R^2S 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 α¹ defined in claim 38),

42. Use according to claim 26 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R¹⁸ and R^!9 is a methyl group; each of R²⁰, R²¹ and R²⁴ is a hydrogen atom, or R^2! is a hydrogen atom and R²⁰ and K²⁴ together represent a single bond;

R¹⁷ and R²³ together represent an oxo group; each of R²³ and R²⁹ represents a hydrogen atom or R²³ and R^2ξ> together represent an epoxy linkage; and

R²³ 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.

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 III, keto-trilostane or a pharmacologically acceptable salt or ester thereof:

Tπlostane Tπiostane II

Keto-Trilosiane Tπlostanc lit

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 (1) or a pharmacologically acceptable salt or ester thereof:

(I) wherein:

R¹ is an aikyl group having from 1 to 6 carbon atoms, an alkeny] group having from 2 to 6 carbon atoms or an aikyny] group having from 2 to 6 carbon atoms; R² is hydroxy], 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):

(II) ("I)

wherein R^π is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxy! group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R¹⁴J₂ wherein each group R¹⁴ is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, each of R¹² 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 R³ and R⁶ together represent a single bond; each of R⁷, R^s, R⁹ and R¹⁰ 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(R¹⁵)? wherein each group R¹⁵ 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 R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or R⁷, R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached represent a 5- to 9-membered heterocyclyl group, said 5- to 9-mernbered heterocyclyl group optionally being substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group α defined below); substituent group α represents a group consisting of a halogen atom, a hydroxy! group, a cyano group, an amino group, an alky] group having from 1 to 6 carbon atoms, an aikoxy 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 alkylsulfoπyl group having from 1 to 6 carbon atoms, a phenyl group and a group of formula -N (R¹⁶)? wherein each group R¹⁶ 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 (1) is a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof:

(Ia) wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined in claim 45.

47. A topical formulation according to claim 45 or claim 46, wherein R¹ 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 R^" is hydroxy!, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (O) wherein n is 0, 1 or 2, and R¹¹ is an alkyl group having from 1 to 4 carbon atoms, a liydroxyl group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula ~~N(R^U)₂ wherein each group R¹⁴ is the same or different and is hydrogen or an alky! 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 R¹³ is the same or different and is hydrogen or an alkyl group having from 3 to 4 carbon atoms.

50. A topical formulation according to any one of claims 45 to 48, wherein R² is hydroxy!, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R¹¹ is a methyl group, an ethyl group, a hydroxy! 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.

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 alky! 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 R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or R⁷, R⁸, R⁹ and R^t0 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 substitueπts (said substituents are the same or different and are selected from substituent group α¹ defined below), and substituent group α^! represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an aikyl group having from 1 to 4 carbon atoms, an aikoxy group having from 1 to 4 carbon atoms, a phenyl group and a group of formula -N(R^{1 a})2 wherein each group R^!6a 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 R , R , R and R¹⁰ 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 R³ and R⁶ together represent a single bond.

59. A topical formulation of a compound of formula (ϊa) or a pharmacologically acceptable salt or ester thereof according to claim 46, wherein: R¹ 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^{1 ]} 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(R¹⁴)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^1Ξ 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 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 R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or R⁷, R⁸, R⁹ and R¹⁰ 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 α^! defined below), and substituent group α' 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^16a)₂ wherein each group R^I6a 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 hydroxy!, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R^π is a methyl group, an ethyl group, a hydroxy! group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethyiamino group, or a group of formula (III) 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; R³ is a methyl group; R⁴ is a methyl group; each of R³ and R⁶ is a hydrogen atom, or R³ and R⁶ together represent a single bond; and each of R⁷ and R⁸ is a hydrogen atom and R⁹ and R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or

R⁷, R⁸, R⁹ and R^!0 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 α¹ defined below), and substituent group α¹ represents a group consisting of a halogen atom, a hydroxy! group, an amino group, an alky! group having from 1 to 4 carbon atoms, an alkoxy group having from I to 4 carbon atoms, a phenyl group and a group of formula -N(R^16a)₂ wherein each group R^16a 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; each of R⁵ and R⁶ is a hydrogen atom, or R^D and R⁶ together represent a single bond; and

R⁷, R^s, R⁹ and R¹⁰ 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, danazo! and stanozolol and pharmacologically acceptable salts and esters thereof:

EUiisle rone Danazol

Stanozoloi

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: .17

(IV)

wherein:

R¹⁸, R¹⁹ and R²¹ 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 alky] 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 aikanoyioxy group having from I to 7 carbon atoms, a group of formula (II) as defined in claim 45 or a group of formula (111) as defined in claim 45, or

R¹⁷ and R²² together represent an oxo group, an ethylenedioxy group or a propylenedioxy group; each of R²⁰ and R²⁴ is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R²⁰ 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(R³⁰J₂ wherein each group R³⁰ is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or

R^2D 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 heterocyclyi group, said 5- to 9-rnembered heterocyclyl group optionally being substituted with from 1 to 7 siibstituents (said substituents are the same or different and are selected from substitυeπt group α 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:

wherein R¹⁷, R¹⁸, R^§9, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ are as defined in claim 63.

I ft

65. A topical formulation according to claim 63 or claim 64, wherein each of R and R¹⁹ 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 R¹⁸ and R¹⁹ 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 R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond.

68. A topical formulation according to any one of claims 63 to 66, wherein each of R²⁰, R²¹ and R²'¹ is a hydrogen atom or R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond. 69. A topical formulation according to any one of claims 63 to 68, wherein R¹⁷ is hydrogen or an alley! group having from 1 to 4 carbon atoms.

70. A topical formulation according to any one of claims 63 to 68, wherein R¹⁷ is hydrogen. 71. A topical formulation according to any one of claims 63 to 70, wherein R²² is hydroxy!, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R^{1 j} is an alky] 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^M)i wherein each group R^M 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 ~ and R is the same or different and is hydrogen or an alky! 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

I O I l group, or a group of formula (III) wherein m is 0 or 1 , and each of R ~ and R 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 R¹⁷ and R^" 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 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^2S 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 a¹ defined in claim 60). 76. A topical formulation according to any one of claims 63 to 74, wherein R²ⁱ 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^" , R^*" , R^" and R^" together with the carbon atoms to which they are attached represent an isoxazolyi 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 R¹⁹ is the same or different and is hydrogen or an alkyl group having from I 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 R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond;

R¹⁷ is a hydrogen atom or an alky! group having from i to 4 carbon atoms; R~ is hydroxy], an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is O₁ 1 or 2, and R^M is an alkyl group having from I to 4 carbon atoms, a hydroxy! group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R^! )? 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 R¹² and R^{i 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

R^" is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R is a cyano group and R^" and R^" together with the carbon atom to which they are attached represent a carbonyl group, or

R^~ , R^" , R^" 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 α¹ 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: each of R^{i S} and R¹⁹ is a methyl group; each of R²⁰, R²¹ and R^2A is a hydrogen atom, or R²' is a hydrogen atom and R²⁰ and R^2A together represent a single bond;

Rⁱ⁷ is a hydrogen atom; R²² is hydroxy!, an aikanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R^{1 1} is a methyl group, an ethyl group, a hydroxy! group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimethylamino group, or a group of formula (HI) 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; 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

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 alky] 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 alky] group having from 1 to 4 carbon atoms, or R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond;

R¹⁷ 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

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 heterocycly] group optionally being substituted with from I to 3 substitiients (said substitυents are the same or different and are selected from substituent group α¹ 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 R¹⁸ and R.¹⁹ is a methyl group; each of R" , R and R^" is a hydrogen atom, or R is a hydrogen atom and R and R²⁴ together represent a single bond;

R¹⁷ and R²² together represent an oxo group; each of R and R" represents a hydrogen atom or R and R together represent an epoxy linkage; and

R²⁵, R²⁶, R²⁷ and R^2S 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 tπiostane, trilostαne II, trliostane III, keto-triiostane or a pharmacologically acceptable sait or ester thereof:

Trilσstmie Trilostone il

Keto-Trilosiane Triloslaπc IiI 82. A topical formulation according to any one of claims 44 to 81 for the prevention or treatment of a deπnatologica! 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. 83. A topical formulation according to claim 82, wherein said dernialological 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 celluϋte, fibrocystic breast condition, naevi, telangiectasia, senile elastosis, keloids, ainhum, Peyronie's disease, sun exposure related dermatological conditions, dermatological treatment of the sinus and superficial benign neoplastic conditions.

84. A topical formulation according to claim 82, 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 ceilulite, fibrocystic breast condition, port wine naevi, strawberry naevi, senile elastosis, solar elastosis, keratosis, solar chelitis, lipoma, angioma and dermatofibroma.

85. A topical formulation according to claim 82, 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 fibrocystic breast condition.

86. A topical formulation according to claim 82, 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.

87. A method 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, 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. 88. A method according to claim 87, wherein said steroid has one or more of the following activities:

(a) the ability to reduce the maturation of preadipocytes into adipocytes;

(d) the ability to modify fibrosis.

89. A method according to claim 87 or claim 88, 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, fibrocystic breast condition, naevi, telangiectasia, senile elastosis, keloids, ainhurn, Peyronie's disease, sun exposure related dermatological conditions, dermatological treatment of the sinus and superficial benign neoplastic conditions.

90. A method according to claim 87 or claim 88, 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 celϊulite, fibrocystic breast condition, port wine naevi, strawberry naevi, senile eiastosis, solar elastosis, keratosis, solar chelitis, lipoma, angioma and dermatofibroma. 91. A method according to claim 87 or claim 88, 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 fibrocystic breast condition.

92. A method according to claim 87 or claim 88, 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.

93. A method according to any one of claims 87 to 92, wherein said ethisterone or derivative thereof is a compound of the following formula (I) or a pharmacologically acceptable salt or ester thereof:

(0

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 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 ] to 7 carbon atoms, a group of formula (II) or a group of formula (HI):

(H) (ill)

wherein R^{1 j} is hydrogen, an alkyl group having from 3 to 6 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R¹^)₂ wherein each group R¹⁴ is the same or different and is hydrogen or an alkyi group having from 1 to 6 carbon atoms, each of R¹² 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 R^ is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms; eacli of R⁵ and R⁶ is the same or different and is hydrogen or an aikyl group having from 1 to 6 carbon atoms or R⁵ and R⁶ together represent a single bond; each of R⁷, R⁸, R⁹ and R¹⁰ is the same or different and is hydrogen, an alky! group having from 1 to 6 carbon atoms, a hydroxy! group, an alkoxy group having from I to 6 carbon atoms or a group of formula -N(R^I5)₂ wherein each group R¹⁵ is the same or different and is hydrogen or an alky! group having from 1 to 6 carbon atoms, or

R⁷, R⁸, R⁹ and R^Iϋ together with the carbon atoms to which they are attached represent a 5- to 9-membered helerocyciy] 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 substiluent group α defined below);

SLibstituent group α represents a group consisting of a halogen atom, a hydroxyl group, a cyano group, an amino group, an alky! group having from I 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 alkylsiilfonyl group having from ! to 6 carbon atoms, a phenyl group and a group of formula -N(R¹⁶J₂ wherein eacli group R^t6 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms. 94. A method according to claim 93, 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, R⁸, R⁹ and R^ll) are as defined in claim 93. 95. A method according to claim 93 or claim 94, wherein R¹ is an alky! 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.

96. A method according to claim 93 or claim 94, wherein R¹ is a methyl group or an ethynyi group.

97. A method according to any one of claims 93 to 96, 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^{1 1} 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 ^' )τ wherein each group R^N is the same or different and is hydrogen or an alkyl group having from I to 4 carbon atoms or a group of formula (111) wherein m is 0, 1 or 2, and each of R ^~ and Rⁿ is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.

98. A method according to any one of claims 93 to 96, wherein R" is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (H) wherein n is 0 and R^{l !} is a methyl group, an ethyl group, a hydroxy! group, a methoxy group, an ethoxy group, an amino group, a methylamino group or a dimelhylamiπo group, or a group of formula (III) 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. 99. A method according to any one of claims 93 to 96, wherein R² is hydroxy!.

100. A method according to any one of claims 93 to 99, wherein R³ is hydrogen or an alky! group having from I to 4 carbon atoms.

101. A method according to any one of claims 93 to 99, wherein R³ is a methyl group.

102. A method according to any one of claims 93 to 101, wherein K⁴ is hydrogen or an alky! group having from 1 to 4 carbon atoms.

103. A method according to any one of claims 93 to 101, wherein K⁴ is a methyl group.

104. A method according to any one of claims 93 to 103, wherein each of R⁷ and R⁸ is a hydrogen atom and R⁹ and R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or R⁷, R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyl group, said 5- to 7-membered helerocyclyl group optionally being substituted with from 1 to 3 substititents (said subslituents are the same or different and are selected from substituent group α¹ defined below), and substituent group α^f represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an aikyl group having from 1 to 4 carbon atoms, an aikoxy group 5 having from ! to 4 carbon atoms, a phenyl group and a group of formula -N(R^l6n)₂ wherein each group R^l6il is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms.

105. A method according to any one of claims 93 to ! 03, wherein R⁷, R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached represent an isoxazoiyl group. 10 106. A method according to any one of claims 93 to 105, wherein each of R⁵ and R⁶ is a hydrogen atom or R⁵ and R⁶ together represent a single bond. 107. A method of a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof according to claim 94, wherein:

R¹ is an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having ] 5 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 π is 0, 1 or 2, and R^{1 1} is an alkyl group having from 1 to 4 carbon atoms, a hydroxy! group, an aikoxy group having from 1 to 4 carbon atoms or a group of formula ™N(R¹⁴)₂ wherein each group R¹⁴ is the same or different and is hydrogen or an 0 alkyl group having from I to 4 carbon atoms or a group of formula (III) wherein m is 0, 1 or 2, and each of R¹² 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; 5 each of R⁵ and R⁶ is a hydrogen atom, or R³ and R⁶ together represent a single bond; and each of R⁷ and R⁸ is a hydrogen atom and R⁹ and R¹⁰ together with the carbon atom to which they are attached represent a carbonyl group, or

R⁷, R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached 30 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 α¹ defined below), and substituent group α^ι represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an a iky! 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. ¹¹J₂ wherein each group R^16a is the same or different and is hydrogen or an alky! group having from 1 to 4 carbon atoms.

108, A method of a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof according to claim 94, wherein: R¹ is a methyl group or an ethynyl group;

R² is hydroxyl, an aikanoyloxy 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 dimelhylamino group, or a group of formula (III) wherein m is 0 or 3 , and each of R¹² and R¹³ is the same or different and is hydrogen, a methyl group or an ethyl group;

R³ is a methyl group;

R^ is a methyl group; each of R^s and R⁶ is a hydrogen atom, or R⁵ and R⁶ together represent a single bond; and each of R⁷ and R^s is a hydrogen atom and R⁹ and R¹⁰ together with the carbon atom to which they are attached represent a carbonyi group, or

R⁷, R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached represent a 5- to 7-membered heterocyclyi 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 α¹ defined below), and substituent group α¹ represents a group consisting of a halogen atom, a hydroxyl group, an amino group, an alky! 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^16a)2 wherein each group R^16a is the same or different and is hydrogen or an alky! group having from 1 to 4 carbon atoms. 109. A method of a compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof according to claim 94, wherein:

R.¹ is a methyl group or an ethyny! group;

Rr is hydroxy!;

R³ is a methyl group;

R is a methyl group; each of R³ and R is a hydrogen atom, or R^s and R together represent a single bond; and

1 10. A method according to claim 94, wherein said compound of formula (Ia) or a pharmacologically acceptable salt or ester thereof is selected from ethisterone, danazo! and stanozolol and pharmacologically acceptable salts and esters thereof:

Ethisterone Danazoi

Slαnozolol 1 1 1. A method according to any one of claims 86 to 92, wherein said trilostane or derivative thereof is a compound of the following formula (IV) or a pharmacologically acceptable salt or ester thereof:

(IV)

wherein:

R¹⁸, R¹⁹ and R²¹ are the same or different and each is hydrogen or an alky] group having from 1 to 6 carbon atoms;

R¹⁷ is hydrogen, an alky! group having from 1 to 6 carbon atoms or an alkenyl group having from 2 to 6 carbon atoms,

R²² is hydroxy!, 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 93 or a group of formula (III) as defined in claim 93, or

R¹⁷ and R²² together represent an oxo group, an ethylenedioxy group or a propylenedioxy group; each of R²⁰ and R²⁴ is the same or different and is hydrogen or an alky] group having from 1 to 6 carbon atoms or R²⁰ and R²⁴ together represent a single bond; each of R²³ and R²⁹ is the same or different and is hydrogen or an alky] group having from I to 6 carbon atoms or R²³ and R²⁹ together represent an epoxy linkage; each of R , R" , R^" and R^~ is the same or different and is hydrogen, an alkyl group having from I to 6 carbon atoms, a cyano group, a hydroxy! group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R³⁰)₂ wherein each group R³⁰ is the same or different and is hydrogen or an alkyl group having from I to 6 carbon atoms, or

R and R and/or R and R" together with the carbon atom to which they are attached represent a carbony! group, or

R" , R , R and R" together with the carbon atoms to which they are attached represent a 5- to 9-membered heterocyclyi group, said 5- to 9-membered heterocyciyl group optionally being substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group α as defined in claim 93). ! 12. A method according to claim I M , wherein said compound of formula (IV) is a compound of formula (IVa) or a pharmacologically acceptable salt or ester thereof:

(IVa) wherein R¹⁷, R^{1 B}, R¹⁹, R²⁰, R²¹, R²², R²³, R^M, R²⁵, R²⁶, R²⁷, R^2B and R²⁹ are as defined in claim 1 1 1 .

1 13. A method according to claim 1 1 1 or claim 1 12, wherein each of R¹⁸ and R¹⁹ is the same or different and is hydrogen or an aikyl group having from 1 to 4 carbon atoms.

1 14. A method according to claim 1 1 3 or claim 1 12, wherein each of R^{I S} and R¹ is a methyl group. 1 15. A method according to any one of claims 1 1 1 to 1 14, wherein 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 R^2t is a hydrogen atom and R² and R² together represent a single bond. 1 16. A method according to any one of claims 1 1 1 to 1 14, wherein each of R²⁰, R³¹ and R²⁴ is a hydrogen atom or R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond.

1 17. A method according to any one of claims 1 1 1 to 1 16, wherein R¹⁷ is hydrogen or an alky] group having from I to 4 carbon atoms.

1 18. A method according to any one of claims 1 1 1 to 1 16, wherein R¹⁷ is hydrogen.

1 19. A method according to any one of claims 1 1 1 to 1 18, wherein R²² is hydroxy!, an alkanoyloxy group having from 2 to 5 carbon atoms, a group of formula (II) wherein n is 0, 1 or 2, and R^{1 1} is an alky! group having from 1 to 4 carbon atoms, a hydroxy! group, an alkoxy group having from ! to 4 carbon atoms or a group of formula -N(R¹⁴J₂ wherein each group R¹⁴ is the same or different and is hydrogen or an alky! 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 ^~ and R¹³ is the same or different and is hydrogen or an alky] group having from 1 to 4 carbon atoms. 120. A method according to any one of claims 1 1 1 to 1 18, wherein R²² is hydroxy!, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R^{1 1} is a methyl group, an ethyl group, a hydroxy! group, a methoxy group, an ethoxy group, an amino group, a melhylamino group or a dimethylamino group, or a group of formula (III) 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.

121. A method according to any one of claims 1 1 1 to 1 18, wherein R^j7 and R²² together represent an oxo group.

122. A method according to any one of claims 3 1 1 to 121 , wherein each of R²³ and R²⁹ represents a hydrogen atom or R²³ and R²⁹ together represent an epoxy linkage. 123. A method according to any one of claims 1 1 1 to 122, wherein R²⁵ is hydrogen or an alky! group having from 1 to 4 carbon atoms, R²⁶ is a cyano group and R²⁷ and R^2S together with the carbon atom to which they are attached represent a carbonyl group, or R²\ 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 α¹ defined in claim 104). ] 24. A method according to any one of claims 1 1 1 to 122, wherein R²³ is hydrogen, R²⁶ is a cyano group and R²⁷ and R^2B together with the carbon atom to which they are attached represent a carboπyl group, or

R²⁵, R²⁶, R²⁷ and R^2B together with the carbon atoms to which they are attached represent an isoxazolyl group.

125. A method according to claim 1 12 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R¹⁸ and R¹⁹ is the same or different and is hydrogen or an alky! 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 alky! group having from 1 to 4 carbon atoms, or R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond;

R¹⁷ is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;

R²² is hydroxy!, 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 hydroxy! group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -N(R^N)i wherein each group R^M 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 R¹² and R¹³ is the same or different and is hydrogen or an alkyl group having from 3 to 4 carbon atoms; each of R²³ and R²⁹ represents a hydrogen atom or R²³ and R²⁹ together represent an epoxy linkage; and

R²³ is hydrogen or an a!ky! group having from 1 to 4 carbon atoms, R² is a cyano group and R²⁷ and R^2S together with the carbon atom to which they are attached represent a carbony! group, or

R²^ R²⁶, R²⁷ and R^2S 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 α¹ defined in claim 104). 126. A method according to claim 1 12 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R¹⁸ and R¹⁹ is a methyl group; each of R²⁰, R²¹ and R²⁴ is a hydrogen atom, or R²¹ is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond;

R^π is a hydrogen atom; R²² is hydroxy], an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R^{1 1} is a methyl group, an ethyl group, a hydroxy! group, a methoxy group, an ethoxy group, an amino group, a rnethylamino group or a dimethylamino group, or a group of formula (III) 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; each of R²³ and R²⁹ represents a hydrogen atom or R²³ and R²⁹ together represent an epoxy linkage; and

R²³ is hydrogen, R²⁶ is a cyano group and R²⁷ and R^2S together with the carbon atom to which they are attached represent a carbonyl group, or

R²\ R²⁶, R²⁷ and R²⁸ together with the carbon atoms to which they are attached represent an isoxazolyl group.

127. A method according to claim 1 32 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, 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; each of R²⁰, R^2! 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 R²⁰ and R²⁴ together represent a single bond;

R" , R" , R" 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 siibstituents are the same or different and are selected from subslituent group α¹ defined in claim 104). 128. A method according to claim 1 12 of a compound of formula (IVa) or a pharmacologically acceptable salt and ester thereof, wherein: each of R^{! S} and R¹⁹ is a methyl group; each of R²⁰, R²¹ and R²⁴ is a hydrogen atom, or R^2t is a hydrogen atom and R²⁰ and R²⁴ together represent a single bond;

R^2D 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

R²³, R²⁶, R²⁷ and R²⁸ together with the carbon atoms to which they are attached represent an isoxazolyl group. 129. A method according to claim 1 12, 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:

Tritαstane Trilosianc I!

Kcto-Trilostaπe Trilostane 111