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WO2006054119A1 - Formulations topiques a utiliser dans le traitement ou la prevention d'etats dermatologiques - Google Patents

Formulations topiques a utiliser dans le traitement ou la prevention d'etats dermatologiques Download PDF

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Publication number
WO2006054119A1
WO2006054119A1 PCT/GB2005/050209 GB2005050209W WO2006054119A1 WO 2006054119 A1 WO2006054119 A1 WO 2006054119A1 GB 2005050209 W GB2005050209 W GB 2005050209W WO 2006054119 A1 WO2006054119 A1 WO 2006054119A1
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carbon atoms
hydrogen
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different
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Gerald Curtis
David Bar-Or
George Margetts
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Stegram Pharmaceuticals Ltd
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Stegram Pharmaceuticals Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • 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.
  • underlying fat asdipose
  • 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.
  • adipocytes fat celis
  • 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.
  • 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 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, ⁇ n 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
  • topical formulations are also suitable for preventing or treating these other conditions as well.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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:
  • R 1 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;
  • R 2 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):
  • R 11 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 R 12 and R 13 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 R 3 and R 4 is the same or different and is hydrogen or an alky!
  • each of R 3 and R 6 is the same or different and is hydrogen or an alky! group having from 1 to 6 carbon atoms or R 3 and R 6 together represent a single bond; each of R 7 , R 8 , R 9 and R 10 is the same or different and is hydrogen, an alkyl group having from 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 6 carbon atoms or a group of formula -N(R 1 ⁇ ) 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 R 7 and R 8 and/or R 9 and R 10 together with the carbon atom to which they are attached represent a carbonyl group, or
  • R 7 , R 8 , R 9 and R 10 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 ⁇ defined below);
  • substituent group ⁇ 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(R 16 )2 wherein each group R 16 is the same or different
  • triloslane and derivatives thereof include compounds of the following formula (IV) and pharmacologically acceptable salts and esters thereof:
  • R 1 S , R 19 and R 21 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
  • R 17 and R 22 together represent an oxo group, an ethylenedioxy group or a propyienedioxy group; each of R 20 and R 24 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms or R 20 and R 24 together represent a single bond; each of R 23 and R 29 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 .
  • each of R 2s , R 26 , R 27 and R 28 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(R 30 J 2 wherein each group R 30 is the same or different and is hydrogen or an alkyl group having from 1 to 6 carbon atoms, or R R 2255 a anndd I R 26 and/or R 27 and R 2S together with the carbon atom to which they are attached represent a carbonyl group, or R 25 , R 26 , R 27 and R 28 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 s ⁇ bstituents are the same or different and are selected from substituent group ⁇ defined
  • R 7 , R 8 , R 9 and R 10 together with the carbon atoms to which they are attached represent an optionally subsitituted 5- to 9-membered heterocyclyl group or R 2D , R 26 , R 27 and R 28 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
  • R 8 , R 9 and R 10 together with the carbon atoms to which they are attached and an isoxazolyl group for R 23 , R 26 , R 27 and R 28 together with the carbon atoms to which they are attached.
  • the alky! group having from 1 to 6 carbon atoms in the definitions of R 1 , R 3 , R 4 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R M , R 15 , R 16 , R !7 , R 18 , R 19 , R 20 , R 21 , R 33 , R 2 ⁇ R 25 , R 26 , R 27 , R 2S , R 29 , R 30 and substituent group ⁇ 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!
  • the alkenyl group having from 2 to 6 carbon atoms in the definition of R 1 and R 17 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-hexe ⁇ yl, 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 R 1 and R 17 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-buty ⁇ yl, 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-hexyny
  • 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.
  • dimethyibutylthio group 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 ⁇ is a sulf ⁇ ny!
  • 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-butanesulf ⁇ nyl group, a tert- butanesulfinyl group, an n-pentanesulfinyl group, an isopentanesulfinyl group, a 2- methylbutanesulfinyl group, a neopentanesulfinyl group, an n-hexanesulfjny!
  • the aikylsulfonyl group having from 1 to 6 carbon atoms in the definition of substituent group ⁇ is a sulfonyl group (-SO 2 -) 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- butanesulfo ⁇ yl group, an isobutanesulfonyl group, an s-butanesulfonyl group, a tert- butanesulfo ⁇ yl group, an n-pentanesulfonyl group, an isopent
  • 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
  • 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 sometimes contain one or more asymmetric centres, and can therefore form optical isomers (including diastereoisomers).
  • 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.
  • this protecting group 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.
  • 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.
  • 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;
  • lower alkoxycarbonyloxyalkyl 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)eth
  • 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;
  • 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.
  • 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 2 5 4,6-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
  • ester-forming residues of an amino acid such as glutamate and aspartate
  • carbamoyl groups which may optionally be substituted with 1 or 2 alkyl groups having from 1 to 6 carbon atoms as defined above;
  • (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.
  • Preferred compounds of formula (I) are compounds of formula (Ia) and pharmacologically acceptable salts and esters thereof:
  • R 2 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 R 14 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 R 12 and R 13 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms;
  • R 2 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 R 12 and R 13 is the same or different and is hydrogen, a methyl group or an ethyl group; (v) R 2 is hydroxyl;
  • R 3 is hydrogen or an alkyl group having from 1 to 4 carbon atoms;
  • R 3 is a methyl group;
  • R 4 is hydrogen or an alkyl group having from 1 to 4 carbon atoms;
  • R 4 is a methyl group;
  • each of R 7 and R 8 is a hydrogen atom and R and R 10 together with the carbon atom to which they are attached represent a carbonyl group, or
  • R 7 , R 8 , R 9 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 ⁇ 1 defined below), and substituent group ⁇ 1 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(R 163 J 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; (xi) R 7 , R 8 , R 9 and R 10 together with the carbon atoms to which they are attached represent an isoxazoly! group; and
  • each of R 5 and R 6 is a hydrogen atom or R 5 and R 6 together represent a single bond.
  • 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), R 3 selected from (vi) to (vii), R 4 selected from (viii) to (ix), R 7 ,
  • R 8 , R 9 and R 10 selected from (x) to (xi) and R 3 and R 6 selected from (xia) are also preferred.
  • 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 and stanozolol are known synthetic steroid hormones having antiandrogen activity.
  • Ethisterone (17 ⁇ -hydroxypregn-4-en-20-y ⁇ -3-o ⁇ e) is a progestogen that has been used in the past to treat menstrual disorders and as a component of combined oral contraceptives. Danazo!
  • each of R 20 , R 21 and R 24 is the same or different and is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms or R 21 is a hydrogen atom and R 2 and R " together represent a single bond;
  • each of R 20 , R 21 and R 2A is a hydrogen atom or R 21 is a hydrogen atom and R 20 and R 24 together represent a single bond;
  • R 17 is hydrogen or an alkyl group having from 1 to 4 carbon atoms
  • R 22 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 R 11 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 14 Ji wherein each group R 14 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 12 and R 13 is the same or different and is hydrogen or an alkyl group having from 1 to 4 carbon atoms; (xix) R 22 is hydroxyl, an alkanoyloxy group having 2 or 3 carbon atoms, a group of formula (II) wherein n is 0 and R n is a methyl group, an ethyl group, a hydroxyl group, a methoxy group
  • R 2i , R 26 , R 27 and R 28 together with the carbon atoms to which they are attached represent an isoxazolyl group.
  • 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:
  • 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 etha ⁇ ol 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, sorbita ⁇ 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,
  • 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.
  • 0.01 mg/ml formulation preferably 0.1 mg/ml formulation, most preferably 1 mg/ml formulation
  • 100 mg/ml formulation preferably 25 mg/ml formulation, most preferably 10 mg/ml formulation
  • 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 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
  • 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).
  • 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.
  • 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.
  • 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 ⁇ M and added to the ceils.
  • 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)

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Abstract

Cette invention concerne des compositions topiques contenant un stéroïde choisi dans le groupe composé d'éthistérone et de dérivés de celle-ci et de trilostane et de dérivés de celui-ci, ainsi que l'utilisation de ces stéroïdes dans la fabrication d'un médicament topique destiné à prévenir ou à traiter un état dermatologique pouvant être ainsi prévenu ou traité par modification de la croissance et de l'interaction d'un ou de plusieurs vaisseaux sanguins, adipocytes et fibroblastes et/ou par modification de la fibrose.
PCT/GB2005/050209 2004-11-22 2005-11-22 Formulations topiques a utiliser dans le traitement ou la prevention d'etats dermatologiques Ceased WO2006054119A1 (fr)

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GB0425633A GB2420281A (en) 2004-11-22 2004-11-22 Topical formulations for use in the treatment or prevention of dermatological conditions

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227457B2 (en) 2009-06-22 2012-07-24 Dmi Acquisition Corp. Method for treatment of diseases
EP2468282A3 (fr) * 2005-07-12 2012-09-12 DMI Biosciences, Inc. Procédés et produits de traitement des maladies
US9351979B2 (en) 2012-12-19 2016-05-31 Ampio Pharmaceuticals, Inc. Methods of treatment of diseases

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9173836B2 (en) 2003-01-02 2015-11-03 FemmeParma Holding Company, Inc. Pharmaceutical preparations for treatments of diseases and disorders of the breast
EP2104489A2 (fr) * 2006-12-26 2009-09-30 FemmePharma Holding Company, Inc. Administration topique de danazol

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004060322A2 (fr) * 2003-01-02 2004-07-22 Femmepharma Holding Company, Inc. Preparations pharmaceutiques permettant le traitement de maladies et d'affections du sein

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE531437A (fr) * 1953-08-26
US5869090A (en) * 1998-01-20 1999-02-09 Rosenbaum; Jerry Transdermal delivery of dehydroepiandrosterone
FR2819409B1 (fr) * 2001-01-17 2004-11-19 Sederma Sa Utilisation de diosgenine dans des compositions a usage cosmetique ou dermopharmaceutique
FR2825277B1 (fr) * 2001-05-30 2004-10-15 Oreal Composition cosmetique et/ou dermatologique et/ou pharmaceutique contenant au moins un compose ihnibiteur de l'enzime 3, b-hsd
FR2831441B1 (fr) * 2001-10-25 2003-12-26 Oreal Utilisation cosmetique de derives de la dhea
AU2003301809A1 (en) * 2002-05-13 2004-06-07 Children's Hospital Los Angeles Treatment and prevention of abnormal scar formation in keloids and other cutaneous or internal wounds or lesions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004060322A2 (fr) * 2003-01-02 2004-07-22 Femmepharma Holding Company, Inc. Preparations pharmaceutiques permettant le traitement de maladies et d'affections du sein

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2468282A3 (fr) * 2005-07-12 2012-09-12 DMI Biosciences, Inc. Procédés et produits de traitement des maladies
US8586568B2 (en) 2005-07-12 2013-11-19 Ampio Pharmaceuticals, Inc. Methods and products for treatment of diseases
US8722651B2 (en) 2005-07-12 2014-05-13 Ampio Pharmaceuticals, Inc. Methods and products for treatment of diseases
US8227457B2 (en) 2009-06-22 2012-07-24 Dmi Acquisition Corp. Method for treatment of diseases
US9233113B2 (en) 2009-06-22 2016-01-12 Ampio Pharmaceuticals, Inc. Method for treatment of diseases
US9987292B2 (en) 2009-06-22 2018-06-05 Ampio Pharmaceuticals, Inc. Method for treatment of diseases
US9351979B2 (en) 2012-12-19 2016-05-31 Ampio Pharmaceuticals, Inc. Methods of treatment of diseases
US10058562B2 (en) 2012-12-19 2018-08-28 Ampio Pharmaceuticals, Inc. Methods of treatment of diseases

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