US20050026889A1 - 17Afla,21-dihydroxypregnene esters as antiandrogenic agents - Google Patents

17Afla,21-dihydroxypregnene esters as antiandrogenic agents Download PDF

Info

Publication number
US20050026889A1
US20050026889A1 US10/486,386 US48638604A US2005026889A1 US 20050026889 A1 US20050026889 A1 US 20050026889A1 US 48638604 A US48638604 A US 48638604A US 2005026889 A1 US2005026889 A1 US 2005026889A1
Authority
US
United States
Prior art keywords
hydrogen
compounds
dione
acyl
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/486,386
Other languages
English (en)
Inventor
Mauro Ajani
Luigi Moro
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cosmo SpA
Original Assignee
Cosmo SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cosmo SpA filed Critical Cosmo SpA
Assigned to COSMO SPA. reassignment COSMO SPA. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AJANI, MAURO, MORO, LUIGI
Publication of US20050026889A1 publication Critical patent/US20050026889A1/en
Priority to US12/457,870 priority Critical patent/US8143240B2/en
Priority to US13/398,222 priority patent/US20120149671A1/en
Priority to US14/103,707 priority patent/US8865690B2/en
Priority to US14/474,765 priority patent/US9211295B2/en
Priority to US14/885,488 priority patent/US9895379B2/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • 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
    • A61P17/08—Antiseborrheics
    • 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
    • A61P17/10—Anti-acne agents
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • the present invention relates to 17 ⁇ ,21-dihydroxypregnene esters, processes for the preparation thereof and the use thereof as antiandrogenic agents.
  • corticosteroids have been used as anti-inflammatory, anti-rheumatic, anti-allergic and anti-shock agents.
  • 11-deoxy-hydrocortisone esters and derivatives thereof have been widely used as anti-inflammatories.
  • Carboxylic acids 17 or 21 monoesters having no more than six carbon atoms are also known.
  • U.S. Pat. No. 3,152,154 discloses the preparation of 21-hydroxypregna-4,9-diene-3,20-dione-17 ⁇ -butyrate, which is used as an intermediate for the preparation of 3,21-diacyloxy-17 ⁇ -butanoyloxypregna-3,5,9-triene-20-one wherein the 3 and 21 acyls are the same and are acetyl, propanoyl, butanoyl and isobutanoyl. All of the examples cited in these documents concern compounds wherein the 17 ⁇ and 21 positions are esterified with the same acyl group.
  • U.S. Pat. No. 3,530,038 discloses a process for the preparation of 11 ⁇ -17 ⁇ -21-trihydroxy steroids which comprises subjecting 11-deoxy-17 ⁇ -OR-21-OR′ steroids, wherein R is a carboxylic acid residue of 1-18 carbon atoms and R′ is hydrogen or an acyl of 1 to 18 carbon atoms, to microbiological oxidation with Curvularia for obtaining the corresponding 11 ⁇ -hydroxy steroid.
  • U.S. Pat. No. 3,780,177 discloses the preparation of 21-hydroxy-pregna-4,9-diene-3,20-dione-17 ⁇ -butanoate by means of orthobutyrates and the use thereof as an intermediate for the preparation of 6 ⁇ ,9 ⁇ -difluoroprednisolone 17-butanoate-21 ester derivatives.
  • the present invention relates to compounds of formula (I) wherein: R 1 and R 2 , which can be the same or different, are hydrogen or a C 3 -C 18 acyl group, with the provisos that:
  • the invention relates to compounds of formula (II) wherein: R 1 and R 2 , which can be the same or different, are hydrogen or a C 3 -C 18 acyl group, with the proviso that:
  • the invention relates to a process for the preparation of compounds of formula (I) or (II) in which R 1 and R 2 are both acyl groups, which process comprises reacting the corresponding compounds, wherein R 1 and R 2 are hydrogen, with carboxylic acids anhydrides or active esters in inert solvents and at temperatures ranging from ⁇ 5° C. to the reaction mixture boiling temperature.
  • Still a further object of the invention relates to a process for the preparation of compounds of formula (I) or (II) wherein one of R 1 or R 2 is hydrogen and the other is acyl, which process comprises:
  • Preferred compounds of formula (I) are:
  • the test was carried out on sexually immature female hamsters aged 6-8 weeks and weighing 65-90 grams.
  • the compounds of the invention proved active at doses ranging from 10 to 4000 micrograms.
  • the compounds of the invention can be used as suitable pharmaceutical compositions for the topical and/or systemic treatment, through the oral, cutaneous or mucosal route, of conditions such as: acne, seborrhea, hirsutism, alopecia, mastodynia, prostate hyperplasia and carcinoma, virilization syndromes in the female, early puberty, inhibition of sexual aggressiveness in the male, contraception in the male.
  • conditions such as: acne, seborrhea, hirsutism, alopecia, mastodynia, prostate hyperplasia and carcinoma, virilization syndromes in the female, early puberty, inhibition of sexual aggressiveness in the male, contraception in the male.
  • compounds of formula (I) or (II) wherein R 1 and R 2 are both acyl groups are prepared by esterification of 17 ⁇ ,21-dihydroxypregna-4-ene-3,20-dione or 17 ⁇ ,21-dihydroxypregna-4,9-diene-3,20-dione hydroxy groups with active esters containing the desired acyl group.
  • acyl derivatives with hindering aliphatic chains such as those with high number of carbon atoms or branched, can be prepared.
  • Suitable active esters for this reaction are trifluoroethyl butyrate or trifluoroethyl octadecanoate, which can both attain excellent esterification yields with the aid of a lipase in inert anhydrous solvents at temperatures ranging from 20 to 50° C. and with reaction times ranging from 20 to 100 hours.
  • lipases are PPL (porcine pancreatic lipase) or those from Candida cylindracea.
  • the 21 hydroxyl is selectively esterified with allyloxycarbonyl chloride, benzyloxy carbonyl chloride, tert-butylcarbonyl chloride in dimethylformamide or isobutene at temperatures from ⁇ 5 to 40° C.
  • the resulting 21 monoester is then subjected to esterification with anhydrides of carboxylic acids of 7 carbon atoms in the presence of 4-dimethylaminopyridine as catalyst.
  • Alternative to the esterification in 17 is the use of the carboxylic acid in the presence of dicyclohexylcarbodiimide.
  • Active esters such as trifluoroethyl derivatives or N-acylphthalimide or N-acylbenzotriazoles are further alternatives.
  • the protection in 21 is removed with, for example, tetrakis(triphenylphosphine) Pd and triphenyl phosphine in dichloromethane or tetrahydrofuran to obtain 17 ⁇ -acyl-21-hydroxypregna-4-ene-3,20-dione or 17 ⁇ -acyl-21-hydroxypregna-4,9-diene-3,20-dione.
  • the resulting residue was added with further 10 ml of trifluoroethyl butanoate and 50 ml of tetrahydrofuran, the resulting solution was added with 0.8 g of Bacillus subtilis protease and the suspension was stirred for 2 days at 45° C., adding further protease at regular time intervals for total 80 mg.
  • the protease was filtered off, the filtrate was removed under vacuum and the residue was chromatographed on a silica gel column with a dichloromethane/methanol 99:1 mixture. The less polar fraction was evaporated to obtain 1 g (2.06 mM) of 17 ⁇ ,21-dibutanoyl-pregna-4,9-diene-3,20-dione.
  • Step a A solution of 2 g of NaOH in 20 ml of water was added with 25 ml of tetrahydrofuran and 5 g (14.5 mM) of 17 ⁇ ,21-dihydroxy-pregna-4,9-diene-3,20-dione. The mixture was stirred at 0° C., then 2.4 ml of allyl chloroformate was dropwise added. After stirring for about 0.5 hours at this temperature, the mixture was carefully neutralized with hydrochloric acid and extracted with dichloromethane. The organic extract was concentrated under vacuum and the residue was subjected to the reaction of the subsequent step.
  • Step b Crude 17 ⁇ -hydroxy-21-allylcarbonyloxy-pregna-4,9-diene-3,20-dione was dissolved in 15 g of trifluoroethyl octadecanoate and 150 ml of tetrahydrofuran, the resulting solution was added with 4 g of Bacillus subtilis protease and the suspension was stirred for 2 days at 45° C., adding further protease at regular time intervals to 3 g total. The protease was filtered off, the filtrate was removed under vacuum and the residue was chromatographed on a silica gel column with a dichloromethane/methanol 99:1 mixture. The less polar fraction was evaporated off to obtain a residue of 17 ⁇ -octadecanoyl-21-allylcarbonyloxy-pregna-4,9-diene-3,20-dione.
  • Step c the residue from the previous step was dissolved in 50 ml of dichloromethane and added with 35 mg of triphenylphosphine and 35 mg of palladium triphenylphosphine. The resulting mixture was stirred for 0.5 hours at room temperature. The solution was concentrated under vacuum, the residue was taken up twice with dichloromethane, then chromatographed on a silica gel column with a dichloromethane/methanol 99:1 mixture. The richer fraction was evaporated to obtain a neat residue, which was used as such for the subsequent step.
  • Step d the residue (6,2 g) of 17 ⁇ -octadecanoyl-21-hydroxy-pregna-4-ene-3,20-dione was dissolved in 4 ml butyric anhydride in the presence of 0.5 g of tributylmethylammonium chloride. The mixture was stirred at room temperature for 2 hours, then poured in ice and the resulting product was separated from water by extraction. The extract was washed to neutrality with water and concentrated under vacuum, the residue was crystallized from methanol to obtain 5.5 g (8.05 mM) of 17 ⁇ -octadecanoyl-21-butanoyl-pregna-4,9-diene-3,20-dione. This compound was used for the preparation of a pharmaceutical formulation in the form of a cream suitable for cutaneous administration.
  • the compounds of Examples 1-5 were formulated in suitable formulations, for example in the form of liposome emulsions or suspensions for the transmucosal administration to provide either systemic or topical action, creams, gel and the like.
  • Topical Mean difference of treatment Daily dosage ( ⁇ g) the areas (mm 2 ) % inhibition Carrier (acetone) — 0.0 — TP 4 22.7 ⁇ 2.3 — TP + A 4 + 400 3.7 ⁇ 1.1 84 DHT 4 20.8 ⁇ 2.5 — DHT + A 4 + 400 9.7 ⁇ 1.8 53
  • Topical Mean difference of treatment Daily dosage ( ⁇ g) the areas (mm 2 ) % inhibition Carrier (acetone) — 0.0 — TP 4 22.7 ⁇ 2.3 — TP + Ex. 1 4 + 400 2.4 ⁇ 1.1 89 DHT 4 20.8 ⁇ 2.5 — DHT + Ex. 1 4 + 400 3.7 ⁇ 0.7 82

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Dispersion Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US10/486,386 2001-08-10 2002-07-24 17Afla,21-dihydroxypregnene esters as antiandrogenic agents Abandoned US20050026889A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US12/457,870 US8143240B2 (en) 2001-08-10 2009-06-24 17α, 21-dihydroxypregnene esters as antiandrogenic agents
US13/398,222 US20120149671A1 (en) 2001-08-10 2012-02-16 17alpha, 21-dihydroxypregnene esters as antiandrogenic agents
US14/103,707 US8865690B2 (en) 2001-08-10 2013-12-11 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents
US14/474,765 US9211295B2 (en) 2001-08-10 2014-09-02 17 alpha, 21-dihydroxypregnene esters as antiandrogenic agents
US14/885,488 US9895379B2 (en) 2001-08-10 2015-10-16 17alpha, 21-dihydroxypregnene esters as antiandrogenic agents

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT2001MI001762A ITMI20011762A1 (it) 2001-08-10 2001-08-10 Esteri di 17alfa,21-diidrossipregnene, loro uso come agenti anti-androgenetici e procedimenti per la loro preparazione
ITMIO1A0011762 2001-08-10
PCT/EP2002/008226 WO2003014141A1 (en) 2001-08-10 2002-07-24 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/008226 A-371-Of-International WO2003014141A1 (en) 2001-08-10 2002-07-24 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/457,870 Division US8143240B2 (en) 2001-08-10 2009-06-24 17α, 21-dihydroxypregnene esters as antiandrogenic agents

Publications (1)

Publication Number Publication Date
US20050026889A1 true US20050026889A1 (en) 2005-02-03

Family

ID=11448271

Family Applications (6)

Application Number Title Priority Date Filing Date
US10/486,386 Abandoned US20050026889A1 (en) 2001-08-10 2002-07-24 17Afla,21-dihydroxypregnene esters as antiandrogenic agents
US12/457,870 Active 2025-03-07 US8143240B2 (en) 2001-08-10 2009-06-24 17α, 21-dihydroxypregnene esters as antiandrogenic agents
US13/398,222 Abandoned US20120149671A1 (en) 2001-08-10 2012-02-16 17alpha, 21-dihydroxypregnene esters as antiandrogenic agents
US14/103,707 Expired - Lifetime US8865690B2 (en) 2001-08-10 2013-12-11 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents
US14/474,765 Expired - Lifetime US9211295B2 (en) 2001-08-10 2014-09-02 17 alpha, 21-dihydroxypregnene esters as antiandrogenic agents
US14/885,488 Expired - Lifetime US9895379B2 (en) 2001-08-10 2015-10-16 17alpha, 21-dihydroxypregnene esters as antiandrogenic agents

Family Applications After (5)

Application Number Title Priority Date Filing Date
US12/457,870 Active 2025-03-07 US8143240B2 (en) 2001-08-10 2009-06-24 17α, 21-dihydroxypregnene esters as antiandrogenic agents
US13/398,222 Abandoned US20120149671A1 (en) 2001-08-10 2012-02-16 17alpha, 21-dihydroxypregnene esters as antiandrogenic agents
US14/103,707 Expired - Lifetime US8865690B2 (en) 2001-08-10 2013-12-11 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents
US14/474,765 Expired - Lifetime US9211295B2 (en) 2001-08-10 2014-09-02 17 alpha, 21-dihydroxypregnene esters as antiandrogenic agents
US14/885,488 Expired - Lifetime US9895379B2 (en) 2001-08-10 2015-10-16 17alpha, 21-dihydroxypregnene esters as antiandrogenic agents

Country Status (14)

Country Link
US (6) US20050026889A1 (ja)
EP (1) EP1421099B1 (ja)
JP (1) JP4354809B2 (ja)
KR (1) KR100889595B1 (ja)
CN (1) CN1246328C (ja)
AT (1) ATE289318T1 (ja)
AU (1) AU2002328956B2 (ja)
CA (1) CA2454675C (ja)
DE (1) DE60203013T2 (ja)
ES (1) ES2238595T3 (ja)
IT (1) ITMI20011762A1 (ja)
MX (1) MXPA04001274A (ja)
PT (1) PT1421099E (ja)
WO (1) WO2003014141A1 (ja)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100184735A1 (en) * 2007-05-03 2010-07-22 Richard Hochberg Locally active "soft" antiandrogens
US9486458B2 (en) * 2007-08-03 2016-11-08 Cassiopea Spa Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US10603327B2 (en) 2015-06-22 2020-03-31 Cassiopea S.P.A. High concentration formulation

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2880276A1 (fr) * 2005-01-05 2006-07-07 Lefebvre Dominique Caparros Utilisation des anti-androgenes dans le traitement des comportements agressifs ou impulsifs induits par des maladies du systeme nerveux central
ITMI20051695A1 (it) * 2005-09-14 2007-03-15 Cosmo Spa Uso di 17a-esteri c3-c10 del 9,11-deidrocortexolone cme agenti anti-gonadotropinici
AU2014233572B2 (en) * 2007-08-03 2016-03-03 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
KR101591482B1 (ko) * 2008-05-28 2016-02-03 레베라겐 바이오파마 인코포레이티드 질환의 치료를 위한 ＮＦ-κＢ 의 비호르몬성 스테로이드 조절제
EP2556083A4 (en) 2010-04-05 2013-12-04 Validus Biopharma Inc NONHORMONAL STEROID MODULATORS OF NF-KAPPA-B FOR DISEASE TREATMENT
ITMI20132157A1 (it) 2013-12-20 2015-06-21 Cosmo Dermatos Srl Cortexolone 17alfa-propionate for use in the treatment of skin wounds and/or atrophic skin disorders . cortexolone 17alfa-propionato per uso nel trattamento delle ferite della pelle e/o disordini atrofici della pelle.
EP3006453A1 (en) * 2014-10-08 2016-04-13 Cosmo Technologies Ltd. 17alpha-monoesters and 17alpha,21-diesters of cortexolone for use in the treatment of tumors
US10799514B2 (en) 2015-06-29 2020-10-13 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kappa beta for treatment of disease
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions
IT202100008429A1 (it) 2021-04-06 2022-10-06 Farmabios Spa Processo per la preparazione di cortexolone 17α-propionato e sua nuova forma cristallina idrata
CN116135871A (zh) * 2021-11-16 2023-05-19 石家庄迪斯凯威医药科技有限公司 一种具有抗耐药性的抗菌化合物
CN115073546A (zh) * 2022-06-01 2022-09-20 浙江神洲药业有限公司 一种新型雄激素受体抑制剂的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2985650A (en) * 1958-05-28 1961-05-23 Syntex Sa 6alpha-ammonio-derivatives of 11-keto cortical hormones
US3152154A (en) * 1961-06-24 1964-10-06 Vismara Francesco Spa 17-monoesters of 17alpha, 21-dihydroxy steroids and process for the preparation thereof
US4670427A (en) * 1984-01-20 1987-06-02 Schering Aktiengesellschaft 1α,2α-methylene-6-methylene- and 6α-methylpregnenes, their preparation and pharmaceutical use
US5264428A (en) * 1990-02-16 1993-11-23 Kanoldt Arzneimittel Gmbh Use of stigmasta-4-en-3-one in the treatment of androgen dependent diseases

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL6605515A (ja) 1966-04-25 1967-10-26
NL6605514A (ja) * 1966-04-25 1967-10-26
US3780177A (en) * 1967-06-16 1973-12-18 Warner Lambert Co 17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use
JPS5910799B2 (ja) 1975-07-15 1984-03-12 大正製薬株式会社 プレグナン系ステロイド １７−エステル類の製法
DE3243482A1 (de) 1982-11-22 1984-05-24 Schering AG, 1000 Berlin und 4709 Bergkamen Neue 6(alpha)-methylkortikoide, ihre herstellung und verwendung
JPH08135789A (ja) 1994-11-09 1996-05-31 Komatsu Ltd 車両の油圧式駆動装置の変速装置およびその変速制御方法
DE19653730C2 (de) 1996-12-11 1999-06-24 Schering Ag Immobilisierte Proteine aus Rohextrakt und deren Verwendung zur Umsetzung von Estern
JP2004530703A (ja) 2001-05-22 2004-10-07 ファイザー・プロダクツ・インク 結晶形アジスロマイシン
ES2273061T3 (es) 2002-08-02 2007-05-01 Schering Aktiengesellschaft Agentes moduladores de receptores de progesterona con actividad antigonadotropa elevada para el control de fertilidad femenina y para la terapia por reemplazo hormonal.

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2985650A (en) * 1958-05-28 1961-05-23 Syntex Sa 6alpha-ammonio-derivatives of 11-keto cortical hormones
US3152154A (en) * 1961-06-24 1964-10-06 Vismara Francesco Spa 17-monoesters of 17alpha, 21-dihydroxy steroids and process for the preparation thereof
US4670427A (en) * 1984-01-20 1987-06-02 Schering Aktiengesellschaft 1α,2α-methylene-6-methylene- and 6α-methylpregnenes, their preparation and pharmaceutical use
US5264428A (en) * 1990-02-16 1993-11-23 Kanoldt Arzneimittel Gmbh Use of stigmasta-4-en-3-one in the treatment of androgen dependent diseases

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100184735A1 (en) * 2007-05-03 2010-07-22 Richard Hochberg Locally active "soft" antiandrogens
US8552061B2 (en) 2007-05-03 2013-10-08 Yale University Locally active “soft” antiandrogens
US9486458B2 (en) * 2007-08-03 2016-11-08 Cassiopea Spa Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US10603327B2 (en) 2015-06-22 2020-03-31 Cassiopea S.P.A. High concentration formulation
US10980819B2 (en) 2015-06-22 2021-04-20 Cassiopea S.P.A. High concentration formulation
US11213531B2 (en) 2015-06-22 2022-01-04 Cassiopea S.P.A. High concentration formulation
US11883415B2 (en) 2015-06-22 2024-01-30 Cassiopea S.P.A. High concentration formulation

Also Published As

Publication number Publication date
US20140154306A1 (en) 2014-06-05
US9211295B2 (en) 2015-12-15
PT1421099E (pt) 2005-05-31
JP2005504762A (ja) 2005-02-17
US20150216878A1 (en) 2015-08-06
CA2454675C (en) 2009-05-26
WO2003014141A1 (en) 2003-02-20
US20120149671A1 (en) 2012-06-14
US8865690B2 (en) 2014-10-21
US9895379B2 (en) 2018-02-20
JP4354809B2 (ja) 2009-10-28
ITMI20011762A1 (it) 2003-02-10
ITMI20011762A0 (it) 2001-08-10
US8143240B2 (en) 2012-03-27
ES2238595T3 (es) 2005-09-01
US20160263127A1 (en) 2016-09-15
CN1246328C (zh) 2006-03-22
KR20040023748A (ko) 2004-03-18
CA2454675A1 (en) 2003-02-20
EP1421099B1 (en) 2005-02-16
KR100889595B1 (ko) 2009-03-20
AU2002328956B2 (en) 2007-08-16
ATE289318T1 (de) 2005-03-15
DE60203013D1 (de) 2005-03-24
CN1541220A (zh) 2004-10-27
DE60203013T2 (de) 2006-02-09
US20090264396A1 (en) 2009-10-22
MXPA04001274A (es) 2005-06-06
EP1421099A1 (en) 2004-05-26

Similar Documents

Publication Publication Date Title
US9895379B2 (en) 17alpha, 21-dihydroxypregnene esters as antiandrogenic agents
US20230104965A1 (en) Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
AU2002328956A1 (en) 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents
EP0503388B1 (en) Pregna-21-oic acid esters
AU2014233572B2 (en) Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
Suzuki et al. General and facile method for determination of configuration of steroid-17-yl methyl glycolates at C-20 based on kinetic examination

Legal Events

Date Code Title Description
AS Assignment

Owner name: COSMO SPA., ITALY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:AJANI, MAURO;MORO, LUIGI;REEL/FRAME:015875/0918

Effective date: 20031203

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION