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WO1994011385A1 - Steroides 17-alpha-acyle inhibant 5-alpha-reductase - Google Patents

Steroides 17-alpha-acyle inhibant 5-alpha-reductase Download PDF

Info

Publication number
WO1994011385A1
WO1994011385A1 PCT/US1993/011235 US9311235W WO9411385A1 WO 1994011385 A1 WO1994011385 A1 WO 1994011385A1 US 9311235 W US9311235 W US 9311235W WO 9411385 A1 WO9411385 A1 WO 9411385A1
Authority
WO
WIPO (PCT)
Prior art keywords
androst
butylcarboxamide
salt
diisopropylcarboxamide
ene
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.)
Ceased
Application number
PCT/US1993/011235
Other languages
English (en)
Inventor
Robert Lee Webb
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to US08/436,292 priority Critical patent/US5561124A/en
Priority to EP94902304A priority patent/EP0669931A1/fr
Priority to JP6512505A priority patent/JPH08503473A/ja
Publication of WO1994011385A1 publication Critical patent/WO1994011385A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
    • 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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • 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
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic

Definitions

  • substituted alkyl is linear or branched C]_-Ci2 substituted with one or more substituents selected from the group consisting of: aryl, acyloxy, amino, N- acylamino, oxo, carboxyalkyl, halogen and protected -OH;
  • cycloalkyl is nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12, optionally containing one or more heteroatoms, and optionally substituted with one or more substituents selected from the group consisting of: aryl, hydroxyalkyl, alkyl, alkoxy, acyloxy, amino, N-acylamino, oxo, carboxyalkyl, halogen and protected -OH; and
  • aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms and when C is 4 the aromatic ring contains at
  • ⁇ -eipmer as used herein is meant that the 17 ⁇ -acyl substituent of the steroidal 5 ⁇ reductase inhibitors disclosed herein as starting material is transformed to the ⁇ -position.
  • Preferred compounds of the invention and compounds used in the invented pharmaceutical compositions and the invented methods include:
  • cycloalkyl and substituted cycloalkyl as used herein include: cyclohexyl, 4-hydroxy- cyclohexyl, ethylcyclohexyl, propyl 4-methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl.
  • halogen as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
  • alkyl and “alkylidene” and derivatives thereof and in all carbon chains as used herein is meant a linear or branched monovalent or divalent carbon chain having C ⁇ -C ⁇ carbons. Examples of alkyl as used herein indued: -CH3, -CH2-CH3, -CH2- CH 2 -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -(CH 2 )3-CH3, -CH 2 -
  • Chemically alfuzosin is designated as N-[3-[(4- amino-6,7-dimethoxy-2-quinazolinyl)methylamino]- propyl]tetrahydro-2-furancarboxamide.
  • Minoxidil is designated as 2,4- pyrimidineadiamine, 6- (1-piperidinyl) -,3-oxide.
  • Minoxidil is the active ingredient in Rogaine® which is sold as topical solution for stimulating hair growth by the Upjohn Company, Kalamazoo, Michigan.
  • Parenteral administration which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • Fraction 1 All of the fractions designated Fraction 1, were combined and concentrated to approximately 1000 mL. The volume was divided and lyophylized. A methanolic solution of the residue from each flask was diluted to approximately 50 mL, and water added until the solution was cloudy ( ⁇ 25 mL) . Each cloudy solution was allowed to sit at room temperature overnight during which time the sample crystallized. The mixtures were filtered and the residues washed with water and dried in a vacuum oven at 60°C for 16 hours

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés stéroïdiens 17α-acyle inhibant 5α-réductase, des compositions pharmaceutiques contenant lesdits composés et des procédés d'utilisation desdits composés, afin d'inhiber la 5-α-réductase des stéroïdes. Elle concerne également de nouveaux procédés utilisés dans la préparation desdits composés.
PCT/US1993/011235 1992-11-18 1993-11-18 Steroides 17-alpha-acyle inhibant 5-alpha-reductase Ceased WO1994011385A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US08/436,292 US5561124A (en) 1992-11-18 1993-11-18 17-α-acyl steroids which inhibit 5-α-reductase
EP94902304A EP0669931A1 (fr) 1992-11-18 1993-11-18 Steroides 17-alpha-acyle inhibant 5-alpha-reductase
JP6512505A JPH08503473A (ja) 1992-11-18 1993-11-18 ５−アルファ−レダクターゼを阻害する１７−アルファーアシルステロイド

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929224148A GB9224148D0 (en) 1992-11-18 1992-11-18 Compounds
GB9224148.8 1992-11-18

Publications (1)

Publication Number Publication Date
WO1994011385A1 true WO1994011385A1 (fr) 1994-05-26

Family

ID=10725271

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/011235 Ceased WO1994011385A1 (fr) 1992-11-18 1993-11-18 Steroides 17-alpha-acyle inhibant 5-alpha-reductase

Country Status (4)

Country Link
EP (1) EP0669931A1 (fr)
JP (1) JPH08503473A (fr)
GB (1) GB9224148D0 (fr)
WO (1) WO1994011385A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
US5618806A (en) * 1992-04-30 1997-04-08 Smithkline Beecham Corporation 17α and 17β-substituted estra-1,3,5(10)-triene-3-carbboxlic acid
US5641877A (en) * 1992-11-18 1997-06-24 Smithkline Beecham Corporation 17-α and 17-β substituted acyl-3-carboxy-3, 5-dienes and use in inhibiting 5-α-reductase
US5683995A (en) * 1992-11-18 1997-11-04 Smithkline Beecham Corporation 17 substituted acyl-3-carboxy 3,5-diene steroidals as α-reductase inhibitors
US5843953A (en) * 1994-10-25 1998-12-01 Merck & Co., Inc. 7-substituted 4-aza cholanic acid derivatives and their use
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
USRE39056E1 (en) 1995-09-15 2006-04-04 Merck & Co, Inc. 4-Azasteroids for treatment of hyperandrogenic conditions
LU102470A1 (en) * 2020-03-16 2021-11-09 Jiangsu Lianhuan Pharmaceutical Co Ltd Epristeride impurity and preparation method and application thereof
CN113831387A (zh) * 2021-10-18 2021-12-24 湖南科瑞生物制药股份有限公司 非那雄胺异构体17α-非那雄胺的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19750073A1 (de) * 1997-11-12 1999-05-20 Bosch Gmbh Robert Schaltungsträgerplatte

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4970204A (en) * 1989-08-23 1990-11-13 Smithkline Beecham Corporation 3-substituted nitro-steroid derivatives as 5-α-reductase inhibitors
US4970199A (en) * 1987-06-18 1990-11-13 Merck & Co., Inc. Steroidal glycolipids as host resistance stimulators against viral infection
US5100917A (en) * 1989-12-29 1992-03-31 Merrell Dow Pharmaceuticals Inc. Novel a-nor-steroid-3-carboxylic acid derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4039669A (en) * 1975-08-01 1977-08-02 Sterling Drug Inc. Composition for topical application and use thereof
ES2105108T3 (es) * 1992-04-20 1997-10-16 Sankyo Co Esteroides para el tratamiento de la hipertrofia prostatica, su preparacion y su utilizacion.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4970199A (en) * 1987-06-18 1990-11-13 Merck & Co., Inc. Steroidal glycolipids as host resistance stimulators against viral infection
US4970204A (en) * 1989-08-23 1990-11-13 Smithkline Beecham Corporation 3-substituted nitro-steroid derivatives as 5-α-reductase inhibitors
US5100917A (en) * 1989-12-29 1992-03-31 Merrell Dow Pharmaceuticals Inc. Novel a-nor-steroid-3-carboxylic acid derivatives

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Journal of Chromatography, Volume 631, issued 1993, BOPPANA et al., "Normal-Phase High-Performance Liquid Chromatography Determination of Epristeride, a Prostatic Steroid 5-alpha-Reductase Enzyme Inhibitor, in Human Plasma", pages 251-254, entire document. *
Journal of Medicinal Chemistry, Volume 33, No. 3, issued 1990, HOLT et al., "Inhibition of Steroid 5-alpha-Reductase by Unsaturated 3-Carboxysteroids", pages 943-950, entire document. *
Journal of Medicinal Chemistry, Volume 33, No. 3, issued 1990, HOLT et al., "Steroidal A Ring Aryl Carboxylic Acids: A New Class of Steroid 5-alpha-Reductase Inhibitors", pages 937-942, entire document. *
Journal of Steroid Biochemistry and Molecular Biology, Volume 37, No. 4, issued 1990, BRANDT et al., "Studies on the Mechanism of Steroid 5-alpha-Reductase Inhibition by 3-Carboxy A-Ring Aryl Steroids", pages 575-579, entire document. *
See also references of EP0669931A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618806A (en) * 1992-04-30 1997-04-08 Smithkline Beecham Corporation 17α and 17β-substituted estra-1,3,5(10)-triene-3-carbboxlic acid
US5641877A (en) * 1992-11-18 1997-06-24 Smithkline Beecham Corporation 17-α and 17-β substituted acyl-3-carboxy-3, 5-dienes and use in inhibiting 5-α-reductase
US5641765A (en) * 1992-11-18 1997-06-24 Smithkline Beecham Corporation 17-αand 17-βsubstituted acyl-3-carboxy-3,5-dienes and use in inhibiting 5-α-reductase
US5683995A (en) * 1992-11-18 1997-11-04 Smithkline Beecham Corporation 17 substituted acyl-3-carboxy 3,5-diene steroidals as α-reductase inhibitors
US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
US5843953A (en) * 1994-10-25 1998-12-01 Merck & Co., Inc. 7-substituted 4-aza cholanic acid derivatives and their use
USRE39056E1 (en) 1995-09-15 2006-04-04 Merck & Co, Inc. 4-Azasteroids for treatment of hyperandrogenic conditions
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
LU102470A1 (en) * 2020-03-16 2021-11-09 Jiangsu Lianhuan Pharmaceutical Co Ltd Epristeride impurity and preparation method and application thereof
CN113831387A (zh) * 2021-10-18 2021-12-24 湖南科瑞生物制药股份有限公司 非那雄胺异构体17α-非那雄胺的制备方法

Also Published As

Publication number Publication date
JPH08503473A (ja) 1996-04-16
GB9224148D0 (en) 1993-01-06
EP0669931A4 (fr) 1995-10-04
EP0669931A1 (fr) 1995-09-06

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