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WO1999067270A1 - Esters d'acide cycloalkyl-carboxylique de 7.alpha.methyl-estr-4-en-3-one 17.beta.-ol (19-nor 7.alpha-methyltestosterone) - Google Patents

Esters d'acide cycloalkyl-carboxylique de 7.alpha.methyl-estr-4-en-3-one 17.beta.-ol (19-nor 7.alpha-methyltestosterone) Download PDF

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Publication number
WO1999067270A1
WO1999067270A1 PCT/EP1999/004101 EP9904101W WO9967270A1 WO 1999067270 A1 WO1999067270 A1 WO 1999067270A1 EP 9904101 W EP9904101 W EP 9904101W WO 9967270 A1 WO9967270 A1 WO 9967270A1
Authority
WO
WIPO (PCT)
Prior art keywords
ment
buciclate
compound
testosterone
alpha
Prior art date
Application number
PCT/EP1999/004101
Other languages
English (en)
Inventor
Dirk Leysen
Hendrikus Adrianus Antonius Van Der Voort
Jaap Van Der Louw
Original Assignee
Akzo Nobel N.V.
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 Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to AU45130/99A priority Critical patent/AU4513099A/en
Publication of WO1999067270A1 publication Critical patent/WO1999067270A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C07J1/0074—Esters
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • the invention is in the field of androgenic hormones, more specifically derivatives of testosterone.
  • Testosterone derivatives are known. Testosterone itself, the natural male hormone, has many known drawbacks as far as methods of administration are concerned. It has a short-lasting activity, is insoluble in the usual pharmaceutically acceptable media, and is not very potent. The more potent dihydrotestosterone (5 ⁇ -reduced form of testosterone) is considered a health-risk, notably for the prostate.
  • MENT 7 ⁇ -methyl-19-nortestosterone
  • related compounds such as disclosed in FR 4.521 M and US 5,342,834.
  • MENT suffers from a bad solubility and short duration of action.
  • male contraception may comprise a regimen of administration of hormones in which a progestagen serves to achieve a contraceptive effect and an androgen serves to supplement the resulting decreased testosterone level.
  • a progestagen serves to achieve a contraceptive effect
  • an androgen serves to supplement the resulting decreased testosterone level.
  • male contraception is performed with an androgenic hormone alone.
  • the regular androgen intake needed for this requires androgens which are improved as to potency and duration of action, and for which a practical way of administration is available.
  • an androgen which has a favourable relationship of potency and solubility, as a weak androgen will require more of it to be dissolved in order to attain the same activity than in the case of a more potent androgen.
  • R stands for cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and R' is hydrogen or a straight chain or branched chain alkyl group of 2-6 carbon atoms.
  • the invention is the compound (7 ⁇ ,17 ⁇ )-17-[[(tr ⁇ s , -4- butylcyclohexyl)carbonyl]oxy]-7-methylestr-4-en-3-one, which has the following structural formula II:
  • This preferred compound of the invention is also to be referred to as 7 ⁇ -methyl-19- nortestosterone buciclate, in short MENT buciclate.
  • the compounds of the invention have a significantly better solubility than could be expected on the basis of the known testosterone derivatives, including MENT. Moreover, the compounds of the invention have a surprisingly higher RDP than the known compounds.
  • the compounds of the invention can be prepared by esterification of the 17-OH group of MENT with a suitable carboxylic acid or carboxylic acid derivative, such as, in the case of the preferred compound, ⁇ rar ⁇ -4-butylcyclohexanecarboxylic acid or derivatives thereof.
  • a suitable carboxylic acid or carboxylic acid derivative such as, in the case of the preferred compound, ⁇ rar ⁇ -4-butylcyclohexanecarboxylic acid or derivatives thereof.
  • This esterification may be carried out using methods well known in the art or readily available from the chemical literature, for example, using methods and catalysts described in Advanced Organic Chemistry, J. March, 4th Ed, pages 1281-1282, 1992, or analogously with the compounds disclosed in US 4,948,790.
  • MENT can be prepared as disclosed in FR 4.521 M and US 5,342,834.
  • the invention also pertains to each of the above compounds, and particularly MENT buciclate, as a medicine.
  • the compounds of the invention being potent androgens, they can be used in, inter alia, male contraception and male or female hormone replacement therapy.
  • the invention also pertains to a method of treatment of androgen insufficiency, by administering to a human male or female an effective amount of a compound of the invention, such as MENT buciclate.
  • the invention also is in the use of of a compound of the invention, such as MENT buciclate for the preparation of a medicine for treating androgen insufficiency.
  • the term "androgen insufficiency" is to be understood to pertain to all kinds of diseases, disorders, and symptoms in which a male or a female suffers from too low a testosterone level, such as in hypogonadal men.
  • the androgen insufficiency to be treated by the compound of the invention is the reduction of the testosterone level which a human male incurs as a result of age (the compound of the invention is then used for male hormone replacement therapy), or when he is subject to male contraception.
  • the compound of the invention especially serves to neutralise the effect of regimens of male hormone contraception in which a sterilitant such as a progestagen or LHRH (luteinizing hormone releasing hormone) is administered regularly, e.g. daily, or it is used as the sole male contraceptive substance.
  • a sterilitant such as a progestagen or LHRH (luteinizing hormone releasing hormone) is administered regularly, e.g. daily, or it is used as the sole male contraceptive substance.
  • the invention also relates to pharmaceutical formulations comprising a compound of the invention, such as MENT buciclate and a pharmaceutically acceptable carrier.
  • the carrier may be in a solid form or liquid form
  • the formulation may be an oral dosage unit such as a tablet or, preferably, an oral solution, e.g. in a capsule.
  • Methods and compositions for making such dosage units are well-known to those skilled in the art. For example, conventional techniques for making tablets and pills, containing active ingredients, are described in the standard reference, Gennaro et al, Remington's Pharmaceutical Sciences,
  • the compound can also be administered via an implant, a patch, or any other suitable device for the sustained release of an androgen composition.
  • the preferred oral dosage unit is that of a capsule containing the compound of the invention taken up in a liquid medium as described below.
  • the compounds of the invention and notably MENT buciclate, have a solubility in oily media, which makes them particularly suitable for a liquid pharmaceutical formulation comprising a compound as defined above, and preferably MENT buciclate, dissolved in a pharmaceutically acceptable oil.
  • Suitable oils are, e.g. arachis oil, oleic acid, ricinus oil, sesam oil and the like. Arachis oil is preferred.
  • the preferred injection device is a needleless injection system, e.g. as described in US 5,599,302.
  • the compound may also be suspended in an aqueous medium, but the above solutions in oil are preferred.
  • Methods and compositions for making liquids suitable for parenteral administration are known in the art, see e.g. Remington's, pages 1545 ff.
  • any capsule made from a pharmaceutically acceptable wall material can be employed.
  • Methods and compositions for making capsules suitable for oral administration are known in the art, see e.g. Remington's, pages 1658 ff.
  • a preferred material is a softgel such as used for Andriol® capsules.
  • the invention also pertains to a method of treatment of androgen insufficiency, by administering to a human male, by injection or by means of an oral dosage unit, an effective amount of MENT buciclate dissolved in a pharmaceutically acceptable oil.
  • the invention also is in the use of MENT buciclate for the preparation of a medicine for treating androgen insufficiency by injecting into a human male an effective amount of MENT buciclate dissolved in a pharmaceutically acceptable oil, or by orally administering such an oily solution.
  • the dose of and regimen of administration of the compounds as defined above, or a pharmaceutical composition thereof, to be administered will obviously depend on the therapeutic effect to be achieved and will vary with the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered, and/or or the particular contraceptive or HRT regimen in which it is used. Typical doses are 100 mg or more per three months upon intramuscular administration and 50-250 mg, more preferably 80 mg per day upon oral administration.
  • Example 2a 25 EExxaammppllee 22bb > > 220000 > 250
  • Example 2f 50 ⁇ 10 EExxaammppllee 22gg 1100 25

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Endocrinology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un nouvel androgène (7α,17β)-17-[[(trans-4-butylcyclohexyl)carbonyl]oxy]-7méthylestr-4-en-3-one (buciclate de 7α-méthyl-19-nortestostérone -MENT-) et des esters de cycloalkyle associés. Ce composé se distingue favorablement des autres dérivés testostérone en ce qu'il possède une bonne solubilité dans des milieux huileux, et en ce qu'il démontre notamment un bon pouvoir de dissolution par rapport à la testostérone. Ce composé est spécialement conçu pour être administré par injection.
PCT/EP1999/004101 1998-06-19 1999-06-14 Esters d'acide cycloalkyl-carboxylique de 7.alpha.methyl-estr-4-en-3-one 17.beta.-ol (19-nor 7.alpha-methyltestosterone) WO1999067270A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU45130/99A AU4513099A (en) 1998-06-19 1999-06-14 Cycloalkyl-carboxylic acid esters of 7.alpha.methyl-estr-4-en-3-one 17.beta.-ol (19-nor 7.alpha.-methyltestosterone)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98202051.3 1998-06-19
EP98202051 1998-06-19

Publications (1)

Publication Number Publication Date
WO1999067270A1 true WO1999067270A1 (fr) 1999-12-29

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/004101 WO1999067270A1 (fr) 1998-06-19 1999-06-14 Esters d'acide cycloalkyl-carboxylique de 7.alpha.methyl-estr-4-en-3-one 17.beta.-ol (19-nor 7.alpha-methyltestosterone)

Country Status (4)

Country Link
AR (1) AR018888A1 (fr)
AU (1) AU4513099A (fr)
CO (1) CO5050334A1 (fr)
WO (1) WO1999067270A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101539A1 (fr) * 2002-05-30 2003-12-11 Akzo Nobel N.V. Injection contraceptive auto-administree d'une solution huileuse
WO2003101374A3 (fr) * 2002-05-30 2004-02-26 Akzo Nobel Nv Utilisation de nouveaux esters d'etonogestrel
US7323454B2 (en) 2002-05-30 2008-01-29 N.V. Organon Etonogestrel esters
US7718640B2 (en) 2003-03-14 2010-05-18 Bayer-Schering Pharma Ag Methods and pharmaceutical compositions for reliable achievement of acceptable serum testosterone levels
US7884222B2 (en) 2003-03-04 2011-02-08 Resolution Chemicals Limited Process for the production of tibolone
CN105732754A (zh) * 2014-12-01 2016-07-06 台湾永光化学工业股份有限公司 烷基酸睾酮化合物的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4948790A (en) * 1987-08-26 1990-08-14 Sydney Archer Long-acting androgenic compounds and pharmaceutical compositions thereof
US5342834A (en) * 1989-04-07 1994-08-30 The Population Council, Inc. Method for androgen supplementation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4948790A (en) * 1987-08-26 1990-08-14 Sydney Archer Long-acting androgenic compounds and pharmaceutical compositions thereof
US5342834A (en) * 1989-04-07 1994-08-30 The Population Council, Inc. Method for androgen supplementation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HUNT W L ET AL: "Sexual activity in castrated male rabbits after oral administration of 7.alpha.-methyl-19-nortestosterone 17-(1-adamantoate)", PHYSIOLOGY AND BEHAVIOR, vol. 11, no. 6, 1973, pages 893 - 896, XP002082863 *
MATLIN, S. A. ET AL: "Long-acting androgens: analytical and preparative HPLC of testosterone esters", JOURNAL OF HIGH RESOLUTION CHROMATOGRAPHY AND CHROMATOGRAPHY COMMUNICATIONS., vol. 10, no. 4, April 1987 (1987-04-01), DR.ALFRED HUETHIG VERLAG. HEIDELBERG., DE, pages 186 - 190, XP002115189, ISSN: 0935-6304 *
RAJALAKSHMI M ET AL: "Effect of two new androgen esters on serum levels of testosterone in castrated rhesus monkey", CONTRACEPTION, vol. 42, no. 2, 1990, pages 235 - 240, XP002082864 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101539A1 (fr) * 2002-05-30 2003-12-11 Akzo Nobel N.V. Injection contraceptive auto-administree d'une solution huileuse
WO2003101374A3 (fr) * 2002-05-30 2004-02-26 Akzo Nobel Nv Utilisation de nouveaux esters d'etonogestrel
JP2005533036A (ja) * 2002-05-30 2005-11-04 アクゾ・ノベル・エヌ・ベー 油性溶液の自己投与型避妊注射
US7323454B2 (en) 2002-05-30 2008-01-29 N.V. Organon Etonogestrel esters
AU2003246740B2 (en) * 2002-05-30 2009-01-08 N.V. Organon Use of new etonogestrel esters
US7884222B2 (en) 2003-03-04 2011-02-08 Resolution Chemicals Limited Process for the production of tibolone
US7718640B2 (en) 2003-03-14 2010-05-18 Bayer-Schering Pharma Ag Methods and pharmaceutical compositions for reliable achievement of acceptable serum testosterone levels
US8338395B2 (en) 2003-03-14 2012-12-25 Bayer Intellectual Property Gmbh Methods and pharmaceutical compositions for reliable achievement of acceptable serum testosterone levels
CN105732754A (zh) * 2014-12-01 2016-07-06 台湾永光化学工业股份有限公司 烷基酸睾酮化合物的合成方法
CN105732754B (zh) * 2014-12-01 2017-12-26 台湾永光化学工业股份有限公司 烷基酸睾酮化合物的合成方法

Also Published As

Publication number Publication date
AR018888A1 (es) 2001-12-12
CO5050334A1 (es) 2001-06-27
AU4513099A (en) 2000-01-10

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