WO2003053993A1 - Androgenic 14.alpha, 17.alpha-ethenosteroids - Google Patents

Androgenic 14.alpha, 17.alpha-ethenosteroids Download PDF

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WO2003053993A1
WO2003053993A1 PCT/EP2002/014282 EP0214282W WO03053993A1 WO 2003053993 A1 WO2003053993 A1 WO 2003053993A1 EP 0214282 W EP0214282 W EP 0214282W WO 03053993 A1 WO03053993 A1 WO 03053993A1
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alpha
compounds
androgenic
male
methyl
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PCT/EP2002/014282
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French (fr)
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Dirk Leysen
Joseph Maria Gerardus Barbara Cals
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Akzo Nobel N.V.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • 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 relates to 14 ⁇ ,17 ⁇ -ethenosteroids and is in the field of steroids for use as androgens.
  • Androgenic steroids such as testosterone and its derivatives
  • testosterone As a medicine 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.
  • Oral dosage forms e.g. solid dosage forms such as tablets and capsules, are among the most widely accepted forms of administration.
  • R is O, (H,H), (H,OH), ⁇ OH, wherein OH is optionally etherified or esterified;
  • R 2 is hydrogen, or (C,. 1S ) acyl; and the dotted lines indicate one or two optional bonds, have powerful androgenic activity.
  • An particular embodiment of the invention is the group of compounds in which R, is oxo.
  • a specific embodiment of the invention is 17 ⁇ -hydroxy-7 ⁇ -methyl-14 ⁇ ,17 ⁇ - ethenoestr-4-en-3-one.
  • the stereochemical indicators ⁇ and ⁇ should be interpreted to lead to compounds within the group defined by formula I.
  • 7 ⁇ -methyl-14 ⁇ ,17 ⁇ -ethenosteroids of the invention have the natural configurations 5 ⁇ , 8 ⁇ , 9 ⁇ , lO ⁇ , and 13 ⁇ .
  • (C,. 15 ) acyl means an acyl group derived from a carboxylic acid having 1- 15 carbon atoms, like formyl, acetyl, propanoyl, butyryl, 2-methylpropanoyl, pentanoyl, pivaloyl, hexanoyl etc. Also included within the definition of (C,. 15 ) acyl are acyl groups derived from dicarboxylic acids, like hemi-maloyl, hemi-succinoyl, hemi-glutaroyl, and so on. Preferred is hemi-succinoyl.
  • the compounds of the invention may be produced by various methods known in the art of organic chemistry in general, and especially in the art of the chemistry of steroids (see, for example: Fried, J. et al, Organic Reactions in Steroid Chemistry, Volumes I and II, Nan ⁇ ostrand Reinhold Company, New York, 1972).
  • a convenient starting material for the preparation of compounds of formula I wherein R, is oxo; R 2 is hydrogen; and the dotted lines indicate a ⁇ 4 double bond, is for instance a compound of formula II, whose synthesis is known in literature [Rasmusson, G.H. et al, Steroids 22, 107 (1973)].
  • the invention also pertains to the compounds described hereinbefore as a medicine.
  • the compounds of the present invention being potent androgens, can be used in, int.al., 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 any of the above compounds.
  • the invention also is in the use of any of the above compounds 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.
  • the androgens can be administered principally via any suitable route available to the skilled person.
  • oral administration is preferred, most preferably in the form of a solid dosage unit such as a tablet or a capsule.
  • the invention also relates to pharmaceutical formulations comprising a compound as described hereinbefore and a pharmaceutically acceptable carrier.
  • the carrier may be in a solid form or liquid form, and the formulation may be an oral dosage unit such as a tablet or 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.
  • 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 dose of and regimen of administration of the compounds of the invention, 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 dosage amounts are 0.001-5 mg per kg body weight.
  • the transactivative androgen activity of the compounds of the invention was measured in Chinese hamster ovary cells (CHO) transfected with the human androgen receptor (hAR), in combination with a mouse mammary tumor virus (MMTV), and luciferase receptor gene (incubation time 16 h, temperature 37 °C) and compared with the activity of 5 ⁇ -dihydrotestosterone [Schoonen, W.G.E.J.; de Ries, R.J.H.; Joosten, J.W.H.; Mathijssen-Mommers, G.J.W.; Kloosterboer, H.J., Analyt. Biochem. 261 . , 222-224 (1998)]. Results are collected in Table 1.

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

Abstract

The invention makes steroids available having formula (I) wherein R1 is O, (H,H), (H, OH), NOH, wherein OH is optionally etherified or esterified; R2 is hydrogen, or (C1-15)acyl; and the dotted lines indicate one or two optional bonds, for use as androgenic medicines.

Description

ANDROGENIC 14.ALPHA, 17.ALPHA. -ETHENOSTEROIDS
The invention relates to 14α,17α-ethenosteroids and is in the field of steroids for use as androgens.
Androgenic steroids, such as testosterone and its derivatives, are known. As a medicine 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. In the field of pharmaceutical preparations in general it is a common desire for a medicinal agent to be orally active. Oral dosage forms, e.g. solid dosage forms such as tablets and capsules, are among the most widely accepted forms of administration. In the field of androgens, a particular desire exists for the oral administration in connection with a utility such as male contraception. Since in the area of female contraception the word "pill" has almost become a synonym for reliable birth-control, it is evident that also in the case of male contraception oral activity is desired, so as to enable providing a male "pill."
In Solo et al (J Med Chemistry, 1970 Nol 13 pages 751-754) an attempt to make androgenic compounds is disclosed by synthesizing and testing androgenic steroids with an α-etheno bridge between carbon positions 14 and 17 of a steroid skeleton. The compounds were found to be inactive. Other steroids with an 14,17-etheno bridge in α-position of the steroid skeleton were prepared, but again no biological activity was found (Scholz et al Liebigs Ann Chem 1989, pp 151-158; Bull and Thomson, J. Chem. Soc. Perkin Trans. 1; 1990; pp 241-251).
Surprisingly, it is found that steroids having formula I
Formula I
Figure imgf000002_0001
wherein R, is O, (H,H), (H,OH), ΝOH, wherein OH is optionally etherified or esterified; R2 is hydrogen, or (C,.1S) acyl; and the dotted lines indicate one or two optional bonds, have powerful androgenic activity.
An particular embodiment of the invention is the group of compounds in which R, is oxo. A specific embodiment of the invention is 17β-hydroxy-7α-methyl-14α,17α- ethenoestr-4-en-3-one. The stereochemical indicators α and β should be interpreted to lead to compounds within the group defined by formula I.
It is understood that the 7α-methyl-14α,17α-ethenosteroids of the invention have the natural configurations 5α, 8β, 9α, lOβ, and 13β.
The term (C,.15) acyl means an acyl group derived from a carboxylic acid having 1- 15 carbon atoms, like formyl, acetyl, propanoyl, butyryl, 2-methylpropanoyl, pentanoyl, pivaloyl, hexanoyl etc. Also included within the definition of (C,.15) acyl are acyl groups derived from dicarboxylic acids, like hemi-maloyl, hemi-succinoyl, hemi-glutaroyl, and so on. Preferred is hemi-succinoyl.
The compounds of the invention may be produced by various methods known in the art of organic chemistry in general, and especially in the art of the chemistry of steroids (see, for example: Fried, J. et al, Organic Reactions in Steroid Chemistry, Volumes I and II, Nan Νostrand Reinhold Company, New York, 1972).
A convenient starting material for the preparation of compounds of formula I wherein R, is oxo; R2 is hydrogen; and the dotted lines indicate a Δ4 double bond, is for instance a compound of formula II, whose synthesis is known in literature [Rasmusson, G.H. et al, Steroids 22, 107 (1973)].
Figure imgf000003_0001
II III
A possible synthesis route for compounds of the invention starts with the Diels- Alder reaction of II with phenyl vinyl sulphone according to the procedure described by Bull [Bull, J.R., Thomson, R.I., J. Chem. Soc, Perkin Trans. I, 241 (1990)]. The resulting product III is treated with a reducing agent (sodium amalgam, Raney- nickel, magnesium/methanol etc.) in order to remove the phenylsulphonyl group. Deprotection of 17-OH (if still necessary) produces 3-methoxy-7α-methyl-14α,14α- ethenoestra-l,3,5(10)-rrien-17β-ol. Birch reduction [Caine, D., in Org. Reactions 23, p. 1, Wiley, New York, 1976] and, finally, hydrolysis gives 17β-hydroxy-7α- methyl-14α,l 7α-ethenoestr-4-en-3-one. The latter compound can be converted, by methods known in the art, to other compounds of the invention.
The invention also pertains to the compounds described hereinbefore as a medicine. The compounds of the present invention being potent androgens, can be used in, int.al., male contraception and male or female hormone replacement therapy. Thus the invention also pertains to a method of treatment of androgen insufficiency, by administering to a human male or female an effective amount of any of the above compounds. The invention also is in the use of any of the above compounds for the preparation of a medicine for treating androgen insufficiency. In the context of the invention, 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. In particular, 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. In the context of 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.
The androgens can be administered principally via any suitable route available to the skilled person. As indicated above, oral administration is preferred, most preferably in the form of a solid dosage unit such as a tablet or a capsule. The invention also relates to pharmaceutical formulations comprising a compound as described hereinbefore and a pharmaceutically acceptable carrier. Thus the carrier may be in a solid form or liquid form, and the formulation may be an oral dosage unit such as a tablet or 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; The Science and Practice of Pharmacy (20th ed., Publisher: Lippincott Williams & Wilkins; Baltimore; USA, see especially Part 5: Pharmaceutical Manufacturing). 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 dose of and regimen of administration of the compounds of the invention, 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 dosage amounts are 0.001-5 mg per kg body weight.
The invention will be further explained hereinafter with reference to the following Examples.
Example 1
17β-Hvdroxy-7α-methyl-l 4 .17α-ethenoestr-4-en-3-one.
Figure imgf000005_0001
i) - A mixture of 3-methoxy-7 -methylestra-l,3,5(10),14,16-pentaen-17-ol acetate [II; Rasmusson, G.H. et al, Steroids 22, 107 (1973); 55 g] and phenyl vinyl sulphone (82 g) in a mixture of dry benzene (150 ml) and dry cyclohexane (200 ml), in a sealed tube, was heated at 150 °C for 72 h. The reaction mixture was cooled, concentrated and chromatographed directly on silica gel (toluene/ethyl acetate 98:2). Crystallization (diisopropyl ether) afforded 3-methoxy-7α-methyl-16α- (phenylsulphonyl)-14α,17α-ethenoestra-l,3,5(10)-trien-17β-ol acetate (38 g). ii) - Magnesium (5.0 g) was added to a mixture of dry methanol (317 ml) and dry tetrahydrofuran (79 ml) and the mixture was heated at 50 °C. The product obtained in the previous step (5.0 g) was added in one portion and heating was continued at 60 °C for 1 h. The reaction mixture was cooled and quenched with a saturated aquesous solution of ammonium chloride. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded 3-methoxy-7 -methyl-14α,17α-ethenoestra-l,3,5(10)-trien-17β-ol (2.2 g). The product was further purified by crystallization (CH2Cl2/MeOH; 8.1 g → 2.5 g). iii) - Lithium (3.2 g) was added to a refluxing solution of the product obtained in the previous step (2.5 g) in dry tetrahydrofuran (68 ml) and liquid ammonia (227 ml) and the reaction mixture was stirred for 1.5 h. t-Butanol (2.8 ml) was added and stirring was continued for 30 min. Ethanol was added and the ammonia was allowed to evaporate. Water was added and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure, to give 3-methoxy-7α-methyl-14α,l 7α- ethenoestra-2,5(10)-dien-17β-ol (3.1 g). The product was used in the following step without further purification. iv) - A solution of the product obtained in the previous step (3.1 g) in acetone (24 ml) was treated with hydrochloric acid (2 M, 2.4 ml). After 1 h stirring at room temperature, another portion of hydrochloric acid (2 M, 1.2 ml) was added and stirring was continued for 1.5 h. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography gave a product (1.60 g) which was further purified by crystallization (diisopropyl ether), to give 17β-hydroxy-7α-methyl- 14α, 17α-ethenoestr-4-en-3-one. 'H-NMR (CDC13) δ 6.10 (d, 1H, J = 6.7 Hz), 5.91 (d, 1H, J = 6.7 Hz), 5.84 (bs, 1H), 0.91 (d, 3H, J = 6.3 Hz), 0.90 (s, 3H).
Example 2
Androgen activity.
The transactivative androgen activity of the compounds of the invention was measured in Chinese hamster ovary cells (CHO) transfected with the human androgen receptor (hAR), in combination with a mouse mammary tumor virus (MMTV), and luciferase receptor gene (incubation time 16 h, temperature 37 °C) and compared with the activity of 5α-dihydrotestosterone [Schoonen, W.G.E.J.; de Ries, R.J.H.; Joosten, J.W.H.; Mathijssen-Mommers, G.J.W.; Kloosterboer, H.J., Analyt. Biochem. 261., 222-224 (1998)]. Results are collected in Table 1.
Table 1. Androgen activity of the compounds of the invention.
Example Androgen activity (%)

Claims

Claims
1. A steroid having formula I
Formula I
Figure imgf000007_0001
wherein
R, is O, (H,H), (H,OH), NOH, wherein OH is optionally etherified or esterified;
R2 is hydrogen, or (CM5) acyl; and the dotted lines indicate one or two optional bonds.
2. The compound 17β-hydroxy-7α-methyl-14α,17α-ethenoestr-4-en-3-one.
3. Steroid according to claim 1 or 2 for use as a medicine.
/(• Use of a steroid according to claim 1 or 2 for the manufacture of a medicine with androgenic activity.
PCT/EP2002/014282 2001-12-21 2002-12-16 Androgenic 14.alpha, 17.alpha-ethenosteroids WO2003053993A1 (en)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KALYAN SUNDARAM ET AL: "7ALPHA-METHYL-NORTESTOSTERONE (MENT): THE OPTIMAL ANDROGEN FOR MALECONTRACEPTION", ANNALS OF MEDICINE, BLACKWELL SCIENTIFIC PUBLICATIONS LTD., TORQUAY,, GB, vol. 25, 1993, pages 199 - 205, XP000828460 *
SOLO, ALAN J. ET AL: "Ring-D-bridged steroid analogs. VIII. Testosterone analogs", J. MED. CHEM. (1970), 13(4), 751-4, XP002200884 *

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