EP2167525A2 - Dérivé de 17 -cyano-19-androst-4-ène, son utilisation, et médicament contenant ce dérivé - Google Patents

Dérivé de 17 -cyano-19-androst-4-ène, son utilisation, et médicament contenant ce dérivé

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Publication number
EP2167525A2
EP2167525A2 EP08760962A EP08760962A EP2167525A2 EP 2167525 A2 EP2167525 A2 EP 2167525A2 EP 08760962 A EP08760962 A EP 08760962A EP 08760962 A EP08760962 A EP 08760962A EP 2167525 A2 EP2167525 A2 EP 2167525A2
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EP
European Patent Office
Prior art keywords
cyano
androst
methylene
methyl
hydrogen
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.)
Withdrawn
Application number
EP08760962A
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German (de)
English (en)
Inventor
Joachim Kuhnke
Jan Huebner
Rolf Bohlmann
Thomas Frenzel
Ulrich Klar
Frederik Menges
Sven Ring
Steffen Borden
Hans-Peter Muhn
Katja Prelle
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Bayer Intellectual Property GmbH
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Bayer Schering Pharma AG
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Publication date
Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP2167525A2 publication Critical patent/EP2167525A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • 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
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • A61P15/18—Feminine 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
    • 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
    • A61P5/34—Gestagens
    • 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
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
    • 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
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/007—3 membered carbocyclic rings in position 6-7
    • 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
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/008—3 membered carbocyclic rings in position 15/16

Definitions

  • the invention relates to certain 17ß-cyano-19-androst-4-ene derivatives, their use and derivatives containing gestagenic drugs, for example, for the treatment of pre-, peri- and postmenopausal as well as premenstrual complaints.
  • the literature discloses compounds with gestagenic, antimineralcorticoid, anti-drogenic or antiestrogenic action based on a steroid skeleton which are derived, for example, from 19-androst-4-en-3-one or a derivative thereof (the numbering of the steroid skeleton is, for example, Fresenius / Görlitzer 3rd edition 1991 "Organic chemical nomenclature" p. 60 ff.).
  • WO 2006072467 A1 discloses the gestagenic compound 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -dimethylene-3-oxo-17-pregn-4-ene-21,17 ⁇ -carbolactone (drospirenone), which is used, for example, in an oral contraceptive and a preparation used to treat postmenopausal symptoms.
  • drospirenone due to its relatively low affinity for the progestagen receptor and its comparatively high ovulation inhibitory dose, drospirenone is included in the contraceptive in the relatively high daily dose of 3 mg.
  • drospirenone is characterized by the fact that it has aldosteronantagonist (antimineralcorticoid) and antiandrogenic effects in addition to gestagenic effects.
  • WO 2006072467 A1 further proposes an 18-methyl-19-nor-17-pregn-4-ene-21,17-carbolactone and also pharmaceutical preparations containing it which have a higher progestational potency than Drospirenone.
  • US Pat. No. 3,705,179 discloses steroids which have an antiandrogenic activity and are suitable for the treatment of diseases which occur in the Related to androgens.
  • 17 ⁇ -cyano-17 ⁇ -methyl-androst-4-en-3-one derivatives are disclosed.
  • the object of the present invention is to provide compounds which have a strong binding to the gestagen receptor.
  • the compounds should preferably also have an antimineralcorticoid effect.
  • the present invention relates to a 17 ⁇ -cyano-19-androst-4-ene derivative having the general chemical formula 1
  • Z is selected from the group comprising O, two hydrogen atoms, NOR and NNHSO 2 R, wherein R is hydrogen or C 1 -C 4 -alkyl,
  • R 1 , R 2 are independently hydrogen or methyl or
  • R 1 and R 2 together form methylene or omitted to form a double bond between C 1 and C 2 ,
  • R 4 is hydrogen or halogen
  • R 6a , R 6b together form methylene or 1,2-ethanediyl or R 6a is hydrogen and R 6b is selected from the group comprising hydrogen,
  • R 7 is selected from the group comprising hydrogen, C 1 -C 4 -alkyl,
  • R 6a is hydrogen and R 6b and R 7 together form methylene or omitted to form a double bond between C 6 and C 7
  • R 6a is methyl and R 6b and R 7 are omitted to form a double bond between C 6 and C 7,
  • R 15 , R 16 are hydrogen or together form methylene
  • R 17 is selected from the group comprising hydrogen, C 1 -C 4 -alkyl and allyl
  • the compounds of the general chemical formula A excluded from the present invention are the following compounds:
  • the numbering of the C-skeleton of the derivative according to the invention with the general chemical formula 1 follows in a conventional manner the numbering of a steroid skeleton, for example described in Fresenius, loc. Cit.
  • the numbering of the radicals indicated in the claims corresponds in an analogous manner to their binding position on the C-skeleton of the derivative.
  • the radical R 4 binds to the C 4 position of the derivative according to the invention.
  • C 1 -C 4 -alkyl is in each case to be understood as meaning a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, especially the unbranched radicals. Particularly preferred are methyl, ethyl and n-propyl.
  • alkyl radicals attached in the 17 ⁇ -position may be perfluorinated, so that in this case R 17 may also be trifluoromethyl, pentafluoroethyl, n-heptafluoropropyl, isoheptafluoropropyl, n-nonafluorobutyl, iso-nonafluorobutyl and tert-nonafluorobutyl.
  • C 2 -C 3 -alkenyl is preferably vinyl or allyl.
  • Halogen is in each case fluorine, chlorine, bromine or iodine.
  • Isomers are to be understood as meaning chemical compounds having the same empirical formula but differing chemical structure. All possible isomers and mixtures of isomers (racemates) are expressly included, the 17 ⁇ -cyano position being specified in the derivative according to the invention.
  • constitutional isomers and stereoisomers are distinguished.
  • Constitutional isomers have the same molecular formula, but differ in how their atoms or atomic groups are linked. These include functional isomers, positional isomers, tautomers or valence isomers.
  • Stereoisomers basically have the same structure (constitution) and thus also the same molecular formula, but differ in the spatial arrangement of the atoms.
  • configuration isomers and conformational isomers are distinguished.
  • Configuration isomers are stereoisomers that can only be converted into each other by bond breaking. These include enantiomers, diastereomers and E / Z (ice / trans) isomers.
  • Enantiomers are stereoisomers that behave in the same way as image and mirror image and have no plane of symmetry. All stereoisomers, which are not enantiomers are called diastereomers. A special case is E / Z (ice / trans) isomers of double bonds. Conformational isomers are stereoisomers that can be converted into each other by the rotation of single bonds. For the delimitation of the Isomehe species from each other see also the IUPAC rules, Section E (Pure Appl. Chem. 45, 11-30 (1976)).
  • the derivatives of general chemical formula 1 according to the invention also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, also the racemates and enantiomers. These are also to be understood as meaning double bond isomers.
  • the derivatives according to the invention can also be present in the form of solvates, in particular of hydrates, the compounds according to the invention accordingly containing polar solvents, in particular of water, as structural element of the crystal lattice of the compounds according to the invention.
  • the polar solvent, in particular water may be present in a stoichiometric or even unstoichiometric ratio.
  • stoichiometric solvates hydrates, we also speak of hemi, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates.
  • R 1 and R 2 are each hydrogen or together form methylene, more preferably ⁇ -methylene. More preferably, R 1 is ⁇ -methyl.
  • R 4 is preferably hydrogen or chlorine.
  • R 6a and R 6b preferably together form 1, 2-ethanediyl or are each hydrogen.
  • R 7 is preferably selected from the group comprising hydrogen and methyl, where the methyl group may be both ⁇ - ⁇ and ⁇ - ⁇ .
  • R 6b and R 7 preferably together form methylene, where the methylene group may be both ⁇ - ⁇ and ⁇ - ⁇ .
  • R 17 is preferably selected from the group comprising hydrogen and methyl.
  • radicals R 6a , R 6b , R 7 , R 15 and R 16 may be both ⁇ - and ß-constantly.
  • 17 ⁇ -cyano-19-nor-androst-4-ene derivatives of the invention selected from the group comprising:
  • the novel compounds of general chemical formula 1 can be used alone or in combination with estrogens in contraceptive medicines.
  • the derivatives according to the invention are therefore particularly suitable for the preparation of a medicament for oral contraception and for the treatment of pre-, peri- and post-menopausal complaints, including the use in preparations for hormone replacement therapy (HRT).
  • HRT hormone replacement therapy
  • Treatment with the derivatives of the invention preferably takes place on humans, but can also be carried out on related mammalian species, such as, for example, dogs and cats.
  • the derivatives according to the invention are combined with at least one suitable pharmaceutically acceptable additive, for example a carrier.
  • the additive is suitable, for example, for parenteral, preferably oral, administration.
  • These are pharmaceutically suitable organic or inorganic inert adjunct materials, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
  • the medicaments can be in solid form, for example as Tablets, dragees, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions.
  • auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for varying the osmotic pressure or buffers.
  • Oily solutions for example solutions in sesame oil, castor oil and cottonseed oil, are particularly suitable for parenteral administration.
  • solubilizers such as benzyl benzoate or benzyl alcohol, may be added. It is also possible to incorporate the derivatives of the invention into a transdermal system and thus to apply them transdermally. For oral administration in particular tablets, dragees, capsules, pills, suspensions or solutions in question.
  • the dosage of the derivatives according to the invention in contraceptive preparations should be 0.01 to 10 mg per day.
  • the daily dose for the treatment of premenstrual disorders is about 0.1 to 20 mg.
  • the gestagenic derivatives according to the invention are preferably administered orally in contraceptive preparations and in the medicaments for the treatment of premenstrual symptoms.
  • the daily dose was preferably administered once.
  • the gestagenic and estrogenic active ingredient components are preferably administered orally together in contraceptive preparations.
  • the daily dose was preferably administered once.
  • Suitable estrogens are synthetic estrogens, preferably ethinylestradiol, but also mestranol.
  • the estrogen was administered in a daily amount equivalent to that of 0.01 to 0.04 mg of ethinylestradiol.
  • Suitable starting materials for the 17 ⁇ -cyanoandrost-4-en-3-one derivatives described herein are various steroidal starting materials, such as androst-4-ene-3,17-dione (see, for example, J. Am. Chem. Soc , 3727 (1965)), or the partially reduced analogs, such as testosterone or prasterone.
  • Suitable starting materials which carry a 15 ⁇ , 16 ⁇ or also 15 ⁇ , 16 ⁇ -methylene group are likewise known from the literature (for example 15 ⁇ , 16 ⁇ -methylene-androst-5-en-17-one-3 ⁇ -ol, see Chem. Ber. 106, 888 (1973); the corresponding ⁇ 4-3,17-dione, see DE-A 21 09 555 (1972)
  • the 15 ⁇ , 16 ⁇ -methylene-androst-4-ene-3,17-dione is in Izv. Nauk SSSR Ser.
  • nitrile in position 17 (C 17 ) of the steroid skeleton can be done in many ways. Both single-stage and multi-stage variants are considered here. Preference is given here to methods which ultimately mean the replacement of an oxygen function by cyanide. Many possible process variants are described in Science of Synthesis Houben-Weyl Methods of Molecular Transformations Category 3 Volume 19 pp. 197-213 (2004 Georg Thieme Verlag Stuttgart, New York) and in Houben-Weyl Methods of Organic Chemistry Volume E5 Part 2 P. 1318-1527 (1985 Georg Thieme Verlag Stuttgart, New York).
  • a 17-ketosteroid with tosylmethyl isocyanide in suitable solvents such as dimethoxyethane, dimethyl sulfoxide, ethers, alcohols or else mixtures thereof, using suitable bases, such as alkali metal alkoxides, alkali metal hydrides, potassium hexamethyldisilazide, or alkali metal amides, such as lithium diisopropylamide, in a temperature range of 0 0 C to 100 0 C implemented.
  • suitable bases such as alkali metal alkoxides, alkali metal hydrides, potassium hexamethyldisilazide, or alkali metal amides, such as lithium diisopropylamide, in a temperature range of 0 0 C to 100 0 C implemented.
  • 17-epimer mixtures can be separated by chromatography, fractional crystallization or by a combination of these methods.
  • a suitable leaving group at position 17 such as a halide (preferably iodine or bromine), or even a sulfonic acid ester of a 17-alcohol against cyanide comes into consideration.
  • a suitable leaving group at position 17 such as a halide (preferably iodine or bromine), or even a sulfonic acid ester of a 17-alcohol against cyanide comes into consideration.
  • cyanide sources inorganic cyanides such as lithium, sodium and potassium cyanide are preferably used.
  • a 17-ketone was converted into the corresponding 17-exomethylene compound by means of a Wittig olefination, which after hydroboration and oxidation to the aldehyde can be converted to the corresponding 17-carbaldehyde oxime. Dehydration of the oxime then leads to 17-nitrile.
  • the introduction of the nitrile can be carried out either at the beginning of a synthesis sequence or at any later time, provided that any further functional groups present are suitably protected.
  • the 17-cyano compounds may optionally be alkylated, resulting in stereochemically uniform 17 ⁇ -cyano-17 ⁇ -substituted derivatives.
  • the 17-cyanosteroid was deprotonated in a suitable solvent, such as ethers, for example tetrahydrofuran.
  • a suitable solvent such as ethers, for example tetrahydrofuran.
  • various bases may be used, for example, an alkali amide such as lithium diisopropylamide.
  • an alkylating agent such as an alkyl or alkenyl halide
  • the dienol ether bromination of compound 5 can be carried out, for example, analogously to the procedure of Steroids 1, 233 (1963).
  • the Bromwasserstoffabspaltung succeeds by heating the 6-bromine compound with basic reagents, such as LiBr or Li 2 CO 3 , in aprotic solvents, such as dimethylformamide, at temperatures from 50 0 C to 120 0 C or by the 6-bromo compounds in a solvent, such as collidine or lutidine, are heated to compound 6.
  • Compound 7 is prepared by methenylation of the 6,7-double bond by known methods, e.g. with dimethylsulfoxonium methylide (see, for example, DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US-A 4,291,029, J. Am. Chem. Soc., 84, 867 (1962)) into a Compound 8 converted to give a mixture of ⁇ - and ß-isomers, for example can be separated into the individual isomers by chromatography.
  • dimethylsulfoxonium methylide see, for example, DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US-A 4,291,029, J. Am. Chem. Soc., 84, 867 (1962)
  • Compound 8 converted to give a mixture of ⁇ - and ß-isomers, for example can be separated into the individual isomers by chromatography.
  • the synthesis of the spirocyclic compound 12 is based on 2, which was first converted into a 3-amino-3,5-diene-dehydrate 9.
  • the 6-hydroxymethylene Dehvat 10 was obtained.
  • compound 13 can be prepared by reaction with th-methylsulfoxonium iodide using bases such as alkali metal hydroxides, alkali alcoholates, in suitable solvents such as dimethylsulfoxide , represent.
  • compound 10 can be dehydrated with, for example, hydrochloric acid in dioxane / water. It is also possible to produce 6-methylene from 11 (see DE-A 34 02 3291, EP-A 0 150 157, US-A 4,584,288, J. Med. Chem., 34, 2464 (1991)).
  • 6-methylene compounds Another way to prepare 6-methylene compounds is to directly react the 4 (5) unsaturated 3-ketones, such as compound 2, with acetals of formaldehyde in the presence of sodium acetate with e.g. Phosphorus oxychloride or phosphorus pentachloride in suitable solvents such as chloroform (see, e.g., K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982)).
  • suitable solvents such as chloroform
  • the 6-methylene compounds can be used to prepare compounds of general formula 1 in which R 6a is methyl and R 6b and R 7 are omitted to form a double bond between C 6 and C 7, is used.
  • 6-methyl-4,6-dien-3-one derivatives can also be prepared directly (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb, Ann. 712 (1983)).
  • R 6b represents an ⁇ -methyl function
  • R 6b represents an ⁇ -methyl function
  • the targeted representation of 6ß-methyl compounds is possible.
  • the 4-en-3-ones such as compound 2, for example, with ethylene glycol, trimethyl orthoformate in dichloromethane in the presence of catalytic amounts of an acid, eg p-toluenesulfonic acid, converted to the corresponding 3-ketals.
  • an acid eg p-toluenesulfonic acid
  • the double bond isomerizes to position 5 (C 5 ).
  • Selective epoxidation of this 5-double bond is achieved, for example, by using organic peracids, for example m-chloroperbenzoic acid, in suitable solvents, such as dichloromethane.
  • the epoxidation can also be carried out with hydrogen peroxide in the presence of, for example, hexachloroacetone or 3-nitrotrifluoroacetophenone.
  • the formed 5,6 ⁇ -epoxides can then be opened axially using appropriate alkylmagnesium halides or alkyllithium compounds. This gives 5 ⁇ -hydroxy-6 ⁇ -alkyl compounds.
  • the cleavage of the 3-keto protective group can be carried out by treatment under mild acidic conditions (acetic acid or 4N hydrochloric acid at 0 ° C.) to obtain the 5 ⁇ -hydroxy function.
  • the compounds obtained with the general chemical formula I, in which Z is an oxygen atom, can be converted by reaction with hydroxylamine hydrochloride in the presence of a tertiary amine at temperatures between -20 and + 40 0 C in their corresponding oximes (general chemical formula I with Z in the meaning of NOH, where the hydroxy group can be syn or antistatic).
  • Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyhdin, 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1, 5-diazabicyclo [5.4.0] undec-5-ene (DBU), pyridine being preferred.
  • the compounds according to the invention are surprisingly distinguished by strong gestagenic activity and are highly active in the pregnancy maintenance test in the rat after subcutaneous administration.
  • Rats were mated overnight during Proestrus. The mating was controlled on the morning of the following day by the assessment of a vaginal smear. The presence of sperm was assessed as day 1 of an incipient pregnancy. On day 8 of pregnancy the animals were ovariectomized under ether anesthesia. Treatment with test compound and exogenous estrogen (estrone, 5 ⁇ g / kg / day) was performed subcutaneously once a day from day 8 to day 15 or day 21 of pregnancy. The first application on day 8 was performed two hours before castration. Intact control animals received vehicle only.
  • the animals were sacrificed under CO 2 atmosphere and live fetuses (beating heart fetuses) and implantation sites (early resorptions and dead fetuses including autolysis and atrophic placentas) in both uterine horns.
  • live fetuses beating heart fetuses
  • implantation sites early resorptions and dead fetuses including autolysis and atrophic placentas
  • malformations In uteri without fetuses or implantation sites, the number of nidation sites was determined by staining with 10% ammonium sulfide solution.
  • the pregnancy maintenance rate was calculated as the quotient of the number of live fetuses and the total number of nidation sites (both resorbed and dead fetuses and nidation sites).
  • ED50 pregnancy-preserving doses
  • the derivatives of general chemical formula 1 according to the invention have a very strong gestagenic activity. It has also been found that the derivatives of the invention show in vitro antimineralcorticoid activity. They should therefore have in vivo potassium retiring, natriuretic (antimeralcorticoid) effect. These properties were determined by the test described below:
  • DMEM Dulbecco's Modified Eagle Medium: 4500 mg / ml glucose, PAA, # E15-009) with 10% FCS (Biochrom, S0115, Lot # 615B), 4 mM L-glutamine was used as a culture medium , 1% penicillin / streptomycin, 1 mg / ml G418 and 0.5 ⁇ g / ml puromycin.
  • Reporter cell lines were grown at a density of 4x10 4 cells per well in white, 96-well opaque tissue culture plates (PerkinElmer, # P12-106-017) and in 6% DCC-FCS (charcoal treated serum, for removal in serum contained interfering components).
  • the compounds to be tested were added eight hours later and the cells were incubated with the compounds for 16 hours. The experiments were carried out in triplicate. At the end of the incubation, the effector-containing medium was removed and replaced with lysis buffer. After luciferase assay substrate (Proega, # E1501) was added, the 96-well plates were then placed in a microplate luminometer (Pherastar, BMG labtech) and the luminescence was measured. The IC50 values were determined using a Software for calculating dose-response relationships evaluated. Table 1 shows experimental results:
  • reaction mixture was poured onto ice-cold, half-saturated sodium chloride solution, the precipitated product filtered off with suction, washed with water and dried overnight in a vacuum oven (50 0 C, 200 mbar). 17 ⁇ -Cyano-3-methoxy-15 ⁇ , 16 ⁇ -methylene-androstane-3 (4), 5 (6) -diene (23.7 g) were obtained as beige crystals.
  • reaction mixture was treated at -15 ° C with 30 ml of 2 M hydrochloric acid, stirred for 0.5 hours at room temperature, added to water, extracted three times with ethyl acetate, dried over sodium sulfate, concentrated in vacuo, and on silica gel with hexane / ethyl acetate (0-50%) chromatographed. 17 ⁇ -Cyano-7 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one (149 mg) was obtained.
  • reaction mixture was allowed to warm slowly to room temperature overnight.
  • the reaction was stopped by the addition of saturated ammonium chloride solution, extracted with ethyl acetate, washed with water and saturated sodium chloride solution. Drying of the organic phase with sodium sulfate, evaporation to dryness and flash chromatography on silica gel [hexane / ethyl acetate (0-30%)] afforded 17 ⁇ -cyano-3-methoxy-17 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androstane-3 (cf. 4), 5 (6) -dies (6.5 g).
  • Example 9a According to the method of Example 9a was obtained from 1 g of 17-cyano-3-methoxy-15ß, 16ß-methylene-androstane-3 (4), 5 (6) -diene with allyl bromide as the alkylating agent after flash chromatography 17 ⁇ -allyl -17 ⁇ -cyano-3-methoxy-15 ⁇ , 16 ⁇ -methylene-androstane-3 (4), 5 (6) -diene (358 mg).
  • Example 2 The method of Example 2 was obtained from 5.90 g of 17 ⁇ -cyano-17 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one after crystallization from ethyl acetate and flash chromatography of the mother liquors on silica gel [hexane / Ethyl acetate (0-50%)] 17 ⁇ -cyano-6 ⁇ -hydroxymethyl-17 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one (2.22 g).
  • Example 2 The procedure of Example 2 was used to obtain from 3.0 g of 17 ⁇ -cyano-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one after flash chromatography on silica gel [hexane / ethyl acetate (0-50%)] 17 ⁇ -Cyano-6 ⁇ -hydroxymethyl-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one (850 mg).
  • Example 3a By the method of Example 3a was obtained from 700 mg of 17 ⁇ -cyano-6 ⁇ -hydroxymethyl-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one after flash chromatography on silica gel [hexane / ethyl acetate (0-50 %)] 17 ⁇ -cyano-15 ⁇ , 16 ⁇ -methylene-6 ⁇ -tosyloxy-methyl-androst-4-en-3-one (880 mg) and in its precursor as minor component 17 ⁇ -cyano-6-exo-methylene-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one (22 mg).
  • Example 9a By the method of Example 9a was obtained from 5.29 g 17 ⁇ -cyano-15 ⁇ , 16 ⁇ -methylene-3ß-isopropylsilyoxy-androst-5 (6) -en with Me-I as alkylating agent after In flash chromatography, the mixture of the 17-epimers of 17-cyano-17-methyl-15 ⁇ , 16 ⁇ -methylene-3 ⁇ -triisopropylsilyoxy-androst-5 (6) -ens (3.65 g).
  • Example 12b By the method of Example 12b was obtained from 1, 9 g of the 17-epimers of 17-cyano-3ß-hydroxy-17-methyl-15 ⁇ , 16 ⁇ -methylene-androst-5 (6) -ens after preparative HPLC chromatography 17ß -Cyano-17 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one (335 mg).
  • the 17-epimer of 17-cyano-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one was obtained from 7 g of the 17-epimer of the 17-cyano group after work-up by the method of Example 1a.
  • Example 6 By the method of Example 6 was obtained from 7.6 g of the 17-epimers of 17-cyano-3-methoxy-15 ⁇ , 16 ⁇ -methylene-androst-3 (4), 5 (6) -diene by preparative HPLC chromatography Part of the crude product obtained 17 ⁇ -cyano-15 ⁇ , 16 ⁇ -methylene-androsta-4,6-dien-3-one (48 mg)
  • 17 ⁇ -cyano-androst-4-en-3-one was reacted analogously to the procedure specified in Example 1a, with trimethyl orthoformate being exchanged for methyl orthoformate. 17 ⁇ -Cyano-3-ethoxy-androst-3,5-diene was obtained.
  • 17 ⁇ -Cyano-androsta-4,6-dien-3-one was reacted analogously to the instructions given in Example 8, using ethylmagnesium bromide instead of the methylmagnesium bromide used there. 17 ⁇ -Cyano-7 ⁇ -ethyl-androst-4-en-3-one was obtained
  • 17 ⁇ -cyano-androsta-4,6-dien-3-one was reacted analogously to the instructions given in Example 7. 17 ⁇ -Cyano-6 ⁇ , 7 ⁇ -methylene-androst-4-en-3-one and 17 ⁇ -cyano-6 ⁇ , 7 ⁇ -methylene-androst-4-en-3-one were obtained.
  • 17 ⁇ -Cyano-6 ⁇ -hydroxymethyl-androst-4-en-3-one was reacted analogously to the examples given in Examples 3a and 3b, the intermediate tosylate being reacted further in crude form. 17 ⁇ -cyano-6,6-ethylidene-androst-4-en-3-one was obtained.
  • 17 ⁇ -Cyano-3,3-ethanediylbisoxy-androst-5-ene was reacted analogously to the method given in Example 9a. 17 ⁇ -Cyano-3,3-ethanediylbisoxy-17 ⁇ -methyl-androst-5-ene was obtained.
  • 17-Cyano-3,3-ethanediylbisoxy-androst-5-ene was reacted analogously to the method given in Example 9a, allyl bromide being used instead of the methyl iodide used there. 17 ⁇ -Allyl-17 ⁇ -cyano-3,3-ethanediylbisoxy-androst-5-ene was obtained.
  • Example 16a 16 ⁇ -bismethylene-3 ⁇ , 5 ⁇ -dihydroxy-androstan-17-one (Angew. Chemie 1982, 94, 718-719) and tert-butyldimethylsilyl chloride as a silylating reagent after crystallization were obtained from 6 ⁇ , 7 ⁇ -15 ⁇ 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-3 ⁇ -tert-butyldimethylsilyloxy-5 ⁇ -hydroxy-androstan-17-one.
  • 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-3 ⁇ -tert-butyldimethylsilyloxy-17-cyano-5 ⁇ -hydroxyandrostan-17-one was synthesized analogously to the methods given in Examples 9a and 16c. implemented. There were obtained 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-3 ⁇ -5 ⁇ -bis-hydroxy-17 ⁇ -cyano-17 ⁇ -methyl-androstane.
  • 17 ⁇ -Allyl-6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bisnethylene-3 ⁇ -5 ⁇ -bis-hydroxy-17 ⁇ -cyano-androstane was reacted analogously to the method given in Example 3Oe. 17 ⁇ -Allyl-6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-17 ⁇ -cyano-androst-4-en-3-one were obtained.
  • 17-cyano-15SS be 16ss-methylene-androst-4-en-3-one dissolved in 8 ml of pyridine and cooled to 0 0 C. After addition of 0.32 ml of sulfuryl chloride is stirred for 1.5 hours at this temperature. After addition of saturated aqueous sodium bicarbonate solution, water and ethyl acetate, the phases are separated and the organic phase washed with water and saturated aqueous sodium chloride solution. After drying the organic phase over Nathumsulfat and filtration is concentrated and the product recrystallized from ethyl acetate. 4-Chloro-17 ⁇ -cyano-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one (211 mg) is obtained.
  • Example 36 17 ⁇ -Cyano-17 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androsta-4,6-dien-3-one
  • 17.7 g of 17 ⁇ -cyano-3-methoxy-17 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androstane-3 (4), 5 (6) -diene are obtained according to the method of Example 6 from 17 ⁇ -cyano- 17 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androsta-4,6-dien-3-one (5.84 g).
  • Example 7 According to the method of Example 7 is obtained from 3.0 g of 17 ⁇ -cyano-17 ⁇ -methyl-15ß, 16ß-methylene-androsta-4,6-dien-3-one after HPLC separation of the crude product on silica gel as a non-polar fraction 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-17 ⁇ -cyano-17 ⁇ -methyl-androst-4-en-3-one (475 mg) and as polar fraction 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-17 ⁇ -cyano-17 ⁇ - methyl-androst-4-en-3-one (1.2 g).
  • Example 9a gives 18.0 g of 17 ⁇ -cyano-3-methoxy-15 ⁇ , 16 ⁇ -methylene-androstane-3 (4), 5 (6) -diene and the use of ethyl iodide instead of methyl iodide after crystallization 17 ⁇ -cyano-17 ⁇ -ethyl-3-methoxy-15 ⁇ , 16 ⁇ -methylene-androstane-3 (4), 5 (6) -diene (6.85 g) and after flash chromatography of the mother liquor 17 ⁇ -cyano-17 ⁇ - ethyl-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one (338 mg).
  • Example 6 According to the method of Example 6, 6.0 g of 17 ⁇ -cyano-17 ⁇ -ethyl-3-methoxy-15 ⁇ , 16 ⁇ -methylene-androstane-3 (4), 5 (6) -diene are obtained after crystallization and subsequent flash reaction. Chromatography of the mother liquor 17 ⁇ -cyano-17 ⁇ -ethyl-15 ⁇ , 16 ⁇ -methylene-androsta-4,6-dien-3-one (4.87 g).
  • Example 7 By the method of Example 7 is obtained from 2.5 g of 17 ⁇ -cyano-17 ⁇ -ethyl-15ß, 16ß-methylene-androsta-4,6-dien-3-one by HPLC separation of the crude product on silica gel as a nonpolar fraction 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-17 ⁇ -cyano-17 ⁇ -ethyl-androst-4-en-3-one (290 mg) and as the polar fraction 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bis-methylene-17 ⁇ -cyano-17 ⁇ - ethyl-androst-4-en-3-one (670 mg).
  • Example 8 According to the method of Example 8 is obtained from 1, 0 g 17ß-cyano-17 ⁇ -ethyl-15ß, 16ß-methylene-androsta-4,6-dien-3-one after HPLC separation of the crude product on silica gel as non-polar fraction 17ß -Cyano-17 ⁇ -ethyl-7 ⁇ -methyl-15 ⁇ , 16 ⁇ -methylene-androst-4-en-3-one (165 mg) and as a polar fraction 17 ⁇ -cyano-17 ⁇ -ethyl-7 ⁇ -methyl-15 ⁇ , 16 ⁇ - methylene-androst-4-en-3-one (292 mg).
  • Androst-4-en-17-one (see, for example, HeIv. Chim. Acta (45) 1962, 2575) is reacted analogously to the method given in Example 1b. After chromatography of the resulting crude product on silica gel with a mixture of ethyl acetate and n-hexane, the product-containing fractions are concentrated and rechromatographed by HPLC. Besides 17 ⁇ -cyanoandrost-4-ene, 17 ⁇ -cyanoandrost-4-ene is obtained. 17-Cvanoandrost-4-ene

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Abstract

La présente invention concerne des dérivés de 17ß-cyano-19-nor-androst-4-ène présentant une activité gestagène, ainsi que certains de leurs solvates, hydrates, stéréoisomères, diastéréoisomères, énantiomères et sels, sous réserve que certains composés soient exceptés. Ces dérivés sont représentés par la formule chimique générale (1) suivante. Dans cette formule, Z est choisi dans le groupe O, deux atomes d'hydrogène, NOR et NNHSO2R, R étant hydrogène ou C1-C4-alkyle. R1 et R2 sont indépendamment l'un de l'autre hydrogène ou méthyle, ou forment ensemble un méthylène ou sont absents en cas de constitution d'une double liaison entre C1 et C2. R4 est hydrogène ou halogène. En outre, on a soit d'une part R6a et R6b qui forment ensemble un méthylène ou un 1,2-éthanediyle (ou encore R6a qui est hydrogène alors que R6b est choisi dans le groupe hydrogène, méthyle et hydroxyméthylène) et R7 qui est choisi dans le groupe hydrogène, C1-C4-alkyle, C2-C3-alcényle et cyclopropyle, soit d'autre part R6a qui est hydrogène et R6b et R7 qui forment ensemble un méthylène ou qui sont absents en cas de constitution d'une double liaison entre C6 et C7, ou bien encore R6a qui est méthyle, et R6b et R7 qui sont absents en cas de constitution d'une double liaison entre C6 et C7. R15 et R16 sont hydrogène ou forment ensemble un méthylène. R17 est choisi dans le groupe hydrogène, C1-C4-alkyle et allyle.
EP08760962A 2007-06-12 2008-06-12 Dérivé de 17 -cyano-19-androst-4-ène, son utilisation, et médicament contenant ce dérivé Withdrawn EP2167525A2 (fr)

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DE102007027635A DE102007027635A1 (de) 2007-06-12 2007-06-12 17ß-Cyano-19-androst-4-en-Derivat, dessen Verwendung und das Derivat enthaltende Arzneimittel
US94365107P 2007-06-13 2007-06-13
PCT/EP2008/057427 WO2008152112A2 (fr) 2007-06-12 2008-06-12 DÉRIVÉ DE 17β-CYANO-19-ANDROST-4-ÈNE, SON UTILISATION, ET MÉDICAMENT CONTENANT CE DÉRIVÉ

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WO2010066349A1 (fr) * 2008-12-12 2010-06-17 Bayer Schering Pharma Aktiengesellschaft UTILISATION DE DÉRIVÉS DE 17β-CYANO-19-ANDROST-4-ÈNE POUR PRODUIRE UN MÉDICAMENT À LIBÉRATION PROLONGÉE DESTINÉ À ÊTRE ADMINISTRÉ PAR VOIE PARENTÉRALE, ET MÉDICAMENT À LIBÉRATION PROLONGÉE CONTENANT DES DÉRIVÉS DE 17β-CYANO-19-ANDROST-4-ÈNE DESTINÉ À ÊTRE ADMINISTRÉ PAR VOIE PARENTÉRALE
WO2012059594A1 (fr) 2010-11-04 2012-05-10 Bayer Pharma Aktiengesellschaft Antagonistes de récepteur de minéralocorticoïde pour le traitement de l'obésité induite par corticoïde
CN105085596A (zh) * 2015-08-18 2015-11-25 湖北竹溪人福药业有限责任公司 一种羧酸黄体酮的制备方法

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GB1089945A (en) * 1965-09-23 1967-11-08 British Drug Houses Ltd Steroidal-6-spirocyclopropyl-4-en-3-ones
DE1593516C3 (de) * 1966-08-25 1975-05-15 Schering Ag, 1000 Berlin Und 4619 Bergkamen 4-Halogen-1,2 alpha; 6,7 betabismethylen-delta hoch 4-3-ketosteroide, Verfahren zu ihrer Herstellung sowie diese Steroide enthaltende Mittel
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NZ222103A (en) * 1986-10-10 1990-08-28 Gist Brocades Nv 9-alpha-hydroxy steroids and pharmaceutical preparations containing them
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DE102007027637A1 (de) * 2007-06-12 2008-12-18 Bayer Schering Pharma Aktiengesellschaft 17ß-Cyano-19-nor-androst-4-en-Derivat, dessen Verwendung und das Derivat enthaltende Arzneimittel

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WO2008152112A2 (fr) 2008-12-18
WO2008152112A3 (fr) 2009-04-30
CN101679479A (zh) 2010-03-24
DE102007027635A1 (de) 2008-12-18
KR20100037596A (ko) 2010-04-09
US20100292184A1 (en) 2010-11-18
JP2010529174A (ja) 2010-08-26
IL202325A0 (en) 2010-06-30
CA2692997A1 (fr) 2008-12-18
RU2010100337A (ru) 2011-07-20
MX2009013631A (es) 2010-01-20

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