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WO2010066354A1 - UTILISATION DE DÉRIVÉS DE 17β-CYANO-18A-HOMO-19-NOR-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-18A-HOMO-19-NOR-ANDROST-4-ÈNE DESTINÉ À ÊTRE ADMINISTRÉ PAR VOIE PARENTÉRALE - Google Patents

UTILISATION DE DÉRIVÉS DE 17β-CYANO-18A-HOMO-19-NOR-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-18A-HOMO-19-NOR-ANDROST-4-ÈNE DESTINÉ À ÊTRE ADMINISTRÉ PAR VOIE PARENTÉRALE Download PDF

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Publication number
WO2010066354A1
WO2010066354A1 PCT/EP2009/008493 EP2009008493W WO2010066354A1 WO 2010066354 A1 WO2010066354 A1 WO 2010066354A1 EP 2009008493 W EP2009008493 W EP 2009008493W WO 2010066354 A1 WO2010066354 A1 WO 2010066354A1
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Prior art keywords
homo
androst
cyano
methylene
hydrogen
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German (de)
English (en)
Inventor
Norbert Schmees
Katja Prelle
Joachim Kuhnke
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Bayer Pharma AG
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Bayer Schering Pharma AG
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    • 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
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
    • 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

Definitions

  • the present invention relates to the use of certain 17 ⁇ -cyano-18 ⁇ -homo-19-nor-androst-4-ene derivatives for the manufacture of a medicament in depot form for parenteral administration, and depot medicines themselves for parenteral administration containing these 17 ⁇ -cyano -18A-homo-19-nor-androst-4-ene derivatives.
  • 17 ⁇ -cyano-18 ⁇ -homo-19-nor-androst-4-ene derivatives themselves, their use and derivatives containing gestagenic drugs, for example for the treatment of pre-, peri-and postmenopausal as well as premenstrual disorders, are disclosed in of the unpublished PCTVE P20O8 / 004428, the disclosure of which is given below.
  • the literature discloses compounds with gestagenic, antimineralcorticoid, anti-drogenic or antiestrogenic action based on a steroid skeleton which are derived, for example, from 19-nor-androst-4-en-3-one or a derivative thereof (the numbering of the steroid skeleton For example, see Fresenius / Görlitzer, 3rd edition, 1991, "Organochemical 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 as well as 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.
  • the object of the invention described therein is to provide compounds which have a strong binding to the gestagen receptor.
  • the compounds should preferably also have an antimineralcorticoid effect.
  • R is selected from the group comprising O, two hydrogen atoms, NOR and NNHSO 2 R, wherein R is hydrogen or C r C 4 alkyl,
  • 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 either together form methylene or form a double bond between C 6 and C 7 ,
  • R 9 , R 10 are hydrogen or to form a double bond between
  • 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 AIIyI, wherein at least one of the substituents R 4, R 6a, R 6b, R 7, R 15, R 16 and R 17 is not hydrogen or R 6b and R 7 are omitted to form a double bond between C 6 and C 7, or to form a double bond omitted between C 1 and C 2 ,
  • 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.
  • OR in NOR and NHSO 2 R in NNHSO 2 R can be syn or antistatic.
  • dC- 4- alkyl is a straight-chain or branched alkyl radical, namely methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Particularly preferred are methyl, ethyl and n-propyl, especially the unbranched radicals.
  • Particularly preferred are methyl, ethyl and n-propyl.
  • alkyl radicals attached in the 17 ⁇ -position may be perfluorinated so that R 17 in this case 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 of the same empirical formula but of different chemical structure. There are expressly all possible lent isomers and mixtures of isomers (racemates) expressly included, wherein the 17ß-cyano-position in the derivative of the invention is specified.
  • 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 that 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 differentiation of the isomerism species from each other, see also the IUPAC rules, Section E (Pure Appl. Chem. 45, 11-30 (1976)).
  • the derivatives having the general chemical formula 1 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 may 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, especially 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.
  • the compounds or derivatives of general formula 1 have a good gestagen effect in vivo.
  • some interesting compounds of the invention act as antagonists to the mineralocorticoid receptor.
  • R 15 and R 16 together form methylene, where both an ⁇ -terminal and a ⁇ -methylene group may be bonded in these positions.
  • 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.
  • novel compounds of general chemical formula 1 can be used alone or in combination with estrogens in contraceptive medicines.
  • the compounds of general formula 1 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
  • the compounds of general formula 1 are also particularly well suited for the treatment of premenstrual disorders, such as headache, depressive moods, water retention and mastodynia.
  • Particularly preferred is the use of the compounds of general formula 1 for the preparation of a medicament with gestagen and antimineralcorticoid effect.
  • Treatment with the compounds of general formula 1 preferably takes place on humans, but can also be carried out on related mammalian species, such as, for example, dogs and cats.
  • the compounds of the general formula 1 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.
  • oils 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 compounds of general formula 1 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 compounds of general formula 1 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 solid derivatives according to the invention are preferably administered orally in contraceptive preparations and in the medicaments for the treatment of premenstrual disorders.
  • the daily dose is preferably administered once.
  • the gestagenic and estrogenic active ingredient components are preferably administered orally together in contraceptive preparations.
  • the daily dose is preferably administered once.
  • Suitable estrogens are synthetic estrogens, preferably ethinylestradiol, but also mestranol.
  • the estrogen is administered in a daily amount equivalent to that of 0.01 to 0.04 mg of ethinylestradiol.
  • the isomer mixtures can be separated by customary methods, such as, for example, crystallization, chromatography or salt formation, into the enantiomers, E / Z isomers or epimers.
  • Suitable starting materials for the 17 ⁇ -cyano-18a-homo-19-nor-androst-4-en-3-one derivatives described in PCT / EP2008 / 004428 are various steroidal starting materials, for example 18a-homo-19-nor androst-4-ene-3,17-dione or even the partially reduced analogs.
  • 15 ⁇ , 16 ⁇ -Methylene-3-methoxy-18a-homo-19-nor-androst-3,5-dien-17-one (WO 2006/072467 A1) is suitable as starting material for 15 ⁇ , 16 ⁇ -methylenated 17-cyano derivatives.
  • 15 ⁇ , 16 ⁇ -methylenated precursors suitable for the synthesis of the corresponding 17-cyanosteroids are also known, e.g. 17 ⁇ -hydroxy-15 ⁇ , 16 ⁇ -methylene-18a-homo-19-nor-androst-4-en-3-one in DE-A 22 07 421 (1973).
  • a 17-keto steroid with tosylmethyl isocyanide in suitable solvents such as dimethoxy- ethane, dimethyl sulfoxide, ethers, alcohols or mixtures thereof using suitable bases such as alkali metal alkoxides, alkali metal hydrides, potassium hexamethyldisilazid, or alkali amides such as lithium diisopropylamide , reacted in a temperature range from 0 0 C to 100 0 C.
  • suitable bases such as alkali metal alkoxides, alkali metal hydrides, potassium hexamethyldisilazid, or alkali amides such as lithium diisopropylamide , reacted in a temperature range from 0 0 C to 100 0 C.
  • Any 17-epimer mixtures which may be formed 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 a sulfonyl 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 a sulfonyl 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 is converted into the corresponding 17-exomethylene compound by means of a Wittig olefination which, after hydroboration and oxidation, 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 optionally present further functional groups are suitably protected.
  • the 17-cyano compounds may optionally be alkylated, resulting in stereochemically uniform 17 ⁇ -cyano-17 ⁇ -substituted derivatives.
  • the 17-cyanosteroid is 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 3 can be converted into the 17-cyano derivative 5.
  • the introduction of a 6,7-double bond via bromination of 3,5-dienol ether 5 and subsequent hydrogen bromide cleavage see, eg, J. Fried, JA Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, p 265-374).
  • 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 ° C or by the 6-bromo compounds in a solvent such as collidine or Lutidine, are heated to compound 6. If not the enol ether, but an unsaturated ketone such as 2, this can be easily converted into a type 5 dienol ether.
  • Compound 7 is prepared by methenylation of the 6,7-double bond according to known methods, for example 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; Chem. Soc., 84, 867 (1962)) into a compound 8 to give a mixture of the ⁇ - and ⁇ -isomers, which can be separated, for example by chromatography, into the individual isomers.
  • Compounds of type 7 can be obtained as described in the examples or analogously to these instructions using analogous to the reagents described there.
  • the synthesis of the spirocyclic compound 12 is based on 2, which is first converted into a 3-amino-3,5-diene derivative 9. By reaction with formalin in alcoholic solution, the 6-hydroxymethylene derivative 10 is obtained. After conversion of the hydroxy group into a leaving group, such as a mesylate, tosylate (compound 11) or benzoate, compound 13 can be prepared by reaction with trimethylsulfoxonium iodide using bases, such as alkali metal hydroxides, alkali metal alkoxides, in suitable solvents, such as dimethyl sulfoxide , represent.
  • bases such as alkali metal hydroxides, alkali metal alkoxides
  • 6-methylene group compound 10 For the introduction of a 6-methylene group compound 10 can be reacted with e.g. Hydrochloric acid in dioxane / water are dehydrated. 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 for the preparation of compounds having the general chemical 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.
  • a method described in Tetrahedron 21, 1619 (1965) may be used in which isomerization of the double bond by heating the 6-methylene compounds in ethanol with 5% palladium-carbon catalyst either with hydrogen or by heating with a small Volume cyclohexene was pretreated is achieved.
  • the isomerization can also be carried out with a non-pretreated catalyst if a small amount of cycloaddition to the reaction mixture lohexen is added.
  • the occurrence of small amounts of hydrogenated products can be prevented by adding an excess of sodium acetate.
  • R 6b represents an ⁇ -methyl function
  • R 6b represents an ⁇ -methyl function
  • suitable solvent such as, for example, ethanol
  • 6 ⁇ -methyl derivatives are obtained in very good yields.
  • Small amounts of 6 ⁇ -methyl compound can be acid isomerized (Tetrahedron 1619 (1965)).
  • 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.
  • Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,5-diazabicyclo [5.4.0] undec-5-ene (DBU), pyridine being preferred.
  • DBN non-5-ene
  • DBU 1,5-diazabicyclo [5.4.0] undec-5-ene
  • pyridine being preferred. This is analogous to that described in WO-A 98/24801 for the preparation of corresponding 3-oxyimino derivatives of drospirenone.
  • PCTVE P2008 / 004428 are surprisingly characterized by strong gestagenic activity and are highly effective 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 exo- estrogen (estrone, 5 ⁇ g / kg / day) was administered subcutaneously once daily 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 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 having the general chemical formula 1 have a very strong gestagenic activity. It has also been found that the derivatives of the general chemical formula 1 show antimineralcorticoid activity in vitro. 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, white, opaque tissue culture plates (PerkinElmer, # P12-106-017) and maintained in 6% DCC-FCS (charcoal treated serum, for removal of interfering components contained in the serum).
  • 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 evaluated using a software for calculating dose-response relationships. Table 1 shows experimental results:
  • HPLC separations were carried out on a chiral normal phase, Chiralpak AD-H 5 ⁇ generally being used as the stationary phase. Usually, it was eluted with a mixture of hexane and ethanol. In some cases, however, other eluent mixtures, such as mixtures of methanol and ethanol were used:
  • Example 3 By the method of Example 3 with ethyl magnesium bromide in ether instead of the methyl magnesium bromide was obtained by fractionation 1 as 17ß-cyano-7 ⁇ -ethyl-18a-homo-19-nor-androst-4-en-3-one and fraction II 17ß -Cyano-7 ⁇ -ethyl-18a-homo-19-nor-androst-4-en-3-one.
  • Example 3 According to the method of Example 3 with vinylmagnesium bromide instead of methylmagnesium bromide was obtained according to HPLC as fraction 1 17ß-cyano-7 ⁇ -vinyl-18a homo-19-nor-androst-4-en-3-one and fraction I1 17ß -Cyano-7 ⁇ -vinyl-18a-homo-19-nor-androst-4-en-3-one.
  • fraction 17 was obtained by HPLC as 17 ⁇ -cyano-7 ⁇ -cyclopropyl-18a-homo-19-nor-androst-4-en-3-one and as fraction I1 17 ⁇ - Cyano-7 ⁇ -cyclopropyl-18a-homo-19-nor-androst-4-en-3-one.
  • 17 ⁇ -Cyano-15 ⁇ , 16 ⁇ -methylene-18 ⁇ -homo-19-nor-androst-4-en-3-one was reacted analogously to the procedure given in Example 1a for the dienol ether, which without purification was analogous to that given in Example 2b Regulation was further processed.
  • 17 ⁇ -Cyano-15 ⁇ , 16 ⁇ -methylene-18a-homo-19-nor-androst-4,6-dien-3-one was obtained.
  • 17 ⁇ -Cyano-15 ⁇ , 16 ⁇ -methylene-18 ⁇ -homo-19-nor-androst-4,6-dien-3-one was reacted analogously to the procedure given in Example 9. Work-up and HPLC separation gave 17 ⁇ -cyano-6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-18 ⁇ -homo-19-nor-androst-4-en-3-one and 17 ⁇ -cyano-6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -bismethylene-18a-homo-19-nor-androst-4-en-3-one.
  • 17 ⁇ -cyano-17 ⁇ was obtained according to the instructions given in Examples 10a and 10b -methyl-15SS, 16ss-methylene-18a-homo-19-nor-androst-4-en-3-one.
  • 17 ⁇ -Cyano-17 ⁇ -ethyl-15 ⁇ 16 ⁇ -methylene-3-methoxy-18 ⁇ -homo-19-nor-androst-3,5-diene 17 ⁇ -cyano-17 ⁇ -ethyl-15 ⁇ was prepared analogously to Example 2b , 16 ⁇ -methylene-18 ⁇ -homo-19-nor-androsta-4,6-dien-3-one.
  • 17 ⁇ -cyano-17 ⁇ -methyl-15 ⁇ 16 ⁇ -methylene-18 ⁇ -homo-19-nor-androsta-4,6-dien-3-one
  • 17 ⁇ -cyano-17 ⁇ -methyl is obtained analogously to the procedure given in Example 9 -6 ⁇ , 7 ⁇ -methylene-15 ⁇ , 16 ⁇ -methylene-18 ⁇ -homo-19-nor-androst-4-en-3-one and 17 ⁇ -cyano-17 ⁇ -methyl-6 ⁇ , 7 ⁇ -methylene-15 ⁇ , 16 ⁇ -methylene -18a-homo-19-nor-androst-4-en-3-one.
  • Pyridine is on 100 mg of 17-cyano-17 ⁇ -methyl-15SS, 16ss-methylene-18a-homo-19-nor-androst-4-en-3 in 1 mL and cooled to 0 0 C. After addition of 42 .mu.l Sulfurylchlorid 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 is washed with water and saturated aqueous sodium chloride solution. After drying the organic phase over sodium sulfate and filtration is concentrated.
  • the compounds of general chemical formula 1 described in PCT / EP2008 / 004428 are also suitable for intravaginal or intrauterine administration.
  • physiologically acceptable solutions e.g. an aqueous or oily solution with or without suitable solubilizers, dispersants or emulsifiers.
  • suitable oils include, for example, peanut oil, cotton seed oil, castor oil or sesame oil. The selection is by no means limited to this.
  • intravaginal or intrauterine administration special systems such as an intravaginal system (eg vaginal ring, VRS) or an intrauterine system (IUS) may be used. which release an active substance of the present invention from a reservoir also over an extended period of time (e.g., 1, 2, 3, 4 or 5 years).
  • an intrauterine system MIRENA ® is mentioned as representative. This is a T-shaped, levonorgestrel-releasing intrauterine system of BAYER SCHERING PHARMA AG.
  • an application via an implanted depot system may consist of an inert carrier material, such as e.g. a biodegradable polymer or a synthetic silicone polymer.
  • an inert carrier material such as e.g. a biodegradable polymer or a synthetic silicone polymer.
  • These depot systems release the drug in a controlled manner over an extended period of time (e.g., 3 months to 3 years) and are implanted subcutaneously.
  • an equivalent daily amount corresponding to the daily oral dosage is released daily.
  • the oral doses to be used in contraceptive preparations 0.01 to 10 mg per day.
  • the daily dose for the treatment of premenstrual disorders is about 0.1 to 20 mg.
  • a formulation according to the invention for example from an IUS, an amount of 0.005 to 10 mg of a compound of general formula 1 is released daily.
  • estrogens can be administered with a system according to the invention.
  • Suitable estrogens in the case of contraceptive preparations are synthetic estrogens, preferably ethinylestradiol, but also mestranol.
  • the estrogen is administered in a daily amount equivalent to that of 0.01 to 0.04 mg of ethinylestradiol.
  • the present invention therefore relates to the use of 17 ⁇ -cyano-18a-homo-19-nor-androst-4-ene derivatives 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 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, methyl and
  • R 7 is selected from the group comprising hydrogen, C 1 -C 4 -alkyl,
  • R 6a is hydrogen and R 6b and R 7 either together form methylene or below
  • R 9 , R 10 are hydrogen or to form a double bond between
  • R 15 , R 16 are hydrogen or together form methylene
  • R 17 is selected from the group comprising hydrogen, C r C 4 alkyl and allyl
  • R 4 wherein at least one of the substituents R 4, R 6a, R 6b, R 7, R 15, R 16 and R 17 is not hydrogen or R 6b and R 7 are omitted to form a double bond between C 6 and C 7, or to form a double bond omitted between C 1 and C 2 ,
  • the compound of the general formula 1 is preferably used in an intrauterine system or a vaginal ring.
  • an implanted depot system can also be used for the application of a compound of general formula 1.
  • Z is selected from the group comprising O, NOH and NNHSO 2 H,
  • R 4 is hydrogen or chlorine
  • R 6a , R 6b together form 1, 2-ethanediyl or are each hydrogen
  • R 7 is selected from the group comprising hydrogen and methyl, R 6b and R 7 together form methylene and / or
  • R is selected from the group comprising hydrogen and methyl.
  • the present invention relates to depot pharmaceuticals for parenteral administration containing as active ingredient at least one compound of general formula 1.
  • the local application is, for example, an intrauterine or intravaginal administration of at least one compound of general formula 1 and in the corresponding pharmaceutical application form for example an intrauterine system (IUS) or a vaginal ring (IVR).
  • IUS intrauterine system
  • IVR vaginal ring
  • Intrauterine systems or vaginal rings as galenic application forms are well known to those skilled in the art.
  • intrauterine Sytem is for example the product Mirena ® from Bayer Schering Pharma AG and as a vaginal ring called the product Nuva- ring ®.
  • inventive parenteral administration of the compounds of general formula 1 can analogously be done as in the above products and pharmaceutical dosage forms for the compounds of general formula 1 according analogously as for example the products Mirena ® or Nuvaring ® accessible.
  • Intrauterine implantable depot systems of a biodegradable polymer or a synthetic silicone polymer, consisting of a drug-containing core in appropriate polymer-drug mixing ratio, surrounded by a desired daily release rate ensuring polymer membrane are spent in the uterine lumen of rats .
  • the female animals are castrated beforehand and pretreated with estradiol for three days.
  • the implants of different length (5-20 mm) and a limited diameter (1.1 to 2 mm) remain in the rat uterus for between 4 and 14 days in order to examine the local and systemic gestagenic effects of the released active substance on the basis of various parameters in different tissues.
  • gestagen-regulated marker genes eg IGFBP-1
  • gestagenic systemic effect on the mamma on the basis of the expression of gestagen-regulated marker genes eg RankL
  • 3) gestagenic systemic effect on the pituitary gland on the basis of the LH level (reduction of the estrogen-induced increased LH level).
  • the compounds of general formula 1 show a significant progestational effect in the uterus of a corresponding comparable to treatment with a containing levonorgestrel as depot system is MIRENA ®.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Reproductive Health (AREA)
  • Epidemiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Steroid Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Orthopedics, Nursing, And Contraception (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les dérivés de 17ß-cyano-18a-homo-19-nor-androst-4-ène de formule chimique générale (1) qui présentent une activité gestagène peuvent être utilisés pour produire des médicaments à libération prolongée permettant d'administrer lesdits composés par voie parentérale, par exemple par voie intra-utérine ou intra-vaginale, par exemple sous la forme d'un système intra-utérin ou d'un anneau vaginal. Cette invention concerne également lesdits systèmes qui comportent au moins un composé de formule chimique générale (1) et qui sont conçus pour une utilisation parentérale, en particulier intra-utérine ou intra-vaginale.
PCT/EP2009/008493 2008-12-12 2009-11-28 UTILISATION DE DÉRIVÉS DE 17β-CYANO-18A-HOMO-19-NOR-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-18A-HOMO-19-NOR-ANDROST-4-ÈNE DESTINÉ À ÊTRE ADMINISTRÉ PAR VOIE PARENTÉRALE Ceased WO2010066354A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705179A (en) * 1971-03-15 1972-12-05 American Home Prod Antiandrogenic steroids
DE2226552A1 (de) * 1971-06-01 1973-01-04 Roussel Uclaf Ungesaettigte, eine cyanogruppe enthaltende steroidderivate und verfahren zu deren herstellung
US5182381A (en) * 1982-03-01 1993-01-26 Roussel Ulcaf Intermediates for 3-keto-19-nor-Δ4,9 -steroids
WO1998024801A1 (fr) * 1996-12-01 1998-06-11 Schering Aktiengesellschaft Oxyiminopregnancarbolactone
WO2006072467A1 (fr) * 2004-12-30 2006-07-13 Schering Aktiengesellschaft 18-methyl-19-nor-17-pregn-4-en-21,17-carbolactones et preparations pharmaceutiques contenant ces derniers
WO2008000521A1 (fr) * 2006-06-29 2008-01-03 Bayer Schering Pharma Aktiengesellschaft 18-methyl-19-nor-androst-4-en-17,17-spiroéthers (18-methyl-19-nor-20- spirox-4-en-3-one) et préparations pharmaceutiques les contenant
WO2008151745A1 (fr) * 2007-06-12 2008-12-18 Bayer Schering Pharma Aktiengesellschaft Dérivé de 17bêta-cyano-18a-homo-19-nor-androst-4-ène, son utilisation, et médicament contenant ce dérivé

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705179A (en) * 1971-03-15 1972-12-05 American Home Prod Antiandrogenic steroids
DE2226552A1 (de) * 1971-06-01 1973-01-04 Roussel Uclaf Ungesaettigte, eine cyanogruppe enthaltende steroidderivate und verfahren zu deren herstellung
US5182381A (en) * 1982-03-01 1993-01-26 Roussel Ulcaf Intermediates for 3-keto-19-nor-Δ4,9 -steroids
WO1998024801A1 (fr) * 1996-12-01 1998-06-11 Schering Aktiengesellschaft Oxyiminopregnancarbolactone
WO2006072467A1 (fr) * 2004-12-30 2006-07-13 Schering Aktiengesellschaft 18-methyl-19-nor-17-pregn-4-en-21,17-carbolactones et preparations pharmaceutiques contenant ces derniers
WO2008000521A1 (fr) * 2006-06-29 2008-01-03 Bayer Schering Pharma Aktiengesellschaft 18-methyl-19-nor-androst-4-en-17,17-spiroéthers (18-methyl-19-nor-20- spirox-4-en-3-one) et préparations pharmaceutiques les contenant
WO2008151745A1 (fr) * 2007-06-12 2008-12-18 Bayer Schering Pharma Aktiengesellschaft Dérivé de 17bêta-cyano-18a-homo-19-nor-androst-4-ène, son utilisation, et médicament contenant ce dérivé

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ELGER W ET AL: "Conception and pharmacodynamic profile of drospirenone", STEROIDS, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, vol. 68, no. 10-13, 1 November 2003 (2003-11-01), pages 891 - 905, XP004479938, ISSN: 0039-128X *
NICKISCH K ET AL: "Aldosterone antagonists. 4. Synthesis and activities of steroidal 6,6-ethylene-15,16-methylene 17-spirolactones", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 34, 1 January 1991 (1991-01-01), pages 2464 - 2468, XP002375413, ISSN: 0022-2623 *

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