Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J21/001—Lactones
  • C07J21/003—Lactones at position 17
• • 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
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • 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
  • A61P5/26—Androgens
• • 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
  • A61P5/30—Oestrogens
• • 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
  • C07J53/008—3 membered carbocyclic rings in position 15/16

Definitions

• the invention relates to 15 ⁇ ,16 ⁇ -methylene-17-hydroxy-19-nor-17-pregna-4-en-3-one-21-carboxylic acid ⁇ -lactone derivatives with progestational action, use thereof and medicinal products containing the derivatives, for example for the treatment of pre-, peri- and postmenopausal and of premenstrual complaints.
• WO 2006072467 A1 discloses the compound 6 ⁇ ,7 ⁇ -15 ⁇ ,16 ⁇ -dimethylene-3-oxo-17-pregn-4-ene-21,17 ⁇ -carbolactone (drospirenone), which has progestational action and has been used for example in an oral contraceptive and in a preparation for the treatment of postmenopausal complaints. Owing to its comparatively low affinity for the progestogen receptor and its comparatively high ovulation-inhibiting dose, however, drospirenone is contained in the contraceptive at the relatively high daily dose of 3 mg.
• Drospirenone is, moreover, also characterized in that in addition to the progestational action it also has aldosterone-antagonistic (antimineralocorticoid) and antiandrogenic action. These two properties make drospirenone very similar in its pharmacological profile to the natural progestogen, progesterone, which however, unlike drospirenone, is not sufficiently bioavailable orally.
• WO 2006072467 A1 further proposes an 18-methyl-19-nor-17-pregn-4-ene-21,17-carbolactone and pharmaceutical preparations containing this, which have a higher progestational potency than drospirenone.
• U.S. Pat. No. 3,705,179 discloses steroids that display antiandrogenic activity and are suitable for the treatment of diseases that are linked to androgens.
• the aim of the present invention is to make compounds available that bind strongly, and preferably more strongly than drospirenone, to the progestogen receptor. Moreover, the compounds should preferably also have antimineralocorticoid action and, with respect to the androgen receptor, a neutral to slightly androgenic action.
• Another essential aim of the present invention consists of achieving a balanced action profile with respect to the progestational action to the antimineralocorticoid action, so that the ratio of the progestational action to the antimineralocorticoid action is less than with drospirenone.
• the present invention describes the novel 15,16-methylene-17-hydroxy-19-nor-17-pregna-4,20(Z)-dien-3-one-21-carboxylic acid ⁇ -lactone derivatives of general formula I,
• Z denotes oxygen, two hydrogen atoms, a group ⁇ NOR 1 or ⁇ NNHSO 2
• R 1 denotes hydrogen, C 1 -C 10 -alkyl, aryl, C 7 -C 20 -aralkyl
• R 4 denotes hydrogen or halogen
• R 6a , R 6b which may be identical or different, denote hydrogen, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl or together denote methylene or 1,2-ethanediyl
• R 7 denotes hydrogen, C 1 -C 10 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, R 6a , R 7 together, denote a bond, an oxygen or a methylene group
• R 18 denotes hydrogen, C 1 -C 3 -
• the residues R 6a , R 6b and R 7 and the three-membered ring can each be in the ⁇ or ⁇ position.
• Z denotes oxygen, a group ⁇ NOR 1
• R 1 denotes hydrogen, C 1 -C 6 -alkyl, aryl, C 7 -C 12 -aralkyl
• R 4 denotes hydrogen or halogen
• R 6a , R 6b which may be identical or different, denote hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or together denote methylene or 1,2-ethanediyl
• R 7 denotes hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, R 6a , R 7 together, denote a bond, or a methylene group
• R 18 denotes hydrogen, C 1 -C 2 -alkyl
• Z denotes oxygen, a group ⁇ NOR 1 , R 1 denotes hydrogen, C 1 -C 3 -alkyl, R 4 denotes hydrogen, chlorine or bromine, R 6a , R 6b which may be identical or different, denote hydrogen, C 1 -C 3 -alkyl, C 2 -C 4 -alkenyl, or together denote methylene or together denote 1,2-ethanediyl, R 7 denotes hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 2 -C 4 -alkenyl, R 6a , R 7 together, denote a bond, or a methylene group, R 18 denotes hydrogen, methyl.
• the numbering of the carbon backbone of the derivatives according to the invention with the general chemical formula I follows the numbering of a steroid structure in the usual way, as described for example in Fresenius, loc. cit.
• the numbering of the residues stated in the claims corresponds in a similar manner to their bonding position on the carbon backbone of the derivative, as far as this relates to R 4 , R 6 , R 7 and R 18 .
• the residue R 4 binds to the C 4 -position of the derivative according to the invention.
• the groups NOR′ and NNHSO 2 R′ each bind with a double bond via N to the carbon backbone of the derivative according to ⁇ NOR′ or ⁇ NNH—SO 2 R′.
• OR′ in NOR′ and NHSO 2 R′ in NNHSO 2 R′ can be in syn- or anti-position.
• Alkyl groups R 1 , R 6a , R 6b , R 7 , R 18 , R 19 , R 20 , R 21a , R 21b and R 22 are to be considered to be linear or branched alkyl groups with 1-10 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
• the alkyl groups R 1 , R 6a , R 6b , R 7 , R 18 , R 19 , R 20 , R 21a , R 21b and R 22 can be perfluorinated or can be substituted with 1-5 halogen atoms, hydroxyl groups, C 1 -C 4 -alkoxy groups, C 6 -C 12 -aryl groups (which can be substituted with 1-3 halogen atoms).
• Alkenyl groups R 6a and R 6b are to be considered to be linear or branched alkene groups with 2-10 carbon atoms, such as for example vinyl, propenyl, butynyl, pentenyl, isobutenyl, isopentenyl.
• Alkynyl groups R 6a and R 6b are to be considered to be linear or branched alkyne groups with 2-10 carbon atoms, such as for example ethynyl, propynyl, butynyl, pentynyl, isobutynyl, isopentynyl.
• the alkenyl and alkynyl groups R 6a and R 6b can be substituted with 1-5 halogen atoms, hydroxyl groups, C 1 -C 3 -alkoxy groups, C 6 -C 12 -aryl groups (which can be substituted with 1-3 halogen atoms).
• cycloalkyl groups R 7 consideration may be given to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
• the cycloalkyl groups R 7 can be substituted with halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, —NH 2 , —NO 2 , —N 3 , —CN, C 1 -C 10 -alkyl, C 1 -C 10 -acyl, C 1 -C 10 -acyloxy groups.
• aryl residue R 1 , R 6a , R 6b and R 7 consideration may be given to substituted and unsubstituted carbocyclic or heterocyclic residues with one or more heteroatoms, e.g. phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which can be singly or multiply substituted with halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, —NH 2 , —NO 2 , —N 3 , —CN, C 1 -C 10 -alkyl, C 1 -C 10 -acyl, C 1 -C 10 -acyloxy groups.
• heteroatoms e.g. phenyl, naphthyl, furyl, thienyl,
• the aralkyl groups in R 1 and R 7 can contain up to 14, preferably 6 to 10, carbon atoms in the ring and 1 to 8, preferably 1 to 4, atoms in the alkyl chain.
• aralkyl residues consideration may be given for example to benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
• the rings can be singly or multiply substituted with halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, —NO 2 , —N 3 , —CN, C 1 -C 20 -alkyl, C 1 -C 20 -acyl, C 1 -C 20 -acyloxy groups.
• Halogen means fluorine, chlorine or bromine.
• the derivatives with the general chemical formula I include all stereoisomers and mixtures thereof.
• the derivatives according to the invention can also be in the form of solvates, in particular of hydrates, and the compounds according to the invention accordingly contain polar solvents, in particular water, as structural element of the crystal lattice of the compounds according to the invention.
• the polar solvent, in particular water can be present in stoichiometric proportions or even in nonstoichiometric proportions.
• Stoichiometric solvates and hydrates are also called hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates.
• the compounds or derivatives according to the invention have good progestational action. Furthermore, some interesting compounds according to the invention interact with the mineralocorticoid receptor and are able to impart an antagonistic action. Moreover, the compounds according to the invention have a neutral to slightly androgenic action with respect to the androgen receptor. Another property of the compounds is that the bonds of these compounds to the progesterone receptor and to the mineralocorticoid receptor are balanced relative to one another, namely so that the ratio of their capacity for binding to the progesterone receptor to the capacity for binding to the mineralocorticoid receptor is less than in the case of drospirenone.
• the antimineralocorticoid action of these compounds at given progestational action is less than with drospirenone. If the dosage of a given compound according to the invention is based on its progestational action, the antimineralocorticoid action of this compound at this dosage is therefore less than with drospirenone.
• novel compounds with the general chemical formula I can be used alone or in combination with estrogen in medicinal products for contraception.
• the derivatives according to the invention are therefore suitable in particular for the production of a medicinal product for oral contraception and for the treatment of pre-, peri- and postmenopausal complaints, including use in preparations for hormone replacement therapy (HRT).
• HRT hormone replacement therapy
• the derivatives according to the invention are moreover especially well suited to the treatment of premenstrual complaints, such as headaches, depressive moods, water retention and mastodynia.
• the use of the derivatives according to the invention is especially preferred for the production of a medicinal product with progestational, and preferably also antimineralocorticoid and neutral to slightly androgenic action.
• Treatment with the derivatives according to the invention is preferably applied to humans, but can also be carried out on related mammalian species, for example dog and cat.
• the derivatives according to the invention are combined with at least one suitable pharmaceutically harmless additive, for example a carrier.
• the additive is for example suitable for parenteral, preferably oral, application.
• Relevant materials are pharmaceutically suitable organic or inorganic inert additives, for example water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
• the medicinal products can be in solid form, for example as tablets, coated tablets, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions.
• they also contain excipients, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for altering the osmotic pressure or buffers.
• excipients such as preservatives, stabilizers, wetting agents or emulsifiers, salts for altering the osmotic pressure or buffers.
• oily solutions are suitable in particular, for example solutions in sesame oil, castor oil and cottonseed oil.
• solubilizers can be added, for example benzyl benzoate or benzyl alcohol.
• consideration may be given in particular to tablets, coated tablets, capsules, pills, suspensions or solutions.
• administration routes are intravaginal or intrauterine administration. This is possible with physiologically tolerated solutions such as, for example, an aqueous or oily solution with or without suitable solubilizers, dispersants or emulsifiers.
• physiologically tolerated solutions such as, for example, an aqueous or oily solution with or without suitable solubilizers, dispersants or emulsifiers.
• suitable oils are peanut oil, cottonseed oil, castor oil or sesame oil. The selection is by no means restricted thereto.
• intravaginal or intrauterine administration it is possible to use special systems such as an intravaginal system (e.g. vaginal ring, VRS) or an intrauterine system (IUS) which release an active substance of the present invention from a reservoir over a prolonged period (e.g. 1, 2, 3, 4 or 5 years).
• an intravaginal system e.g. vaginal ring, VRS
• IUS intrauterine system
• MIRENA® A representative example of an intrauterine system which may be mentioned is MIRENA®. This is a T-shaped, levonorgestrel-releasing intrauterine system from Bayer Schering Pharma AG.
• an implanted depot system composed of an inert carrier material such as, for example, a biodegradable polymer or a synthetic silicone polymer.
• an implanted depot system composed of an inert carrier material such as, for example, a biodegradable polymer or a synthetic silicone polymer.
• These depot systems release the active ingredient in a controlled manner over a prolonged period (e.g. 3 months to 3 years) and are implanted subcutaneously.
• the dosage of the derivatives according to the invention in contraceptive preparations should be 0.01 to 10 mg per day.
• the daily dose in the treatment of premenstrual complaints is around 0.1 to 20 mg.
• the progestational derivatives according to the invention are preferably administered orally in contraceptive preparations and in medicinal products for the treatment of premenstrual complaints.
• the daily dose is preferably administered as a single dose.
• the aforementioned dosages relate to oral administration forms.
• the appropriate dosage equivalent to the aforementioned oral dosages, is released continuously each day from the depot systems described above and employed in the long term.
• a depot formulation for example an IUS, releases per day an amount of 0.005 to 10 mg of a compound of general formula 1.
• the progestational and estrogenic active components are preferably applied together orally in contraceptive preparations.
• the daily dose is preferably administered as a single dose.
• estrogens consideration may be given to synthetic estrogens, preferably ethinylestradiol, but also mestranol, and natural estrogens, including phytoestrogens.
• the estrogen is administered in a daily amount that corresponds to the pharmacological action of 0.01 to 0.04 mg ethinylestradiol. This amount relates to an oral administration form. If a different administration route is chosen, an appropriate dosage amount equivalent to the aforementioned oral dosage is to be used.
• CF values greater than 1 are characterized by a lower affinity for the progesterone receptor, and CF values of less than 1 are characterized by higher affinity.
• test was carried out as in 1, with the following modifications: cytosol from mineralocorticoid receptor-expressing insect cells (Hi5) was used, and the reference substance was 3 H-aldosterone.
• test was carried out as in 1, with the following modifications: cytosol from androgen receptor—expressing insect cells (Hi5) was used, and the reference substance was 3 H-testosterone.
• the culture medium used for culture of the cells used for the assay was DMEM (Dulbecco's Modified Eagle Medium: 4500 mg/ml glucose; PAA, #E15-009) with 10% FCS (Biochrom, S0115, batch #6158), 4 mM L-glutamine, 1% penicillin/streptomycin, 1 mg/ml 6418 and 0.5 ⁇ g/ml puromycin.
• DMEM Dulbecco's Modified Eagle Medium: 4500 mg/ml glucose; PAA, #E15-009) with 10% FCS (Biochrom, S0115, batch #6158), 4 mM L-glutamine, 1% penicillin/streptomycin, 1 mg/ml 6418 and 0.5 ⁇ g/ml puromycin.
• Reporter cell lines (CHO K1 cells stably transfected with a fusion protein from the PR-ligand-binding domain and a Gal4-transactivation domain and a reporter construct, which contained luciferase under the control of a Gal-4-responsive promoter) were seeded at a density of 4 ⁇ 10 4 cells per well in white, opaque tissue culture plates each with 96 wells (PerkinElmer, #P12-106-017) and kept in culture medium with 3% DCC-FCS (serum treated with activated charcoal to remove interfering components contained in the serum). The test compounds were added eight hours later, and the cells were incubated with the compounds for 16 hours. The tests were carried out in triplicate.
• the production of the starting compounds is not described here, these are known to a person skilled in the art or can be prepared similarly to known compounds or methods described here.
• the isomeric mixtures can be separated into the individual compounds by the usual methods, for example crystallization, chromatography or salt formation.
• the salts are prepared in the usual way, by adding, to a solution of the compounds with the general chemical formula I, the equivalent amount or an excess of a base or acid, which is optionally in solution, if necessary separating the precipitate or processing the solution in the usual way.
• the dienol ether bromination of compounds 3, 12 or 17 can for example be carried out as for the specification from Steroids 1, 233 (1963).
• Hydrogen bromide elimination with formation of the compounds with the general chemical formulae 4, 13 or 18 is achieved by heating the 6-bromo compound with basic reagents, for example with LiBr or Li 2 CO 3 , in aprotic solvents, such as dimethylformamide, at temperatures of 50-120° C. or alternatively by heating the 6-bromo compounds in a solvent, such as collidine or lutidine.
• R 4 can be carried out, for example, starting from a compound of formula 6, 11, 13, 14, 16 or 18, by epoxidation of the 4,5-double bond with hydrogen peroxide under alkaline conditions and reaction of the resultant epoxides in a suitable solvent with acids with the general formula H—R 4 , where R 4 can be a halogen atom, preferably chlorine or bromine.
• R 4 can be a halogen atom, preferably chlorine or bromine.
• Compounds in which R 4 has the meaning bromine can for example be reacted with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in dimethylformamide in the presence of copper(I) iodide to compounds in which R 4 has the meaning fluorine.
• halogen can be introduced directly by reaction with sulfuryl chloride or sulfuryl bromide in the presence of a suitable base, for example pyridine, with R 4 having the meaning chlorine or bromine.
• a suitable base for example pyridine
• R 4 having the meaning chlorine or bromine.
• Compound 4 is converted by methenylation of the 6,7-double bond by 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, U.S. Pat. No. 4,291,029; J. Am. Chem. Soc.
• Compound 18 (R 6a , R 6b together form methylene) can also be produced after converting the hydroxyl group into a leaving group, such as a mesylate, tosylate or even benzoate (see DE-A 34 02 3291, EP-A. 0 150 157, U.S. Pat. No. 4,584,288; J. Med. Chem. 34, 2464 (1991)).
• suitable solvents such as chloroform
• the 6-methylene compounds can be used for the preparation of compounds of general formula 18, in which R 6a is methyl and R 6b and R 7 together form an additional bond.
• compound 17 (X ⁇ OR 22 ) can be used as precursor.
• the direct preparation of 6-methyl-4,6-digin-3-one derivatives has been described (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983)).
• the selective preparation of 6 ⁇ -methyl compounds is also possible.
• the 4-en-3-ones such as compound 16 are reacted for example with ethylene glycol, trimethyl orthoformate in dichloromethane in the presence of catalytic amounts of an acid, for example p-toluenesulfonic acid, to the corresponding 3-ketals.
• an acid for example p-toluenesulfonic acid
• This ketalization there isomerisation of the double bond into position 5.
• Selective epoxidation of this 5-double bond is achieved for example by using organic per-acids, 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 5,6 ⁇ -epoxides formed can then be opened axially using appropriate alkylmagnesium halides or alkyllithium compounds. In this way, 5 ⁇ -hydroxy-6 ⁇ -alkyl compounds are obtained.
• the 3-keto protecting group can be cleaved, obtaining the 5 ⁇ -hydroxy function, by treatment in mild acidic conditions (acetic acid or 4N hydrochloric acid at 0° C.).
• the introduction of a 7-alkyl, 7-alkenyl or 7-alkynyl group to compounds of general formula 14 is effected by 1,6-addition of a corresponding organometallic compound to the precursor of general formula 13 under the action of copper salts.
• Divalent metals such as magnesium and zinc, are preferred; chlorine, bromine and iodine are preferred as counter ion.
• Suitable copper salts are monovalent or divalent copper compounds, for example copper chloride, copper bromide or copper acetate.
• the reaction takes place in an inert solvent, for example tetrahydrofuran, diethyl ether or dichloromethane.
• the compounds 6, 11, 13, 14, 16, 18 or 20 obtained in which Z stands for an oxygen atom, can be converted by reaction with hydroxylamine hydrochloride, alkyloxyamine hydrochlorides or sulfonyl hydrazines in the presence of a tertiary amine at temperatures between ⁇ 20 and +40° C. to their corresponding EIZ-configured oximes or sulfonyl hydrazones (general formula I with Z denoting ⁇ NOR 1 , ⁇ NNHSO 2 R 1 )).
• 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.
• An analogous method is described for example in WO 98/24801 for the production of corresponding 3-oxyimino derivatives of drospirenone.
• the 3-oxo group can be removed for example following the instructions given in DE-A 28 05 490 by reductive cleavage of a thioketal of the 3-keto compound on a suitable precursor, for example compounds of the general formulae 6, 11, 13, 14, 16, 18 or 20.
• spirolactones to compounds of the general formulae 6 or 11 is carried out starting from the corresponding 17-hydroxypropenyl compounds 5 or 10, by oxidation.
• Oxidation processes that may be mentioned are for example the Jones oxidation, oxidation with potassium permanganate for example in an aqueous system of tert.-butanol and sodium dihydrogen phosphate, oxidation with sodium chlorite in aqueous tert.-butanol, optionally in the presence of a chlorine trap, for example 2-methyl-2-butene, or by oxidation with manganese dioxide.
• the spirolactone can be introduced directly from the ketones of general formulae 1 or 7 optionally also after cleavage of the enol ethers in 1 or ketals in 7 according to the method described by Georges Sturtz et al. in Tetrahedron Letters 47 (1976).
• Compound 1 in Scheme 2 in each case has a double bond between C5 and Ce or C5 and C10 and another double bond between C2 and C3 or C3 and C4.
• a spatula tip of molecular sieve 4 ⁇ , 700 mg N-methylmorpholino-N-oxide, and 90 mg tetrabutylammonium perruthenate are added to a solution of 1.06 g of the compound prepared according to Example 1s in 32 ml dichloromethane and it is stirred at 23° C. for approx. 16 hours. It is concentrated by evaporation and the residue is purified by chromatography. 878 mg of the title compounds is isolated.
• triphenylphosphine 27.1 g 4-nitrobenzoic acid, and 30.9 ml azodicarboxylic acid diisopropyl ester are added to a solution of 43.9 g of 3-methoxy-17 ⁇ -hydroxyestra-1,3,5(10),15-tetraene in 1.6 l tetrahydrofuran and it is stirred for 23° C. for 2 hours.
• Saturated sodium chloride solution is added, it is extracted with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate.
• Example 3 200 mg of the compound prepared according to Example 2 using ethylmagnesium chloride is reacted and, after processing and purification, 81 mg of the title compound A is isolated along with a still contaminated mixture, which contains proportions of the title compound B.
• Example 3 210 mg of the compound prepared according to Example 2 using vinylmagnesium chloride is reacted and, after processing and purification, 16 mg of the title compound A is isolated along with a still contaminated mixture, which contains proportions of the title compound B.
• Example 3 200 mg of the compound prepared according to Example 2 using cyclopropylmagnesium bromide is reacted and, after processing and purification, 71 mg of the title compound A is isolated along with a still contaminated mixture, which contains proportions of the title compound B.
• Example 8 1.13 g of the compound prepared according to Example 2 is reacted and, after processing and purification, 46 mg of the title compound A and 222 mg of the title compound B are isolated.
• Inert depot systems amenable to intrauterine implantation and composed of a biodegradable polymer or a synthetic silicone polymer consisting of an active ingredient-containing core in the appropriate polymer-active ingredient mixing ratio, surrounded by a polymer membrane ensuring the desired daily release rate, are introduced into the lumen of the rat uterus.
• the female animals are castrated beforehand and pretreated with estradiol for three days.
• the implants of different length (5-20 mm) and a restricted diameter (1.1 to 2 mm) remain for between 4 and 14 days in the rat uterus in order to investigate the local and systemic progestational effect of the released active ingredient on the basis of various parameters in different tissues.
• the following parameters are measured: 1) local progestational effect on the uterus, on the basis of the weight of the uterus, the histologically detectable epithelial height and the expression of progestogen-regulated marker genes (e.g. IGFBP-1); 2) systemic progestational effect on the mammary gland on the basis of the expression of progestogen-regulated marker genes (e.g. RankL), 3) systemic progestational effect on the pituitary on the basis of the LH level (reduction in the estrogen-induced elevation of the LH level).
• progestogen-regulated marker genes e.g. IGFBP-1
• systemic progestational effect on the mammary gland on the basis of the expression of progestogen-regulated marker genes
• RankL systemic progestational effect on the pituitary on the basis of the LH level (reduction in the estrogen-induced elevation of the LH level).
• the compounds of the present invention show a significant progestational effect in the uterus which is comparable to a corresponding treatment with a levonorgestrel-containing depot system such as MIRENA®.
• the compounds in Examples 1, 3-6 and 8-9 possess improved selectivity on the progesterone receptor (PR) compared with the mineralocorticoid receptor (MR) expressed by the ratio of the competition factors CF-PR/CF-MR.
• the ratios are in a range from 0.41 to 2.46 and are therefore well below that of DRSP (5.4

Landscapes

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

Applications Claiming Priority (3)

Related Parent Applications (1)

Related Child Applications (1)

Publications (1)

Family

ID=40548690

Family Applications (2)

Family Applications After (1)

Country Status (26)

Cited By (1)

Families Citing this family (2)

Citations (5)

Family Cites Families (5)

• 2007
  • 2007-12-29 DE DE102007063495A patent/DE102007063495A1/de not_active Withdrawn
• 2008
  • 2008-12-23 NZ NZ586453A patent/NZ586453A/en not_active IP Right Cessation
  • 2008-12-23 JP JP2010540082A patent/JP5600071B2/ja not_active Expired - Fee Related
  • 2008-12-23 TW TW097150356A patent/TW200940074A/zh unknown
  • 2008-12-23 UA UAA201009129A patent/UA98834C2/ru unknown
  • 2008-12-23 WO PCT/EP2008/011165 patent/WO2009083272A2/de active Application Filing
  • 2008-12-23 AR ARP080105699A patent/AR069962A1/es unknown
  • 2008-12-23 KR KR1020107014303A patent/KR20100102136A/ko not_active Application Discontinuation
  • 2008-12-23 ES ES08867523.6T patent/ES2539121T3/es active Active
  • 2008-12-23 BR BRPI0821666-5A patent/BRPI0821666A2/pt not_active IP Right Cessation
  • 2008-12-23 CN CN2008801234339A patent/CN101910192B/zh not_active Expired - Fee Related
  • 2008-12-23 CA CA2710495A patent/CA2710495C/en not_active Expired - Fee Related
  • 2008-12-23 PE PE2008002179A patent/PE20091336A1/es not_active Application Discontinuation
  • 2008-12-23 AU AU2008342916A patent/AU2008342916A1/en not_active Abandoned
  • 2008-12-23 EP EP08867523.6A patent/EP2238149B1/de not_active Not-in-force
  • 2008-12-23 EA EA201000982A patent/EA201000982A1/ru unknown
  • 2008-12-23 US US12/810,860 patent/US20100311702A1/en not_active Abandoned
  • 2008-12-24 PA PA20088810701A patent/PA8810701A1/es unknown
  • 2008-12-26 UY UY31580A patent/UY31580A1/es not_active Application Discontinuation
  • 2008-12-29 CL CL2008003919A patent/CL2008003919A1/es unknown
• 2010
  • 2010-05-27 IL IL206019A patent/IL206019A0/en unknown
  • 2010-06-29 DO DO2010000199A patent/DOP2010000199A/es unknown
  • 2010-06-29 EC EC2010010315A patent/ECSP10010315A/es unknown
  • 2010-06-29 CO CO10078685A patent/CO6290675A2/es not_active Application Discontinuation
  • 2010-07-28 ZA ZA2010/05395A patent/ZA201005395B/en unknown
• 2011
  • 2011-06-08 HK HK11105768.6A patent/HK1151532A1/xx not_active IP Right Cessation
• 2013
  • 2013-01-10 US US13/738,751 patent/US8987239B2/en not_active Expired - Fee Related

Patent Citations (5)

Also Published As

Similar Documents

Legal Events