Classifications

• • 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
• • 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
  • 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
  • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring

Definitions

• the invention relates to certain 17-hydroxy-19-nor-21-carboxylic acid steroid ⁇ -lactone derivatives, their use and the derivatives containing drugs with Gestagener effect, for example, for the treatment of pre-, peri- and postmenopausal and of premenstrual Complaints.
• the literature discloses compounds with gestagenic, antimineralcorticoid, antiandrogenic 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 is for example, Fresenius / Görlitzer 3rd edition 1991 "Organic chemical nomenclature" p. 60 ff.).
• WO 2006072467 A1 discloses the progestin compound 6 ⁇ , 7 ⁇ , 15 ⁇ , 16 ⁇ -dimethylene-3-oxo-17-pregn-4-ene-21,17 ⁇ -carbolactone (drospirenone), which is obtained, for example, in an oral contraceptive as well as a preparation used to treat postmenopausal complaints.
• 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 also characterized by its aldosterone antagonist (antimineralcorticoid) and anti-androgenic effects in addition to the gestagenic effect.
• 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 gestagen content Have potency as drospirenone.
• US Pat. No. 3,705,179 discloses steroids which have antiandrogenic activity and are useful in the treatment of androgen related diseases.
• U.S. Patent No. 2,918,463 discloses 17-carboxyalkylated 17-hydroxy-19-nor-butrostene-3-ones, inter alia, 17 ⁇ - (2-carboxyvinyl) -17 ⁇ -hydroxy-19-nor-androst-4- en-3-on lactone.
• the compounds described are intended to block the action of desoxycorticosterone acetate on the content of sodium and potassium in the urine and at the same time have a salt-binding effect in a higher concentration. In addition, these compounds should also be effective against hypertension.
• 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 as well as a neutral to slightly androgenic effect with regard to the androgen receptor.
• Another essential aim of the present invention is also to achieve a balanced effect profile with regard to the progestational effect on the antimineralcorticoid effect in such a way that the ratio of proteic to antimineralocorticoid action is lower than in the case of drospirenone.
• the invention relates to a 17-hydroxy-19-nor-21-carboxylic acid steroid ⁇ -lactone derivative having the following chemical formula I:
• Z is selected from the group comprising oxygen, two hydrogen atoms, NOR 'and NNHSO 2 R', wherein R 1 is hydrogen, d-to-alkyl, aryl or C 7 -C 20 -aralkyl,
• R 4 is selected from the group comprising hydrogen and halogen
• R 6a , R 6b are each independently selected from the group comprising hydrogen, C 1 -C 6 -alkyl, C 2 -C 10 -alkenyl and C 2 -C 10 -alkynyl, or together form methylene or 1,2-ethanediyl and
• R 7 is selected from the group comprising hydrogen, C 1 -C 10 -alkyl,
• R 6a , R 7 together form an oxygen atom or methylene or omitted to form a double bond between C 6 and C 7, and
• R 15 is hydrogen and R i ea R i6b j j ewe
• s are independently selected from the group comprising hydrogen and Ci-Ci O alkyl, or together form methylene or 1, 2-ethanediyl
• R 15 , R 16a together form an oxygen atom or form a double bond between C 15 and C 16 and R 16b is hydrogen or C 1 -C 10 -alkyl
• R 18 is hydrogen or d-Ca-alkyl
• the numbering of the C-skeleton of the derivative according to the invention with the general chemical formula I usually follows 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 as far as R 4 , R 6 , R 7 , R 15 , R 16 and R 18 are concerned.
• 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.
• Alkyl in R ', R 6a , R 6b , R 7 , R 16a and R 16b and in R 19 , R 20 , R 21a , R 21b and R 22 in the general chemical formulas given below are straight-chain or branched C 1-10 carbonyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
• Alkyl in R 18 is in particular methyl, ethyl, propyl or isopropyl understand.
• alkyl groups R 1 , R 6a , R 6b , R 7 , R 16a , R 16b and R 18 can also be perfluorinated or by 1-5 halogen atoms, hydroxy groups, C 1 -C 4 alkoxy groups, C 6 -C 12 aryl groups (den in turn may be substituted by 1-3 halogen atoms) may be substituted.
• alkyl may therefore also be hydroxymethylene (HO-CH 2 ), hydroxyethylene (HO-C 2 H 4 ), hydroxypropylene (HO-C 3 H 6 ) and hydroxybutylene (HO-C 4 H 8 ) and their isomers.
• Alkenyl in R 6a , R 6b and R 7 are straight or branched chain alkenyl groups having 2-10 carbon atoms, such as vinyl, propenyl, butenyl, pentynyl, isobutenyl, isopentenyl.
• Alkynyl in R 6a , R 6b and R 7 are straight or branched chain alkynyl groups having 2-10 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, isobutinyl, isopentinyl.
• alkenyl and alkynyl groups R 6a , R 6a and R 7 may be substituted by 1-5 halogen atoms, hydroxy groups, dC 3 alkoxy groups, C 6 -C 12 aryl groups (which in turn may be substituted by 1-3 halogen atoms).
• Cycloalkyl in R 7 is to be understood as meaning cycloalkyl groups having 3-6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• the cycloalkyl groups R 7 may be substituted by halogen, OH O-alkyl, CO 2 H, CO 2 -alkyl, NH 2, NO 2, N 3, CN, C 1 -C 0 - alkyl, C 1 -C O -acyl, dC 10 acyloxy groups substituted.
• Aryl in R ' is to be understood as meaning substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, for example phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which are simple or more times by halogen, OH, O-alkyl, CO 2 H, CO 2 - alkyl, NH 2, NO 2, N 3, CN, d-do-alkyl, C 1 -C 0 -acyl, Ci-Cio-acyloxy Groups, may be substituted.
• aryl is mentioned as a substituent on alkyl, alkenyl or alkynyl, it is in particular aryl groups having 6-12 ring carbon atoms.
• Aralkyl in R 'and R 7 is to be understood as meaning aralkyl groups which contain up to 14 carbon atoms, preferably 6 to 10 C atoms, in the ring and 1 to 8, preferably 1 to 8, in the alkyl chain 4, carbon atoms may contain.
• Suitable aralkyl radicals are, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
• the rings may be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, NO 2 , N 3 , CN, C 1 -C 20 -alkyl, C 1 -C 20 -alkyl, CrCl 2 -Acyloxy groups be substituted.
• alkoxy (O-alkyl) is mentioned as a substituent on alkyl, it concerns alkoxy groups with 1-4 carbon atoms, and, as far as Alkoxy is mentioned as substituent at alkenyl and Al kinyl, it concerns Alkoxy phenomenon with 1- 3 carbon atoms.
• Alkoxy may in particular be methoxy, ethoxy and propoxy.
• acyl (CO-alkyl) is mentioned as a substituent on cycloalkyl and aryl, are acyl groups having 1-10 carbon atoms, and, as far as acyl is mentioned as a substituent on aralkyl, are acyl groups having 1-20 carbon atoms , Acyl may in particular be formyl, acetyl, propionyl and butyryl.
• acyloxy (O-CO-alkyl) is mentioned as a substituent on cycloalkyl and aryl, it is Acyloxy phenomenon having 1-10 carbon atoms, and, as far as acyloxy is mentioned as a substituent on aralkyl, are acyloxy groups having 1-20 carbon - atoms.
• Acyloxy may in particular be formyloxy, acetyloxy, propionyloxy and butyryloxy.
• Halogen is fluorine, chlorine or bromine.
• Z is selected from the group comprising oxygen, NOR 'and NNHSO 2 R'.
• Z is oxygen
• 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, methyl, ethyl and vinyl.
• R 6a , R 7 together form methylene.
• R 6a and R 7 are eliminated to form a double bond between C 6 and C 7 .
• R 15 is hydrogen
• R 15 , R 16a account for forming a double bond between C 15 and C 16, or R 15 , R 16a together form an oxygen atom.
• R 16a is hydrogen and R 16b is methyl.
• R 16a and R 16b are hydrogen.
• R 16a and R 16b together form methylene or 1,2-ethanediyl.
• R 18 is hydrogen or methyl.
• Z is oxygen, a group NOR ', wherein R 1 is hydrogen, C 1 -C 6 alkyl, aryl or
• R 4 is hydrogen or halogen, and either:
• R 6a R 6b are independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -
• C ⁇ alkynyl or together are methylene or 1, 2-ethanediyl form and R 7 is hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 - alkynyl .
• R 6a, R 7 eliminated to form a double bond between C 6 and C 7, or together form methylene
• R 6b is selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 2 -C 6 -
• R 15 is hydrogen and R 16a , R 16b independently of one another are hydrogen or C 1 -C 6 -alkyl or together form methylene or 1,2-ethanediyl,
• R 15, R 16a omitted to form a double bond between C 15 and C 16 and R 16b is hydrogen or C r C 6 alkyl
• R 18 is hydrogen, methyl or ethyl.
• Z is oxygen or a group NOR ', where R' is hydrogen or C 1 -C 3 -
• R 4 is hydrogen, chlorine or bromine
• R, R independently of one another are hydrogen, C 1 -C 3 -alkyl or C 2 -C 4 -alkenyl or together form methylene or 1,2-ethanediyl and R 7 is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl or C 2 -C 4 -alkenyl, or:
• R r C 3 alkyl or C 2 -C 4 alkenyl 6b is hydrogen,
• R 15 is hydrogen
• R 16a , R 16b are hydrogen or together form methylene or 1,2-ethanediyl
• R 15 , R 16a are omitted to form a double bond between C 15 and C 16 and R 16b is hydrogen
• R 18 is hydrogen or methyl.
• the compound having the general chemical formula I expressly included, wherein the position of the unsaturated ⁇ -lactone ring in the derivative according to the invention may occur in two isomeric forms.
• Each of the abovementioned substituents on the steroid skeleton can be present both in an ⁇ and in a ⁇ position.
• the substituents on the steroid backbone that contain a double bond and in which the double bond on each carbon atom carries at least one non-hydrogen substituent may also be both E- and Z-configured.
• Groups bound to two adjacent carbon atoms of the skeleton, for example an oxygen atom, methylene or 1,2-ethanediyl, are bonded either in the ⁇ , ⁇ position or in the ⁇ , ⁇ position.
• derivatives according to the invention 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 in a stoichiometric or unstoichiometric ratio.
• stoichiometric solvates hydrates, we also speak of hemi, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates.
• suitable salts are the physiologically tolerated salts of organic and inorganic bases, for example the readily soluble alkali metal and alkaline earth metal salts, and the salts of N-methylglucamine, D-methylglucamine, ethylglucamine , Lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethyl-aminomethane, aminopropanediol, Sovak's base, 1-amino-2,3,4-butanetriol.
• the physiologically acceptable salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid and the like.
• the compounds or derivatives according to the invention have a good gestagenic activity.
• some interesting compounds of the invention interact with the mineralocorticoid receptor and are capable of mediating antagonist activity.
• the compounds according to the invention have a neutral to mild androgenic effect with regard to the androgen receptor.
• Another property of the majority of the compounds is that the bonds of these compounds to the progesterone receptor and to the mineralocorticoid receptor are relatively balanced, such that the ratio of their ability to bind to the progesterone receptor to bind to the mineralocorticoid receptor is less than that of drospirenone ,
• the antimineralcorticoi- de effect of these compounds is less given given given Gestagener effect than drospirenone. If the dosage of a given compound according to the invention is determined on the basis of its gestagenic action, the antimineralcorticoid effect of this compound is thus lower at this dosage than in drospirenone.
• novel compounds having the general chemical formula I can be used alone or in combination with estrogen in medicaments for contraception.
• 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 postmenopausal complaints, including the use in preparations for hormone replacement therapy (HRT).
• HRT hormone replacement therapy
• the derivatives according to the invention for the preparation of a medicament with gestagenic, preferably also antiimineralcorticoider and neutral to mildly androgenic effect.
• 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 may be in solid form, for example as Tablets, drapes, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions.
• 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.
• an intravaginal or intrauterine administration may be considered.
• 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, cottonseed 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 may be an active substance of the present invention from a reservoir over an extended period of time (e.g. 1, 2, 3, 4 or 5 years).
• MIRENA is taken as a proxy.
• 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.
• 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 is preferably administered once.
• the above dosages refer to oral administration forms.
• the equivalent dosage equivalent to the above-mentioned oral dosages is released continuously per day from the longer term depot systems described above. From a depot formulation, for example from an IUS, an amount of from 0.005 to 10 mg of a compound of general formula 1 is released daily.
• 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, as well as natural estrogens, including phytoestrogens.
• the estrogen is administered in a daily amount that corresponds to the pharmacological effect of 0.01 to 0.04 mg of ethinylestradiol. This amount refers to an oral administration form. If a different route of administration is chosen, a corresponding dosage amount equivalent to the above oral dosage should be used.
• the gestagenic, antimineralcorticoid and androgenic or antiandrogenic activity of the compounds according to the invention was investigated by the following methods:
• KF competition factor
• DMEM Dulbecco's Modified Eagle Medium: 4500 mg / ml glucose, PAA, # E15-009) with 10% FCS (Biochrom, S0115, Lot # 615B) 1 mM 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 (CHO K1 cells stably transfected with a fusion protein from the PR ligand binding domain and a Gal4 transactivation domain and a reporter construct containing the luciferase under the control of a Gal4-responsive promoter) were grown at a density of 4x10 4 cells per well Well grown in white, 96-well opaque tissue culture plates (PerkinElmer, # P12-106-017) and maintained in culture medium with 3% DCC-FCS (charcoal treated serum, for removal of interfering components contained in the serum). The too investigating compounds were added eight hours later and the cells were incubated with the compounds for 16 hours. The experiments were carried out in triplicate.
• Reporter cell lines (MDCK cells) expressing the human mineralocorticoid receptor and transiently containing a reporter construct containing luciferase under the control of a steroid hormone responsive promoter.
• DMEM EARLE 'S MEM (PAA, Cat .: E15-025) was provided as culture medium with 100 U penicillin / 0.1 mg / ml streptomycin (PAA, Cat: P11-010), 4 mM L- Glutamine (PAA, Cat: M11-004) and fetal calf serum (BIO Witthaker, Cat: DE 14-801 F).
• RPMI medium without phenol red provided with 100 U penicillin / 0.1 mg / ml streptomycin (PAA, Cat: P11-010), 4 mM L-glutamine (PAA, Cat: M11-004) and fetal calf serum (BIO Witthaker, Cat: DE14-801F).
• the isomer mixtures can be separated into the individual compounds by customary methods, such as, for example, crystallization, chromatography or salt formation.
• the preparation of the salts is carried out in a customary manner by adding a solution of the compound of the general formula I with the appropriate amount or an excess of a base or acid, which may be in solution, optionally separating the precipitate or in usually the solution works up.
• the compounds of general chemical formula I are prepared starting from compounds having the general chemical formula 1a (Scheme 2) or 1b (Scheme 3), according to the methods given in Scheme 1, wherein R 4 , R 6a , R 6b , R 7 , R 15 , R 18 and Z have the meanings given above, with the proviso that R 6 , R 7 in the compound of the general chemical formula 8b together form oxygen or methylene, and in which R 16a , R 16b in the compounds having the general chemical formulas 32a and
• C 40c are independently hydrogen, C 1 -C are 0 -alkyl, U is an oxygen atom, two alkoxy groups OR 19 or a C 2 -C 0 alkylene-dioxy ⁇ . ⁇ , which may be straight or branched, wherein R 19 is a C 1 -C 4 -alkyl radical,
• R 20 is a C 1 -C 20 -alkyl radical
• X is an NR 21a R 21b group or an alkoxy group OR 22 ,
• R 21a , R 21b independently of one another are hydrogen, C 1 -C 4 -alkyl or together form a C 4 -C 10 - ⁇ , ⁇ -alkylene group which may be straight-chain or branched, and
• R 22 is a C 1 -C 20 alkyl radical.
• the dienol ether bromination of compounds 4, 7, 9 or 11 can be carried out, for example, analogously to the procedure of Steroids 1, 233 (1963).
• the hydrogen bromide cleavage to form the compounds of general chemical formula 5, 8a, 10 or 12 is accomplished by heating the 6-bromo compound with basic reagents such as LiBr or Li 2 CO 3 in aprotic solvents such as dimethylformamide at temperatures of 50 ° C. 120 0 C or by heating the 6-bromo compounds in a solvent such as collidine or lutidine.
• R 4 can, for example, starting from a compound having one of the general chemical formulas 3, 5, 6, 8a, 8b or 10 by epoxidation of the 4,5-double bond with hydrogen peroxide under alkaline conditions and reaction of the resulting Epoxides in a suitable solvent with acids having the general chemical formula HR 4 , where R 4 may be a halogen atom, preferably chlorine or bromine.
• R 4 may be a halogen atom, preferably chlorine or bromine.
• Compounds in which R 4 has the meaning of bromine can be reacted, for example, with methyl 2,2-difluoro-2- (fluorosulfonyl) acetate in dimethylformamide in the presence of copper (I) iodide to give compounds in which R 4 has the meaning Has fluorine.
• halogen starting from a compound having one of the general chemical formulas 3, 5, 6, 8a, 8b or 10, by reaction with sulfuryl chloride or sulfuryl bromide in the presence of a suitable base, such as pyridine, with R 4 meaning chlorine or Bromine can be introduced directly.
• a suitable base such as pyridine
• Compound 5 or 12 is prepared by methenylation of the 6,7-double bond by known processes, 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, US Pat. Chem. Soc. 84, 867 (1962)) into a compound 8b or 13 (R 6 , R 7 together form a methylene group) to give a mixture of the ⁇ - and ⁇ -isomers, which can be separated for example by chromatography in the individual isomers.
• dimethylsulfoxonium methylide see for example DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US-A 4,291, US Pat. Chem. Soc. 84, 867 (1962)
• compound 8b or 13 R 6 , R 7 together form a methylene group
• compound 10 can be prepared by reaction with trimethylsulfoxonium iodide using bases such as alkali hydroxides, alkali alcoholates in suitable solvents such as dimethylsulfoxide.
• the 6-methylene compounds can be used to prepare compounds of general chemical formula 10 in which R 6a is methyl and R 6b and R 7 together form an additional bond.
• Tetrahedron 21, 1619 (1965) described method in which an 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 amount of cyclohexene was pretreated, can be achieved.
• the isomerization can also be carried out with a non-pretreated catalyst if a small amount of cyclohexene is added to the reaction mixture.
• the occurrence of small amounts of hydrogenated products can be prevented by adding an excess of sodium acetate.
• the direct preparation of 6-methyl-4,6-dien-3-one derivatives is described (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb, Ann., 712 (1983)).
• the targeted representation of 6ß-methyl compounds is possible.
• the 4-en-3-ones such as compound 8a, for example, with ethylene glycol, trimethyl orthoformate in dichloromethane in the presence of catalytic amounts of an acid, for example p-toluenesulfonic acid, converted to the corresponding 3-ketals.
• an acid for example p-toluenesulfonic acid
• the double bond isomerizes to position C 5 .
• Selective epoxidation of this 5-double bond is achieved, for example, by using organic peracids, for example of m-chloroperbenzoic acid, in a suitable solvent, 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. In this way, 5 ⁇ -hydroxy-6 ⁇ -alkyl compounds are obtained.
• the cleavage of the 3-keto protecting group can be carried out by treatment under mild acidic conditions (acetic acid or 4N hydrochloric acid at 0 0 C) to give the 5 ⁇ -hydroxy function.
• the introduction of a 7-alkyl, 7-alkenyl or 7-alkynyl group to form compounds having the general chemical formula 6 is carried out by 1,6-addition of a corresponding organometallic compound to the precursor having the general chemical formula 5 under the action of copper salts.
• copper salts Preferred are divalent metals such as magnesium and zinc; as counterions, chlorine, bromine and iodine are preferred.
• Suitable copper salts are monovalent or divalent copper compounds, such as, for example, copper chloride, copper bromide or copper acetate.
• the reaction is carried out in an inert solvent such as tetrahydrofuran, diethyl ether or dichloromethane.
• tertiary bases examples include 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- en (DBU), with pyridine being preferred.
• An analogous process is described, for example, in WO-A 98/24801 for the preparation of corresponding 3-oxyimino derivatives of drospirenone.
• the 3-oxo group for example, according to the procedure given in DE-A 28 05 490 by reductive cleavage of a thioketal of 3-keto compound on a suitable precursor, such as for example, compounds with one of the general chemical formulas 3, 5, 6, 8a, 8b, 10, 11 or 12, are removed.
• spirolactones into compounds having one of the general chemical formulas 3 or 8b takes place, starting from the corresponding 17-hydroxypropenyl compounds 2 or 13, by oxidation.
• Oxidation processes according to Jones oxidation with potassium permanganate, for example in an aqueous system of tert-butanol and sodium dihydrogenphosphate, oxidation with sodium chlorite in aqueous tert-butanol, if appropriate in the presence of a chlorine scavenger, for example in the presence of 2-methyl-2-butene, or called by oxidation with manganese dioxide.
• R 15 and R 18 have the abovementioned meanings and R i ea R i6b jn 32a together form methylene, in 32b together form 1, 2-ethanediyl and in 32c independently of one another hydrogen, C r Ci 0 alkyl and R 20 Ci-Cao Alkyl.
• the compounds 30 to 1a in Scheme 2 each carry a double bond between C 5 and C 6 or between C 5 and C 10 and another double bond between C 2 and C 3 or between C 3 and C 4 .
• U is an oxygen atom, two alkoxy groups OR 19 , a C 2 -C 10 -alkylene- ⁇ , ⁇ -dioxy group, which may be straight-chain or branched, is where
• R 19 is a dC ⁇ o-alkyl radical.
• the compounds 38 to 1b in Scheme 3 each carry a double bond between C 4 and C 5 or between C 5 and C 6 or between C 5 and C 10 .
• Example 1a dienol ether formation: 17 ⁇ -Hydroxy-3-methoxy-19-nor-17 ⁇ -pregna-3,5,20 (Z) -triene-21-carboxylic acid ⁇ -lactone
• Example 1d (Lindlar hydrogenation): 17 ⁇ (Z) - (3'-hydroxypropen-1'-yl) -3,3-dimethoxy-17 ⁇ -hydroxyestra-5 (10) -ene
• Example 2 700 mg of the compound prepared according to Example 1 were reacted using vinylmagnesium chloride, and after working up and purification, 46 mg of the title compound A were isolated in addition to a still contaminated mixture containing proportions of the title compound B.
• Example 5b 2.83 g of the compound prepared according to Example 5b were reacted analogously to Example 1c, and after working up and purification, 1.64 g of the title compound were isolated.
• Example 5d 100 mg of the compound prepared according to Example 5d were reacted analogously to Example 1e, and after working up and purification, 116 mg of the title compound were isolated, which were reacted further without purification.
• Example 5d (16,16 cycloropanation from 16-methylene): 3,3-Dimethoxy-i6,16- (1,2-ethanediyl) -estra-5 (10) -en-17-one
• Example 5e (16,16-methylene from silyl enol ether): 3,3-dimethoxy-16-methylene-estra-5 (10) -en-17-one
• Example 6b 6.35 g of the compound prepared according to Example 6b were reacted analogously to Example 1c, and after work-up and purification, 3.02 g of the title compound were isolated.
• Example 6c 7.86 g of the compound according to Example 6c were reacted in analogy to Example 1d, and after work-up, 6.35 g of the title compound were isolated, which was further reacted without purification.
• Example 1b 10.0 g of the compound prepared according to Example 1 b were reacted in analogy to Example 1a, and after work-up, 10.9 g of the title compound were isolated, which was reacted further without purification.
• Example 7 200 mg of the compound prepared according to Example 7 were reacted using vinylmagnesium chloride, and after working up and purification, 74 mg of the title compound A were isolated in addition to a still contaminated mixture containing proportions of the title compound B.
• Example 17a In analogy to Example 15, 517 mg of the compound shown in Example 17a were reacted letong, and after work-up and purification, 156 mg of the title compound were isolated.
• Example 15a In analogy to Example 15a, 840 mg of the compound prepared according to Example 1b were reacted, and after work-up and purification, 524 mg of the title compound were isolated.
• Example 16a In analogy to Example 16a, 540 mg of the compound prepared according to Example 17 were reacted, and after work-up and purification 80 mg of the title compound were isolated.
• Example 19 (Corey Cyclopropanation): 17 ⁇ -Hydroxy-18-methyl-6 ⁇ , 7 ⁇ -methylene-19-nor-17 ⁇ -pregna-4,20 (Z) -dien-3-one-21-carboxylic acid ⁇ -lactone ( A) and 17 ⁇ -hydroxy-18-methyl-6 ⁇ , 7 ⁇ -methylene-19-nor-17 ⁇ -pregna-4,20 (Z) -diene-3-one-21-carboxylic acid ⁇ -lactone (B)
• Example 16 1.28 g of the compound shown in Example 1 were reacted, and after work-up and purification, 66 mg of the title compound A and 112 mg of the title compound B were isolated.
• 1 H-NMR (CDCl 3 ) of A: ⁇ 0.58 (1H), 0.89-1, 58 (9H), 1, 12 (3H), 1, 68-2.11 (6H), 2 , 22 (1H), 2.29-2.52 (3H), 6.02 (1H), 6.15 (1H), 7.50 (1H) ppm.
• 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. Implants of varying length (5-20 mm) and a limited diameter (1.1 to 2 mm) remain in the rat uterus for 4 to 14 days to reduce the local and systemic gestagenic effects of the released drug by different parameters in different tissues - search.
• progestogen-regulated marker genes e.g., IGFBP-1
• gestagenic systemic effect on mamma by expression of gestagen-regulated marker genes e.g., Rank L
• gestagenic pituitary systemic action by LH level lowering of estrogen-induced elevated LH level
• the compounds of the present invention show a significant gestagenic effect in the uterus which is comparable to a corresponding treatment with a levonorin.

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