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WO2009083270A1 - Dérivé de 15,16-méthylène-stéroïde-17,17-lactol, son utilisation, et médicaments contenant le dérivé - Google Patents

Dérivé de 15,16-méthylène-stéroïde-17,17-lactol, son utilisation, et médicaments contenant le dérivé Download PDF

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Publication number
WO2009083270A1
WO2009083270A1 PCT/EP2008/011163 EP2008011163W WO2009083270A1 WO 2009083270 A1 WO2009083270 A1 WO 2009083270A1 EP 2008011163 W EP2008011163 W EP 2008011163W WO 2009083270 A1 WO2009083270 A1 WO 2009083270A1
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Prior art keywords
methylene
oxidoestra
propenyl
methyl
hydroxy
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PCT/EP2008/011163
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German (de)
English (en)
Inventor
Ulrich Klar
Joachim Kuhnke
Rolf Bohlmann
Jan HÜBNER
Sven Ring
Thomas Frenzel
Frederik Menges
Steffen Borden
Hans Peter Muhn
Katja Prelle
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Bayer Pharma AG
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Bayer Schering Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/008—3 membered carbocyclic rings in position 15/16
    • 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
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids

Definitions

  • the invention relates to 15,16-methylene-steroid-17,17-lactol derivatives, their use and the derivatives containing drugs with Gestagener effect, for example, for the treatment of pre-, peri- and postmenopausal as well as 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 gestagen-acting compound 6 ⁇ , 7 ⁇ -15 ⁇ , 16 ⁇ -dimethylene-3-oxo-17-pregna-4-ene-21,17 ⁇ -carbolactone (drospirenone), which can be obtained, for example, in an oral contraceptive a preparation for the treatment of 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 distinguished by the fact that it has, in addition to the gestagenic action, aldosterone antagonist (antimineralcorticoid) and antiandrogenic action. These two properties make drospirenone in its pharmacological profile very similar to the progesterone progesterone, which unlike drospirenone, is not sufficiently orally bioavailable.
  • WO 2006/072467 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.
  • WO 93/13122 A1 discloses 3-methylsulfonylhydrazono and 3-oxyimino steroids with a 15,16-methylene group and their use as antiandrogens.
  • 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 the proteus to the antimineralocorticoid effect is lower than in the case of drospirenone.
  • the present invention accordingly relates to 15,16-methylene-steroid-17,17-lactol derivatives having the general chemical formula I,
  • Z is selected from the group comprising oxygen, two hydrogen atoms, NOR 'or NNHSO 2 R', wherein R 'is hydrogen, C 1 -C 10 alkyl, aryl or
  • 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 10 -alkyl, 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, C 3 -C 12 -cycloalkyl, C 2 -C 10 -alkenyl and C 2 -C 10 -alkynyl,
  • R 6a , R 7 together form an oxygen atom or a methylene group or are omitted to form a double bond between C 6 and C 7 and R 6b is selected from the group comprising hydrogen, C r C 10 alkyl, C 1 -
  • R 18 is selected from the group comprising hydrogen and C 1 -C 3 -alkyl
  • R 22 is selected from the group comprising hydrogen, C 1 -C 6 -alkyl, aryl, C 7 -C 20 -aralkyl,
  • the numbering of the C-skeleton of the derivatives according to the invention with the general chemical formulas I and Ia follows in the usual way 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 derivatives, as far as R 4 , R 6 , R 7 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 and R 7 is to be understood as meaning straight-chain or branched-chain alkyl groups having 1-10 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl , Isopentyl, neopentyl, hexyl, heptyl, decyl.
  • Alkyl in R 18 is in particular methyl, ethyl, propyl or isopropyl and R 22 is methyl, ethyl, pyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neo-pentyl, hexyl.
  • alkyl groups R ', R 6a , R 6b , R 7 , R 18 and R 22 may further be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C 1 -C 4 alkoxy groups, C 6 -C 12 aryl groups (which in turn may be substituted by 1-3 Halogen atoms may be substituted) substituted.
  • alkyl can therefore also be used for hydroxymethylene (HO-CH 2 ), hydroxyethylene (HO-C 2 H 4 ),
  • 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, CrC 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 10 -alkyl, -C 10 -acyl, C 1 - C 10 acyloxy groups substituted.
  • Aryl in R 'and R 22 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, the one or more times by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, NH 2, NO 2, N 3, CN, Ci-Ci o alkyl, Ci-Ci O -acyl dC 10 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 22 is to be understood as meaning aralkyl groups which may contain up to 14 carbon atoms, preferably 6 to 10 C atoms, in the ring and 1 to 8, preferably 1 to 4, carbon atoms in the alkyl chain.
  • Suitable aralkyl radicals are, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
  • the rings can be mono- or polysubstituted by halogen, OH 1 O-alkyl, CO 2 H, CO 2 -alkyl, NO 2, N 3, CN, Ci-C 20 -alkyl, C 1 -C 20 -acyl, C 20 -acyloxy groups substituted.
  • alkoxy (O-alkyl) is mentioned as a substituent on alkyl, it is alkoxy groups having 1-4 carbon atoms, and as far as alkoxy is mentioned as a substituent on alkenyl and alkynyl, it is alkoxy groups having 1-3 carbon atoms , Alkoxy may in particular be methoxy, ethoxy and propoxy.
  • acyl As far as acyl (CO-alkyl) is mentioned as a substituent on cycloalkyl and aryl, it is 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. Among these, chlorine is preferred.
  • Z is selected from the group comprising oxygen, NOR 'and NNHSO 2 R 1 .
  • 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 and R 7 together form methylene.
  • R 6a and R 7 are eliminated to form a double bond between C 6 and C 7 .
  • R 18 is hydrogen or methyl.
  • R 22 is hydrogen
  • R 22 is selected from the group comprising methyl, ethyl and isopropyl.
  • Z is oxygen or a group NOR ', in which R 1 is hydrogen, C 1 -C 6 -alkyl, aryl or C 7 -C 12 -aralkyl,
  • R 4 is hydrogen or halogen
  • R 6a, R 6b are each independently selected from the group comprehensively hydrogen, C r C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, or together form methylene or 1, 2- Ethanediyl and R 7 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, or:
  • R 6a , R 7 together form methylene or omitted to form a double bond between C 6 and C 7 and
  • R 6b is selected from the group comprising hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl,
  • R 18 is hydrogen or C 1 C 2 -alkyl
  • R 22 is hydrogen, C 1 -C 3 alkyl or C 7 -C 12 aralkyl.
  • Z is oxygen or a group NOR ', where R' is hydrogen or C 1 -C 3 -
  • R 4 is hydrogen
  • R 6a , R 6b are each, independently of one another, 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 -alkyi, C 3 C 4 -Cycloalkyl or C 2 -C 4 alkenyl,
  • R 6a , R 7 together form methylene or omitted to form a double bond between C 6 and C 7 and R 6b is selected from the group comprising hydrogen, C r C 3 alkyl and
  • R 18 is hydrogen or methyl
  • R 22 is hydrogen or C 1 -C 3 alkyl.
  • 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 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, 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.
  • suitable salts are the physiologically tolerated salts of organic and inorganic bases, such as, for example, the readily soluble alkali and alkaline earth salts, and the salts of N-methylglucamine, D-methylglucamine, ethylglucamine, lysine , 1, 6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.
  • the physiologically acceptable salts of organic and inorganic acids are suitable, such as of 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 of the invention have a neutral to mild androgenic effect on 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 mineral cortisol Co-receptor are balanced relative to each other, in such a way that in them the ratio of the binding ability to the progesterone receptor to the binding ability to the mineralocorticoid receptor is lower than 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.
  • Molds are preferred according to the invention where R in compounds Nos. 1-40 denotes hydrogen (H) and in compounds Nos. 41-80 methyl (CH 3 ).
  • the structural formulas denote the respective lactols, while the chemical names represent the tautomeric forms with opened lactol ring.
  • novel compounds of general chemical formulas I and Ia alone or in combination with estrogen, can be used in contraceptive formulations
  • the derivatives according to the invention are therefore particularly suitable for the preparation of a medicament for oral contraception and for the treatment of preoperative, peptic and postmenopausal symptoms, including the use in preparations for hormone replacement therapy (HRT).
  • HRT hormone replacement therapy
  • the derivatives according to the invention are also particularly well suited for the treatment of premenstrual disorders, such as headache, depressive moods, water retention and mastodynia
  • the derivatives according to the invention for the preparation of a medicament with gestagenic, preferably also antiimineralcorticoid and neutral to mildly androgenic action
  • treatment with the derivatives according to the invention preferably takes place on humans, but can also be carried out on related mammalian species, for example on dogs and cats
  • suitable pharmaceutically acceptable additive for example a carrier.
  • the additive is suitable, for example, for parenteral, preferably oral, administration.
  • pharmaceutically acceptable 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. If appropriate, they also contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts for varying the osmotic pressure or buffers. Oily solutions, for example solutions in sesame oil, castor oil and cottonseed oil, are particularly suitable for parenteral administration. To increase solubility, 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.
  • intravaginal or intrauterine administration can be achieved by 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, including an active substance of the present invention from a reservoir over an extended period of time (e.g. , 2, 3, 4 or 5 years).
  • MIRENA is taken as a proxy. This is a T-shaped, levonorgestrel-releasing intrauterine system of BAYER SCHERING PHARMA AG.
  • an application via an implanted depot system of an inert carrier material such as a biodegradable polymer or a synthetic Silicone polymer done.
  • These depot systems release the active ingredient over a longer period in a controlled manner (eg 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-mentioned dosages relate 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.
  • a depot formulation for example from an IUS, an amount of 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.
  • CEEs Conjugated Equine Estrogens
  • KF competition factor
  • DMEM Dulbecco's Modified Eagle Medium: 4500 mg / ml glucose; PAA, # E15-009
  • FCS Biochrom, S0115, lot # 615B
  • penicillin / streptomycin 1 mg / ml G418
  • 0.5 ⁇ g / ml puromycin 1.
  • 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 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.
  • 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 1 S MEM (PAA, Cat: E15-025) was provided with 100U penicillin / 0.1 mg / ml streptomycin (PAA, Cat P11-010), 4mM L-glutamine (PAA, Cat M11-004) and fetal calf serum (BIO Witthaker, Cat DE14-801F)
  • Reporter cell lines (PC3 cells) expressing the androgen receptor and a reporter construct containing luciferase under the control of a steroid hormone-responsive promoter were used
  • RPMI medium without phenol red (PAA, # E15-49), provided with 100 U penicillin / 0.1 mg / ml streptomycin (PAA, Cat P11-010), 4 mM L was used as culture medium -Glutam ⁇ n (PAA, Cat M11-004) and fetal calf serum (BIO Witthaker, Cat DE14-801 F) used
  • the isomer mixtures can be separated into the individual compounds by customary methods such as, for example, crystallization, chromatography or salt formation takes place in the usual way by a solution of the compounds having the general chemical formulas I and Ia with the equivalent amount or an excess of a base or acid, which is optionally in solution, is added, if appropriate the precipitate is separated off or the solution is worked up in a customary manner.
  • R 6 , R 7 in 5 and 6 together form oxygen or methylene
  • 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, where R 19 is a C 1 -C 20 -alkyl radical, R 20 Ci ⁇ o-alkyl radical,
  • X is an NR 21a R 21b group or an alkoxy group OR 23 ,
  • R 21a R 21b are each independently of one another hydrogen, C 1 -C 10 -alkyl or together form a C 4 -C 10 - ⁇ , ⁇ -alkylene group which may be straight-chain or branched, R 23 is a C 1 -C 20 -alkyl radical is.
  • the compounds 2 and 3 in Scheme 1 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 .
  • the compounds 7 to 9 in Scheme 1 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 .
  • the dienol ether bromination of compounds 3, 12 or 17 can be carried out, for example, analogously to the procedure of Steroids 1, 233 (1963).
  • the hydrogen bromide cleavage to form the compounds having the general chemical formulas 4, 13 or 18 is achieved 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 50-120 0 C. or by heating the 6-bromo compounds in a solvent such as collidine or lutidine.
  • R4 can, for example, starting from a compound having one of the general chemical formulas 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 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 2,2-difluoro-2- (fluorosulfonyl) acetic acid methyl ester in dimethylformamide in the presence of copper (I) iodide to give compounds in which R 4 is fluorine has.
  • halogen starting from a compound having one of the general chemical formulas 6, 11, 13, 14, 16 or 18, 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 4 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, US Pat. Chem. Soc., 84, 867 (1962)) into a compound 5 (R 6 , R 7 together form a methylene group) to give a mixture of the ⁇ - and ⁇ -isomers obtained, for example, by chromatography can be separated into the individual isomers.
  • Compounds of type 5 can be obtained as described in the examples or analogously to these instructions using analogous reagents described there.
  • X NR 21a R 21b
  • compound 18 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.
  • suitable solvents such as chloroform
  • the 6-methylene compounds can be used to prepare compounds of general chemical formula 18 in which R 6a is methyl and R 6b and R 7 together form an additional bond.
  • 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)).
  • R 6b represents an ⁇ -methyl function
  • R 6a , R 6b together form methylene
  • the best results are achieved by transfer hydrogenation (J. Chem. Soc. 3578 (1954)). If the 6-methylene derivatives 18 are heated in a suitable solvent, such as, for example, ethanol, in the presence of a hydride donor, for example cyclohexene, 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 16, 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 alkyl magnesium halides or alkyl lithium compounds. In this way 5 ⁇ -hydroxy-6 ⁇ -alkyl compounds are obtained.
  • Keto-protecting 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.
  • mild acidic conditions acetic acid or 4N hydrochloric acid at 0 ° C.
  • Basic elimination of the 5 ⁇ -hydroxy function with, for example, dilute aqueous sodium hydroxide gives the 3-keto-4-ene compounds having a ⁇ -position 6-alkyl group.
  • Alternatively here to give the ketal cleavage under more severe conditions with aqueous hydrochloric acid or with another strong acid) the corresponding 6 ⁇ -alkyl compounds.
  • the introduction of a 7-alkyl, 7-alkenyl or 7-alkynyl group to form compounds with the general chemical formula 14 is carried out by 1,6-addition of a corresponding organometallic compound to the precursor with the general chemical formula 13 under the Influence of copper salts.
  • copper salts Preferred are divalent metals, such as magnesium and zinc, as the counterion, 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.
  • the compounds 6, 11, 13, 14, 16, 18 or 20 in which Z is an oxygen atom can be obtained by reaction with hydroxylamine hydrochloride, alkyloxyamine hydrochlorides or sulfonylhydrazines in the presence of a tertiary amine
  • Suitable tertiary bases are 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 98/24801 A1 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 6, 11, 13, 14, 16, 18 or 20, are removed.
  • spirolactols 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 process for example, the oxidation according to Swern, the oxidation with N-methylmorpholine-N-oxide and catalytic Amounts of tetrabutylammonium peruthenate or by oxidation with manganese dioxide called.
  • the compound 1 in Scheme 2 carries in each case one double bond between C 5 and C 6 or between C 5 and C 10 and a further double bond between C 2 and C 3 or between C 3 and C 4 .
  • Example 1a dienone formation from dienol ether:
  • Example 3 81 mg of the compound shown in Example 3 were reacted, and after work-up and purification 69 mg of the title compound were isolated.
  • 1 H NMR (CD 2 Cl 2 ): ⁇ 0.30-0.45 (1H), 0.79-1, 32 (18H), 1, 38-1, 95 (8H), 2.04 ( 1 H), 2.16-2.36 (4H), 2.45 + 2.56 (1H), 3.96 (1H), 5.66 + 5.69 (1H), 5.73- 5.91 (2H), 6.08 + 6.12 (1H) ppm.
  • Example 5 In analogy to Example 2, 90 mg of the compound shown in Example 5 were reacted, and after work-up and purification, 65 mg of the title compound were isolated.
  • Example 7c 300 mg of the compounds prepared according to Example 7c were reacted, and after work-up, 300 mg of the title compounds were isolated, which were reacted further without purification.
  • Example 7d In analogy to Example 1c, 278 mg of the compounds prepared according to Example 7d were reacted, and after work-up, 347 mg of the title compounds were isolated, which were reacted further without purification.
  • Example 7d (oxidation of 17-OH): 15 ⁇ , 16 ⁇ -methylene-estra-5-en-3,17-dione-3-ethylene ketal and 15 ⁇ , 16 ⁇ -methylene-estra-5 (10) -en-3, 17 -dione 3-ethylene
  • Example 7e (3-enol ether to ethylene ketal): 15 ⁇ , 16 ⁇ -methylene-17 ⁇ -hydroxyestra-5-en-3-one-3-ethylene ketal and 15 ⁇ , 16 ⁇ -methylene-17 ⁇ -hydroxyestra-5 (10) -en-3 -one-3-ethylene
  • intrauterine implantable depot systems made 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 placed 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 investigate the local as well as systemic gestagenic effect of the released active substance on the basis of various parameters in different tissues.
  • the following parameters are determined: 1) gestagene local effect on the uterus on the basis of the uterine weight, the histologically detectable epithelium height and the expression of gestagen-regulated marker genes (eg IGFBP-1); 2) 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 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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  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne des dérivés de (15, 16)-méthylène-stéroïde-(17, 17)-lactol, de formule chimique générale I, ainsi que leurs formes tautomères de formule chimique générale Ia, où R4, R6a, R6b, R7, R18, R22 et Z sont tels que définis dans la revendication 1, ainsi que leurs solvates, hydrates, stéréoisomères et sels. L'invention concerne en outre : l'utilisation de ces dérivés pour la fabrication d'un médicament destiné à la contraception orale et au traitement de troubles pré-ménopausiques, péri-ménopausiques et post-ménopausiques; et des médicaments qui contiennent de tels dérivés. Les dérivés selon l'invention présentent une action gestagène et en outre, dans des cas préférés, une action antiminéralocorticoïde et neutre à légèrement androgène.
PCT/EP2008/011163 2007-12-29 2008-12-23 Dérivé de 15,16-méthylène-stéroïde-17,17-lactol, son utilisation, et médicaments contenant le dérivé Ceased WO2009083270A1 (fr)

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Cited By (1)

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WO2012059594A1 (fr) 2010-11-04 2012-05-10 Bayer Pharma Aktiengesellschaft Antagonistes de récepteur de minéralocorticoïde pour le traitement de l'obésité induite par corticoïde

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