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  • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
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  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0062—Estrane derivatives substituted in position 17 alfa not substituted in position 17 beta
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  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
  • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
  • C07J1/0074—Esters
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  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic

Definitions

• This invention relates to new compounds as pharmaceutical active ingredients that have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo exert a contraceptive action by their preferential action on the ovary, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds.
• the chemical compounds are novel, steroidal, tissue-selective estrogens.
• Oral contraceptives that consist of the most varied combinations of an estrogen with a gestagen are the most frequently used contraceptive of women. They act according to the endocrine principle. Although such contraceptives are very effective, undesirable side effects may occur, however, such as, e.g., irregular bleeding, nausea, vomiting, depression, weight gain or headaches. More serious diseases are also sometimes observed, such as thrombo-embolisms, stroke, liver adenoma, gallbladder diseases or hypertension, which indicate that no effective contraceptives without side effects are now available. The medical necessity for a new contraceptive method thus exists.
• An ideal contraceptive method is a method that operates directly on the ovarian follicle without influencing the endocrine hypothalamo-pituitary-ovarian axis. This can be achieved with a chemical compound that impairs the folliculogenesis, for example by destroying a paracrine interaction between the egg cell and the granulosa cells, and thus provides that
• Follicular growth is the development of an ovarian follicle from the primordial stage to the large antral follicle that is ready to burst. Only an optimally built-up antral follicle has the potential to ovulate a mature egg cell.
• Gonadotrophins such as, e.g., FSH (follicle-stimulating hormone)
• FSH follicle-stimulating hormone
• Gonadotrophins are mainly involved in the late steps of folliculogenesis, i.e., the development from the early antral follicle to the large ovulatory follicle. Additional modulators of folliculogenesis are also discussed in the late folliculogenesis, however (Elvin et al. (1999), Mol Cell Endocrinol 13: 1035-1048).
• Estrogen receptor ⁇ was recently discovered as a second subtype of the estrogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 353-365).
• the expression pattern of ER ⁇ differs from that of the ER ⁇ (Kuiper et al. (1996), Endocrinology 13.8: 863-870).
• ER ⁇ is functional in the male animal also arises through studies of ER ⁇ -(ERKO) or ER ⁇ -( ⁇ ERKO)-knockout mice: Male ERKO mice (Hess, R. A. et al. 1997, Nature 390: 509-512) have considerable fertility disorders. As a result, the important function of estrogens with respect to maintaining testis function relative to fertility is confirmed.
• ER ⁇ and ER ⁇ have significantly different amino acid sequences in their ligand binding domains and transactivation domains. This suggests that (1) ER subtypes bind to their ligands with different affinity and (2) ligands can show a different agonistic and/or antagonistic potential on the two receptor subtypes.
• new steroidal compounds based on the building block of the estradiol that is unsubstituted in 8-position are described that carry in 11 ⁇ -position a hydrocarbon radical that contains an individual linear chain with a length of 5 to 9 carbon atoms. These compounds have an ER ⁇ -agonistic/ER ⁇ -antagonistic profile of action. Based on this mixed estrogen receptor profile, these compounds are suitable as improved estrogens for the treatment of estrogen-induced disorders and for contraception together with a gestagen.
• the object of this invention is therefore to provide compounds that have in vitro a dissociation with respect to the binding to estrogen receptor preparations from rat prostates and rat uteri and that exert a contraceptive action in vivo by their preferential action on the ovary without influencing other estrogen-sensitive organs, such as, e.g., the uterus or the liver. These compounds also are to be used for contraception in men as well as for treating benign or malignant proliferative diseases of the ovary.
• R 2 means hydrogen, halogen (F, Cl, Br, I);
• R 18 means hydrogen, an alkyl or acyl radical (both straight-chain or branched-chain, saturated or unsaturated with up to 6 carbon atoms), a trifluoromethyl group;
• R 19 means an R 20 R 21 N group, in which R 20 and R 21 , independently of one another, mean hydrogen, a C 1 -C 5 -alkyl radical, a group C(O)R 22 , in which R 22 means a hydrocarbon radical (optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, partially or completely halogenated) with up to 10 carbon atoms, an optionally substituted C 3 -C 7 -cycloalkyl radical, an optionally substituted C 4 -C 15 -cycloalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or, together with the N-atom, means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical);
• R 3 means R 18 O, R 19 SO 2 O or OC(O)R 22 , with R 18 , R 19 and R 22 in the meaning that is indicated under R 2 , and in addition R 18 means an aryl, hetaryl or aralkyl radical;
• R 6 , R 6′ each mean hydrogen or R 6 means an additional bond with R 7 ;
• R 7 , R 7′ each mean hydrogen, or R 7 means an additional bond with R 6 ;
• R 8 means an alkyl or alkenyl radical (straight-chain or branched-chain, partially or completely halogenated), in each case with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical;
• R 11 means an n-pentyl or n-hexyl radical
• R 14 means hydrogen or an additional bond with R 15 ;
• R 15 means hydrogen or an additional bond with R 14 or R 16 ;
• R 16 means hydrogen or an additional bond with R15;
• R 15′ , R 16′ independently of one another, mean hydrogen, halogen, a group R 18 O, R 19 SO 2 O or OC(O)R 22 , with R 18 , R 19 and R 22 in the meaning that is indicated under R 2 ;
• R 17 , R 17′ each mean a hydrogen atom
• R 17 , R 17′ together mean a group ⁇ CR 23 R 24 , in which R 23 and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together represent an oxygen atom.
• a fluorine, chlorine, bromine or iodine atom can always stand for a halogen atom; a fluorine atom is preferred in each case.
• hydrocarbon radicals which can be partially or completely halogenated, are fluorinated radicals.
• Hydrocarbon radical R 18 is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl or hexyl radical.
• Alkoxy group OR 18 can contain 1 to 6 carbon atoms, whereby methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.
• Representatives of the C 1 -C 5 -alkyl radicals R 20 and R 21 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl.
• R 22 As representatives of straight-chain or branched-chain hydrocarbon radicals R 22 with 1 to a maximum of 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl can be mentioned; methyl, ethyl, propyl and isopropyl are preferred.
• perfluorinated alkyl groups for example, trifluoromethyl, pentafluorethyl and nonafluorobutyl can be mentioned.
• Representatives of the partially fluorinated alkyl groups are, for example, 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 6,6,6,5,5,4,4,3,3-nonafluorohexyl, etc.
• a C 3 -C 7 -cycloalkyl group a cyclopropyl, butyl, pentyl, hexyl or heptyl group can be mentioned.
• a C 4 -C 15 -cycloalkylalkyl radical has 3 to 7 carbon atoms in the cycloalkyl portion; typical representatives are the cycloalkyl groups that are mentioned directly above.
• the alkyl portion has up to 8 carbon atoms.
• an aryl radical is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred.
• heteroaryl radical examples include the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2-or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.
• substituents for an aryl or heteroaryl radical for example, a methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen-(fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C 1-8 -alkyl) or di(C 1-8 -alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, can be mentioned.
• An aralkyl radical is a radical that contains in the ring up to 14, preferably 6 to 10, C atoms and in the alkyl chain 1 to 8, preferably 1 to 4, C atoms.
• aralkyl radicals for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are suitable.
• the rings can be substituted in one or more places 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 -acyl, or C 1 -C 20 -acyloxy groups.
• the alkyl groups or hydrocarbon radicals can be partially or completely fluorinated or substituted by 1-5 halogen atoms, hydroxy groups or C 1 -C 4 -alkoxy groups.
• a vinyl or allyl radical is primarily defined with a C 2 -C 5 -alkenyl radical.
• One or more hydroxyl groups at C atoms 3, 16 and 17 can be esterified with an aliphatic, straight-chain or branched-chain, saturated or unsaturated C 1 -C 14 -mono- or polycarboxylic acid or an aromatic carboxylic acid or with an ⁇ - or ⁇ -amino acid.
• Suitable as such carboxylic acids for esterification are, for example:
• Monocarboxylic acids formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, elaidic acid.
• Dicarboxylic acids oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid, and mesaconic acid.
• Aromatic carboxylic acids benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and p-toluic acid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, and isonicotinic acid.
• amino acids the representatives of these classes of substances that are known sufficiently to one skilled in the art are suitable, for example, alanine, ⁇ -alanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline, etc.
• R 2 means a hydrogen or halogen atom or a hydroxy group
• R 3 means a group R 18 —O—, R 19 SO 2 —O— or —O—C(O)R 22 , with R 18 , R 19 and R 22 in each case in the meaning that is indicated under R 2 ,
• R 6 and R 7 each mean a hydrogen atom
• R 6′ means a hydrogen atom, a hydroxy group, a group R 22 in the meaning that is indicated under R 2 ;
• R 7′ means a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 , with R 18 , R 19 and R 22 in each case in the meaning that is indicated under R 2 ;
• R 8 means a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl- or prop-1-inyl radical;
• R 9 means a hydrogen atom or together with R 11 an additional bond
• R 11 means an n-pentyl or n-hexyl group
• R 14 , R 15 and R 16 in each case mean a hydrogen atom
• R 16′ means a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 , with R 18 , R 19 , and R 22 in each case in the meaning that is indicated under R 2 ;
• R 17 and R 17′ mean a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R 19 SO 2 —O—; a group R 18 and a group —C(O)R 22 or —O—C(O)R 22 ; a group R 18 —O— and a group R 18 —; a group R 18 —O— and a group —O—C(O)R 22 , in all above cases with R 18 , R 19 and R 22 in each case in the meaning that is indicated under R 2 ; and
• R 17 and R 17′ together mean a group ⁇ CR 23 R 24 , in which R 23 and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together mean an oxygen atom.
• R 2 means a hydrogen atom or a fluorine atom or a hydroxy group
• R 3 means a group R 18 —O—, R 19 SO 2 —O— or —O—C(O)R 22 , with R 18 , R 19 , and R 22 in each case in the meaning that is indicated under R 2 ;
• R 6 and R 7 in each case mean a hydrogen atom
• R 6′ means a hydrogen atom or a hydroxy group
• R 7′ means a hydrogen atom, a fluorine or chlorine atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 , with R 18 , R 19 and R 22 in each case in the meaning that is indicated under R 2 ;
• R 8 means a straight-chain or branched-chain, optionally partially or completely fluorinated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl radical or prop-1-inyl radical;
• R 11 means an n-pentyl group or n-hexyl group
• R 14 , R 15 and R 16 in each case mean a hydrogen atom
• R 16′ means a hydrogen atom, a fluorine or chlorine atom or a group R 18 —O or —R 22 , with R 18 and R 22 in each case in the meaning that is indicated under R 2 ;
• R 17 and R 17′ mean a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R 19 SO 2 —O—; a group R 18 and a group —C(O)R 22 or —O—C(O)R 22 ; a group R 18 —O— and a group R 18 —; a group R 18 —O— and a group —O—C(O)R 22 , in all above cases with R 18 , R 19 and R 22 in each case in the meaning that is indicated under R 2 ; or
• R 17 and R 17′ together mean a group ⁇ CR 23 R 24 , in which R 23 and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together mean an oxygen atom.
• this invention relates to 8 ⁇ -substituted estra-1,3,5(10)-triene derivatives of general formula I, in which
• estratriene derivatives of general formula I are estratriene derivatives of general formula I
• R 17 and R 17′ mean a group R 18 —O— and a group R 18 —; a group R 18 — and a group —O—C(O)R 22 , with R 18 and R 22 in each case in the meaning that is indicated under R 2 .
• R 17 and R 17′ are a hydroxy group and a hydrogen atom, a C 1 -C 4 -alkyl group or a C 2 -C 4 alkenyl group
• R 17 and R 17′ are a hydroxy group and a hydrogen atom, a methyl, ethinyl or prop-1-inyl group.
• the new compounds are suitable for inhibiting folliculogenesis and ovulation, for male contraception and for treating benign and malignant proliferative diseases of the ovary.
• the compounds of general formula I according to the invention can be used by themselves, i.e., without the additional administration of gestagens for contraception.
• esters of the 8 ⁇ -substituted estratrienes according to the invention may have advantages compared to the unesterified active ingredients with respect to their method of administration, their type of action, strength and duration of action.
• steroids on which the 8 ⁇ -substituted estra-1,3,5(10)-triene skeleton is based and which are substituted in 11-position with a ⁇ -position n-pentyl group or n-hexyl group are described for contraception, which have in vitro dissociation with respect to binding to estrogen receptor preparations from rat prostates and rat uteri and which have in vivo preferably an inhibition of folliculogenesis and ovulation: these substances have a contraceptive action over a wide dose range without influencing other estrogen-sensitive organs, such as, e.g., the uterus or the liver.
• these compounds can be used for male contraception and for treatment of benign or malignant proliferative diseases of the ovary.
• the invention also relates to pharmaceutical preparations that contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids thereof) for the production of pharmaceutical agents, especially for the indications below.
• the compounds can be used for the following indications both after oral and parenteral administration.
• novel selective estrogens that are described in this patent can be used as individual components in pharmaceutical preparations or in combination especially with GnRH-antagonists, progesterone receptor antagonists, mesoprogestins or gestagens or tissue-selective gestagens (action on A/B-form type).
• the substances and the pharmaceutical agents that contain them are especially suitable for ovarian contraception, for the treatment of benign or malignant proliferative diseases of the ovary, such as, e.g., ovarian cancer, and granulosa cell tumors.
• the compounds can be used for treating male fertility disorders and prostatic diseases.
• the amount of a compound of general formula I′ that is to be administered varies within a wide range and can cover any effective amount.
• the amount of the compound that is administered can be 0.01 ⁇ g/kg-100 mg/kg of body weight, preferably 0.04 ⁇ g/kg-1 mg/kg of body weight, per day.
• this corresponds to a dose of 0.8 ⁇ g to 8 g, preferably 3.2 ⁇ g to 80 mg, daily.
• a dosage unit contains 1.6 ⁇ g to 2000 mg of one or more compounds of general formula I′.
• the compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations.
• the pharmaceutical compositions or pharmaceutical agents contain as active ingredients one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances.
• the production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants as well as other commonly used vehicles and diluents can be used.
• the compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously.
• the compounds can also be implanted in the tissue.
• the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.
• a pharmaceutically compatible vehicle such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.
• the active ingredients can be dissolved or suspended in a physiologically compatible diluent.
• diluents very often oils with or without the addition of a solubilizer, a surfactant, a suspending agent or an emulsifying agent are used. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
• the compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated so that a delayed release of active ingredient is made possible.
• implants can contain, for example, biodegradable polymers, or synthetic silicones such as, for example, silicone rubber.
• active ingredients can be added to, for example, a patch.
• intravaginal systems e.g., vaginal rings
• intrauterine systems e.g., pessaries, coils, IUDs, Mirena®
• active compounds of general formula I for local administration various polymers are suitable, such as, for example, silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.
• the compounds can also be formulated as cyclodextrin clathrates.
• the compounds are reacted with ⁇ -, ⁇ -, or ⁇ -cyclodextrin or derivatives of the latter (PCT/EP95/02656).
• the compounds of general formula I can also be encapsulated with liposomes.
• Immature female rats are hypophysectomized. This day is defined as day 0. From day 1-day 4, subcutaneous and/or oral treatment is carried out with the active substance in combination with 17 ⁇ -estradiol. The animals were autopsied on day 5. The ovary is removed and analyzed macroscopically, e.g., organ weights, and microscopically, e.g., histological evaluation of the follicles, so-called follicle staging.
• Immature female rats are hypophysectomized. This day is defined as day 0. From day 1-day 4, subcutaneous and/or oral treatment is carried out with the active substance in combination with 17 ⁇ -estradiol. On day 5, a subcutaneous injection with PMSG (pregnant mare serum gonadotrophin) is carried out. On day 7, hCG is administered intraperitoneally to trigger ovulation. On day 8, the ovary is removed and analyzed macroscopically (e.g., organ weights) and/or microscopically (e.g., histological evaluation of the follicles, so-called follicle staging). The tubes are flushed and checked for the presence of egg cells.
• PMSG pregnant mare serum gonadotrophin
• Immature female rats are treated (day 1) subcutaneously with PMSG (pregnant mare serum gonadotrophin) at the age of 23 days. On the same day, as well as 24 and 48 hours later, the animals receive the active substance, administered subcutaneously or orally. 54 hours after the PMSG injection, the animals receive an intraperitoneal injection of hCG to trigger ovulation. Autopsy is carried out 16 hours after the hCG is administered. The tubes are flushed and checked for the presence of eggs cells.
• PMSG pregnant mare serum gonadotrophin
• Another possibility to detect in vivo the dissociated estrogen action of the substances according to the invention consists in the fact that after a one-time administration of the substances in rats, effects on the expression of 5HT2a-receptor and serotonin transporter protein and mRNA levels in ER ⁇ -rich brain areas can be measured. Compared to the effect on the serotonin receptor and transporter expression, the effect on the LH-secretion is measured. Substances with higher binding to the rat prostate—compared to the rat uterus estrogen receptor—are more potent with respect to increasing the expression of serotonin receptors and transporters, in comparison to their positive effect on the LH release.
• the density of serotonin receptors and transporters is determined in brain sections using radioactive ligands, and the corresponding mRNA is determined using in situ hybridization. The method is described in the literature: G. Fink & B. E. H. Sumner 1996 Nature 383: 306; B. E. H. Sumner et al. 1999 Molecular Brain Research, in press.
• Etherification and/or esterification of free hydroxy groups is carried out according to methods that are common to one skilled in the art.
• the compounds according to the invention can be present in carbon atoms 6, 7, 15, 16 and 17 as ⁇ , ⁇ -stereoisomers.
• the compounds in most cases accumulate as mixtures of the corresponding ⁇ , ⁇ -isomers.
• the mixtures can be separated by, for example, chromatographic processes.
• 17-Substituents are also introduced according to known processes by nucleophilic addition of the desired substituent or a reactive precursor thereof and are optionally further built up.
• estratriene-carboxylic acid esters are produced from the corresponding hydroxy steroids analogously to processes that are also known (see, e.g., Pharmazeutician Wirkstoffe, Synthesen, Patente, füren [Pharmaceutical Active Ingredients, Syntheses, Patents, Applications]; A. Kleemann, J. Engel', Georg Thieme Verlag Stuttgart 1978. Arzneistoff, Fort Coloure [Pharmaceutical Agents, Improvements] 1972 to 1985; A. Kleemann, E. Lindner, J. Engel (Editors), VCH 1987, pp. 773-814).
• estratriene-sulfamates according to the invention are available in a way that is known in the art from the corresponding hydroxy steroids by esterification with sulfamoyl chlorides in the presence of a base (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)).
• the production of the sulfamates according to the invention with one or more additional hydroxyl groups in the molecule is also possible in that the starting material is suitable hydroxy-steroid ketones.
• the starting material is suitable hydroxy-steroid ketones.
• one or more hydroxyl groups that are present are subjected to sulfamoylation.
• the sulfamate groups optionally can be converted with a desired acyl chloride in the presence of a base into the (N-acyl)sulfamates in question.
• oxosulfamates or oxo-(N-acyl)sulfamates are converted by reduction into the corresponding hydroxysulfamates or hydroxy-(N-acyl)sulfamates (Steroids 61, 710-717 (1996)).
• Sodium borohydride and the borane-dimethyl sulfide complex are suitable as proper reducing agents.
• Functionalizations at carbon atom 2 are possible by, for example, electrophilic substitution after prior deprotonation of the 2-position of the corresponding 3-(2-tetrahydropyranyl)- or 3-methyl ether with a lithium base (e.g., methyllithium, butyllithium).
• a fluorine atom can be introduced by reaction of the C—H-activated substrate with a fluorinating reagent such as N-fluoromethane sulfonimide (WO 94/24098).
• variable substituents in rings B, C and D of the estratriene skeleton can basically be carried out according to the chemical teaching that is known to one skilled in the art, with which the corresponding estratriene derivatives that are not substituted in 8-position are produced (see, i.a.: Steroide [Steroids], L. F. Fieser, M. Fieser, Verlag Chemie, Weinheim/Bergstr., 1961; Organic Reactions in Steroid Chemistry, J. Fried, J. A. Edwards, Van Nostrand Reinhold Company, New York, Cincinnati, Toronto, London, Melbourne, 1972; Medicinal Chemistry of Steroids, F. J. Zeelen, Elsevier, Amsterdam, Oxford, New York, Tokyo, 1990).
• substituents such as hydroxyl or alkyloxy groups, alkyl, alkenyl or alkinyl groups or halogen, especially fluorine.
• Substituents according to general formula I can also be introduced in the stage of estratrienes that are already substituted in 8-position, however. This can be useful or necessary especially in the case of multiple substitutions of the desired final compound.
• 11-keto-estratetraene derivatives (U.S. Pat. No. 3,491,089, Tetrahedron Letters, 1967, 37, 3603), which are substituted stereoselectively in 8 ⁇ -position in the reaction with diethylaluminum cyanide, are used.
• 8 ⁇ -substituted estra-1,3,5(10),9(11)-tetraenes which in turn can be converted into 8 ⁇ -aldehydes, are obtained.
• a functionalization e.g., by Wittig reactions with subsequent removal of protective groups, results in the-8 ⁇ -steroids according to the invention.
• the 11-oxidized estradiol derivatives that are first obtained in this sequence can be further reacted to form many substitution patterns on the steroid like the double bond C(9)—C(11) according to methods that are known to one skilled in the art.
• an 11 ⁇ -hydroxy group can be converted into an 11 ⁇ -fluorine atom according to the process that is described by Vorbrüggen et al.
• THF tetrahydrofuran
• THP tetrahydropyran-2-yl
• DHP dihydropyran
• DMSO dimethyl sulfoxide
• MTBE methyl-tert-butyl ether
• DIBAH diisobutylaluminum hydride
• LTBAH lithium-tri-tert.-butoxyaluminum hydride.
• the aqueous phase was extracted several times with ether, the combined organic phases were washed with water and saturated sodium chloride solution, dried with magnesium sulfate and concentrated by evaporation in a vacuum. The oily residue was separated on silica gel by column chromatography.
• the crude imine that was thus obtained was dissolved in 4 ml of ethanol/water (5:1) and mixed with 376 mg of p-toluenesulfonic acid.
• the reaction solution was heated to 60° C. until the conversion was completed. Then, the reaction solution was concentrated by evaporation, the residue was taken up in ethyl acetate and washed several times with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. After purification by column chromatography (cyclohexane/ethyl acetate 3:1), 83 mg of aldehyde 18 was obtained as a colorless foam.
• the crude imine that was thus obtained was dissolved in 4.3 ml of ethanol/water (5:1) and mixed with 411 mg of p-toluenesulfonic acid.
• the reaction solution was heated to 60° C. until the conversion was completed. Then, the reaction solution was concentrated by evaporation, the residue was taken up in ethyl acetate and washed several times with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. After purification by column chromatography (cyclohexane/ethyl acetate 3:1), 86 mg of aldehyde 19 was obtained as a colorless foam.

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