EP1322662A1 - 19-nor-17 alpha-pregna-1,3,5(10)-trien-17 beta-ols dotes d'un noyau de 21,16 alpha-lactone - Google Patents

19-nor-17 alpha-pregna-1,3,5(10)-trien-17 beta-ols dotes d'un noyau de 21,16 alpha-lactone

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Publication number
EP1322662A1
EP1322662A1 EP01974292A EP01974292A EP1322662A1 EP 1322662 A1 EP1322662 A1 EP 1322662A1 EP 01974292 A EP01974292 A EP 01974292A EP 01974292 A EP01974292 A EP 01974292A EP 1322662 A1 EP1322662 A1 EP 1322662A1
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EP
European Patent Office
Prior art keywords
triene
pregna
group
lactone
estra
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01974292A
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German (de)
English (en)
Inventor
Gerd Müller
Uwe Kollenkirchen
Dirk Kosemund
Karl-Heinrich Fritzemeier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP1322662A1 publication Critical patent/EP1322662A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals

Definitions

  • the present invention relates to novel 19-nor-17 ⁇ -pregna-1, 3,5 (10) -trien-17-ols with a 21, 16 -Laktonring ⁇ , processes for their preparation and pharmaceutical compositions containing them as well as 17 ⁇ -cyanomethyltechnischestra-1, 3,5 (10) -trienes, representing -trien-17-ols intermediates on the way to the 19-nor-17 ⁇ -pregna- 1, 3,5 (10).
  • the 19-nor-17 ⁇ - prregna-1,3,5 (10) -triene-17ß-ols with a 21, 16 ⁇ - lactone ring represent novel selective estrogens which, in contrast to classic estrogens, such as estradiol, favor preference one of the two known estrogen receptors, estrogen receptor alpha (ER ⁇ ; Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53 (and EP- A-0 798 378); Tremblay et al. (1997) Molecular Endocrinology 11: 353-365).
  • classic estrogens such as estradiol
  • Estrogens exert their physiological effect via a receptor protein, the estrogen receptor (ER). It is a core transcription factor that can be activated by ligands. Until a few years ago it was assumed that estrogens exert their effect via a single receptor.
  • ER estrogen receptor
  • ERß has recently been discovered as the 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 ERß differs from that of the ER ⁇ (Kuiper et al (1996), Endocrinology. 138: 863-870).
  • ERß predominates over ER ⁇ in the rat prostate, while ER ⁇ predominates in rat uterus.
  • a selective estrogen effect could be achieved due to the different tissue distribution by subtype-specific ligands.
  • Substances with preference for ERß compared to ER ⁇ in the in vitro receptor binding test were described by Kuiper et al. (Kuiper et al. (1996), Endocrinology 138: 863-870).
  • ERß have selective estrogens in their own patent applications (DE 199 06 159, DE 199 17 930 and DE 199 54 105), as well as in a patent application by Sumitomo Chemicals Co. [JP11292872; JP 1998-90296].
  • the present invention is based on the surprising finding that 19-nor-17 ⁇ - pregna-1, 3,5 (10) -trienes have a 21, 16 ⁇ -Laktonring a higher binding affinity for ER ⁇ .
  • the present invention consequently relates to 19-nor-17 ⁇ - pregna-1,3,5 (10) -trienes having a 21, 16 ⁇ -lactone ring of the general formula (II)
  • R 1 halogen atom, hydroxyl, methyl, trifluoromethyl, methoxy or ethoxy group or hydrogen atom,
  • R 2 halogen atom, hydroxyl group, straight or branched chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms or hydrogen atom,
  • R 8 ⁇ or ⁇ -hydrogen atom, ⁇ or ⁇ -position, straight or branched chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms or ⁇ - or ⁇ -position cyano group,
  • R 9 ⁇ or ß-hydrogen atom, ⁇ - or ß-methyl, ethyl, trifluoromethyl or pentafluoroethyl group, R 11 ⁇ or ß-nitrooxy group, or ß-hydroxyl or mercapto group, ⁇ -or ß-position halogen atom, ⁇ - ° of the ß-position chloromethyl group, ⁇ or ß-positioned, straight- or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 17 carbon atoms, ⁇ - ° of the ß - consulting, straight or branched, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, optionally substituted ⁇ -or beta-position aryl or heteroaryl radical or a hydrogen atom,
  • R 14 is in the ⁇ or ⁇ position, straight or branched chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10
  • R 14 and R 15 together form a 14 ⁇ , 15ß-methylene group which is optionally substituted by one or two halogen atoms, and
  • R 18 is hydrogen atom, methyl, C 2 _ 6 -acyl or tri (C 1, 4 -alkyl) silyl group or a group R 19 S0 2 -, where R 19 is a group R 20 R 21 N-, where R 20 and R 21 independently of one another are a hydrogen atom, a C 1-4 alkyl radical, a group C (O) R 22 , in which R 22 is a straight-chain or branched hydrocarbon radical having up to 12 carbon atoms and also up to three
  • May contain double bonds represents a C 3.7 cycloalkyl radical, an aryl radical or a combination of these structural features, or together with the N atom represent a polymethyleneimino radical having 4 to 6 C atoms or a morpholino radical, the 3,17 ⁇ -dihydroxy-2 -methoxy-19-nor-17 ⁇ - pregna-1, 3.5 (10) -triene-21, 16 ⁇ -lactone is excluded.
  • the substances described in the present invention represent ER ⁇ selective estrogens which differ from the compounds mentioned by a novel structure type and a specific activity profile.
  • R 1 , R 2 , R 7 to R 9 , R 11 , R 13 to R 15 and R 18 have the meaning given above, 19-Nor-17 ⁇ - prregna-1, 3.5 (10) -trienes are preferred in which R 1, R 2, R 7, R 8, R 1 and R to R 15 represent a hydrogen atom 13, R 9 represents a C, _ 4 alkyl group and R 18 is a hydrogen atom or a methyl group in which R 1, R 2, R 7, R 8, R 9 and R to R 15 represents a hydrogen atom 13, R 11 is a C ⁇ alkyl group, C 1 _ 6 alkoxy group, vinyl group or phenyl group and R 18 a Represents hydrogen atom or a methyl group, or in which R 1 , R 2 , R 8 , R 9 , R 11 and R 13 to R 15 represent a hydrogen atom, R 7 represents a C 1-4 alkyl group, C 1 -C 4 -alkoxy group, Means vinyl group or phenyl
  • Examples of preferred 19-nor-17 ⁇ - pregna-1,3,5 (10) -trienes with a 21, 16 ⁇ -lactone ring are:
  • Examples of preferred 19-nor-17 ⁇ - pregna-1,3,5 (10) -trienes with a 21, 16 ⁇ -lactone ring and additional double bonds are:
  • the present invention also relates to ⁇ 17 - or 17-cyanomethylated estra-1, 3,5 (10) -trienes of general formula (I '),
  • R 1 , R 2 , R 4 , R 7 to R 9 , R 11 , R 13 to R 15 , R 18 and R 23 independently of one another have the following meaning: R 1 halogen atom, hydroxyl, methyl, trifluoromethyl, methoxy or ethoxy group or hydrogen atom, R 2 halogen atom, hydroxyl group, straight or branched chain, saturated or unsaturated alkoxy group having 2 to 6 carbon atoms or hydrogen atom, R 7 ⁇ or ß-halogen atom, ⁇ or ß-position, straight or branched chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms, straight or branched chain, saturated or unsaturated alkoxy group with up to 6 Carbon atoms, optionally substituted aryl or heteroaryl radical or hydrogen atom, R 8 or ß-hydrogen atom,
  • R 11 ⁇ -o he ß-position nitrooxy, tooli ⁇ -or ß-position hydroxyl or mercaptan, ⁇ - ° of the ß-position halogen atom, ⁇ - ° of the ß-position chloromethyl group, ⁇ or ß-position, straight - or branched chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms, ⁇ - ° the ⁇ -position, straight or branched chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms atoms, optionally substituted ⁇ -or beta-position aryl or hetero- roarylrest or hydrogen atom, R 13 methyl or ethyl group,
  • R 14 is ⁇ or ⁇ , straight or branched chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms or an ⁇ or ⁇ hydrogen atom
  • R 15 ⁇ - the ß-standing, straight or branched chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10
  • R 14 and R 15 together represent a 14 ⁇ , 15 ⁇ -lvlethylene- or 14ß, 15ß-methylene group, optionally substituted with one or two halogen atoms,
  • R 18 is hydrogen, methyl, C 2 . 6 -acyl or tri (C 1, 4 alkyl) silyl group or a group R 19 SO 2 ", where R 19 is a group R 20 R 21 N-, where R 20 and R 21 independently of one another are a hydrogen atom, a C ., _ 5 alkyl radical, a group C (O) R 22 , wherein R 22 is a straight-chain or branched hydrocarbon radical having up to 12 carbon atoms, which may also contain up to three double bonds, a C 3,7 -cycloalkyl radical, an aryl radical or represents a combination of these structural features, or together with the
  • N atom is a polymethyleneimino radical having 4 to 6 carbon atoms or a morpholino radical
  • R 23 hydrogen, silyl C 2 6 -acyl or tri (C 1. 4 alkyl).
  • R 1 , R 2 , R 7 to R 9 , R 11 , R 13 to R 15 , R 18 and R 23 have the meaning given above, are intermediates on the way to the 19-Nor-17 ⁇ -pregna- 1 , 3,5 (10) -triene with a 21.16 ⁇ - lactone ring of the general formula (II).
  • the 17ß- cyanomethylated estra-1, 3,5 (10) -trienes of general formula (I) are formed in the preparation of 19-nor-17 ⁇ -pregna-1, 3,5 (10) -trienes of general formula ( II).
  • R 1 , R 2 , R 7 to R 9 , R 1 , R 13 to R 5 , R 18 and R 23 have the meaning given above, with those compounds in which R 1 , R 2 , R 7 , R 8 , R 1 , R 13 to R 15 and R 23 represent a hydrogen atom, R 9 represents a C 1-4 alkyl group and R 18 represents a hydrogen atom or a methyl group in which R 1 , R 2 , R 7 , R 8 , R 9 , R 13 to R 15 and R 23 represent a hydrogen atom, R 11 represents a C ⁇ alkyl group, C ⁇ alkoxy group, vinyl group or phenyl group and R 18 represents a hydrogen atom or a methyl group, or .
  • R 1 , R 2 , R 8 , R 9 , R 11 , R 3 to R 15 and R 23 represent a hydrogen atom
  • R 7 represents a C 1-4 alkyl group, C 1-4 alkoxy group, vinyl group or phenyl group and R 18 represents a hydrogen atom or means a methyl group.
  • a halogen atom can always be a fluorine, chlorine, bromine or iodine atom; a fluorine atom is preferred in each case.
  • the alkoxy groups can each contain 1 to 6 carbon atoms, with methoxy, ethoxy-propoxy-isopropoxy and fetf-butyloxy groups being preferred.
  • alkylthio groups include, for example, the methylthio, ethylthio and trifluoromethylthio groups.
  • an aryl radical is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred.
  • aryl always includes a heteroaryl radical.
  • a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3- furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyI, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyI or 3- or 4-pyridazinyl radical.
  • substituents for an aryl or heteroaryl radical are methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), Hydroxy-, amino-, mono (C., _ 8 -alkyl) - or di (C., _ 8 -alkyl) amino, where both alkyl groups are identical or different, di (aralkyl) amino, where both aralkyl groups are identical or different are mentioned.
  • straight or branched chain alkyl groups with 1-17 carbon atoms include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl; Methyl, ethyl, propyl and isopropyl are preferred.
  • the alkyl groups can be partially or completely fluorinated or substituted by 1-5 halogen atoms, hydroxyl groups or C - (- C4-alkoxy groups.
  • Trifluoromethyl, pentafluoroethyl and nonafluorobutyl may be mentioned as perfluorinated alkyl groups.
  • Representatives of the partially fluorinated alkyl groups for example 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 9,9,9,8,8,7,7,6,6-nonafluorohexyl etc.
  • Monochloromethylene, monofluoromethylene or difluoromethylene can represent the halogen-substituted 14,15-methylene group.
  • R 11 in the meaning of ⁇ or ⁇ , straight or branched chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group can, according to the invention, be selected from the following groups:
  • X is CH 2 , CH-C ⁇ alkyl or C (C 1.8 alkyl) 2
  • A is a hydrogen atom, a C jg alkyl group, a C 3 -C 7 cycloalkyl group or together with X is a C 3 -C 7 - ring system forms
  • C and D are independently a hydrogen atom, a C j.
  • C 1-4 alkyl group means a straight-chain or branched alkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and octyl.
  • C 3 -C 7 cycloalkyl group means a mono- or bicyclic group, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the hydroxyl group on the carbon atom 3 can be esterified with an aliphatic, straight or branched chain, saturated or unsaturated carbon carboxylic acid.
  • carboxylic acids for esterification are: acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid or pivalic acid.
  • Examples of a tri (C 1 4 -alkyl) group are a trimethylsilyl group and a tert-butyldimethyl group.
  • R 1 , R 2 , R 4 , R 7 to R 9 , WR 13 to R 15 and R 18 die have the meaning given above and R 23 represents a hydrogen atom, a butyryl or eri-butyldimethyl group, is reacted with lithium acetonitrile.
  • the 19-nor-17 ⁇ - pregna-1,3,5 (10) -trienes with a 21, 16 ⁇ - lactone ring of the general formula (II) can be prepared by using a compound of the general formula (III),
  • R 1 , R 2 , R 4 , R 7 to R 9 , R 11 , R 13 to R 15 and R 8 have the meaning given above and R 23 represents an acetyl or trimethylsilyl group, is reacted with lithium acetonitrile.
  • the 19-nor-17 ⁇ - prregna-1,3,5 (10) -triene with a 21, 16 ⁇ -lactone ring can be prepared in a one-step process from the corresponding 17-oxo compounds or from the 17 ⁇ -cyanomethylated estra- 1, 3.5 (10) -triene done.
  • the substituents R 14 , R 15 and R 23 are of particular importance for lactone formation.
  • the preparation of the compounds of the invention ie, ⁇ of 17 - or 17p cyanomethylated estra-1, 3,5 -trienes (10) and the 19-nor-17 ⁇ -pregna-1, 3,5 (10) - triene 21 , 16 ⁇ -lactone ring is based on the reaction of substituted or unsaturated in the rings B, C, and D 17-keto steroids with a protected or unprotected 16 ⁇ -hydroxy function.
  • the 16-hydroxy function is introduced in a conventional manner by alkaline hydrolysis of the 16 ⁇ -bromine compounds or by reaction of silyl or acylenol ethers with peracids and subsequent hydrolysis.
  • the present invention encompasses the novel substances as active pharmaceutical ingredients, their production, their therapeutic use and the pharmaceutical administration forms which contain the new substances.
  • the chemical compounds are new steroidal selective estrogens.
  • novel selective estrogens described in the present patent can be used as individual components in pharmaceutical preparations or in combination in particular with gestagens, androgens or antiestrogens. Like other estrogens, the novel selective estrogens are suitable for the treatment of diseases caused by estrogen deficiency and for contraception.
  • the substances and the pharmaceuticals containing them are suitable, for example, as components of oral contraceptives, for example in combination with a progestogen. They can also be used for the treatment of peri- and postmenopausal complaints, especially hot flashes, sleep disorders, irritability, mood swings, incontinence, vaginal atrophy and hormone deficiency-related mood disorders in the peri- or postmenopausal woman.
  • the substances are also suitable for hormone substitution and the therapy of hormone deficiency-related complaints in the case of surgical, medicinal or other-related ovarian dysfunction.
  • the substances are also suitable for the therapy of osteoporosis in men and women, also in combination with androgens.
  • the substances are also used for the prophylaxis of hormone deficiency-related bone mass loss and osteoporosis, for the prevention of cardiovascular diseases, in particular vascular diseases, such as atherosclerosis, and for the prevention of hormone deficiency-related neurodegenerative diseases, such as Alzheimer's disease, as well as hormone deficiency-related impairment of the ability of men and women to learn, memory impairment in men and women, and memory impairment in men and women.
  • cardiovascular diseases in particular vascular diseases, such as atherosclerosis
  • hormone deficiency-related neurodegenerative diseases such as Alzheimer's disease
  • hormone deficiency-related impairment of the ability of men and women to learn memory impairment in men and women
  • memory impairment in men and women and memory impairment in men and women.
  • the substances for the treatment of inflammatory diseases of the immune system in particular autoimmune diseases, such as. B. rheumatoid arthritis can be used.
  • Another area of application is the use of the substances to promote wound healing, as well as to prevent changes in the skin due to age and hormone deficiency.
  • Another area of application is the treatment of prostate cancer.
  • the novel estrogens which are part of this invention, are particularly well suited as an estrogenic component of combination preparations for contraception.
  • the target organs of the estrogen in combination preparations are in particular the pituitary, the ovary and the endometrium. These organs express ER ⁇ (Kuiper et al. (1996), Endocrinology 138: 863-870).
  • the novel ER ⁇ selective estrogens act with greater selectivity on these target organs than previously known estrogens such as estradiol and ethinyl estradiol.
  • estrogen replacement therapy in postmenopausal women or in women with other-related ovarian dysfunction reduces the risk of cardiovascular diseases compared to women who have not been treated with estrogen (Grady et al. 1992, Ann. Intern. Med. 117 : 1016-1037).
  • estrogens have a protective effect against neurodegenerative diseases, e.g. Alzheimer's disease (Henderson 1997, Neurology 48 (Suppl. 7): 27-35; Birge 1997, Neurology 48 (Suppl. 7): 36-41), a protective effect on brain functions such as memory and learning ability (McEwen et al 1997, Neurology 48 (Suppl. 7): 8-15; Sherwin 1997, Neurology 48 (Suppl. 7): 21-26), as well as against mood swings due to hormone deficiency (Halbreich 1997, Neurology 48 (Suppl. 7): 16-20 ).
  • classic estrogens such as estradiol and conjugated estrogens from horse urine, are used either alone or in combination with a gestagen.
  • the selective estrogens described in the present invention are particularly well suited as estrogen components of estrogen / progestogen combination preparations: New studies on ER ⁇ knockout mice have proven that ER ⁇ is to be regarded as an essential mediator of the estrogen effect in the bone, in the vascular system and in the brain is. With the novel ER ⁇ selective estrogens, a more specific effect on these target organs of the ERT is achieved.
  • the substances In the test for protection against estrogen deficiency-induced bone mass loss in the female ovariectomized (ovx) rat, the substances have high estrogenic activity. Furthermore, they efficiently inhibit FSH secretion and stimulate uterine growth in the ovx rat.
  • the binding affinity of the new selective estrogens was tested in competition experiments using 3H estradiol as a ligand on estrogen receptor preparations from rat prostate and rat uterus.
  • the preparation of the prostatacytosol and the estrogen receptor test with the prostatacytosol were carried out as described by Testas et al. (1981). (Testsas J. et al., 1981, Endocrinology 109: 1287-1289).
  • Ovariectomized rats were treated with different doses of the test substances 10 days after ovariectomy. Treatment was performed subcutaneously using osmotic pumps. On day 8 after the start of treatment, the animals were sacrificed, uterine moisture and fresh weight were determined and the FSH level in the serum was determined.
  • RBA * Relative binding affinity
  • RBA of the reference substance estradiol 100 Uterine growth test in the ovariectomized rat
  • Half-maximum bone protection (ED50) stimulation of the uterine weight and lowering of the FSH level is achieved by a dose of 1 (bone protection) or 4 ⁇ g / kg (uterine stimulation ; FSH reduction) caused by subcutaneous application.
  • the substance is therefore as potent as the reference estrogen estradiol.
  • compositions or pharmaceuticals according to the invention contain as active ingredient one or more of the compounds according to the invention, optionally in a mixture with other pharmacologically or pharmaceutically active substances.
  • the pharmaceuticals are produced in a known manner, it being possible to use the known and customary pharmaceutical auxiliaries and other customary excipients and diluents.
  • auxiliaries are, for example, those which are recommended or indicated in the following references as auxiliaries for pharmacy, cosmetics and related fields: Ullmans Encyklopadie der Technische Chemie, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., H. v. Czetsch-Lindenwald, auxiliaries for pharmacy and neighboring areas; Pharm. Ind., Issue 2, 1961, page 72 u. ff .: Dr. HP Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas, Cantor KG. Aulendorf in practise 1971.
  • the compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously.
  • the connections can also be implanted into the tissue.
  • Capsules, pills, tablets, coated tablets, etc. can be used for oral administration.
  • the dosage units can contain a pharmaceutically acceptable carrier, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silica, talc, etc.
  • the active ingredients can be dissolved or suspended in a physiologically acceptable diluent. Oils with or without the addition of a solubilizer, a surface-active agent, a suspending or emulsifying agent are very often used as diluents.
  • oils 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 in such a way that a delayed release of the active ingredient is made possible.
  • implants can contain, for example, biodegradable polymers or synthetic silicones such as silicone rubber.
  • the active ingredients can also be incorporated into a plaster for percutaneous application, for example.
  • Various polymers such as silicone polymers, ethylene vinyl acetate, polyethylene or are suitable for the local administration of intravaginal (for example vaginal rings) or intrauterine systems (for example pessaries, spirals, IUS, Mirena®) loaded with active compounds of the general formula I polypropylene.
  • intravaginal for example vaginal rings
  • intrauterine systems for example pessaries, spirals, IUS, Mirena®
  • the compounds can also be formulated as cyclodextrin clathrates.
  • the connection fertilize with ⁇ -, ß- or ⁇ -cyclodextrin or derivatives of these implemented (PCT / EP95 / 02656).
  • the compounds of the general formula I can also be encapsulated with liposomes.
  • Example 1 1, 28 g (2.5 mmol) of 3.16 ⁇ -bis (te / -butyldimethylsilyloxy) estra-1, 3.5 (10) -trien-17-one is reacted in accordance with Example 1.
  • the crude product obtained dissolves one in tetrahydrofuran, with tet ⁇ -butyldimethylsilyl groups still present being split by adding tetrabutylammonium fluoride. After adding water, extraction with ethyl acetate and concentration, the crude product is chromatographed according to Example 1 over silica gel 60 (0.040-0.063 mm).
  • Example 4 961 mg (2.5 mmol) of 17-oxo-18a-homo-estra-1,3,5 (10) -triene-3,16 ⁇ -diyl diacetate are reacted in accordance with Example 1 and the crude product obtained is separated by chromatography. The following products are isolated: a) 3, 17 ⁇ -dihydroxy-18a-homo-19-nor-17 ⁇ -pregna-1, 3.5 (10) -triene-21, 16 ⁇ -lactone 454 mg (53% of theory ) ( 1 H-NMR data and melting point see Table 1) b) 17 ⁇ -cyanomethyl-18a-homo-estra-1, 3.5 (10) -triene-3.16 ⁇ , 17 ⁇ -triol 188 mg (22% of theory . Th.)
  • Example 5 1.00 g (2.5 mmol) of 1 ⁇ -methoxy-17-oxo-estra-1,3,5 (10) -triene-3,16 ⁇ -diyldiacetate are reacted according to Example 1 and the crude product obtained is chroma- separated graphically. The following products are isolated: a) 3,17ß-dihydroxy-1 1ß-methoxy-19-nor-17 ⁇ -pregna-1, 3,5 (10) -triene-21, 16 ⁇ -lactone
  • Example 8 921 mg (2.5 mmol) of 17-oxo-estra-1, 3, 5 (10), 9 (11) -triene-3,16 ⁇ -diyl diacetate are reacted in accordance with Example 1 and the crude product obtained is separated by chromatography. The following products are isolated: a) 3, 17 ⁇ -dihydroxy-19-nor-17 ⁇ -pregna-1, 3.5 (10), 9 (11) -tetraen-21, 16 ⁇ -lactone 375 mg (46% of theory .) ( 1 H-NMR data and melting point see Table 1) b) 17 ⁇ -cyanomethyl-estra-1, 3.5 (10), 9 (11) -tetraen-3.16 ⁇ , 17 ⁇ -triol 122 mg (15 % of theory)

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Abstract

La présente invention concerne de nouveaux 19-nor-17 alpha -prégna-1,3,5(10)-trién-17 beta -ols dotés d'un noyau de 21,16 alpha -lactone de formule (II), des procédés de production desdits composés et préparations pharmaceutiques les contenant, ainsi que des oestra-1,3,5(10)-triènes 17 alpha -cyanométhylés qui sont des produits intermédiaires dans la production de 19-nor-17 alpha -prégna-1,3,5(10)-trién-17 beta -ols. Ces 19-nor-17 alpha -prégna-1,3,5(10)-trién-17 beta -ols constituent de nouveaux oestrogènes sélectifs qui présentent, au contraire d'oestrogènes classiques tels que l'oestradiol, une préférence en faveur de l'un des deux récepteurs d'oestrogènes connus, le récepteur d'oestrogènes alpha.
EP01974292A 2000-09-27 2001-09-25 19-nor-17 alpha-pregna-1,3,5(10)-trien-17 beta-ols dotes d'un noyau de 21,16 alpha-lactone Withdrawn EP1322662A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10048634A DE10048634A1 (de) 2000-09-27 2000-09-27 19-Nor-17alpha-pregna-1,3,5(10)-trien-17beta-ole mit einem 21, 16alpha-Laktonring
DE10048634 2000-09-27
PCT/EP2001/011061 WO2002026763A1 (fr) 2000-09-27 2001-09-25 19-NOR-17α-PREGNA-1,3,5(10)-TRIEN-17β-OLS DOTES D'UN NOYAU DE 21,16α-LACTONE

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EP1322662A1 true EP1322662A1 (fr) 2003-07-02

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EP01974292A Withdrawn EP1322662A1 (fr) 2000-09-27 2001-09-25 19-nor-17 alpha-pregna-1,3,5(10)-trien-17 beta-ols dotes d'un noyau de 21,16 alpha-lactone

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EP (1) EP1322662A1 (fr)
AU (1) AU2001293843A1 (fr)
DE (1) DE10048634A1 (fr)
HU (1) HUP0300504A3 (fr)
IL (1) IL151782A0 (fr)
NO (1) NO20025201D0 (fr)
WO (1) WO2002026763A1 (fr)

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DE10214180A1 (de) * 2002-03-27 2003-10-16 Schering Ag 11beta-lankgettig-substituierte 19-Nor-17alpha-pregna-1,3,5(10)-trien-17beta-ole mit einem 21,16alpha-Laktonring

Family Cites Families (4)

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Publication number Priority date Publication date Assignee Title
US3920634A (en) * 1974-08-30 1975-11-18 Lilly Co Eli 2,3-Dihydroestra-1,3,5(10)-trieno (16{60 ,17{60 -{62 ) furan-17{62 ols
DE19906159A1 (de) * 1999-02-09 2000-08-10 Schering Ag 16-Hydroxyestratriene als selektiv wirksame Estrogene
DE19917930A1 (de) * 1999-04-15 2000-10-19 Schering Ag Ent-Steroide als selektiv wirksame Estrogene
DE19954105A1 (de) * 1999-11-02 2001-05-17 Schering Ag 18-Nor-Steroide als selektiv wirksame Estrogene

Non-Patent Citations (1)

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Title
See references of WO0226763A1 *

Also Published As

Publication number Publication date
IL151782A0 (en) 2003-04-10
NO20025201L (no) 2002-10-30
NO20025201D0 (no) 2002-10-30
HUP0300504A3 (en) 2003-12-29
DE10048634A1 (de) 2002-04-18
WO2002026763A1 (fr) 2002-04-04
HUP0300504A2 (hu) 2003-06-28
AU2001293843A1 (en) 2002-04-08

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