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WO2005113576A1 - Phenylester substitue par aminosulfonyle ou aminosulfonylamino comme promedicaments a base d'oestriol et d'oestetrol - Google Patents

Phenylester substitue par aminosulfonyle ou aminosulfonylamino comme promedicaments a base d'oestriol et d'oestetrol Download PDF

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Publication number
WO2005113576A1
WO2005113576A1 PCT/EP2005/005258 EP2005005258W WO2005113576A1 WO 2005113576 A1 WO2005113576 A1 WO 2005113576A1 EP 2005005258 W EP2005005258 W EP 2005005258W WO 2005113576 A1 WO2005113576 A1 WO 2005113576A1
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WIPO (PCT)
Prior art keywords
group
triene
sulfamoylbenzoate
compounds according
tert
Prior art date
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Ceased
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PCT/EP2005/005258
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German (de)
English (en)
Inventor
Ralf Wyrwa
Peter Droescher
Sven Ring
Walter Elger
Birgitt Schneider
Alexander Hillisch
Gudrun Reddersen
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Bayer Pharma AG
Original Assignee
Schering AG
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Application filed by Schering AG filed Critical Schering AG
Priority to EP05747926A priority Critical patent/EP1747231A1/fr
Priority to JP2007517048A priority patent/JP2007538027A/ja
Publication of WO2005113576A1 publication Critical patent/WO2005113576A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • 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
    • C07J41/0072—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens

Definitions

  • the invention relates to estriol and estetrol prodrugs of the general formula I
  • Estrogens control a wealth of functions at the cellular level. They play a central role in the functions of the genital organs in both sexes. In addition, estrogen effects in the central nervous system play an important role in the organization of the CNS, the modulation of behavior, the control of gonadotropin secretion of the pituitary gland. Other pituitary hormones are also modulated by estrogens.
  • ER ⁇ and ER ⁇ Their action is mediated by at least two known receptors, ER ⁇ and ER ⁇ , which are expressed in very different concentrations throughout the organism, that is also outside the genital organs () .
  • the ovaries secreted by the ovary dominate in the organism, whereby the secretion of estradiol is in the foreground.
  • the placenta forms large amounts of estrogen, with very large amounts of estriol being secreted especially in later stages of pregnancy (2> .
  • estrogens develop predominantly "peripherally" through the aromatization of testosterone or adrenal androgens in various organs of success, such as the CNS, bone, adipose tissue or the intestine.
  • This organ-selective adaptation allows the physiological estrogen effects in men at very low estradiol levels in the human body Blood.
  • the loss of estrogens or their impaired formation (defect or inhibition of aromatase) is accompanied by disorders of a broad spectrum of organ and metabolic functions (3) . This spectrum includes disorders or loss of the reproductive function, disorders in the carbohydrate and lipid metabolism, but especially disorders of the skeletal system ⁇ 4) .
  • adolescence abnormalities of length growth dominate, in older age changes in bone density.
  • the loss of bone mass (osteoporosis) is the most dreaded consequence of estrogen deficiency after the end of lengthening, because it is associated with increased brittleness of the bone and is a frequent cause of disability in old age (5) .
  • Estrogens have important circulatory functions in women. Their effects are an important factor in reducing the risk of female morbidity in terms of cardiovascular morbidity and mortality. The loss of estrogens leads to unfavorable changes in lipoproteins and endothelial functions with regard to vessel dilation and the prevention of clot formation (6) .
  • urogenital functions are estrogen-modulated.
  • the structure and regeneration of epithelia and muscles in urethra and urinary bladder is positively influenced by estrogens (7) .
  • estrogens can be administered orally and parenterally.
  • natural estrogens such as estradiol or its derivatives, eg. B. Estradiolvalerat applied.
  • a large role in oral estrogen therapy play estrogen mixtures, which are obtained from the urine of pregnant mares, the so-called conjugated estrogens. These represent sulphates, including estrone and estrogens typical of the horse (equilin and equilenin). They are hydrolytically split after absorption into the organism, releasing the therapeutically relevant "parent estrogens.” These estrogens dominate all forms of the climacteric substitution therapy. However, despite some oral bioavailability, they play no role in hormonal contraception. The main reason for this is a lack of control of uterine bleeding by the state of the art natural estrogens and their derivatives (esters).
  • An essential feature of conventional estrogen therapy is the need for much higher doses than would be required for parenteral use. This is why an oral estrogen treatment or therapy has other metabolic effects than an equivalent parenteral, even if natural estrogens are used ' 9 '.
  • ethinyl estradiol has particularly strong hepatic estrogenicity, as it is only inactivated in the liver after a delay of ' 10 '.
  • Estrogen-sensitive hepatic functions affect the renin-angiotensin-aldosterone system and thus the blood pressure regulation ' 11 '. For the musculature and the skeletal system, a decrease in the Nepali IGF-I synthesis is unfavorable ' 12 '.
  • Estradiol is often given a 40-fold higher dose for oral therapy than a therapeutically equivalent transdermal therapy.
  • the high dose required for oral therapy has correspondingly the disadvantage of strong estrogen effects in the liver, into which the entire applied quantity after absorption first reaches the portal blood and where most of the substance is metabolized ' 13 '.
  • DE 100 27 887.6 A1 discloses steroidally active compounds which are bound to erythrocytes via a group -SO 2 NR 1 R 2 and accumulate there.
  • concentration ratio of the compounds between erythrocytes and plasma is 10-1000, preferably 30-1000, so that one can speak of a deposit formation in the erythrocytes. Due to the strong binding of the compounds to the erythrocytes is the Metabolism avoided during liver passage. Disadvantageously, despite a reduced metabolization with the indicated dosages no therapeutically relevant drug levels are given.
  • R 21 is where R 20 , R 21 and R 22 are a C 1-5 alkyl group, a C 3-8 cycloalkyl group, an aryl group, a group or C3 ⁇ cycloalkylene-C 1 -alkyl group and R 20 also may be a hydrogen, or R 2 is a group -SO 2 NH 2 or -NHSO 2 NH 2, wherein R 2, R 3 and X
  • R 20 ; a C 2 . 5- Heterocycloalkyloxy group or a group Y and
  • the compounds according to the invention have estrogenic activity.
  • C 1-5 -alkyl group is understood as meaning a branched or straight-chain alkyl radical having 1 to 5 carbon atoms which may be substituted by halogen atoms, a hydroxy group or a nitrile group, for example a methyl, ethyl , n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl or n-pentyl group.
  • aryl group is understood to mean a substituted or unsubstituted aryl radical having 6 to 15 carbon atoms, for example a phenyl group, a substituted phenyl group, such as a halophenyl group or a nitrophenyl group, or a naphthyl group.
  • C 1-4 -alkylene-aryl group is understood to mean a disubstituted alkyl radical which is at least substituted by an aryl radical. Both radicals together have 7 to 15 carbon atoms, it being possible for the group to carry further substituents, for example a halogen atom. Examples are a benzyl group or a halobenzyl group.
  • Application is understood to mean a disubstituted alkyl radical which is substituted by at least one C 3-8 -cycloalkyl radical. Both radicals together have 7 to 15 carbon atoms on, wherein the group can carry further substituents, such as a halogen atom. Examples are a cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl group.
  • C 3-8 cycloalkylene-C 1- alkyl is meant a disubstituted C ⁇ cycloalkylene radical in the sense of the present application, which is substituted with a C 1-4 alkyl group at least. Both radicals together have 7 to 15 carbon atoms, which group may carry further substituents, such as a halogen atom, for example, a propylcyclohexyl or butylcyclohexyl group.
  • C p F 2p + ⁇ group is understood according to the present invention, a perfluorinated alkyl radical, such as a trifluoromethyl and Pentafluorethylrest.
  • tri (C 1-6 -alkyl) silyloxy group is understood to mean, for example, a trimethylsilyloxy, a triisopropylsilyloxy, a thexyldimethylsilyloxy or a tert-butyldimethylsilyloxy group.
  • C 2-5 -Heterocycloalkyloxy-group means a C, 2- 5 understood -Heterocycloalkyloxy group with a nitrogen or oxygen atom as a hetero atom in the invention, wherein the binding of the C 1-5 -Heterocycloalkyloxy group on the oxygen atom is at 2, 3 or 4.
  • One example is the perhydropyranoxy group.
  • halogen atom is understood to mean a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, bromine atom.
  • the number "n” is preferably 0, 1 and 2 and more preferably 0.
  • STEROID is preferably a steroidal ABCD ring system of general sub-formulas II B and II C.
  • R 1 represents a group -SO 2 NH or -NHSO 2 NH 2 , with the remainder - SO 2 NH 2 being particularly preferred. Mentioned radicals are thus in the m-position of the group Y in relation to the ester group, via which the group Y is bound to the steroid.
  • R 1 preferably represents a group -SO 2 NH 2 , wherein R 2 , R 3 , X 1 and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy or a methoxy group, or
  • R 2 is preferably a group -SO 2 NH 2 , wherein R 1 , R 3 , X 1 and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy or a methoxy group, or.
  • R 3 is preferably a group -SO 2 NH 2 , wherein R 1 , R 2 , X 1 and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy or a methoxy group.
  • R 4 , R 16 and R 17 are each preferably and independently of one another hydroxy, trimethylsilyloxy, tert-butyldimethylsilyloxy, benzoate, acetate, propionate, valerate, butcyclate or cyclopentylpropionate, with the hydroxy group being particularly preferred ,
  • R 15 is preferably a hydrogen atom.
  • the radicals R 15 , R 16 and R 17 can be arranged both in the ⁇ and in the ⁇ position.
  • salts of the compounds of general formula I come as inorganic acids, inter alia, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and as organic acids, inter alia, acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, oxalic acid, Salicylic acid, tartaric acid, citric acid, lactic acid, malic acid, mandelic acid, cinnamic acid and methanesulfonic acid into consideration.
  • the compounds of the invention have estrogenic activity in oral administration, hepatic effects, unlike conventional estrogens, as far as possible avoided.
  • the compounds according to the invention do not bind themselves to the estrogen receptor, but rather are released from them by ester cleavage, the therapeutically relevant steroid.
  • Rats are ovariectomized and taken after a 14-day wait in the experiment. The animals are then treated for three days (Day 1-3) and then killed (Day 4). Thereafter, the organ weights are determined and estrogen-modulated factors of hepatic secretion are determined in the serum, that is in the rat, the increase of angiotensinogen and the drop in total and HDL cholesterol.
  • estriol did not achieve a doubling of uterine weights even at very high dosages.
  • a fraction of the dose tested for estriol is sufficient to induce a corresponding growth of the uterus.
  • estrogen effects in the liver appear very clearly under treatment with underivatized estriol.
  • the hepatic estrogenicity in the substances according to the invention is predominantly not reduced in comparison with estriol, but can be achieved in relation to the much lower dose with the therapeutically relevant effects in the uterus.
  • estriol in the rat's liver compared to estradiol reflects a difficult oxidation of the 17 ⁇ -OH function of this estrogen by the presence of the 16 ⁇ -OH group and inactivation in the rat.
  • An undiminished uterine effect in the uterus compared to other natural estrogens (estradiol) is especially useful when progestogens increase the 17ß-hydroxysteroid dehydrogenase in the uterus and estradiol in the uterine mucosa is degraded very rapidly.
  • FIGS. 1 and 2 show different interactions of estradiol and estriol with progesterone in the vagina and in the uterus of ovariectomized guinea pigs, treatment day 1-7, autopsy day 8.
  • progesterone attenuates the uterotropic effects of estradiol, while enhancing the corresponding effects of estriol.
  • estradiol and estriol conflicting interactions were observed in the case of estradiol and estriol. This is also surprising because estriol is generally regarded as a much weaker estrogen. Progesterone attenuates the uterotropic effects of estradiol, while the corresponding effects of estriol are significantly enhanced at all tested dosages of estriol. The observed interaction is specific to the uterus. The increase in weight of the vagina by estriol is not or not increased to the same extent by progesterone, the inhibitory effects of progesterone dominate.
  • estradiol are superior to estradiol with regard to the prevention of breakthrough and intermediate bleeding under the simultaneous treatment with a gestagen. Since estriol in the liver is rapidly inactivated by conjugation (glucuronidation, sulfation) in humans, unlike the rat, no estrogen-modulated liver functions are found even in very high oral doses of estriol. Accordingly, substances according to the invention can be used in humans, other than estradiol and ethinylestradiol, in fully uterotropic doses without having to accept undesirable effects in the liver.
  • compositions of the invention are prepared in a known manner with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical excipients according to the desired mode of administration with a suitable dosage.
  • the preferred formulations consist of a dosage form which is suitable for oral administration.
  • dosage forms are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms.
  • parenteral preparations such as injection solutions come into consideration.
  • Further examples of preparations which may be mentioned are suppositories and vaginal administration agents.
  • Corresponding tablets for example, by mixing the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve a Depot effect such as carboxyl polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, are obtained.
  • excipients for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve a Depot effect such as carboxyl poly
  • dragees can be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example Polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
  • Solutions or suspensions with the compounds of general formula I according to the invention may additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. flavorings such as vanillin or orange extract. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • the capsules containing the compounds of the general formula I can be prepared, for example, by mixing the compound (s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatine capsules.
  • an inert carrier such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
  • estriol and estetrol prodrugs according to the invention can be synthesized according to the following examples, these serving for the more detailed explanation, without limiting the invention.
  • the compounds of the general formula IIA-D it is possible to use a known basic steroid body.
  • the following basic steroid bodies can be used, for example: estrone, estriol and estetrol.
  • the functional groups can be protected by methods known to the person skilled in the art or converted into corresponding functionalities.
  • keto groups can be reduced to hydroxy compounds by methods known to those skilled in the art and converted into enone and enol compounds. Double bonds Can be converted into dihydroxy compounds by methods known to those skilled in the art.
  • An estrogen is dissolved in a base, e.g. Pyridine and an organic solvent, e.g. Chloroform dissolved and cooled.
  • a base e.g. Pyridine
  • an organic solvent e.g. Chloroform dissolved and cooled.
  • To the solution is added the appropriate amount of a Chlorsulfonylphenylcarbonklarechlorides.
  • the reaction mixture is stirred until complete reaction at room temperature. Subsequently, the reaction mixture is stirred into concentrated ammonia solution.
  • the mixture is concentrated and acidified with an acid, e.g. 10% HCL acidified.
  • the precipitate is filtered off, washed with water, dried and chromatographed on silica gel. There are obtained corresponding Estrogensulfamoylbenzoate.
  • the conversion to the sulfamides according to the invention is carried out by methods known to those skilled in the art, starting from corresponding amines by means of sulfamide, sulfamoyl chloride or aminosulfonyl isocyanate (Burke, Burke et al., J. Chem. Soc., Perk. Trans 2, 1984, 1851, M. Preiss Chem. Ber., 1978, 1915; C.H. Lee et al., J. Org. Chem., 1990, 6104.).
  • Example 2 The substance is prepared analogously to Example 1 starting from 3,17 ⁇ -di (tert-butyldimethylsilyloxy) estra-1,3,5 (10) -triene-16 ⁇ -ol via the intermediates 3,17 ⁇ -di (tert-butyldimethylsilyloxy) estra -1, 3,5 (10) -triene-16 ⁇ -yl 4-sulfamoylbenzoate (5) and 3-hydroxy-17 ⁇ -tert-butyldimethylsilyloxyestra-1,3,5 (10) -triene-16 ⁇ -yl 4'- sulfamoyl benzoate (6).
  • the substance is prepared analogously to Example 3 starting from 3,17 ⁇ -di (tert-butyldimethylsilyloxy) estra-1,3,5 (10) -triene-16 ⁇ -ol via the intermediates 3,17 ⁇ -di (tert-butyldimethylsilyloxy) estra -1, 3,5 (10) -triene-16 ⁇ -yl 3'-sulfamoylbenzoate (11) and 3-hydroxy-17 ⁇ -tert-butyldimethylsilyloxyestra-1, 3,5 (10) -triene-16 ⁇ -yl 3 ' -sulfamoylbenzoate (12).

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Abstract

La présente invention concerne des promédicaments à base d'oestriol et d'oestétrol de formule générale (I), dans lesquels le groupe Y est lié au stéroïde, un procédé de production desdits promédicaments, des compositions pharmaceutiques contenant ces composés ainsi que leur utilisation dans la production de médicaments à effet oestrogène.
PCT/EP2005/005258 2004-05-21 2005-05-10 Phenylester substitue par aminosulfonyle ou aminosulfonylamino comme promedicaments a base d'oestriol et d'oestetrol Ceased WO2005113576A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP05747926A EP1747231A1 (fr) 2004-05-21 2005-05-10 Phenylester substitue par aminosulfonyle ou aminosulfonylamino comme promedicaments a base d'oestriol et d'oestetrol
JP2007517048A JP2007538027A (ja) 2004-05-21 2005-05-10 エストリオール及びエステトロールプロドラッグ類

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004025985.2 2004-05-21
DE102004025985A DE102004025985A1 (de) 2004-05-21 2004-05-21 Estriol- und Estetrol-Prodrugs

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Publication Number Publication Date
WO2005113576A1 true WO2005113576A1 (fr) 2005-12-01

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PCT/EP2005/005258 Ceased WO2005113576A1 (fr) 2004-05-21 2005-05-10 Phenylester substitue par aminosulfonyle ou aminosulfonylamino comme promedicaments a base d'oestriol et d'oestetrol

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EP (1) EP1747231A1 (fr)
JP (1) JP2007538027A (fr)
AR (1) AR049108A1 (fr)
DE (1) DE102004025985A1 (fr)
GT (1) GT200500120A (fr)
PA (1) PA8633801A1 (fr)
PE (1) PE20060314A1 (fr)
SV (1) SV2006002122A (fr)
TW (1) TW200612962A (fr)
UY (1) UY28910A1 (fr)
WO (1) WO2005113576A1 (fr)

Cited By (6)

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WO2007062874A3 (fr) * 2005-11-30 2007-07-12 Schering Ag Promedicaments de sulfonate de sulfamoyle
WO2007062877A3 (fr) * 2005-11-29 2007-11-08 Bayer Schering Pharma Ag PROMEDICAMENTS DE SUBSTANCES ERβ-SELECTIVES, PROCEDES DE REALISATION ASSOCIES ET COMPOSITIONS PHARMACEUTIQUES CONTENANT CES COMPOSES
CN100396693C (zh) * 2006-11-08 2008-06-25 浙江大学 1,4-孕二烯-16β-甲基-17α,21-二羟基物的制备方法
US7507725B2 (en) 2000-05-31 2009-03-24 Schering Ag Compounds with sulphonamide group and pharmaceutical compositions containing these compounds
US7534780B2 (en) 2004-05-21 2009-05-19 Bayer Schering Pharma Aktiengesellschaft Estradiol prodrugs
CN102079771A (zh) * 2010-12-10 2011-06-01 郑州大学 具有抗肿瘤活性的雌甾氨基酸酯化合物及其合成方法

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DE102004025966A1 (de) * 2004-05-21 2005-12-15 Schering Ag Estradiol-Prodrugs

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US7507725B2 (en) 2000-05-31 2009-03-24 Schering Ag Compounds with sulphonamide group and pharmaceutical compositions containing these compounds
US7534780B2 (en) 2004-05-21 2009-05-19 Bayer Schering Pharma Aktiengesellschaft Estradiol prodrugs
WO2007062877A3 (fr) * 2005-11-29 2007-11-08 Bayer Schering Pharma Ag PROMEDICAMENTS DE SUBSTANCES ERβ-SELECTIVES, PROCEDES DE REALISATION ASSOCIES ET COMPOSITIONS PHARMACEUTIQUES CONTENANT CES COMPOSES
WO2007062874A3 (fr) * 2005-11-30 2007-07-12 Schering Ag Promedicaments de sulfonate de sulfamoyle
CN100396693C (zh) * 2006-11-08 2008-06-25 浙江大学 1,4-孕二烯-16β-甲基-17α,21-二羟基物的制备方法
CN102079771A (zh) * 2010-12-10 2011-06-01 郑州大学 具有抗肿瘤活性的雌甾氨基酸酯化合物及其合成方法

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DE102004025985A1 (de) 2005-12-15
JP2007538027A (ja) 2007-12-27
EP1747231A1 (fr) 2007-01-31
PE20060314A1 (es) 2006-05-25
PA8633801A1 (es) 2006-03-24
AR049108A1 (es) 2006-06-28
UY28910A1 (es) 2005-12-30
GT200500120A (es) 2006-01-24

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