WO2001018028A1 - Novel c13-substituted estra-1,3,5(10)-triene-3-yl-sulfamates, a method for producing the same and pharmaceutical compositions containing these compounds for inhibiting oestrone sulfatase - Google Patents

Novel c13-substituted estra-1,3,5(10)-triene-3-yl-sulfamates, a method for producing the same and pharmaceutical compositions containing these compounds for inhibiting oestrone sulfatase Download PDF

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WO2001018028A1
WO2001018028A1 PCT/EP2000/008374 EP0008374W WO0118028A1 WO 2001018028 A1 WO2001018028 A1 WO 2001018028A1 EP 0008374 W EP0008374 W EP 0008374W WO 0118028 A1 WO0118028 A1 WO 0118028A1
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sulfamate
estra
homo
trien
acetyl
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PCT/EP2000/008374
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German (de)
French (fr)
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WO2001018028A8 (en
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Sigfrid Schwarz
Dirk Kosemund
Gerd Müller
Margit Richter
Olaf Peters
Ina Scherlitz-Hofmann
Thomas Michel
Walter Elger
Gudrun Reddersen
Birgitt Schneider
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Jenapharm Gmbh & Co. Kg
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Priority to EP00967631A priority Critical patent/EP1212346A1/en
Priority to AU77739/00A priority patent/AU7773900A/en
Priority to JP2001522251A priority patent/JP2003508542A/en
Publication of WO2001018028A1 publication Critical patent/WO2001018028A1/en
Publication of WO2001018028A8 publication Critical patent/WO2001018028A8/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0072Normal 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/24Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32Antioestrogens

Definitions

  • the invention relates to new Estra-1, 3,5 (10) -trien-3-yl sulfamates which, in the C 13 position, contain a C 2 -C 5 alkyl, C 2 -C alkenyl or C 2 - C 5 alkynyl and have an acyl, oxycarbonyl, aminocarbonyl, sulfonyl or aminosulfonyl radical on the nitrogen atom of the sulfamate group.
  • the invention also relates to processes for the preparation of the compounds according to the invention and pharmaceutical compositions which contain these compounds.
  • the compounds according to the invention have proven to be steroid sulfatase inhibitors which do not have an estrogenic effect.
  • estrogens are primarily synthesized and secreted by the ovaries. Accordingly, in sexually mature women, the blood levels of estradiol, estrone and estrone sulfate fluctuate over the course of the cycle. In human pregnancy, the placenta secretes much higher amounts of estrogen than the ovary. In addition to these estrogen sources, peripheral estrogen sources play a role in the human organism, which are of primary importance when ovarian estrogen secretion has ceased or has not yet been established. These estrogen sources have also been shown to be of great physiological importance for the male sex.
  • BEST ⁇ TIGUMGSKOPIE found that factor 50-300 times higher estrogen levels were generated in breast cancer via sulfatase activity (cleavage of estrone sulfate) than via aromatase (Pasqualini JR et al., Estrone sulfatase versus estrone sulfotransferase in human breast cancer: potential clinical applications. J. Steroid Biochem. And Mol. Biol. 69 (1999) 287-292). Similar findings were also made by other groups. In breast tissue, 10-fold more estrone is generated from androstenedione via sulfatase than from aromatase.
  • sulfatase inhibitors can very effectively inhibit the growth of estrogen-dependent tumors, since they greatly reduce the estrogen concentration in the tumor tissue itself.
  • sulfatase inhibitors are therefore increasingly being sought which are not themselves estrogenic and, as a result of the hydrolysis, do not give rise to any estrogenic products.
  • 2-methoxy-estrone-3-O-sulfamate is a potent sulfatase inhibitor which has no estrogenic effect on uterine growth in ovariectomized rats.
  • Estrone-3-O-sulfamates are also described as sulfatase inhibitors in WO 93/05064.
  • the Estro ⁇ -3-O-sulfamate unsubstituted by nitrogen is a strong sulfatase inhibitor (cf. Horwarth et al. In J. Med. Chem. 1994, 37, pp. 219-221, in particular Fig. 3 on page 220).
  • this substance also shows strong estrogenic effects as described by Elger W. et al. in J. Steroid Biochem. Mol. Biol. 55 (1995), pp. 395-403.
  • Further estrone-3-O-sulfamates are disclosed as sulfatase inhibitors in WO 99/33858. These compounds have essentially no estrogenic activity.
  • Sulfamoyloxy compounds with more than one sulfamate group in the molecule in particular those which are sulfamoylated at the positions characteristic of the estrogenic action, including substituents or side chains (e.g. in the 7- and / or 11-position), which can be located on the periphery of the steroid structure, a significant increase in Have sulfatase activity with reduced estrogenic activity.
  • 3,17-disulfamoyloxydef ⁇ vate show good sulfatase activity.
  • monosulfamates also have good sulfatase inhibition with low estrogenicity, with the exception of the ring A sulfamates.
  • Ring A sulfamates are known from WO 97/14712 - as mentioned above - as compounds with a pronounced strong estrogenic action.
  • the object of the present invention was to provide further steroid sulfatase inhibitors which themselves have no estrogenic action and which, as a result of the hydrolysis, do not give any estrogenic products.
  • R 2 is hydrogen, d-Cio-alkyl, -CC 10 alkoxyalkyl, C 3 -C 0 cycloalkyl, C 2 -C 10 -
  • R 3 represents H or R, R 4 -CC 7 alkyl, d-dy-haloalkyl, C 2 -C 17 alkenyl, C 2 -C 7 alkynyl, C 3 -C 10 -
  • R 5 , R 6 independently of one another are hydrogen, dC 5 -alkyl, dC 5 -haloalkyl, aryl, aryl-dC 3 -alkyl, -C-C 3 -alkylaryl or together with the nitrogen atom to which they are bound, a polymethyleneimino radical Form 2-6 carbon atoms or a morpholino radical
  • R 7 , R 9 independently of one another are H, OH, halogen, dC 5 alkoxy or dC 5 - haloalkoxy
  • R 8 is H, OH, d-Cs-alkyl, Ci-d- haloalkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, or
  • Is halogen, Rio, R11 are hydrogen or R 10 and Rn together represent a CH 2 group
  • R ⁇ 2 , R ⁇ 3 , ⁇ 4 independently of one another are H, OH, CC 5 alkoxy or C 1 -C 5 haloalkoxy, or R 12 is halogen, or
  • physiologically compatible salts are alkali or alkaline earth salts, in particular sodium, potassium or ammonium salts.
  • Usual physiologically compatible inorganic or organic acids with which free hydroxyl groups of the compounds of the general formula I can be esterified examples are phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid.
  • alkyl means a branched or unbranched hydrocarbon chain.
  • Haloalkyl correspondingly means a mono- or polysubstituted, branched or unbranched hydrocarbon chain.
  • Alkenyl means a branched or unbranched hydrocarbon chain with at least one double bond.
  • Alkynyl means a branched or unbranched hydrocarbon chain with at least one triple bond.
  • Alkoxy means a branched or unbranched carbon chain which is interrupted by one or more oxygen atoms.
  • the alkoxy radical can be substituted one or more times with halogen.
  • aryl stands for a phenyl radical, which can be optionally substituted, or for a heteroaryl radical, for example for pyridine, picoline, lutidine, collidine, quinoline, acridine, pyridazine, pyrimidine, pyrazine, triazine, pterins, pyrrole, indole, pyrazole , Imidazole, 1, 2,3-thazole, 1, 2,4-triazole, tetrazole, oxazole, thiazole, thiodiazole.
  • R 2 is hydrogen.
  • R 1 very particularly preferably denotes the acyl radical -COR 3 .
  • R15 stands for ethyl or propyl.
  • Very particularly preferred compounds of the invention are the following:
  • the strong sulfatase-inhibiting activity of the compounds 0 according to the invention manifests itself in a reduced cleavage of oestrone sulfate in organs and tissues of ovariectomized rats. Characteristically, the rate of toluene extractable metabolites of oestrone sulfate in the blood is also greatly reduced.
  • the activity profile of the compounds according to the invention therefore allows them to be used for the production of medicaments for the treatment of estrogen-dependent diseases, namely 5 for all therapies in which the sulfatase activity is to be inhibited and an estrogenic side reaction is undesirable.
  • An example is the treatment of estrogen-dependent tumor diseases.
  • the present invention therefore also relates to pharmaceutical compositions which contain at least one compound of the general formula I, optionally together with pharmaceutically acceptable auxiliaries and / or carriers.
  • These pharmaceutical compositions and medicaments can be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular application.
  • they contain at least one compound of the general formula I.
  • the medicaments of the invention are known with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage in a known manner Manufactured way.
  • the preferred preparations are in a dosage form which is suitable for oral administration. Such forms of administration are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or even depot forms.
  • parenteral preparations such as injection solutions are also suitable.
  • Suppositories and agents for vaginal use may also be mentioned as preparations.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, 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 one Depot effects such as carboxylpolymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained.
  • auxiliaries 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 one Depot effects such as carboxyl
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Solutions or suspensions with the compounds of the general formula I according to the invention can additionally taste-improving agents such as saccharin, Cyclamate or sugar and z.
  • B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.
  • Capsules containing the compounds of general formula I can be prepared, for example, by mixing the compound (s) of general formula I with an inert carrier such as milk sugar or sorbitol and encapsulating them in gelatin capsules.
  • an inert carrier such as milk sugar or sorbitol
  • Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.
  • Suitable dosages for the compounds according to the invention are from 0.001 to 10 mg per day, depending on the body weight, age and constitution of the patient, it being possible for the necessary daily dose to be applied by single or multiple administration.
  • Another object of the invention is the process for the preparation of the compounds of general formula I according to the invention
  • Example 4 363 mg of the sulfamate obtained in Example 1 a were dissolved in a mixture of 5 ml of pyndine and 5 ml of dichloromethane. With stirring, 3.63 g of stearic acid chloride were added to this solution. Stirring was continued for 22 hours at room temperature, then 10 ml of water were added with ice cooling and stirred for a further 24 hours at room temperature. The organic phase was separated off and washed successively with 2N aqueous hydrochloric acid, water, 2N aqueous potassium hydroxide solution and water. After drying over anhydrous sodium sulfate, the extract was concentrated in a vacuum rotary evaporator. The title compound was obtained as a light yellow foam Example 4
  • Ovariectomized adult rats are treated orally with dosages of the compound according to the invention between 1-300 ⁇ g. 24 hours after application, leukocyte and organ homogenates of these animals are examined for their ability to split oestrone sulfate.
  • the substances according to the invention inhibit the hydrolysis of oestrone sulfate in the dose range between 50-90%. If animals are treated with oestrone sulfate 24 hours after treatment with a substance according to the invention, its hydrolysis products can be extracted from the plasma after one hour. Substances according to the invention reduce the extracted fraction by approximately 75%.

Abstract

The invention relates to novel C13-substituted estra-1,3,5(10)-triene-3-yl-sulfamates of the general formula (I), in which R1 represents the acyl radical, oxycarbonyl radical, aminocarbonyl radical, sulfonyl radical or aminosulfonyl radical and R15 stands for C2-C5 alkyl, C2-C5 alkenyl or C2-C5-alkinyl. The invention also relates to a method for producing these compounds and to pharmaceutical compositions which contain said compounds. The inventive compounds of the general formula (I) inhibit the activity of steroid sulfatases (EC 3.1.6.2) and do not exhibit any oestrogenic action.

Description

NEUE C-13 -SUBSTITUIERTE ESTRA- 1 , 3 , 5 ( 10 ) -TRIEN-3 -YL-SULFAMATE , VERFAHREN ZU DEREN HERSTELLUNG UND DIESE VERBINDUNGEN ENTHALTENDE PHARMAZEUTISCHE ZUSAMMENSETZUNGEN NEW C-13 SUBSTITUTED ESTRA- 1, 3, 5 (10) -TRIEN-3 -YL SULFAMATES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS
Die Erfindung betrifft neue Estra-1 ,3,5(10)-trien-3-yl-sulfamate, die in C13-Position einen C2-C5-AIkyl-, C2-C -Alkenyl- oder C2-C5-Alkinylrest aufweisen, und am Stickstoffatom der Sulfamatgruppierung einen Acyl-, Oxycarbonyl-, Aminocarbonyl-, Sulfonyl- oder Aminosulfonylrest besitzen. Gegenstand der Erfindung sind auch Verfahren zur Herstellung der erfindungsgemäßen Verbindungen und pharmazeutische Zusammensetzungen, die diese Verbindungen enthalten. Die erfindungsgemäßen Verbindungen haben sich als Steroidsulfatasehemmer erwiesen, die keine cstrogene Wirkung aufweisen.The invention relates to new Estra-1, 3,5 (10) -trien-3-yl sulfamates which, in the C 13 position, contain a C 2 -C 5 alkyl, C 2 -C alkenyl or C 2 - C 5 alkynyl and have an acyl, oxycarbonyl, aminocarbonyl, sulfonyl or aminosulfonyl radical on the nitrogen atom of the sulfamate group. The invention also relates to processes for the preparation of the compounds according to the invention and pharmaceutical compositions which contain these compounds. The compounds according to the invention have proven to be steroid sulfatase inhibitors which do not have an estrogenic effect.
Östrogeπe werden im menschlichen Organismus vorwiegend von den Ovarien synthetisiert und sezerniert. Entsprechend schwanken bei geschlechtsreifen Frauen die Blutspiegel an Östradiol, Östron und Östronsulfat im Verlauf des Zyklus. In der menschlichen Gravidität sezerniert die Plazenta noch wesentlich höhere Östro- genmengen als das Ovar. Neben diesen Östrogenquellen spielen im menschlichen Organismus periphere Östrogenquellen eine Rolle, die in erster Linie dann Bedeutung erlangen, wenn die ovarielle Östrogensekretion erloschen oder noch nicht etabliert ist. Diese Östrogenquellen sind erwiesenermaßen auch beim männlichen Geschlecht von großer physiologischer Bedeutung.In the human organism, estrogens are primarily synthesized and secreted by the ovaries. Accordingly, in sexually mature women, the blood levels of estradiol, estrone and estrone sulfate fluctuate over the course of the cycle. In human pregnancy, the placenta secretes much higher amounts of estrogen than the ovary. In addition to these estrogen sources, peripheral estrogen sources play a role in the human organism, which are of primary importance when ovarian estrogen secretion has ceased or has not yet been established. These estrogen sources have also been shown to be of great physiological importance for the male sex.
Verschiedene Gewebe besitzen eine enzymatische Ausstattung (Purohit A et al. Regulation of aromatase and sulphatase in breast tumor cells. 150 (1996) S65), die im Gewebe die Umwandlung adrenaler Steroide in Östron und Östradiol bewirkt. Deren Wirkung erfolgt autokrin bzw. parakrin am Ort der Biosynthese, ohne daß im Blut nennenswerte Östrogenspiegel auftreten müssen. Ein weiterer Mechanismus, über den biologisch relevante Östrogenmengen im Gewebe entstehen, ist die hydrolytische Spaltung von Ostrogenkonjugaten, speziell von Östronsulfat. Von besonderer pathologischer Bedeutung ist in diesem Zusammenhang die Generierung von Östron im Endometrium und in Brustgewebe und den Tumoren, die von diesem Gewebe ausgehen, da hierdurch das Tumorwachstum stimuliert werden kann. Es wurdeDifferent tissues have an enzymatic equipment (Purohit A et al. Regulation of aromatase and sulphatase in breast tumor cells. 150 (1996) S65), which causes the conversion of adrenal steroids into estrone and estradiol. Their effect is autocrine or paracrine at the site of the biosynthesis, without significant estrogen levels having to occur in the blood. Another mechanism by which biologically relevant amounts of estrogen are created in the tissue is the hydrolytic cleavage of estrogen conjugates, especially of estrone sulfate. In this context, the generation of estrone in the endometrium and in breast tissue and the tumors that originate from this tissue is of particular pathological importance, since this can stimulate tumor growth. It was
BESTÄTIGUMGSKOPIE gefunden, daß in Mammakarzinom über Sulfataseaktivität (Spaltung von Östronsulfat) Faktor 50-300-fach höhere Östrogenmengen generiert wurden als über die Aromatase (Pasqualini JR et al., Estrone sulfatase versus estrone sulfotransferase in human breast cancer: potential clinical applications. J. Steroid Biochem. and Mol. Biol. 69 (1999) 287- 292). Entsprechende Befunde wurden auch von anderen Grijppen erhoben. Im Brustgewebe wird 10-fach mehr Östron aus Androstendion via Sulfatase generiert als über die Aromatase.BESTÄTIGUMGSKOPIE found that factor 50-300 times higher estrogen levels were generated in breast cancer via sulfatase activity (cleavage of estrone sulfate) than via aromatase (Pasqualini JR et al., Estrone sulfatase versus estrone sulfotransferase in human breast cancer: potential clinical applications. J. Steroid Biochem. And Mol. Biol. 69 (1999) 287-292). Similar findings were also made by other groups. In breast tissue, 10-fold more estrone is generated from androstenedione via sulfatase than from aromatase.
Es kann daher als erwiesen gelten, daß Sulfatasehemmer das Wachstum östrogenabhängiger Tumore sehr wirksam hemmen können, da sie die Östrogenkonzentration im Tumorgewebe selbst stark reduzieren.It can therefore be proven that sulfatase inhibitors can very effectively inhibit the growth of estrogen-dependent tumors, since they greatly reduce the estrogen concentration in the tumor tissue itself.
Unter therapeutischen Gesichtspunkten wird deshalb verstärkt nach Sulfatasehemmern gesucht, die selbst nicht östrogen sind und im Ergebnis der Hydrolyse auch keine östro- genen Produkte ergeben. So beschreiben beispielsweise Purohit A. et al. in J. Steroid Biochem. Molec. Biol. Vol. 64, No. 5-6, Seiten 269-275 (1998), daß 2-Methoxy-Estron-3- O-sulfamat ein potenter Sulfatasehemmer ist, der keine östrogene Wirkung auf das uterine Wachstum in ovariektomierten Ratten zeigt. Estron-3-O-sulfamate werden als Sulfatasehemmer auch in WO 93/05064 beschrieben. Das am Stickstoff unsubstituierte Estroπ-3-O-sulfamat ist ein starker Sulfatasehemmer (vgl. Horwarth et al. in J. Med. Chem. 1994, 37, S. 219-221 , insbesondere Fig. 3 auf Seite 220). Allerdings zeigt diese Substanz auch starke östrogene Wirkung wie von Elger W. et al. in J. Steroid Biochem. Mol. Biol. 55 (1995), S. 395-403 beschrieben wurde. Weitere Estron-3-O-sulfamate werden als Sulfatasehemmer in WO 99/33858 offenbart. Diese Verbindungen besitzen im wesentlichen keine östrogene Aktivität.From a therapeutic point of view, sulfatase inhibitors are therefore increasingly being sought which are not themselves estrogenic and, as a result of the hydrolysis, do not give rise to any estrogenic products. For example, Purohit A. et al. in J. Steroid Biochem. Molec. Biol. Vol. 64, No. 5-6, pages 269-275 (1998) that 2-methoxy-estrone-3-O-sulfamate is a potent sulfatase inhibitor which has no estrogenic effect on uterine growth in ovariectomized rats. Estrone-3-O-sulfamates are also described as sulfatase inhibitors in WO 93/05064. The Estroπ-3-O-sulfamate unsubstituted by nitrogen is a strong sulfatase inhibitor (cf. Horwarth et al. In J. Med. Chem. 1994, 37, pp. 219-221, in particular Fig. 3 on page 220). However, this substance also shows strong estrogenic effects as described by Elger W. et al. in J. Steroid Biochem. Mol. Biol. 55 (1995), pp. 395-403. Further estrone-3-O-sulfamates are disclosed as sulfatase inhibitors in WO 99/33858. These compounds have essentially no estrogenic activity.
In Bioorg. & Med. Chem. Lett. 7, 24, 3075-3080 (1997) wird N-Acetyl-estron-3-O- sulfamat als Sulfatasehemmer beschrieben. Diese Verbindung besitzt jedoch eine starke östrogene Wirksamkeit, die Ethinylestradiol hinsichtlich ihrer systemischen oralen Wirksamkeit übertrifft, (vgl. WO 97/14712).In Bioorg. & Med. Chem. Lett. 7, 24, 3075-3080 (1997) describes N-acetyl-estrone-3-O-sulfamate as a sulfatase inhibitor. However, this compound has a strong estrogenic activity which exceeds ethinylestradiol in terms of its systemic oral activity (cf. WO 97/14712).
Auch in DE 197 12 488 A1 werden Steroidsulfamate beschrieben, die dieDE 197 12 488 A1 also describes steroid sulfamates, which the
Steroidsulfatase hemmen. Diese Verbindungen zeigen eine geringe oder keine östrogene Wirkung. Es wird geschildert, daß bestimmte steroidaleInhibit steroid sulfatase. These compounds show little or no estrogenic activity. It is described that certain steroidal
Sulfamoyloxyverbindungen mit mehr als einer Sulfamatgruppierung im Molekül, insbesondere solche, die an den für die estrogene Wirkung charakteristischen Positionen, einschließlich Substituenten oder Seitenketten (z. B. in 7- und/oder 11- Stellung), die sich an der Peripherie des Steroidgerüstes befinden können, sulfamoyliert sind, eine deutliche Erhöhung der Sulfataseaktivität bei verminderter estrogener Wirkung aufweisen. So zeigen insbesondere 3,17-Disulfamoyloxydefϊvate eine gute Sulfataseaktivität. Gemäß DE 197 12 488 A1 weisen auch Monosulfamate eine gute Sulfatasehemmung bei geringer Östrogenität auf, ausgenommen die Ring A-Sulfamate. Ring A-Sulfamate sind aus WO 97/14712 - wie oben erwähnt - als Verbindungen mit ausgeprägt starker östrogener Wirkung bekannt.Sulfamoyloxy compounds with more than one sulfamate group in the molecule, in particular those which are sulfamoylated at the positions characteristic of the estrogenic action, including substituents or side chains (e.g. in the 7- and / or 11-position), which can be located on the periphery of the steroid structure, a significant increase in Have sulfatase activity with reduced estrogenic activity. For example, 3,17-disulfamoyloxydefϊvate show good sulfatase activity. According to DE 197 12 488 A1, monosulfamates also have good sulfatase inhibition with low estrogenicity, with the exception of the ring A sulfamates. Ring A sulfamates are known from WO 97/14712 - as mentioned above - as compounds with a pronounced strong estrogenic action.
Aufgabe der vorliegenden Erfindung war es, weitere Steroidsulfatasehemmer bereitzustellen, die selbst keine östrogene Wirkung zeigen und auch im Ergebnis der Hydrolyse keine östrogenen Produkte ergeben.The object of the present invention was to provide further steroid sulfatase inhibitors which themselves have no estrogenic action and which, as a result of the hydrolysis, do not give any estrogenic products.
Überraschenderweise wurde nun gefunden, daß neue Cι3-substituierte Estra-1 ,3,5(10)- trien-3-yl-sulfamate der allgemeinen Formel I, deren physiologisch verträgliche Salze oder EsterSurprisingly, it has now been found that new C 3 -substituted Estra-1, 3.5 (10) - trien-3-yl sulfamates of the general formula I, their physiologically tolerable salts or esters
Figure imgf000005_0001
Figure imgf000005_0001
(I), in der Ri COR3, COOR4, CONR5R6, S02R4, S02NR5R6 bedeutet,(I), in which Ri denotes COR 3 , COOR 4 , CONR 5 R 6 , S0 2 R 4 , S0 2 NR 5 R 6 ,
R2 Wasserstoff, d-Cio-Alkyl, Cι-C10-Alkoxyalkyl, C3-Cι0-Cycloalkyl, C2-C10-R 2 is hydrogen, d-Cio-alkyl, -CC 10 alkoxyalkyl, C 3 -C 0 cycloalkyl, C 2 -C 10 -
Alkenyl, C2-Cι0-Alkinyl, Aryl, Aryl-CrC3-alkyl oder Cι-C3-Alkylaryl, COR3;Alkenyl, C 2 -C 0 -alkynyl, aryl, aryl-CrC 3 -alkyl or Cι-C 3 -alkylaryl, COR 3 ;
COOR4; CONR5R6; S02R ; S02NR5R6 bedeuten,COOR 4 ; CONR 5 R 6 ; S0 2 R; S0 2 NR 5 R 6 mean
R3 H oder R darstellt, R4 Cι-Cι7-Alkyl, d-dy-Halogenalkyl, C2-C17-Alkenyl, C2-Cι7-Alkinyl, C3-C10-R 3 represents H or R, R 4 -CC 7 alkyl, d-dy-haloalkyl, C 2 -C 17 alkenyl, C 2 -C 7 alkynyl, C 3 -C 10 -
Cycloalkyl, Aryl, Aryl-d-C3-alkyl, d-C3-Alkylaryl bedeutet, R5, R6 unabhängig voneinander Wasserstoff, d-C5-Alkyl, d-C5-Halogenalkyl, Aryl, Aryl-d-C3-alkyl, Cι-C3-Alkylaryl bedeuten oder zusammen mit dem Stickstoffatom, an dem sie gebunden sind, einen Polymethyleniminorest mit 2-6 C-Atomen oder einen Morpholinorest bilden, R7, R9 unabhängig voneinander H, OH, Halogen, d-C5-Alkoxy oder d-C5- Halogenalkoxy bedeuten R8 H, OH, d-Cs-Alkyl, Ci-d-Halogenalkyl, C2-C5-Alkenyl, C2-C5-Alkinyl oderMeans cycloalkyl, aryl, aryl-dC 3 -alkyl, dC 3 -alkylaryl, R 5 , R 6 independently of one another are hydrogen, dC 5 -alkyl, dC 5 -haloalkyl, aryl, aryl-dC 3 -alkyl, -C-C 3 -alkylaryl or together with the nitrogen atom to which they are bound, a polymethyleneimino radical Form 2-6 carbon atoms or a morpholino radical, R 7 , R 9 independently of one another are H, OH, halogen, dC 5 alkoxy or dC 5 - haloalkoxy R 8 is H, OH, d-Cs-alkyl, Ci-d- haloalkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, or
Halogen bedeutet, Rio, R11 Wasserstoff bedeuten oder R10 und Rn zusammen eine CH2-Gruppe darstellen,Is halogen, Rio, R11 are hydrogen or R 10 and Rn together represent a CH 2 group,
2, Rι3, ι4 unabhängig voneinander H, OH, C C5-Alkoxy oder C1-C5- Halogenalkoxy bedeuten, oder R12 Halogen bedeutet, oder2 , Rι 3 , ι 4 independently of one another are H, OH, CC 5 alkoxy or C 1 -C 5 haloalkoxy, or R 12 is halogen, or
R13 und Rι zusammen Sauerstoff darstellen oder zusammen für eine =CXY-Gruppe stehen, wobei X und Y unabhängig voneinander Wasserstoff, Halogen oder eine Ci-Cs-Alkylgruppe bedeuten, oder R13, Rι4 unabhängig voneinander d-C5-Alkyl, C -C5-Alkenyl oder C2-C5-Alkinyl bedeuten, R15 C2-C5-Alkyl, C2-C5-Alkenyl oder C2-C5-Alkinyl bedeutet,R 1 3 and R 5 together represent oxygen or together represent a = CXY group, where X and Y independently of one another denote hydrogen, halogen or a Ci-Cs-alkyl group, or R 13, R 4 independently of one another dC 5 alkyl, C - Are C 5 alkenyl or C 2 -C 5 alkynyl, R 1 5 is C 2 -C 5 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl,
Rs, Rs, R10, Rι2, R13, R15 unabhängig voneinander α- oder ß-ständig sind und in den Ringen B und C bis zu 2 zusätzliche Doppelbindungen vorhanden sein können,Rs, Rs, R10, Rι 2 , R13, R 1 5 independently of one another are α- or ß-permanent and up to 2 additional double bonds can be present in the rings B and C,
die Aktivität der Steroidsulfatase (EC 3.1.6.2) äußerst wirksam hemmen und keine östrogene Wirkung aufweisen.inhibit the activity of steroid sulfatase (EC 3.1.6.2) extremely effectively and have no estrogenic effect.
Im Sinne der Erfindung sind physiologisch verträgliche Salze Alkali- oder Erdalkaiisalze, insbesondere Natrium-, Kali- oder Ammoniumsalze.For the purposes of the invention, physiologically compatible salts are alkali or alkaline earth salts, in particular sodium, potassium or ammonium salts.
Übliche physiologisch verträgliche anorganische oder organische Säuren, mit denen freie Hydroxygruppen der Verbindungen der allgemeinen Formel I verestert sein können, sind beispielsweise Phosphorsäure, Schwefelsäure, Oxalsäure, Maleinsäure, Fumarsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Salicylsäure, Adipinsäure und Benzoesäure.Usual physiologically compatible inorganic or organic acids with which free hydroxyl groups of the compounds of the general formula I can be esterified, Examples are phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid.
Alkyl bedeutet im Sinne der Erfindung eine verzweigte öder unverzweigte Kohlenwasserstoffkette. Halogenalkyl bedeutet entsprechend eine einfach oder mehrfach mit Halogen substituierte, verzweigte oder unverzweigte Kohlenwasserstoffkette. Alkenyl bedeutet eine verzweigte oder unverzweigte Kohlenwasserstoffkette mit mindestens einer Doppelbindung. Alkinyl bedeutet eine verzweigte oder unverzweigte Kohlenwasserstoffkette mit mindestens einer Dreifachbindung.For the purposes of the invention, alkyl means a branched or unbranched hydrocarbon chain. Haloalkyl correspondingly means a mono- or polysubstituted, branched or unbranched hydrocarbon chain. Alkenyl means a branched or unbranched hydrocarbon chain with at least one double bond. Alkynyl means a branched or unbranched hydrocarbon chain with at least one triple bond.
Alkoxy bedeutet eine verzweigte oder unverzweigte Kohlenstoffkette, die durch ein oder mehrere Sauerstoffatome unterbrochen ist. Im Fall von Halogenalkoxy kann der Alkoxyrest ein- oder mehrfach mit Halogen substituiert sein.Alkoxy means a branched or unbranched carbon chain which is interrupted by one or more oxygen atoms. In the case of haloalkoxy, the alkoxy radical can be substituted one or more times with halogen.
Aryl steht im Sinne der Erfindung für einen Phenylrest, der gegebenenfalls substituiert sein kann, oder für einen Heteroarylrest, beispielsweise für Pyridin, Picolin, Lutidin, Collidin, Chinolin, Acridin, Pyridazin, Pyrimidin, Pyrazin, Triazin, Pterine, Pyrrol, Indol, Pyrazol, Imidazol, 1 ,2,3-Thazol, 1 ,2,4— Triazol, Tetrazol, Oxazol, Thiazol, Thiodiazol.For the purposes of the invention, aryl stands for a phenyl radical, which can be optionally substituted, or for a heteroaryl radical, for example for pyridine, picoline, lutidine, collidine, quinoline, acridine, pyridazine, pyrimidine, pyrazine, triazine, pterins, pyrrole, indole, pyrazole , Imidazole, 1, 2,3-thazole, 1, 2,4-triazole, tetrazole, oxazole, thiazole, thiodiazole.
In einer bevorzugten Ausführungsform der Erfindung bedeutet R2 Wasserstoff. Ganz besonders bevorzugt bedeutet R1 den Acylrest -COR3. R15 steht in einer bevorzugten Ausführungsform für Ethyl oder Propyl.In a preferred embodiment of the invention, R 2 is hydrogen. R 1 very particularly preferably denotes the acyl radical -COR 3 . In a preferred embodiment, R15 stands for ethyl or propyl.
Ganz besonders bevorzugte Verbindungen der Erfindung sind die folgenden:Very particularly preferred compounds of the invention are the following:
1 ) 17-Oxo-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-formyl)sulfamat1) 17-Oxo-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-formyl) sulfamate
2) 17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat2) 17-Oxo-1 8a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
3) 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat3) 17β-Hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
4) 17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-propionyl)sulfamat 5) 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-propionyl)sulfamat4) 17-oxo-1 8a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-propionyl) sulfamate 5) 17β-hydroxy-18a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-propionyl) sulfamate
6) 17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-butyryl)sulfamat6) 17-Oxo-1 8a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-butyryl) sulfamate
7) 17α-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-butyryl)sulfamat7) 17α-Hydroxy-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-butyryl) sulfamate
8) 17-Oxo-l 8a-homo-estra-1 , 3,5(10)-trien-3-yl-(N-valeryl)sulfamat ) 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-valeryl)sulfamat 0 17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-hexanoyl)sulfamat 1 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-hexanoyl)sulfamat 2 17-Oxo-l 8a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-decanoyl)sulfamat 3 17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-stearoyl)sulfamat 4 17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-cyclopentancarbonyl)sulfamat 5 17-Oxo-l 4α, 15α-methylen-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 6 17ß-Hydroxy-2-methoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-[N-(2,2- dimethyl)propionyl]sulfamat 7 16 -Fluor-17ß-hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 8 17ß-Hydroxy-7α-methyl-18a-homo- estra-1 , 3,5(10)-trien-3-yl-(N-acetyl)sulfamat 9 13-Ethyl-17-hydroxy-18, 19-dinor-17 -pregna-1 ,3,5(10)-trien-20-in-3-yl-(N- acetyl)sulfamat 0 17ß-Methoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-formyl)sulfamat 1 17-Oxo-18a-homo-estra-1 , 3, 5(10),8-tetraen-3-yl-(N-acetyl)sulfamat 2 17ß-Hydroxy-13-propyl-gona-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 3 17-Oxo-l 3-propyl-gona-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 4 16α-Fluor-17-oxo-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 5 16ß-Fluor-17-oxo-18a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-acetyl)sulfamat 6 16 -Fluor-17ß-hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat8) 17-Oxo-1 8a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-valeryl) sulfamate ) 17ß-Hydroxy-18a-homo-estra-1, 3.5 (10) -trien-3-yl- (N-valeryl) sulfamate 0 17-oxo-1 8a-homo-estra-1, 3.5 ( 10) -triene-3-yl- (N-hexanoyl) sulfamate 1 17β-hydroxy-18a-homo-estra-1, 3,5 (10) -triene-3-yl- (N-hexanoyl) sulfamate 2 17- Oxo-l 8a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-decanoyl) sulfamate 3 17-Oxo-l 8a-homo-estra-1, 3.5 (10) -trien-3-yl- (N-stearoyl) sulfamate 4 17-oxo-1 8a-homo-estra-1, 3.5 (10) -trien-3-yl- (N-cyclopentane carbonyl) sulfamate 5 17-oxo -l 4α, 15α-methylene-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 6 17ß-hydroxy-2-methoxy-18a-homo-estra- 1,3,5 (10) -trien-3-yl- [N- (2,2-dimethyl) propionyl] sulfamate 7 16 -fluoro-17β-hydroxy-18a-homo-estra-1,3,5 (10 ) -trien-3-yl- (N-acetyl) sulfamate 8 17β-hydroxy-7α-methyl-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 9 13-ethyl-17-hydroxy-18, 19-dinor-17-prregna-1, 3,5 (10) -trien-20-in-3-yl- (N-acetyl) sulfamate 0 17ß-methoxy-18a -homo-estra-1, 3,5 (10) -trien-3-yl- (N-formyl) sulfamate 1 17-oxo-18a-homo-estra-1, 3, 5 (10), 8-tetraen 3-yl (N- acetyl) sulfamate 2 17β-hydroxy-13-propyl-gona-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 3 17-oxo-l 3-propyl-gona-1,3 , 5 (10) -trien-3-yl- (N-acetyl) sulfamate 4 16α-fluoro-17-oxo-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N -acetyl) sulfamate 5 16β-fluoro-17-oxo-18a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-acetyl) sulfamate 6 16 -fluoro-17ß-hydroxy-18a -homo-estra-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
16 -Fluor-17α-hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 8 16ß-Fluor-17ß-hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 9 16ß-Fluor-17 -hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 0 2-Methoxy-17-oxo-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 1 17ß-Hydroxy-2-methoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 2 2,17ß-Dimethoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acety!)sulfamat 3 17ß-tert.Butoxy-2-methoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)suifamat 4 16α-Fluor-2-methoxy-17-oxo-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N- acetyl)sulfamat 5 16α-Fluor-17ß-hydroxy-2-methoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N- acetyl)sulfamat 6 2-Ethoxy-17-oxo-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat16 -Fluoro-17α-hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 8 16ß-fluoro-17ß-hydroxy-18a-homo-estra- 1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 9 16ß-fluoro-17-hydroxy-18a-homo-estra-1,3,5 (10) -trien-3-yl - (N-acetyl) sulfamate 0 2-methoxy-17-oxo-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 1 17ß-hydroxy-2- methoxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 2 2,17ß-dimethoxy-18a-homo-estra-1, 3.5 (10) -trien-3-yl- (N-acety!) sulfamate 3 17ß-tert-butoxy-2-methoxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl ) suifamat 4 16α-fluoro-2-methoxy-17-oxo-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 5 16α-fluoro-17ß-hydroxy -2-methoxy-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 6 2-ethoxy-17-oxo-18a-homo-estra-1,3 , 5 (10) -trien-3-yl- (N-acetyl) sulfamate
2-Ethoxy-17ß-hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 8 18a-Homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat 39) 17-Methylen-18a-homo-estra-1 ,3,5(10)-then-3-yl-(N-acetyl)sulfamat2-ethoxy-17β-hydroxy-18a-homo-estra-1, 3.5 (10) -trien-3-yl- (N-acetyl) sulfamate 8 18a-homo-estra-1, 3.5 (10) -trien-3-yl- (N-acetyl) sulfamate 39) 17-methylene-18a-homo-estra-1,3,5 (10) -then-3-yl- (N-acetyl) sulfamate
40) 17-Difluormethylen-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat40) 17-difluoromethylene-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
41 ) 17-Ethyliden-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat41) 17-Ethylidene-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
42) 17-Oxo-l 8a-homo-13 -estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat42) 17-Oxo-1 8a-homo-13-estra-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
5 43) 17ß-Hydroxy-18a-homo-13α-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat5 43) 17β-Hydroxy-18a-homo-13α-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
44) 17-Oxo-l 8a-homo-13 -estra-1 ,3,5(10),8-tetraen-3-yl-(N-acetyl)sulfamat44) 17-Oxo-l 8a-homo-13-estra-1,3,5 (10), 8-tetraen-3-yl- (N-acetyl) sulfamate
45) 17-Oxo-18a-homo-estra-1 ,3,5(10),6,8-pentaen-3-yl-(N-acetyl)sulfamat45) 17-Oxo-18a-homo-estra-1, 3.5 (10), 6,8-pentaen-3-yl- (N-acetyl) sulfamate
46) 17-Oxo-18a-homo-estra-1 ,3,5(10),7-tetraen-3-yl-(N-acetyl)sulfamat46) 17-Oxo-18a-homo-estra-1, 3.5 (10), 7-tetraen-3-yl- (N-acetyl) sulfamate
47) 17-Oxo-18a-homo-estra-1 ,3,5(10), 8(14)-tetraen-3-yl-(N-acetyi)sulfamat 10 48) 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl(N-trifluoracetyl)sulfamat47) 17-Oxo-18a-homo-estra-1, 3,5 (10), 8 (14) -tetraen-3-yl- (N-acetyi) sulfamate 10 48) 17ß-hydroxy-18a-homo-estra -1,3,5 (10) -trien-3-yl (N-trifluoroacetyl) sulfamate
49) 17-Oxo-l 8a-homo-1 , 3, 5(10)-trien-3-yl-(N-nonafluorvaleroyl)sulfamat49) 17-Oxo-1 8a-homo-1, 3, 5 (10) -trien-3-yl- (N-nonafluorvaleroyl) sulfamate
50) 17-0x0-2 -trifluormethoxy-18a-homo-estra-1 ,3,5(10)-then-3-yl-(N-acetyl)sulfamat50) 17-0x0-2 -trifluoromethoxy-18a-homo-estra-1,3,5 (10) -then-3-yl- (N-acetyl) sulfamate
Es war überraschend, daß der Ersatz der Cι3-Methylgruppe, wie sie für Estra-1 ,3,5(10)- 15 trien-De vate charakteristisch ist, durch eine 13-ständige C2-C5-Alkylgruppe, die gegebenenfalls Doppel- oder Dreifachbindungen enthalten kann, zum vollständigen Verschwinden der östrogenen Wirkung führt, ohne eine sulfatasehemmende Aktivität der Verbindungen zu beeinträchtigen.It was surprising that the replacement of the C 3 methyl group, as is characteristic of Estra-1, 3.5 (10) - 15 trien-De vate, by a 13-position C 2 -C 5 alkyl group, which, if appropriate May contain double or triple bonds, leads to the complete disappearance of the estrogenic effect without impairing a sulfatase-inhibiting activity of the compounds.
Die starke sulfatasehemmende Aktivität der erfindungsgemäßen Verbindungen 0 manifestiert sich in einer reduzierten Spaltung von Oestronsulfat in Organen und Geweben von ovariektomierten Ratten. Charakteristischerweise wird auch die Rate Toluol-extrahierbarer Metabolite von Oestronsulfat im Blut stark gesenkt. Daher erlaubt es das Wirkprofil der erfindungsgemäßen Verbindungen, diese zur Herstellung von Arzneimitteln zur Behandlung östrogenabhängiger Erkrankungen einzusetzen, nämlich 5 für alle Therapien, bei denen die Sulfataseaktivität gehemmt werden soll und eine östrogene Nebenreaktion unerwünscht ist. Als Beispiel sei die Behandlung östrogenabhängiger Tumorerkrankungen genannt.The strong sulfatase-inhibiting activity of the compounds 0 according to the invention manifests itself in a reduced cleavage of oestrone sulfate in organs and tissues of ovariectomized rats. Characteristically, the rate of toluene extractable metabolites of oestrone sulfate in the blood is also greatly reduced. The activity profile of the compounds according to the invention therefore allows them to be used for the production of medicaments for the treatment of estrogen-dependent diseases, namely 5 for all therapies in which the sulfatase activity is to be inhibited and an estrogenic side reaction is undesirable. An example is the treatment of estrogen-dependent tumor diseases.
Gegenstand der vorliegenden Erfindung sind deshalb auch pharmazeutische 0 Zusammensetzungen, die mindestens eine Verbindung der allgemeinen Formel I enthalten, gegebenenfalls zusammen mit pharmazeutisch verträglichen Hilfs- und/oder Trägerstoffen. Diese pharmazeutischen Zusammensetzungen und Arzneimittel können zur oralen, rektalen, vaginalen, subcutanen, percutanen, intravenösen oder intramuskulären Applikation vorgesehen sein. Sie enthalten neben üblichen Träger- und/oder Verdünnungsmitteln mindestens eine Verbindung der allgemeinen Formel I. Die Arzneimittel der Erfindung werden mit den üblichen festen oder flüssigen Trägerstoffen oder Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutisch-technischen Hilfsstoffen entsprechend der gewünschten Applikationsart mit einer geeigneten Dosierung in bekannter Weise hergestellt. Die bevorzugten Zubereitungen bestehen in einer Darreichungsform, die zur oralen Applikation geeignet ist. Solche Darreichungsformeπ sind beispielsweise Tabletten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Lösungen oder Suspensionen oder auch Depotformen.The present invention therefore also relates to pharmaceutical compositions which contain at least one compound of the general formula I, optionally together with pharmaceutically acceptable auxiliaries and / or carriers. These pharmaceutical compositions and medicaments can be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular application. In addition to the usual carriers and / or diluents, they contain at least one compound of the general formula I. The medicaments of the invention are known with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage in a known manner Manufactured way. The preferred preparations are in a dosage form which is suitable for oral administration. Such forms of administration are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or even depot forms.
Selbstverständlich kommen auch parenterale Zubereitungen wie Injektionslösungen in Betracht. Weiterhin seien als Zubereitungen beispielsweise auch Suppositorien und Mittel zur vaginalen Anwendung genannt.Of course, parenteral preparations such as injection solutions are also suitable. Suppositories and agents for vaginal use may also be mentioned as preparations.
Entsprechende Tabletten können beispielsweise durch Mischen des Wirkstoffs mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln wie Dextrose, Zucker, Sorbit, Mannit, Polyvinylpyrrolidon, Sprengmitteln wie Maisstärke oder Alginsäure, Bindemitteln wie Stärke oder Gelantine, Gleitmitteln wie Magnesiumstearat oder Talk und/oder Mitteln zur Erzielung eines Depoteffektes wie Carboxylpolymethylen, Carboxylmethylcellulose, Celluloseacetatphthalat oder Polyvinylacetat, erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, 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 one Depot effects such as carboxylpolymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.
Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Polyvinylpyrrolidon oder Schellack, Gummitarabicum, Talk, Titanoxid oder Zucker, hergestellt werden. Dabei kann auch die Drageehülle aus mehreren Schichten bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. The coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
Lösungen oder Suspensionen mit den erfindungsgemäßen Verbindungen der allgemeinen Formel I können zusätzlich geschmacksverbessernde Mittel wie Saccharin, Cyclamat oder Zucker sowie z. B. Aromastoffe wie Vanillin oder Orangenextrakt enthalten. Sie können außerdem Suspendierhilfsstoffe wie Natriumcar- boxymethylcellulose oder Konservierungsstoffe wie p-Hydroxybenzoate enthalten.Solutions or suspensions with the compounds of the general formula I according to the invention can additionally taste-improving agents such as saccharin, Cyclamate or sugar and z. B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.
Die Verbindungen der allgemeinen Formel I enthaltende Kapseln köhnen beispielsweise hergestellt werden, indem man die Verbindung(en) der allgemeinen Formel I mit einem inerten Träger wie Milchzucker oder Sorbit mischt und in Gelatinekapseln einkapselt.Capsules containing the compounds of general formula I can be prepared, for example, by mixing the compound (s) of general formula I with an inert carrier such as milk sugar or sorbitol and encapsulating them in gelatin capsules.
Geeignete Suppositorien lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln wie Neutralfetten oder Polyethylenglykol bzw. deren Derivaten herstellen.Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.
Geeignete Dosierungen für die erfindungsgemäßen Verbindungen betragen von 0,001 bis 10 mg pro Tag, je nach Körpergewicht, Alter und Konstitution des Patienten, wobei die notwendige Tagesdosis durch Einmal- oder Mehrfachabgabe appliziert werden kann.Suitable dosages for the compounds according to the invention are from 0.001 to 10 mg per day, depending on the body weight, age and constitution of the patient, it being possible for the necessary daily dose to be applied by single or multiple administration.
Ein weiterer Gegenstand der Erfindung ist das Verfahren zur Herstellung der erfindungsgemäßen Verbindungen der allgemeinen Formel IAnother object of the invention is the process for the preparation of the compounds of general formula I according to the invention
(I),(I)
Figure imgf000011_0001
Figure imgf000011_0001
worin die Reste R-, bis R15 die oben angegebene Bedeutung haben, indem man in an sich bekannter Weisewherein the radicals R- to R 15 have the meaning given above, by in a manner known per se
a) geeignete Estra-1 ,3,5(10)-trien-3-yl-sulfamat-Derivate mit den Resten R2 und R7 bis R15 wie oben angegeben, welche am Stickstoffatom des Sulfamatrestes mindestens ein Wasserstoffatom tragen, mit einer geeigneten aktivierten Carbonsäure, Sulfon- saure oder Amidosulfonsaure oder einem geeigneten aktivierten Kohlensauremonoester oder Kohlensauremonoamida) suitable Estra-1, 3,5 (10) -trien-3-yl-sulfamate derivatives with the radicals R 2 and R 7 to R 15 as indicated above, which carry at least one hydrogen atom on the nitrogen atom of the sulfamate radical, with a suitable activated carboxylic acid, sulfonic acidic or amidosulfonic acid or a suitable activated carbonic acid monoester or carbonic acid monoamide
oderor
b) geeignete 3-Hydroxy-estra-1 ,3,5(10)-tπen-Derιvate mit den Resten R7 bis R15 wie oben angegeben mit einer aktivierten (N-COR3)amιdosulfonsaure, (N- COOR4)amιdosulfonsaure, (N-CONR5R6)amιdosulfonsaure, (N-S02R4) amidosulfonsaure oder (N-S02NR5R6)arnιdosulfonsaure,b) suitable 3-hydroxy-estra-1, 3,5 (10) -tπen-Derιvate with the radicals R 7 to R 15 as indicated above with an activated (N-COR 3 ) amidosulfonic acid, (N-COOR 4 ) amidosulfonic acid , (N-CONR 5 R6) amidosulfonic acid, (N-S0 2 R 4 ) amidosulfonic acid or (N-S0 2 NR 5 R 6 ) arnidosulfonic acid,
jeweils gegebenenfalls in Gegenwart einer Base umsetzt, die so erhaltenen Produkte gegebenenfalls in geeigneter Weise weiter umsetzt und gegebenenfalls die so erhaltenen Produkte in physiologisch vertragliche Metallsalze oder Ester überfuhrtin each case, if appropriate, in the presence of a base, the products thus obtained, if appropriate, further reacted in a suitable manner and, if appropriate, the products thus obtained converted into physiologically acceptable metal salts or esters
Die Herstellung der 3-Hydroxy-estra-1 ,3,5(10)-tπen-Deπvate mit den Resten R7 bis R15 erfolgt nach den in der Steroidchemie üblichen Verfahren, wie sie beispielhaft in Liebigs Ann Chem 702 (1967) 141-148, beschrieben werden Estra-1 , 3,5(10)-tπen-3-yl-sulfa- mat-Deπvate mit den Resten R2 und R7 bis R15 können in Analogie zu Verfahren, wie sie beispielhaft in Steroιds 61 (1996) 710-717 erläutert werden bereitgestellt werdenThe 3-hydroxy-estra-1, 3,5 (10) -tπen-Deπvate with the radicals R 7 to R 15 is produced by the methods customary in steroid chemistry, as exemplified in Liebigs Ann Chem 702 (1967) 141 -148, Estra-1, 3,5 (10) -tπen-3-yl-sulfate-mat-Deπvate with the radicals R 2 and R 7 to R 15 can be described in analogy to methods such as those exemplified in Steroids 61 (1996) 710-717
Die folgenden Beispiele sollen die Erfindung naher eriautern, ohne sie darauf einzuschränkenThe following examples are intended to illustrate the invention without restricting it
Beispiel 1example 1
17-Oxo-l 8a-homo-estra-1 3,5(10)-trιen-3-yl-(N-acetyl)sulfamat a) 6 0 g (0 021 mol) 18a-Methylestron und 13 7 ml (0 123 mol) 2,4,6-Collιdιn wurden in 1 45 I Dichlormethan gelost, bei Raumtemp portionsweise mit 18 4 g (0 159 mol) Amidosulfonsaurechloπd versetzt und 4 h unter Ruckfluß gehalten Die abgekühlte Reaktionsmischung wurde zunächst dreimal mit jeweils 300 ml Wasser, dann zweimal mit jeweils 200 ml ges Natπumhydrogencarbonatlosung und schließlich mit Wasser neutral gewaschen Die organische Phase wurde mit Natriumsulfat getrocknet, das Losungsmittel abdestilliert und der Ruckstand aus Essigsaureethylester umkπstallisiert Man erhielt 17-Oxo-18a-homo-estra-1 ,3,5(10)- tπen-3-yl-sulfamat, Schmp 180-182 °C (Essigsaureethylester) b) 5 5 g des erhaltenen Sulfamats wurden in 55 2 ml Pyndin gelost und bei Raumtemp mit 55 2 ml (0 500 mol) Essigsaureanhydπd versetzt Die Reaktionsmischung wurde 15 h bei Raumtemp gerührt und dann auf zerstoßenes 'Eis gegeben Der17-oxo-l 8a-homo-estra-1 3,5 (10) -trιen-3-yl- (N-acetyl) sulfamate a) 6 0 g (0 021 mol) 18a-methyltrone and 13 7 ml (0 123 mol) 2,4,6-Collιdιn were dissolved in 1 45 I dichloromethane, 18 4 g (0 159 mol) amidosulfonic acid chloride were added in portions at room temperature and the mixture was kept under reflux for 4 h. The cooled reaction mixture was first three times with 300 ml water, then washed twice with 200 ml of saturated sodium bicarbonate solution and finally with water until neutral. The organic phase was dried with sodium sulfate, the solvent was distilled off and the residue was removed Reconstalled ethyl acetate 17-oxo-18a-homo-estra-1, 3.5 (10) - tπen-3-yl-sulfamate, mp 180-182 ° C. (ethyl acetate) b) 5 5 g of the sulfamate obtained were obtained in 55 2 ml of pyndin were dissolved and 55 2 ml (0 500 mol) of acetic anhydride were added at room temperature. The reaction mixture was stirred at room temperature for 15 h and then poured onto crushed ice
Niederschlag wurde abfiltriert, mit Wasser neutral gewaschen und getrocknet Umkπstallisation aus Aceton/n-Hexan ergab die Titelverbmdung, Schmp 204-206 °C (Aceton/n-Hexan)Precipitate was filtered off, washed neutral with water and dried. Re-installation from acetone / n-hexane gave the title compound, mp 204-206 ° C. (acetone / n-hexane)
Beispiel 2Example 2
17-Oxo-l 8a-homo-estra-1 3,5(10)-trιen-3-yl-(N-propιonyl)sulfamat17-oxo-1 8a-homo-estra-1 3,5 (10) -trιen-3-yl- (N-propionyl) sulfamate
500 mg des in Beispiel 1 a erhaltenen Sulfamats wurden in einem Gemisch aus 17 ml500 mg of the sulfamate obtained in Example 1a were mixed in a mixture of 17 ml
Dichlormethan und 0,2 ml Tπethylamm gelost Man gab nacheinander 175 mg 4- Dimethylamino- pyndin und 3,7 ml Propionsaureanhydπd zu und rührte das Reaktionsgemisch 20 Stunden bei Raumtemperatur Danach wurde mit verdünnter wäßriger Chlorwasser- stoffsaure zersetzt Nach Abtrennung der organischen Phase wusch man diese mit gesättigter wäßriger Natπumhydrogencarbonat-Losung und mit Wasser, trocknete die Losung über wasserfreiem Natriumsulfat und engte im Vakuumrotationsverdampfer ein Der Ruckstand wurde aus Aceton umkπstallisiert , wobei man die Titelverbmdung erhielt, Fp 187 - 188 °C (Aceton) (Zersetzung)Dichloromethane and 0.2 ml of methylamine dissolved 175 mg of 4-dimethylamino-pyndine and 3.7 ml of propionic anhydride were added in succession and the reaction mixture was stirred for 20 hours at room temperature. It was then decomposed with dilute aqueous hydrochloric acid. After the organic phase had been separated off, it was washed with saturated aqueous sodium bicarbonate solution and with water, the solution dried over anhydrous sodium sulfate and concentrated in a vacuum rotary evaporator. The residue was re-installed from acetone to give the title compound, mp 187-188 ° C. (acetone) (decomposition)
Beispiel 3 17-Oxo-l 8a-homo-estra-1 ,3, 5(10)-trιen-3-yl (N-stearoyl)sulfamatExample 3 17-Oxo-1 8a-homo-estra-1, 3, 5 (10) -trιen-3-yl (N-stearoyl) sulfamate
363 mg des in Beispiel 1 a erhaltenen Sulfamats wurden in einem Gemisch aus 5 ml Pyndin und 5 ml Dichlormethan gelost Unter Ruhren versetzte man diese Losung mit 3,63 g Steaπnsaurechloπd Man ließ 22 h bei Raumtemperatur weiterruhren, dann gab man unter Eiskuhlung 10ml Wasser zu und rührte weitere 24 Stunden bei Raumtemperatur Anschließen wurde die organische Phase abgetrennt und nacheinander mit 2N wäßriger Chlorwasserstoffsaure, Wasser, 2N-waßπger Kahumhydroxidlosung und Wasser gewaschen Nach Trocknung über wasserfreiem Natriumsulfat wurde der Extrakt im Vakuumrotationsverdampfer eingeengt Hierbei fiel die Titelverbmdung als hellgelber Schaum an Beispiel 4363 mg of the sulfamate obtained in Example 1 a were dissolved in a mixture of 5 ml of pyndine and 5 ml of dichloromethane. With stirring, 3.63 g of stearic acid chloride were added to this solution. Stirring was continued for 22 hours at room temperature, then 10 ml of water were added with ice cooling and stirred for a further 24 hours at room temperature. The organic phase was separated off and washed successively with 2N aqueous hydrochloric acid, water, 2N aqueous potassium hydroxide solution and water. After drying over anhydrous sodium sulfate, the extract was concentrated in a vacuum rotary evaporator. The title compound was obtained as a light yellow foam Example 4
17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl (N-benzoyl)sulfamat 360 mg des in Beispiel 1a erhaltenen Sulfamats wurden in einem Gemisch aus 5 ml Dichlormethan und 5 ml Benzoylchlorid gelöst. Nach Zugabe von 1 ,2 ml Benzoylchlorid unter Rühren ließ am das Gemisch 70 h bei Raumtemperatur stehen. Danach wurde entsprechend Beispiel 3 aufgearbeitet. Das erhaltene Rohprodukt chromatographierte man an Kieselgel (Eluent: Cyclohexan/Ethylacetat = 1/2 v/v). Auf diese Weise erhielt man die Titelverbindung als amorphen Festkörper. MS (Elektrospray-Ionisation): 466,4 (M-H)+;468,3 (M+H)+; 490,6 (M+Na)+.17-Oxo-1 8a-homo-estra-1, 3,5 (10) -trien-3-yl (N-benzoyl) sulfamate 360 mg of the sulfamate obtained in Example 1a were mixed in a mixture of 5 ml of dichloromethane and 5 ml Dissolved benzoyl chloride. After adding 1.2 ml of benzoyl chloride with stirring, the mixture was left to stand at room temperature for 70 h. It was then worked up according to Example 3. The crude product obtained was chromatographed on silica gel (eluent: cyclohexane / ethyl acetate = 1/2 v / v). In this way, the title compound was obtained as an amorphous solid. MS (electrospray ionization): 466.4 (MH) + ; 468.3 (M + H) + ; 490.6 (M + Na) + .
Beispiel 6Example 6
17-Oxo-l 3a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-trifluoracetyl)sulfamat 363 mg des in Beispiel 1a erhaltenen Sulfamats wurden in 4 ml Pyridin gelöst. Zu der auf - 10 °C abgekühlten Lösung ließ man unter heftigem Rühren 2 ml17-Oxo-l 3a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-trifluoroacetyl) sulfamate 363 mg of the sulfamate obtained in Example 1a were dissolved in 4 ml of pyridine. 2 ml was added to the solution, cooled to -10 ° C., with vigorous stirring
Trifluoracetanhydrid zutropfen, wobei man das Gemisch sich auf Raumtemperatur erwärmen ließ. Nach weiterem 2-stündigen Rühren wurde der Ansatz auf Eis gegossen und das Reaktionsprodukt in Dichlormethan aufgenommen. Der Extrakt wurde mit verdünnter Salzsäure und mehrfach mit Wasser bis zur Neutralität gewaschen, über wasserfreiem Natriumsulfat getrocknet und im Vakuum zur Trockene eingeengt. Das erhaltene Produkt wurde mittels Flash-Chromatographie an 32g Kieselgel 60 (0,040 -Add trifluoroacetic anhydride dropwise, allowing the mixture to warm to room temperature. After stirring for a further 2 hours, the mixture was poured onto ice and the reaction product was taken up in dichloromethane. The extract was washed with dilute hydrochloric acid and several times with water until neutral, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The product obtained was purified by means of flash chromatography on 32 g of silica gel 60 (0.040 -
0,063 mm)unter Verwendung von Toluen/Chloroform/ Methanol 40:40:10 als Eluenten gereinigt. Die Titelverbindung ließ sich bei -10 °aus Acetonlösung mit n-Hexan amorph ausfällen. MS (ESI): 458,3 (M-H)+; 939,1 ; [2(M-H) + Naf. 19F-NMR (CF3COOH /0.063 mm) using toluene / chloroform / methanol 40:40:10 as eluent. The title compound was precipitated amorphously from n-hexane at -10 ° from acetone solution. MS (ESI): 458.3 (MH) + ; 939.1; [2 (MH) + Naf. 19 F NMR (CF 3 COOH /
DMSO):59,502 ppm.DMSO): 59.502 ppm.
Beispiel 7Example 7
17-Oxo-l 3a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-cvclopentancarbonyl)sulfamat17-Oxo-l 3a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-cvclopentanecarbonyl) sulfamate
363 mg des in Beispiel 1 a erhaltenen Sulfamats wurden in 3,5 ml Dichlormethan aufgerührt. Zu diesem Gemisch gab man 256 mg gepulvertes Kaliumhydroxid zu, wobei sich das Steroid löste. Anschließend tropfte man innerhalb von 10 Minuten 0,18 ml Cyclopentan- carbonsäurechlorid zu. Man ließ noch 2 Stunden bei Raumtemperatur rühren, gab 3 ml Wasser zu und versetzte mit verdünnter Salzsäure bis pH I .Die organische Phase wurde abgetrennt, mit Wasser neutral gewaschen, über wasserfreiem Natriumsulfat getrocknet und im Vakuum eingeengt. Den Rückstand reinigte man mittels Flash- Chromatographie an Kieselgel 60 (0,040 - 0,015 mm) mit Chloroform/Toluen/Methanol 25:25:10 als Eluenten, wobei die Titelverbindung als festes Harz anfiel. MS (El) m/z 459,2077 (M+).363 mg of the sulfamate obtained in Example 1a were stirred in 3.5 ml of dichloromethane. 256 mg of powdered potassium hydroxide were added to this mixture, and the steroid dissolved. Then 0.18 ml was added dropwise within 10 minutes Cyclopentane carboxylic acid chloride. The mixture was stirred for a further 2 hours at room temperature, 3 ml of water were added and dilute hydrochloric acid was added to pH I. The organic phase was separated off, washed with water until neutral, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel 60 (0.040-0.015 mm) using chloroform / toluene / methanol 25:25:10 as eluent, the title compound being obtained as a solid resin. MS (El) m / z 459.2077 (M + ).
Beispiel 7Example 7
Ovariektomierte adulte Ratten werden mit Dosierungen der erfindungsgemäßen Verbindung zwischen 1-300μg oral behandelt. 24 Stunden nach Applikation werden Leukozyten- und Organhomogeπate dieser Tiere auf ihre Fähigkeit untersucht Oestronsulfat zu spalten. Die erfindungsgemäßen Substanzen hemmen die Hydrolyse von Oestronsulfat im genannten Dosisbereich zwischen 50-90%. Werden Tiere 24 Stunden nach Behandlung mit einer erfindungsgemäßen Substanz mit Oestronsulfat behandelt, so lassen sich dessen Hydrolyseprodukte nach einer Stunde aus dem Plasma extrahieren. Erfindungsgemäße Substanzen reduzieren den extrahierten Anteil um ca. 75%. Ovariectomized adult rats are treated orally with dosages of the compound according to the invention between 1-300μg. 24 hours after application, leukocyte and organ homogenates of these animals are examined for their ability to split oestrone sulfate. The substances according to the invention inhibit the hydrolysis of oestrone sulfate in the dose range between 50-90%. If animals are treated with oestrone sulfate 24 hours after treatment with a substance according to the invention, its hydrolysis products can be extracted from the plasma after one hour. Substances according to the invention reduce the extracted fraction by approximately 75%.

Claims

Patentansprüche claims
1. Neue Cι3-substituierte Estra-1 , 3,5(10)-trien-3-yl-sulfamate der allgemeinen Formel1. New Cι 3 -substituted estra-1, 3,5 (10) -trien-3-yl sulfamates of the general formula
Figure imgf000016_0001
Figure imgf000016_0001
(I),(I)
in derin the
Ri COR3, COOR4, CONRsRe, S02R4, S02NR5R6 bedeutet,Ri COR 3 , COOR 4 , CONRsRe, S0 2 R 4 , S0 2 NR 5 R 6 means
R2 Wasserstoff, d-Cio-Alkyl, d-Cio-Alkoxyalkyl, C3-Cι0-Cycloalkyl, C2-Cιo-Alkenyl,R 2 is hydrogen, d-Cio-alkyl, d-Cio-alkoxyalkyl, C 3 -Cι 0 cycloalkyl, C 2 -Cιo alkenyl,
C2-Cιo-Alkinyl, Aryl, Aryl-d-C3-alkyl oder d-C3-Alkylaryl, COR3; COOR4; CONR5R6;C 2 -C 10 -alkynyl, aryl, aryl-dC 3 -alkyl or dC 3 -alkylaryl, COR 3 ; COOR 4 ; CONR 5 R 6 ;
S02R4; S02NR5R6 bedeuten,S0 2 R 4 ; S0 2 NR 5 R 6 mean
R3 H oder R darstellt,R 3 represents H or R,
R4 Cι-Cι7-Alkyl, d-Cι7-Halogenalkyl, C2-Cι7-Alkenyl, C2-Cι7-Alkinyl, C3-C10-R 4Cι-7 alkyl, d-Cι 7 haloalkyl, C 2 -Cι 7 alkenyl, C 2 -Cι 7 alkynyl, C 3 -C 10 -
Cycloalkyl, Aryl, Aryl-Ci-Cs-alkyl, d-C3-Alkylaryl bedeutet,Means cycloalkyl, aryl, aryl-Ci-Cs-alkyl, dC 3 -alkylaryl,
R5, Re unabhängig voneinander Wasserstoff, Ci-Cs-Alkyl, Ci-Cs-Halogenalkyl,R 5 , Re independently of one another are hydrogen, Ci-Cs-alkyl, Ci-Cs-haloalkyl,
Aryl, Aryl-d-C3-alkyl, Cι-C3-Alkylaryl bedeuten oder zusammen mit demAryl, aryl-dC 3 alkyl, -CC 3 alkylaryl mean or together with the
Stickstoffatom einen Polymethyleniminorest mit 2-6 C-Atomen oder einenNitrogen atom is a polymethyleneimino radical with 2-6 C atoms or one
Morpholinorest bilden,Form morpholino residue,
R7, R9 unabhängig voneinander H, OH, Halogen, Cι-C5-Alkoxy oder C1-C5-R 7, R 9 are independently H, OH, halo, Cι-C 5 alkoxy or C 1 -C 5 -
Halogenalkoxy bedeutenHalogenalkoxy mean
R8 H, OH, Ci-Cs-Alkyl, Ci-Cs-Halogenalkyl, C2-C5-Alkenyl, C2-C5-Alkinyl oderR 8 is H, OH, Ci-Cs-alkyl, Ci-Cs-haloalkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl or
Halogen bedeutet,Halogen means
R10, R11 Wasserstoff bedeuten oder Ri0 und Rn zusammen eine CH2-Gruppe darstellenR 10 , R 11 are hydrogen or R i0 and Rn together represent a CH 2 group
R12, R13, Rι4 unabhängig voneinander H, OH, Ci-Cs-Alkoxy oder C1-C5-R12, R13, Rι 4 independently of one another H, OH, Ci-Cs-alkoxy or C 1 -C 5 -
Halogenalkoxy bedeuten, oder Rι2 Halogen bedeutet, oderHalogenalkoxy mean, or Rι 2 halogen, or
R13 und R14 zusammen Sauerstoff darstellen oder zusammen für eine =CXY- Gruppe stehen, wobei X und Y unabhängig voneinander Wasserstoff, Halogen oder eine Ci-Cs-Alkylgruppe bedeuten, oderR 13 and R 14 together represent oxygen or together represent a = CXY group, where X and Y independently of one another denote hydrogen, halogen or a Ci-Cs-alkyl group, or
R13, R14 unabhängig voneinander Ci-Cs-Alkyl, C2-C5-AIkenyl oder C2-C5-Alkinyl bedeuten,R 13 , R 14 independently of one another are Ci-Cs-alkyl, C 2 -C 5 -alkenyl or C 2 -C 5 -alkynyl,
R15 C2-C5-Alkyl, C2-C5-Alkenyl oder C2-C5-Alkinyl bedeutet, Rs, Rg, Rio, Ri2, R13, R15 unabhängig voneinander α- oder ß-ständig sind und in den Ringen B und C bis zu 2 zusätzliche Doppelbindungen vorhanden sein können, deren physiologisch verträgliche Salze oder Ester.R 15 is C 2 -C 5 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl, Rs, Rg, Rio, Ri2, R13, R15 independently of one another are α- or β-permanent and in the Rings B and C may contain up to 2 additional double bonds, their physiologically tolerable salts or esters.
2. Verbindungen nach Anspruch 1 , dadurch gekennzeichnet, daß einer der Substituenten Ri COR3 mit R3 in der in Anspruch 1 genannten Bedeutung darstellt.2. Compounds according to claim 1, characterized in that one of the substituents Ri represents COR 3 with R 3 in the meaning given in claim 1.
3. Verbindungen nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß der Substituent R2 Wasserstoff bedeutet.3. Compounds according to claim 1 or 2, characterized in that the substituent R 2 is hydrogen.
4. Verbindungen nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß der Substituent R15 Ethyl oder Propyl bedeutet.4. Compounds according to any one of claims 1 to 3, characterized in that the substituent R 15 is ethyl or propyl.
5. Verbindungen nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß diese Verbindungen sind:5. Compounds according to one of claims 1 to 4, characterized in that these compounds are:
1 ) 17-Oxo-l 8a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-formyl)sulfamat1) 17-Oxo-1 8a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-formyl) sulfamate
2) 17-Oxo-18a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-acetyl)sulfamat2) 17-Oxo-18a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-acetyl) sulfamate
3) 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat3) 17β-Hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
4) 17-Oxo-l 8a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-propionyl)sulfamat 5) 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-propionyl)sulfamat4) 17-oxo-1 8a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-propionyl) sulfamate 5) 17β-hydroxy-18a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-propionyl) sulfamate
6) 17-Oxo-l 8a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-butyryl)sulfamat6) 17-Oxo-1 8a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-butyryl) sulfamate
7) 17α-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-butyryl)sulfamat7) 17α-Hydroxy-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-butyryl) sulfamate
8) 17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-valeryl)sulfamat8) 17-Oxo-1 8a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-valeryl) sulfamate
9) 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-valeryl)sulfamat 10) 17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-hexanoyl)sulfamat 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-hexanoyl)sulfamat9) 17β-hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-valeryl) sulfamate 10) 17-oxo-1 8a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-hexanoyl) sulfamate 17β-Hydroxy-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-hexanoyl) sulfamate
17-Oxo-l 8a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-decanoyl)sulfamat17-oxo-1 8a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-decanoyl) sulfamate
17-Oxo-l 8a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-stearoyl)sulfamat17-Oxo-1 8a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-stearoyl) sulfamate
17-Oxo-l 8a-homo-estra-1 , 3, 5(10)-trien-3-yl-(N-cyclopentancarbonyl)sulfamat17-Oxo-1 8a-homo-estra-1, 3, 5 (10) -trien-3-yl- (N-cyclopentane carbonyl) sulfamate
17-Oxo-l 4α,15α-methylen-18a-homo-estra-1 , 3,5(10)-trieπ-3-yl-(N- acetyl)sulfamat17-oxo-l 4α, 15α-methylene-18a-homo-estra-1, 3,5 (10) -trieπ-3-yl- (N-acetyl) sulfamate
17ß-Hydroxy-2-methoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-[N-(2,2- dimethyl)propionyl]sulfamat17β-Hydroxy-2-methoxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- [N- (2,2-dimethyl) propionyl] sulfamate
16α-Fluor-17ß-hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N- acetyl)sulfamat16α-fluoro-17β-hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
17ß-Hydroxy-7 -methyl-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N- acetyl)sulfamat17β-hydroxy-7-methyl-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
13-Ethyl-17-hydroxy-18, 19-dinor-17 -pregna-1 ,3,5(10)-trien-20-in-3-yl-(N- acetyl)sulfamat13-ethyl-17-hydroxy-18, 19-dinor-17-pregna-1, 3,5 (10) -trien-20-in-3-yl- (N-acetyl) sulfamate
17ß-Methoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-formyl)sulfamat17β-methoxy-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-formyl) sulfamate
17-Oxo-l 8a-homo-estra-1 , 3, 5(10),8-tetraen-3-yl-(N-acetyl)sulfamat17-Oxo-1 8a-homo-estra-1, 3, 5 (10), 8-tetraen-3-yl- (N-acetyl) sulfamate
17ß-Hydroxy-13-propyl-gona-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat17β-Hydroxy-13-propyl-gona-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
17-Oxo-l 3-propyl-gona-1 , 3, 5(10)-trien-3-yl-(N-acetyl)sulfamat17-oxo-l 3-propyl-gona-1, 3, 5 (10) -trien-3-yl- (N-acetyl) sulfamate
16α-Fluor-17-oxo-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat16α-fluoro-17-oxo-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
16ß-Fluor-17-oxo-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat16β-fluoro-17-oxo-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
16α-Fluor-17ß-hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N- acetyl)sulfamat16α-fluoro-17β-hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
16α-Fluor-17α-hydroxy-18a-homo-estra-1 , 3,5(10)-trien-3-yl-(N- acetyl)sulfamat16α-fluoro-17α-hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
16ß-Fluor-17ß-hydroxy-18a-homo-estra-1 , 3,5(10)-trien-3-yl-(N- acetyl)sulfamat16β-fluoro-17ß-hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
16ß-Fluor-17α-hydroxy-18a-homo-estra-1 , 3,5(10)-trien-3-yl-(N- acetyl)sulfamat16β-fluoro-17α-hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
2-Methoxy-17-oxo-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat2-methoxy-17-oxo-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
17ß-Hydroxy-2-methoxy-18a-homo-estra-1 , 3,5(10)-trien-3-yl-(N- acetyl)sulfamat17β-Hydroxy-2-methoxy-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
2, 17ß-Dimethoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat2, 17β-dimethoxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
17ß-tert.Butoxy-2-methoxy-18a-homo-estra-1 , 3,5(10)-trien-3-yl-(N- acetyl)sulfamat 34) 16α-Fluor-2-methoxy-17-oxo-18a-homo-estra-1 , 3,5(10)-trien-3-yl-(N- acetyl)sulfamat17β-tert-butoxy-2-methoxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 34) 16α-fluoro-2-methoxy-17-oxo-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
35) 16α-Fluor-17ß-hydroxy-2-methoxy-18a-homo-estra-1 , 3,5(10)-trien-3-yl-(N- acetyl)sulfamat 36) 2-Ethoxy-17-oxo-18a-homo-estra-1 ,3,5(10)-trieπ-3-yl-(N-acetyl)sulfamat35) 16α-fluoro-17β-hydroxy-2-methoxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate 36) 2-ethoxy-17-oxo -18a-homo-estra-1,3,5 (10) -trieπ-3-yl- (N-acetyl) sulfamate
37) 2-Ethoxy-17ß-hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat37) 2-Ethoxy-17β-hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
38) 18a-Homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat38) 18a-Homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
39) 17-Methylen-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat39) 17-methylene-18a-homo-estra-1,3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
40) 17-Difluormethylen-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)suifamat 41 ) 17-Ethyliden-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat40) 17-difluoromethylene-18a-homo-estra-1, 3.5 (10) -trien-3-yl- (N-acetyl) suifamate 41) 17-ethylidene-18a-homo-estra-1, 3.5 (10) -triene-3-yl- (N-acetyl) sulfamate
42) 17-Oxo-18a-homo-13α-estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat42) 17-Oxo-18a-homo-13α-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
43) 17ß-Hydroxy-18a-homo-13 -estra-1 ,3,5(10)-trien-3-yl-(N-acetyl)sulfamat43) 17β-Hydroxy-18a-homo-13-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
44) 17-Oxo-18a-homo-13α-estra-1 ,3,5(10),8-tetraen-3-yl-(N-acetyl)sulfamat44) 17-Oxo-18a-homo-13α-estra-1, 3,5 (10), 8-tetraen-3-yl- (N-acetyl) sulfamate
45) 17-Oxo-l 8a-homo-estra-1 ,3,5(10),6,8-pentaen-3-yl-(N-acetyl)sulfamat 46) 17-Oxo-l 8a-homo-estra-1 ,3,5(10),7-tetraen-3-yl-(N-acetyl)sulfamat45) 17-Oxo-1 8a-homo-estra-1, 3.5 (10), 6,8-pentaen-3-yl- (N-acetyl) sulfamate 46) 17-Oxo-1 8a-homo-estra -1, 3.5 (10), 7-tetraen-3-yl- (N-acetyl) sulfamate
47) 17-Oxo-18a-homo-estra-1 , 3,5(10), 8(14)-tetraen-3-yl-(N-acetyl)sulfamat47) 17-Oxo-18a-homo-estra-1, 3,5 (10), 8 (14) -tetraen-3-yl- (N-acetyl) sulfamate
48) 17ß-Hydroxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl(N-trifluoracetyl)sulfamat48) 17β-Hydroxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl (N-trifluoroacetyl) sulfamate
49) 17-Oxo-18a-homo-1 , 3, 5(10)-trien-3-yl-(N-nonafluorvaleroyl)sulfamat49) 17-Oxo-18a-homo-1, 3, 5 (10) -trien-3-yl- (N-nonafluorvaleroyl) sulfamate
50) 17-Oxo-2 -trifluormethoxy-18a-homo-estra-1 ,3,5(10)-trien-3-yl-(N- acetyl)sulfamat50) 17-Oxo-2-trifluoromethoxy-18a-homo-estra-1, 3,5 (10) -trien-3-yl- (N-acetyl) sulfamate
6. Verfahren zur Herstellung von neuen C13-substituierten Estra-1 , 3,5(10)-trien-3-yl- sulfamaten der allgemeinen Formel I,6. Process for the preparation of new C13-substituted Estra-1, 3,5 (10) -trien-3-yl-sulfamates of the general formula I,
Figure imgf000019_0001
Figure imgf000019_0001
(D,(D,
worin die Reste Ri bis Rι5 die in Anspruch 1 angegebene Bedeutung haben, indem man wherein the radicals R 1 to R 5 have the meaning given in claim 1 by
PCT/EP2000/008374 1999-09-08 2000-08-28 Novel c13-substituted estra-1,3,5(10)-triene-3-yl-sulfamates, a method for producing the same and pharmaceutical compositions containing these compounds for inhibiting oestrone sulfatase WO2001018028A1 (en)

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AU77739/00A AU7773900A (en) 1999-09-08 2000-08-28 Novel c13-substituted estra-1,3,5(10)-triene-3-yl-sulfamates, a method for producing the same and pharmaceutical compositions containing these compounds
JP2001522251A JP2003508542A (en) 1999-09-08 2000-08-28 Novel C13-substituted estra-1,3,5 (10) -trien-3-yl-sulphamate, process for producing the same and pharmaceutical composition containing the compound

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US8026229B2 (en) 2001-08-13 2011-09-27 Sterix Limited Antitumor-active 2-alkoxyestradiol sulfamates
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USRE42132E1 (en) 2003-02-19 2011-02-08 Sterix Limited Antitumoral D-homoestra-1,3,5(10)-trien-3-yl 2-substituted sulfamates
WO2004074307A1 (en) * 2003-02-19 2004-09-02 Schering Aktiengesellschaft 2-substituted estra-1,3,5(10)-triene-3-yl sulfamate with an anti-tumour action
JP4933250B2 (en) * 2003-02-19 2012-05-16 ステリックス リミティド Antitumor activity 2-substituted estra-1,3,5 (10) -trien-3-ylsulfamate
US8492570B2 (en) 2003-02-19 2013-07-23 Sterix Limited 2-substituted estra-1,3,5(10)-triene-3-yl sulfamate with an anti-tumor action

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