WO2000014104A1 - 11β-FLUORO- 7α-(14, 14,15,15,15- PENTAFLUORO-6- METHYL-10-THIA- 6-AZAPENTADECYL) ESTRA-1,3,5(10)- TRIENE-3, 17β-DIOL AS A CRYSTALLINE SOLVATE - Google Patents

11β-FLUORO- 7α-(14, 14,15,15,15- PENTAFLUORO-6- METHYL-10-THIA- 6-AZAPENTADECYL) ESTRA-1,3,5(10)- TRIENE-3, 17β-DIOL AS A CRYSTALLINE SOLVATE Download PDF

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Publication number
WO2000014104A1
WO2000014104A1 PCT/DE1999/002894 DE9902894W WO0014104A1 WO 2000014104 A1 WO2000014104 A1 WO 2000014104A1 DE 9902894 W DE9902894 W DE 9902894W WO 0014104 A1 WO0014104 A1 WO 0014104A1
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Prior art keywords
azapentadecyl
estra
triene
thia
methyl
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PCT/DE1999/002894
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German (de)
French (fr)
Inventor
Wolfgang Beckmann
Gabriele Winter
Christian Ewers
Jürgen Westermann
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Schering Aktiengesellschaft
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Priority to AU11498/00A priority Critical patent/AU1149800A/en
Publication of WO2000014104A1 publication Critical patent/WO2000014104A1/en

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    • 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

Definitions

  • the invention relates to a crystalline modification of the compound 11 ⁇ -fluoro-7 ⁇ - (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) - triene-3,17ß-diol (formula I).
  • Compound I is described in International Patent Application WO 98/07740 as an antiestrogen, which i.a. is suitable for tumor therapy.
  • Compound I can be prepared by the process described in patent application WO 98/07740. This process provides Compound I as a white foam. This arises when compound I is obtained from a large number of organic solvents and solvent mixtures (e.g. ethanol, ethanol / n-hexane, ethyl acetate n-hexane, methanol / ether), even if compound I has been purified beforehand by chromatography.
  • organic solvents and solvent mixtures e.g. ethanol, ethanol / n-hexane, ethyl acetate n-hexane, methanol / ether
  • This foam is amorphous and it can contain varying proportions of nanocrystalline components.
  • the foam-like consistency of compound I prepared according to WO 98/07740 complicates all stages of the preparation, in particular the isolation and drying of the active ingredient. For example, the residual solvent contained in the foam can only be insufficiently removed by drying become. Since the solids extraction according to the prior art is a concentration without crystallization, there is naturally no purification. In addition, the handling of the compound I is made more difficult in all further stages of its conversion into a pharmaceutical preparation due to the foam-like consistency.
  • the object of the present invention is therefore to provide a completely crystalline solid form of compound I and a process for its preparation.
  • the compound I prepared by the process to be created should be easy to handle, even in larger quantities (at least in the kg range).
  • compound I can be crystallized from a number of solvents and solvent mixtures (water / ethanol mixtures with 50 to 90% water content, water / methanol mixtures and dimethylformamide and acetonitrile). A completely crystalline phase is obtained. This phase is retained even when drying. Due to its completely crystalline form, the solid is not only in a well-defined form compared to the amorphous, which contains parts of nanocrystalline material, but also in a thermodynamically much more stable form.
  • the process is also characterized in that the crystallization leads to purification.
  • the compound I can be crystallized by stirring the amorphous foam in a water / ethanol mixture.
  • Another variant of the process according to the invention consists in a displacement crystallization of the compound I from a solution in an alcohol, for example methanol or ethanol, by adding water as a displacement agent. This crystallization takes place via an oily intermediate phase.
  • This method of displacement crystallization is also particularly suitable for
  • a preferred variant of the method provides for the addition of seed crystals of the crystalline modification of the compound I in the slightly unsaturated or in the slightly supersaturated region. For this, e.g. 2% seed based on the dissolved solid of compound I was added. The amount of seed is only determined by the process parameters, such as the rate of addition of the antisolvent, and is not subject to any fundamental restrictions, neither downwards nor upwards.
  • the seed is preferably added as a slurry in a mixture of water / ethanol.
  • Crystallization by the processes described according to the invention produces an easily stirrable suspension of the crystalline form of compound I, which can be easily isolated and dried and can also be handled well in all further stages of its conversion into a pharmaceutical preparation.
  • This uniform, reproducibly available crystal modification of the active pharmaceutical ingredient 11 ⁇ -fluoro-7 ⁇ - (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10 ) -triene-3,17ß-diol offers considerable advantages for the development of a validated manufacturing process, for quality control, for official approval and for the galenical preparation of the pharmaceutical preparations.
  • the solid form described is the only known and reproducible crystalline modification of compound I. It is surprising that compound I could be obtained in crystalline form at all, since its tendency to crystallize due to the long (and lipophilic) side chain on carbon atom 7 and the associated unfavorable Packing effects were not expected in the case of a crystalline arrangement.
  • This crystalline form is suitable for galenical processing according to processes known per se to form tablets, dragees, gel capsules, granules, suppositories, implants, injectable sterile aqueous and oily solutions, in intrapterine systems or intravaginal release systems.
  • the crystalline form of the compound I can be used for all the indications already mentioned in the international patent application No. WO 98/07740 as well as in all other indications open, such as therapy for estrogen-dependent diseases, for example breast carcinoma (second-line therapy of the tamoxifen -resistant breast cancer; for the adjuvant treatment of breast cancer instead of tamoxifen), endometrial cancer, prostatic hyperplasia, anovulatory infertility and melanoma.
  • the crystalline form of compound I can also be used as a component in the products described in EP 346 014 B1, which contain an estrogen and a pure antiestrogen, for simultaneous, sequential or separate use for the selective estrogen therapy of peri- or post-menopausal women .
  • the compound I can also be used together with antigestagens (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310 542 A).
  • the compounds of general formula I can be used for the production of medicaments for the treatment of endometriosis and endometrial carcinomas. Furthermore, the compounds of general formula I can be used to prepare pharmaceutical compositions for male and female
  • the crystalline modification of compound I described is an ansolvate. It was characterized by X-ray powder diffractometry and thermonalytical methods (e.g. differential thermal analysis in combination with thermogravimetry). IR spectroscopic investigations showed no clear differences between the amorphous material and the crystalline solvate.
  • Figure 1 shows the X-ray powder diffractogram of the solvate.
  • Table 1 shows the D values and relative intensities of the strongest reflections. The intensities can vary due to texture effects.
  • the differential thermal analysis (DTA) measurement with a heating rate of 5 K / min showed a melting point of 105 ° C ⁇ 2 K (onset temperature of the melt endotherm) for the solvate.
  • the thermogravimetric measurement (TG) carried out simultaneously shows a mass loss of less than 0.6% in the range below 60 ° C, which is due to the release of unbound water adsorbed on the surface.
  • Figure 3 shows the DTA / TG thermogram of the solvate.
  • Figure 2 shows the X-ray powder diffractogram
  • the batch is stirred for a further 24 h. Completely crystalline material is formed.
  • Example 3 2 g of 11 ⁇ -fluoro-7 ⁇ - (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) -triene-3, 17 ⁇ -diol are dissolved in 20 ml of ethanol at room temperature and 20 ml of water are slowly added over a period of 60 min. The mixture is stirred at room temperature for 16 h. Completely crystalline material is formed.
  • Example 5 1,472 kg of purified 11 ⁇ -fluoro-7 ⁇ - (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) prepared according to the state of the art (WO 98/07740) ) estra-1, 3,5 (10) -triene-3,17ß-diol are dissolved in 14.5 l ethanol and slowly mixed with 7 l water (microfiltered) at 20 ° C.

Abstract

The present invention relates to crystalline 11β-fluoro- 7α-(14, 14,15,15,15- pentafluoro-6- methyl-10-thia- 6-azapentadecyl) estra-1,3,5(10)- triene-3, 17β-diol (compound (1)) in the form of a solvate. The crystalline solvate of compound (1) is produced by extracting compound (1) from water or water/ethanol by means of stirring or by extracting said compound (1) from a solvent such as ethanol or methanol with water by means of displacement crystallisation. Seed crystals can be added to the compound from a prior crystallisation stock in order to achieve said crystallisation. Crystallisation is associated with purification of compound (1). The crystalline form of compound (1) can be processed in a similar manner to the amorphous form thereof for pharmaceutical preparations that can be used to treat estrogen-related illnesses such as mammary carcinoma.

Description

11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol als kristallines Ansolvat 11β-Fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1,3,5 (10) -triene-3,17ß-diol as a crystalline solvate
Die Erfindung betrifft eine kristalline Modifikation der Verbindung 11 ß-Fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1 , 3,5(10)- triene-3,17ß-diol (Formel I).The invention relates to a crystalline modification of the compound 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) - triene-3,17ß-diol (formula I).
Figure imgf000003_0001
Figure imgf000003_0001
Verbindung I ist beschrieben in der Internationalen Patentanmeldung WO 98/07740 als Antiestrogen, das u.a. zur Tumortherapie geeignet ist. Verbindung I kann nach dem in der Patentanmeldung WO 98/07740 beschriebenen Verfahren hergestellt werden. Dieses Verfahren liefert die Verbindung I als weißen Schaum. Dieser entsteht bei der Gewinnung der Verbindung I aus einer Vielzahl von organischen Lösemittel und Lösemittelgemischen (z.B. Ethanol, Ethanol/n-Hexan, Etylacetat n-Hexan, Methanol/Ether), auch wenn die Verbindung I zuvor durch Chromatographie gereinigt wurde.Compound I is described in International Patent Application WO 98/07740 as an antiestrogen, which i.a. is suitable for tumor therapy. Compound I can be prepared by the process described in patent application WO 98/07740. This process provides Compound I as a white foam. This arises when compound I is obtained from a large number of organic solvents and solvent mixtures (e.g. ethanol, ethanol / n-hexane, ethyl acetate n-hexane, methanol / ether), even if compound I has been purified beforehand by chromatography.
Dieser Schaum ist amorph und er kann wechselnde Anteile an nanokristallinen Bestanteilen enthalten. Die schaumartige Konsistenz der gemäß WO 98/07740 hergestellten Verbindung I erschwert sämtliche Stufen der Herstellung, insbesondere der Isolierung und Trocknung des Wirkstoffs. So kann z.B durch Trocknung das im Schaum enthaltene Restlösemittel nur unzureichend entfernt werden. Da es sich bei der Feststoffgewinnung nach dem Stand der Technik um eine Einengung ohne Kristallisation handelt, ergibt sich naturgemäß auch keine Aufreinigung. Zudem wird durch die schaumartige Konsistenz die Handhabung der Verbindung I in allen weiteren Stufen ihrer Überführung in ein pharmazeutisches Präparat erschwert.This foam is amorphous and it can contain varying proportions of nanocrystalline components. The foam-like consistency of compound I prepared according to WO 98/07740 complicates all stages of the preparation, in particular the isolation and drying of the active ingredient. For example, the residual solvent contained in the foam can only be insufficiently removed by drying become. Since the solids extraction according to the prior art is a concentration without crystallization, there is naturally no purification. In addition, the handling of the compound I is made more difficult in all further stages of its conversion into a pharmaceutical preparation due to the foam-like consistency.
Aufgabe der vorliegenden Erfindung ist es deshalb, eine vollständig kristalline Festkörperform von Verbindung I und ein Verfahren zu deren Herstellung zur Verfügung zu stellen. Die nach dem zu schaffenden Verfahren hergestellte Verbindung I soll, auch in größeren Mengen (mindestens im kg-Bereich),gut handhabbar sein.The object of the present invention is therefore to provide a completely crystalline solid form of compound I and a process for its preparation. The compound I prepared by the process to be created should be easy to handle, even in larger quantities (at least in the kg range).
Es wurde nunmehr gefunden, daß die Kristallisation von Verbindung I aus einer Reihe von Lösungsmitteln und Lösungsmittelgemischen (Wasser/Ethanol- Gemische mit 50...90% Wasseranteil, Wasser/Methanol-Gemische sowie Dimethylformamid und Acetonitril) gelingt. Dabei wird eine vollständig kristalline Phase erhalten. Diese Phase bleibt auch beim Trocknen erhalten. Aufgrund seiner vollständig kristallinen Form liegt der Festkörper nicht nur in einer gegenüber der amorphen, Anteile nanokristallinen Materials aufweisenden Form, wohl definierten, sondern auch in einer thermodynamsich wesentlich stabileren Form vor.It has now been found that compound I can be crystallized from a number of solvents and solvent mixtures (water / ethanol mixtures with 50 to 90% water content, water / methanol mixtures and dimethylformamide and acetonitrile). A completely crystalline phase is obtained. This phase is retained even when drying. Due to its completely crystalline form, the solid is not only in a well-defined form compared to the amorphous, which contains parts of nanocrystalline material, but also in a thermodynamically much more stable form.
Das Verfahren ist auch dadurch gekennzeichnet, daß es bei der Kristallisation zu einer Aufreinigung kommt.The process is also characterized in that the crystallization leads to purification.
Die Kristallisation der Verbindung I kann durch Ausrühren des amorphen Schaums in einem Wasser/Ethanol-Gemisch vorgenommen werden.The compound I can be crystallized by stirring the amorphous foam in a water / ethanol mixture.
Eine weitere Variante des erfindungsgemäßen Verfahrens besteht in einer Verdrängungskristallisation der Verbindung I aus einer Lösung in einem Alkohol, z.B. Methanol oder Ethanol, durch den Zusatz von Wasser als Verdrängungsmittel. Diese Kristallisation läuft über eine ölige Zwischenphase ab. Diese Methode der Verdrängungskristallisation ist insbesondere auch zurAnother variant of the process according to the invention consists in a displacement crystallization of the compound I from a solution in an alcohol, for example methanol or ethanol, by adding water as a displacement agent. This crystallization takes place via an oily intermediate phase. This method of displacement crystallization is also particularly suitable for
Gewinnung der kristallinen Form der Verbindung I in größeren Mengen in einemObtaining the crystalline form of compound I in larger amounts in one
Ansatz (mindestens kg-Bereich) geeignet.Approach (at least kg range) suitable.
Eine bevorzugte Variante des Verfahrens sieht den Zusatz von Saatkristallen der kristallinen Modifikation der Verbindung I im leicht untersättigten oder im leicht übersättigten Bereich vor. Dazu werden z.B. 2% Saat bezogen auf den gelösten Feststoff der Verbindung I zugesetzt. Dabei wird die Menge Saat nur durch die Prozeßparameter wie der Zugabegeschwindigkeit des Antisolvents bestimmt und unterliegt keinen prinzipiellen Einschränkungen, weder nach unten noch nach oben. Die Saat wird bevorzugt als Anschlämmung in einer Mischung aus Wasser/Ethanol zugegeben.A preferred variant of the method provides for the addition of seed crystals of the crystalline modification of the compound I in the slightly unsaturated or in the slightly supersaturated region. For this, e.g. 2% seed based on the dissolved solid of compound I was added. The amount of seed is only determined by the process parameters, such as the rate of addition of the antisolvent, and is not subject to any fundamental restrictions, neither downwards nor upwards. The seed is preferably added as a slurry in a mixture of water / ethanol.
Bei der Kristallisation nach den erfindungsgemäßen beschriebenen Verfahren entsteht eine leicht rührbare Suspension der kristallinen Form der Verbindung I, die sich leicht isolieren und trocknen und auch in allen weiteren Stufen ihrer Überführung in ein pharmazeutisches Präparat gut handhaben läßt. Diese einheitliche, reproduzierbar erhältliche Kristallmodifikation des pharmazeutischen Wirkstoffs 11 ß-Fluoro-7α-(14, 14, 15,15, 15-pentafluoro-6- methyl-10-thia-6-azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol bietet für die Entwicklung eines validierten Herstellverfahrens, für die Qualitätskontrolle, für die behördliche Zulassung und für die galenische Zubereitung der pharmazeutischen Präparate erhebliche Vorteile.Crystallization by the processes described according to the invention produces an easily stirrable suspension of the crystalline form of compound I, which can be easily isolated and dried and can also be handled well in all further stages of its conversion into a pharmaceutical preparation. This uniform, reproducibly available crystal modification of the active pharmaceutical ingredient 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10 ) -triene-3,17ß-diol offers considerable advantages for the development of a validated manufacturing process, for quality control, for official approval and for the galenical preparation of the pharmaceutical preparations.
Die beschriebene Festkörperform ist die einzige bislang bekannte und reproduzierbar herstellbare kristalline Modifikation der Verbindung I. Daß die Verbindung I in kristalliner Form überhaupt erhalten werden konnte, ist überraschend, da deren Kristallisationsneigung aufgrund der langen (und lipophilen) Seitenkette am Kohlenstoffatom 7 und damit verbundenen ungünstigen Packungseffekten im Falle einer kristallinen Anordnung nicht zu erwarten war. Diese kristalline Form eignet sich zur galenischen Verarbeitung nach an sich bekannten Verfahren zu Tabletten, Dragees, Gelkapseln, Granulaten, Suppositorien, Implantaten, injizierbaren sterilen wäßrigen und öligen Lösungen, in intrapterinen Systemen oder intravaginalen Freisetzungssystemen.The solid form described is the only known and reproducible crystalline modification of compound I. It is surprising that compound I could be obtained in crystalline form at all, since its tendency to crystallize due to the long (and lipophilic) side chain on carbon atom 7 and the associated unfavorable Packing effects were not expected in the case of a crystalline arrangement. This crystalline form is suitable for galenical processing according to processes known per se to form tablets, dragees, gel capsules, granules, suppositories, implants, injectable sterile aqueous and oily solutions, in intrapterine systems or intravaginal release systems.
Die kristalline Form der Verbindung I läßt sich für alle bereits in der Internationalen Patentanmeldung Nr. WO 98/07740 erwähnten Indikationen sowie in allen anderen Antiestrogenen offenstehenden Indikationen einsetzen, wie Therapie von estrogen-abhängigen Erkrankungen, zum Beispiel Mammacarcinom (second-line Therapie des Tamoxifen-resistenten Mammacarcinoms; zur adjuvanten Behandlung des Mammacarcinoms anstelle von Tamoxifen), Endometriumcarcinom, Prostatahyperplasie, anovulatorische Infertilität und Melanom. Die kristalline Form der Verbindung I kann außerdem als Komponente in den in der EP 346 014 B1 beschriebenen Produkten verwendet werden, die ein Estrogen und ein reines Antiestrogen enthalten, und zwar zur gleichzeitigen, sequentiellen oder getrennten Verwendung für die selektive Estrogentherapie peri- oder postmenopausaler Frauen. Die Verbindung I kann außerdem gemeinsam mit Antigestagenen (kompetitiven Progesteronantagonisten) zur Behandlung hormonabhängiger Tumoren verwendet werden (EP 310 542 A).The crystalline form of the compound I can be used for all the indications already mentioned in the international patent application No. WO 98/07740 as well as in all other indications open, such as therapy for estrogen-dependent diseases, for example breast carcinoma (second-line therapy of the tamoxifen -resistant breast cancer; for the adjuvant treatment of breast cancer instead of tamoxifen), endometrial cancer, prostatic hyperplasia, anovulatory infertility and melanoma. The crystalline form of compound I can also be used as a component in the products described in EP 346 014 B1, which contain an estrogen and a pure antiestrogen, for simultaneous, sequential or separate use for the selective estrogen therapy of peri- or post-menopausal women . The compound I can also be used together with antigestagens (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310 542 A).
Weitere Indikationen, in denen die Verbindung I zum Einsatz kommen kann, ist der männliche Haarausfall, eine diffuse Alopecie, eine durch eine Chemotherapie hervorgerufene Alopecie sowie Hirsutismus (Hye-Sun Oh und Robert C. Smart, Proc. Natl. Acad. Sei. USA, 93 (1996) 12525 - 12530).Further indications in which the compound I can be used are male hair loss, diffuse alopecia, chemotherapy-induced alopecia and hirsutism (Hye-Sun Oh and Robert C. Smart, Proc. Natl. Acad. Sei. USA , 93 (1996) 12525-12530).
Außerdem können die Verbindungen der allgemeinen Formel I zur Herstellung von Medikamenten zur Behandlung der Endometriose und von Endometrialkarzinomen verwendet werden. Ferner kann man die Verbindungen der allgemeinen Formel I zur Herstellung pharmazeutischer Zusammensetzungen für die männliche und weiblicheIn addition, the compounds of general formula I can be used for the production of medicaments for the treatment of endometriosis and endometrial carcinomas. Furthermore, the compounds of general formula I can be used to prepare pharmaceutical compositions for male and female
Fertilitätskontrolle einsetzen (männliche Fertilitätskontrolle: DE-A 195 10 862.0).Use fertility control (male fertility control: DE-A 195 10 862.0).
Die beschriebene, kristalline Modifikation der Verbindung I ist ein Ansolvat. Sie wurde mit Röntgenpulverdiffraktometrie und thermonalytischen Verfahren (z.B. Differenzthermoanalyse in Kombination mit Thermogravimetrie) charakterisiert. IR-spektroskopische Untersuchungen zeigten keine klaren Unterschiede zwischen dem amorphen Material und dem kristallinen Ansolvat.The crystalline modification of compound I described is an ansolvate. It was characterized by X-ray powder diffractometry and thermonalytical methods (e.g. differential thermal analysis in combination with thermogravimetry). IR spectroscopic investigations showed no clear differences between the amorphous material and the crystalline solvate.
Die Röntgenpulverdiagramme wurden mit Germanium-monochromatisierter CuKα- Strahlung (λ = 1 ,540598 Ä) aufgenommen. Die Messung erfolgte mit einem linearen ortsempfindlichen Detektor, der eine Winkelauflösung von 0,08° besitzt.The X-ray powder diagrams were recorded with Germanium-monochromatized CuKα radiation (λ = 1, 540598 Ä). The measurement was carried out using a linear, location-sensitive detector with an angular resolution of 0.08 °.
Abbildung 1 zeigt das Röntgenpulverdiffraktogramm des Ansolvats.Figure 1 shows the X-ray powder diffractogram of the solvate.
In Tabelle 1 sind die D-Werte und relativen Intensitäten der stärksten Reflexe zusammengestellt. Die Intensitäten können aufgrund von Textureffekten variieren.Table 1 shows the D values and relative intensities of the strongest reflections. The intensities can vary due to texture effects.
Die Differenzthermoanalyse-Messung (DTA) mit einer Heizrate von 5 K/min ergaben eine Schmelzpunkt von 105°C ± 2 K (Onset-Temperatur der Schmelzendotherme) für das Ansolvat. Die dazu simultan durchgeführte thermogravimetrische Messung (TG) zeigt einen Masseverlust kleiner als 0.6 % im Bereich unterhalb 60°C, der auf die Abgabe von ungebundenen, an der Oberfläche adsorbiereten Wasser zurückzuführen ist.The differential thermal analysis (DTA) measurement with a heating rate of 5 K / min showed a melting point of 105 ° C ± 2 K (onset temperature of the melt endotherm) for the solvate. The thermogravimetric measurement (TG) carried out simultaneously shows a mass loss of less than 0.6% in the range below 60 ° C, which is due to the release of unbound water adsorbed on the surface.
Abbildung 3 zeigt das DTA/TG-Thermogramm des Ansolvats. Zum Vergleich sind das Röntgenpulverdiffraktogramm (Abbildung 2) und dasFigure 3 shows the DTA / TG thermogram of the solvate. For comparison, the X-ray powder diffractogram (Figure 2) and that
DTA TG-Thermogramm (Abbildung 4) des Schaums, der nach dem Stand derDTA TG thermogram (Figure 4) of the foam according to the state of the
Technik durch das in der Internationalen Patentanmeldung Nr. WO 98/07740 beschriebenen Verfahren hergestellt wurde, dargestellt.Technique produced by the method described in International Patent Application No. WO 98/07740.
Die folgenden Beispiele dienen der näheren Erläuterung der Erfindung: The following examples serve to explain the invention in more detail:
Beispiel 1example 1
100 mg 11 ß-Fluoro-7α-(14, 14, 15,15, 15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol (in seiner amorphen Form) werden bei 50°C in 10 ml Wasser oder bei 30 bis 50°C in 5 ml eines Ethanol/Wasser-Gemisch mit einem Anteil von 10 % Ethanol suspendiert. Der100 mg of 11β-fluoro-7α- (14, 14, 15.15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) -triene-3.17ß -diol (in its amorphous form) are suspended at 50 ° C in 10 ml of water or at 30 to 50 ° C in 5 ml of an ethanol / water mixture containing 10% ethanol. The
Ansatz wird über 24 h nachgerührt. Es bildet sich vollständig kristallines Material.The batch is stirred for a further 24 h. Completely crystalline material is formed.
Beispiel 2Example 2
47 mg 11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol werden in 1 ml Acetonitril bei Raumtemperatur gelöst und es wird 1 ml Wasser über einen Zeitraum von 2 h langsam zudosiert. Es bildet sich vollständig kristallines Material.47 mg of 11β-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1,3,5 (10) -triene-3,17ß diol are dissolved in 1 ml of acetonitrile at room temperature and 1 ml of water is slowly metered in over a period of 2 h. Completely crystalline material is formed.
Beispiel 3 2 g 11ß-Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol werden in 20 ml Ethanol bei Raumtemperatur gelöst und es werden 20 ml Wasser über eine Zeit von 60 min langsam zugegeben. Der Ansatz wird über 16 h bei Raumtemperatur nachgerührt. Es bildet sich vollständig kristallines Material.Example 3 2 g of 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) -triene-3, 17β-diol are dissolved in 20 ml of ethanol at room temperature and 20 ml of water are slowly added over a period of 60 min. The mixture is stirred at room temperature for 16 h. Completely crystalline material is formed.
Beispiel 4Example 4
3.8 g 11 ß-Fluoro-7α-(14, 14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol werden in 38 ml Ethanol bei Raumtemperatur gelöst und es werden 38 ml Wasser über eine Zeit von 30 bis 60 min langsam zugegeben. Zu dem Ansatz werden 80 mg 11 ß-Fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1 ,3,5(10)- triene-3,17ß-diol (in seiner Form als kristallines Ansolvat) in einer Anschlämmung in 500 μl einer 1 :2- Mischung von Wasser und Ethanol als Saat gegeben. Der Zusatz erfolgt, wenn das Mischungsverhältnis von Solvent und Antisolvent 70:30 beträgt. Der Ansatz wird über 1 h bei Raumtemperatur nachgerührt. Es bildet sich kristallines Material mit einer Ausbeute von 3,4 g.3.8 g of 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) -triene-3.17ß diol are dissolved in 38 ml of ethanol at room temperature and 38 ml of water are slowly added over a period of 30 to 60 min. 80 mg of 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) - triene are added to the batch -3,17ß-diol (in its form as a crystalline solvate) in a slurry in 500 ul of a 1: 2 mixture of water and ethanol as seeds. The addition is made when the mixing ratio of solvent and antisolvent is 70:30. The mixture is stirred at room temperature for 1 h. Crystalline material is formed with a yield of 3.4 g.
Beispiel 5 1 ,472 kg nach Stand der Technik (WO 98/07740) hergestelltes, gereinigtes 11 ß- Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra- 1 ,3,5(10)-triene-3,17ß-diol werden in 14,5 I Ethanol gelöst und langsam bei 20°C mit 7 I Wasser (mikrofiltriert) versetzt. Anschließend wird eine Suspension aus 57 g kristallinem 11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol, hergestellt nach einem der vorstehenden Beispiele, 152 ml Wasser und 304 ml Ethanol zur Lösung im Rührwerk hinzugegeben (Animpfen!). Danach werden weitere 10,5 I Wasser zugegeben. Nach einer Nachrührzeit von 3 Stunden sowie Aufarbeitung durch Filtrieren und Trocknen werden 1 ,15 kg reines, kristallines 11 ß-Fluoro-7α- (14,14,15, 15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1 , 3, 5(10)- triene-3,17ß-diol (Ausbeute 78%) isoliert.Example 5 1,472 kg of purified 11β-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) prepared according to the state of the art (WO 98/07740) ) estra-1, 3,5 (10) -triene-3,17ß-diol are dissolved in 14.5 l ethanol and slowly mixed with 7 l water (microfiltered) at 20 ° C. A suspension of 57 g of crystalline 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) -triene-3,17ß-diol, prepared according to one of the preceding examples, 152 ml of water and 304 ml of ethanol were added to the solution in the stirrer (inoculate!). Then another 10.5 l of water are added. After stirring for 3 hours and working up by filtration and drying, 1.15 kg of pure, crystalline 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6- azapentadecyl) estra-1, 3, 5 (10) - triene-3,17ß-diol (yield 78%) isolated.
Mit der Kristallisation ist ein Aufreinigungseffekt verbunden. Im Falle des beschriebenen Betriebsansatzes sinkt die Summe aller Verunreinigungen nach HPLC-Analytik von 4,67% auf 1 ,14%. A purification effect is associated with the crystallization. In the case of the operating approach described, the total of all impurities decreases from 4.67% to 1.14% according to HPLC analysis.

Claims

Patentansprüche:Claims:
1. Kristallines 11 ß-Fiuoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol (Verbindung I)1. Crystalline 11β-fiuoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3,5 (10) -triene-3, 17ß-diol (compound I)
Figure imgf000011_0001
Figure imgf000011_0001
Kristallines 11 ß-Fiuoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol in der Form des Ansolvats.Crystalline 11β-fiuoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1,3,5 (10) -triene-3,17ß- diol in the form of the solvate.
Verfahren zur Kristallisation von 11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro- 6-methyl-10-thia-6-azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß amorphes 11 ß-Fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra- 1 ,3,5(10)-triene-3,17ß-diol in einem Lösungsmittel oderProcess for the crystallization of 11β-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3,5 (10) -triene-3 , 17ß-diol according to claim 1 or 2, characterized in that amorphous 11β-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1 , 3,5 (10) -triene-3,17ß-diol in a solvent or
Lösungsmittelgemisch ausgerührt wird.Solvent mixture is stirred.
Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß aus Wasser ausgerührt wird.A method according to claim 3, characterized in that it is extracted from water.
5. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß aus Dimethylformamid oder Acetonitril ausgerührt wird. 5. The method according to claim 3, characterized in that is extracted from dimethylformamide or acetonitrile.
6. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß aus einem6. The method according to claim 3, characterized in that from a
Wasser/Ethanolgemisch ausgerührt wird.Water / ethanol mixture is stirred.
7. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß aus einem Wasser/Methanolgemisch ausgerührt wird.7. The method according to claim 3, characterized in that is stirred from a water / methanol mixture.
8. Verfahren nach Anspruch 6, daß aus einem Wasser/Ethanolgemisch mit einem Wasseranteil von 50 bis 90% ausgerührt wird.8. The method according to claim 6, that is stirred from a water / ethanol mixture with a water content of 50 to 90%.
9. Verfahren zur Kristallisation von 11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro- 6-methyl-10-thia-6-azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß in einem Lösungsmittel gelöstes 11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol aus der Lösung durch Zusatz von Wasser verdrängt wird.9. Process for the crystallization of 11β-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) -triene -3,17ß-diol according to claim 1 or 2, characterized in that 11 ß-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-) dissolved in a solvent azapentadecyl) estra-1, 3,5 (10) -triene-3,17ß-diol is displaced from the solution by adding water.
10. Verfahren nach Anspruch 9, dadurch gekennzeichnet, daß das Lösungsmittel Ethanol oder Methanol ist.10. The method according to claim 9, characterized in that the solvent is ethanol or methanol.
11. Verfahren nach Anspruch 9 oder 10, dadurch gekennzeichnet, daß der Lösung von 11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol Saatkristalle deren kristallinen Modifikation zugesetzt werden.11. The method according to claim 9 or 10, characterized in that the solution of 11 ß-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra- 1, 3,5 (10) -triene-3,17ß-diol seed crystals whose crystalline modification are added.
12. Verfahren nach Anspruch 11 , dadurch gekennzeichnet, daß 2% Saatkristalle bezogen auf gelöstes 1 1 ß-Fluoro-7α-(14,14,15,15,15- pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß- diol zugesetzt werden.12. The method according to claim 11, characterized in that 2% seed crystals based on dissolved 1 1 ß-fluoro-7α- (14,14,15,15,15- pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) -triene-3.17β-diol can be added.
13. Verfahren nach Anspruch 12, dadurch gekennzeichnet, daß die Saatkristalle als Anschlämmung in Wasser/Ethanol zugegeben werden. 13. The method according to claim 12, characterized in that the seed crystals are added as a slurry in water / ethanol.
14. Kristallines 11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol hergestellt nach dem Verfahren gemäß Anspruch 3.14. Crystalline 11β-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3,5 (10) -triene-3, 17ß-diol produced by the process according to claim 3.
15. Kristallines 11 ß-Fluoro-7 -( 14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol hergestellt nach dem Verfahren gemäß Anspruch 9.15. Crystalline 11β-fluoro-7 - (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3,5 (10) -triene-3, 17ß-diol produced by the method according to claim 9.
16. Pharmazeutische Präparate, dadurch gekennzeichent, daß sie die kristalline Form von 11 ß-Fluoro-7α-(14, 14, 15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol gemäß Anspruch 1 oder 2 sowie einen pharmazeutisch verträglichen Träger enthalten.16. Pharmaceutical preparations, characterized in that they have the crystalline form of 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3,5 (10) -triene-3,17ß-diol according to claim 1 or 2 and a pharmaceutically acceptable carrier.
17. Pharmazeutische Präparate, dadurch gekennzeichent, daß sie die kristalline Form von 11 ß-Fluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol gemäß Anspruch 14 sowie einen pharmazeutisch verträglichen Träger enthalten.17. Pharmaceutical preparations, characterized in that they have the crystalline form of 11β-fluoro-7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3,5 (10) -triene-3,17ß-diol according to claim 14 and a pharmaceutically acceptable carrier.
18. Pharmazeutische Präparate, dadurch gekennzeichent, daß sie die kristalline Form von 11 ß-Fluoro-7α-(14,14,15,15,15-pentafiuoro-6-methyl-10-thia-6- azapentadecyl)estra-1 ,3,5(10)-triene-3,17ß-diol gemäß Anspruch 15 sowie einen pharmazeutisch verträglichen Träger enthalten.18. Pharmaceutical preparations, characterized in that they have the crystalline form of 11β-fluoro-7α- (14,14,15,15,15-pentafiuoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3,5 (10) -triene-3,17ß-diol according to claim 15 and a pharmaceutically acceptable carrier.
19. Verfahren zur Herstellung pharmezeutischer Präparate, enthaltend den Schritt der galenischen Verarbeitung der kristallinen Form von 1 1 ß-Fluoro- 7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra- 1 ,3,5(10)-triene-3,17ß-diol gemäß Anspruch 1 , 2, 14 oder 15 mit einem pharmazeutische verträglichen Träger. 19. A process for the preparation of pharmaceutical preparations, comprising the step of galenically processing the crystalline form of 1 1 ß-fluoro- 7α- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl ) estra- 1, 3,5 (10) -triene-3,17ß-diol according to claim 1, 2, 14 or 15 with a pharmaceutically acceptable carrier.
0. Verwendung der kristallinen Form von 11 ß-Fluoro-7α-(14,14,15,15,15- pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1 , 3,5(10)-triene-3,17ß- diol gemäß Anspruch 1 , 2, 14 oder 15 zur Herstellung von Arzneimitteln. 0. Use of the crystalline form of 11β-fluoro-7α- (14, 14, 15, 15, 15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1, 3.5 (10) - triene-3,17ß-diol according to claim 1, 2, 14 or 15 for the manufacture of medicaments.
PCT/DE1999/002894 1998-09-05 1999-09-06 11β-FLUORO- 7α-(14, 14,15,15,15- PENTAFLUORO-6- METHYL-10-THIA- 6-AZAPENTADECYL) ESTRA-1,3,5(10)- TRIENE-3, 17β-DIOL AS A CRYSTALLINE SOLVATE WO2000014104A1 (en)

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WO2001076608A1 (en) * 2000-04-07 2001-10-18 Schering Aktiengesellschaft Compositions for use as penetration promoters in transdermal formulations for highly lipophilic active ingredients
DE102010030538A1 (en) 2010-06-25 2011-12-29 Bayer Schering Pharma Aktiengesellschaft 6,7-Dihydro-5H-benzo [7] annulene derivatives, process for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments
WO2013083568A1 (en) 2011-12-08 2013-06-13 Bayer Intellectual Property Gmbh 6,7-dihydro-5h-benzo[7]annulene derivatives, methods for the production thereof, pharmaceutical preparations that contain said 6,7-dihydro-5h-benzo[7]annulene derivatives, and use thereof to produce drugs

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WO1998007740A1 (en) * 1996-08-20 1998-02-26 Schering Aktiengesellschaft 7α-(κ-AMINOALKYL)ESTRATRIENES, PROCESS FOR PREPARING THE SAME, PHARMACEUTICAL PREPARATIONS CONTAINING SAID 7α-(κ-AMINOALKYL)ESTRATRIENES AND THEIR USE FOR PREPARING MEDICAMENTS

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WO1998007740A1 (en) * 1996-08-20 1998-02-26 Schering Aktiengesellschaft 7α-(κ-AMINOALKYL)ESTRATRIENES, PROCESS FOR PREPARING THE SAME, PHARMACEUTICAL PREPARATIONS CONTAINING SAID 7α-(κ-AMINOALKYL)ESTRATRIENES AND THEIR USE FOR PREPARING MEDICAMENTS

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001076608A1 (en) * 2000-04-07 2001-10-18 Schering Aktiengesellschaft Compositions for use as penetration promoters in transdermal formulations for highly lipophilic active ingredients
DE102010030538A1 (en) 2010-06-25 2011-12-29 Bayer Schering Pharma Aktiengesellschaft 6,7-Dihydro-5H-benzo [7] annulene derivatives, process for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments
WO2011161101A1 (en) 2010-06-25 2011-12-29 Bayer Pharma Aktiengesellschaft 6,7-dihydro-5h-benzo[7]annulene derivatives, process for preparation thereof, pharmaceutical preparations comprising them, and the use thereof for production of medicaments
WO2013083568A1 (en) 2011-12-08 2013-06-13 Bayer Intellectual Property Gmbh 6,7-dihydro-5h-benzo[7]annulene derivatives, methods for the production thereof, pharmaceutical preparations that contain said 6,7-dihydro-5h-benzo[7]annulene derivatives, and use thereof to produce drugs
DE102011087987A1 (en) 2011-12-08 2013-06-13 Bayer Intellectual Property Gmbh 6,7-Dihydro-5H-benzo [7] annulene derivatives, process for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments

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