DE10303669A1 - New quaternary ammonioalkyl carbonate esters useful for treating bacterial and fungal infections and potentially useful for regulating cholesterol biosynthesis - Google Patents

New quaternary ammonioalkyl carbonate esters useful for treating bacterial and fungal infections and potentially useful for regulating cholesterol biosynthesis Download PDF

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DE10303669A1
DE10303669A1 DE2003103669 DE10303669A DE10303669A1 DE 10303669 A1 DE10303669 A1 DE 10303669A1 DE 2003103669 DE2003103669 DE 2003103669 DE 10303669 A DE10303669 A DE 10303669A DE 10303669 A1 DE10303669 A1 DE 10303669A1
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methyleneoxycarbonyloxy
iodide
androsten
triethylammonium
atoms
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Helmut Kasch
Brigitte Schlegel
Albert Härtl
Raimund Eck
Waldemar Künkel
Cathrin Franke
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Hans-Knoll-Institut fur Naturstoff-Forschung Ev
Hans Knoell Institut fuer Naturstoffforschung
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Hans-Knoll-Institut fur Naturstoff-Forschung Ev
Hans Knoell Institut fuer Naturstoffforschung
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J75/00Processes for the preparation of steroids in general
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J5/00Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond

Abstract

Quaternary ammonioalkyl carbonate esters (I) are new. Quaternary ammonioalkyl carbonate esters of formula (I) are new. A = a fused ring system, a 3-7C spirostane or CHR(CH2)m, all optionally substituted with 1-12C alkyl; R = alkyl; m = 5-24; n = 1-3; R1 = H or Me; R2, R3, R4 = 1-12C alkyl; 3-8C cycloalkyl, 3-12C alkenyl, 4-8C cycloalkenyl, 3-12C alkynyl, aryl(1-4C)alkyl, (1-4C alkoxy)methyl, hydroxyethyl, hydroxypropyl or propargyl, or NR3R4 is an N-containing heterocycle or an N-containing aromatic immonium group; Y = bromide, iodide, chloride or tosylate. An Independent claim is also included for a process for preparing (I).

Description

Die Erfindung betrifft Tetraalkylammoniumsalze vom Kohlensäureestertyp der allgemeinen Formel I,

Figure 00010001
worin
A= ein Trägermolekül bestehend aus anellierten Ringen, das aus zwei und mehr Ringen, auch Spirostanen (mit 3 bis 7-C-Atomen), oder ein Kohlenwasserstoffrest
Figure 00010002
wobei das Trägermoleküle neben den für die Anbindung der Carbonyloxyalkylammoniumreste erforderlichen OH-Gruppen, weitere funktionelle Gruppen, auch Alkylseitenketten (mit 1 bis 12 C-Atomen, R= zusätzliches Alkyl) enthalten kann,
mit m= 5 bis 24,
n= 1 bis 3,
R1= H oder Methyl,
R2, R3 und R4 = Alkyl (mit 1 bis 12 C-Atomen), Cycloalkyl (mit 2 bis 8 C-Atomen), Alkenyl (mit 3 bis 12 C-Atomen), Cycloalkenyl (mit 4 bis 8 C-Atomen), Alkinyl (mit 3 bis 12 C-Atomen), Aralkyl (mit Alkyl von 1 bis 4 C-Atomen), Alkyloxymethyl (mit Alkyl von 1 bis 4) Hydroxyethyl, Hydroxypropyl und/oder Propargyl,
wobei R3 und R4 auch Bestandteil eines stickstoffhaltigen Heterocyclus wie Urotropin, Morpholin, Imidazolyl, Oxazol, Pyrazol, Tamoxifen, Pyrrolidin sein kann und – ohne den Substituenten R2 – auch Bestandteil eines stickstoffhaltigen aromatischen Immoniumsalzes wie Pyridin, Dimethylaminopyridin oder Dipyridyl sein kann,
Y= Bromid, Iodid, Chlorid oder Tosyloxy bedeutet.The invention relates to tetraalkylammonium salts of the carbonic acid ester type of the general formula I,
Figure 00010001
wherein
A = a carrier molecule consisting of fused rings, consisting of two or more rings, also spirostanes (with 3 to 7 C atoms), or a hydrocarbon residue
Figure 00010002
the carrier molecule may contain, in addition to the OH groups required for the attachment of the carbonyloxyalkylammonium radicals, further functional groups, and also alkyl side chains (with 1 to 12 C atoms, R = additional alkyl),
with m = 5 to 24,
n = 1 to 3,
R1 = H or methyl,
R2, R3 and R4 = alkyl (with 1 to 12 C atoms), cycloalkyl (with 2 to 8 C atoms), alkenyl (with 3 to 12 C atoms), cycloalkenyl (with 4 to 8 C atoms), Alkynyl (with 3 to 12 C atoms), aralkyl (with alkyl from 1 to 4 C atoms), alkyloxymethyl (with alkyl from 1 to 4) hydroxyethyl, hydroxypropyl and / or propargyl,
where R3 and R4 can also be part of a nitrogen-containing heterocycle such as urotropin, morpholine, imidazolyl, oxazole, pyrazole, tamoxifen, pyrrolidine and - without the substituent R2 - can also be part of a nitrogen-containing aromatic immonium salt such as pyridine, dimethylaminopyridine or dipyridyl,
Y = bromide, iodide, chloride or tosyloxy.

AryI in Resten wie Aralkyl und dergleichen bedeutet insbesondere Phenyl oder Alkylphenyl (Alkyl mit 1 bis 4 C-Atomen).AryI means in residues such as aralkyl and the like in particular phenyl or alkylphenyl (alkyl with 1 to 4 carbon atoms).

Aus der Literatur bekannt sind Verbindungen in Kombination mit einem Lokalanästhetikum (N. Kasch, C. Goldschmidt WO 2001, 01/45678 A3) oder aber von Mono- und Bis-Tetraalkylammoniumsaizen langkettiger aliphatischer Ether, die aufgrund antibakterieller Wirksamkeit, aber Oberflächenaktivität, nur für Desinfektionszwecke und nicht für topische und systemische Anwendungen genutzt werden können.Compounds in are known from the literature Combination with a local anesthetic (N. Kasch, C. Goldschmidt WO 2001, 01/45678 A3) or from mono- and bis-tetraalkylammonium seeds long-chain aliphatic ether, which due to antibacterial effectiveness, but surface activity, only for disinfection purposes and not for topical and systemic applications can be used.

Der Erfindung liegt die Aufgabe zugrunde, neue Tetraalkylammoniumsalze vom Kohlensäureestertyp zur Verfügung zu stellen, sowie Verfahren zu ihrer Herstellung aufzuzeigen, deren biologische Aktivität durch das Trägermolekül und die charakteristische Ammoniumstruktur geprägt ist, bei denen die an und für sich zu erwartende Tensidwirkung stark zurückgedrängt ist und damit der Weg zur pharmakologischen Nutzung dieser Verbindungsklasse geebnet wird.The invention is based, new task Carbonic ester type tetraalkylammonium salts are available , as well as to show processes for their production, their biological activity through the carrier molecule and the characteristic ammonium structure, in which the and for themselves expected surfactant effect is strongly suppressed and thus the way to pharmacological use of this class of compounds is leveled.

Aus der Literatur sind die Ausgangsmaterialien für die Herstellung bekannt. Die erfindungsgemäßen Verbindungen sind neu, ihre biologische Wirksamkeit wurde bisher nicht beschrieben.The starting materials are from the literature for the Manufacturing known. The compounds according to the invention are new, their biological effectiveness has not yet been described.

Die Aufgabe wird erfindungsgemäß dadurch gelöst, dass neue Tetraalkylammoniumsalze vom Kohlensäureestertyp zur Verfügung gestellt werden.The object is achieved in that new tetraalkylammonium salts of the carbonic acid ester type provided become.

Erfindungsgemäß bevorzugte Verbindungen sind beispielsweise:
N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-triethylammonium-iodid,
N-(3β-Ethylidenoxycarbonyloxy-5-androsten-l7-on), N,N,N-triethylammonium-iodid,
N-(3β-Methylenoxycarbonyloxy-5-cholesten), N,N,N-triethylammonium-bromid,
N-(3β-Methylenoxycarbonyloxy-24-ethyl-5-cholesten), N,N,N-triethylammonium-bromid,
N-(3β-Methylenoxycarbonyloxy-24-ethyl-5,22-cholestadien), N,N,N-triethylammonium-iodid,
N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-trimethylammonium-chlorid,
N,N-Dimethyl, N-hexyl, N-(3β-methylenoxycarbonyloxy-5-androsten-l7-on)-ammonium-iodid,
N,N-Diethyl, N-methyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-ammonium-iodid,
N,N-Dimethyl, N-butyl, N-(3β-methylenoxycarbonyloxy-5-androsten-l7-on)-ammonium-iodid,
N,N-Dimethyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on), N-propargyl-ammonium-iodid,
N,N-Dimethyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on), N-propinyl-ammonium-iodid,
N,N-Dimethyl, N-dodecyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-ammonium-iodid,
N,N-Dimethyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on), N-propenyl-ammonium-iodid,
N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-tripropyl-ammonium-iodid,
N-Methyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-imidazolonium-iodid,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-pyrrolidinium-hydrochlorid,
N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-pyridinium-iodid,
N-Methyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-pyrrolidinium-iodid,
N-(3β-Methylenoxycarbonyloxy-5-androsten-17β-ol), N,N,N-triethyl-ammonium-iodid,
N-(17β-Methylenoxycarbonyloxy-5-androsten-3-on), N,N,N-triethyl-ammonium-iodid,
N-(17β-Methylenoxycarbonyloxy-5-androsten-3β-ol), N,N,N-triethyl-ammonium-iodid,
N,N'-[3β,17β-(Di-methylenoxycarbonyloxy)-5-androsten]-(N,N,N)-,(N',N',N')-bis-triethyl-ammonium-diodid
N-[3-Methoxy-17β-methylenoxycarbonyloxy-estra-1,3,5(10)-trien], N,N,N-triethyl-ammonium-iodid,
N-[17β-methylenoxycarbonyloxy-3-sulfamoyloxy-estra-1,3,5(10)-trien], N,N,N-triethyl-ammonium-iodid
N-[17β-methylenoxycarbonyloxy-3-oxysulfonyloxy-estra-1,3,5(10)-trien], N,N,N-triethyl-ammonium-iodid
N-[17β-methylenoxycarbonyloxy-3-oxysulfonylpropyl-estra-1,3,5(10)-trien], N,N, N-triethyl-ammonium-iodid
N-[3-Methoxy-17β-methylenoxycarbonyloxy-estra-1,3,5(10),9(11)-tetraen], N,N N-triethyl-ammonium-iodid,
N-(1-Methylenoxycarbonyloxy-dodecyl), N,N,N-triethyl-ammonium-iodid
N,N'-[1,12-(Di-methylenoxycarbonyloxy)-dodecyl]-(N,N,N)-,(N',N',N')-bis-triethyl-ammonium-diodid
Compounds preferred according to the invention are, for example:
N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-triethylammonium iodide,
N- (3β-ethylidenoxycarbonyloxy-5-androsten-l7-one), N, N, N-triethylammonium iodide,
N- (3β-methyleneoxycarbonyloxy-5-cholestene), N, N, N-triethylammonium bromide,
N- (3β-methyleneoxycarbonyloxy-24-ethyl-5-cholestene), N, N, N-triethylammonium bromide,
N- (3β-methyleneoxycarbonyloxy-24-ethyl-5,22-cholestadiene), N, N, N-triethylammonium iodide,
N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-trimethylammonium chloride,
N, N-dimethyl, N-hexyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-l7-one) ammonium iodide,
N, N-diethyl, N-methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) ammonium iodide,
N, N-dimethyl, N-butyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-l7-one) ammonium iodide,
N, N-dimethyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N-propargylammonium iodide,
N, N-dimethyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N-propynylammonium iodide,
N, N-dimethyl, N-dodecyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) ammonium iodide,
N, N-dimethyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N-propenyl-ammonium iodide,
N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-tripropyl-ammonium iodide,
N-methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) -imidazolonium iodide,
N- (3β-methylenoxycarbonyloxy-5-androsten-17-one) -pyrrolidinium hydrochloride,
N- (3β-methylenoxycarbonyloxy-5-androsten-17-one) pyridinium iodide,
N-methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) pyrrolidinium iodide,
N- (3β-methyleneoxycarbonyloxy-5-androsten-17β-ol), N, N, N-triethylammonium iodide,
N- (17β-methyleneoxycarbonyloxy-5-androsten-3-one), N, N, N-triethylammonium iodide,
N- (17β-methyleneoxycarbonyloxy-5-androsten-3β-ol), N, N, N-triethylammonium iodide,
N, N '- [3β, 17β- (di-methylenoxycarbonyloxy) -5-androsten] - (N, N, N) - (N', N ', N') - bis-triethyl-Ammoni to-diodid
N- [3-methoxy-17β-methyleneoxycarbonyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide,
N- [17β-methyleneoxycarbonyloxy-3-sulfamoyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide
N- [17β-methyleneoxycarbonyloxy-3-oxysulfonyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide
N- [17β-methyleneoxycarbonyloxy-3-oxysulfonylpropyl-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide
N- [3-methoxy-17β-methyleneoxycarbonyloxy-estra-1,3,5 (10), 9 (11) -tetraen], N, N N-triethylammonium iodide,
N- (1-methyleneoxycarbonyloxy dodecyl), N, N, N-triethylammonium iodide
N, N '- [1,12- (di-methylenoxycarbonyloxy) dodecyl] - (N, N, N) - (N', N ', N') - bis-triethyl-ammonium-diodid

Gegenstand der vorliegenden Erfindung sind ferner pharmazeutische Zusammensetzungen, die als Wirkstoff mindestens ein Tetraalkylammoniumsalz vom Kohlensäureestertyp der allgemeinen Formel I enthalten, wobei diesen Zusammensetzungen gegebenenfalls geeignete Hilfs-, Träger- und Zusatzstoffe und/oder Stabilisatoren beigefügt sind.Object of the present invention are also pharmaceutical compositions that act as an active ingredient at least one carbonic ester type tetraalkylammonium salt of general formula I, these compositions optionally suitable auxiliary, carrier and additives and / or stabilizers are added.

Die erfindungsgemäßen Verbindungen besitzen neben einer antibakteriellen eine bevorzugte antimykotische Wirkung, wobei die spezifische Antcandida-Wirkung hervorzuheben ist. Darüber hinaus sind die erfindungsgemäßen Verbindungen als potentielle HMG-Co-A-Reduktasehemmer einzustufen, die die Cholesterinbiosynthese zu regulieren vermögen. Überraschend ist die verminderte bzw. bei einigen Verbindungen nicht vorhandene Tensidwirkung, die sehr durch das verwendete Trägermolekül und die Aminkomponente beeinflusst wird.The compounds of the invention also have an antibacterial a preferred antifungal activity, wherein the specific Antcandida effect is to be emphasized. About that in addition, the compounds of the invention classified as a potential HMG-Co-A reductase inhibitor, the cholesterol biosynthesis able to regulate. Surprised is the reduced or not available for some connections Surfactant effect, which is very influenced by the carrier molecule and the amine component becomes.

Aufgrund ihrer spezifischen Partialwirkungen können die Wirkstoffkomponenten für den Einsatz bei Mykosen und als Cholesterinsenker eingesetzt werden, auch nicht zuletzt deshalb, weil keine hormonellen Nebenwirkungen auftreten.Due to their specific partial effects, the Active ingredient components for used for mycoses and as a cholesterol-lowering agent, not least because there are no hormonal side effects occur.

Die Arzneimittel der Erfindung werden mit den üblichen festen oder flüssigen Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutisch technischen Hilfsstoffen entsprechend der gewünschten Applikationsroute mit einer geeigneten Dosierung in an sich bekannter Weise hergestellt. Die bevorzugten Zubereitungen bestehen in Darreichungsformen, die zur topischen Anwendung in Form transdermaler Systeme bestehen. Orale Applikationen in Form von Tabletten, Dragees, Pillen, Pulver und Depotformen sind ebenfalls geeignet.The drugs of the invention will with the usual solid or liquid diluents and usually used pharmaceutical technical auxiliaries accordingly the desired one Application route with a suitable dosage in a known manner Manufactured way. The preferred preparations consist of dosage forms, which exist for topical application in the form of transdermal systems. Oral applications in the form of tablets, coated tablets, pills, powder and deposit forms are also suitable.

Zur Herstellung der erfindungsgemäßen Verbindungen werden Verbindungen der allgemeinen Formeln II,

Figure 00050001
worin
A und n die oben angegebene Bedeutungen haben,
n= 1 bis 3 ist, in an sich bekannter Weise mit Chlorameisensäurechlormethylester oder durch Umsetzung mit Phosgen und anschließender Reaktion mit Paraformaldehyd (Acetaldehyd) nach der Henry-Methode mit ZnCl2 in Carbonsäure-α-chloralkylester (mit Alkyl = Methyl oder Ethyl) umgewandelt und diese mit einem Amin, NR2R3R4, worin R2, R3 und R4 die oben angegebenen Bedeutungen haben, in einem geeigneten Lösungsmittel, wie Aceton, DMF, Methylenchlorid oder einer entsprechenden Lösungsmittelkombi-nation, in Gegenwart von Iodid, Bromid, Tosylat oder Chlorid in Form von Salzen umgesetzt, isoliert und diese gegebenenfalls in an sich bekannter Weise oxidiert, verethert, acyliert, wozu unter anderem ein Säurederivat für Veresterungen, wie ein Carbonsäureanhydrid, Carbonsäurehalogenid, wie Carbosäurechlorid oder ein Sulfamoylhalogenid wie Sulfamoylchlorid in Gegenwart eines geeigneten Lösungsmittels und einer protonenabstrahierenden Base genutzt werden.To prepare the compounds according to the invention, compounds of the general formulas II,
Figure 00050001
wherein
A and n have the meanings given above,
n = 1 to 3, in a manner known per se with chloromethyl chloromate or by reaction with phosgene and subsequent reaction with paraformaldehyde (acetaldehyde) according to the Henry method with ZnCl 2 in carboxylic acid α-chloroalkyl ester (with alkyl = methyl or ethyl) and this with an amine, NR 2 R 3 R 4 , in which R 2 , R 3 and R 4 have the meanings given above, in a suitable solvent, such as acetone, DMF, methylene chloride or a corresponding solvent combination, in the presence of iodide , Bromide, tosylate or chloride in the form of salts, isolated and optionally oxidized, etherified, acylated in a manner known per se, including an acid derivative for esterifications such as a carboxylic acid anhydride, carboxylic acid halide such as carboxylic acid chloride or a sulfamoyl halide such as sulfamoyl chloride in the presence a suitable solvent and a proton-emitting base.

Die pharmazeutischen Zubereitungen, die mindestens ein erfindungsgemäßes Tetraalkylammoniumsalz vom Kohlensäureestertyp enthalten, umfassen pharmazeutisch verträgliche Hilfs-, Träger- und Zusatzstoff und/oder Stabilisatoren.The pharmaceutical preparations the at least one tetraalkylammonium salt according to the invention of the carbonic acid ester type included, include pharmaceutically acceptable auxiliary, carrier and Additive and / or stabilizers.

Die nachfolgenden Beispiele dienen dazu, die Erfindung näher zu erläutern, ohne sie in irgendeiner Weise einzuschränken.The following examples serve to the invention in more detail to explain without restricting them in any way.

Experimenteller Teil Experimental part

Beispiel 1example 1

N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on)-N,N,N-triethyl-ammonium-iodidN- (3β-Methylenoxycarbonyloxy-5-androsten-17-one) -N, N, N-triethyl-ammonium iodide

300 mg 3β-Hydroxy-5-androsten-l7-on werden mit 1,2 mmol Chlorameisensäurechlormethylester und 3 mmol Triethylamin in Gegenwart von 3 mmol Natriumiodid in 3 ml Aceton zur Umsetzung gebracht. Das Ammoniumsalz kristallisiert aus der Acetonlösung aus und kann durch Umkristallisation aus Methylenchlorid/n-Hexan aufgereinigt werden.
F: 208 bis 211 °C
IR [cm-1]: 1635 (CO)
MS [m/z]: ES+ 446,6 [M+]
300 mg of 3β-hydroxy-5-androsten-l7-one are reacted with 1.2 mmol of chloromethyl chloroformate and 3 mmol of triethylamine in the presence of 3 mmol of sodium iodide in 3 ml of acetone. The ammonium salt crystallizes out of the acetone solution and can be purified by recrystallization from methylene chloride / n-hexane.
F: 208-211 ° C
IR [cm -1 ]: 1635 (CO)
MS [m / z]: ES + 446.6 [M + ]

Beispiel 2Example 2

N-(3β-Methylenoxycarbonyloxy-5-cholesten)-N,N,N-triethyl-ammonium-chloridN- (3 β -Methylenoxycarbonyloxy-5-cholesten) -N, N, N-triethyl-ammonium chloride

300 mg 3β-Hydroxy-5-cholesten werden mit 1,2 mmol Triphosgen in Gegenwart von Triethylamin in 3β-Chlorcarbonyloxy-5-cholesten überführt und anschließend mit 2 mmol Paraformaldehyd in DMF in Gegenwart von wasserfreiem ZnCl2 unter kurzem Erhitzen in 3β-Chlormethylenoxycarbonyloxy-5-cholesten umgewandelt. Der durch chromatographische Reinigung erhältliche Chlormethylester wird mit 3 mmol Triethylamin in das Ammoniumsalz überführt und das Salz aus Methylenchlorid/n-Hexan kristallisiert.
MS [m/z]: ES+ 544,9 [M+]
300 mg of 3β-hydroxy-5-choleste are converted into 3β-chlorocarbonyloxy-5-choleste with 1.2 mmol triphosgene in the presence of triethylamine and then with 2 mmol paraformaldehyde in DMF in the presence of anhydrous ZnCl 2 with brief heating in 3β-chloromethyleneoxycarbonyloxy -5-choles ten converted. The chloromethyl ester obtainable by chromatographic purification is converted into the ammonium salt with 3 mmol of triethylamine and the salt is crystallized from methylene chloride / n-hexane.
MS [m / z]: ES + 544.9 [M + ]

Beispiel 3Example 3

N-(17β-Methylenoxycarbonyloxy-5-androsten-3-on)-N,N,N-triethylammonium-iodidN- (17β-Methylenoxycarbonyloxy-5-androsten-3-one) -N, N, N-triethylammonium iodide

200 mg 17β-Iodmethylenoxycarbonyloxy-5-androsten-3-on, hergestellt aus 17β-chlormethylenoxycarbonyloxy-5-androsten-3-on durch Umsetzung mit Natriumiodid in Aceton, werden in 2 ml Aceton gelöst und bei Raumtemperatur mit 3 mmol Triethylamin versetzt. Das auskristallisierende Ammoniumsalz wird abgetrennt und aus Methylenchlorid/n-Hexan kristallisiert.
F: 208 bis 311 °C
200 mg of 17β-iodomethyleneoxycarbonyloxy-5-androsten-3-one, prepared from 17β-chloromethyleneoxycarbonyloxy-5-androsten-3-one by reaction with sodium iodide in acetone, are dissolved in 2 ml of acetone and mixed with 3 mmol of triethylamine at room temperature. The crystallizing ammonium salt is separated off and crystallized from methylene chloride / n-hexane.
F: 208 to 311 ° C

Claims (4)

Tetraalkylammoniumsalze vom Kohlensäureestertyp der Formel I,
Figure 00080001
worin A= ein Trägermolekül bestehend aus anellierten Ringen, das aus zwei und mehr Ringen, auch Spirostanen (mit 3 bis 7-C-Atomen), oder ein Kohlenwasserstoffrest
Figure 00080002
wobei das Trägermoleküle neben den für die Anbindung der Carbonyloxyalkylammoniumreste erforderlichen OH-Gruppen, weitere funktionelle Gruppen, auch Alkylseitenketten (mit 1 bis 12 C-Atomen, R= zusätzliches Alkyl) enthalten kann, mit m= 5 bis 24, n= 1 bis 3, R1= H oder Methyl, R2, R3 und R4 = Alkyl (mit 1 bis 12 C-Atomen), Cycloalkyl (mit 2 bis 8 C-Atomen), Alkenyl (mit 3 bis 12 C-Atomen), Cycloalkenyl (mit 4 bis 8 C-Atomen), Alkinyl (mit 3 bis 12 C-Atomen), Aralkyl (mit Alkyl von 1 bis 4 C-Atomen), Alkyloxymethyl (mit Alkyl von 1 bis 4) Hydroxyethyl, Hydroxypropyl und / oder Propargyl, wobei R3 und R4 auch Bestandteil eines stickstoffhaltigen Heterocyclus wie Urotropin, Morpholin, Imidazolyl, Oxazol, Pyrazol, Tamoxifen, Pyrrolidin sein kann und – ohne den Substituenten R2 – auch Bestandteil eines stickstoffhaltigen aromatischen Immoniumsalzes wie Pyridin, Dimethylaminopyridin oder Dipyridyl sein kann, Y= Bromid, Iodid, Chlorid oder Tosyloxy bedeutet.
Carbonic acid ester type tetraalkylammonium salts of formula I,
Figure 00080001
where A = a carrier molecule consisting of fused rings, that of two or more rings, also spirostanes (with 3 to 7 C atoms), or a hydrocarbon residue
Figure 00080002
the carrier molecule may contain, in addition to the OH groups required for the attachment of the carbonyloxyalkylammonium radicals, further functional groups, and also alkyl side chains (with 1 to 12 C atoms, R = additional alkyl), with m = 5 to 24, n = 1 to 3 , R1 = H or methyl, R2, R3 and R4 = alkyl (with 1 to 12 C atoms), cycloalkyl (with 2 to 8 C atoms), alkenyl (with 3 to 12 C atoms), cycloalkenyl (with 4 to 8 C atoms), alkynyl (with 3 to 12 C atoms), aralkyl (with alkyl from 1 to 4 C atoms), alkyloxymethyl (with alkyl from 1 to 4) hydroxyethyl, hydroxypropyl and / or propargyl, where R3 and R4 can also be part of a nitrogen-containing heterocycle such as urotropin, morpholine, imidazolyl, oxazole, pyrazole, tamoxifen, pyrrolidine and - without the substituent R2 - can also be part of a nitrogen-containing aromatic immonium salt such as pyridine, dimethylaminopyridine or dipyridyl, Y = bromide, iodide , Chloride or tosyloxy means.
Tetraalkylammoniumsalze vom Kohlensäureestertyp gemäß Anspruch 1, ausgewählt aus der Gruppe N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-triethylammonium-iodid, N-(3β-Ethylidenoxycarbonyloxy-5-androsten-17-on), N,N,N-triethylammonium-iodid, N-(3β-Methylenoxycarbonyloxy-5-cholesten), N,N,N-triethylammonium-bromid, N-(3β-Methylenoxycarbonyloxy-24-ethyl-5-cholesten), N,N,N-triethylammonium-bromid, N-(3β-Methylenoxycarbonyloxy-24-ethyl-5,22-cholestadien), N,N,N-triethylammonium-iodid, N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-trimethylammonium-chlorid, N,N-Dimethyl, N-hexyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-ammonium-iodid, N,N-Diethyl, N-methyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-ammonium-iodid, N,N-Dimethyl, N-butyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-ammonium-iodid, N,N-Dimethyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on), N-propargylammonium-iodid, N,N-Dimethyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on), N-propinylammonium-iodid, N,N-Dimethyl, N-dodecyl, N-(3β- methylenoxycarbonyloxy-5-androsten-17-on)-ammonium-iodid, N,N-Dimethyl, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on), N-propenyl- ammonium-iodid, N-(3β-Methylenoxycarbonyloxy-5-androsten-17-on), N,N,N-tripropyl-ammonium-iodid, N-Methyl, N-(3β-methylenoxycarbonyloxy-5-androsten-l7-on)-imidazolonium-iodid, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-pyrrolidinium-hydrochlorid, N-(3β-methylenoxycarbonyloxy-5-androsten-17-on)-pyridinium-iodid, N-Methyl, N-(3β-methylenoxycarbonyloxy-5-androsten-l7-on)-pyrrolidinium-iodid, N-(3β-Methylenoxycarbonyloxy-5-androsten-17β-ol), N,N,N-triethyl-ammonium-iodid, N-(17β-Methylenoxycarbonyloxy-5-androsten-3-on), N, N N-triethyl-ammonium-iodid, N-(17β-Methylenoxycarbonyloxy-5-androsten-3β-ol), N, N N-triethyl-ammonium-iodid, N,N'-[3β,17β-(Di-methylenoxycarbonyloxy)-5-androsten]-(N,N,N)-,(N',N',N')-bis-triethyl-ammonium-diodid N-[3-Methoxy-17β-methylenoxycarbonyloxy-estra-1,3,5(10)-trien], N,N,N-triethylammonium-iodid, N-[17β-methylenoxycarbonyloxy-3-sulfamoyloxy-estra-1,3,5(10)-trien], N,N,N-triethyl-ammonium-iodid N-[17β-methylenoxycarbonyloxy-3-oxysulfonyloxy-estra-1,3,5(10)-trien], N,N,N-triethyl-ammonium-iodid N-[17β-methylenoxycarbonyloxy-3-oxysulfonylpropyl-estra-1,3,5(10)-trien], N,N, N-triethyl-ammonium-iodid N-[3-Methoxy-17β-methylenoxycarbonyloxy-estra-1,3,5(10),9(11)-tetraen], N,N N-triethyl-ammonium-iodid, N-(1-Methylenoxycarbonyloxy-dodecyl), N, N, N-triethyl-ammonium-iodid N,N'-[1,12-(Di-methylenoxycarbonyloxy)-dodecyl]-(N,N,N)-,(N',N',N')-bis-triethyl-ammonium-diodid.Carbonic acid ester type tetraalkylammonium salts according to claim 1, selected from the group N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-triethylammonium iodide, N- (3β-ethylideneoxycarbonyloxy-5-androsten-17- on), N, N, N-triethylammonium iodide, N- (3β-methyleneoxycarbonyloxy-5-cholestene), N, N, N-triethylammonium bromide, N- (3β-methyleneoxycarbonyloxy-24-ethyl-5-cholestone) , N, N, N-triethylammonium bromide, N- (3β-methyleneoxycarbonyloxy-24-ethyl-5,22-cholestadiene), N, N, N-triethylammonium iodide, N- (3β-methyleneoxycarbonyloxy-5-androsten- 17-one), N, N, N-trimethylammonium chloride, N, N-dimethyl, N-hexyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) -ammonium iodide, N, N-diethyl , N-methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) ammonium iodide, N, N-dimethyl, N-butyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) -ammonium iodide, N, N-dimethyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N-propargylammonium iodide, N, N-dimethyl, N- (3β-methyleneoxycarbonyloxy-5-androsten- 1 7-one), N-propynylammonium iodide, N, N-dimethyl, N-dodecyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) -ammonium iodide, N, N-dimethyl, N- ( 3β-methyleneoxycarbonyloxy-5-androsten-17-one), N-propenylammonium iodide, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-tripropylammonium iodide, N -Methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-l7-one) -imidazolonium iodide, N- (3β-methyleneoxycarbonyloxy-5-androsten-17-one) -pyrrolidinium hydrochloride, N- (3β-methyleneoxycarbonyloxy- 5-androsten-17-one) -pyridinium iodide, N-methyl, N- (3β-methyleneoxycarbonyloxy-5-androsten-l7-one) -pyrrolidinium-iodide, N- (3β-methyleneoxycarbonyloxy-5-androstene-17β- ol), N, N, N-triethylammonium iodide, N- (17β-methyleneoxycarbonyloxy-5-androsten-3-one), N, N, N-triethylammonium iodide, N- (17β-methyleneoxycarbonyloxy-5 -androsten-3β-ol), N, N N-triethylammonium iodide, N, N '- [3β, 17β- (dimethyleneoxycarbonyloxy) -5-androstening] - (N, N, N) -, ( N ', N', N ') - bis-triethylammonium diodide N- [3-methoxy-17β-methyleneoxycarbonyloxy-est ra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide, N- [17β-methyleneoxycarbonyloxy-3-sulfamoyloxy-estra-1,3,5 (10) -triene], N , N, N-triethylammonium iodide N- [17β-methyleneoxycarbonyloxy-3-oxysulfonylo xy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide N- [17β-methyleneoxycarbonyloxy-3-oxysulfonylpropyl-estra-1,3,5 (10) -triene ], N, N, N-triethylammonium iodide N- [3-methoxy-17β-methyleneoxycarbonyloxy-estra-1,3,5 (10), 9 (11) -tetraen], N, N N-triethyl- ammonium iodide, N- (1-methyleneoxycarbonyloxy-dodecyl), N, N, N-triethyl-ammonium iodide N, N '- [1.12- (dimethyleneoxycarbonyloxy) -dodecyl] - (N, N, N ) - (N ', N', N ') - bis-triethyl-ammonium-diodid. Verfahren zur Herstellung von Tetraalkylammoniumsalzen vom Kohlensäureestertyp der Formel I entsprechend Anspruch 1, gekennzeichnet dadurch, dass man Verbindungen der allgemeinen Formeln II,
Figure 00110001
worin A und n die oben angegebene Bedeutungen haben, n= 1 bis 3 ist, in an sich bekannter Weise mit Chlorameisensäurechlormethylester oder durch Umsetzung mit Phosgen und anschließender Reaktion mit Paraformaldehyd (Acetaldehyd) nach der Henry-Methode mit ZnCl2 in Carbonsäure-α-chloralkylester (mit Alkyl = Methyl oder Ethyl) umwandelt und diese mit einem Amin, NR2R3R4, worin R2, R3 und R4 die oben angegebenen Bedeutungen haben, in einem geeigneten Lösungsmittel, wie Aceton, DMF, Methylenchlorid oder einer entsprechenden Lösungsmittelkombination, in Gegenwart von Iodid, Bromid, Tosylat oder Chlorid in Form von Salzen umsetzt, isoliert und diese gegebenenfalls in an sich bekannter Weise oxidiert, verethert, acyliert, wozu unter anderem ein Säurederivat für Veresterungen, wie ein Carbonsäureanhydrid, Carbonsäurehalogenid, wie Carbosäurechlorid oder ein Sulfamoylhalogenid wie Sulfamoylchlorid in Gegenwart eines geeigneten Lösungsmittels und einer protonenabstrahierenden Base genutzt werden.
Process for the preparation of tetraalkylammonium salts of the carbonic ester type of the formula I according to claim 1, characterized in that compounds of the general formulas II,
Figure 00110001
in which A and n have the meanings given above, n = 1 to 3, in a manner known per se with chloromethyl chloroformate or by reaction with phosgene and subsequent reaction with paraformaldehyde (acetaldehyde) according to the Henry method with ZnCl 2 in carboxylic acid-α- chloroalkyl ester (with alkyl = methyl or ethyl) and this with an amine, NR 2 R 3 R 4 , wherein R 2 , R 3 and R 4 have the meanings given above, in a suitable solvent, such as acetone, DMF, methylene chloride or an appropriate combination of solvents, in the presence of iodide, bromide, tosylate or chloride in the form of salts, isolated and optionally oxidized, etherified, acylated in a manner known per se, for which purpose, inter alia, an acid derivative for esterifications, such as a carboxylic acid anhydride, carboxylic acid halide, such as Carboxylic acid chloride or a sulfamoyl halide such as sulfamoyl chloride in the presence of a suitable solvent and a proton jet the base can be used.
Pharmazeutische Zusammensetzung enthaltend mindestens ein Tetraalkylammoniumsalz vom Kohlensäureestertyp entsprechend Anspruch 1 gegebenenfalls mit pharmazeutisch verträglichen Hilfs-, Träger- oder Zusatzstoffen und/oder Stabilisatoren.Pharmaceutical composition containing at least a carbonic ester type tetraalkylammonium salt according to claim 1 optionally with pharmaceutically acceptable auxiliary, carrier or Additives and / or stabilizers.
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