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DE3405632A1 - Novel pleuromutilin derivatives, processes for their preparation, and their use - Google Patents

Novel pleuromutilin derivatives, processes for their preparation, and their use

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Publication number
DE3405632A1
DE3405632A1 DE19843405632 DE3405632A DE3405632A1 DE 3405632 A1 DE3405632 A1 DE 3405632A1 DE 19843405632 DE19843405632 DE 19843405632 DE 3405632 A DE3405632 A DE 3405632A DE 3405632 A1 DE3405632 A1 DE 3405632A1
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DE
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Prior art keywords
formula
acid addition
compound
preparation
pleuromutilin derivatives
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DE19843405632
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German (de)
Inventor
Erfinder Wird Nachtraeglich Benannt Der
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Sandoz AG
Sandoz Patent GmbH
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Sandoz AG
Sandoz Patent GmbH
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Priority to DE19843405632 priority Critical patent/DE3405632A1/en
Priority to AT85810049T priority patent/ATE29132T1/en
Priority to DE8585810049T priority patent/DE3560511D1/en
Priority to EP85810049A priority patent/EP0153277B1/en
Priority to KR1019850000904A priority patent/KR920001990B1/en
Priority to PH31854A priority patent/PH21588A/en
Priority to ES540464A priority patent/ES8606262A1/en
Priority to AU38773/85A priority patent/AU585209B2/en
Priority to IE37585A priority patent/IE58232B1/en
Priority to FI850654A priority patent/FI90414C/en
Priority to GR850415A priority patent/GR850415B/el
Priority to HU85567A priority patent/HU194819B/en
Priority to DK072885A priority patent/DK164664C/en
Priority to NZ211131A priority patent/NZ211131A/en
Priority to CA000474419A priority patent/CA1249281A/en
Priority to DD85273318A priority patent/DD253616A5/en
Priority to UA3857485A priority patent/UA7031A1/en
Priority to IL74355A priority patent/IL74355A/en
Priority to SU853857485A priority patent/SU1582985A3/en
Priority to ZA851190A priority patent/ZA851190B/en
Priority to PL1985251972A priority patent/PL145848B1/en
Priority to JP60029186A priority patent/JPH068278B2/en
Publication of DE3405632A1 publication Critical patent/DE3405632A1/en
Priority to US06/860,266 priority patent/US4675330A/en
Priority to MYPI87002186A priority patent/MY102919A/en
Priority to SG692/90A priority patent/SG69290G/en
Priority to HK1036/90A priority patent/HK103690A/en
Priority to CY1565A priority patent/CY1565A/en
Priority to FI921848A priority patent/FI88714C/en
Priority to LV960238A priority patent/LV5764B4/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to novel pleuromutilin derivatives of the formula <IMAGE> in which R1 represents ethyl or vinyl and R2 represents an aminoalkyl group or a five-membered saturated heterocycle, and to their acid addition salts and quaternary salts, as well as to processes for their preparation and to their use.

Description

Neue Pleuromutilinderivate, Verfahren zu ihrer Herstellung und ihre Ver-New pleuromutilin derivatives, processes for their preparation and their Ver

wendung Die Erfindung betrifft neue Pleuromutilinderivate der Formel worin R1 für Äthyl oder Vinyl und R2 für eine Aminoalkylgruppe oder für einen füfgliedrigen gesättigten Heterocyclus stehen, und ihre Säureadditione- und Quartärsalze, sowie Verfahren zu ihrer Herstellung und ihre Verwendung.Use The invention relates to new pleuromutilin derivatives of the formula where R1 is ethyl or vinyl and R2 is an aminoalkyl group or a five-membered saturated heterocycle, and their acid addition and quaternary salts, and processes for their preparation and their use.

Erfindungsgemäß gelangt man zu den Verbindungen der Formel I, indem man eine Verbindung der Formel worin R1 obige Bedeutung besitzt, mit einem Aktivester einer Verbindung der Formel HOOC-R2I III worin R2I die gleiche Bedeutung wie R2 besitzt, wobei jedoch die in R2 enthaltenen Aminogruppen durch eine Schutzgruppe geschützt rind, umsetzt und die Schutzgruppe anschließend abspaltet und die erhaltenen Verbindungen gewünschtenfalls in ihre Säureadditionsalze oder Quartärsalze überführt.According to the invention, the compounds of the formula I are obtained by adding a compound of the formula where R1 has the above meaning with an active ester of a compound of the formula HOOC-R2I III where R2I has the same meaning as R2, but the amino groups contained in R2 are protected by a protective group, reacts and then cleaves the protective group and the compounds obtained, if desired converted into their acid addition salts or quaternary salts.

Das erfindungsgemäße Verfahren kann beispielsweise durchgeführt werden, Indem man eine Verbindung der Formel II und eine Verbindung der Formel III In einem unter den Reaktionsbedingungen inerten Lösungsmittel, z.B. In einem Di(nieder)alkylcarbonsäureamid wie Dimethylformamid, löst oder suspendiert und die Reaktion bei Raumtemperatur oder erhöhter Temperatur, vorzugsweise bei Raumtemperatur, ablaufen läßt. Dr(r an.The method according to the invention can be carried out, for example, By combining a compound of the formula II and a compound of the formula III in one Solvent inert under the reaction conditions, e.g. in a di (lower) alkylcarboxamide such as dimethylformamide, dissolves or suspended and the reaction at room temperature or elevated temperature, preferably at room temperature, can run off. Dr (r on.

schließende Abspaltung der Schutzgruppe kann nach an sich bekannten Methoden durchgeführt werden, beispielsweise durch reduktive Entechützung mit Pd/Aktivkohle und Wasserstoff oder durch Behandeln mit Trifluoressigsäure. Aus dem Reaktionsgemisch kann nach an sich bekannten Methoden das Endprodukt isoliert und gegebenenfalls gereinigt werden.Final cleavage of the protective group can be carried out according to known methods Methods can be carried out, for example by reductive deprotection with Pd / activated carbon and hydrogen or by treating with trifluoroacetic acid. From the reaction mixture The end product can be isolated and, if appropriate, by methods known per se getting cleaned.

Die Verbindungen der Formel | können In ihre Säureadditionssalze überführt werden und umgekehrt. Aus den Verbindungen der Formel I können nach an sich bekannten Methoden die entsprechenden Quartärsalze erhalten werden.The compounds of the formula | can be converted into their acid addition salts and vice versa. From the compounds of the formula I can be according to known Methods the corresponding quaternary salts can be obtained.

Die Verbindungen der Formel 1 und ihre pharmakologisch verträglichen Säureadditions- und Quartäersalze besitzen bei geringer Toxizität interessante biologische, insbesondere antimikrobielle Eigenschaften und können daher als Heilmittel verwendet werden. Sie entfalten eins Hemmwirkung gegen Bakterien, wie rlch durch Untersuchungen in vitro mit dem Reihenverdünnungstest unter Verwendung verschiedener Bakterienstämme, z. B.The compounds of formula 1 and their pharmacologically acceptable Acid addition and quatene salts have interesting biological, especially antimicrobial properties and therefore can be used as medicinal products will. They develop an inhibitory effect against bacteria, as shown by studies in vitro with the serial dilution test using different bacterial strains, z. B.

von Staph, aureus, Staph, epidermidis, Strept, pyogenes, Strept, aronos, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaria, Salmonella typhimurium, Enterobacter agglomerans, Strept, pneumoniae, Strept, faecalis, Aerococcus viridans, Haemophilus spp. und Neisseria gonorrh., an einer Konzentration von ca. 0.015 bis 50 µg/ml, und in vivo durch Versuche an Mäusen zeigen läßt. Insbesondere wurde auch eine Hemmwirkung gegen Mykoplemon, z.B. gegen Mycoplas me hominir, Mycoplasma pneumoniae und Ureaplasma urealyticum, und Chlamydien, z. B. gegen Chlamydia trachomatis gefunden, die sich ab einer Konzentration von ca. 0,02 bis 5 µg/ml zeigte. Daher können die erfindungsgemäßen Verbindungen als antibakteriell wirksame Antibiotika verwendet werden.from staph, aureus, staph, epidermidis, strept, pyogenes, strept, aronos, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaria, Salmonella typhimurium, Enterobacter agglomerans, Strept, pneumoniae, Strept, faecalis, Aerococcus viridans, Haemophilus spp. and Neisseria gonorrh., at one concentration from approx. 0.015 to 50 µg / ml, and in vivo by experiments on mice lets show. In particular, an inhibitory effect against mycoplemon, e.g. against Mycoplas me hominir, Mycoplasma pneumoniae and Ureaplasma urealyticum, and chlamydia, z. B. found against Chlamydia trachomatis, which are found from a concentration of showed about 0.02 to 5 µg / ml. Therefore, the compounds of the invention can be used as antibacterial antibiotics are used.

Die Verbindungen der Formel 1 können in freier Form oder in Form pharmazeutisch unbedenklicher Säureadditionssalze verwendet werden, wobei die Salze größenordnungsmäßig die gleich Wirksamkeit besitzen wie die entsprechenden freien Basen. Geeignete Säureadditionssalze sind die Hydrochloride, Hydrogenfumarate und Naphthalin-1,5-sulfonat.The compounds of formula 1 can be in free form or in pharmaceutical form harmless acid addition salts are used, the salts being of the order of magnitude which have the same effectiveness as the corresponding free bases. Suitable acid addition salts are the hydrochlorides, hydrogen fumarates and naphthalene-1,5-sulfonate.

Die Verbindungen der Formel 1 können oral oder parenteral verabreicht werden. Als indifferente Hilfs- oder Zusatzstoffe zur Herstellung entsprechender galenischer Verabreichungsformen lassen sich Süßstoffe, Aromen, farbstoffe, Konservierungsmittel, Füll- bzw. Trägerstoffe, beispielsweise Verdünnungsmittel, wie Kalziumkarbonat, Natriumkarbonat, Lactose, Polyvinylpyrrolidon, Mannit oder Talkum, Granulier-und Zerfallhilfsmittel, wie Stärke oder Alginsäure, Bindemittel, wie Stärke, Gelatine oder Akazis, und Gleitmittel, wie Magnesiumstearat, Stearinsäure oder Talkum, verwenden.The compounds of formula 1 can be administered orally or parenterally will. As indifferent auxiliaries or additives for the production of corresponding galenic forms of administration, sweeteners, flavors, colors, preservatives, Fillers or carriers, for example diluents such as calcium carbonate, Sodium carbonate, lactose, polyvinylpyrrolidone, mannitol or talc, granulating and Disintegration aids, such as starch or alginic acid, binders, such as starch, gelatin or acacis, and lubricants such as magnesium stearate, stearic acid or talc.

Oral verabreichbare Zubereitungen können übliche Suspendiermittel enthalten, beispielsweise Methylcellulose, Tragacanth oder Natriumalginat. Als Netzmittel eignen sich beispielsweise Lecitin, Polyoxyäthylenstearat oder Polyoxyäthylensorbitanmonooleat. Als Konservierungsmittel läßt sich bei spleisweise Äthyl-o-hydroxybenzoat verwenden. Zur Herstellung von Kapsein kann man als Verdünnungsmittel beispielsweise Kalziumkarbonat, Kalziumphospaht oder Kaolin einsetzen.Orally administrable preparations can be customary suspending agents contain, for example methyl cellulose, tragacanth or sodium alginate. As a wetting agent for example lecithin, polyoxyethylene stearate or polyoxyethylene sorbitan monooleate are suitable. Ethyl o-hydroxybenzoate can be used as a preservative in splits. Calcium carbonate, for example, can be used as a diluent to produce capsules. Use calcium phosphate or kaolin.

Die Verbindungen der Formel I können in ähnlicher Weise wie für diese Verwendung bekannte Standardverbindungen, z. B. wie Erythromycin, singesetzt werden.The compounds of formula I can be used in a similar manner as for this Use known standard connections, e.g. B. such as erythromycin, are set individually.

Eine geeignete Tagesdosis für eine bestimmte Verbindung der Formel 1 hängt von einer Anzahl von Faktoren ab, z.B. von Ihrer relativen Aktivität. A suitable daily dose for a particular compound of the formula 1 depends on a number of factors, e.g. your relative Activity.

Diese ist z.B. für 14-O-[1-(2-Amino-3-methlbutyrmido)-2-methylpropyl-2-ylthioacetyl]-19,20-dihydromutilin. Hydrochlorid in einer septikämischen Modellinfektion der Maus bestimmt worden und beträgt etwa 40 mg/kg Körpergewicht (ED50 für perorale Verbreichung) im Vergleich zu 68 mg/kg Körpergewicht für Erythromycin. Die erfindungsgemäßen Verbindungen können daher In ähnlicher oder niedrigerer Doaierung angewendet werden als die allgemein für Erythromycin (z. B. 4x500 mg) eingesetzte Dosis.This is e.g. for 14-O- [1- (2-Amino-3-methylbutyrmido) -2-methylpropyl-2-ylthioacetyl] -19,20-dihydromutilin. Hydrochloride has been determined in a septicemic model infection of the mouse and is about 40 mg / kg body weight (ED50 for oral administration) in comparison to 68 mg / kg body weight for erythromycin. The compounds according to the invention can can therefore be used in a similar or lower manner than in general dose used for erythromycin (e.g. 4x500 mg).

Die Ausgangsverbindungen der Formel II sind neu und können erhalten worden, Indem man eine Verbindung der Formal worin R1 obige Bedeutung besitzt und R5 für Chlor, Brom oder eine -O.SO2.R6-Gruppe, wobei R6 Alkyl oder Aryl bedeutet, steht, mit einer Verbindung der Formel umsetzt. Diese Umsetzung kann beispielsweise ausgeführt werden, indem man in einer Lösung von Natrium in einem wasserfreien niederen Alkohol, z.5. In Äthanol oder Methanol, eine Verbindung der Formel V löst. Zu dieser Lösung wird nun dl. Lösung einer Verbindung der Formel IV in einem unter den Reaktionsbedingungen Inerten Lösungsmittel, z.B. In einem aliphatischen Keton, wle Äthylmethylketon oder Aceton, zugesetzt. Die Reaktion verläuft vorzugsweise bei Raumtemperatur bis zur Siedetemperatur des Reaktionsgemisches, insbesondere bei 25 bis 55°C, und dauert beispielsweise zwischen 7 und 15 Stunden.The starting compounds of the formula II are new and can be obtained by making a compound of the formula in which R1 has the above meaning and R5 is chlorine, bromine or an -O.SO2.R6 group, where R6 is alkyl or aryl, with a compound of the formula implements. This reaction can be carried out, for example, by in a solution of sodium in an anhydrous lower alcohol, z.5. In ethanol or methanol, a compound of formula V dissolves. This solution is now dl. Solution of a compound of the formula IV in a solvent which is inert under the reaction conditions, for example in an aliphatic ketone, such as ethyl methyl ketone or acetone, is added. The reaction preferably proceeds from room temperature to the boiling point of the reaction mixture, in particular from 25 to 55 ° C., and lasts, for example, between 7 and 15 hours.

Die Ausgangsprodukte der Formeln III, IV und V sind bekannt oder analog zu bekannten Methoden bzw. wie In den Beispielen beschrieben herstellbar.The starting products of the formulas III, IV and V are known or analogous can be prepared using known methods or as described in the examples.

Die Verbindungen der Formel V sind beispielsweise wie in F.J.Carroll, J.D.The compounds of the formula V are, for example, as in F.J. Carroll, J.D.

White und M.E.Wall, J.Org.Chem. 28/1240(1963) beschrieben erhältlich.White and M.E.Wall, J.Org.Chem. 28/1240 (1963) available.

Die als Substituenten aufscheinenden Alkylgruppen bedeuten vorzugsweise niedere Alkylgruppent insbesondere mit 1 bb 4 Kohlenstoffatomen. Steht R2 für einen Heterocyclus, so kann dieser ein oder zwei Heteroatome enthalten, wobei ein Heteroatom Stickstoff und das gegebenenfalls vorhendene zweite Heteroatom Schwefel ist.The alkyl groups appearing as substituents are preferably lower alkyl groups, in particular with 1 bb 4 carbon atoms. R2 stands for one Heterocycle, this can contain one or two heteroatoms, one heteroatom Nitrogen and the optionally present second heteroatom is sulfur.

Als Schutzgruppen für die Aminofunktion in den Ausgangsverbindungen der Formel III können die allgemein als Aminoschutzgruppen bekannten eingesetzt werden, beispielsweise -CO.O.CH2.C6H5, -CO.O.C(CH3)3 oder -CO.O.CH2.CCl3.As protective groups for the amino function in the starting compounds of the formula III, those generally known as amino protective groups can be used for example -CO.O.CH2.C6H5, -CO.O.C (CH3) 3 or -CO.O.CH2.CCl3.

In den nachfolgenden Beispielen, die die Erfindung näher erläutern, ihren Umfang aber in keiner Weise einschränken sollen, erfolgen alle Temperaturangaben in Celsiusgraden.In the following examples, which explain the invention in more detail, but are not intended to limit their scope in any way, all temperature data are given in degrees Celsius.

Beispiel 1: 14-O-[1-(2-Amino-3-methylbutyrylamino)-2-methylpropyl-2-ylthioacetyl]-19,20-dihydromutilin-hydrochlorid: Eine Lösung von 1,85 g Z-Valin-4-nitrophenylester und 2,35 g 14-O-[(1-Amino-2-methylpropan-2-yl)thioacetyl]-19,20-dihydromutilin in 30 ml Dimethylformamid wird 1 Stunden bei 20 gehalten. Das Reaktionsgemisch wird anschließend auf Wasser gegossen und wiederholt mit Essigsäureäthylester ausgeschüttelt. Nach Rückwaschen der organIschen Phase mit 0,1 N Salzsäure und anschließend mit NaCl-gesättigtem Wasser erhält man die geschützte Titelverbindung, die ohne weiter Reinigung zur Entschützung eingesetzt wird.Example 1: 14-O- [1- (2-Amino-3-methylbutyrylamino) -2-methylpropyl-2-ylthioacetyl] -19,20-dihydromutilin hydrochloride: A solution of 1.85 g of Z-valine-4-nitrophenyl ester and 2.35 g of 14-O - [(1-amino-2-methylpropan-2-yl) thioacetyl] -19,20-dihydromutilin in 30 ml of dimethylformamide is kept at 20 for 1 hour. The reaction mixture is then poured into water and extracted repeatedly with ethyl acetate. After backwashing the organic phase with 0.1 N hydrochloric acid and then with NaCl-saturated water gives the protected title compound, which without further Purification is used for deprotection.

Eine Lösung von 3,1 g dieser Z-geschützten Verbindung in 150 ml Äthanol wird mit 60 mg Pd/Aktivkohle (Palladium auf Aktivkohle, 10%ig) versetzt und unter Wasserstoffatmosphäre 1 Stunde gerührt. Man erhält in praktisch quantitativer Ausbeute die Titelverbindung.A solution of 3.1 g of this Z-protected compound in 150 ml of ethanol is mixed with 60 mg Pd / activated carbon (palladium on activated carbon, 10%) and under Stirred hydrogen atmosphere for 1 hour. The yield is practically quantitative the title compound.

Das Verfahren kann auch mit BOC-Valin 4-nltrophenylester durchgeführt werden, wobei die Entschützung folgendermaßen ausgeführt wird: 3 mMol der BOC-geschützten Verbindung werden bei -10° in 25 ml Trifluoressigsäure gelöst und bei dieser Temperatur 10 Minuten gehalten.The process can also be carried out with BOC valine 4-nitrophenyl ester where deprotection is carried out as follows: 3 mmol of the BOC-protected Compound are dissolved in 25 ml of trifluoroacetic acid at -10 ° and at this temperature Held for 10 minutes.

Anschließend bringt man das Reaktionsgemisch auf 25°, läßt weitere 2 Stunden reagieren und gießt in der Folge auf 100 ml 10%ige NaHCO3-Lö-Sung. Nach wiederholtem Extrahieren mit Essigsäureäthylester und RUckwaschen der organischen Phase erhält man das Rohprodukt, das über Kiessigel (Laufmittel: CHCl3/CH3OH = 7/1) chromatographiert wird.The reaction mixture is then brought to 25 ° and more is left React for 2 hours and then pour onto 100 ml of 10% NaHCO3 solution. To repeated extraction with ethyl acetate and backwashing of the organic Phase, the crude product is obtained, which is poured over Kiessigel (mobile phase: CHCl3 / CH3OH = 7/1) is chromatographed.

Analog wie in Beispiel 1 beschrieben, können auch folgende Verbindungen der Formel erhalten werden: BP: R R v . | | 2 -CSsZ2 -CM2. NM2 3 - n - -CH.C3 (D) bH2 4 ~ - -1i. CH2 . CH Cl13 NM2 CM3 5 -C2H5 -C1a.CH3 (D) NH2 6 -CHeCH2 -CH.0M3 (L) 2 7 -n- | H 8 - n 1 j (L) M 9 - 1 r -CH2CM20 NR2 10 w e -CH - CR-CH 3 NH2 CM3 (L> 11 - n - . (D) NMR-Spektren (CDCl3) Beispiel: Spektrum: 1 5.62 (d, 1H, H14, JH14H13 = 7,5 Hz); 7.72 (t, 1H, NHCO); 3.42 (d, 1H, N-CH-CO, J = 6,23 Hz); 3.32 (d, 1H, H11, JH11H10 = 6,23 Hz); AB-System: (VA = 3.17, VB = 3.27, JAB = 15 Hz, S-CH2-CO).Analogously to that described in Example 1, the following compounds of the formula can also be obtained: BP: RR v. | | 2 -CSsZ2 -CM2. NM2 3 - n - -CH.C3 (D) bH2 4 ~ - -1i. CH2. CH Cl13 NM2 CM3 5 -C2H5 -C1a.CH3 (D) NH2 6 -CHeCH2 -CH.0M3 (L) 2 7 -n- | H 8 - n 1 j (L) M. 9 - 1 r -CH2CM20 NR2 10 we -CH - CR-CH 3 NH2 CM3 (L> 11 - n -. (D) NMR Spectra (CDCl3) Example: Spectrum: 15.62 (d, 1H, H14, JH14H13 = 7.5 Hz); 7.72 (t, 1H, NHCO); 3.42 (d, 1H, N-CH-CO, J = 6.23 Hz); 3.32 (d, 1H, H11, JH11H10 = 6.23 Hz); AB system: (VA = 3.17, VB = 3.27, JAB = 15 Hz, S-CH2-CO).

2 7.68 (t, 1H, NH); 5.73 (d, 1H, H14, JH14H13 = 8,75 Hz); 3.75 (s, 2H, CO-CH2-NH2); 3.38 (d, 1H, H11, JH11H10 = 6,25 Hz); 3.28 (m, 2H,#C-CH2-NH); 1.25, 1.26 (s, s, 6H, gem. CH3).2 7.68 (t, 1H, NH); 5.73 (d, 1H, H14, JH14H13 = 8.75 Hz); 3.75 (s, 2H, CO-CH2-NH2); 3.38 (d, 1H, H11, JH11H10 = 6.25 Hz); 3.28 (m, 2H, # C-CH2-NH); 1.25, 1.26 (s, s, 6H, according to CH3).

3 7.78 (t, 1H, NH); 5.74 (d, 1H, H14, JH14H13 = 8,75 Hz); 4.03 (q, 1H, -CH-CH3, J = 7,3 Hz); 3.37 (d, 1H,H11, JH11H10 = 6,25 Hz); 1.25 (s, 2xCH3, gem. CH3); 3.3 (m, 2H#C-Ch2-NH).3 7.78 (t, 1H, NH); 5.74 (d, 1H, H14, JH14H13 = 8.75 Hz); 4.03 (q, 1H, -CH-CH3, J = 7.3 Hz); 3.37 (d, 1H, H11, JH11H10 = 6.25 Hz); 1.25 (s, 2xCH3, acc. CH3); 3.3 (m, 2H # C-Ch2-NH).

4 7.76 (t, 1H, NH); 5.76 (d,1H,H14, JH14H13 = 8,75 Hz); J = 3,75 Hz, J = 8,75 Hz); 3.25 (d, 2H, CH-CH2-NH2); AB-System: (VA = 3.17, VB = 3.25, JAB = 15 Hz, -S-CH2CO).4,776 (t, 1H, NH); 5.76 (d, 1H, H14, JH14H13 = 8.75 Hz); J = 3.75 Hz, J = 8.75 Hz); 3.25 (d, 2H, CH-CH2-NH2); AB system: (VA = 3.17, VB = 3.25, JAB = 15 Hz, -S-CH2CO).

5 5.64 (d, 1H, H14, JH14J13 = 8,1 Hz); 3.56 (q, 1H, CH3-CH, J = 7,5 Hz); 3.44 (d, 1H, H11, JH11H10 = 6,25 Hz); AB-System: (VA = 3.17, VB = 3.25, JAB = 15 Hz, S-CH2-CO); ABX-System: (VA = 3.33, VB = 3.25, VX = 7.75, JAB = 13,4 Hz, JAX = JBX = 7,5 Hz, C-CH2-NH).5.564 (d, 1H, H14, JH14J13 = 8.1 Hz); 3.56 (q, 1H, CH3-CH, J = 7.5 Hz); 3.44 (d, 1H, H11, JH11H10 = 6.25 Hz); AB system: (VA = 3.17, VB = 3.25, JAB = 15 Hz, S-CH2-CO); ABX system: (VA = 3.33, VB = 3.25, VX = 7.75, JAB = 13.4 Hz, JAX = JBX = 7.5 Hz, C-CH2-NH).

6 7.74 (t, 1H, NH); 5.75 (d, 1H, H14, JH14H13 = 8,75 Hz); J = 7,5 Hz); 3.36 (d, 1H, H11, JH11H10 = 6,25 Hz); AB-System: (VA = 3.17, VB = 3.24, 15 Hz, S-CH2-CO); 1.4 (d, 3H, 7,5 Hz).6 7.74 (t, 1H, NH); 5.75 (d, 1H, H14, JH14H13 = 8.75 Hz); J = 7.5 Hz); 3.36 (d, 1H, H11, JH11H10 = 6.25 Hz); AB system: (VA = 3.17, VB = 3.24, 15 Hz, S-CH2-CO); 1.4 (d, 3H, 7.5 Hz).

7 7.72 (t, 1H, NH); 5.77 (d, 1H, H14, JH14H13 = 8,75 Hz); AB-System: (VA = 4.29, VB = 4.13, JAB = 10 Hz, 5-CH2-NH); 3.36 (m, 1H, H11).7 7.72 (t, 1H, NH); 5.77 (d, 1H, H14, JH14H13 = 8.75 Hz); AB system: (VA = 4.29, VB = 4.13, JAB = 10 Hz, 5-CH2-NH); 3.36 (m, 1H, H11).

8 8.07 (m, 1H, NH); 5.76 (d, 1H, H14, JH14J13 = 8,75 Hz); 3,84 (dd, 1H, J = 5 Hz, J = 8,75 Hz); 3.38 (d, 1H, H11, JH11H10 = 6,25 Hz); AB-System: (VA = 3.17, VB = 3.23, JAB = 15 Hz, 5-CH2-CO); 3.25 (m, 2H, #C-CH2-NH).8 8.07 (m, 1H, NH); 5.76 (d, 1H, H14, JH14J13 = 8.75 Hz); 3.84 (dd, 1H, J = 5 Hz, J = 8.75 Hz); 3.38 (d, 1H, H11, JH11H10 = 6.25 Hz); AB system: (VA = 3.17, VB = 3.23, JAB = 15 Hz, 5-CH2-CO); 3.25 (m, 2H, # C-CH2-NH).

9 5.62 (d, 1H, H14, JH14H13 = 7,5 Hz); 3.24 (d, 1H, H11, JH11H10 = 6,25 Hz); ABX-System: (VA = 3.34, VB = 3.26, VX = 7.38, JAB = 13,5 Hz, JAX = JBX = 7,5 Hz, NH-CH2-C#); 3.83 (t, 2H, NH2-CH2, J = 5 Hz); 2.38 (t, 2H, CH2CO, J = 3 Hz). 9 5.62 (d, 1H, H14, JH14H13 = 7.5 Hz); 3.24 (d, 1H, H11, JH11H10 = 6.25 Hz); ABX system: (VA = 3.34, VB = 3.26, VX = 7.38, JAB = 13.5 Hz, JAX = JBX = 7.5 Hz, NH-CH2-C #); 3.83 (t, 2H, NH2-CH2, J = 5 Hz); 2.38 (t, 2H, CH2CO, J = 3 Hz).

10 7.68 (m, 1H, NH); 5.74 (d, 1H, H14, JH14H13 = 8,75 Hz); 3.2 (s, 2H, S-CH2-CO); 3.38 (m, 1H, H11); 3.25 (d, 1H, CH-CH3, J = 3,75 Hz).10 7.68 (m, 1H, NH); 5.74 (d, 1H, H14, JH14H13 = 8.75 Hz); 3.2 (s, 2H, S-CH2-CO); 3.38 (m, 1H, H11); 3.25 (d, 1H, CH-CH3, J = 3.75 Hz).

11 8.05 (t, 1H, NH, NH-CH2-C#); 5.73 (d, 1H, H14, JH14H13 = 8,75 Hz); 4.48 (dd, 1H, J = 8,75, J' = 6,25); 1.25, 1.22 (s, s, gem. CH3); AB-System: (VA = 3.18, VB = 3.24, JAB = 15 Hz, S-CH2-CO).11 8.05 (t, 1H, NH, NH-CH2-C #); 5.73 (d, 1H, H14, JH14H13 = 8.75 Hz); 4.48 (dd, 1H, J = 8.75, J '= 6.25); 1.25, 1.22 (s, s, according to CH3); AB system: (VA = 3.18, VB = 3.24, JAB = 15 Hz, S-CH2-CO).

Das als Ausgangsprodukte benötigte 14-O-[(1-Amino-2-methylpropan-2-yl)thioacetyl]-19,20-dihydromutilin kann folgendermaßen erhalten werden: 4,6 g Natrium werden in 500 ml Äthanol (absolut) gelöst, mit 14,1 g 3-Amino-2-methyl-2-methyl-2-propylmercaptan [F.I.Carroll, J.D. White und M.E.Wall, J. Org. Chem. 28, 1240 (1963)] versetzt und 1 Stunde bei 25° gerührt. Das Reaktionsgemisch wird anschließend mit einer Lösung aus 53,2 g Pleuromutilin-22-O-tosylat in 300 ml Äthylmethylketon versetzt und 15 Stunden bei 250 gehalten. Min gießt in der Folge auf Eiswasser und extrahiert wiederholt mit Essigsäureäthylester. Nach Rückwaschen der organischen Phase mit NaCl-gesättigtem Wasser erhält man ein Rohprodukt, das über Kieselgel (Laufmittel: CHCl3/CH3OH = 7/1) chromatographiert wird.The 14-O - [(1-amino-2-methylpropan-2-yl) thioacetyl] -19,20-dihydromutilin required as starting materials can be obtained as follows: 4.6 g of sodium are used in 500 ml of ethanol (absolute) dissolved with 14.1 g of 3-amino-2-methyl-2-methyl-2-propyl mercaptan [F.I. Carroll, J.D. White and M.E.Wall, J. Org. Chem. 28, 1240 (1963)] and Stirred for 1 hour at 25 °. The reaction mixture is then mixed with a solution from 53.2 g of pleuromutilin-22-O-tosylate in 300 ml of ethyl methyl ketone and 15 Held at 250 hours. Min then pours onto ice water and extracts repeatedly with ethyl acetate. After backwashing the organic phase with NaCl-saturated Water, a crude product is obtained, which over silica gel (mobile phase: CHCl3 / CH3OH = 7/1) is chromatographed.

NMR (CDCl3): 5.8 )(d, 1H, H14, JH14H13 = 9 Hz); 3.38 (d, 1H, H11, JH11H10 = 6,3 Hz); 3.17 (s, 2H, S-CH2-CO); 2.63 (s, 2H, N-CH2-C#); 1.7 (b, 2H, NH2); 1.28 (s, 6H, 2 x CH3).NMR (CDCl3): 5.8) (d, 1H, H14, JH14H13 = 9 Hz); 3.38 (d, 1H, H11, JH11H10 = 6.3 Hz); 3.17 (s, 2H, S-CH2-CO); 2.63 (s, 2H, N-CH2-C #); 1.7 (b, 2H, NH2); 1.28 (s, 6H, 2 x CH3).

Claims (2)

Patentansprüche: 1. Neue Pleuromutilinderivate der Formel worin R1 für Äthyl oder Vinyl und R2 für eine Aminoalkylgruppe oder für einen fünfglidrigen gesättigten Heterocyclus stehen, und ihre Säureadditions- und Quartärsalze.Claims: 1. New pleuromutilin derivatives of the formula where R1 is ethyl or vinyl and R2 is an aminoalkyl group or a five-membered saturated heterocycle, and their acid addition and quaternary salts. 2. Verfahren zur Herstellung neuer Pleuromutilinderivate der Formel worin R1 für Äthyl oder Vinyl und R2 für eine Aminoeikylgruppe oder für einen fünfgliedrigen gesättigten Heterocyclus stehen, und ihrer Säureadditions- und Quartärsalze, dadurch gekennzeichnet, daß man eine Verbindung der Formel worin R1 obige Bedeutung besitzt, mit einem Aktivester einer Verbindung der Formel HOOC-R2I worin R2¹ die gleiche Bedeutung wie R2 besitzt, wobei Jedoch die in enthaltenen Aminogruppen durch eine Schutzgruppe geschützt sind, umsetzt und die Schutzgruppe anschließend abspaltet und die erhaltenen Verbindungen gewünschtenfalls in ihre Säureadditionssalze oder Quartärsalze überführt.2. Process for the preparation of new pleuromutilin derivatives of the formula wherein R1 is ethyl or vinyl and R2 is an amino alkyl group or a five-membered saturated heterocycle, and its acid addition and quaternary salts, characterized in that a compound of the formula wherein R1 has the above meaning with an active ester of a compound of the formula HOOC-R2I wherein R2¹ has the same meaning as R2, but the amino groups contained in are protected by a protective group, reacts and then cleaves the protective group and the compounds obtained in their if desired Acid addition salts or quaternary salts transferred.
DE19843405632 1984-02-17 1984-02-17 Novel pleuromutilin derivatives, processes for their preparation, and their use Withdrawn DE3405632A1 (en)

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Application Number Priority Date Filing Date Title
DE19843405632 DE3405632A1 (en) 1984-02-17 1984-02-17 Novel pleuromutilin derivatives, processes for their preparation, and their use
AT85810049T ATE29132T1 (en) 1984-02-17 1985-02-11 NEW PLEUROMUTILIN DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND THEIR USE.
DE8585810049T DE3560511D1 (en) 1984-02-17 1985-02-11 Pleuromutilin derivatives, process for their preparation and their use
EP85810049A EP0153277B1 (en) 1984-02-17 1985-02-11 Pleuromutilin derivatives, process for their preparation and their use
KR1019850000904A KR920001990B1 (en) 1984-02-17 1985-02-14 Method for preparing fluromuterine derivative
PH31854A PH21588A (en) 1984-02-17 1985-02-14 Pleuromutilin derivatives and method of use thereof
DD85273318A DD253616A5 (en) 1984-02-17 1985-02-15 PROCESS FOR PREPARING NEW PLEUNROMUTILINE DERIVATIVES
ZA851190A ZA851190B (en) 1984-02-17 1985-02-15 Pleuromutilin derivatives,process for their preparation and their use
IE37585A IE58232B1 (en) 1984-02-17 1985-02-15 Pleuromutilin derivatives, process for their preparation and their use
FI850654A FI90414C (en) 1984-02-17 1985-02-15 Process for the preparation of therapeutically useful pleuromutilin derivatives
GR850415A GR850415B (en) 1984-02-17 1985-02-15
HU85567A HU194819B (en) 1984-02-17 1985-02-15 Process for producing pleuromutilin derivatives and pharmaceutical compositions containing them
DK072885A DK164664C (en) 1984-02-17 1985-02-15 PLEUROMUTILIN DERIVATIVES, PROCEDURES FOR PREPARING THEREOF, CHEMOTHERAPEUTIC PREPARATION AND FEED OR DRINKING WATER ADDITIVE PREPARATIONS CONTAINING A PLEUROMUTIL DERIVATIVE
NZ211131A NZ211131A (en) 1984-02-17 1985-02-15 Antibacterial and antiparasitic pleuromutilin derivatives and veterinary compositions thereof
CA000474419A CA1249281A (en) 1984-02-17 1985-02-15 Pleuromutilin derivatives process for their preparation and their use
ES540464A ES8606262A1 (en) 1984-02-17 1985-02-15 Pleuromutilin derivatives, process for their preparation and their use.
UA3857485A UA7031A1 (en) 1984-02-17 1985-02-15 METHOD OF OBTAINING PLEUROMUTILIN DERIVATIVES OR THEIR HYDROCHLORIDES
IL74355A IL74355A (en) 1984-02-17 1985-02-15 Pleuromutilin derivatives,their preparation and compositions containing them
SU853857485A SU1582985A3 (en) 1984-02-17 1985-02-15 Method of producing deoivatives of pleuromutiline or their hydrochlorides
AU38773/85A AU585209B2 (en) 1984-02-17 1985-02-15 Pleuromutilin derivatives, processes for their preparation and their uses
PL1985251972A PL145848B1 (en) 1984-02-17 1985-02-15 Method of obtaining novel pleuromutiline derivatives
JP60029186A JPH068278B2 (en) 1984-02-17 1985-02-16 Pluromutilin derivative, production method and use thereof
US06/860,266 US4675330A (en) 1984-02-17 1986-05-06 Pleuromutilin derivatives process for their preparation and their use
MYPI87002186A MY102919A (en) 1984-02-17 1987-09-29 Pleuromutilin derivatives process for their preparation and their use.
SG692/90A SG69290G (en) 1984-02-17 1990-08-22 Pleuromutilin derivatives,process for their preparation and their use
HK1036/90A HK103690A (en) 1984-02-17 1990-12-13 Pleuromutilin derivatives, process for their preparation and their use
CY1565A CY1565A (en) 1984-02-17 1991-05-17 Novel pleuromutilin derivatives,process for their production and their use
FI921848A FI88714C (en) 1984-02-17 1992-04-24 Pleuromutilin derivatives promoting growth
LV960238A LV5764B4 (en) 1984-02-17 1996-07-16 New Derivatives To Heal For Healing By Their Satisfaction And Their Usage

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001127A1 (en) * 1996-07-04 1998-01-15 Biochemie Gesellschaft Mbh Veterinary use of a pleuromutilin derivative
WO1999021855A1 (en) * 1997-10-29 1999-05-06 Smithkline Beecham P.L.C. Pleuromutilin derivatives as antimicrobials
NO331772B1 (en) * 1996-07-04 2012-03-26 Biochemie Gmbh Veterinary use of a pleuromutiline derivative

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9918037D0 (en) * 1999-07-30 1999-09-29 Biochemie Gmbh Organic compounds
DE10036184A1 (en) * 2000-07-24 2002-02-14 Aventis Cropscience Gmbh Substituted sulfonylaminomethylbenzoic acid (derivatives) and process for their preparation
EP1908750A1 (en) * 2006-10-05 2008-04-09 Nabriva Therapeutics Forschungs GmbH Process for the preparation of pleuromutilins

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001127A1 (en) * 1996-07-04 1998-01-15 Biochemie Gesellschaft Mbh Veterinary use of a pleuromutilin derivative
US6130250A (en) * 1996-07-04 2000-10-10 Biochemie Gesellschaft M.B.H. Veterinary use of a pleuromutilin derivative
RU2197237C2 (en) * 1996-07-04 2003-01-27 Биохеми Гезельшафт Мбх Method for treating animal diseases induced by bacteria (variants) and method for manufacturing a medicinal product
NO331772B1 (en) * 1996-07-04 2012-03-26 Biochemie Gmbh Veterinary use of a pleuromutiline derivative
WO1999021855A1 (en) * 1997-10-29 1999-05-06 Smithkline Beecham P.L.C. Pleuromutilin derivatives as antimicrobials
EP1452534A1 (en) * 1997-10-29 2004-09-01 Smithkline Beecham Plc Pleuromutlin derivatives as antimicrobials
EP1930330A1 (en) * 1997-10-29 2008-06-11 Smithkline Beecham Plc Pleuromutilin derivatives as antimicrobials

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