DE1956237A1 - Spiro-pyrrolizidone-oxindoles - Google Patents

Spiro-pyrrolizidone-oxindoles

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Publication number
DE1956237A1
DE1956237A1 DE19691956237 DE1956237A DE1956237A1 DE 1956237 A1 DE1956237 A1 DE 1956237A1 DE 19691956237 DE19691956237 DE 19691956237 DE 1956237 A DE1956237 A DE 1956237A DE 1956237 A1 DE1956237 A1 DE 1956237A1
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Prior art keywords
formula
spiro
oxindoles
parts
lower alkyl
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Pending
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DE19691956237
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German (de)
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Ekkehard Prof Dr Winterfeld
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BASF SE
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BASF SE
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Priority to DE19691956237 priority Critical patent/DE1956237A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems

Abstract

Spiro-pyrrolizidone-oxindoles. Novel cpds. of formula (I) (where R1 = H, lower alkyl, aryl, MeO or NO2; R2 = H or lower alkyl; R3 = lower alkyl or aralkyl) are intermediates for pharmaceutical spiro-indolines, (I) may be prepd. by treating the corresp. 1-pyrrolidino-3-oxo-5,6,11-11b-tetrahydro-3H-indolo 3,2-g -indolizidine derivs. with an alkali metal alcoholate derived from R3OH, in the presence of O2.

Description

Spiro-pyrrolizidon-oxindole Die Erfindung betrifft neue Spiro-pyrrolizidon-oxindole der Formel I in der R1 ein Wasserstoffatom oder eine niedrige verzweigte oder geradkettige Alkyl-, Aryl-, Methoxy- oder Nitrogruppe, R2 ein Wasserstoffatom oder eine niedrige Alkylgruppe und R5 eine niedrige Alkyl- oder Aralkylgruppe bedeutet.Spiro-pyrrolizidone-oxindoles The invention relates to new spiro-pyrrolizidone-oxindoles of the formula I. in which R1 is a hydrogen atom or a lower branched or straight-chain alkyl, aryl, methoxy or nitro group, R2 is a hydrogen atom or a lower alkyl group and R5 is a lower alkyl or aralkyl group.

Die Erfindung betrifft außerdem ein Verfahren zur Herstellung dieser Verbindungen.The invention also relates to a method for producing these Links.

Nach bekannten Verfahren werden Indolderivate der Formel (1) Uber Oxydation mit Bleitetraacetat, Alkalihypochlorit oder tert.-Butoxychlorid zunächst in substituierte Indolemine der Formel (2) und anschließend unter Säurebehandlung in die Spirooxindole der Formel (3) überrUhrt. (H. Zinner und J. Shavel jr. According to known processes indole derivatives of the formula (1) Uber Oxidation with lead tetraacetate, alkali hypochlorite or tert-butoxychloride first into substituted indolemines of the formula (2) and then under acid treatment into the spirooxindoles of the formula (3). (H. Zinner and J. Shavel Jr.

J. org. Chem. )1, 1765 (1966) und N. Finch und W.T. Taylor, J. Amer. Chem. Soc. 84, 1318, 3871 (1962).) Die für diesen Synthesegang notwendigen Agentien sowie die für die Umlagerung b > c notwendige Behandlung mit Säuren ist nicht allen für eine solche Synthese in Betracht kommenden Substanzen zuträglich, auch wird die in (2), Ring b gezeigte Indoleninbildung durch Akzeptorsubstituenten im aromatischen Ring (a) vereitelt.J. org. Chem.) 1, 1765 (1966) and N. Finch and WT Taylor, J. Amer. Chem. Soc. 84, 1318, 3871 (1962).) The agents necessary for this synthesis process and the treatment with acids necessary for the rearrangement b> c are not beneficial for all substances considered for such a synthesis, also the indolenine formation shown in (2), ring b is caused by acceptor substituents in the aromatic ring (a ) foiled.

Es wurde nun gefunden, daß man aus Indolderivaten der Formel II Spiro-pyrrolizidon-oxindole der Formel I erhält, wenn man jene in Gegenwart von Sauerstoff mit Alkali-Alkoholat in Alkohol erhitzt. R1, R2 und R3 haben in diesem Formelschema die gleiche Bedeutung wie in Formel I.It has now been found that indole derivatives of the formula II Spiro-pyrrolizidone-oxindoles of the formula I are obtained when they are heated in the presence of oxygen with an alkali metal alcoholate in alcohol. In this formula scheme, R1, R2 and R3 have the same meaning as in formula I.

Für die Ausführung dieses Verfahrens empfiehlt sich allgemein folgende Arbeitsweise: Die Indolo-Indolizidone der Formel II (5 Gewichtsteile) werden mit einer Lösung des entsprechenden Alkalimetalls (Natrium oder Kalium, vorzugsweise Natrium) (i bis 2 Gewichtsteile) in der 10- bis 20-fachen Menge des primären Alkohols, wie z.B. Methanol, Äthanol, Benzylalkohol, vorzugsweise Methanol, in normaler Raumatmosphäre (Stickstoff und Sauerstoff) 5 bis 8 Stunden, vorzugsweise auf ungefähr 60 bis ungefähr 1000C erhitzt. Die Reaktion kann auch unter Druck ausgeführt werden.The following are generally recommended for performing this procedure Method of operation: The indolo-indolizidones of the formula II (5 parts by weight) are with a solution of the appropriate alkali metal (sodium or potassium, preferably Sodium) (1 to 2 parts by weight) in 10 to 20 times the amount of the primary alcohol, such as methanol, ethanol, benzyl alcohol, preferably methanol, in normal room atmosphere (Nitrogen and oxygen) 5 to 8 hours, preferably about 60 to about Heated to 1000C. The reaction can also be carried out under pressure.

Als Alkohole bzw. Alkoholate werden primäre aliphatische oder aliphatisch-aromatische Alkohole bevorzugt.The alcohols or alcoholates used are primary aliphatic or aliphatic-aromatic Alcohols preferred.

Nach diesem Verfahren können generell Verbindungen der Formel II mit Substituenten oben angegebener Bedeutung im aromatischen Ring (a) und im Ring (c) umgesetzt werden.According to this process, compounds of the formula II can generally be used with Substituents of the meaning given above in the aromatic ring (a) and in the ring (c) implemented.

X+ bedeutet in diesem Formelschema eine Gruppierung mit Elektronenmangel, die dann in (b) als negativer Rest im Molekül gebunden ist (X-).In this formula scheme, X + means a group with a lack of electrons, which is then bound in (b) as a negative residue in the molecule (X-).

Die Reaktionsprodukte trennt man zweckmäßigerweise durch Eingießen in Wasser und Abfiltrieren oder Extraktion mit Methylenchlorid, Chloroform oder Essigsäureäthylester ab. Die Verfahrensprodukte fallen im allgemeinen in hoher Ausbeute (80 bis 90 % der Theorie) und in so hoher Reinheit an, daß keine Umkristallisation nötig ist.The reaction products are expediently separated by pouring in water and filtering off or extraction with methylene chloride, chloroform or Ethyl acetate. The products of the process generally fall in high yield (80 to 90% of theory) and in such high purity that no recrystallization is necessary.

Das neue Verfahren bietet eine breite Möglichkeit zur Umsetzung empfindlicher Verbindungen der Formel II, weil dafür keine aggressiven Oxydationsmittel erforderlich sind. Das Verfahren gestaltet sich zudem präparativ einfacher.The new method offers a wide range of options for implementing more sensitive Compounds of the formula II because they do not require any aggressive oxidizing agents are. The procedure is also simpler in terms of preparation.

Die hohe Ausbeute bei diesen milden oxydativen Bedingungen ist ebenso überraschend wie der hohe Reinheitsgrad, in der die Verfahrensprodukte erhalten werden.The high yield under these mild oxidative conditions is also As surprising as the high degree of purity in which the process products are obtained will.

Nach den bekannten Verfahren dagegen ist die Substanzklasse der Formel II nicht in Spiro-oxindole überführbar, wahrscheinlich wegen der Säurelabilität der Enamingruppierung (2).According to the known methods, however, the substance class is the formula II cannot be converted into spiro-oxindoles, probably because of the acid instability the enamine grouping (2).

Die auf die erfindungsgemäße Weise erhältlichen neuen Spiropyrrolizidon-Oxindole sind sehr variationsfähige Substanzen (potentielle B-Dicarbonylverbindungen) und daher vielseitige Ausgangsstoffe für weitere Synthesen. Sie dienen z.B. als Ausgangsstoffe für die pharmazeutisch-chemisch interessanten Spiroindoline. (J.A. Weisbach et al. J. Med. Chem. 7, 735, (1964).The new spiropyrrolizidone oxindoles obtainable in the manner according to the invention are very varied substances (potential B-dicarbonyl compounds) and therefore versatile starting materials for further syntheses. They serve, for example, as starting materials for the pharmaceutically and chemically interesting spiroindolines. (J.A. Weisbach et al. J. Med. Chem. 7, 735, (1964).

Man kann aber auch Oxindole selbst als Entzündungshemmer und als Uterus-stimulierende Substanzen verwenden. (H.C. Chou, Proc. Soc. Exptl. Med 28,. 779 (1931), K.K.Chen und T.Q. Chou, Chinese J. Physiol. 14, 319 (1939).But one can also use Oxindole itself as an anti-inflammatory and as a uterus-stimulating agent Use substances. (H.C. Chou, Proc. Soc. Exptl. Med 28, 779 (1931), K.K.Chen and T.Q. Chou, Chinese J. Physiol. 14, 319 (1939).

Beispiel 1 500 mg 1-Pyrrolidino-3-oxo-5,6,11 ,11b-tetrahydro-3H-indolo-3,2g]indolizidin (R1 = R2 - H) -gibt man zu einer Lösung von 100 mg Natrium in 30 cm3 absol. Methanol und erhitzt 5 Stunden unter Rückfluß im Sieden. Nach Eingießen in Wasser und Extraktion mit Methylenchlorid zieht man das Lösungsmittel im Vakuum ab und kristallisiert den Rückstand aus Aceton/Diäthyläther. Example 1 500 mg of 1-pyrrolidino-3-oxo-5,6,11,11b-tetrahydro-3H-indolo-3.2g] indolizidine (R1 = R2 - H) - is added to a solution of 100 mg sodium in 30 cm3 absol. Methanol and refluxed for 5 hours. After pouring into water and extraction with Methylene chloride is drawn off the solvent in vacuo and the crystallized Residue from acetone / diethyl ether.

Man erhält 485 mg (84 %) farblose Kristalle der Verbindung 2', 5-Dioxo-7-pyrrolidino-7a-methoxy-2, 2', 3, 3',5, 7a-hexahydro-1H-pyrrolizin-[1-spiro-3']-indol (R¹=R²=H, R³=Methyl).485 mg (84%) of colorless crystals of the compound 2 ', 5-dioxo-7-pyrrolidino-7a-methoxy-2, are obtained, 2 ', 3, 3', 5, 7a-hexahydro-1H-pyrrolizine- [1-spiro-3 '] - indole (R¹ = R² = H, R³ = methyl).

Beispiel 2 Setzt man wie unter Beispiel 1 angegeben 10 Teile der Vertindung gemäß Formel II (R = R' = H) mit einer Lösung von 2 Teilen Na in 600 Teilen Äthanol um, so erhält man 9 Teile (78 %) der Verbindung 2', 5-Dioxo-7-pyrrolidino-7a-äthoxy-2, 2', 3, 3', 5, 7a-hexahydro-1H-pyrrolizidin-[1-spiro-3']-indol (R=R¹=H; R"=C2H5) Schmelzpunkt ab 225°C unter Zersetzung. Example 2 As indicated in Example 1, 10 parts of the Connection according to formula II (R = R '= H) with a solution of 2 parts of Na in 600 Parts of ethanol to give 9 parts (78%) of the compound 2 ', 5-dioxo-7-pyrrolidino-7a-ethoxy-2, 2 ', 3, 3', 5, 7a-hexahydro-1H-pyrrolizidine- [1-spiro-3 '] - indole (R = R¹ = H; R "= C2H5) Melting point from 225 ° C with decomposition.

Analyse: C20H23N303 (353,2) Ber. C 68,01 H 6,57 N 11,89 Gef. C 67,73 H 6,28 N 11,37 Beispiel 3 Setzt man wie in Beispiel 1 angegeben 10 Teile der Verbindung gemäß Formel II (R=H; R'=CH3) mit einer Lösung von 2 Teilen Natrium in 600 Teilen Methanol um, so erhält man 10 Teile (86 %) der Verbindung 2', 5-Dioxo-7-pyrrolidino-7a-methoxy-2-methoxy-2-methyl-2', 3, 3', 5, 7a-hexahydro-1H-pyrrolizin [1-spiro-3']-indol (R=H; R'=-2-CH3; R"=CH3) vom Schmelzpunkt 185°C unter Zersetzung.Analysis: C20H23N303 (353.2) calc. C 68.01 H 6.57 N 11.89 Found C 67.73 H 6.28 N 11.37 Example 3 As indicated in Example 1, 10 parts of the compound are used according to formula II (R = H; R '= CH3) with a solution of 2 parts of sodium in 600 parts Methanol to give 10 parts (86%) of the compound 2 ', 5-dioxo-7-pyrrolidino-7a-methoxy-2-methoxy-2-methyl-2', 3, 3 ', 5, 7a-hexahydro-1H-pyrrolizine [1-spiro-3'] - indole (R = H; R '= - 2-CH3; R "= CH3) melting point 185 ° C with decomposition.

Analyse: C20H23N303 (353,2) Ber. C 68,01 H 6,57 N.11,89 Gef. C 68,44 H 6,87 N 12,04 Beispiel 4 Setzt man wie in Beispiel 1 angegeben 10 Teile der Verbindung gemäß Formel II (R =CH3; R' = H) mit einer Lösung von 2 Teilen Natrium in 600 Teilen Methanol um, so erhält man 10 Teile (86 %) der Verbindung 2', 5-Dioxo-7-pyrrolidino-7a-methoxy-2, 2', 3, 3', 5, 7a-hexyhydro-1H-pyrrolizin [1-spiro-3']-7'-methylindol (R=-7'-CH3, R'= H, R" = CH3) vom Schmelzpunkt 220°C unter Zersetzung.Analysis: C20H23N303 (353.2) calc. C 68.01 H 6.57 N 11.89 Found C 68.44 H 6.87 N 12.04 Example 4 Set as indicated in Example 1 10 parts of the compound according to formula II (R = CH3; R '= H) with a solution of 2 Parts of sodium in 600 parts of methanol give 10 parts (86%) of the compound 2 ', 5-Dioxo-7-pyrrolidino-7a-methoxy-2, 2', 3, 3 ', 5, 7a-hexyhydro-1H-pyrrolizine [1-spiro-3 '] - 7'-methylindole (R = -7'-CH3, R' = H, R "= CH3) melting point 220 ° C with decomposition.

Analyse: C20H23N3O3 (353,2) Ber. C 68,01 H 6,57 N 11,89 Gef. C 68,30 H 6,75 N 11,49 Beispiel 5 Setzt man wie in Beispiel 1 angegeben 10 Teile der Verbindung gemäß Formel II (R=OCH3; R'=H) mit einer Lösung von 2 Teilen Natrium in 600 Teilen Methanol um, so erhält man 10 Teile (86 %) der Verbindung 2', 5-Dioxo-7-pyrrolidino-7a-methoxy-2, 2', 3, 3', 5, 7a-hexahydro-1H-pyrrolizin- [1-spiro-3'] -5'-methoxy-indol (R = = = H; R" 1 CH3) vom Schmelzpunkt 17300 unter Zersetzung.Analysis: C20H23N3O3 (353.2) calc. C 68.01 H 6.57 N 11.89 Found C 68.30 H 6.75 N 11.49 Example 5 As indicated in Example 1, 10 parts of the compound are used according to formula II (R = OCH3; R '= H) with a solution of 2 parts of sodium in 600 parts Methanol to give 10 parts (86%) of the compound 2 ', 5-dioxo-7-pyrrolidino-7a-methoxy-2, 2 ', 3, 3', 5, 7a-hexahydro-1H-pyrrolizine- [1-spiro-3 '] -5'-methoxy-indole (R = = = H; R "1 CH3) melting point 17300 with decomposition.

Analyse: C20H23N3O4 (369,2) Ber. C 65,06 H 7,28 N 11,39 Gef. C 64,89 H 7,27 X 11,30Analysis: C20H23N3O4 (369.2) calc. C 65.06 H 7.28 N 11.39 Found: C 64.89 H 7.27 X 11.30

Claims (5)

Patent ansprüche 1. Spiro-pyrrolizidon-oxindole der Formel I wobei R1 ein Wasserstoffatom oder eine niedrige verzweigte oder geradkettige Alkyl-, Aryl-, Methoxy- oder Nitrogruppe, 112 ein Wasserstoffatom oder eine niedrige Alkylgruppe und R3 eine niedrige Alkyl- oder Aralkylgruppe bedeutet.Claims 1. Spiro-pyrrolizidone-oxindoles of the formula I. where R1 is a hydrogen atom or a lower branched or straight-chain alkyl, aryl, methoxy or nitro group, 112 is a hydrogen atom or a lower alkyl group and R3 is a lower alkyl or aralkyl group. 2. Verfahren zur Herstellung von Verbindungen gemäß Anspruch 1, dadurch gekennzeichnet, daß man Indazolderivate der Formel II in Gegenwart von Sauerstoff mit einem Alkali-Alkoholat (R3O-) in einem Alkohol (HOR3) erhitzte wobei die Reste R1, R2> R3 die im Anspruch 1 angegebene Bedeutung haben.2. Process for the preparation of compounds according to Claim 1, characterized in that indazole derivatives of the formula II heated in the presence of oxygen with an alkali alcoholate (R3O-) in an alcohol (HOR3) where the radicals R1, R2> R3 have the meaning given in claim 1. 3. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, daß man die Reaktion in einer Lösung von Natrium in Methanol durchführt.3. The method according to claim 2, characterized in that the The reaction is carried out in a solution of sodium in methanol. 4. Verfahren gemäß Ansprüchen 2 und 5, dadurch gekennzeichnet, daß man die Reaktion im Temperaturbereich von 60 bis 100°C durchführt.4. Process according to Claims 2 and 5, characterized in that the reaction is carried out in the temperature range from 60 to 100.degree. 5. Verfahren gemäß Ansprüchen 2 bis 4, dadurch gekennzeichnet, daß die Reaktionsdauer. 5 bis 8 Stunden beträgt.5. Process according to Claims 2 to 4, characterized in that the reaction time. 5 to 8 hours.
DE19691956237 1969-11-08 1969-11-08 Spiro-pyrrolizidone-oxindoles Pending DE1956237A1 (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7700641B2 (en) 2005-04-11 2010-04-20 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their uses as therapeutic agents
US7799798B2 (en) 2005-04-11 2010-09-21 Xenon Pharmaceuticals Inc. Spiroheterocyclic compounds and their uses as therapeutic agents
US8101647B2 (en) 2008-10-17 2012-01-24 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8263606B2 (en) 2008-10-17 2012-09-11 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8445696B2 (en) 2009-10-14 2013-05-21 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US8450358B2 (en) 2009-06-29 2013-05-28 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
US9504671B2 (en) 2010-02-26 2016-11-29 Xenon Pharmaceuticals Inc. Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents
US9682033B2 (en) 2015-02-05 2017-06-20 Teva Pharmaceuticals International Gmbh Methods of treating postherpetic neuralgia with a topical formulation of a spiro-oxindole compound

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7799798B2 (en) 2005-04-11 2010-09-21 Xenon Pharmaceuticals Inc. Spiroheterocyclic compounds and their uses as therapeutic agents
US7935721B2 (en) 2005-04-11 2011-05-03 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their uses as therapeutic agents
US7700641B2 (en) 2005-04-11 2010-04-20 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their uses as therapeutic agents
US8106087B2 (en) 2005-04-11 2012-01-31 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their uses as therapeutic agents
US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
US8916580B2 (en) 2008-10-17 2014-12-23 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8101647B2 (en) 2008-10-17 2012-01-24 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US9458178B2 (en) 2008-10-17 2016-10-04 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8415370B2 (en) 2008-10-17 2013-04-09 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their uses as therapeutic agents
US8263606B2 (en) 2008-10-17 2012-09-11 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8883840B2 (en) 2009-06-29 2014-11-11 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
US8450358B2 (en) 2009-06-29 2013-05-28 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
US9480677B2 (en) 2009-06-29 2016-11-01 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
US8742109B2 (en) 2009-10-14 2014-06-03 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US9260446B2 (en) 2009-10-14 2016-02-16 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US8445696B2 (en) 2009-10-14 2013-05-21 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US9695185B2 (en) 2009-10-14 2017-07-04 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US9504671B2 (en) 2010-02-26 2016-11-29 Xenon Pharmaceuticals Inc. Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents
US9682033B2 (en) 2015-02-05 2017-06-20 Teva Pharmaceuticals International Gmbh Methods of treating postherpetic neuralgia with a topical formulation of a spiro-oxindole compound

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