WO1991009035A1 - Procede de transformation d'allo-isomeres des oxindolalcaloides pentacycliques ayant la formule c21h24n2o¿4? - Google Patents

Procede de transformation d'allo-isomeres des oxindolalcaloides pentacycliques ayant la formule c21h24n2o¿4? Download PDF

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Publication number
WO1991009035A1
WO1991009035A1 PCT/AT1990/000122 AT9000122W WO9109035A1 WO 1991009035 A1 WO1991009035 A1 WO 1991009035A1 AT 9000122 W AT9000122 W AT 9000122W WO 9109035 A1 WO9109035 A1 WO 9109035A1
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WIPO (PCT)
Prior art keywords
atom
isomer
isomers
allo
hydrogen ions
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Application number
PCT/AT1990/000122
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German (de)
English (en)
Inventor
Klaus Keplinger
Dietmar Keplinger
Franz Scheidl
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Immodal Pharmaka Gesellschaft M.B.H.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by Immodal Pharmaka Gesellschaft M.B.H. filed Critical Immodal Pharmaka Gesellschaft M.B.H.
Publication of WO1991009035A1 publication Critical patent/WO1991009035A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • the invention relates to a process for converting allo-isomers of pentacyclic oxindole alkaloids having the formula C 21 H 24 N 2 O 4 , in which both on the C 3 atom and on the C 20 Atom is the hydrogen atom in the ⁇ position.
  • Pentalcyclic oxindole alkaloids have four centers of asymmetry, namely at the carbon atoms C-3, C-7, C-15 and C-20. Since all naturally occurring oxindoles known to date have the C-15 hydrogen atom bonded ⁇ -permanently, the number of possible isomers is limited to eight.
  • the various stereoisomers are referred to as normal, pseudo, allo and epiallo, based on the configuration of the hydrogen atom at C-3 and C-20. Furthermore, the two isomers of a series differ in the configuration on the C-7 atom.
  • Lactam carbon of the oxindole ring lies below the plane of the rings C and D, the A isomers are those with the
  • Lactam carbonyl grouping above the C-D ring level referred to as B isomers Lactam carbonyl grouping above the C-D ring level referred to as B isomers.
  • the C-7 atom of the A series has the S configuration and in the B series the R configuration. While isomers of the pseudo series are too unstable for steric reasons to be able to exist for a long time and quickly rearrange themselves into the corresponding normal compounds, the oxindole alkaloids of the allo, epiallo and normal series can be genuinely made from plant material, in particular from Uncaria species. be preserved. (Phillipson et al: Alkaloids of Uncaria, Lloydia, Vol. 41, No. 6, Nov-Dec. 1978, pages 503 to 570). In the normal series, the configuration at the C-7 atom can only be changed because the corresponding pseudoisomers are too energy-rich.
  • alkaloids of Uncaria pteropoda, J. Chem. Soc. (C), 1966, pages 2245 to 2249 can be achieved by means of pyridine or acetic acid.
  • alkaloids As ingredients of a large number of plants, alkaloids have therapeutic efficacy. Since alkaloids are medium-strong plant bases that have lipophilic properties in free form, they are not very soluble in water, and readily soluble in organic solvents such as ethyl acetate, chloroform, lower alcohols, etc. Examples of this are shown in the GB-PSen
  • Pentacyclic oxindole alkaloids of the allo and epiallo series can be isomerized, at least theoretically, by changing the configuration on the C-3 atom or C-7 atom, with all four possible isomers being in equilibrium. Since there are relatively large differences in the therapeutic efficacy of the individual isomers and, at least in the drugs investigated, a larger proportion of less effective allo isomers can very often be found, the invention has set itself the task of providing a process for converting the allo isomers create. Furthermore, a process is also to be developed in which the conversion of the allo-isomers in connection with the extraction of the oxindole alkaloids from herbal drugs can take place, and is preferably achieved directly in the extraction of the alkaloid mixture from the drugs.
  • the object is achieved in that the hydrogen atoms on the C-3 atom or C-20 atom are folded by the action of hydrogen ions from the ⁇ - to the ⁇ -position, an epiallo when folded over on the C-3 atom -Isomer and a normal isomer is generated when the C-20 atom is flipped.
  • the isomers of the pentacyclic oxindole alkaloids have the following structural formulas:
  • oxindole alkaloid mixtures Because of their only slightly different physical and chemical properties, oxindole alkaloid mixtures have hitherto been used primarily as chromatographic methods, which are relatively complex. Synthetic production methods are not yet known.
  • the benzene ring of the oxindole fragment provides coverage for the C-3 atom.
  • the allo-B isomer (2) has a greater tendency to isomerize at the C-20 atom, which may have similar causes, so that less the epiallo-B isomer (4), but mainly that normal B isomer (6) is formed.
  • an intermediate step is therefore preferably switched on, so that the allo-B isomer (2) first into the allo-A isomer (1 ) and this is then converted into the epiallo B isomer (2).
  • the conversion of the allo-B isomer (2) into the allo-A isomer (1) can be carried out, for example, in the manner indicated using pyridine.
  • nascent hydrogen is additionally used.
  • the acidic solution is mixed with a metal which develops the nascent hydrogen, in particular zinc granules.
  • the treatment with hydrogen ions takes place in a cation-selective ion exchange column, since the origin of the hydrogen ions has no influence on the conversion of the isomers.
  • Other suitable hydrogen ion donors can also be used. Since pure alkaloids were available in insufficient amounts for broad evidence, sample material in the form of dried and ground root wood from Uncaria tomentosa (WILLD.DC) was also used. Studies on several plants have shown that the alkaloid distribution is subject to only very slight fluctuations, which should be genetically determined.
  • the amount of the total alkaloids is variable and varies between 0.2% by weight and 0.5% by weight. This amount is likely to depend on different soil and growth conditions. However, these parameters are only partially known.
  • 4 kg of the drug material were treated in a percolator with 30 1 1% hydrochloric acid for 12 hours at 50 ° C to 60 ° C, the hydrochloric acid being circulated.
  • the percolate is then concentrated in a rotary evaporator to 20% of the original volume, that is to say about 6 l, and then filtered, the subsequent process steps taking place at room temperature.
  • a preferred embodiment of the process for obtaining the alkaloids further provides that, after the treatment with hydrogen ions, the acidic solution is alkalized and, preferably repeatedly, extracted with an organic solvent, whereupon the organic solvent is separated off.
  • the acidic extraction of the drug material should also have the additional effect that the nascent hydrogen is able to convert the apparently less stable tetracyclic oxindole alkaloids into compounds that are separated from the apparently more stable pentacyclic oxindole alkaloids in the subsequent process steps.
  • the higher stability of the pentacyclic oxindole alkaloids could be due to their fifth ring, which is replaced by an oxygenated side chain and an ethyl or vinyl group in the case of the tetracyclic oxindole alkaloids.
  • solid sodium chloride is added to the solution at least to the point of saturation and / or acetone in an amount of 10% by volume.
  • 1 1 of ethyl acetate and solid sodium carbonate are added until a pH between 8 and 9 is reached.
  • the pentacyclic oxindole alkaloids which are now sparingly water-soluble due to alkalization, are taken over into the organic phase and dissolved in ethyl acetate, whereupon the aqueous phase and the solids are separated off.
  • the addition of ethyl acetate and the shaking out of the aqueous phase are repeated two to three times and then all organic phases are combined.
  • another 2 1 5% hydrochloric acid is added to the organic phase, mixed.
  • the organic phase is separated off and the acidic, aqueous phase containing the alkaloids is mixed with acetone.
  • Solid sodium carbonate is then again added until a pH of 8 to 9 is reached. Now 1 1 more ethyl acetate is added, shaken out and the organic
  • a particular advantage of the method according to the invention lies in the fact that injection solutions can also be prepared in a simple manner.
  • the organic solvent is removed by evaporation to dryness, the alkaloids are dissolved in 15% hydrochloric acid.
  • the hydrochloric acid solution can then be neutralized with sodium hydroxide solution and adjusted to be isotonic. If the hydrochloric acid solution is carefully evaporated, the alkaloids are in their water-soluble, orally administrable hydrochloride form. This takes place, for example, at a maximum of 40 ° C. in a water bath, so that the alkaloid mixture enriched with the desired isomers crystallizes out.
  • the pentacyclic oxindole alkaloids are again dissolved in dilute hydrochloric acid and isotonic with sodium hydroxide solution and sodium chloride. Any further acidification should positively shift the equilibrium situation in the desired direction.
  • the oxindole alkaloids, an oxindole alkaloid mixture or a plant-based drug containing the oxindole alkaloids are preferably dissolved in an acid whose hydrogen ions bring about the folding.
  • the alkaloid mixture enriched with epiallo and / or normal isomers can then be alkalized and, preferably repeatedly, extracted with an organic solvent, whereupon the organic solvent is separated from the non-organic phase and then evaporated.
  • the alkaloid mixture obtained in this way can be further processed into therapeutically usable preparations.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On utilise des ions d'hydrogène afin de transformer des allo-isomères des oxindolalcaloïdes ayant la formule C21H24N2O4, dans lesquels l'atome d'hydrogène est situé en position α aussi bien sur l'atome C-3 que sur l'atome C-20. Les ions d'hydrogène font basculer l'atome d'hydrogène sur l'atome C-3 ou sur l'atome C-20 de la position α à la position β. Lorsque ce basculement se produit au niveau de l'atome C-3, on obtient un épiallo-isomère et lorsqu'il se produit au niveau de l'atome C-20, on obtient un isomère normal. A cet effet, on dissout de préférence les oxindolalcaloïdes, un mélange d'oxindolalcaloïdes ou un médicament d'origine végétale contenant les oxindolalcaloïdes dans un acide dont les ions d'hydrogène provoquent le basculement. Lors de la macération d'un médicament d'origine végétale, le mélange d'alcaloïdes enrichi d'épialloisomères et/ou d'isomères normaux peut être ensuite alcalinisé et de préférence extrait à plusieurs reprises avec un solvant organique, le solvant organique étant ensuite séparé de la phase non organique et évaporé. Le mélange d'alcaloïdes ainsi obtenu peut être traité afin de préparer des compositions thérapeutiques.
PCT/AT1990/000122 1989-12-14 1990-12-14 Procede de transformation d'allo-isomeres des oxindolalcaloides pentacycliques ayant la formule c21h24n2o¿4? WO1991009035A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT284389A AT392970B (de) 1989-12-14 1989-12-14 Verfahren zur gewinnung eines ueberwiegend pentacyclische oxindolalkaloide enthaltenden alkaloidgemisches
ATA2843/89 1989-12-14

Publications (1)

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WO1991009035A1 true WO1991009035A1 (fr) 1991-06-27

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AT (1) AT392970B (fr)
AU (1) AU6967291A (fr)
WO (1) WO1991009035A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0665231A1 (fr) * 1994-01-24 1995-08-02 IMMODAL PHARMAKA GESELLSCHAFT m.b.H. Procédé d'obtention d'alcoloides d'oxindole
AT400950B (de) * 1994-02-04 1996-04-25 Immodal Pharmaka Gmbh Verfahren zur technischen herstellung definierter isomerengemische aus verbindungen mit spirozyklischen - aminocarboxyl- und/oder spirozyklischen - aminocarbonyl-systemen
US7238374B2 (en) 1997-01-20 2007-07-03 Klaus Keplinger Process and substances for the release of a growth-regulating factor from endothelial cells

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982001130A1 (fr) * 1980-10-07 1982-04-15 K Keplinger Composition permettant de modifier la croissance de cellules vivantes, preparation et utilisation d'une telle composition
WO1986000524A1 (fr) * 1984-07-06 1986-01-30 Klaus Keplinger Alcaloides d'oxindole aux proprietes stimulant le systeme immunitaire et preparations les contenant

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE853059C (de) * 1949-01-07 1952-10-20 Hermann Michael Reinhardt Mauerverband aus Blocksteinen ohne aussen sichtbare Moertelfugen
CH558858A (it) * 1971-06-26 1975-02-14 Idrisspatent Anstalt Procedimento per la costruzione di opere murarie e gruppo di blocchi per realizzarlo.
DE3415484A1 (de) * 1984-04-26 1985-11-21 Jörg 6708 Neuhofen Redeker Dialysegeraet

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982001130A1 (fr) * 1980-10-07 1982-04-15 K Keplinger Composition permettant de modifier la croissance de cellules vivantes, preparation et utilisation d'une telle composition
WO1986000524A1 (fr) * 1984-07-06 1986-01-30 Klaus Keplinger Alcaloides d'oxindole aux proprietes stimulant le systeme immunitaire et preparations les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of the Chemical Society, Section C, Organic Chemistry, 1986, K.C. Chan et al.: "Alkaloids of Uncaria pteropoda. Isolation and Structures of Pteropodine and Isopteropodine", pages 2245-2249. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0665231A1 (fr) * 1994-01-24 1995-08-02 IMMODAL PHARMAKA GESELLSCHAFT m.b.H. Procédé d'obtention d'alcoloides d'oxindole
AT400950B (de) * 1994-02-04 1996-04-25 Immodal Pharmaka Gmbh Verfahren zur technischen herstellung definierter isomerengemische aus verbindungen mit spirozyklischen - aminocarboxyl- und/oder spirozyklischen - aminocarbonyl-systemen
US7238374B2 (en) 1997-01-20 2007-07-03 Klaus Keplinger Process and substances for the release of a growth-regulating factor from endothelial cells

Also Published As

Publication number Publication date
AT392970B (de) 1991-07-25
ATA284389A (de) 1990-12-15
AU6967291A (en) 1991-07-18

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