EP0127634A1 - Derives de pyrrolocoumarine, leur fabrication et leur utilisation - Google Patents

Derives de pyrrolocoumarine, leur fabrication et leur utilisation

Info

Publication number
EP0127634A1
EP0127634A1 EP19830903528 EP83903528A EP0127634A1 EP 0127634 A1 EP0127634 A1 EP 0127634A1 EP 19830903528 EP19830903528 EP 19830903528 EP 83903528 A EP83903528 A EP 83903528A EP 0127634 A1 EP0127634 A1 EP 0127634A1
Authority
EP
European Patent Office
Prior art keywords
hydroxyl
hydrogen
formula
alkyl
derivatives
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP19830903528
Other languages
German (de)
English (en)
Inventor
Frans Carl De Schryver
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KU Leuven
Original Assignee
KU Leuven
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
Publication date
Application filed by KU Leuven filed Critical KU Leuven
Publication of EP0127634A1 publication Critical patent/EP0127634A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • This invention relates to novel pyrrolocoumarin derivatives which are useful in the pharmaceutical and dyestuff industries, as well as to methods of preparing such derivatives and to pharmaceutical compositions containing the same.
  • novel pyrrolocoumarin derivatives of the present invention may be represented by the following general formula I:
  • R 4 and R 8 each are hydrogen or C 1-4 alkyl
  • R 6 is hydrogen or hydroxyl
  • R 5 and R 9 each are hydrogen, hydroxyl, C 1-4 alkyl or C 1-4 alkoxy, with the proviso that R 6 can only be hydroxyl when represents a single bond, and that R 5 and R 9 are different from hydroxyl when R 6 is hydroxyl.
  • R 4 and R 8 each are hydrogen or C 1-4 alkyl
  • R 5 and R 9 each are hydrogen, hydroxyl, C 1 _ 4 alkyl or C 1-4 alkoxy.
  • the C 1-4 alkyl group may be straight or branched and may be methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, isobutyl or tert. butyl, with reference for methyl and ethyl.
  • the C 1-4 alkoxy group may be straight or branched and may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.butoxy, isobutoxy or tert.butoxy, with special preference for methoxy and ethoxy groups.
  • the pyrrolocoumarin derivatives of formula Ia have pharmacological activities and may be used e.g. in the photochemotherapy of psoriasis. Derivatives outside the scope of formula Ia but covered by formula I will have coloring properties and may be used e.g. as fluorescent colors in laser devices. Further, some of the derivatives of formula I may be useful as intermediates in the synthesis of pharmacologically or otherwise useful derivatives of the same general formula I.
  • furocoumarin derivatives have been disclosed in literature as useful agents in the photochemotherapy of psoriasis (J. Investigative Dermatology, 77, 39-44 (1981) and Br.J. Dermatology, 101, 379-389 (1978) .
  • the derivatives of the present invention differ from these known compounds in terms of chemical structure.
  • the pyrrolocoumarin derivatives of the present invention may be prepared along various routes. Preferably, howevsr, their preparation involves a cyclization reaction wherein a compound of formula II
  • R 4 -CO-CH 2 -COOH III to form a dihydropyrrolocoumarin derivative of formula Ib:
  • R is C 1-4 alkyl
  • R 4 and R 8 each are hydrogen or C 1-4 alkyl
  • R 6 is hydrogen or hydroxyl
  • R 5 and R 9 each are hydrogen, hydroxyl, C 1-4 alkyl or C 1-4 alkoxy, with the proviso that R 5 and R 9 are different from hydroxyl if R 6 is hydroxyl.
  • the above cyclization reaction is of the type known as a "Pechmann reaction” and may be effected in accordance with generally known principles (compare “Organic Reactions", Volume VII, pages 1 and following, London 1953).
  • the resulting compound of formula Ib has a single bond between its positions 6 and 7. In case it is desired to have a double bond there, the synthesis may be continued by subjecting the compound of formula Ib to dehydrogenation (if R 6 is hydrogen) or dehydration (if R 6 is hydroxyl).
  • the route of synthesis chosen may sometimes be completed by converting the resulting derivatives of formula Ib or Ia to other derivatives of the same general formula.
  • a compound of formula Ib or Ia may be subjected to alkylation at its 8-position when R 8 is hydrogen.
  • compounds of formula Ib or Ia may be subjected to alkylation at their 5-position and / or 9-position if R 5 and / or R 9 are hydroxyl groups. Reaction conditions for such alkylation reactions will be known to those skilled in the art and may be derived from handbooks, compare Houben-Weyl,
  • compositions comprising an effective amount of a compound of formula Ia together with a pharmaceutical carrier or diluent.
  • Such compositions may have the form of dosage units and can be used for topical, intraperitoneal or any other type of application.
  • the starting compounds of formula II may be prepared from easily accessible starting materials in a way known to those skilled in the art. Some of the various conceivable routes have been shown in the next part of the description.
  • N-acetyl-m-anisidine (33.0 g) is added to a suspension of sodium hydride (10 g) in boiling p-xylene (400 ml) and agitated under reflux for one hour. After adding dimethyl sulphate (28.0 g), the mixture is agitated under reflux for another hour. The reaction mixture is concentrated in vacuo and extracted with ethyl acetate.
  • N.acetyl-N-methyl-m-anisidine (23 g) is heated under reflux in 50% sulfuric acid (150 ml) for 6 hours. After cooling, the mixture is neutralized with 20% aqueous sodium hydroxide and extracted with diethyl ether. The extract is concentrated and the resulting crude product is destilled in vacuo, thus giving N-methyl-m-anisidine (bp 131 ° C / 17 Torr) in 60% yield.
  • 6-hydroxy-N-methyl-2,3-dihydroindole-2-one (32 g) are dissolved into anhydrous tetrahydrofurane (1400 ml) and a suspension of lithium aluminum hydride (39 g) in anhydrous tetrahydrofurane (150 ml) is added goal.
  • the reaction mixture is refluxed under agitation for 6 hours and ice water (1700 ml) is added after after cooling.
  • the mixture is neutralized with 6N hydrochloric acid and extracted 8 times with ethyl acetate (300 ml).
  • the organic phase is dried upon sodium sulphate and extracted 5 times with 1N hydrochloric acid (150 ml each).
  • the aqueous phase is evaporated to dryness (residueA).
  • the organic phase is also evaporated to dryness (residueB) and ice acetic acid (130 ml) and sodium borohydride (5 g) are added as.
  • the mixture is agitated for two hours, chilled with ice and diluted with water (400 ml). Then, the mixture is neutralized with aqueous potassium hydroxide and potassium hydrogen carbonate, and extracted with ethyl acetate.
  • the organic phase is re-extracted with 1N hydrochloric acid and the re-extract is evaporated to dryness after adding residue A starting, thus giving 6-hydroxy-N-methyl-2,3-dihydroindole hydrochloride in 56% yield.
  • the resulting precipitate is collected by filtration and washed with diethyl ether and chloroform. The organic phases are combined and concentrated in vacuo. The residu is dissolved into 10% aqueous hydrochloric acid (250 ml), extracted with ethyl acetate (a small amount) and precipitated with potassium hydrogen carbonate.
  • the second precipitate is extracted with diethyl ether and the organic phase is dried upon sodium sulfate and concentrated in vacuo.
  • the residu is destilled in vacuo
  • N-ethyl-m-anisidine (0.1 mmHg), thus giving N-ethyl-m-anisidine (bp 80 ° C / 0.1 mmHg) in 73% yield.
  • N-ethyl-m-anisidine is reacted with chloroacetyl chloride under the conditions of example 1d, thus giving N-ethyl-N-chloroacetyl-m-anisidine in 66% yield.
  • N-ethyl-N-chloroacetyl-m-anisidine is converted to 1-ethyl-6-hydroxy-2,3-dihydroindole-2-one under the conditions of example 1e in 70% yield.
  • the reaction mixture is cooled with ice and, after an addition of ice under nitrogen gas, is poured into water (1 1).
  • the mixture is neutralized with 6N hydrochloric acid and extracted 5 times with ethyl acetate (200 ml).
  • the organic phase is extracted 3 times with 1N hydrochloric acid (50 ml) and the aqueous phase is washed with water and concentrated in vacuo (residueA).
  • the ethyl acetate phace is also concentrated and its residueis dissolved into acetic acid (50 ml).
  • sodium borohydride (3.8 g) is added in portions to the agitated solution.
  • the mixture is agitated for another two hours, cooled in ice and poured into water (300 ml).
  • ResidueB The resulting mixture is neutralized with potassium hydrogen carbonate and worked up in the same way as above (residueB). Residues A and B are combined and dissolved into methanol (150 ml). After treating with activated carbon, the solution is concentrated and its residueis dried upoO P 2 O 5 and KOH, thus giving 1-ethyl-6-hydroxy-2,3-dihydroindole hydrochloride in 74% yield.
  • the resulting crude product is purified by chromatography on silica gel (with toluene-ethyl acetate 80:20 as elution agent) and recrystallized from ethyl acetate, thus giving 8-ethyl-4-methyl-1H-pyrrolo- [3,2-g ] -chromen-2-one (mp 114.5 - 115 ° C) in 64% yield.
  • 6-nitro-2,3-dihydroindoles (115 g) are dissolved into diethyl ether (2000 ml) and pyridine (56 ml) and a solution of benzoyl chloride (98.5 g) in diethyl ether (100 ml) are added.
  • the precipitate is collected by filtration and washed with water.
  • the aqueous solutions are neutralized with sodium carbonate and potassium hydrogen carbonate and thereupon 4 times extracted with a mixture of ethyl acetate and n-butanol (3: 1).
  • the organic phase is dried with sodium sulphate and re-extracted 3 times with 2N hydrochloric acid (100 ml each) and one time with water (50 ml).
  • the aqueous phase is washed with diethyl ether (a small amount) and concentrated in vacuo, thus giving 6-hydroxy-2,3-dihydroindole hydrochloride in 66% yield.

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

Abstract

Nouveaux dérivés de pyrrolocoumarine de formule générale (I) où .... représente une liaison simple ou double, R4 et R8 représentent chacun un hydrogène ou un alcoyle comportant entre 1 et 4 atomes de carbone, R6 représente un hydrogène ou un hydroxyle, et R5 ainsi que R9 représentent chacun un hydrogène, un hydroxyle, un alcoyle comportant entre 1 et 4 atomes de carbone ou un alkoxy comportant entre 1 et 4 atomes de carbone, à condition que R6 ne puisse être qu'un hydroxyle lorsque .... représente une liaison simple et que R5 ainsi que R9 ne représentent pas un hydroxyle lorsque R6 est un hydroxyle; ces dérivés sont utiles comme ingrédients actifs dans des produits pharmaceutiques, comme colorants et comme produits intermédiaires. Une classe préférée de formule (Ia) où R4 et R8 représentent chacun un hydrogène ou un alcoyle comportant entre 1 et 4 atomes de carbone, et R5 ainsique R9 représentent chacun un hydrogène, un hydroxyle, un alcoyle comportant entre 1 et 4 atomes de carbone ou un alkoxy comportant entre 1 et 4 atomes de carbone, peut être utilisée dans des compositions pharmaceutiques pour la photochimiothérapie du psoriasis. Les composés de formule (I) peuvent être préparés par une réaction de cyclisation conforme à Pechmann, suivie de préférence par une réaction de déshydrogénation ou déshydratation afin de former des composés de formule (Ia).
EP19830903528 1982-11-29 1983-11-24 Derives de pyrrolocoumarine, leur fabrication et leur utilisation Withdrawn EP0127634A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
LU84492 1982-11-29
LU84492A LU84492A1 (de) 1982-11-29 1982-11-29 Cumarin-derivate,verfahren zu ihrer herstellung und diese verbindungen enthaltende pharmazeutische praeparate

Publications (1)

Publication Number Publication Date
EP0127634A1 true EP0127634A1 (fr) 1984-12-12

Family

ID=19729986

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19830903528 Withdrawn EP0127634A1 (fr) 1982-11-29 1983-11-24 Derives de pyrrolocoumarine, leur fabrication et leur utilisation

Country Status (3)

Country Link
EP (1) EP0127634A1 (fr)
LU (1) LU84492A1 (fr)
WO (1) WO1984002133A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0716650B1 (fr) * 1993-09-03 1999-03-24 Smithkline Beecham Plc Nouveaux derives d'indole et d'indoline en tant qu'antagonistes du recepteur de 5ht1d
US5688808A (en) * 1994-12-22 1997-11-18 Ligand Pharmaceuticals Incorporated Steroid receptor modulator compounds and methods
US6696459B1 (en) 1994-12-22 2004-02-24 Ligand Pharmaceuticals Inc. Steroid receptor modulator compounds and methods

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3201421A (en) * 1962-05-09 1965-08-17 Dept Of Chemistry Preparation of alkyl psoralens
US3565912A (en) * 1969-01-27 1971-02-23 Upjohn Co 5-lower-alkanoyl-2,3-bis(p-methoxyphenyl)indoles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8402133A1 *

Also Published As

Publication number Publication date
WO1984002133A1 (fr) 1984-06-07
LU84492A1 (de) 1984-06-13

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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Effective date: 19841031

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Inventor name: DE SCHRYVER, FRANS, CARL