Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-11-18
1990-04-10
Lee:, Mary
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540599, 540544, 540553, 544 96, 544 55, 544295, 544343, 514250, 5142288, 5142268, 514212, 514218, A61K 31495, C07D41300, C07D41700, C07D40300
Patent
active
049161245
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel indoloquinoxalines with substituents in the 6-position containing cyclic groups of the general formula I ##STR5## wherein R.sub.1 represents hydrogen or one or several, preferably 1 to 4, similar or different substituents in the positions 1-4 and/or 7-10, selected from halogen, lower alkyl-/alkoxy-group having not more than 4 carbon atoms, trifluoromethyl group, trichloromethyl group; ##STR6## wherein Y is CH.sub.2, NH, O or S and a is 2, 3 or 4 and wherein also the bond --C.dbd.N-- can be saturated; Z is alkyl having 1-6 carbon atoms, Cl, Br or CF.sub.3 and than 4 carbon atoms, and the physiologically acceptable addition products of the compounds with acids and halogen adducts, preferably adducts with iodine, iodine monochloride or iodine monobromide.
The novel indoloquinoxalines according to the present invention have a high antiviral effect and several of the compounds show a high anti-cancer effect.
A suitable group of compounds are compounds wherein X is a group ##STR7## wherein Y=NH, O eller S and a is 2 or 3.
The invention also relates to methods for preparing the novel indoloquinoxalines.
The compounds can be prepared by reaction of 6H-indolo(2,3-b)quinoxalines in the 6-position with a reactive compound containing the residue --CHR.sub.3 X. Suitable solvents in this context are such as dimethylsulphoxide, dimethylformamide and dimethylacetamide. Alkylation in the 6-position is favoured by low temperature during the reaction. Minor amounts of 5-alkylated 5H-indolo(2,3-b)quinoxalines are formed as byproduct in said alkylation. Previously ethanol has been used as solvent in this type of alkylation, F. Knotz, Sci. Pharm, 39, 20 (1970), F. Knotz, W. Wendelin, Sci. Pharm., 43, 249 (1975). This is unsuitable since with solvents of this type and at the stated temperature a relatively unfavorable isomer ratio is obtained. The 5-alkylated substances have an essentially lower activity.
The 5-alkylated products can a like unalkylated starting material, if any, be removed by chromatography for instance on silica gel with a suitable eluent, for instance methylene chloride/methanol. The starting materials can be prepared by condensation of isatines with o-phenylene diamines. If unsymmetrical o-phenylene diamine is used for this, which is necessary for for instance preparation of 1-, 2-, 3- or 4-mono substituted starting materials, generally isomeric mixtures are obtained which can be difficult to separate. These difficulties can be avoided by preparing 6H-indolo(2,3-b)quinoxalines by condensation of oxindoles with 2-nitroso toluidines as is shown below. R can be hydrogen or a nitrogen containing basic alkyl residue. With aminoalkyl groups as substituent ##STR8## the active compounds can be prepared in one stage.
Another way to avoid the difficulties is to use N-alkylated o-phenylene diamines whereby 5-alkylated 5H-indolo(2,3-b)quinoxalines are obtained. Then the substituent in 5-position can be removed by boiling with hydrogen bromide dissolved in acetic acid. ##STR9##
The 5-alkylated 5H-inodlo(2,3-b) quinoxalines can be thermally rearranged to 6-alkylated 6H-indolo(2,3-b)quinoxalines. R can be an aminoalkyl group. Thus, by this rearrangement reaction there is an alternative preparation method for the active compounds.
The anion of indoloquinoxalines was found to be easily alkylated by chloroacetonitrile whereby 6-cyanomethylindoloquinoxalines are obtained which by suitable reduction can be converted to 6-(2-aminoethyl)indoloquinoxalines. Substances of this type also can be prepared as shown below. ##STR10##
6-cyanomethyl-6H-indolo(2,3-b)quinoxalines are also suitable as starting materials for preparing for instance 6-(.DELTA.-2-thiazolino-2-methyl)-6H-indolo(2,3-b)quinoxalines and 6-(.DELTA.-2-imidazolino-2-methyl)-6H-indolo(2,3-b)quinazolines. When preparing the last mentioned class of substances the addition of sulphur is suitable.
The bases easily can be transformed into physiologically acceptable addition compounds such as hydrochloride, oxalate, tartrate and halogen ad
REFERENCES:
Chem. Abstracts, vol. 84, (1976) 84:180,166z.
Chem. Abstracts, vol. 66, (1967), No. 1282v.
Chemical Abstracts, vol. 66, (1967), No. 1283c.
Chemical Abstracts, vol. 104, (1986), No. 186375v.
Akerfeldt Stig G.
Bergman Jan O. E.
Lee: Mary
Lundblad Lief
Whittenbaugh Robert C.
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