Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-11-18
1991-02-05
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544343, 544337, C07D48704, A61K 31495
Patent
active
049905104
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel substituted indoloquinoxalines of the general formula I ##STR3## wherein R.sub.1 represents one or several, preferably 1 to 4, similar or different substituents in the positions 1-4 and/or 7-14 10, selected from halogen, preferably Br, lower alkyl/alkoxy group having not more than 4 carbon atoms, trifluoromethyl group, trichloromethyl group; a nitrogen containing basic residue such as N.sub.2, NHR.sub.4 or NR.sub.5 R.sub.6 wherein R.sub.4, R.sub.5 and R.sub.6 independently are lower alkyl or cykloalkyl and n is an integer of from 1 to 4 and than 4 carbon atoms, acids and halogen adducts, preferably adducts with iodine iodine monochloride or iodine monobromide.
The novel substituted`d 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 --(CH.sub.2).sub.n --R.sub.2 wherein R.sub.2 is --N(CH.sub.3).sub.2 and n is 1.
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 6-position with a reactive compound containing the residue --CHR.sub.3 X. Suitable solvents in this context are e.g. dimethylsulphoxide, dimethylformamide and dimethylacetamide. Alkylation in 6-position is favored 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 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-nitrosotoluidines as is shown below. R can be hydrogen or a nitrogen containing basic alkyl residue. With aminoalkyl groups as substituent ##STR4## 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. ##STR5##
The 5-alkylated 5H-indolo(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 anions of indoloquinoxalines are easily alkylated by chloroacetonitrile whereby 6-cyanomethylindoloquinoxalines are obtained which by a suitable reduction can be converted to 6-(2-aminoethyl)indoloquinoxalines. Compounds of this type ban also be prepared as shown below. ##STR6## The bases easily can be converted to physiologically acceptable addition compounds such as hydrochloride, oxalate, tartrate and halogen adducts, preferably adducts with iodine, iodine monochloride or iodine monobromide.
A very interesting group of compounds according to the present invention are the adducts between phosphonoalkanoic acids, such as phosphonoformic acid, phosphonoacetic acid, phosphonopropionic acid, phosphonoglycolic acid and phosphonobutyric acid, and their 0-acetyl derivatives, and the indoloquinoxalines of formula I. The last menti
REFERENCES:
Morrison et al., Textbook, "Organic Chemistry", Allyn and Bacon, Inc., 1973, Bost., MA., U.S., p. 733.
15-Pharmacodynamics, vol. 66, 1967, 1282v Biological Characteristics of Phenazine Derivatives. II. Their Cytotoxic Effect on Cultured Cells, Katagiri et al. 1283c Biological Characteristics of Phenazine Derivatives. III. Antimycoplasma Effect, Ken Katagiri et al.
28-Heterocycles, vol. 84, 1976, 180166z Experiments on the Production of Antiviral and Antimicrobial Substances, 6, New 6-Substituted Endolo[2,3-b]quinoxalines, Knotz et al.
28-Heterocycles, vol. 104, 1986, 104:186375v Synthesis of Some New Indophenazinylpyrazoline and Isoxazoline Derivatives, Abdel Rahman et al.
Bergman Jan O. E.
kerfeldt Stig G.
Ford John M.
Leif Lundblad
LandOfFree
Substituted indoloquinoxalines does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted indoloquinoxalines, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted indoloquinoxalines will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-10591