Uses of indolo-2 [2,3b] -quinoxalines

Details Uses of indolo-2 [2,3b] -quinoxalines Uses of indolo-2 [2,3b] -quinoxalines

2001-03-19

2002-10-15

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06465466

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new uses of indolo-2,3b]-quinoxalines of the general formula I
wherein R
1
represents hydrogen or one or several, preferably 1 to 4, similar or different substitutions in the positions 1-4 and/or 7-10, selected from halogen, preferably Br, lower alkyl/alkoxy group having not more than 4 carbon atoms, trifluoromethyl group, trichloromethyl group; and in one of the positions 7-10 R
1
can be a hydroxyl group; X is a group —(CH
2
)
n
,—R
2
wherein R
2
represents a nitrogen containing basic residue such as NH
2
, NHR
4
, or NR
5
R
6
wherein R
4
, R
5
and R
6
independently are lower alkyl or cycloalkyl and n is an integer of from 1 to 4 and R
3
represents hydrogen, lower alkyl/-cycloalkyl group having not more 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, as DNA protecting agent both in the initial phase and in the promoting phase of carcinogenesis and which agent also reduces or eliminates the effect of promoters and which agent has effects which protect for oxidative stress and effects of gamma-irradiation. Thus, the compounds used according to the present invention activate the defense of the body against carcinogenesis, oxidative stress and gamma-irradiation.
BACKGROUND OF THE INVENTION
It is known that free radicals (oxidative stress) of different types are associated with a range of diseases such as ischemic or reperfusion injury, thrombosis and embolism, atherosclerosis, allergic/inflammatory conditions such as bronchial asthma and rheumatoid arthritis, diseases caused by ionizing radiation or ultra violet light, conditions related to neurodegenerative diseases, for instance Parkinson's disease and Alzheimer's diseases, ageing, apoptosis, necrosis and cirrhosis, cataract, physical stress, diabetes, autoimmune diseases, intoxication, colitis, hematocrosis, neoplasms and toxicity of antineoplastic or immuno suppressive agents, premature aging or consequences of viral or bacterial infections and endogeneous or exogeneous chemicals present in air, food, general environmental contamination or lifestyle related exposure. An explanation for these conditions and diseases can be that the endogenous protecting capacity is not sufficiently active to protect the tissue against radical damage. Lipid peroxidation or DNA-oxidation caused by excess generation of radicals can effect significant damaging pathways in the above conditions and diseases. The compounds used according to the present invention probably enter into the cell where they activate parts of the genome.
Oxidative stress can be chemically, physically or biologically induced. Chemically induced oxidative stress is caused by a compound which gives rise to tissue damage. Physically induced stress is caused by e.g. 1) radiation, such as radioactive or ionizing radiation or UV radiation; 2) by physical blockage of blood flow; biologically induced oxidative stress is the defense by the body itself, with over-reaction of oxidases in phagocytes, extra and intra cellular. One example is in HIV patients. Other examples are asthma, rheumatoid arthritis, diabetes etc, cf. above.
SUMMARY OF THE INVENTION
Different conditions such as inflammations, infections, gamma-radiation, UV radiation and deficiency of vitamns/antioxidants give rise to oxidative stress, which leads to the different conditions and diseases stated above. Use of the compounds according to the present invention in preparations to be administered via different carriers will thus protect the body against oxidative stress and prevent the outburst of different diseases caused by such oxidative stress.
Indolo-[2,3b]-quinoxalines of the general formula I wherein R
1
, is a hydroxyl group in one of the positions 7-10 are prepared by means of a process described in the following section. Especially compounds wherein R
1
is a hydroxyl group on position 9 show interesting properties for the use according to the present invention.
Substituted indolo-quinoxalines of formula I have previously been demonstrated to possess valuable activity against several types of virus, and several of the compounds also have been demonstrated to show a potent anti-cancer effect, cf. our previous patents EP 0 238 459 and U.S. Pat. No. 4,990,510. Furthermore, they have also been shown to be inactive as enzyme inhibitors, cf. Harmenberg, et al., Antimicrobial agents and Chemotherapy, November 1988, pp 1720-1724.
Indolo-quinoxaline derivatives hydroxylated in the positions 7, 8, 9 or 10, especially 9, are of interest as metabolites or possible metabolites of biologically active quinoxaline derivatives such as 1b. Such hydroxylated derivatives possess interesting antiviral and anticancer properties in addition to their effect as DNA protecting agents and their effects to protect from oxidative stress.
The hydroxylated substances according to the present invention cannot be made by means of the methods described in our about mentioned patents. Thus, reaction of phenylene diamines and methoxyisatin, such as shown in Scheme 1, does not give indoloquinoxalines but spirocyclic substances which cannot be converted to the desired substances.
Hydroxylation according to Scheme 2 does not function either
A compound of the general formula II
can be prepared by subjecting a compound of the general formula III
to mononitration with one equivalent of potassium nitrate or sodium nitrate in sulfuric acid whereby a compound according to the general formula IV
is obtained, which latter compound by catalytic hydrogenation followed by diazotization with nitrous acid and then conversion of the diazonium ion obtained to the 9—OH group by treatment with a Cu-based catalyst composed of Cu (NO
3
)
2
and Cu
2
O is converted to the compound of formula II.
The process is illustrated in the following Scheme 3
The preparation of these compounds according to the invention is illustrated in the following examples 1-5.
The compounds used according to the present invention unexpectedly have been found to possess a number of specific properties. Thus, they are not mutagenic or carcinogenic and they do not induce preneoplastic lesions and have not a DNA adduct forming activity. The in vivo toxicity in mammals is extremely low. Furthermore, the compounds used in the present invention reduce the spontaneous mutation frequency in the Salmonella assay.
The compounds do not induce oxidative stress. They reduce or even inhibit oxidative stress in vivo and down-regulate oxidative stress below control values.
The compounds are thus useful for reducing or eliminating oxidative stress induced by chemicals and for down-regulating an over-reaction by the immune system. Furthermore, the compounds are useful for activating the cellular defense system, i.e., the cells' own protection for infectious and inflammations.
The compounds can be used in combination with drugs to reduce side effects like mutagenicity (chemotherapy, drugs for AIDS treatment), oxidative stress (amines and nitro compounds) and over-reactions of the immune system.
Another important use of the compounds is to prevent negative health effects induced by UV light, i.e. sun radiation. Examples of these are inflammations, DNA lesions and free radicals. A further important use of the compounds is to slow down the Dorian-Gray syndrome (premature aging induced by oxidative stress) in HIV/AIDS patients.
A further object of the invention is the use of the compounds to increase the body weight when medical treatment/disease leads to loss of body weight. Examples are chemotherapy, irradiation and HIV/AIDS.
Another object according to the invention is the use of the compounds for treatment of human beings and animals after accidental exposure of irradiation to down-regulate oxidative stress and activate cellular defense processes.
A further important object according to the invention is the use of the compounds to reduce extracellular leakage of oxy

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