Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-15
1996-09-10
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 76, A61K 31435, C07D22118
Patent
active
055546226
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/EP93/02581, filed on Sep. 23, 1993.
The present invention relates to novel asymmetrically substituted bisnaphthalimides, to the preparation thereof and to the use thereof for controlling diseases.
U.S. Pat. No. 4,841,052 discloses compounds in which two naphthalimide residues are connected together via a bridge containing an aromatic residue. These compounds are used as sensitizers in electrophotographic toners. U.S. Pat. No. 4,874,863 describes bisnaphthalimides which are suitable as carcinostatics. Similar is true of the substances of U.S. Pat. No. 5,086,059 which additionally contain ethylene bridges on their naphthalene residues.
The invention relates to asymmetrically substituted bisnaphthalimides of the formula I ##STR2## in which A, B and D are identical or different and are straight-chain or branched alkylidene groups, cycloalkylidene or phenylene radicals, C.sub.1 -C.sub.6 -alkyl or aryl or benzyl groups which can be substituted by C.sub.1 -C.sub.6 -alkyl groups, halogen atoms, CF.sub.3 --, nitro, hydroxyl, NR.sub.2.sup.3, OR.sup.4, COOR.sup.5, CONR.sub.2.sup.6, CONHR.sup.7, NHCOR.sup.8, SO.sub.2 NHR.sup.9 or SO.sub.m R.sup.10 groups, or together are a --CH.sub.2 --, --C.sub.2 H.sub.4 -- or C.sub.3 H.sub.6 -- group, nitro, amino, C.sub.1 -C.sub.6 -alkyl CF.sub.3, hydroxyl, NR.sub.2.sup.3, OR.sup.4, COOR.sup.5, CHO, CONR.sub.2.sup.6, CONHR.sup.7, NHCOR.sup.8, SO.sub.2 NHR.sup.9, SO.sub.m R.sup.10, COR.sup.11, ureido, C.sub.1 -C.sub.6 -alkylureido, N.dbd.C.dbd.S or N.dbd.C.dbd.O groups, -alkyl, cycloalkyl or aryl groups, m is the number 0, 1 or 2, and is a single or double bond,
Preferred alkylidene groups for A, B and D are those with 1-8 and, in particular, those with 1-4 carbon atoms. Preferred cycloalkylidene radicals are those with 3-7 carbon atoms.
Aryl groups to be particularly mentioned for R.sup.1 -R.sup.8 are phenyl groups. The latter are preferably substituted by 1-2 of the said radicals. Preferred cycloalkyl radicals for R.sup.3 -R.sup.11 are those with 3-7 carbon atoms. X and Y are preferably nitro, amino or methyl groups or chlorine atoms and X' and Y' are preferably hydrogen.
The novel compounds can be prepared in accordance with the following reaction scheme: ##STR3##
Naphthalic anhydrides II are reacted with one equivalent or with an up to 50% excess of a polyamine III in an organic solvent such as dioxane, ethanol or dimethylformamide at from 20.degree. to 150.degree. C. The solution obtained in this way is concentrated, and the residue is purified, for example, by recrystallization or chromatography. The monoimide obtained in this way is subsequently reacted with the anhydride V, and purified, as described above.
The compounds obtained in this way can subsequently, if required, be converted into their salts with physiologically tolerated acids. To do this, the bases are taken up, for example, in ethanol, dichloromethane or ether, and the salt is precipitated with the acid. Suitable acids are citric acid, tartaric acid, lactic acid, phosphoric acid, alkanesulfonic acids, in particular methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, toluenesulfonic acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and, in particular, hydrochloric acid.
The starting materials of the formula V with a single bond in the 5-membered ring can be prepared by processes disclosed in the literature (J. Amer. Chem. Soc. 93, 737 (1971)). The corresponding compounds with a double bond in the 5-membered ring are obtained from those with a single bond by the process described for pyracycloquinones in J. Amer. Chem. Soc. 91, (1969) 917.
The polyamines III can be bought or prepared by known processes.
The novel compounds activate non-specific immune cells which kill tumor cells. They can therefore be employed for cancers such as cancer of the bowel, lungs and breast as well as leukemia. They are administered in doses
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patent: 4841052 (1989-06-01), Harnisch et al.
patent: 4874863 (1989-10-01), Brana et al.
patent: 5086059 (1992-02-01), Ardecky
patent: 5359070 (1994-10-01), Cherney
Petracek F. J. in "Principles of Psychopharmacology" N. G. Clark and J. del Gindice eds. (1970) Academic Press, N.Y. pp. 166-7.
Berlanga Jos e M. C.
Bra na Miguel F.
Keilhauer Gerhard
Moset Marina M.
P erez de Vega Mar ia J.
Huang Evelyn
Ivy C. Warren
Knoll Aktiengesellschaft
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