Certain isoquinoline derivatives having anti-tumor properties

Details Certain isoquinoline derivatives having anti-tumor properties Certain isoquinoline derivatives having anti-tumor properties

1994-12-29

1997-09-02

Rotman, Alan L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514309, 514103, 514141, 514142, C07D40112, C07D40712, A61K 3144, A61K 3147

Patent

active

056631790

DESCRIPTION:

BRIEF SUMMARY
CROSS REFERENCE

This application is a 371 of PCT/EP93/01802 filed 07/08/93
This is invention relates to anilide derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their medical use. In particular it relates to compounds and compositions which are capable of sensitizing multidrug-resistant cancer cells to chemotherapeutic agents.
In many patients, the efficacy of cancer chemotherapy is initially poor or decreases after initial treatment due to the development of resistance to anticancer drugs, known as multidrug-resistance. Multidrug-resistance is a process whereby malignant cells become resistant to structurally diverse chemotherapeutic agents following treatment with a single anti-tumour drug. This acquired drug resistance can be a major clinical obstacle in the treatment of cancer. Some tumours are intrinsically multidrug-resistant, and hence do not respond to chemotherapy.
It has been shown that this type of resistance can be reversed by some calcium channel blockers such as nicardipine and verapamil, by antiarrhythmic agents such as amiodarone and quinidine, as well as by natural products such as cepharanthine. However, these compounds exert their multidrug resistant cell sensitizing activity only at very high doses, well above their intrinsic toxic level, and this severely limits their clinical use in the field of cancer chemotherapy.
A novel group of compounds has now been found which can sensitize multidrug-resistant cancer cells to chemotherapeutic agents at dose levels at which these novel compounds show no toxicity.
Thus, the present invention provides a compound of formula (I): ##STR3## and salts and solvates thereof, including physiologically acceptable salts and solvates thereof, in which:
A represents an oxygen or a sulphur atom, a bond or a group (CH.sub.2).sub.l NR.sup.7 (where l represents zero or 1 and R.sup.7 represents a hydrogen atom or a methyl group);
B represents a C.sub.1-4 alkylene chain optionally substituted by a hydroxyl group, except that the hydroxyl group and moiety A cannot be attached to the same carbon atom when A represents an oxygen or sulphur atom or a group (CH.sub.2).sub.l NR.sup.7, or when A represents a bond B may also represent a C.sub.2-4 alkenylene chain; C.sub.1-4 alkoxy or C.sub.1-4 alkylthio group; group; group --(CH.sub.2).sub.n -- where n represents 1 or 2; ##STR4## is attached at the benzene ring 3 or 4 position relative to the carboxamide substituent, provided that when the group is attached at the benzene ring 3 position then R.sup.4 must be attached at the benzene ring 6 position; and ##STR5## Het represents an optionally substituted bicyclic or tricyclic ring selected from quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinolin-3-yl, quinolin-2-yl, quinoxalin-2-yl, naphthalen-1-yl, naphthalen-2-yl, indol-2-yl, 4-oxo-4H-1-benzopyran-2-yl, phenazin-1-yl and phenothiazin-1-yl or an aryl substituted monocyclic ring selected from 2-aryl-4-thiazolyl, 2-aryl-5-thiazolyl, 5-aryl-2-thienyl, 2-aryl-4-triazolyl and 1-aryl-4-pyrazolyl where aryl represents a phenyl or pyridyl ring optionally substituted by a halogen atom or a trifluoromethyl, C.sub.1-4 alkyl or C.sub.1-4 alkoxy group. The above mentioned bicyclic or tricyclic rings may be unsubstituted or substituted by one, two or three groups selected from C.sub.1-4 alkyl and C.sub.1-4 alkoxy. Quinolin-4-yl rings may also be substituted in the ring 2 position by phenyl or phenyl substituted by C.sub.1-4 alkoxy. Indol-2-yl rings may also be substituted in the ring 3 position by benzoyl; C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, amino or nitro group; represent 2 or 3; C.sub.1-4 alkoxy or C.sub.1-4 alkylthio group; bond or a linking atom selected from --O-- or --S--; and hydrogen atom or a C.sub.1-4 alkyl group).
As used herein, an alkyl group, either as such or as part of an alkoxy or alkylthio group may be a straight chain or branched chain alkyl group, for example a methyl, ethyl or prop-2-yl group.
A halogen substituent may be a fluorine, chlorine, bromine

REFERENCES:
Palmer et al., Journal of Medicinal Chemistry, vol. 31, No. 3, Mar. 1988, 707-712.
Palmer et al., Journal of Medicinal Chemistry, vol. 31, No. 4, pp. 707-712, Feb. 1988.

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