Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-03-07
1991-03-05
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 514275, 514313, 514343, 514253, 514310, 544237, 544238, 544328, 544331, 546264, 546159, A61K 3150, C07
Patent
active
049978357
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The invention relates to substituted 2-acylpyridine-.alpha.-(N)-hetarylhydrazones, their preparation and their use as medicaments for the treatment of microbial and in particular mycobacterial infections, as well as malaria and malignant tumours.
The pharmaceutical activity of heterocyclic substituted 2-acylpyridines is known. Thus, compounds of the 2-acylpyridine-thiosemicarbazone type have a pharmaceutical activity in the treatment of bacterial and in particular mycobacterial diseases, such as leprosy and tuberculosis. They are also suitable as agents for the treatment of malaria and malignant tumours.
However, the high toxicity of these compounds is disadvantageous. Thus, for example, K. C. Agrawal et al in Biochem. Pharmacol, 23, pp. 2421-2429, 1974 reports on the serious gastrointestinal toxicity of 5-hydroxypyridine-2-(carbox)-aldehyde-thiosemicarbazone, a compound having antileukemic activity. Inter alia L. Weinstein in Pharmacol. Basis Ther, 5th edition, pp. 1201 to 1223, 1973 refers to the anorexia, nausea and vomitting effects caused by thiosemicarbazones and their derivatives in general.
Therefore the problem of the present invention is to provide novel compounds and pharmaceutical active substances, whose activity is superior to that of compounds of the 2-acylpyridine-thiosemicarbazone type, whilst simultaneously reducing the toxicity.
To solve this problem, the novel substituted 2-acylpyridine-.alpha.-(N)-hetarylhydrazones of general formula I ##STR1## are proposed, in which R.sub.1 stands for hydrogen, halogen, an alkyl group with 1 to 8 C-atoms, a benzyloxy, benzo, amino, or acetamino group, R.sub.2 hydrogen, an alkyl group with 1 to 8 C-atoms, an amino or a phenyl group, R.sub.3 hydrogen or an alkyl group with 1 to 3 C-atoms and R.sub.4 a radical of general formulas II, III or IV ##STR2## in which R.sub.5 stands for hydrogen, halogen, an alkyl or alkoxy group with 1 to 4 C-atoms, a benzo group or a dialkylamino or substituted dialkylamino group with 1 to 3 C-atoms in the alkyl radicals, in which hydrogen if R.sub.4 is a pyridyl radical, R.sub.4 is a pyridyl radical and R.sub.5 are 3', 4'-benzo, 5', 6'-benzo or 6'-methyl groups, hydrogen if R.sub.4 is a pyridyl radical and R.sub.2 a phenyl group, hydrogen if R.sub.4 is a pyridyl radical and R.sub.1 is a 5 or 6-methyl group or a 3,4-benzo group, hydrogen if R.sub.2 is an amino or methyl group, R.sub.2 is methyl, R.sub.4 is a pyridyl radical and R.sub.5 is a 5', 6'-benzo group, are given in the subclaims.
Inventively it has been surprisingly found that the introduction of the .alpha.-(N)-hetaryl group in place of the thioamide group in combinations of the 2-acylpyridine-thiosemicarbazone type leads to a dramatic reduction in the toxicity with respect to mammals, whilst maintaining or increasing the pharmaceutical activity (cf. Table 1).
TABLE 1 ______________________________________
Acute toxicity of PH22(I) pyridine-2-aldehyde-TSC(11) and
thiacetazone (III) in the case of rats and mice.
LD.sub.50 (mg/kg
body weight)
______________________________________
I >2000 Rat, subc.
II 30 Rat, subc.
II 40 Mouse i.p.
(Cancer Res. 25, 1454 (1965)
III 1000-2000 Mouse, subc.
(J. Pharm. Pharmacol. 2, 764 (1950)
III 950 Mouse, p.o.
(Comptes Rendus Soc. Biol. 1310
(1950)
______________________________________
known manner the corresponding substituted pyridine aldehydes or ketones
are reacted with the corresponding hydrazines.
The activity of the inventive compounds as growth inhibitors for in particular mycobacteria, as well as for malaria parasites and tumour cells was proved in that the minimum inhibitory concentration (MIC) and the concentration necessary for a semimaximum propagation rate inhibition (I.sub.50) were determined using typical representatives of the inventive compounds.
For inhibiting the growth of various mycobacteria strains, there was a 5 to 200 times increased activity of the inventive compounds compared with commercially available products (cf. Table 2).
There was also found to be a sy
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Schaper Klaus-Jurgen
Seydel Joachim K.
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