Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-07-18
1997-07-22
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514256, 514318, 514326, 544238, 544295, 544331, 544357, 544364, 544366, 544405, 546194, 546210, A61K 31495, C07D40114
Patent
active
056504110
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT application Ser. No. PCT/EP 94/00380, filed Feb. 9, 1994, which claims priority from European Application Serial No. 93.200,474.0, filed on Feb. 19, 1993.
The present invention is concerned with substituted azolone derivatives which are potent anti-Helicobacter agents and which may be used in a monotherapy in the eradication of Helicobacter pylori and related species.
U.S. Pat. No. 4,791,111 discloses 4-(4-phenyl-1-piperazinyl)phenols which are intermediates in the preparation of [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H -imidazoles and 1H-1,2,4-triazoles.
In U.S. Pat. No. 4,931,444 there are described 4-(4-phenyl-1-piperazinyl)phenols having 5-lipoxygenase inhibiting activity. The present compounds are distinguished therefrom by their useful anti-Helicobacter activity.
Afflictions of the gastro-enteric tract are widespread. Modern medicine still fails to cure a lot of them, in particular those related to the presence in the gastric mucosa of the bacterium Helicobacter, e.g. chronic gastritis, duodenal ulcer and duodenal ulcer relapse. Dual therapies in the eradication of Helicobacter, comprising the separate administration of two antibiotic drugs, have not been satisfactory up till now, because of one or more of the following reasons: a low eradication rate, numerous side effects and development of resistance by Helicobacter.
Triple therapies comprising the administration of two antibiotics and a bismuth compound have been shown to be effective, but are very demanding for the patients and are also complicated by side effects.
The present invention is concerned with the use for the manufacture of a medicament for treating Helicobacter-related diseases of a compound of formula ##STR3## the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
X and Y each independently are CH or N;
R.sup.1, R.sup.2 and R.sup.3 each independently are hydrogen or C.sub.1-4 alkyl;
R.sup.4 and R.sup.5 each independently are hydrogen, halo, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, hydroxy, trifluoromethyl, trifluoromethyl or difluoromethyloxy;
Z is C.dbd.O or CHOH; and
Ar is phenyl optionally substituted with up to three substituents selected from hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, halo, trifluoromethyl, triC.sub.1-4 alkylsilyloxy, nitro, amino and cyano or pyridinyl substituted with hydroxy or C.sub.1-4 alkyloxy; and
--A-- is a radical of formula ##STR4## The present invention is also concerned with a method of treating subjects suffering from Helicobacter-related diseases said method comprising administering to said subjects an effective anti-Helicobacter amount of a compound of formula (I).
Further, the present invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound having the formula (I), a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein X, Y, R.sup.1 to R.sup.5, Z, Ar and --A-- are as defined in hereinabove, provided that Ar is other than 4-hydroxyphenyl, 3-C.sub.1-4 alkyl-4-hydroxyphenyl or 3,5-diC.sub.1-4 alkyl-4-hydroxyphenyl, when X.dbd.N and Q is a radical of formula (a-1).
The present invention is also concerned with a compound having the formula (I), a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein X, Y, R.sup.1 to R.sup.5, Z, Ar and
--A-- are as defined hereinabove, provided that Ar is other than 4-hydroxyphenyl, 3-C.sub.1-4 alkyl-4-hydroxyphenyl, 3,5-diC.sub.1-4 alkyl-4-hydroxyphenyl or 4-methoxyphenyl when X.dbd.N and --A-- is a radical of formula (a-1).
As used in the foregoing definitions halo defines fluoro, chloro, bromo and iodo; C.sub.1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-m
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H. Rautelin et al., "In Vitro Activity of Antifungal Azoles against Helicobacter pylori" Eur. J. Clin. Microbiol. Infect. Dis., vol. 11(3), 273-4, 1992.
D. Steinhilber et al., "Effects of Novel Antifungal Azole Derivatives on the 5-Lipoxygenase and Cyclooxygenase Pathway", Arzneim.-Forsch/Drug Res. 40(II), Nr. 11 (1990), 1260-3.
J. Ahmed et al., "Eicosainoid Synthesis and Helicobacter Pylori Associated Gastritis: Increase In Leukotriene C.sub.4 Generation Associated With H. Pylori Colonization", Prostaglandins 44:75-86, 1992.
Heeres Jan
Mostmans Joseph Hector
Odds Frank Christopher
Stokbroekx Raymond Antoine
Van der Aa Marcel Jozef Maria
Janssen Pharmaceutica N.V.
McKane Joseph
Metz Charles J.
Myers, Jr. Richard S.
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