Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-03-03
2000-09-05
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546156, 546152, 546159, 546168, 546170, 546172, 546157, 546178, 546173, 546180, 514312, 514313, 514314, A61K 3147, C07D21516, C07D21538, C07D21512, C07D21520
Patent
active
061143499
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to quinoline-4-carboxylic acid derivatives and related compounds, processes for their preparation, and their use.
Viral infections in man and animals, in particular in man, are widespread. In spite of intensive efforts, up to now, however, there has still been no success in finding chemotherapeutics which causally or symptomatically interfere with the course of the disease, which is caused virally or retrovirally, with a recognizably substantial success. Treatment of viral and, in particular, retroviral disorders by means of chemotherapeutics is therefore only very imperfect. On account of the highly increasing number of people globally who are infected with the HIV virus, this type of retroviral virus infection in particular is a growing problem worldwide.
The retrovirus called human immunodeficiency virus (HIV) is assumed, inter alia, to be the cause of the complex disease which is called AIDS (Acquired Immune Deficiency Syndrome). AIDS causes a progressive destruction of the immune system of the sick person, associated with a destruction of the peripheral and of the central nervous system. An important step in the replication cycle of retroviruses is the reverse transcription of the RNA genome of the virus by the endogenous virus enzyme reverse transcriptase, which produces DNA copies of the HIV sequence. It is known that some compounds, such as, for example, azidothymidine (AZT), can function as inhibitors of reverse transcriptase. They are therefore used for the treatment of AIDS. AZT and similar compounds of the nucleoside type such as DDC or DDI, however, are characterized by a very narrow therapeutic breadth or by very severe toxicity which occurs even in the therapeutic range (see, for example, Hirsch, M. S. J. Infect. Dis. 157 (1988), 427-431). In addition, the problem of formation of resistance against chemotherapeutics is still largely unsolved.
Iminoquinoline derivatives having antiviral activity against the HIV virus are described in the patent application EP 93109965.9. Quinoxalinone derivatives with related structures having antiviral activity are described in the patent application EP 509.398.
The 4-cyano-substituted quinoline-2(1H)-thiones of the formulae a and b are known from the literature (see Senthil et al., Ind. J.Chem., Sect. B. 1989, 28B (12), 1017-209). ##STR3##
Compounds of the general structure c where R' is hydrogen, alkyl, aryl or benzyl, R" is hydrogen, alkyl and R"' is 3-tropanol (N-8-methyl-8-azabicyclo[3.2.1]octan-3-ol or endo N-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine have been proposed as potential 5-HT.sub.3 receptor antagonists (J. Med. Chem. 1992, 35, 4893-4902) ##STR4##
The preparation of the 2-oxo-1,2-dihydroquinolinecarboxylic acid d starting from isatin and malonic acid or 2-oxindole is likewise known from the literature (J. Am. Chem. Soc. 75 (1953), 5305). The preparation of 2-oxo-1,2-dihydro-3-ethylquinolinecarboxylic acid (e) from 2-oxindole and 2-oxobutyric acid is carried out in a similar manner (Bull. Chem. Soc. Jpn., Vol. 50 (8) (1977), 1959-63). ##STR5##
In the patent application WO 93/11115 2-(1H)-quinolinone derivatives of the formula f having an aryl substituent in the 3-position and R equal to an alkoxycarbonyl substituent are claimed as selective noncompetitive NMDA and/or AMPA receptor antagonists for the treatment of diseases such as, for example, neurodegenerative disorders or schizophrenia. An antiviral activity of these derivatives, however, is not mentioned anywhere. ##STR6##
It has now surprisingly been found that certain quinoline derivatives have a high antiviral activity, in particular against the human immunodeficiency virus (HIV).
The invention accordingly relates to compounds of the formula I ##STR7## and their tautomeric forms, of the formula Ia ##STR8## in which: I) fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, alkyl, cycloalkyl, alkoxy, alkoxy(alkoxy), alkylthio, alkylsulfinyl, alkylsulfonyl, nitro, amino, azido, alkylamino, dialkylamino, piperidino, morpholino, 1-pyrr
REFERENCES:
M. S. Hirsch, "Azidothymidine," J. Infect. Dis., vol. 157, No. 3, pp. 427-431, Mar. 1988.
M. Senthil et al., "Synthesis of Thieno[2,3-b]quinolines-A Convenient Approach," Ind. J. Chem., vol. 28B, pp. 1017-1020, Dec. 1989.
H. Hayashi et al., "5-HT.sub.3 Receptor Antagonists. 1. New Quinoline Derivatives," J. Med. Chem., vol. 35, pp. 4893-4902, 1992.
P. Julian et al., "Studies in the Indole Series. XIV. Oxindole-3-Acetic Acid," J. Am. Chem. Soc., vol. 75, pp. 5305-5309, Nov. 5, 1953.
A. Ide et al., "Photoreaction of 4-Substituted Quinoline N-Oxide and 2(1H)-Quinolinone in Propionic Acid," Bull. Chem. Soc. Japan, vol. 50, No. 8, pp. 1959-1963, Aug., 1977.
L. Mastafanova et al., Chemical Abstracts, vol. 89, No. 5, Abstract No. 43065e, p. 598, Jul. 1978.
H. Hayashi et al., Chemical Abstracts, vol. 118, No. 5, Abstract No. 38750n, p. 668, Feb. 1, 1993.
K. Suzuki et al., Chemical Abstracts, vol. 121, No. 15, Abstract No. 179581g, p. 1081, Oct. 10, 1994.
R. Fujita et al., Chemical Abstracts, vol. 124, No. 13, Abstract No. 175786s, p. 1264, Mar. 25, 1996.
Kirsch Reinhard
Kleim Jorg-Peter
Riess Gunther
Rosenstock Bernd
Rosner Manfred
Davis Zinna Northington
Hoechst Aktiengesellschaft
Robinson Binta
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