Derivatives of hydroxyphenylsulfanylbenzoic and...

Details Derivatives of hydroxyphenylsulfanylbenzoic and... Derivatives of hydroxyphenylsulfanylbenzoic and...

2000-12-19

2001-10-16

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S398000, C544S399000, C546S152000, C546S174000, C562S431000, C562S432000, C514S311000, C514S557000

Reexamination Certificate

active

06303612

ABSTRACT:

TECHNICAL FIELD
The invention concerns derivatives of hydroxyphenylsulfanylbenzoic and hydroxyphenylsulfanylarylacetic acids, methods of their synthesis and pharmaceutical preparations with antiinflammatory and/or antiasthmatic activities produced of them.
BACKGROUND ART
The products of arachidonic acid biotransformation play an important role in pathological processes of inflammation. Leukotrienes, as pathophysiological mediators of asthma and various inflammatory diseases, originate with the oxidative metabolism of arachidonic acid in the presence of lipoxygenases (Taylor G. W., Clarke S. R.:
Trends Pharmacol. Sci.
7, 100 (1986)). Compounds influencing the biosynthesis of leukotrienes and antagonizing their biological functions are in the focus of research interest. Peptide leukotrienes C
4
, D
4
and E
4
are characterized as components of, slow reacting substance A″ (SRS-A), which induces anaphylactic reaction (Samuelson B.:
Science
22, 563(1983)). The SRS-A is a mediator of inflammation in bronchial constriction and increases the vascular permeability in diseases associated with acute hypersensitivity (von Sprecher A. et al.:
Chimia
46, 304 (1992)). Furthermore, it has been observed that it stimulates aggregation and degranulation of human neutrofils and promotes chemotaxis and chemokinesis of leukocytes and other cells which are involved in the development of the inflammatory process (Djuric S. W. et al.:
Drugs Fut.
17, 819 (1992)). Another leukotriene, LTB
4
, is a mediator in the release of lysosomal enzymes and stimulates the formation of superoxide. Therefore, this substance is supposed to be an important mediator in many inflammatory diseases (Bray M. A.:
Agents Actions
19, 1 (1986)). In connection with this pathological performance of leukotrienes, great attention has been devoted to the utilization of antileukotrienics for the treatment of allergic respiratory diseases. The compounds characterized by combined antileukotrienic effects appear to be especially advantageous. Now it has been found that the title acids connected with suitable structural fragments offer substances with multiple mechanism of antileukotrienic activity, for instance with inhibition of LT biosynthesis combined with antagonistic effect towards peptido-leukotrienes. Fragments used for this purpose, e.g. the 2,4-dihydroxyacetophenone or 2-hydroxymethylquinoline radicals, are known pharmacophores of selective LTD
4
antagonists (Dillard R. D. et al.:
J. Med. Chem.
34, 2768(1991), Sirois B. et al.:
Agents Actions
34, 117 (1991)).
DISCLOSURE OF THE INVENTION
The invention consists in new derivatives of hydroxyphenylsulfanylbenzoic and hydroxyphenylsulphanylarylacetic acids of the general formula I
in which X represents H, a halogen or NO
2
group, n represents 0 or 1 m represents 2 to 4, if Z is 4-acetyl-3-hydroxy-2-propylphenoxy II
or a piperazine residue of the general III, in which R represents an alkyl C
1
-C
4
, benzyl, substituted benzyl or carboxymethoxyethyl,
or m represents 1, if Z is 2-quinolinyl of the general formula IV, in which R′ represents H or a halogen
Compounds of the general formula I can be prepared by organic synthetic methods, the compounds bearing the residue Z=II or III being advantageously prepared by reacting an ester of &ohgr;-haloalkoxy phenylsulfanylbenzoic or -arylacetic acid of the general formula V
in which Hal represents a chlorine, bromine or iodine atom, R
1
represents a lower alkyl, preferably methyl or ethyl, m, n and X represent the same as in formula I, with a compound of the general formula VI
Z—H  (VI)
in which Z has the same meaning as in formulas II and III. The reaction of compounds V and VI may be carried out usually in the presence of a suitable organic or inorganic base, preferably in the presence of an anhydrous alkali metal carbonate or an alkali metal hydroxide or triethylamine or trimethylamine, in a boiling lower ketone, typically in acetone or 2-butanone. The esters obtained may be converted to the corresponding acids I by the use of usual methods of hydrolysis, for instance by influence of an alkaline hydroxide in an aqueous-alcoholic solution at the temperature of 60-110° C., preferably at the boiling temperature of the employed aqueous-alcoholic mixture. The resulting alkali salt may be transferred into the free acid by the use of an acceptable organic or inorganic acid.
Compounds I bearing the fragment Z of the general formula II or IV may be likewise prepared by reacting hydroxyphenylsulfanylbenzoate or hydroxyphenylsulfanylarylacetate of the general formula VII
in which n and X haze the same meaning as in formula I and R
1
represents the same as in formula V with a compound of general formula VIII
 Z(CH
2
)
m
Hal  (VIII)
in which Z is as defined in formulae II and IV, m has the same meaning as in formula I and Hal represents chlorine, bromine or iodine.
Compounds I, including their pharmaceutically harmless salts with inorganic or organic bases, which are the object of the invention, are characterized by significant inhibitory activity for leukotrienes (LT) biosynthesis and also by having a high affinity to LT receptors. Both effects are important for the antiinflammatory and antiasthmatic activity of these substances in pharmaceutical preparations which are a further object of the invention. They are at the same time characterized by low toxicity including absence of ulcerogenic effect. These compounds may be used for the preparation of therapeutic compositions containing the active substance in a mixture with pharmaceutically suitable adjuvants, liquid or solid, usually used in the production of drug formulations. Biological activities of compounds I were determined in the following tests:
Ex vivo Inhibition of LTB
4
Production
The production of LTB
4
was determined in rat polymorphonuclear cells from pleural exudate elicited by heat-activated rat serum (Palmer R. M. J., Salmon J. A.:
Immunology
50, 65 (1983)). The cells were stimulated with the Ca ionophore A 23187 (Sigma) and incubated with various concentrations of the drugs tested. The sample containing only buffer was used for the determination of unaffected biosynthesis; the complete inhibition was measured in a sample with 100 &mgr;g of NDGA in 1 ml. LTB
4
was determined in supernatant using a commercial RIA kit (Amersham).
LTB
4
Receptor Binding Study
A slightly modified method of Cheng and coworkers (Cheng J. B. et al.:
J. Pharm. Expl. Ther.
236, 126 (1986)) was used. The membrane fraction was prepared from male guinea-pig spleen; 2 mg of membranes were incubated with 0.3 nM
3
H-LTB
4
at 25° C. for 30 min in 100 &mgr;l of the incubated mixture. The nonspecific binding was determined in the presence of 0.1 &mgr;M LTB
4
. The membranes were filtered though Whatman GF/C paper and washed triply with buffer. The radioactivity was measured by liquid scintillation spectrometry, and the specific binding of
3
H-LTB
4
to the receptor was determined.
LTD
4
Receptor Binding Study
This study was performed according to the method of Burns and coworkers (Burns R. F. et al.:
Life Sci.
33, 645 (1983)). The membrane fraction was prepared from male guinea-pig lungs, and 4 mg of this fraction were incubated with 0.4 nM
3
H-LTD
4
for 60 min at 25° C. in 100 &mgr;l of the incubated mixture. The nonspecific binding was determined in the presence of 0.1 &mgr;M LTD
4
. The filtration of the membranes, washing, and radioactivity measurement were as above.
Antioxidant Effect in vitro
A modified method (Ohkawa H.:
Anal Biochem.
95, 351 (1979)) utilizing the peroxidation of lipids from the hepatic cells membranes was used for the determination of antioxidant effect. The end-product, malonic dialdehyde, was transformed to coloured complex with thiobarbituric acid and determined spectrophotometrically. The antioxidant effect was expressed in % of peroxidation inhibition in the presence of the compound tested in comparison to a control sample.
Inhibition of Carrageenan Edema
(Winter J.:
Proc. Soc. Expl. Biol. Med
111, 544

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