Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-02-10
1998-05-19
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546118, 5483064, 5483071, 5483074, 5483097, 514394, 514395, A61K 31435, A61K 31415, C07D47104
Patent
active
057536716
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB95/01878 filed Aug. 9, 1995. This invention relates to compounds which are dual histamine (H.sub.1) and platelet activating factor (PAF) antagonists, to therapeutic compositions containing such compounds, and to methods for their preparation.
BACKGROUND TO THE INVENTION
Potent H.sub.1 antagonists of various structural types are known, and are useful in treating the symptoms of inflammatory conditions such as allergic rhinitis, and allergic conditions of the skin, which are mediated at least in part by the release of histamine. However, in such conditions, in which histamine release plays a causative role, there may be other mechanisms at work which are not inhibited by treatment with an H.sub.1 antagonist alone. For example PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a wide variety of physiological responses, including hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, increased vascular permeability (oedema/erythema), and accumulation of inflammatory cells in the lower airways.
There is therefore a need for agents which have dual H.sub.1 and PAF antagonistic activity for the improved treatment of conditions mediated by histamine and PAF release. Such conditions include allergic rhinitis, sinusitis, asthma, dermatitis, psoriasis, urticaria, anaphylactic shock, conjunctivitis, pruritis, inflammatory bowel disease and colitis.
International patent application WO-A-92/03423 (British Bio-technology) discloses a series of compounds which are potent antagonists of PAF. The compounds there disclosed are of the general formula (I) ##STR2## with the various substituents A.sub.1, A.sub.2, B and R-R.sup.7 being as defined in the publication itself. Other patent publications which disclose compounds with PAF antagonist activity are EP-B-0404797 (Searle), EP-A-0260613 (Searle), WO 89/08653 (Searle), WO 91/17162 (Pfizer), and WO 92/03422, WO 92/18503, WO 93/02080, WO 93/16075, WO 93/14072 and WO 93/1406 9 (all British Biotech).
U.S. Pat. No. 2,712020, European patent applications EP-A-085959 and EP-A-133534 (Welcome Foundation Ltd); EP-A-270818 (Schering Corporation); and United States patent application Ser. No. 4,254,129 (Richardson Merrell Inc.) all disclose compounds which ar e potent H.sub.1 an tagonists.
Patent applications WO-A-92/14734 (Pfizer); WO-A-92/00293, WO-A-89/10363, WO-A-93/20080, WO-93/20063, WO-A-93/23400, WO-A-93/02081 (all Schering); WO-A-94/08581 (Toray); EP-A-515158 (Schering); EP-A-463873 and EP-A-549364 (Sankyo); EP-A-577957 (Uriach); EP-A-339978, and Japanese patent application published under no 4-226993 (Yoshitomi) all disclose compounds which possess both histamine (H.sub.1) and PAF antagonist activity.
BRIEF DESCRIPTION OF THE INVENTION
The invention makes available a class of compounds with some of the structural features of the potent PAF antagonists of WO-A-92/03423, and some of the structural features of certain known H.sub.1 antagonists, united in a single molecule in such a way as to provide a desirable balance of H.sub.1 and PAF antagonist activity. The class includes compounds which are active when administered by the oral route.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention there is provided a compound of formula (II) ##STR3## wherein A represents .dbd.N--, .dbd.CH--or =CR.sup.1 --, wherein R.sup.1 represents hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 (C.sub.1 -C.sub.6 alkyl), --CONH.sub.2, --CHO, --CH.sub.2 OH, --CF.sub.3, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylsulphanyl, C.sub.1 -C6 alkylsulphinyl, C.sub.1 -C6 alkylsulphonyl, --NH.sub.2, --NHCOCH.sub.3, or --NO.sub.2 ; provided that ring system may be optionally substituted in the 4- and/or 6-positions by methyl; halogen or C.sub.1 -C.sub.6 alkoxy; alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylsulphanyl, cyclopropyl, C.sub.1 -C.sub.6 hydroxyalkyl, (C.sub.1 -C.sub.6 alkyl).sub.2 N--, (C.
Ayscough Andrew Paul
Bowles Stephen Arthur
Miller Andrew
Whittaker Mark
British Biotech Pharmaceuticals Limited
Richter Johann
Stockton Laura L.
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