Imidazo (4,5-C) pyridine derivatives as PAF antagonists

Details Imidazo (4,5-C) pyridine derivatives as PAF antagonists Imidazo (4,5-C) pyridine derivatives as PAF antagonists

1994-02-28

1995-08-29

Dentz, Bernard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Silicon containing doai

514303, 546 14, 546118, A61K 31435, C07D47104

Patent

active

054460328

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB92/01370 filed Jul. 24, 1992.
This invention relates primarily to novel compounds which are antagonists of platelet activating factor.
Platelet activating factor (PAF) is a bioactive phospholipid which has been identified as 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphoryl choline. PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a variety of physiological responses which include hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, and increased vascular permeability (oedema/erythema). It is known that these physiological effects occur in many inflammatory and allergic diseases and PAF has been found to be involved in a number of such disorders including asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immune regulation, transplant rejection, gastric ulceration, psofiasis, and cerebral myocardial and renal ischemia. Thus the compounds of the invention, by virtue of their ability to antagonise the actions of PAF, should be of value in the treatment of any of the above disorders and any other conditions in which PAF is implicated (e.g. embryo implantation).
Compounds which have been disclosed as possessing activity as PAF antagonists include compounds which are strutrurally related to the PAF molecule such as glycerol derivatives (EP-A-0238202), and heterocyclic compounds such as 2,5-diaryl tetrahydrofurans (EP-A-0144804) and imidazopyridine derivatives (EP-A-0260613 and WO-A-8908653).
U.S. Pat. No. 4,914,108 discloses a series of imidazo[4,5-c]pyridines substituted at the pyridine ring nitrogen atom (5-position) with a side chain consisting of an alkyl group linked to a phenylene ring. However, the compounds disclosed therein terminate in a carboxamide group, --C(O)NRR In marked contrast, the present invention provides novel and useful sulphonamide derivatives of .alpha.-amino acids and of .alpha.-amino alcohols and their pharmaceutically acceptable acid addition salts. and pharmaceutical uses thereof as PAF antagonists.
According to a first aspect of the invention there is provided a compound of general formula I; ##STR2## wherein: each of R.sup.1 and R.sup.3 independently represents hydrogen or a --C.sub.1 -C.sub.6 alkyl group; positions of the imidazo[4,5-c]pyridine heterocycle, said group(s) being independently selected from hydrogen, --C.sub.1 -C.sub.6 alkyl, --OC.sub.1 -C.sub.6 alkyl, or halogen; alkyl, or a halogen; alkenyl, --C.sub.2 -C.sub.6 alkynyl, --COC.sub.1 -C.sub.6 alkyl, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --(COC.sub.1 -C.sub.6 alkyl)phenyl, --(CO.sub.2 C.sub.1 -C.sub.6 alkyl)phenyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl or a group --D wherein D represents a group; ##STR3## wherein n is an integer from 0 to 3, and each of R.sup.8 and R.sup.9 is independently hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --CONH.sub.2, --CONHC.sub.1 -C.sub.6 alkyl, --CON(C.sub.1 -C.sub.6 alkyl).sub.2, --CHO, --CH.sub.2 OH, --CF.sub.3, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --SOC.sub.1 -C.sub.6 alkyl, --SO.sub.2 C.sub.1 -C.sub.6 alkyl, --NH.sub.2 or -NHCOMe: --C.sub.1 -C.sub.6 alkyl optionally substituted by one or more halogen atoms, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --(C.sub.1 -C.sub.6 alkyl)CO.sub.2 C.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)N(C.sub.1 -C.sub.6 alkyl).sub.2, C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.3 -C.sub.8 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)C.sub.4 -C.sub.8 cycloalkenyl, --(C.sub.1 -C.sub.6 alkyl) OC.sub.3 -C.sub.8 cycloalkyl, --(C.s

REFERENCES:
patent: 4914108 (1990-04-01), Khanna et al.

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