Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-07-12
1994-10-25
Tsang, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514291, 514303, 546 80, 546 93, 546118, A61K 31435, C07D47104, C07D23500, C07D51900
Patent
active
053589530
DESCRIPTION:
BRIEF SUMMARY
This invention relates to imidazopyridines, specifically to certain 4-substituted-1-(2-methylimidazo[4,5-c]pyrid-1-yl)-benzene and -alkylbenzene derivatives. The compounds possess both histamine (H.sub.1) and platelet activating factor (PAF) antagonist activities and have clinical utility in the treatment of allergic inflammatory conditions of both the respiratory tract, such as allergic rhinitis, sinusitis and asthma, and skin, such as atopic dermatitis and urticaria.
The acute systems of allergic rhinitis, e.g. sneezing, nasal and ocular secretion and itching, are generally well controlled by H.sub.1 -antagonists. However, these agents elicit little or no relief of the congestion caused by both by vasodilation and the oedema due to increased vascular permeability. Furthermore, H.sub.1 -antagonists do not affect the accumulation of inflammatory cells which contribute to both the delayed response and the hyper responsiveness to allergen in chronic disease. The potent oedemogenic activity of PAF together with its known release from and activation of many types of inflammatory features of allergic rhinitis. The compounds of the invention are both PAF and H.sub.1 -antogonists and thus have the potential to ameliorate all the major symptoms of chronic allergic rhinitis.
In addition, while histamine contributes to the acute bronchoconstriction to allergen in asthma, it has little effect on either the delayed bronchoconstrictor responses or the non-specific bronchial hyperresponsiveness associated with the accumulation of inflammatory cells in the lower airways. The involvement of PAF in this inflammatory response, together with its bronchoconstrictor activity, supports the potential role for a dual PAF/H.sub.1 antagonist in the treatment of asthma. Similarly, a dual PAF/H.sub.1 antagonist would be expected to be superior to antihistamines alone for the treatment of allergic cutaneous diseases, such as atopic dermatitis and urticaria, since, while antihistamines reduce itching and reddening, they are less effective against the wheal response associated with the influx of inflammatory cells. The compounds of the invention would also be expected to be of value in the treatment of other conditions in which pathophysiological changes are mediated both by histamine as well as histamine-independent inflammatory events.
In our European patent application no 0310386 we disclose a series of dihydropyridine PAF antagonists wherein the 2-position substituent includes in particular a (2-methylimidazo[4,5-c]pyrid-1-yl)phenyl group. U.S. Pat. No. 3,326,924 discloses certain aza-dibenzocycloheptenes as antihistamines including 3-aza-5-(4-piperidylidene)-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene and its 4-aza analogue (5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine ) as well as 7 and 8-chloro and 7,8 and 9-methyl derivatives thereof.
According to the present invention there are provided compounds having the general formula: ##STR1## and pharmaceutically acceptable salts thereof wherein: X is CH or N; --C(CH.sub.3).sub.2 --, or when Z is CH.dbd.CH, B may form a cyclopentane ring fused to the attached benzene ring; ##STR2## wherein R is H, halo or C.sub.1 -C.sub.4 alkyl; n is 0, 1 or 2;
In the above definition, the term halo means fluoro, chloro, bromo or iodo; alkyl and alkoxy group of 3 or more carbon atoms may be straight or branched-chain, and the linking group A may be attached in either sense when it is asymmetric. When the compounds contain asymmetric centres the compounds can exist as enantiomers and diastereoisomers. Such isomers may be separable by physical methods, e.g. by fractional crystallisation or chromatography of the parent compounds or of a suitable salt or derivatives thereof. The invention includes all the enantiomers whether separated or not.
The pharmaceutically acceptable acid addition salts of the compounds of the formula (I) which form such salts are those formed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromide, sulphate or bisul
REFERENCES:
patent: 5114919 (1992-05-01), Baldwin et al.
patent: 5250681 (1993-10-01), Shoji et al.
Alker et al, CA 118: 22232j (1992).
Alker David
Bass Robert J.
Cooper Kelvin
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
Tsang Cecilia
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