Bicyclic amidine dervatives as inhibitors of nitric oxide synthe

Details Bicyclic amidine dervatives as inhibitors of nitric oxide synthe Bicyclic amidine dervatives as inhibitors of nitric oxide synthe

1996-11-05

1998-09-15

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514471, 514213, 514310, 549 74, 549491, 549492, 540594, 546143, A61K 3138, A61K 3134, A61K 3155, A61K 3147

Patent

active

058078860

DESCRIPTION:

BRIEF SUMMARY
This application is 371 of PCT/GB95/01041 filed May 9, 1995.
This invention relates to bicyclic amidine derivatives, processes for their preparation, compositions containing them and their use in therapy.
Certain amidine derivatives have been described for use in therapeutic applications. N-Phenyl amidine derivatives have been described for use in the treatment of diabetes in U.S. Pat. No. 3669974 (USV Pharmaceutical Corp.) and UK Patent Application 2226562 (Boots). N'N"disubstituted amidines are described for use in the treatment of hypertension, depression and hallucinogenic states in International Patent Application WO 92/04054 (University of Oregon). The use of certain amidines and symmetric bisamidines as analgesics, in the treatment of inflammation and in the treatment of hypertension is described in Belgian Patent No. 717740 and UK Patent No. 1180629 (both of Delalande). Amidine derivatives have also been described for use as herbicides in German Patent Application DE-OS-2321330 (Bayer).
The use of inhibitors of nitric oxide synthetase in the treatment of disease has also been described, for example, in International Patent Applications WO 94/12163 (Abbott), WO 93/13066 and WO 94/12165 (both of Wellcome) and European Patent Applications 446699 (Merrell Dow), 547558 and 558468 (both of Washington University). The use of nitric oxide synthetase inhibitors in therapy is also described in WO 95/00505, WO 95/09619, WO 95/09621 (all of Wellcome), WO 95/10266 (Otsuka), WO 95111231 and WO 95/11014 (both of Searle) which six documents were published after the earliest priority date of this application.
The applicant has previously described the use of guanidine derivatives and amidine derivatives which are inhibitors of nitric oxide synthetase in the treatment inter alia of neurodegenerative disease (WO 94/21621, WO 95/05363). The second of these was published after the earliest priority date of this application.
We have now found a new group of bicyclic amidine derivatives that possesses useful pharmaceutical activity. According to a first aspect of the invention, we provide a compound of formula r ##STR2## wherein D represents a five membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, N or S, optionally substituted at a carbon atom by halogen, trifluoromethyl, alkyl C1 to 6, nitro or cyano, and which is connected to the remainder of the compound of formula I through a carbon atom; 0 to 3, --(CH.sub.2).sub.n Q, or --NXY represents piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinolinyl; groups selected from alkyl C1 to 6, alkoxy C1 to 6, perfluoroalkyl C1 to 6, halogen, nitro or cyano; unsaturated, substituted at a carbon atom by the group --(CH.sub.2).sub.m --NXY, wherein in X and Y are as defined above,
A preferred group of compounds of formula I is defined by formula IA: ##STR3## wherein T represents a C.sub.3-5 saturated or unsaturated alkylene chain substituted by --(CH.sub.2).sub.m --NXY; --O--(CH.sub.2).sub.2 --NH-- substituted by --(CH.sub.2).sub.m --NXY; or --U--(CH.sub.2).sub.a --N(X)--(CH.sub.2).sub.b --; --(CH.sub.2).sub.n Q, or --NXY represents piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinolinyl; 6, trifluoromethyl, halogen, nitro or cyano; --and X represents --(CH.sub.2).sub.n Q, n represents an integer 0 to 5,
We prefer that D represents a five-membered heterocyclic aromatic ring containing one heteroatom selected from O, N or S, optionally substituted at a carbon atom by halogen. We particularly prefer that D represents thienyl, furyl or pyrrolyl, especially thienyl or furyl, more especially thienyl and most especially 2thienyl.
We prefer that T represents a C.sub.3-5 saturated or unsaturated alkylene chain substituted by --(CH.sub.2).sub.m --NXY, particularly a C.sub.3-5 saturated alkylene chain substituted by --(CHM.sub.2).sub.m --NXY, especially a C.sub.3-4 saturated alkylene chain substituted by --(CH.sub.2).sub.m --NXY.
When T represents a C.sub.3-5 saturated or unsaturated alkylene chain substituted by --(CH.sub.2).sub.m --NXY; or

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