Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-11-14
1996-09-03
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514299, 514306, 514403, 514413, 540593, 546112, 546138, 546183, 5483601, 548455, C07D45302, C07D40112, C07D48704, A16K 3155
Patent
active
055523986
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
GB 2125398A (Sandoz Limited) describes a group of bridged piperidinyl ester and amide derivatives having 5-HT.sub.3 receptor antagonist activity. GB 1593146 and EP-A-36269 (Beecham Group p.l.c.) fused azabicyclic amide derivatives having gastric motility enhancing activity.
A class of novel, structurally distinct compounts has not been discovered, which compounds are fused azabicyclic ester derivatives. These compounds have 5-HT.sub.4 receptor antagonist activity.
European Journal of Pharmacology 146 (1988) 187-188, and Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hydroxytryptamine receptor, now designated the 5-HT.sub.4 receptor, and that ICS 205-930, which is also a 5-HT.sub.3 receptor antagonist, acts as an antagonist at this receptor.
PCT/GB9/00650 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT.sub.4 receptor antagonists in the treatment of atrial arrhythmias and stroke.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereo ##STR2## wherein X is of sub-formula (a) or (b): ##STR3## wherein L is N or CR.sub.c wherein R.sub.c is hydrogen, C.sub.1-6 alkoxy, halo, C.sub.1-6 alkyl or cyano; alkoxy; C.sub.2-6 alkanoyl, or C.sub.2-6 alkanoyl C.sub.1-3 alkyl; C.sub.1-6 alkyl group, halo, hydroxy or C.sub.1-6 alkoxy; or C.sub.14 6 alkylthio; amino;
Examples of alkyl or alkyl containing groups include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9 or C.sub.10 branched, straight chained or cyclic alkyl, as appropriate. C.sub.1-4 alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Alkenyl includes all suitable values including E and Z forms.
Aryl includes phenyl and naphthyl optionally substituted by one or two substituents selected from halo, C.sub.1-6 alkoxy and C.sub.1-6 alkyl.
Halo includes fluoro, chloro, bromo and iodo.
L in formula (a) is preferably CH, C--CH.sub.3, C--Cl or COCH.sub.3.
Q in formula (a) is preferably NR.sub.1 and R.sub.1 is preferably hydrogen or a methyl or ethyl group.
R.sub.a is often hydrogen and R.sub.b is often hydrogen or iodo.
R.sub.2 is preferably methoxy.
R.sub.4 is preferably amino.
R.sub.5 when halo is selected from fluoro, chloro, bromo and iodo, preferably chloro.
Suitable values for p and m include p=m=1; p=0, m=1; p=1, m=2; p=2, m=1.
R.sub.q is often hydrogen.
Preferably X--COO--(CH.sub.2).sub.n -- is attached such that the number of carbon atoms between the ester linkage and the azabicydic nitrogen atom is from 2 to 4 carbon atoms.
Specific values of the azabicylic which are of particular interest are as follows: ##STR4## Other azacycles of interest are as described with reference to the Examples.
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically, acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric, a-glycerophosphoric, and glucose-1-phosphoric acids.
Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R.sub.x --T wherein R.sub.x is C.sub.1-6 alkyl, phenyl-C.sub.1-6 alkyl or C.sub.5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R.sub.x include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples oft include halide such as chloride, bromide and iodide.
Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.
The compounds of the formula (I), their pharmaceutically acceptable salts, (incl
REFERENCES:
patent: 4617401 (1986-10-01), Miyano et al.
Bockaert, J. et al. Trends Pharmacol. Sci. 13, 141-145 (1992).
Talley, N. J. Aliment. Pharmacol. Ther. 6, 273-289 (1992).
Sadykov, A. S et al. Chemical Abstract Service No. 100:156848 (1984).
Fessenden, R. J. et al. Organic Chemistry (Willard Grant Pr., Boston), p. 281 (1982).
Gaster Laramie M.
King Francis D.
Wyman Paul A.
Kinzig Charles M.
Lentz Edward T.
Shah Mukund J.
SmithKline Beecham p.l.c.
Venetianer Stephen
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