Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-24
1997-06-10
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514304, 546126, 546133, A61K 3146, C07D45302
Patent
active
056375964
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/01652 filed May 2, 1995.
The present invention relates to new derivatives of 2-azabicycloalkyl-1,2-dihydro-imidazo[1,5-a]indol-3-one, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents.
The present invention provides novel compounds having the general formula (I) ##STR3## wherein each of R, R.sub.1 and R.sub.2, which may be the same or different, is hydrogen, halogen, hydroxy, cyano, C.sub.1 -C.sub.6 alkyl, CF.sub.3, C.sub.1 -C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, formyl, C.sub.2 -C.sub.6 alkanoyl, carboxy, C.sub.1 -C.sub.6 alkoxy-carbonyl, nitro, --N(R.sub.4 R.sub.5) in which each of R.sub.4 and R.sub.5 independently is hydrogen, C.sub.1 -C.sub.6 alkyl, formyl or C.sub.2 -C.sub.6 alkanoyl; or a (R.sub.6 R.sub.7)N--SO.sub.2 group, in which each of R.sub.6 and R.sub.7 independently is hydrogen or C.sub.1 -C.sub.6 alkyl; ##STR4## wherein n is an integer of 1 or 2 and R.sub.8 is hydrogen, C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by phenyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, formyl or C.sub.2 -C.sub.6 alkanoyl; and the pharmaceutically acceptable salts thereof.
The formula reported above for the compounds according to the present invention includes all the possible isomers, in particular stereoisomers, as well as their mixtures. In the compounds of the invention wherein the substituent R.sub.3 is a group a), as defined above, such group may be in the R- or S-configuration, or in mixtures thereof.
Similarly when the substituent R.sub.3 is a group b), as defined above, such group may be in the endo- or exo-configuration or mixtures thereof, the endo being the preferred.
The invention includes within its scope the metabolites and the metabolic precursors or bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
Namely the invention includes compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
A halogen atom may be a fluorine, chlorine, bromine or iodine atom, preferably it is chlorine or bromine. The alkyl, alkenyl, alkynyl, alkoxy and alkylthio group may be a branched or straight chain groups.
A C.sub.1 -C.sub.6 alkyl group is preferably a C.sub.1 -C.sub.4 alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec.butyl or tert.butyl, in particular methyl or ethyl.
A C.sub.1 -C.sub.6 alkoxy group is preferably a C.sub.1 -C.sub.4 alkoxy group e.g. methoxy, ethoxy, propoxy, isopropoxy and butoxy, preferably methoxy and ethoxy.
A C.sub.1 -C.sub.6 alkylthio group is preferably a C.sub.1 -C.sub.4 alkylthio group, e.g. methylthio, ethylthio, propylthio and butylthio, in particular methylthio.
A C.sub.2 -C.sub.4 alkenyl group is preferably allyl.
A C.sub.2 -C.sub.4 alkynyl group is preferably propargyl.
A C.sub.2 -C.sub.6 alkanoyl group is e.g. a C.sub.2 -C.sub.4 alkanoyl group, in particular acetyl and propionyl.
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts, with inorganic acids e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acid, or organic acids e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, fumaric, mandelic and salicylic acid.
Preferred compounds of the invention are the compounds of formula (I) wherein each of R, R.sub.1 and R.sub.2, which may be the same or different, is hydrogen, halogen, cyano, CF.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkoxy or --N(R.sub.4 R.sub.5) in which each of R.sub.4 and R.sub.5 independently is hydrogen, C.sub.1 -C.sub.4 alkyl, formyl or C.sub.2 -C.sub.4 alkanoyl; ##STR5## in which n is 1 or 2 and R.sub.8 is C.sub.1 -C.sub.4 alkyl; and the pharmaceutically acceptable salts thereof.
Examples of preferred compounds according to the invention are the following: one; one; one; one; l-3-one; l-3-one; ndol
REFERENCES:
patent: 3565902 (1971-02-01), Wright et al.
patent: 5364854 (1994-11-01), Varasi et al.
Bermudez et al, Journal of Medicinal Chemistry, "'5-Hydroxytryptamine (5-HT3) receptor antagonists. 2 . . . ", vol. 33, No. 7, pp. 1929-1932, 1990.
Caccia Carla
Heidempergher Franco
Salvati Patricia
Varasi Mario
Dahlen Garth M.
Ivy C. Warren
Pharmacia S.p.A.
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