Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-07-14
1999-10-12
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514262, 514266, 544264, 544265, 544276, 544277, A61K 3152, C07D47330, C07D47334, C07D47338
Patent
active
059655631
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to new bicyclic condensed pyrimidine compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, in particular as tyrosine kinase inhibitors.
2. Description of the Background
EP-A-0414386 discloses 4-substituted pyrido[2,3-d]pyrimidine compounds which are plant fungicides, miticides and insecticides.
WO 90/09178 discloses 6,9-disubstituted purine compounds useful in adenosine-mediated lipolysis, cardiovascular diseases and broncodilatation.
SUMMARY OF THE INVENTION
The present invention provides novel bicyclic condensed pyrimidine compounds having the following general formula (I) ##STR2## wherein X is --CH.sub.2 --, --NH--(CH.sub.2).sub.n --, --O--(CH.sub.2).sub.n -- or --S--(CH.sub.2).sub.n -- in which C.sub.1 -C.sub.4 alkyl or benzyl, or A is a 2,3-fused pyridine ring C-substituted by R.sub.4 which is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen or NR.sub.5 R.sub.6 in which each of R.sub.5 and R.sub.6 independently is H or C.sub.1 -C.sub.4 alkyl; alkyl, halogen, hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, nitro, cyano or CF.sub.3 ; same time, A is pyridine and B is a tetralin ring, R.sub.4 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or halogen and X is as defined above, then each of R.sub.1 and R.sub.2 is other than H; and wherein, when at the same time, A is imidazole, X is --NH--(CH.sub.2).sub.n -- as defined above, and B is an indan ring unsubstituted or substituted by one or more of halogen, hydroxy, C.sub.1 -C.sub.4 alkoxy and nitro, then R.sub.3 is other than C.sub.1 -C.sub.4 alkyl or benzyl.
The X bridge may be located on either of the ring B moieties, preferably it is located on the benzene ring.
The R.sub.3 substituent is only located on the imidazole ring on a N-ring atom.
The R.sub.4 substituent is only located on the pyridine ring, preferably it is attached at the .alpha.-position.
The R.sub.1 and R.sub.2 substituents in tetralin and indan may be on either of the ring moieties, preferably they are attached to the benzene moiety. In 2-oxindole the R.sub.1 and R.sub.2 substituents are preferably located on the benzene moiety. Thus the R.sub.1 and R.sub.2 substituents are preferably attached to the benzene moiety when B is tetralin, indan or 2-oxindole.
The invention includes within its scope all the possible isomers, stereoisomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors (otherwise known as prodrugs) of the compounds of formula (I).
The X bridge is preferably linked to position 1 or 2 when B is tetralin and to position 5 when B is indane or 2-oxindole. Of course only one of the X, R.sub.1 and R.sub.2 substituents can be linked to the same position in ring B.
An alkyl group or an alkyl moiety in a alkoxy group may be branched or straight alkyl chains.
A C.sub.1 -C.sub.4 alkyl group is preferably a C.sub.1 -C.sub.2 alkyl, that is ethyl or methyl.
A C.sub.1 -C.sub.4 alkoxy group is preferably a methoxy or ethoxy group.
A halogen atom is for example fluoro, chloro, bromo or iodio, in particular bromo or fluoro.
It is understood that when A is a 4,5-fused imidazole moiety then a purine ring is formed and when A is a 2,3-fused pyridine moiety then a pyrido[2,3-d]pyrimidine ring is formed.
The term tetralin is meant to refer to 5,6,7,8-tetrahydronaphthalene. In term X when X is --NHCH.sub.2 --, --OCH.sub.2 -- or --SCH.sub.2 -- it is understood that the linkage with the pyrimidine ring occurs through the N, 0 or S atom.
Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts with inorganic acids, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acid or organic acids, e.g. acetic, trifluoracetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acid.
As stated above, the present invention also includes with
REFERENCES:
patent: 3112192 (1963-11-01), Feichtmeir et al.
patent: 4751292 (1988-06-01), Fox
patent: 4853386 (1989-08-01), Friebe et al.
Burke, "Protein-Tyrosine Kinases: Potential Targets for Anticancer Drug Development," Stem Cells, vol. 12, pp. 1-6, 1994.
Ballinari Dario
Brasca Maria Gabriella
Buzzetti Franco
Longo Antonio
Kessinger Ann M.
Pharmacia & Upjohn S.p.A.
Raymond Richard L.
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