Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-25
1998-11-24
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514415, 514418, 544 98, 544128, 544144, 544175, 544337, 544358, 544363, 544364, 544373, 546184, 546201, 546208, 548454, 548455, 548469, 548486, 548488, A61K 3140, C07D20914, C07D20934, C07D21106
Patent
active
058407456
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/05176 of Dec. 22, 1995.
The present invention relates to new hydrosoluble 3-aryl-idene-2-oxindole derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, in particular as tyrosine kinase inhibitors. The present invention provides novel hydrosoluble 3-arylidene-2-oxindole derivatives having the following general formula (I) ##STR1## wherein m is zero, 1 or 2; indole; substituent selected from: unsubstituted or substituted by 1, 2 or 3 hydroxy groups; --(CH.sub.2).sub.n --N(C.sub.1 -C.sub.6 alkyl).sub.2 group in which n is 2 or 3; substituted by phenyl or by 1, 2 or 3 hydroxy groups or phenyl; alkyl substituted by 1, 2 or 3 hydroxy groups or by phenyl; unsubstituted or substituted by halogen or by C.sub.1 -C.sub.4 alkyl; -C.sub.6 alkyl substituted by 1, 2 or 3 hydroxy groups; is C.sub.1 -C.sub.6 alkyl substituted by 1, 2 or 3 hydroxy groups; --CH.sub.2 NHC(NH.sub.2).dbd.NH; --PO(OH).sub.2 ; or a ##STR2## group, wherein p is 1, 2 or 3 and Z is --CH.sub.2 --, --O-- or >N--R.sup.11 in which R.sup.11 is hydrogen or is as R.sup.9 defined above; and the pharmaceutically acceptable salts thereof.
The substituents R.sup.1 O and R.sup.2 may be independently on either of the ring moieties whereas the R.sup.3 substituent is only linked to the benzene moiety.
The invention includes within its scope all the possible isomers, stereoisomers, in particular Z- and E-isomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors (otherwise known as pro-drugs) of the compound of formula (I).
The oxindolylidene substituent is preferably linked to position 1 or 2 when A is tetralin or naphthalene, to position 4 or 5 when A is quinoline and to position 3 when A is indole.
The R.sup.3 substituent is preferably linked to position 5 in the oxindole ring.
The R.sup.2 substituent with reference to the oxindolylidene substituent is preferably linked to the same ring moiety when A is tetralin, whereas it is preferably linked to the other ring moiety when Ar is naphthalene, quinoline or indole.
The OR.sup.1 substituent is preferably located on the same benzene moiety when A is tetralin, quinoline or indole whereas it may be located on either benzene moieties when
Of course only one of the substituents R.sup.1 O and R.sup.2 can be linked to the same ring position.
An alkyl group or an alkyl moiety in an alkanoyl group may be branched or straight alkyl chain.
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.2 -C.sub.6 alkyl group is preferably a C.sub.2 -C.sub.4 alkyl group in particular ethyl.
A C.sub.1 -C.sub.6 alkyl group substituted by 1 to 3 hydroxy groups is, for instance, a C.sub.1 -C.sub.4 alkyl group substituted by 1 or 2 hydroxy groups, typically a --CH.sub.2 OH, --CHOHCH.sub.2 OH or --CH.sub.2 (CHOH).sub.q CH.sub.2 OH group in which q is zero or 1.
A halogen atom is for example chloro, bromo or iodo, in particular chloro.
A C.sub.1 -C.sub.6 alkyl group substituted by phenyl is typically benzyl or phenylethyl.
A C.sub.2 -C.sub.6 alkanoyl group is preferably a C.sub.2 -C.sub.3 alkanoyl group, in particular acetyl or propionyl.
The term tetralin is meant to refer to 5,6,7,8-tetrahydronaphthalene.
Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids or organic, e.g. acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium bases or alkaline-earth metal, especially calcium or magnesium bases, or with organic bases, e.g. acyclic or cyclic amines, preferably triethylamine or piperidine.
As stated above, the present invention also includes with
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Ballinari Dario
Brasca Maria Gabriella
Buzzetti Franco
Longo Antonio
Oswecki Jane C.
Pharmacia S. p. A.
Richter Johann
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