Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-02-09
1997-09-02
Grumbling, Matthew V.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
544373, 544127, C07D47102, C07D40302, C07D40502, A01N 4334
Patent
active
056633467
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new substituted azaindolylidene compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents. The present invention provides compounds having the following general formula (I) ##STR7## wherein one of the groups X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N and the others are CH; R is a group of formula (a), (b), (c) or (d) ##STR8## each of R.sup.1 and R.sup.3 independently, is hydrogen, amino, carboxy, cyano, --SO.sub.3 R.sup.4, --SO.sub.2 NHR.sup.5, ##STR9## --COOR.sup.6, --CONH(CH.sub.2).sub.o Ph, --CONHCH.sub.2 (CHOH).sub.n CH.sub.2 OH, ##STR10## --N(CH.sub.2 CH.sub.2 OH).sub.2, NHCH.sub.2 (CHOH).sub.n CH.sub.2 OH, --NHCONH.sub.2, --NHC (NH.sub.2).dbd.NH, --NHCO(CHOH).sub.n CH.sub.2 OH, ##STR11## --NHSO.sub.2 R.sup.7, --OCH.sub.2 (CHOH).sub.n CH.sub.2 OH, --OOC(CHOH).sub.n CH.sub.2 OH, --OPO(OH).sub.2, --OCH.sub.2 SO.sub.2 NH.sub.2, --CH.sub.2 NH.sub.2, --C(NH.sub.2).dbd.NH, --CH.sub.2 NHC(NH.sub.2).dbd.NH, ##STR12## --CH.sub.2 OH, --CH.sub.2 OOC(CHOH).sub.n CH.sub.2 OH, --CH.sub.2 OPO(OH).sub.2, --PO(OH).sub.2 ;
R.sup.2 is H, C.sub.1 -C.sub.6 alkanoyl, --CH.sub.2 OH, --CH.sub.2 CH.sub.2 CONH.sub.2, --SO.sub.2 Me, --COCH.sub.2 SO.sub.2 NH.sub.2 ;
R.sup.4 is H, --CH.sub.2 (CHOH).sub.n CH.sub.2 OH, C.sub.1 -C.sub.6 alkyl;
R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, --CH.sub.2 (CHOH).sub.n CH.sub.2 OH, --(CH.sub.2).sub.m NMe.sub.2 ;
R.sup.6 is C.sub.1 -C.sub.6 alkyl, unsubstituted or substituted by phenyl, --CH.sub.2 (CHOH).sub.n CH.sub.2 OH;
R.sup.7 is Me, --C.sub.6 H.sub.4 Me;
Z is CH.sub.2, O, NH, NCH.sub.2 CH.sub.2 OH;
n is 0 or 1;
m is 2 or 3;
o is 0, 1, 2 or 3;
p is 1, 2 or 3; is (d) then one of R.sup.1 and R.sup.3 is not H; and the pharmaceutically acceptable salts thereof. In the compounds of the invention each of the substituents R and R.sup.1 may be independently on either of the pyridine or pyrrole moieties of the bicyclic azaindole ring. 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 compounds of formula (I). The substituent R is preferably linked the position 2 or 3 of the azaindole ring, in particular to position 3. The substituent R.sup.1 is preferably on the pyridine moiety. Preferably one of R.sup.1 and R.sup.3 is hydrogen whereas the other not hydrogen. The R.sup.3 substituent is preferably in the 5-position of the oxindole ring (d). The alkyl group and the alkyl moiety in the 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 t-butyl, in particular methyl or ethyl. 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. 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 in its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the calmpounds of formula (I), i.e. compounds which have a different formula to formula (I) above but which, nevertheiess, upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
Preferred compounds of the invention are the compounds of formula (I), wherein
X.sup.1, X.sup.2, X.sup.3 ahd X.sup.4 ar
Ballinari Dario
Brasca Maria Gabriella
Buzzetti Franco
Longo Antonio
Bucknum Michael
Grumbling Matthew V.
Pharmacia S.p.A.
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