Substituted azaindolylidene compounds and process for their preparation

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; 
provided that when R is (a), (b), or (c) then R.sup.1 is not H and when R 
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 are as defined above; 
R is as defined above and is linked in position 2 or 3 of the azaindole 
ring; 
R.sup.2 is hydrogen or C.sub.1 -C.sub.4 alkyl; each of R.sup.1 and R.sup.3, 
independently, is hydrogen, amino, carboxy, cyano, --SO.sub.3 H, 
--SO.sub.2 NH.sub.2, 
##STR13## 
--COOMe, --N(CH.sub.2 CH.sub.2 OH).sub.2, --NH--CH.sub.2 --CHOH--CH.sub.2 
OH, --NHCONH.sub.2, --NHC(NH.sub.2).dbd.NH, --NHCOHOHCH.sub.2 OH, 
##STR14## 
--NHSO.sub.2 Me, --OCH.sub.2 CHOHCH.sub.2 OH, --OOC--CH.sub.2 OH, 
--OOCCHOHCH.sub.2 OH, --OPO(OH).sub.2, --CH.sub.2 NH.sub.2, 
--C(NH.sub.2).dbd.NH, 
##STR15## 
--CH.sub.2 OH, --CH.sub.2 PO(OH).sub.2, --PO(OH).sub.2, provided that when 
R is not (a), (b) or (c) then R.sup.1 is not hydrogen and when R is (d) 
then one of R.sup.1 and R.sup.3 is not hydrogen, and the pharmaceutically 
acceptable salt thereof. 
More preferred compounds of the invention are the compounds of formula (I) 
in which X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are as defined above; 
R is as defined above and is linked in position 3 of the azaindole ring; 
R.sup.2 is hydrogen; each of R.sup.1 and R.sup.3 independently is hydrogen, 
amino, carboxy, cyano, --SO.sub.3 H, --SO.sub.2 NH.sub.2 
##STR16## 
--N(CH.sub.2 CH.sub.2 OH).sub.2, --NHCONH.sub.2, --NHC(NH.sub.2).dbd.NH, 
##STR17## 
--NHSO.sub.2 Me, --OCH.sub.2 CHOHCH.sub.2 OH, --OOCCHOHCH.sub.2 OH, 
--CH.sub.2 NH.sub.2, --C(NH.sub.2).dbd.NH, --CH.sub.2 OH, --PO(OH).sub.2, 
and 
R.sup.3 is preferably linked at position 5 of the oxindole ring; provided 
that when R is (a), (b) or (c) then R.sup.1 is not hydrogen and when R is 
(d) then one of R.sup.1 and R.sup.3 is not hydrogen, and the 
pharmaceutically acceptable salt thereof. 
Examples of specific compounds of the invention are the following 
compounds, which, when appropriate, may be either Z- or E-diastereomers or 
Z,E-mixtures of said diastereomers: 
2-cyano-3-(4-sulfo-7-azaindol-3-yl)acrylamide, sodium salt; 
2-cyano-3-[(N,N-piperazinyl-4-sulfamoyl)-7-azaindol-3-yl]acrylamide; 
2-cyano-3-(4-ureido-7-azaindol-3-yl)acrylamide; 
2-cyano-3-(4-glyceroylamido-7-azaindol-3-yl)acrylamide; 
2-cyano-3-[4-(3-piperidinopropionylamino)-7-azaindol-3-yl]acrylamide; 
2-cyano-3-(4-mesylamino-7-azaindol-3-yl)acrylamide; 
2-cyano-3-[4-(2,3-dihydroxypropoxy)-7-azaindol-3-yl]acrylamide; 
2-cyano-3-(4-aminomethyl-7-azaindol-3-yl)acrylamide; 
2-cyano-3-(4-amidino-7-azaindol-3-yl)acrylamide; 
2-cyano-3-(4-sulfo-7-azaindol-3-yl)thioacrylamide, sodium salt; 
2-cyano-3-[(N,N-piperazinyl-4-sulfamoyl)-7-azaindol-3-yl]thioacrylamide; 
2-cyano-3-(4-ureido-7-azaindol-3-yl)thioacrylamide; 
2-cyano-3-(4-glyceroylamido-7-azaindol-3-yl)thioacrylamide; 
2-cyano-3-[4-(3-piperidinopropionylamino)-7-azaindol-3-yl]thioacrylamide; 
2-cyano-3-(4-mesylamino-7-azaindol-3-yl)thioacrylamide; 
2-cyano-3-[4-(2,3-dihydroxypropoxy)-7-azaindol-3-yl]thioacrylamide; 
2-cyano-3-(4-aminomethyl-7-azaindol-3-yl)thioacrylamide; 
2-cyano-3-(4-amidino-7-azaindol-3-yl)thioacrylamide; 
2-cyano-3-(4-sulfo-7-azaindol-3-yl)acrylonitrile, sodium salt; 
2-cyano-3-[(N,N-piperazinyl-4-sulfamoyl)-7-azaindol-3-yl]acrylonitrile; 
2-cyano-3-(4-ureido-7-azaindol-3-yl) acrylonitrile; 
2-cyano-3-(4-glyceroylamido-7-azaindol-3-yl)acrylonitrile; 
2-cyano-3-[4-(3-piperidinopropionylamino)-7-azaindol-3-yl]acrylonitrile; 
2-cyano-3-(4-mesylamino-7-azaindol-3-yl)acrylonitrile; 
2-cyano-3-[4-(2,3-dihydroxypropoxy)-7-azaindol-3-yl]acrylonitrile; 
2-cyano-3-(4-aminomethyl-7-azaindol-3-yl)acrylonitrile; 
2-cyano-3-(4-amidino-7-azaindol-3-yl)acrylonitrile; 
3-[(7-azaindol-3-yl)methylen]-2-oxindole-5-sulfonic acid, sodium salt; 
5-sulfamoyl-3-[(7-azaindol-3-yl)methylen]oxindole; 
5-(N,N-piperazinylsulfamoyl)-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-[N,N-[4-(2-hydroxyethyl)piperazinylsulfamoyl]-3-[(7-azaindol-3-yl)methyle 
n]-2-oxindole; 
5-diethanolamino-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-ureido-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-guanidino3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-glyceroylamido-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-(3-piperidinopropionylamino)-3-[(7-azaindol-3-yl) methylen]-2-oxindole, 
dihydrochloride; 
5-mesylamino-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-(2,3-dihydroxypropoxy)-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-glyceroyloxy-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
3-[(7-azaindol-3-yl)methylen]-2-oxindol-5-yl-phosphate; 
5-aminomethyl-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-amidinol3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-(2,3-dihydroxypropylamine)-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-carbomethoxy-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-[4-(2-hydroxyethyl)-1-piperazinylmethyl)-3-[(7-azaindol-3-yl)methylen]-2- 
oxindole; 
5-[N,N-[4-(2-hydroxyethyl)piperazinylcarbamoyl]-3-[(7-azaindol-3-yl)methyle 
n]-2-oxindole; 
5-glycoloyloxyl-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-amino-3-[(7-azaindol,3-yl)methylen]-2-oxindole, ditrifluoroacetate; 
5-carboxy-3-[(7-azaindol-3-yl)methylen]-2-oxindole, piperidinium salt; 
5-cyano-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-carboethoxy-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-carbobenzyloxy-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-carbophenylethyloxy-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-phenylcarbamoyl-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
5-benzylcarbamoyl-3-[(7-azaindol-3-yl)methylen]-2-oxindole; 
as well as the free compounds corresponding to the above listed salified 
compounds and the pharmaceutically acceptable salts of the above listed 
free compounds. 
The compounds of the invention, and the pharmaceutically acceptable salts 
thereof, can be obtained by a process comprising: 
a) condensation of an aldehyde of formula (II) 
##STR18## 
wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, R.sup.1 and R.sup.2 are as 
defined above, with a compound of formula (a'), (b'), (c') or (d'), 
respectively: 
##STR19## 
wherein R.sup.3 is as defined above. Each of the substituents R.sup.1 and 
--CHO in a compound of formula (II) may be, independently, on either of 
the pyridine or pyrrole moiety; or 
b) N-alkylation of a compound of formula (III) 
##STR20## 
wherein either R.sup.1 and R.sup.3 are both amino of one of R.sup.1 and 
R.sup.3 is amino and the other is hydrogen, if it is present, and X.sup.1, 
X.sup.2, X.sup.3, X.sup.4, R and R.sup.2 are as defined above, thus 
obtaining, a compound of formula (I) wherein either R.sup.1 and R.sup.3 
are both --N(CH.sub.2 CH.sub.2 OH).sub.2 or --NHCH.sub.2 (CHOH).sub.n 
CH.sub.2 OH, or one is --N(CH.sub.2 CH.sub.2 OH).sub.2 or --NHCH.sub.2 
(CHOH).sub.n CH.sub.2 OH and the other is hydrogen, if it is present, and 
n, X.sup.1, X.sup.2, X.sup.3, X.sup.4, R and R.sup.2 are as defined above; 
or 
c) N-acylation of a compound of formula (III) wherein either R.sup.1 and 
R.sup.3 are both amino or one of R.sup.1 and R.sup.3 is amino and the 
other is hydrogen, if it is present, and X.sup.1, X.sup.2, X.sup.3, 
X.sup.4, R and R.sup.2 are as defined above, thus obtaining a compound of 
formula (I) wherein either R.sup.1 and R.sup.3 are both --NHCO(CHOH).sub.n 
CH.sub.2 OH or 
##STR21## 
or one is --NHCO(CHOH).sub.n CH.sub.2 OH or 
##STR22## 
and the other is hydrogen, if it is present, n, p, Z, X.sup.1, X.sup.2, 
X.sup.3, X.sup.4, R and R.sup.2 are as defined above; or 
d) N-sulfonylation of a compound of formula (III) wherein either R.sup.1 
and R.sup.3 are both amino or one of R.sup.1 and R.sup.3 is amino and the 
other is hydrogen, if it is present, and X.sup.1, X.sup.2, X.sup.3, 
X.sup.4, R and R.sup.2 are as defined above, thus obtaining a compound of 
formula (I) wherein either R.sup.1 and R.sup.3 are both --NHSO.sub.2 
R.sup.7 or one of R.sup.1 and R.sup.3 is --NHSO.sub.2 R.sup.7 and the 
other is hydrogen, if it is present, and R.sup.7, X.sup.1, X.sup.2, 
X.sup.3, X.sup.4, R and R.sup.2 are as defined above; or 
e) N-amidination of a compound of formula (III) wherein either R.sup.1 and 
R.sup.3 are both amino or one of R.sup.1 and R.sup.3 is amino and the 
other is hydrogen, if it is present, and X.sup.1, X.sup.2, X.sup.3, 
X.sup.4, R and R.sup.2 are as defined above, thus obtaining a compound of 
formula (I) wherein either R.sup.1 and R.sup.3 are both 
--NHC(NH.sub.2).dbd.NH or one of R.sup.1 and R.sup.3 is 
--NHC(NH.sub.2).dbd.NH and the other is hydrogen, if it, is present, and 
X.sup.1, X.sup.2, X.sup.3, X.sup.4, R and R.sup.2 are as defined above; or 
f) N-carbamoylation of a compound of formula (III) wherein either R.sup.1 
and R.sup.3 are both amino or one of R.sup.1 and R.sup.3 is amino and the 
other is hydrogen, if it is present, and X.sup.1, X.sup.2, X.sup.3, 
X.sup.4, R and R.sup.2 are as defined above, thus obtaining a compound of 
formula (I) wherein either R.sup.1 and R.sup.3 are both --NHCONH.sub.2 or 
one of R.sup.1 and R.sup.3 is --NHCONH.sub.2 and the other is hydrogen, if 
it is present, and X.sup.1, X.sup.2, X.sup.3, X.sup.4, R and R.sup.2 are 
as defined above; or 
g) O-alkylation of a compound of formula (III) wherein either R.sup.1 and 
R.sup.3 are both hydroxy or one of R.sup.1 and R.sup.3 is hydroxy and the 
other is hydrogen, if it is present, and X.sup.1, X.sup.2, X.sup.3, 
X.sup.4, R and R.sup.2 are as defined above, thus obtaining a compound of 
formula (I) wherein either R.sup.1 and R.sup.3 are both --OCH.sub.2 
(CHOH).sub.n CH.sub.2 OH or --OCH.sub.2 SO.sub.2 NH.sub.2 or one of 
R.sup.1 and R.sup.3 is --OCH.sub.2 (CHOH).sub.n CH.sub.2 OH or --OCH.sub.2 
SO.sub.2 NH.sub.2 and the other is hydrogen, if it is present, and n, 
X.sup.1, X.sup.2, X.sup.3, X.sup.4, R and R.sup.2 are as defined above; or 
h) O-acylation of a compound of formula (III) wherein either R.sup.1 and 
R.sup.3 are both hydroxy or one of R.sup.1 and R.sup.3 is hydroxy and the 
other is hydrogen, if it is present, and X.sup.1, X.sup.2, X.sup.3, 
X.sup.4, R and R.sup.2 are as defined above, thus obtaining a compound of 
formula (I) wherein either R.sup.1 and R.sup.3 are both --OOC(CHOH).sub.n 
CH.sub.2 OH or one of R.sup.1 and R.sup.3 is --OOC(CHOH).sub.n CH.sub.2 OH 
and the other is hydrogen, if it is present, and n, X.sup.1, X.sup.2, 
X.sup.3, X.sup.4, R and R.sup.2 are as defined above; or 
i) O-phosphorylation of a compound of formula (III) wherein either R.sup.1 
and R.sup.3 are both hydroxy or one of R.sup.1 and R.sup.3 is hydroxy and 
the other is hydrogen, if it is present, and X.sup.1, X.sup.2, X.sup.3, 
X.sup.4, R and R.sup.2 are as defined above, thus obtaining a compound of 
formula (I) wherein either R.sup.1 and R.sup.3 are both --OPO(OH).sub.2 or 
one of R.sup.1 and R.sup.3 is --OPO(OH).sub.2 and the other is hydrogen, 
if it is present, and X.sup.1, X.sup.2, X.sup.3, X.sup.4, R and R.sup.2 
are as defined above; or 
k) esterification of a compound of formula (III) wherein either R.sup.1 and 
R.sup.3 are both carboxy or one of R.sup.1 and R.sup.3 is carboxy and the 
other is hydrogen, if it is present, and X.sup.1, X.sup.2, X.sup.3, 
X.sup.4, R and R.sup.2 are as defined above, thus obtaining a compound of 
formula (I) wherein either R.sup.1 and R.sup.3 are both --COOR.sup.6 or 
one of R.sup.1 and R.sup.3 is --COOR.sup.6 and the other is hydrogen, if 
it is, present and R.sup.6, X.sup.1, X.sup.2, X.sup.3, X.sup.4, R and 
R.sup.2 are as defined above; or 
l) ammonia addition to a compound of formula (III) wherein either R.sup.1 
and R.sup.3 are both --C.tbd.N or one of R.sup.1 and R.sup.3 is --C.tbd.N 
and the other is hydrogen, if it is present, and X.sup.1, X.sup.2, 
X.sup.3, X.sup.4, R and R.sup.2 are as defined above, thus obtaining 
compound of formula (I) wherein either R.sup.1 and R.sup.3 are both 
--C(NH.sub.2).dbd.NH or one of R.sup.1 and R.sup.3 is --C(NH.sub.2).dbd.NH 
and the other is hydrogen, if it is present, and X.sup.1, X.sup.2, 
X.sup.3, X.sup.4, R and R.sup.2 are as defined above; or 
m) amination of a compound of formula (III) wherein either R.sup.1 and 
R.sup.3 are both --CH.sub.2 Cl or one of R.sup.1 and R.sup.3 is --CH.sub.2 
Cl and the other is hydrogen, if it is present, and X.sup.1, X.sup.2, 
X.sup.3, X.sup.4, R and R.sup.2 are as defined above; thus obtaining a 
substituted compound of formula (I) wherein either R.sup.1 and R.sup.3 are 
both 
##STR23## 
or one of R.sup.1 and R.sup.3 is 
##STR24## 
and the other is hydrogen, if it is present, and Z, X.sup.1, X.sup.2, 
X.sup.3, X.sup.4, R and R.sup.2 are ss defined above; 
and/or conversion,of a compound of formula (I) into another ompound of 
formula (I) and/or optional salification of a compound of formula (I) or 
conversion of a salt into the corresponding free compound of formula (I) 
and/or, if desired, separation of a mixture of isomers into the single 
isomers. 
The reaction of a compound of formula (II) with a compound of formula (a'), 
(b'), (c') or (d') according to the process step a), may be carried out 
according to known methods, as herebelow described; preferably in the 
presence of a basic catalyst, e.g. pyridine, piperidine, dimethylamine, or 
a suitable alkali metal hydroxide or alkoxide. For example the reaction of 
a compound of formula (II) with a compound of formula (a'), (b'), (c') or 
(d'), respectively, may be carried out under the conditions of the 
Knoevenagel reaction as described, e.g., by G. Jones in Organic Reactions 
15, 204 (1967). Suitable catalysts are organic bases such as pyridine, 
piperidine or diethylamine. The condensation may be performed in an inert 
organic solvent, e.g. pyridine, ethanol, methanol, benzene or dioxane at 
temperatures ranging from about 0.degree. C. to about 100.degree. C. 
Preferably the reaction is carried out in warm ethanol solution in the 
presence of piperidine catalyst. 
The N-alkylation according to process step b) may be carried out according 
to known methods, e.g. as described in Houben-Weyl, Methoden der 
Organischen Chemie, Vol. XI/I, page 311 (1957). Thus, the aromatic amine 
is reacted with ethylene oxide in water, alcoholic or hydroalcoholic 
solution at temperatures from, e.g., 0.degree. C. to 100.degree. C. 
Preferably the reaction is carried out in hydroalcoholic suspension at 
about 70.degree.-80.degree. C. by introducing ethylene oxide gas. On the 
other hand the N-alkylation according to process step b) in order to 
obtain compounds of formula (I) wherein R.sup.1 and/or R.sup.3 is 
--NHCH.sub.2 (CHOH).sub.n CH.sub.2 OH can be carried out by reductive 
amination, i.e. by condensation with an aldehyde of formula CH.sub.2 
OH(CHOH).sub.n CHO in the presence of a reducing agent, e.g. as described 
by Tietze and Eiche in Reactions and Synthesis in the Organic Chemistry 
Laboratory (1988) at page 77. Thus, to the alcoholic solution of the 
aromatic amine and the aldehyde is added portionwise sodium 
cyanoborohydride at temperatures ranging from 0.degree. C. to reflux 
temperature. 
The N-acylation according to process step c) may be carried out by known 
methods, e.g. as described in Houben-Weyl, Vol. E5, part. II, page 960 
(1985). Thus, the aromatic amine is reacted with the corresponding 
carboxylic acid of formula CH.sub.2 OH(CHOH).sub.n COOH or 
##STR25## 
wherein Z, p and n are as defined above by using a condensing agent, such 
as dicyclohexylcarbodiimide (DCCD). Preferably equimolar amounts of amine, 
carboxylic acid and dicyclohexylcarbodiimide are used in an inert solvent 
such as THF or benzene at temperatures from about 0.degree. to 50.degree. 
C. 
The N-sulfonylation according to process step d) may be carried out by 
known methods, e.g. as described in Houben-Weyl, vol. IX, page 609 (1955). 
Thus, equimolar amounts of aromatic amine and sulfochloride of general 
formula R.sup.5 --SO.sub.2 --Cl are reacted in pyridine solution at 
temperatures from, e.g., -10.degree. C. to 50.degree. C. 
The N-amidination according to process step e) may be carried out, e.g., as 
described by P. D. Davis et al. in J. Med. Chem. 1992, 35, 994. Thus, the 
aromatic amine is treated with about 1.5 molar equivalents 
3,5-dimethylpyrazole-1-carboxamidine in refluxing ethanol in the presence 
of about 1 molar equlvalents of NaHCO.sub.3. 
The N-carbamoylation according to pprocess step f) may be carried out, 
e.g., as described in Houben-Weyl, vol. E4, page 362 (1983). Thus, the 
aromatic amine salt, preferably the hydrochloride salt, is reacted with an 
alkali metal cyanate, preferably NaOCN or KOCN, in aqueous or 
hydroalcoholic solution at temperatures ranging, e.g., from about 
50.degree. C. to about 100.degree. C. 
The O-alkylation according to process step g) may be carried out, e.g., as 
described in Houben-Weyl, Vol. VI/3, page 54 (1965). Thus, the phenol is 
first transformed into an alkali metal phenolate by treatment with an 
alkali metal alcoholate or hydroxide or amide. Then the phenolate is 
reacted with a halogenide of general formula XCH.sub.2 (CHOH).sub.n 
CH.sub.2 OH or XCH.sub.2 SO.sub.2 NH.sub.2 (wherein X is chlorine or 
bromine) in an inert solvent such as benzene and THF at temperatures 
ranging from room to reflux temperature. Preferably the reaction is 
carried out in benzene solution by reacting the phenol first with a 
stoechiometric amount of NaNH.sub.2 at room temperature and thin with an 
excess of halogenide at reflux temperature. 
The O-acylation according to process step h) may be carried out by known 
methods, e.g. as described in Houben-Weyl, Vol. VIII, page 543 (1952). 
Thus, the phenol is reacted with the acid halide of general formula 
CH.sub.2 OH(CHOH).sub.n COCl in the presence of an organic base such as 
pyridine or triethylamine at temperatures ranging, e.g., from about 
0.degree. C. to about 50.degree. C. Alternatively the phenol is reacted 
with the acid CH.sub.2 OH(CHOH).sub.n COOH in the presence of a condensing 
agent such as dicyclohexylcarbodiimide (DCCD). Preferably equimolar 
amounts of phenol and DCCD are used and the reaction is conducted in an 
inert solvent such as THF or benzene at temperatures from about 0.degree. 
C. to about 50.degree. C. 
The O-phosphorylation according to process step i) may be carried out by 
known methods, e.g. as described in Houben-Weyl, vol. XII/2, page 143 
(1964). Thus, the phenol is reacted with phosphoric acid or a derivative 
thereof in water or hydroalcoholic solution at temperature ranging from 
room to reflux temperature. Preferably the reaction is carried out in 
polyphosphoric acid (mixture of phosphoric acid and P.sub.2 O.sub.5) which 
acts as reactant and solvent at temperatures ranging from about 50.degree. 
C. to about 100.degree. C. 
The esterification according to process step k) may be carried out by well 
known methods, e.g. as described in Houben-Weyl, vol. VIII, page 508 
(1952). Thus, the mixture of acid and alcohol, dissolved in an inert 
solvent such as benzene or chloroform, is heated to reflux in the presence 
of a mineral acid such as H.sub.2 SO.sub.4 or HCl. Preferably the water 
formed is removed by azeotropic distillation in a Dean-Stark condenser. 
The nitril transformation according to process step 1) may be carried out 
by known methods, e.g. as described in Houben-Weyl, vol. 8, page 697 and 
702 (1952). Thus, to the ether or chloroform solution of the nitril is 
added an equimolar amount of ethanol and the resulting solution is 
saturated with HCl gas. The resulting iminoether hydrochloride is then 
transformed into amidine by reaction with ammonia in absolute ethanol at 
room temperature. 
The amination according to process step m) may be carried out by known 
methods, e.g. as described in Houben-Weyl, vol. II/I, page 24 (1957). 
Thus, a mixture of the chloromethylene and piperazine compound is heated 
to a temperature from, e.g., about 50.degree. C. to about 150.degree. C. 
until the reaction is complete. 
The optional salification of a compound of formula (I) as well as the 
conversion of a salt into the corresponding free compound and the 
separation of a mixtura of isomers into the single isomers as well as the 
conversion of a compound of formula (I) into another compound of formula 
(I) may be carried out according to known methods. 
For example, the amidation of a compound of formula (I), wherein R.sup.1 
and/or R.sup.3 is --SO.sub.3 H, so as to obtain a compound of formula (I), 
wherein R.sup.1 and/or R.sup.3 is --SO.sub.2 NHR.sup.5 or 
##STR26## 
may be carried out by known methods as described above at process step d). 
The conversion of a compound of formula (I) in which R.sup.1 and/or R.sup.3 
is --SO.sub.3 H into the corresponding compound of formula (I) wherein 
R.sup.1 and/or R.sup.3 is --SO.sub.3 R.sup.4 may be carried out by known 
esterification methods, e.g. as described above at process step k). 
The conversion of a compound of formula (I) in which R.sup.1 and/or R.sup.3 
is --CH.sub.2 NH.sub.2 into the corresponding compound of formula (I) 
wherein R.sup.1 and/or R.sup.3 is --CH.sub.2 NH--C(NH.sub.2).dbd.NH may be 
carried out by known amidination methods, e.g. as described above at 
process step e). 
The esterification of a compound of formula (I) wherein R.sup.1 and/or 
R.sup.3 is --CH.sub.2 OH in order to obtain a compound of formula (I) 
wherein R.sup.1 and/or R.sup.3 is --CH.sub.2 OOC(CHOH).sub.n CH.sub.2 OH 
may be carried out as described above at process step k). 
The conversion of a compound of formula (I) in which R.sup.1 and/or R.sup.3 
is --CH.sub.2 OH into the corresponding compound of formula (I) wherein 
R.sup.1 and/or R.sup.3 is --CH.sub.2 OPO(OH).sub.2 may be carried out as 
described above at process step i). 
The conversion of a compound of formula (I) wherein R.sup.1 and/or R.sup.3 
is --COOR.sup.6 and wherein R.sup.6 is preferably methyl into the 
corresponding compound of formula (I) wherein R.sup.1 and/or R.sup.3 is 
##STR27## 
may be carried out by aminolysis, e.g. as described in Houben-Weyl, vol. 
E2, page 983 (1985). Preferably a mixture of the carbomethoxy compound and 
the amine compound of formula 
##STR28## 
is heated to reflux and the formed methanol is removed continuously by 
distillation. 
The optional salification of a compound of formula (I) as well as the 
conversion of a salt into the free compound and the separation of a 
mixture of isomers into the single isomers may be carried out by 
conventional methods. For example, the separation of a mixture of 
geometric isomers, e.g. cis- and trans-isomers, may be carried out by 
fractional crystallization from a suitable solvent or by chromatography, 
either column chromatography or high pressure liquid chromatography. 
The compounds of formula (II) may be obtained according to known methods 
from compounds of formula (IV) 
##STR29## 
wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, R.sup.1 and R.sup.2 are as 
defined above. 
For example, the 3-formylazaindole derivative of formula (IV) can be 
obtained from a compound of formula (V) by formylation with 
N-methyl-formanilide or DMF and phosphorous oxychloride according to the 
well known Vilsmeyer-Haack method (for a review see W. G. Jackson et al. 
in J. Am. Chem., Soc, 103, 533, 1981). The 2-formylazaindole derivatives 
are obtained when the 3-position is occupied. 
The compounds of formuia (IV) are known or may be obtained by known methods 
from known compounds. For example, according to R. R. Lorenz et al. (J. 
Org. chem. 1965, 30, 2531) the various parent azaindoles (IVa) may be 
obtained following the 3-step process herebelow depicted starting from the 
appropriate aminomethylpyridine (V) via the formimidates (VI) and the 
formamidines (VII). 
##STR30## 
Thus 7-azaindole (Iva, X.sup.4 .dbd.N, X.sup.1 .dbd.X.sup.2 .dbd.X.sup.3 
.dbd.CH) is obtained from 2-amino-3-methylpyridine (V, X.sup.4 .dbd.N, 
X.sup.1 .dbd.X.sup.2 .dbd.X.sup.3 .dbd.CH) whilst 4-amino-3-methylpyridine 
(V, X.sup.2 .dbd.N, X.sup.1 .dbd.X.sup.3 .dbd.X.sup.4 .dbd.CH) gives rise 
to 5-azaindole (IVa, X.sup.2 .dbd.N, X.sup.1 .dbd.X.sup.3 .dbd.X.sup.4 
.dbd.CH). The 4-azaindole (IVa, X.sup.1 .dbd.N, X.sup.2 .dbd.X.sup.3 
.dbd.X.sup.4 .dbd.CH) is obtained from 3-amino-2-methylpyridine (V, 
X.sup.1 .dbd.N, X.sup.2 .dbd.X.sup.3 .dbd.X.sup.4 .dbd.CH). 
A compound of formula (III) wherein either R.sup.1 and R.sup.3 are both 
amino, hydroxy, carboxy, cyano, chloromethyl or sulfonic acid or one of 
R.sup.1 and R.sup.3 is amino, hydroxy, carboxy, cyano, chloromethyl or 
sulfonic acid and the other is hydrogen, if it is present, and X.sup.1, 
X.sup.2, X.sup.3, X.sup.4, R and R.sup.2 are as defined above, can be 
obtained by condensation of a compound of formula (II) wherein R.sup.1 is 
hydrogen, amino, hydroxy, carboxy, cyano, chloromethyl or sulfonic acid 
and X.sup.1, X.sup.2, X.sup.3, X.sup.4, and R.sup.2 are as defined above, 
with a compound of formula (a'), (b'), (c') or (d') wherein in the latter 
case, R.sup.3 is hydrogen, amino, hydroxy, carboxy, cyano, chloromethyl or 
sulfonic acid. The compounds of formula (a'), (b'), (c') and (d') are 
known or may be obtained by known methods from known compounds. When in 
the new compounds of the present invention and in the intermediate 
products used for their preparation groups are present which need to be 
protected before submitting them to the hereabove illustrated reactions, 
they may be protected before the reaction takes place and then deprotected 
at the end of the reaction, according to well known methods in organic 
chemistry. 
PHARMACOLOGY 
The compounds of the invention possess specific tyrosine kinase inhibiting 
activity. It is believed that tyrosine kinase inhibitors may be of great 
importance in the control of uncontrollea cellular reproduction, i.e. in 
cellular reproduction disorders. Hence the compounds according to the 
present invention can be useful in the treatment of pathological 
proliferation disorders in mammals, including humans. Typical examples of 
such disorders are tumors, including leukemia, and psoriasis. The 
compounds of the invention can also be useful in inhibiting the 
development of the atheromatous plaque and in the control of angiogenesis 
and as anti-metastatic agents. Recent studies on the molecular basis of 
neoplastic transformation have identified a family of genes, designed 
oncogenes, whose aberrant expression causes tumorigenesis. For example, 
the RNA tumor viruses possess such an oncogene sequence whost expression 
determines neoplastic conversion of infected cells. Several of their 
oncogene-encoded proteins, such as pp60.sup.v-src, p70.sup.gag-yes, 
p130.sup.gag-fps and p70.sup.gag-fgr display protein tyrosine kinase 
activity, that is they catalyse the transfer of the g-phosphate from 
adenosine triphosphate (ATP) to tyrosine residues in protein substrate. In 
normal cells, several growth factor receptors, for example the receptors 
for PDGF, EGF, aTGF and insulin, display tyrosine kinase activity. 
Binding of the growth factor (GF) activates the receptors tyrosine kinase 
to undergo autophosphorylation and to phosphorylate closely adjacent 
molecules on tyrosine. Therefore, it is thought that the phosphorylation 
of these tyrosine kinase receptors plays an important role in signal 
transduction and that the principal function of tyrosine kinase activity 
in normal cells is to regulate cell growth. Perturbation of this activity 
by oncogenic tyrosine kinases that are either overproduced and/or display 
altered substrate specificity may cause loss of growth control and/or 
neoplastic transformation. Accordingly, a specific inhibitor of tyrosine 
kinase can be useful in investigating the mechanism of cancerogenesis, 
cell proliferation and differentiations and it can be effective in 
prevention and chemotherapy of cancer and in other pathological 
proliferative conditions, for instance as mentioned above. The tyrosine 
specific protein kinase activity of the compounds of the invention is 
shown, e.g., by the fact that they are active in the in-vitro and ln-vivo 
test described herebelow. 
In-vitro Assay 
p45 v-abl Kinase Purification 
The enzyme used in our test was the p45 v-abl tyrosine kinase which 
represents the catalytic domain of the Abelson tyrosine kinase (isolated 
from the Abelson murine leukemia virus). The p45 v-abl kinase was produced 
and isolated as described by Wang et al. in J. Biol. chem 260, 64 (1985) 
and by Ferguson et al. in J. Biol. Chem 260, 3652 (1985) and in Biochem J. 
257, 321 (1989). 
p45 v-abl Kinase Assay 
(Val.sup.5 )-Angiotensin II phosphorylation was performed by incubation 
with 40 ng of purified abl-kinase and (g-.sup.32 p)-ATP, in 50 ml of 
buffer containing Tris-HCl 25 mM, Ph 8.0, MgCl.sub.2 10 Mm and 
dithiothreitol 0.1 Mm (kinase buffer). The reaction mixture was incubated 
for the indicated time at 300.degree. C. and the reaction stopped by 
adding 50 ml of 5% trichloroacetic acid. After a brief incubation on ice, 
tubes were centrifuged. The supernatants were spotted on phosphocellulose 
paper squares (Whatman P-81) and washed extensively in acetic acid. The 
radioactivity bound to dried phosphocellulose squares was measured in a 
liquid scintillation counter. IC.sub.50 values were. calculated from 
triplicated determinations of each experimental point. Each inhibitor was 
tested at concentrations ranging from 0 to 400 mg in the presence of fixed 
concentrations of peptide (2 mM) and ATP (50 mM). 
In-vivo Assay 
K562 cell Growth Inhibition Assay 
1 ml of K562 cells, grown in suspension, were incubated for 66 h with or 
without 10% foetal calf serum in the presence of 1 mCi of [.sup.3 
H]-Thymidine. Cells were harvested, washed three times in cold PBS and 
treated with 5% trichloroacetic acid for 5 min. on ice. After a wash in 
ethanol: ether 2:1, the DNA was extracted by 0.5 N NaOH for 2 h at room 
temperature. The extract was counted in a liquid scintillation counter. 
The inhibitory activity data for a representative compound according to 
the present invention, obtained both in the in-vitro p45 v-abl kinase 
assay and in the in-vivo human chronic myeloid leukemia K562 cell growth 
inhibition assay described above, are set out in Table 1. 
TABLE 1 
______________________________________ 
Inhibition of p-45 v-abl kinase and K562 cell growth 
IC.sub.50 (mM) 
v-abl 
K562 
______________________________________ 
5-amino-3-[(7-azaindol-3-yl)methylen]- 
0.09 8.8 
2-oxindole ditrifluoroacetate 
5-cyano-3-[(7-azaindol-3-yl)methylen]- 
0.98 2.52 
2-oxindole 
______________________________________ 
In view of their high activity and low toxicity, the compounds of the 
invention can be used safely in medicine. For example, the approximate 
acute toxicity (LD.sub.50) of the compounds of the invention in the mouse, 
determined by single administration of increasing doses and measured on 
the seventh day after the treatment was found to be negligible. The 
compounds of the invention can be administered in a variety of dosage 
forms, e.g. orally, in the form of tablets, capsules, sugar or film-coated 
tablets, liquid solutions or suspensions; rectally, in the form of 
suppositories; parenterally, e.g. intramuscularly, or by intravenous 
injection of infusion; or topically. The dosage depends on the age, 
weight, condition of the patient and administration route; for example, 
the dosage adopted for oral administration to adult humans may range from 
about 10 to about 150-200 mg per dose, from 1 to 5 time daily. Of course, 
these dosage regimens may be adjusted to provide the optimal therapeutic 
response. 
The invention includes pharmaceutical compositions comprising a compound of 
formula (I) or a pharmaceutically acceptable salt thereof in association 
with a pharmaceutically acceptable excipient (which can be a carrier or 
diluent). The pharmaceutical compositions containing the compounds of the 
invention are usually prepared following conventional methods and are 
administered in a pharmaceutically suitable form. 
For example, the solid oral forms may contain, together with the active 
compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn 
starch or potato starch; lubricants, e.g. silica, talc, stearic acid, 
magnesium or calcium stearate, and/or polyethylene glycols; binding 
agents, e.g. starches, arabic gums, gelatin, methylcellulose, 
carboxymethylcelluose or polyvinyl pyrrolidone; disaggregating agents, 
e.g. a starch, alginic acid, alginates or sodium starch glycolate, 
effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as 
lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and 
pharmacologically inactive substances used in pharmaceutical formulations. 
Said pharmaceutical preparations may be manufactured in known manner, for 
example, by means of mixing, granulating, tabletting, sugar-coating or 
film-coating processes. 
The liquid dispersion for oral administration may be e.g. syrups, emulsions 
and suspensions. The syrup may contain as carrier, for example, saccharose 
or saccharose with glycerine and/or mannitol and/or sorbitol. The 
suspensions and the emulsions may contain as carrier, for example, a 
natural gum, agar, sodium alginate, pectin, methylcellulose, 
carboxymethylcellulose or polyvinyl alcohol. The suspensions or solutions 
for intramuscular injections may contain, together with the active 
compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive 
oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a 
suitable amount of lidocaine hydrochloride. The solutions for intravenous 
injections or infusion may contain as carrier, for example, sterile water 
or, preferable, they may be in the form of sterile aqueous, isotonic 
saline solutions. 
The suppositories may contain, together with the active compound, a 
pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene 
glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or 
lecithin. Compositions for topical application, e.g. creams, lotions, or 
pastes, can be prepared by admixing the active ingredient with a 
conventional oleaginous or emulsifying excipient. A further object of the 
present invention is a combined method of treatment of cancer in mammals, 
including humans, in need of such treatment, said method comprising 
administering: 
1) a compound of formula (I), or a pharmaceutically acceptable salt 
thereof, and 
2) an additional antitumor agent, in amounts and close enough together in 
time sufficient to produce a therapeutically useful effect. 
Object of the present invention is also to provide products containing a 
compound of formula (I), or a pharmaceutically acceptable salt, and an 
additional antitumor agent as a combined preparation for simultaneous, 
separate or sequential use in anti-cancer therapy. 
The term "antitumor agent" is meant to comprise both a single antitumor 
drug and "cocktails" i.e. a mixture of such drugs, according to the 
clinical practice. 
Antitumor agents that can be formulated with a compound of the invention or 
alternatively, can be administered in a combined method of treatment, are 
e.g. doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, 
fluorouracil, melphalan, cyclophosphamide, bleomycin, vinblastine and 
mitomycin or a mixture of two or more thereof. The compounds of the 
invention can therefore be used in a treatment to ameliorate a cancer. 
They may be administered to a patient suffering from a cancer treatable 
with an antitumor agent, for example and anthracycline glycoside such as 
doxorubicin, daunomycin, epirubicin or idarubicin as mentioned above, 
together with the antitumor agent. A compound of the invention and an 
antitumor agent such as an anthracycline glycoside can be administered to 
improve the condition of a patient having a leukemia such as myeloblastic 
leukaemia, lymphoma, sarcoma, neuroblastoma, Wilm's tumor or malignant 
neoplasm of the bladder, breast, lung or thyroid. 
The following examples illustrate but do not limit the invention: