U.S. patent application number 10/900162 was filed with the patent office on 2005-01-13 for new substituted indolinones, their manufacture and their use as medicaments.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Heckel, Armin, Roth, Gerald Juergen, Spevak, Walter, Tontsch-Grunt, Ulrike, Van Meel, Jacobus C. A., Walter, Rainer.
Application Number | 20050009898 10/900162 |
Document ID | / |
Family ID | 26006075 |
Filed Date | 2005-01-13 |
United States Patent
Application |
20050009898 |
Kind Code |
A1 |
Roth, Gerald Juergen ; et
al. |
January 13, 2005 |
New substituted indolinones, their manufacture and their use as
medicaments
Abstract
The present invention relates to substituted indolinones of
general formula 1 wherein R.sub.1 to R.sub.6 and X are defined as
in claim 1, the isomers and the salts thereof, in particular the
physiologically acceptable salts thereof which have valuable
pharmacological properties, especially an inhibitory effect on
various receptor-tyrosine kinases, and cycline/CDK complexes as
well as on the proliferation of endothelial cells and various
tumour cells, pharmaceutical compositions containing these
compounds, their use and processes for preparing them.
Inventors: |
Roth, Gerald Juergen;
(Biberach, DE) ; Heckel, Armin; (Biberach, DE)
; Walter, Rainer; (Biberach, DE) ; Tontsch-Grunt,
Ulrike; (Baden, AT) ; Spevak, Walter;
(Oberrohrbach, AZ) ; Van Meel, Jacobus C. A.;
(Moedling, AT) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim
DE
|
Family ID: |
26006075 |
Appl. No.: |
10/900162 |
Filed: |
July 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10900162 |
Jul 27, 2004 |
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10069557 |
Jul 22, 2002 |
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6794395 |
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10069557 |
Jul 22, 2002 |
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PCT/EP00/08149 |
Aug 22, 2000 |
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Current U.S.
Class: |
514/414 ;
514/418; 548/465; 548/484 |
Current CPC
Class: |
C07D 491/04 20130101;
C07D 401/04 20130101; C07D 403/12 20130101; C07D 401/12 20130101;
C04B 35/632 20130101; A61P 35/00 20180101; A61P 43/00 20180101;
C07D 401/14 20130101; C07D 209/34 20130101 |
Class at
Publication: |
514/414 ;
514/418; 548/484; 548/465 |
International
Class: |
A61K 031/404; C07D
43/02; C07D 209/36 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 14, 2000 |
DE |
100 29 285.2 |
Aug 27, 1999 |
DE |
199 40 829.7 |
Claims
What is claimed is:
1. A compound of the formula (I): 7wherein: X denotes an oxygen or
sulphur atom; R.sub.1 denotes a C.sub.2-3-alkenyl,
C.sub.2-3-alkynyl, aryl, aryl-C.sub.1-3-alkyl, heteroaryl,
heteroaryl-C.sub.1-3-alkyl, trifluoromethyl or cyano group, a
hydroxy, C.sub.1-3-alkoxy, hydroxy-C.sub.1-3-alkyl,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, aryloxy or heteroaryloxy group, a
mercapto, C.sub.1-3-alkylsulphenyl, phenylsulphenyl,
benzylsulphenyl, C.sub.1-3-alkylsulphinyl, phenylsulphinyl,
benzylsulphinyl, C.sub.1-3-alkylsulphonyl, phenylsulphonyl,
benzylsulphonyl, sulpho, C.sub.1-3-alkoxysulphonyl,
phenoxysulphonyl or benzyloxysulphonyl group, an amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino,
hydroxycarbonyl-C.sub.1- -3-alkylamino,
N--(C.sub.1-3-alkyl)-hydroxycarbonyl-C.sub.1-3-alkylamino,
C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-C.sub-
.1-3-alkoxycarbonyl-C.sub.1-3-alkylamino, phenylamino,
N-phenyl-C.sub.1-3-alkylamino, N,N-diphenylamino, benzylamino,
N-benzyl-C.sub.1-3-alkylamino, N,N-dibenzylamino,
C.sub.1-3-alkylcarbonyl- amino, benzoylamino, benzylcarbonylamino
group or an N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino group
wherein the two alkyl groups are optionally replaced by a
C.sub.2-5-n-alkylene bridge or wherein one or both alkyl groups are
optionally replaced by a phenyl or benzyl group, a
C.sub.1-3-alkylsulphonylamino, phenylsulphonylamino or
benzylsulphonylamino group or an
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulp- honylamino group wherein
the two alkyl groups are optionally replaced by a
C.sub.2-5-n-alkylene bridge or wherein one or both alkyl groups are
optionally replaced by a phenyl or benzyl group, an aminosulphonyl,
C.sub.1-3-alkylaminosulphonyl, phenylaminosulphonyl,
benzylaminosulphonyl, di-(C.sub.1-3-alkyl)-aminosulphonyl,
N,N-diphenyl-aminosulphonyl or N,N-dibenzyl-aminosulphonyl group, a
phosphono, (C.sub.1-3-alkoxy)PO(H),
(C.sub.1-3-alkoxy)PO(C.sub.1-3-alkyl)- , (C.sub.1-3-alkoxy)PO(OH),
di-(C.sub.1-3-alkoxy)-PO or (C.sub.2-4-n-alkylenedioxy)-PO group, a
ureido group optionally mono-, di- or trisubstituted by
C.sub.1-3-alkyl groups, a 4- to 7-membered cycloalkyleneimino or
cycloalkyleneiminosulphonyl group, wherein in each case the
methylene group in the 4 position of a 6- or 7-membered
cycloalkyleneimino group is optionally replaced by an oxygen or
sulphur atom, by a sulphinyl, sulphonyl, --NH or
--N(C.sub.1-3-alkyl) group; R.sub.2 denotes a hydrogen, fluorine,
chlorine, bromine or iodine atom, a C.sub.1-6-alkyl or
trifluoromethyl group, a hydroxy, C.sub.1-3-alkoxy, mercapto,
C.sub.1-3-alkylsulphenyl, C.sub.1-3-alkylsulphinyl,
C.sub.1-3-alkylsulphonyl, sulpho, C.sub.1-3-alkoxysulphonyl,
aminosulphonyl, C.sub.1-3-alkylaminosulphonyl or
di-(C.sub.1-3-alkyl)-ami- nosulphonyl group, a nitro, amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, a
C.sub.1-3-alkylcarbonyl, cyano, carboxy, C.sub.1-3-alkoxycarbo-nyl,
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl or
di-(C.sub.1-3-alkyl)-aminocarbonyl group, a phosphono,
(C.sub.1-3-alkoxy)PO(H), (C.sub.1-3-alkoxy)PO(C.sub.1-3-alky- l),
(C.sub.1-3-alkoxy)PO(OH) or di-(C.sub.1-3-alkoxy)-PO group, a 4- to
7-membered cycloalkyleneimino, cycloalkyleneiminocarbonyl or
cycloalkyleneiminosulphonyl group, wherein in each case the
methylene group in the 4 position of a 6- or 7-membered
cycloalkyleneimino group is optionally replaced by an oxygen or
sulphur atom, by a sulphinyl, sulphonyl, --NH or
--N(C.sub.1-3-alkyl) group, or R.sub.1 and R.sub.2 together denote
a methylenedioxy, ethylenedioxy, n-propylene, n-butylene or
1,4-butadienylene group; R.sub.3 denotes a hydrogen atom, denotes a
C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl, trifluoromethyl or
heteroaryl group, a phenyl or naphthyl group mono- or disubstituted
by a fluorine, chlorine, bromine or iodine atom, by a
trifluoromethyl, C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, wherein
if the phenyl or naphthyl group are disubstituted the substituents
are identical or different and are optionally substituted by: a
hydroxy, hydroxy-C.sub.1-3-alkyl or
C.sub.1-3-alkoxy-C.sub.1-3-alkyl group, by a cyano,
cyano-C.sub.1-3-alkyl, cyano-C.sub.2-3-alkenyl,
cyano-C.sub.2-3-alkynyl, carboxy, carboxy-C.sub.1-3-alkyl,
carboxy-C.sub.2-3-alkenyl, carboxy-C.sub.2-3-alkynyl,
C.sub.1-3-alkoxycarbonyl, C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkoxycarbonyl-C.sub.- 2-3-alkenyl or
C.sub.1-3-alkoxycarbonyl-C.sub.2-3-alkynyl group, by a
C.sub.1-3-alkylcarbonyl, C.sub.1-3-alkylcarbonyl-C.sub.1-3-al-kyl,
C.sub.1-3-alkylcarbonyl-C.sub.2-3-alkenyl or
C.sub.1-3-alkylcarbo-nyl-C.s- ub.2-3-alkynyl group, by an
aminocarbonyl, aminocarbonyl-C.sub.1-3-alkyl,
amino-carbonyl-C.sub.2-3-alkenyl, aminocarbonyl-C.sub.2-3-alkynyl,
C.sub.1-3-alkylaminocarbonyl,
C.sub.1-3-alkylaminocarbonyl-C.sub.1-3-alky- l,
C.sub.1-3-alkylaminocarbonyl-C.sub.2-3-alkenyl,
C.sub.1-3-alkylaminocar- bonyl-C.sub.2-3-alkynyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.2-3-alkenyl or
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.2-3-alkynyl group, by a
nitro, nitro-C.sub.1-3-alkyl, nitro-C.sub.2-3-alkenyl or
nitro-C.sub.2-3-alkynyl group, by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl group, by a
C.sub.1-3-alkylcarbonylamino,
C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alky- l,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alkyl,
C.sub.1-3-alkylsulphonylamino,
C.sub.1-3-alkylsulphonylamino-C.sub.1-3-al- kyl,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino or
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino-C.sub.1-3-alkyl
group, by a 4- to 7-membered cycloalkyleneimino,
cycloalkyleneiminocarbonyl, cycloalkyleneiminosulphonyl,
cycloalkyleneimino-C.sub.1-3-alkyl,
cycloalkyleneiminocarbonyl-C.sub.1-3-alkyl or
cycloalkyleneiminosulphonyl- -C.sub.1-3-alkyl group, wherein in
each case the methylene group in the 4 position of a 6- or
7-membered cycloalkyleneimino group is optionally replaced by an
oxygen or sulphur atom, by a sulphinyl, sulphonyl, --NH or
--N(C.sub.1-3-alkyl) group, or by a heteroaryl or
heteroaryl-C.sub.1-3-al- kyl group R.sub.4 denotes a hydrogen atom
or a C.sub.1-3-alkyl group; R.sub.5 denotes a hydrogen atom or a
C.sub.1-3-alkyl group and R.sub.6 denotes a hydrogen, fluorine,
chlorine, bromine or iodine atom, a trifluoromethyl or heteroaryl
group, a C.sub.1-3-alkoxy group optionally substituted by 1 to 3
fluorine atoms, an amino-C.sub.1-3-alkoxy,
C.sub.1-3-alkylamino-C.sub.2-3-alkoxy or
benzylamino-C.sub.2-3-alkoxy group, a
cycloalkyleneimino-C.sub.2-3-alkoxy group with 4 to 7 ring members,
a di-(C.sub.1-3-alkyl)-amino-C.sub.2-3-alkoxy or
C.sub.1-3-alkylmercapto group, a nitro, cyano, carboxy,
C.sub.1-3-alkoxycarbonyl, amino-carbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-amino-carbonyl,
piperidinocarbonyl or tetrazolyl group, a
C.sub.1-3-alkylcarbonylamino group optionally substituted at the
nitrogen atom by a C.sub.1-3-alkyl group, an imidazolyl or
piperazino group optionally substituted at the imino group by a
C.sub.1-3-alkyl group, a C.sub.1-4-alkyl group, which may be
terminally substituted by a hydroxy, C.sub.1-3-alkoxy, carboxy,
C.sub.1-3-alkoxy-carbonyl, amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, phenylamino,
N-phenyl-C.sub.1-3-alkylamino, phenyl-n-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-phenyl-n-C.sub.1-3-alkylamino or
di-(phenyl-n-C.sub.1-3-alkyl)-amino group, by a 4- to 7-membered
cycloalkyleneimino group wherein a methylene group linked to the
imino group is optionally replaced by a carbonyl or sulphonyl group
or one or two hydrogen atoms is optionally replaced by a
C.sub.1-3-alkyl group and/or in each case the methylene group in
the 4 position of a 6- or 7-membered cycloalkyleneimino group is
optionally substituted by a carboxy, C.sub.1-3-alkoxycarbonyl,
aminocarbonyl, C.sub.1-3-alkylaminocar- bonyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl, phenyl-n-C.sub.1-3-alkylamino
or N--(C.sub.1-3-alkyl)-phenyl-n-C.sub.1-3-alkylamino group or is
optionally replaced by an oxygen or sulphur atom, by a sulphinyl,
sulphonyl, --NH or --N(C.sub.1-3-alkyl) group, by a 5- to
7-membered cycloalkenyleneimino group wherein the double bond is
isolated from the nitrogen atom, by a C.sub.4-7-cycloalkylamino,
N--(C.sub.1-3-alkyl)-C.sub- .4-7-cycloalkylamino or
C.sub.5-7-cycloalkenylamino group wherein position 1 of the ring is
not involved in the double bond and wherein the nitrogen atom is
optionally substituted by a C.sub.1-3-alkyl group, by a
C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbony- lamino, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group, or R.sub.6 denotes a group of formula
--N(R.sub.a)--CO--(CH.sub.2).sub.n--R.sub.b (II), wherein R.sub.a
denotes a C.sub.1-3-alkyl group, n one of the numbers 0, 1 or 2 and
R.sub.b denotes an amino, C.sub.1-4-alkylamino, phenylamino,
N--(C.sub.1-4-alkyl)-phenylamino, benzylamino,
N--(C.sub.1-4-alkyl)-benzy- lamino or di-(C.sub.1-4-alkyl)-amino
group or a 4- to 7-membered cycloalkyleneimino group, wherein in
each case the methylene group in the 4 position of a 6- or
7-membered cycloalkyleneimino group is optionally replaced by an
oxygen or sulphur atom, by a sulphinyl, sulphonyl, --NH or
--N(C.sub.1-3-alkyl) group, a group of formula
--N(R.sub.c)--(CH.sub.2).s- ub.m--(CO).sub.o--R.sub.d (III),
wherein R.sub.c denotes a C.sub.1-3-alkyl, C.sub.1-3-alkylcarbonyl,
arylcarbonyl, benzylcarbonyl, C.sub.1-3-alkylsulphonyl,
arylsulphonyl or benzylsulphonyl group, m denotes one of the
numbers 1, 2, 3 or 4, o denotes one of the numbers 0 or 1 and
R.sub.d has the meanings given for R.sub.b hereinbefore or denotes
a di-(C.sub.1-4-alkyl)-amino-C.sub.1-3-alkylamino group optionally
substituted in the 1 position by a C.sub.1-3-alkyl group, or
R.sub.6 denotes an
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino group; wherein
any carboxy, amino or imino group present is optionally substituted
by a group which can be cleaved in vivo, wherein when there is an
imino or amino group they are optionally substituted by the
following groups which can be cleaved in vivo: a hydroxy group, an
acyl group, an allyloxycarbonyl group, a C.sub.1-16-alkoxycarbonyl
group, a phenyl-C.sub.1-6-alkoxycarbonyl group, a
C.sub.1-3-alkylsulphonyl-C.sub.2- -4-alkoxycarbonyl,
C.sub.1-3-alkoxy-C.sub.2-4-alkoxy-C.sub.2-4-alkoxycarbo- nyl or
R.sub.eCO--O--(R.sub.fCR.sub.g)--O--CO group wherein R.sub.e
denotes a C.sub.1-8-alkyl, C.sub.5-7-cycloalkyl, phenyl or
phenyl-C.sub.1-3-alkyl group, R.sub.f denotes a hydrogen atom, a
C.sub.1-3-alkyl, C.sub.5-7-cycloalkyl or phenyl group and R.sub.g
denotes a hydrogen atom, a C.sub.1-3-alkyl or
R.sub.eCO--O--(R.sub.fCR.sub.9)--O group wherein R.sub.e to R.sub.g
are as hereinbefore defined, and additionally a phthalimido group
may be used for an amino group, wherein when there is a carboxy
group it is optionally substituted by the abovementioned ester
groups which can be converted in vivo into a carboxy group, or the
physiologically acceptable salts and isomers thereof.
2. The compound according to claim 1, wherein X denotes an oxygen
atom; R.sub.1 denotes a C.sub.1-3-alkoxy, trifluoromethyl,
di-(C.sub.1-3-alkyl)-amino, pyrrolidino or pyrrolo group, an amino
or C.sub.1-3-alkylamino group wherein an amino-hydrogen atom is
optionally replaced by a C.sub.1-3-alkylcarbonyl,
phenyl-C.sub.1-3-alkylcarbonyl, benzoyl, aminocarbonyl,
C.sub.1-3-alkylsulphonyl, phenylsulphonyl, carboxy-C.sub.1-3-alkyl
or C.sub.1-3-alkyloxycarbonyl-C.sub.1-3-alkyl group, or a phenyl
group optionally substituted by a C.sub.1-3-alkyl group; R.sub.2
denotes a hydrogen atom or a C.sub.1-3-alkoxy group or R.sub.1 and
R.sub.2 together denote a methylenedioxy group; R.sub.3 denotes a
C.sub.1-3-alkyl or a phenyl group substituted by a cyano,
amino-C.sub.1-3-alkyl or
N--(C.sub.1-3-alkanoyl)-amino-C.sub.1-3-alkyl group; R.sub.4
denotes a hydrogen atom; R.sub.5 denotes a hydrogen atom and
R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or iodine
atom, a trifluoromethyl, 4-(C.sub.1-3-alkyl)-piperazino, pyridinyl,
imidazolyl, tetrazolyl, C.sub.1-3-alkoxy or C.sub.1-3-alkylmercapto
group, a nitro, cyano, carboxy or C.sub.1-3-alkyloxycarbonyl group
or a C.sub.1-3-alkylcarbonylamino group optionally substituted at
the nitrogen atom by a C.sub.1-3-alkyl group, a piperidinocarbonyl
group or an aminocarbonyl group optionally substituted by one or
two C.sub.1-3-alkyl groups, a C.sub.1-3-alkyl group optionally
terminally substituted by an amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, phenylamino,
N-phenyl-C.sub.1-3-alkylamino, phenyl-n-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-phenyl-n-C.sub.1-3-alkylamino or
di-(phenyl-n-C.sub.1-3-alkyl)-amino group, by a pyrrolidino,
piperidino, hexamethyleneimino, morpholino, thiomorpholino,
1-oxido-thiomorpholino or piperazino group wherein the piperidino
group may additionally be substituted by one or two C.sub.1-3-alkyl
groups or by a carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl-di-- (C.sub.1-3-alkyl)-aminocarbonyl
or N--(C.sub.1-3-alkyl)-phenyl-n-C.sub.1-3- -alkylamino group, by a
C.sub.5-7-cycloalkylamino or C.sub.5-7-cycloalkenylamino group
wherein position 1 of the ring is not involved in the double bond,
by a C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino, carboxy,
C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group, a C.sub.1-3-alkoxy group, which is terminally substituted by
an amino, C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group,
a group of formula --N(R.sub.a)--CO--(CH.sub.2).sub.n--R.sub.b
(II), wherein R.sub.a denotes a C.sub.1-3-alkyl group, n denotes
one of the numbers 0, 1 or 2 and R.sub.b denotes an amino,
C.sub.1-4-alkylamino or di-(C.sub.1-4-alkyl)-amino group or a
pyrrolidino, piperidino, hexamethyleneimino, morpholino,
thiomorpholino, 1-oxido-thiomorpholino or piperazino group, a group
of formula --N(R.sub.c)--(CH.sub.2).sub.m--(CO)- .sub.o--R.sub.d
(III), wherein R.sub.c denotes a C.sub.1-3-alkyl,
C.sub.1-3-alkylcarbonyl or C.sub.1-3-alkylsulphonyl group, m
denotes one of the numbers 1, 2, 3 or 4, o denotes one of the
numbers 0 or 1 and R.sub.d has the meanings given for Rb
hereinbefore or denotes a
di-(C.sub.1-4-alkyl)-amino-C.sub.1-3-alkylamino group optionally
substituted in the 1 position by a C.sub.1-3-alkyl group, or
R.sub.6 denotes an
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino group.
3. The compound according to claim 2, wherein X denotes an oxygen
atom; R.sub.1 denotes a methoxy, ethoxy, trifluoromethyl, phenyl,
methylphenyl, dimethylamino, pyrrolidino or pyrrolo group, an amino
group which is optionally substituted by a methyl, carboxymethyl,
methoxycarbonylmethyl, acetyl, phenylacetyl, benzoyl,
methanesulphonyl, benzenesulphonyl or aminocarbonyl group; R.sub.2
denotes a hydrogen atom, a methoxy or ethoxy group or R.sub.1 and
R.sub.2 together denote a methylenedioxy group; R.sub.3 denotes an
ethyl group or a phenyl group substituted by a cyano, aminomethyl
or N-acetyl-aminomethyl group; R.sub.4 denotes a hydrogen atom;
R.sub.5 denotes a hydrogen atom and R.sub.6 denotes a hydrogen,
fluorine, chlorine, bromine or iodine atom, a methyl,
trifluoromethyl, methoxy, ethoxy, methylmercapto, cyano, carboxy,
methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,
dimethylaminocarbonyl, piperidinocarbonyl, nitro,
4-methyl-piperazino, imidazolyl, pyridinyl or tetrazolyl group, an
ethyloxy or n-propyloxy group terminally substituted by a
dimethylamino group, a methyl or ethyl group substituted by a
carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl or
dimethylaminocarbonyl group, a C.sub.1-3-alkyl group, which is
optionally terminally substituted by an amino,
C.sub.1-4-alkylamino, cyclohexylamino, benzylamino or phenylamino
group wherein a hydrogen atom of the amino-nitrogen atom is
optionally replaced in each case by a C.sub.1-3-alkyl, benzyl,
acetyl or dimethylaminocarbonyl group, by a piperidino group
optionally substituted by one or two methyl groups, by a piperidino
group substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl or
dimethylaminocarbonyl group, by a pyrrolidino,
3,4-dehydro-piperidino, hexa-methyleneimino, morpholino,
thiomorpholino, 1-oxo-thio-morpholino or piperazino group, a
C.sub.1-3-alkylamino group wherein the hydrogen atom of the
amino-nitrogen atom is replaced by an ethyl or n-propyl group, each
of which is terminally substituted by a dimethylamino group, by a
C.sub.2-3-alkanoyl group which is optionally substituted in the 2
or 3 position by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, pyrrolidino, piperidino, morpholino or
piperazino group, by an aminocarbonyl, methylaminocarbonyl,
dimethylaminocarbonyl, piperidinocarbonyl or methanesulphonyl
group, wherein the C.sub.1-3-alkyl moiety of the
C.sub.1-3-alkylamino group is further optionally substituted by an
aminocarbonyl group, by a C.sub.1-3-alkylaminocarbonyl or
di-(C.sub.1-3-alkyl)-aminocarbonyl group wherein a C.sub.2-3-alkyl
moiety may additionally be terminally substituted by a
dimethylamino group, by a pyrrolidinocarbonyl, piperidinocarbonyl,
morpholinocarbonyl or piperazinocarbonyl group, and wherein the
C.sub.2-3-alkyl moiety of the above-mentioned C.sub.1-3-alkylamino
group is also further optionally terminally substituted by an
amino, C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino,
pyrrolidino, piperidino, morpholino or piperazino group.
4. The compound according to claim 3, wherein R.sub.2 denotes a
hydrogen atom.
5. The compound according to claim 4, wherein R.sub.1 and R.sub.2,
which are identical or different, each denote a C.sub.1-3-alkoxy
group.
6. The compound according to claim 1, wherein X denotes an oxygen
atom; R.sub.1 denotes an amino, methoxy or ethoxy group; R.sub.2
denotes a hydrogen atom or in position 5 a methoxy or ethoxy group;
R.sub.3 denotes a C.sub.1-3-alkyl or a phenyl group substituted by
a cyano, amino-C.sub.1-3-alkyl or
N--(C.sub.1-3-alkanoyl)-amino-C.sub.1-3-alkyl group; R.sub.4 and
R.sub.5 each denote a hydrogen atom and R.sub.6 denotes a methyl or
ethyl group substituted by a methylamino, ethylamino, piperidino or
4-(dimethylaminocarbonyl)-piperidino group, wherein the
amino-hydrogen atom of the methylamino- and ethylamino group is
replaced by a methyl or benzyl group, an
N-dimethylaminomethylcarbonyl-N-methyl-am- ino group or an
N-acetyl-N--(C.sub.2-3-alkyl)-amino group wherein the
C.sub.2-3-alkyl moiety in each case is terminally substituted by a
dimethylamino group.
7. A compound, wherein the compound is
3-(Z)-{1-[4-(N-dimethylaminomethylc-
arbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indo-
linone or the physiologically acceptable salts and isomers
thereof.
8. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claim 1 and one or more
inert carriers and/or diluents.
9. A method of treating haemangiomas, metastasisation, rheumatoid
arthritis, psoriasis, ocular neovascularisation or diabetic
retinopathy, comprising administering to a patient in need thereof
a therapeutically effective amount of a compound according claim
1.
10. A method of inhibiting tumour cell proliferation comprising
contacting a cell with an effective amount of a compound according
to claim 1.
11. A method of inhibiting tumour cell proliferation comprising
administering to a patient a therapeutically effective of a
compound according to claim 1.
12. A method of treating solid tumours, comprising administering to
a patient in need thereof a therapeutically effective amount of a
compound according claim 1.
13. A method of inhibiting endothelial cell proliferation
comprising contacting a cell with an effective amount of a compound
according to claim 1.
14. A method of inhibiting endothelial cell proliferation
comprising administering to a patient a therapeutically effective
amount of a compound according to claim 1.
Description
APPLICATION DATA
[0001] This application is a continuation of U.S. Ser. No.
10/069,557 filed Jul. 22, 2002 which is a 35 USC .sctn. 371 case of
PCT EP 00/08149 which in turn claims priority to German cases DE
199 40 829.7 filed Aug. 27, 1999 and 100 29 285.2 filed Jun. 14,
2000.
[0002] The present invention relates to new substituted indolinones
of general formula 2
[0003] the isomers thereof, the salts thereof, particularly the
physiologically acceptable salts thereof which have valuable
properties.
[0004] The above compounds of general formula I wherein R.sub.4
denotes a hydrogen atom or a prodrug group have valuable
pharmacological properties, in particular an inhibiting effect on
various kinases, especially receptor tyrosine kinases such as
VEGFR2, PDGFR.alpha., PDGFR.beta., FGFR1, FGFR3, EGFR, HER2, IGF1R
and HGFR, as well as complexes of CDK's (Cycline Dependent Kinases)
such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9
with their specific cyclines (A, B1, B2, C, D1, D2, D3, E, F, G1,
G2, H. I and K) and to viral cycline (cf. L. Mengtao in J. Virology
71 (3), 1984-1991 (1997)), to the proliferation of cultivated human
cells, in particular endothelial cells, e.g. in angiogenesis, but
also to the proliferation of other cells, in particular tumour
cells.
[0005] The other compounds of the above general formula I wherein
R.sub.4 does not denote a hydrogen atom or a prodrug group are
valuable intermediate products for preparing the abovementioned
compounds.
[0006] The present invention thus relates to the above compounds of
general formula I, whilst those compounds wherein R.sub.4 denotes a
hydrogen atom or a prodrug group have valuable pharmacological
properties, pharmaceutical compositions containing the
pharmacologically active compounds, the use thereof and processes
for preparing them.
[0007] In the above general formula I
[0008] X denotes an oxygen or sulphur atom,
[0009] R.sub.1 denotes a C.sub.2-3-alkenyl, C.sub.2-3-alkynyl,
aryl, aryl-C.sub.1-3-alkyl, heteroaryl, heteroaryl-C.sub.1-3-alkyl,
trifluoromethyl or cyano group,
[0010] a hydroxy, C.sub.1-3-alkoxy, hydroxy-C.sub.1-3-alkyl,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, aryloxy or heteroaryloxy
group,
[0011] a mercapto, C.sub.1-3-alkylsulphenyl, phenylsulphenyl,
benzylsulphenyl, C.sub.1-3-alkylsulphinyl, phenylsulphinyl,
benzylsulphinyl, C.sub.1-3-alkylsulphonyl, phenylsulphonyl,
benzylsulphonyl, sulpho, C.sub.1-3-alkoxysulphonyl,
phenoxysulphonyl or benzyloxysulphonyl group,
[0012] an amino, C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino,
hydroxycarbonyl-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-hydroxycarbony- l-C.sub.1-3-alkylamino,
C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylamino,
phenylamino, N-phenyl-C.sub.1-3-alkylamino, N,N-diphenylamino,
benzylamino, N-benzyl-C.sub.1-3-alkylamino, N,N-dibenzylamino,
C.sub.1-3-alkylcarbonylamino, benzoylamino or benzylcarbonylamino
group or an N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino group
wherein the two alkyl groups may be replaced by a
C.sub.2-5-n-alkylene bridge or wherein one or both alkyl groups may
be replaced by a phenyl or benzyl group,
[0013] a C.sub.1-3-alkylsulphonylamino, phenylsulphonylamino or
benzyl-sulphonylamino group or an
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsul- phonylamino group wherein
the two alkyl groups may be replaced by a C.sub.2-5-n-alkylene
bridge or wherein one or both alkyl groups may be replaced by a
phenyl or benzyl group,
[0014] an aminosulphonyl, C.sub.1-3-alkylaminosulphonyl,
phenylaminosulphonyl, benzylaminosulphonyl,
di-(C.sub.1-3-alkyl)-aminosul- phonyl, N,N-diphenyl-aminosulphonyl
or N,N-dibenzyl-aminosulphonyl group,
[0015] a phosphono, (C.sub.1-3-alkoxy)PO(H),
(C.sub.1-3-alkoxy)PO(C.sub.1-- 3-alkyl), (C.sub.1-3-alkoxy)PO(OH),
di-(C.sub.1-3-alkoxy)-PO or (C.sub.2-4-n-alkylenedioxy)-PO
group,
[0016] a ureido group optionally mono-, di- or trisubstituted by
C.sub.1-3-alkyl groups,
[0017] a 4- to 7-membered cycloalkyleneimino or
cycloalkyleneiminosulphony- l group, wherein in each case the
methylene group in the 4 position of a 6- or 7-membered
cycloalkyleneimino group may be replaced by an oxygen or sulphur
atom, by a sulphinyl, sulphonyl, --NH or --N(C.sub.1-3-alkyl)
group,
[0018] R.sub.2 denotes a hydrogen, fluorine, chlorine, bromine or
iodine atom,
[0019] a C.sub.1-6-alkyl or trifluoromethyl group,
[0020] a hydroxy, C.sub.1-3-alkoxy, mercapto,
C.sub.1-3-alkylsulphenyl, C.sub.1-3-alkylsulphinyl,
C.sub.1-3-alkylsulphonyl, sulpho, C.sub.1-3-alkoxy-sulphonyl,
aminosulphonyl, C.sub.1-3-alkylaminosulphonyl or
di-(C.sub.1-3-alkyl)-aminosulphonyl group,
[0021] a nitro, amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)-amino group,
[0022] a C.sub.1-3-alkylcarbonyl, cyano, carboxy,
C.sub.1-3-alkoxycarbonyl- , aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-amin-
ocarbonyl group,
[0023] a phosphono, (C.sub.1-3-alkoxy)PO(H),
(C.sub.1-3-alkoxy)PO(C.sub.1-- 3-alkyl), (C.sub.1-3-alkoxy)PO(OH)
or di-(C.sub.1-3-alkoxy)-PO group,
[0024] a 4- to 7-membered cycloalkyleneimino,
cycloalkyleneiminocarbonyl or cycloalkyleneiminosulphonyl group,
wherein in each case the methylene group in the 4 position of a 6-
or 7-membered cycloalkyleneimino group may be replaced by an oxygen
or sulphur atom, by a sulphinyl, sulphonyl, --NH or
--N(C.sub.1-3-alkyl) group, or
[0025] R.sub.1 and R.sub.2 together denote a methylenedioxy,
ethylenedioxy, n-propylene, n-butylene or 1,4-butadienylene
group,
[0026] R.sub.3 denotes a hydrogen atom, denotes a C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl, trifluoromethyl or heteroaryl group,
[0027] a phenyl or naphthyl group optionally mono- or disubstituted
by a fluorine, chlorine, bromine or iodine atom, by a
trifluoromethyl, C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, whilst
in the case of disubstitution the substituents may be identical or
different, which may additionally be substituted
[0028] by a hydroxy, hydroxy-C.sub.1-3-alkyl or
C.sub.1-3-alkoxy-C.sub.1-3- -alkyl group,
[0029] by a cyano, cyano-C.sub.1-3-alkyl, cyano-C.sub.2-3-alkenyl,
cyano-C.sub.2-3-alkynyl, carboxy, carboxy-C.sub.1-3-alkyl,
carboxy-C.sub.2-3-alkenyl, carboxy-C.sub.2-3-alkynyl,
C.sub.1-3-alkoxycarbonyl, C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkoxycarbonyl-C.sub.2-3-alkenyl or
C.sub.1-3-alkoxycarbonyl-C.- sub.2-3-alkynyl group,
[0030] by a C.sub.1-3-alkylcarbonyl,
C.sub.1-3-alkylcarbonyl-C.sub.1-3-alk- yl,
C.sub.1-3-alkylcarbonyl-C.sub.2-3-alkenyl or
C.sub.1-3-alkylcarbonyl-C- .sub.2-3-alkynyl group,
[0031] by an aminocarbonyl, aminocarbonyl-C.sub.1-3-alkyl,
amino-carbonyl-C.sub.2-3-alkenyl, aminocarbonyl-C.sub.2-3-alkynyl,
C.sub.1-3-alkylaminocarbonyl,
C.sub.1-3-alkylaminocarbonyl-C.sub.1-3-alky- l,
C.sub.1-3-alkylaminocarbonyl-C.sub.2-3-alkenyl,
C.sub.1-3-alkylaminocar- bonyl-C.sub.2-3-alkynyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.2-3-alkenyl or
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.2-3-alkynyl group,
[0032] by a nitro, nitro-C.sub.1-3-alkyl, nitro-C.sub.2-3-alkenyl
or nitro-C.sub.2-3-alkynyl group,
[0033] by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl group,
[0034] by a C.sub.1-3-alkylcarbonylamino,
C.sub.1-3-alkylcarbonylamino-C.s- ub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alkyl,
C.sub.1-3-alkylsulphonylamino,
C.sub.1-3-alkylsulphonylamino-C.sub.1-3-al- kyl,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino or
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino-C.sub.1-3-alkyl
group,
[0035] by a 4- to 7-membered cycloalkyleneimino,
cycloalkyleneiminocarbony- l, cycloalkyleneiminosulphonyl,
cycloalkyleneimino-C.sub.1-3-alkyl,
cycloalkyleneiminocarbonyl-C.sub.1-3-alkyl or
cycloalkyleneiminosulphonyl- -C.sub.1-3-alkyl group, wherein in
each case the methylene group in the 4 position of a 6- or
7-membered cycloalkyleneimino group may be replaced by an oxygen or
sulphur atom, by a sulphinyl, sulphonyl, --NH or
--N(C.sub.1-3-alkyl) group,
[0036] or by a heteroaryl or heteroaryl-C.sub.1-3-alkyl group,
[0037] R.sub.4 denotes a hydrogen atom, a C.sub.1-3-alkyl group or
a prodrug group,
[0038] R.sub.5 denotes a hydrogen atom or a C.sub.1-3-alkyl group
and
[0039] R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or
iodine atom,
[0040] a trifluoromethyl or heteroaryl group, a C.sub.1-3-alkoxy
group optionally substituted by 1 to 3 fluorine atoms, an
amino-C.sub.1-3-alkoxy, C.sub.1-3-alkylamino-C.sub.2-3-alkoxy or
benzylamino-C.sub.2-3-alkoxy group, a
cycloalkyleneimino-C.sub.2-3-alkoxy group with 4 to 7 ring members,
a di-(C.sub.1-3-alkyl)-amino-C.sub.2-3-al- koxy or
C.sub.1-3-alkylmercapto group,
[0041] a nitro, cyano, carboxy, C.sub.1-3-alkoxycarbonyl,
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl, piperidinocarbonyl or
tetrazolyl group,
[0042] a C.sub.1-3-alkylcarbonylamino group optionally substituted
at the nitrogen atom by a C.sub.1-3-alkyl group,
[0043] an imidazolyl or piperazino group optionally substituted at
the imino group by a C.sub.1-3-alkyl group,
[0044] a C.sub.1-4-alkyl group, which may be terminally
substituted
[0045] by a hydroxy, C.sub.1-3-alkoxy, carboxy,
C.sub.1-3-alkoxycarbonyl, amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, phenylamino,
N-phenyl-C.sub.1-3-alkylamino, phenyl-n-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-phenyl-n-C.sub.1-3-alkylamino or
di-(phenyl-n-C.sub.1-3-alkyl)-amino group,
[0046] by a 4- to 7-membered cycloalkyleneimino group wherein
[0047] a methylene group linked to the imino group may be replaced
by a carbonyl or sulphonyl group or
[0048] one or two hydrogen atoms may each be replaced by a
C.sub.1-3-alkyl group and/or
[0049] in each case the methylene group in the 4 position of a 6-
or 7-membered cycloalkyleneimino group may be substituted by a
carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
phenyl-n-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-phenyl-n-C.sub.1-3-alkylamino group or
[0050] may be replaced by an oxygen or sulphur atom, by a
sulphinyl, sulphonyl, --NH or --N(C.sub.1-3-alkyl) group,
[0051] by a 5- to 7-membered cycloalkenyleneimino group wherein the
double bond is isolated from the nitrogen atom,
[0052] by a C.sub.4-7-cycloalkylamino,
N--(C.sub.1-3-alkyl)-C.sub.4-7-cycl- oalkylamino or
C.sub.5-7-cycloalkenylamino group wherein position 1 of the ring is
not involved in the double bond and wherein the nitrogen atom may
be substituted by a C.sub.1-3-alkyl group,
[0053] by a C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-a- lkylcarbonylamino, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group,
[0054] or R.sub.6 denotes a group of formula
--N(R.sub.a)--CO--(CH.sub.2).sub.n--Rb (II),
[0055] wherein
[0056] R.sub.a denotes a C.sub.1-3-alkyl group,
[0057] n one of the numbers 0, 1 or 2 and
[0058] R.sub.b denotes an amino, C.sub.1-4-alkylamino, phenylamino,
N--(C.sub.1-4-alkyl)-phenylamino, benzylamino, N--
(C.sub.1-4-alkyl)-benzylamino or di-(C.sub.1-4-alkyl)-amino group
or a 4- to 7-membered cycloalkyleneimino group, wherein in each
case the methylene group in the 4 position of a 6- or 7-membered
cycloalkyleneimino group may be replaced by an oxygen or sulphur
atom, by a sulphinyl, sulphonyl, --NH or --N(C.sub.1-3-alkyl)
group,
[0059] a group of formula
--N(R.sub.c)--(CH.sub.2).sub.m--(CO).sub.o--Rd (III),
[0060] wherein
[0061] R.sub.c denotes a C.sub.1-3-alkyl, C.sub.1-3-alkylcarbonyl,
arylcarbonyl, benzylcarbonyl, C.sub.1-3-alkylsulphonyl,
arylsulphonyl or benzylsulphonyl group,
[0062] m denotes one of the numbers 1, 2, 3 or 4,
[0063] o denotes one of the numbers 0 or 1 and
[0064] R.sub.d has the meanings given for R.sub.b hereinbefore or
denotes a di-(C.sub.1-4-alkyl)-amino-C.sub.1-3-alkylamino group
optionally substituted in the 1 position by a C.sub.1-3-alkyl
group,
[0065] or an N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino
group,
[0066] whilst additionally any carboxy, amino or imino group
present may be substituted by a group which can be cleaved in vivo
(prodrug group),
[0067] and by a group which can be cleaved in vivo from an imino or
amino group is meant, for example, a hydroxy group, an acyl group
such as the benzoyl or pyridinoyl group or a C.sub.1-16-alkanoyl
group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or
hexanoyl group, an allyloxycarbonyl group, a
C.sub.1-16-alkoxycarbonyl group such as the methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl,
hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl,
decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or
hexadecyloxycarbonyl group, a phenyl-C.sub.1-6-alkoxycarbonyl group
such as the benzyloxycarbonyl,
[0068] phenylethoxycarbonyl or phenylpropoxycarbonyl group, a
C.sub.1-3-alkylsulphonyl-C.sub.2-4-alkoxycarbonyl,
C.sub.1-3-alkoxy-C.sub.2-4-alkoxy-C.sub.2-4-alkoxycarbonyl or
R.sub.eCO--O--(R.sub.fCR.sub.g)--O--CO group wherein
[0069] R.sub.e denotes a C.sub.1-8-alkyl, C.sub.5-7-cycloalkyl,
phenyl or phenyl-C.sub.1-3-alkyl group,
[0070] R.sub.f denotes a hydrogen atom, a C.sub.1-3-alkyl,
C.sub.5-7-cycloalkyl or phenyl group and
[0071] R.sub.g denotes a hydrogen atom, a C.sub.1-3-alkyl or
R.sub.eCO--O--(R.sub.fCR.sub.g)--O group wherein R.sub.e to R.sub.g
are as hereinbefore defined,
[0072] and additionally the phthalimido group may be used for an
amino group, whilst the abovementioned ester groups may also be
used as a group which can be converted in vivo into a carboxy
group,
[0073] furthermore the term an aryl group denotes a phenyl or
naphthyl group optionally mono- or disubstituted by a fluorine,
chlorine, bromine or iodine atom or by a trifluoromethyl,
C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, whilst in the case of
disubstitution the substituents may be identical or different,
and
[0074] by a heteroaryl group is meant a monocyclic 5 or 6-membered
heteroaryl group optionally substituted by one or two
C.sub.1-3-alkyl groups, whilst the 6-membered heteroaryl group
contains one, two or three nitrogen atoms and the 5-membered
heteroaryl group contains an imino group optionally substituted by
a C.sub.1-3-alkyl group, an oxygen or sulphur atom or an imino
group optionally substituted by a C.sub.1-3-alkyl group and an
oxygen or sulphur atom or one or two nitrogen atoms, and more-over
a phenyl ring may be fused to the abovementioned mono-cyclic
heterocyclic groups via two adjacent carbon atoms.
[0075] Particular mention should be made of the compounds of the
abovementioned general formula I, wherein
[0076] X and R.sub.1 to R.sub.5 are as hereinbefore defined and
[0077] R.sub.6 is as hereinbefore defined, with the exception of an
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl,
di-(C.sub.1-3-alkyl)-aminoca- rbonyl, piperidinocarbonyl or
tetrazolyl group,
[0078] an imidazolyl or piperazino group optionally substituted by
a C.sub.1-3-alkyl group at the imino group,
[0079] a C.sub.1-4-alkyl group, the terminal carboxy,
C.sub.1-3-alkoxycarbonyl group,
[0080] an N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino
group
[0081] or a group of formula
--N(R.sub.c)--(CH.sub.2).sub.m--(CO).sub.o--R.sub.d (III),
[0082] wherein
[0083] R.sub.c denotes a C.sub.1-3-alkyl group.
[0084] Preferred compounds of the above general formula I are those
wherein
[0085] X denotes an oxygen atom,
[0086] R.sub.1 denotes a C.sub.1-3-alkoxy, trifluoromethyl,
di-(C.sub.1-3-alkyl)-amino, pyrrolidino or pyrrolo group,
[0087] an amino or C.sub.1-3-alkylamino group wherein an
amino-hydrogen atom may be replaced by a C.sub.1-3-alkylcarbonyl,
phenyl-C.sub.1-3-alkylcarbonyl, benzoyl, aminocarbonyl,
C.sub.1-3-alkylsulphonyl, phenylsulphonyl, carboxy-C.sub.1-3-alkyl
or C.sub.1-3-alkyloxycarbonyl-C.sub.1-3-alkyl group, or
[0088] a phenyl group optionally substituted by a C.sub.1-3-alkyl
group,
[0089] R.sub.2 denotes a hydrogen atom or a C.sub.1-3-alkoxy group
or
[0090] R.sub.1 and R.sub.2 together denote a methylenedioxy
group,
[0091] R.sub.3 denotes a C.sub.1-3-alkyl or phenyl group or a
phenyl group substituted by a cyano, amino-C.sub.1-3-alkyl or
N--(C.sub.1-3-alkanoyl)-- amino-C.sub.1-3-alkyl group,
[0092] R.sub.4 denotes a hydrogen atom,
[0093] R.sub.5 denotes a hydrogen atom and
[0094] R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or
iodine atom,
[0095] a trifluoromethyl, 4-(C.sub.1-3-alkyl)-piperazino,
pyridinyl, imidazolyl, tetrazolyl, C.sub.1-3-alkoxy or
C.sub.1-3-alkylmercapto group,
[0096] a nitro, cyano, carboxy or C.sub.1-3-alkyloxycarbonyl group
or a C.sub.1-3-alkylcarbonylamino group optionally substituted at
the nitrogen atom by a C.sub.1-3-alkyl group,
[0097] a piperidinocarbonyl group or an aminocarbonyl group
optionally substituted by one or two C.sub.1-3-alkyl groups,
[0098] a C.sub.1-3-alkyl group, which may be terminally
substituted
[0099] by an amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, phenylamino,
N-phenyl-C.sub.1-3-alkylamino, phenyl-n-C.sub.1-3-alkyl-amin- o,
N--(C.sub.1-3-alkyl)-phenyl-n-C.sub.1-3-alkylamino or
di-(phenyl-n-C.sub.1-3-alkyl)-amino group, by a pyrrolidino,
piperidino, hexamethyleneimino, morpholino, thiomorpholino,
1-oxido-thiomorpholino or piperazino group,
[0100] whilst the piperidino group may additionally be substituted
by one or two C.sub.1-3-alkyl groups or by a carboxy,
C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl-di-(C.sub.1-3-alkyl)-aminocar- bonyl
or N--(C.sub.1-3-alkyl)-phenyl-n-C.sub.1-3-alkylamino group,
[0101] by a C.sub.5-7-cycloalkylamino or
C.sub.5-7-cycloalkenylamino group wherein position 1 of the ring is
not involved in the double bond,
[0102] by a C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-a- lkylcarbonylamino, carboxy,
C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group,
[0103] a C.sub.1-3-alkoxy group, which is terminally substituted by
an amino, C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino
group,
[0104] a group of formula
--N(R.sub.a)--CO--(CH.sub.2).sub.n--R.sub.b (II),
[0105] wherein
[0106] R.sub.a denotes a C.sub.1-3-alkyl group,
[0107] n denotes one of the numbers 0, 1 or 2 and
[0108] R.sub.b denotes an amino, C.sub.1-4-alkylamino or
di-(C.sub.1-4-alkyl)-amino group or a pyrrolidino, piperidino,
hexamethyleneimino, morpholino, thiomorpholino,
1-oxido-thiomorpholino or piperazino group,
[0109] a group of formula
--N(R.sub.c)--(CH.sub.2).sub.m--(CO).sub.o--R.sub.d (III),
[0110] wherein
[0111] R.sub.c denotes a C.sub.1-3-alkyl, C.sub.1-3-alkylcarbonyl
or C.sub.1-3-alkylsulphonyl group,
[0112] m denotes one of the numbers 1, 2, 3 or 4,
[0113] o denotes one of the numbers 0 or 1 and
[0114] R.sub.d has the meanings given for Rb hereinbefore or
denotes a di-(C.sub.1-4-alkyl)-amino-C.sub.1-3-alkylamino group
optionally substituted in the 1 position by a C.sub.1-3-alkyl
group,
[0115] or an N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino
group,
[0116] the isomers and the salts thereof.
[0117] Particularly preferred compounds of the above general
formula I are those wherein
[0118] X denotes an oxygen atom,
[0119] R.sub.1 denotes a methoxy, ethoxy, trifluoromethyl, phenyl,
methylphenyl, dimethylamino, pyrrolidino or pyrrolo group,
[0120] an amino group which may be substituted by a methyl,
carboxymethyl, methoxycarbonylmethyl, acetyl, phenylacetyl,
benzoyl, methanesulphonyl, benzolsulphonyl or aminocarbonyl
group,
[0121] R.sub.2 denotes a hydrogen atom, a methoxy or ethoxy group
or
[0122] R.sub.1 and R.sub.2 together denote a methylenedioxy
group,
[0123] R.sub.3 denotes an ethyl group or a phenyl group optionally
substituted by a cyano, aminomethyl or N-acetyl-aminomethyl
group,
[0124] R.sub.4 denotes a hydrogen atom,
[0125] R.sub.5 denotes a hydrogen atom and
[0126] R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or
iodine atom,
[0127] a methyl, trifluoromethyl, methoxy, ethoxy, methylmercapto,
cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,
dimethylaminocarbonyl, piperidinocarbonyl, nitro,
4-methyl-piperazino, imidazolyl, pyridinyl or tetrazolyl group,
[0128] an ethyloxy or n-propyloxy group terminally substituted by a
dimethylamino group,
[0129] a methyl or ethyl group substituted by a carboxy,
methoxycarbonyl, ethoxycarbonyl, aminocarbonyl or
dimethylaminocarbonyl group,
[0130] a C.sub.1-3-alkyl group, which may be terminally
substituted
[0131] by an amino, C.sub.1-4-alkylamino, cyclohexylamino,
benzylamino or phenylamino group wherein a hydrogen atom of the
amino-nitrogen atom may be replaced in each case by a
C.sub.1-3-alkyl, benzyl, acetyl or dimethylaminocarbonyl group,
[0132] by a piperidino group optionally substituted by one or two
methyl groups,
[0133] by a piperidino group substituted by a carboxy,
methoxycarbonyl, ethoxycarbonyl or dimethylaminocarbonyl group,
[0134] by a pyrrolidino, 3,4-dehydro-piperidino,
hexa-methyleneimino, morpholino, thiomorpholino,
1-oxo-thio-morpholino or piperazino group,
[0135] a C.sub.1-3-alkylamino group wherein the hydrogen atom of
the amino-nitrogen atom is replaced
[0136] by an ethyl or n-propyl group, each of which is terminally
substituted by a dimethylamino group,
[0137] by a C.sub.2-3-alkanoyl group which may be substituted in
the 2 or 3 position by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, pyrrolidino, piperidino, morpholino or
piperazino group,
[0138] by an aminocarbonyl, methylaminocarbonyl,
dimethyl-aminocarbonyl, piperidinocarbonyl or methanesulphonyl
group,
[0139] and additionally the C.sub.1-3-alkyl moiety of the
C.sub.1-3-alkylamino group may be substituted
[0140] by an aminocarbonyl group,
[0141] by a C.sub.1-3-alkylaminocarbonyl or
di-(C.sub.1-3-alkyl)-aminocarb- onyl group wherein a
C.sub.2-3-alkyl moiety may additionally be terminally substituted
by a dimethylamino group,
[0142] by a pyrrolidinocarbonyl, piperidinocarbonyl,
morpholinocarbonyl or piperazinocarbonyl group,
[0143] whilst the C.sub.2-3-alkyl moiety of the above-mentioned
C.sub.1-3-alkylamino group may also be terminally substituted by an
amino, C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino,
pyrrolidino, piperidino, morpholino or piperazino group,
[0144] in particular those compounds of the above general formula I
wherein
[0145] either X, R.sub.1 and R.sub.3 to R.sub.6 are as hereinbefore
defined and R.sub.2 denotes a hydrogen atom,
[0146] or X and R.sub.3 to R.sub.6 are as hereinbefore defined,
R.sub.1 and R.sub.2, which may be identical or different, each
denotes a C.sub.1-3-alkoxy group,
[0147] the isomers and the salts thereof.
[0148] Quite specially preferred compounds of the above general
formula I are those wherein
[0149] X denotes an oxygen atom,
[0150] R.sub.1 denotes an amino, methoxy or ethoxy group,
[0151] R.sub.2 denotes a hydrogen atom or in position 5 a methoxy
or ethoxy group,
[0152] R.sub.3 denotes a methyl, ethyl or phenyl group,
[0153] R.sub.4 and R.sub.5 each denote a hydrogen atom and
[0154] R.sub.6 denotes a methyl or ethyl group substituted by a
methylamino, ethylamino, piperidino or
4-(dimethylaminocarbonyl)-piperidi- no group, wherein the
amino-hydrogen atom of the methylamino- and ethylamino group is
replaced by a methyl or benzyl group, an
N-dimethylaminomethylcarbonyl-N-methyl-amino group or an
N-acetyl-N--(C.sub.2-3-alkyl)-amino group wherein the
C.sub.2-3-alkyl moiety in each case is terminally substituted by a
dimethylamino group,
[0155] and the salts thereof.
[0156] The following particularly useful compounds of general
formula I are mentioned by way of example:
[0157] (a)
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylide-
ne}-5,6-dimethoxy-2-indolinone,
[0158] (b)
3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-pheny-
l-methylidene)-5,6-dimethoxy-2-indolinone,
[0159] (c)
3-(Z)-{1-(4-(dimethylamino-methyl)-anilino]-1-phenyl-methyliden-
e}-5,6-dimethoxy-2-indolinone,
[0160] (d)
3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anil-
ino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone,
[0161] (e)
3-(Z)-(1-{4-[2-(4-dimethylcarboxamide-piperidin-1-yl)-ethyl]-an-
ilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone,
[0162] (f)
3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anil-
ino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone and
[0163] (g)
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-m-
ethylidene}-2-indolinone,
[0164] (h)
3-(Z)-(1-{4-[N-acetyl-N-(2-dimethylamino-ethyl)-amino]-anilino}-
-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and
[0165] (i)
3-(Z)-(1-{4-[N-acetyl-N-(3-dimethylamino-propyl)-amino]1-anilin-
o}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0166] as well as the salts thereof.
[0167] According to the invention, the new compounds may be
obtained, for example, by the following methods known in principle
from the literature:
[0168] a. reaction of a compound of general formula 3
[0169] wherein
[0170] X and R.sub.1 to R.sub.3 are defined as in claims 1 to
4,
[0171] R.sub.7 denotes a hydrogen atom, a protecting group for the
nitrogen atom of the lactam group or a bond to a solid phase
and
[0172] Z.sub.1 denotes a halogen atom, a hydroxy, alkoxy or
arylalkoxy-group, e.g. a chlorine or bromine atom, a methoxy,
ethoxy or benzyloxy group,
[0173] with an amine of general formula 4
[0174] wherein
[0175] R.sub.5 and R.sub.6 are defined as in claims 1 to 4, and if
necessary subsequently cleaving any protecting group used for the
nitrogen atom of the lactam group or cleaving from a solid
phase.
[0176] A protecting group for the nitrogen atom of the lactam group
might be for example an acetyl, benzoyl, ethoxycarbonyl,
tert.butyloxycarbonyl or benzyloxycarbonyl group and
[0177] the solid phase might be a Rink resin such as a
p-benzyloxybenzylalcohol resin, whilst the bond may conveniently be
formed via an intermediate member such as a
2,5-dimethoxy-4-hydroxy-benzy- l derivative.
[0178] The reaction is conveniently carried out in a solvent such
as dimethylformamide, toluene, acetonitrile, tetrahydrofuran,
dimethylsulphoxide, methylene chloride or mixtures thereof,
optionally in the presence of an inert base such as triethylamine,
N-ethyl-diisopropylamine or sodium hydrogen carbonate at
temperatures between 20 and 175.degree. C., whilst any protecting
group used can be cleaved simultaneously by transamidation.
[0179] If Z.sub.1 in a compound of general formula IV denotes a
halogen atom, the reaction is preferably carried out in the
presence of an inert base at temperatures between 20 and
120.degree. C.
[0180] If Z.sub.1 in a compound of general formula IV denotes a
hydroxy, alkoxy or aralkoxy group, the reaction is preferably
carried out at temperatures between 20 and 200.degree. C.
[0181] If any protecting group used subsequently has to be cleaved,
this is conveniently carried out either hydrolytically in an
aqueous or alcoholic solvent, e.g. in methanol/water,
ethanol/water, isopropanol/water, tetrahydrofuran/water,
dioxane/water, dimethylformamide/water, methanol or ethanol in the
presence of an alkali metal base such as lithium hydroxide, sodium
hydroxide or potassium hydroxide at temperatures between 0 and
100.degree. C., preferably at temperatures between 10 and
50.degree. C.,
[0182] or advantageously by transamidation with a primary or
secondary organic base such as butylamine, dimethylamine or
piperidine in a solvent such as methanol, ethanol,
dimethylformamide and mixtures thereof or in an excess of the amine
used at temperatures between 0 and 100.degree. C., preferably at
temperatures between 10 and 50.degree. C.
[0183] Any solid phase used is preferably cleaved using
trifluoroacetic acid and water in the presence of a dialkylsulphide
such as dimethylsulphide at temperatures between 0 and 35.degree.
C., preferably at ambient temperature.
[0184] b. In order to prepare a compound of general formula I
wherein R.sub.1 denotes an amino group:
[0185] Reduction of a compound of general formula 5
[0186] The reduction of a nitro group is preferably carried out by
hydrogenolysis, e.g. with hydrogen in the presence of a catalyst
such as palladium/charcoal or Raney nickel in a solvent such as
methanol, ethanol, ethyl acetate, dimethylformamide,
dimethylformamide/acetone or glacial acetic acid, optionally with
the addition of an acid such as hydrochloric acid or glacial acetic
acid at temperatures between 0 and 50.degree. C., but preferably at
ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but
preferably 3 to 5 bar.
[0187] c. In order to prepare a compound of general formula I
wherein R.sub.1 or/and R.sub.2 denotes one of the abovementioned
substituted sulphinyl or sulphonyl groups:
[0188] oxidation of a compound of general formula 6
[0189] wherein
[0190] R.sub.3 to R.sub.6 are defined as in claims 1 to 4 and one
of the groups R.sub.1 and R.sub.2' denotes one of the substituted
mercapto or sulphinyl groups mentioned above for R.sub.1 and
R.sub.2 and the other one assumes the meanings given above for
R.sub.1 or R.sub.2 with the exception of the mercapto or sulphinyl
groups or both groups R.sub.1' and R.sub.2', denote one of the
substituted mercapto or sulphinyl groups mentioned above for
R.sub.1 and R.sub.2.
[0191] The oxidation is preferably carried out in a solvent or
mixture of solvents, e.g. in water, water/pyridine, acetone,
methylene chloride, acetic acid, acetic acid/acetic anhydride,
dilute sulphuric acid or trifluoroacetic acid, expediently at
temperatures between -80 and 100.degree. C., depending on the
oxidising agent used.
[0192] In order to prepare a corresponding sulphinyl compound of
general formula I the oxidation is expediently carried out with one
equivalent of the oxidising agent used, e.g. with hydrogen peroxide
in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to
20.degree. C. or in acetone at 0 to 60.degree. C., with a peracid
such as performic acid in glacial acetic acid or trifluoroacetic
acid at 0 to 50.degree. C. or with m-chloroperbenzoic acid in
methylene chloride, chloroform or dioxane at -20 to 80.degree. C.,
with sodium metaperiodate in aqueous methanol or ethanol at -15 to
25.degree. C., with bromine in glacial acetic acid or aqueous
acetic acid optionally in the presence of a weak base such as
sodium acetate, with N-bromosuccinimide in ethanol, with
tert.butylhypochlorite in methanol at -80 to -30.degree. C., with
iodobenzodichloride in aqueous pyridine at 0 to 50.degree. C., with
nitric acid in glacial acetic acid at 0 to 20.degree. C., with
chromic acid in glacial acetic acid or in acetone at 0 to
20.degree. C. and with sulphurylchloride in methylene chloride at
-70.degree. C., the resulting thioether-chlorine complex is
expediently hydrolysed with aqueous ethanol.
[0193] In order to prepare a sulphonyl compound of general formula
I the oxidation is expediently carried out starting from a
corresponding sulphinyl compound with one or more equivalents of
the oxidising agent used or starting from a corresponding mercapto
compound, expediently with two or more equivalents of the oxidising
agent used, e.g. with hydrogen peroxide in glacial acetic
acid/acetic anhydride, trifluoroacetic acid or in formic acid at 20
to 100.degree. C. or in acetone at 0 to 60.degree. C., with a
peracid such as performic acid or m-chloroperbenzoic acid in
glacial acetic acid, trifluoroacetic acid, methylene chloride or
chloroform at temperatures between 0 and 60.degree. C., with nitric
acid in glacial acetic acid at 0 to 20.degree. C., with chromic
acid, sodium periodate or potassium permanganate in acetic acid,
water/sulphuric acid or in acetone at 0 to 20.degree. C.
[0194] If according to the invention a compound of general formula
I is obtained which contains an alkoxycarbonyl group, this can be
converted by hydrolysis into a corresponding carboxy compound,
or
[0195] If a compound of general formula I is obtained which
contains an amino or alkylamino group, this may be converted by
alkylation or reductive alkylation into a corresponding alkylamino,
dialkylamino or pyrrolidino compound, or
[0196] If a compound of general formula I is obtained which
contains an amino or alkylamino group, this may be converted by
acylation into a corresponding acyl compound, or
[0197] If a compound of general formula I is obtained which
contains an amino or alkylamino group, this may be converted by
sulphonation into a corresponding sulphonyl compound, for example
into the corresponding alkylsulphonylamino, phenylsulphonylamino,
benzylsulphonylamino or N-alkyl-alkyl-sulphonylamino group, or
[0198] If a compound of general formula I is obtained which
contains an amino group, this can be converted by a reaction of
condensation into a corresponding pyrrolo compound, or
[0199] If a compound of general formula I is obtained which
contains a carboxy group, this may be converted by esterification
or amidation into a corresponding ester or aminocarbonyl compound,
or
[0200] If a compound of general formula I is obtained which
contains a cyano group, this can be converted by reduction into a
corresponding aminomethyl compound, or
[0201] If a compound of general formula I is obtained which
contains an amino or alkylamino group, this may be converted by
reaction with cyanic acid or a corresponding isocyanate into a
corresponding ureido compound.
[0202] The subsequent hydrolysis is preferably carried out in an
aqueous solvent, e.g. in water, methanol/water, ethanol/water,
isopropanol/water, tetrahydrofuran/water or dioxane/water, in the
presence of an acid such as trifluoroacetic acid, hydrochloric acid
or sulphuric acid or in the presence of an alkali metal base such
as lithium hydroxide, sodium hydroxide or potassium hydroxide at
temperatures between 0 and 100.degree. C., preferably at
temperatures between 10 and 50.degree. C.
[0203] The subsequent reductive alkylation is preferably carried
out in a suitable solvent such as methanol, methanol/water,
methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane,
methylene chloride or dimethylformamide optionally with the
addition of an acid such as hydrochloric acid in the presence of
catalytically activated hydrogen, e.g. hydrogen in the presence of
Raney nickel, platinum or palladium/charcoal, or in the presence of
a metal hydride such as sodium borohydride, sodium
cyanoborohydride, lithium borohydride or lithium aluminium hydride
at temperatures between 0 and 100.degree. C., preferably at
temperatures between 20 and 80.degree. C.
[0204] The subsequent alkylation is carried out with an alkylating
agent such as an alkyl halide or dialkyl sulphate such as
methyliodide, dimethylsulphate or propylbromide preferably in a
solvent such as methanol, ethanol, methylene chloride,
tetrahydrofuran, toluene, dioxane, dimethylsulphoxide or
dimethylformamide optionally in the presence of an inorganic or a
tertiary organic base such as potassium carbonate, triethylamine,
N-ethyl-diisopropylamine, pyridine or dimethylaminopyridine,
preferably at temperatures between 20.degree. C. and the boiling
temperature of the solvent used.
[0205] The subsequent acylation is preferably carried out in a
solvent such as methylene chloride, diethylether, tetrahydrofuran,
toluene, dioxane, acetonitrile, dimethylsulphoxide or
dimethylformamide, optionally in the presence of an inorganic or a
tertiary organic base, preferably at temperatures between
20.degree. C. and the boiling temperature of the solvent used. The
acylation with a corresponding acid is preferably carried out in
the presence of a dehydrating agent, e.g. in the presence of
isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl
orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane,
thionylchloride, trimethylchlorosilane, phosphorus trichloride,
phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexyl-carbodiimide/N-hydroxysuccinimide,
N,N'-dicyclohexylcarbodiimide/1-hydroxy-benztriazole,
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-h-
ydroxy-benzotriazole, N,N'-carbonyldiimidazole or
triphenylphosphine/carbo- n tetrachloride, and optionally with the
addition of a base such as pyridine, 4-dimethylamino-pyridine,
N-methyl-morpholine or triethylamine, conveniently at temperatures
between 0 and 150.degree. C., preferably at temperatures between 0
and 100.degree. C., and the acylation with a corresponding reactive
compound such as an anhydride, ester, imidazolide or halide thereof
is optionally carried out in the presence of a tertiary organic
base such as triethylamine, N-ethyl-diisopropylamine,
N-methyl-morpholine or pyridine at temperatures between 0 and
150.degree. C., preferably at temperatures between 50 and
100.degree. C.
[0206] The subsequent sulphonation is preferably carried out in a
solvent such as methylene chloride, diethylether, tetrahydro-furan,
toluene, dioxane, acetonitrile, dimethylsulphoxide or
dimethylformamide optionally in the presence of an inorganic or
tertiary organic base, preferably at temperatures between
20.degree. C. and the boiling temperature of the solvent used. The
sulphonation is carried out with a corresponding reactive compound,
for example the sulphonylhalides, optionally in the presence of a
tertiary organic base such as triethylamine,
N-ethyl-diisopropylamine, N-methyl-morpholine, pyridine or
dimethylaminopyridine at temperatures between 0 and 150.degree. C.,
preferably at temperatures between 50 and 100.degree. C.
[0207] The subsequent condensation for converting an amino group
into a pyrrolo group is expediently carried out in a solvent such
as dimethylformamide, toluene, acetonitrile, tetrahydrofuran,
dimethylsulphoxide, methylene chloride or mixtures thereof,
preferably in the presence of a acid such as formic acid, glacial
acetic acid or trifluoroacetic acid or using the acid as the sole
solvent with condesable 1,4-difunctional n-butylene or
tetrahydrofuran derivatives, for example with
2,5-dimethoxytetrahydrofuran or 2,5-hexanedione, at temperatures
between 0 and 120.degree. C. or the boiling temperature of the
reaction mixture.
[0208] The subsequent esterification or amidation is expediently
carried out by reacting a corresponding reactive carboxylic acid
derivative with a corresponding alcohol or amine as described
hereinbefore.
[0209] The subsequent reduction of a cyano group is preferably
carried out in a suitable solvent such as methanol, methanol/water,
methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane,
methylene chloride or dimethylformamide optionally with the
addition of methanolic ammonia with hydrogen in the presence of a
hydrogenation catalyst, e.g. in the presence of Raney nickel or
palladium/charcoal, at a hydrogen pressure of 1 to 5 bar,
preferably at temperatures between 20.degree. C. and the boiling
temperature of the solvent used.
[0210] The subsequent reaction with a cyanic acid or a
corresponding isocyanate is preferably carried out in a suitable
solvent such as ethanol, tetrahydrofuran or dioxane at temperatures
between 0.degree. C. and the boiling temperature of the reaction
mixture; the cyanic acid used is expediently prepared in the
reaction mixture by reacting a salt of cyanic acid with an acid,
for example by reacting potassium cyanate with glacial acetic
acid.
[0211] In the reactions described hereinbefore, any reactive groups
present such as carboxy, amino, alkylamino or imino groups may be
protected during the reaction by conventional protecting groups
which are cleaved again after the reaction.
[0212] For example, a protecting group for a carboxyl group may be
a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or
tetrahydropyranyl group and
[0213] protecting groups for an amino, alkylamino or imino group
may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,
tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or
2,4-dimethoxybenzyl group and additionally, for the amino group, a
phthalyl group.
[0214] Any protecting group used is optionally subsequently cleaved
for example by hydrolysis in an aqueous solvent, e.g. in water,
isopropanol/water, tetrahydrofuran/water or dioxane/water, in the
presence of a acid such as trifluoroacetic acid, hydrochloric acid
or sulphuric acid or in the presence of an alkali metal base such
as lithium hydroxide, sodium hydroxide or potassium hydroxide, at
temperatures between 0 and 100.degree. C., preferably at
temperatures between 10 and 50.degree. C.
[0215] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group
is cleaved, for example, hydrogenolytically, e.g. with hydrogen in
the presence of a catalyst such as palladium/charcoal in a solvent
such as methanol, ethanol, ethyl acetate, dimethylformamide,
dimethylformamide/acetone or glacial acetic acid, optionally with
the addition of an acid such as hydrochloric acid or glacial acetic
acid at temperatures between 0 and 50.degree. C., but preferably at
ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but
preferably 3 to 5 bar.
[0216] A methoxybenzyl group may also be cleaved in the presence of
an oxidising agent such as cerium (IV)ammonium nitrate in a solvent
such as methylene chloride, acetonitrile or acetonitrile/water at
temperatures of between 0 and 50.degree. C., but preferably at
ambient temperature.
[0217] A 2,4-dimethoxybenzyl group, however, is preferably cleaved
in trifluoroacetic acid in the presence of anisol.
[0218] A tert.butyl or tert.butyloxycarbonyl group is preferably
cleaved by treating with an acid such as trifluoroacetic acid or
hydrochloric acid, optionally using a solvent such as methylene
chloride, dioxane, ethyl acetate or ether.
[0219] A phthalyl group is preferably cleaved in the presence of
hydrazine or a primary amine such as methylamine, ethylamine or
n-butylamine in a solvent such as methanol, ethanol, isopropanol,
toluene/water or dioxane at temperatures between 20 and 50.degree.
C.
[0220] Moreover, chiral compounds of general formula I obtained may
be resolved into their enantiomers and/or diastereomers.
[0221] Thus, for example, the compounds of general formula I
obtained which occur as racemates may be separated by methods known
per se (cf. Allinger N. L. and Eliel E. L. in "Topics in
Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their
optical antipodes and compounds of general formula I with at least
2 asymmetric carbon atoms may be resolved into their diastereomers
on the basis of their physical-chemical differences using methods
known per se, e.g. by chromatography and/or fractional
crystallisation, and, if these compounds are obtained in racemic
form, they may subsequently be resolved into the enantiomers as
mentioned above.
[0222] The enantiomers are preferably separated by column
separation on chiral phases or by recrystallisation from an
optically active solvent or by reacting with an optically active
substance which forms salts or derivatives such as e.g. esters or
amides with the racemic compound, particularly acids and the
activated derivatives or alcohols thereof, and separating the
diastereomeric mixture of salts or derivatives thus obtained, e.g.
on the basis of their differences in solubility, whilst the free
antipodes may be released from the pure diastereomeric salts or
derivatives by the action of suitable agents. Optically active
acids in common use are e.g. the D- and L-forms of tartaric acid or
dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid,
mandelic acid, camphorsulphonic acid, glutamic acid,
N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or
quinic acid. An optically active alcohol may be for example (+)- or
(-)-menthol and an optically active acyl group in amides, for
example, may be a (+)- or (-)-menthyloxycarbonyl group.
[0223] Furthermore, the compounds of formula I obtained may be
converted into the salts thereof, particularly for pharmaceutical
use into the physiologically acceptable salts with inorganic or
organic acids. Acids which may be used for this purpose include for
example hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, fumaric acid, succinic acid, lactic acid, citric
acid, tartaric acid, maleic acid or methanesulphonic acid.
[0224] Moreover, if the new compounds of formula I thus obtained
contain a carboxy group, they may subsequently, if desired, be
converted into the salts thereof with inorganic or organic bases,
particularly for pharmaceutical use into the physiologically
acceptable salts thereof. Suitable bases for this purpose include
for example sodium hydroxide, potassium hydroxide, cyclohexylamine,
ethanolamine, diethanolamine and triethanolamine.
[0225] The compounds of general formulae IV to VII used as starting
materials are known from the literature in some cases or may be
obtained by methods known from the literature or are described in
the Examples.
[0226] As already mentioned, the new compounds of general formula I
wherein R.sub.4 denotes a hydrogen atom or a prodrug group have
valuable pharmacological properties, particularly inhibitory
effects on various kinases, especially on receptor-tyrosine kinases
such as VEGFR2, PDGFR.alpha., PDGFR.beta., FGFR1, FGFR3, EGFR,
HER2, IGF1R and HGFR, as well as on complexes of CDK's (Cycline
Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,
CDK7, CDK8 and CDK9 with their specific cyclines (A, B1, B2, C, D1,
D2, D3, E, F, G1, G2, H, I and K) and on viral cycline, on the
proliferation of cultivated human cells, particularly endothelial
cells, e.g. in angiogenesis, but also on the proliferation of other
cells, particularly tumour cells.
[0227] The biological properties of the new compounds were tested
by the following standard procedure, as follows:
[0228] Human umbilical endothelial cells (HUVEC) were cultivated in
IMDM (Gibco BRL), supplemented with 10% foetal calf serum (FBS)
(Sigma), 50 .mu.M of 9-mercaptoethanol (Fluka), standard
antibiotics, 15 .mu.g/ml of endothelial cell growth factor (ECGS,
Collaborative Biomedical Products) and 100 .mu.g/ml of heparin
(Sigma) on gelatine-coated culture dishes (0.2% gelatine, Sigma) at
37.degree. C., under 5% CO.sub.2 in a water-saturated
atmosphere.
[0229] In order to investigate the inhibitory activity of the
compounds according to the invention the cells were "starved" for
16 hours, i.e. kept in culture medium without growth factors
(ECGS+heparin). The cells were detached from the culture dishes
using trypsin/EDTA and washed once in serum-containing medium. Then
they were seeded out in amounts of 2.5.times.10.sup.3 cells per
well.
[0230] The proliferation of the cells was stimulated with 5 ng/ml
of VEGF.sub.165 (vascular endothelial growth factor; H. Weich, G B
F Braunschweig) and 10 .mu.g/ml of heparin. As a control, 6 wells
in each dish were not stimulated.
[0231] The compounds according to the invention were dissolved in
100% dimethylsulphoxide and added to the cultures in various
dilutions as triple measurements, the maximum dimethyl sulphoxide
concentration being 0.3%.
[0232] The cells were incubated for 76 hours at 37.degree. C., then
for a further 16 hours .sup.3H-thymidine (0.1 .mu.Ci/well,
Amersham) was added in order to determine the DNA synthesis. Then
the radioactively labelled cells were immobilised on filter mats
and the radioactivity incorporated was measured in a
.beta.-counter. In order to determine the inhibitory activity of
the compounds according to the invention the mean value of the
non-stimulated cells was subtracted from the mean value of the
factor-stimulated cells (in the presence or absence of the
compounds according to the invention).
[0233] The relative cell proliferation was calculated as a
percentage of the control (HUVEC without inhibitor) and the
concentration of active substance which inhibits the proliferation
of the cells by 50% (IC.sub.50) was determined.
[0234] The following Table contains the results found:
1 compound (Example No.) IC.sub.50 [.mu.M] 1 0.03 1 (3) 0.27 1 (6)
0.02 1 (8) 0.05 1 (17) 0.04 1 (18) 0.04 1 (50) 0.83 3 0.05 4
0.04
[0235] In addition the compound of Example 1(6) was tested on mice
for its tolerance. The approximate oral LD.sub.50 for this compound
is over 1,000 mg/kg. The compounds of general formula I are
therefore well tolerated.
[0236] In view of their inhibitory effect on the proliferation of
cells, particularly endothelial cells and tumour cells, the
compounds of general formula I are suitable for treating diseases
in which the proliferation of cells, particularly endothelial
cells, plays a part.
[0237] Thus, for example, the proliferation of endothelial cells
and the concomitant neovascularisation constitute a crucial stage
in tumour progression (Folkman J. et al., Nature 339, 58-61,
(1989); Hanahan D. and Folkman J., Cell 86, 353-365, (1996)).
Furthermore, the proliferation of endothelial cells is also
important in haemangiomas, in metastasisation, rheumatoid
arthritis, psoriasis and ocular neovascularisation (Folkman J.,
Nature Med. 1, 27-31, (1995)). The therapeutic usefulness of
inhibitors of endothelial cell proliferation was demonstrated in
the animal model for example by O'Reilly et al. and Parangi et al.
(O'Reilly M. S. et al., Cell 88, 277-285, (1997); Parangi S. et
al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)).
[0238] The compounds of general formula I, their tautomers, their
stereoisomers or the physiologically acceptable salts thereof are
thus suitable, for example, for treating solid tumours, diabetic
retinopathy, rheumatoid arthritis and psoriasis, or other diseases
in which cell proliferation or angiogenesis play a part.
[0239] By reason of their biological properties the compounds
according to the invention may be used on their own or in
conjunction with other pharmacologically active compounds, for
example in tumour therapy, in monotherapy or in conjunction with
other anti-tumour therapeutic agents, for example in combination
with Topoisomerase inhibitors (e.g. Etoposide), mitosis inhibitors
(e.g. Vinblastin, Taxol), compounds which interact with nucleic
acids (e.g. cisplatin, Cyclophosphamide, Adriamycin), hormone
antagonists (e.g. tamoxifen), inhibitors of metabolic processes
(e.g. 5-FU etc.), cytokines (e.g. inter-ferons), kinase inhibitos,
antibodies, or in conjunction with radiotherapy, etc. These
combinations may be administered either simultaneously or
sequentially.
[0240] For pharmaceutical use the compounds according to the
invention are generally used for warm-blooded vertebrates,
particularly humans, in doses of 0.01-100 mg/kg of body weight,
preferably 0.1-15 mg/kg. For administration they are formulated
with one or more conventional inert carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose,
magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric
acid, water, water/ethanol, water/glycerol, water/sorbitol,
water/polyethyleneglycol, propyleneglycol, stearylalcohol,
carboxymethylcellulose or fatty substances such as hard fat or
suitable mixtures thereof in conventional galenic preparations such
as plain or coated tablets, capsules, powders, suspensions,
solutions, sprays or suppositories.
[0241] The following Examples are intended to illustrate the
present invention without restricting it:
[0242] Abbreviations:
[0243]
TBTU=O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)-uronium
hexafluorophosphate
[0244] HOBt=1-hydroxy-1H-benzotriazole
[0245] Preparation of the starting compounds:
EXAMPLE I
[0246] 1-hydroxy-6-nitro-2-indolinone
[0247] 2.0 g of 2,4-dinitrophenylacetic acid (prepared according to
J. Chem. Soc. 1948, 1717) are dissolved in 40 ml ethanol and 6.0 ml
of conc. hydrochloric acid and 4.1 g of tin-(II)-chloride-dihydrate
are added in batches at ambient temperature. The mixture is stirred
for 12 hours at ambient temperature and for 4 hours at 60.degree.
C. After cooling another 2.0 g of tin-(II)-chloride-dihydrate are
added and the mixture is stirred for another 12 hours at ambient
temperature. The reaction mixture is diluted with water, extracted
with methylene chloride and the organic phase is dried over sodium
sulphate. After elimination of the solvent the residue is
triturated with ether and the precipitate is filtered off.
[0248] Yield: 0.6 g (35% of theory),
[0249] R.sub.f value: 0.7 (silica gel, methylene
chloride/methanol=9:1)
[0250] C.sub.8H.sub.6N.sub.2O.sub.4
[0251] ESI mass spectrum: m/z=193 [M-H.sup.-]
EXAMPLE II
[0252] 3,4-Diethoxy-phenylacetic acid
[0253] 0.8 g of 3,4-dihydroxy-phenylacetic acid and 6.9 g of barium
hydroxide octahydrate are dissolved in 50 ml of water and at
ambient temperature 2.9 ml of diethylsulphate are added dropwise.
The solution is stirred for 2 hours at ambient temperature and for
2 hours at 40.degree. C. After this time the solution is acidified
with saturated potassium hydrogen sulphate solution, mixed with
ethyl acetate and the suspension is filtered through Celite. The
phases are separated and the ethyl acetate phase is dried over
sodium sulphate and concentrated by evaporation. The residue
obtained is purified through a silica gel column with toluene/ethyl
acetate/ethanol (4:2:1) as eluant.
[0254] Yield: 0.5 g (42% of theory),
[0255] R.sub.f value: 0.5 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0256] C.sub.12H.sub.16O.sub.4
[0257] ESI mass spectrum: m/z=223 [M-H.sup.-]
EXAMPLE III
[0258] 4,5-diethoxy-2-nitro-phenylacetic acid
[0259] 0.5 g of 3,4-diethoxy-phenylacetic acid are placed in 10 ml
of acetic acid p.a. and 0.5 ml of 65% nitric acid are added
dropwise, so that the internal temperature does not rise above
15.degree. C. The mixture is then heated to 40.degree. C. for 0.5
hours. After this time the solution is poured onto ice water and
the precipitate formed is suction filtered. The product is washed
with water and dried at 100.degree. C.
[0260] Yield: 0.3 g (57% of theory),
[0261] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0262] C.sub.12H.sub.15NO.sub.6
[0263] ESI mass spectrum: m/z=292 [M+Na.sup.+]
EXAMPLE IV
[0264] tert.butyl 2-nitro-4-trifluormethyl-phenylacetate
[0265] 2.6 g of potassium-tert.butoxide are placed in 45 ml of
dimethylformamide and at an internal temperature of -5.degree. C.
1.3 ml of 3-nitro-trifluorotoluene and 1.5 ml of tert.butyl
chloroacetate in 1 ml of dimethylformamide are added dropwise. The
mixture is stirred for another 5 minutes and the solution is then
poured onto ice water and the precipitate formed is suction
filtered.
[0266] Yield: 2.5 g (82% of theory),
[0267] R.sub.f value: 0.4 (silica gel, petroleum ether/ethyl
acetate=10:1)
[0268] Melting point: 45.degree. C.
EXAMPLE V
[0269] 2-nitro-4-trifluoromethyl-phenylacetic acid
[0270] 16.7 g of tert.butyl 2-nitro-4-trifluoromethyl-phenylacetate
and 50 ml of trifluoroacetic acid are dissolved in 50 ml of
methylene chloride and stirred for 3 hours at ambient temperature.
After elimination of the solvent the residue is taken up in
petroleum ether/ether (10:1), suction filtered and dried in vacuo
at 80.degree. C.
[0271] Yield: 13.4 g (98% of theory),
[0272] R.sub.f value: 0.5 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0273] C.sub.9H.sub.6F.sub.3NO.sub.4
[0274] ESI mass spectrum: m/z=248 [M-H.sup.-]
EXAMPLE VI
[0275] 5,6-diethoxy-2-indolinone
[0276] 1.4 g of 4,5-diethoxy-2-nitro-phenylacetic acid are
dissolved in 50 ml of acetic acid, 0.3 g of 10% palladium on carbon
is added and the mixture is hydrogenated for 1 hour at ambient
temperature and 50 psi. The catalyst is filtered off and the
filtrate is concentrated by evaporation.
[0277] Yield: 1.15 g (100% of theory),
[0278] R.sub.f value: 0.5 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0279] The following compounds are prepared analogously to Example
VI:
[0280] (1) 6-trifluoromethyl-2-indolinone
[0281] Prepared from 2-nitro-4-trifluoromethyl-phenylacetic
acid
[0282] (2) 6-bromo-2-indolinone
[0283] Prepared from 4-bromo-6-nitro-phenylacetic acid (according
to Chem. Pharm. bull. (1985), 33, 1414-1418)
EXAMPLE VII
[0284] 6-phenyl-2-indolinone
[0285] 2.4 g of 6-bromo-2-indolinone are placed in 60 ml of
dimethoxyethane, 1.9 g of phenylboric acid in 8 ml of ethanol and
0.3 g of tetrakistriphenylphosphine palladium are added and to this
mixture 12 ml of 2N sodium carbonate solution are added dropwise at
ambient temperature. The mixture is stirred for 6 hours at
85.degree. C. After cooling the catalyst is filtered off, the
solvent is eliminated and the residue is washed with 100 ml of
water and 20 ml of 1N sodium hydroxide solution. The residue is
purified through a silica gel column with petroleum ether/ethyl
acetate (8:2) as eluant.
[0286] Yield: 1.5 g (65% of theory),
[0287] R.sub.f value: 0.45 (silica gel, petroleum ether/ethyl
acetate=1:1)
[0288] Melting point: 167-170.degree. C.
[0289] The following compound is prepared analogously to Example
VII:
[0290] (1) 6-(2-Tolyl)-2-indolinone
[0291] Prepared from 6-bromo-2-indolinone and 2-tolylboric acid
EXAMPLE VIII
[0292] 1-acetyl-5,6-dimethoxy-2-indolinone
[0293] 16.0 g of 5,6-dimethoxy-2-indolinone (according to Hahn;
Tulus; Chem. Ber. 74, 500 (1941)) are dissolved in 170 ml of acetic
anhydride and stirred for more than 3 hours at 130.degree. C. After
cooling the residue is filtered off, washed with ether and dried in
vacuo at 100.degree. C.
[0294] Yield: 15.8 g (81% of theory),
[0295] R.sub.f value: 0.8 (silica gel, methylene
chloride/methanol=10:1)
[0296] C.sub.12H.sub.13NO.sub.4
[0297] ESI mass spectrum: m/z=234 [M-H.sup.-]
[0298] The following compounds are prepared analogously to Example
VIII:
[0299] (1) 1-acetyl-6-methoxy-2-indolinone
[0300] Prepared from 6-methoxy-2-indolinone (prepared according to
Quallich, G. J.; Morrissey, P. M.; Synthesis 1993, 51) and acetic
anhydride
[0301] (2) 1-acetyl-5,6-diethoxy-2-indolinone
[0302] Prepared from 5,6-diethoxy-2-indolinone and acetic
anhydride
[0303] (3) 1-acetyl-6-trifluoromethyl-2-indolinone
[0304] Prepared from 6-trifluoromethyl-2-indolinone and acetic
anhydride
EXAMPLE IX
[0305]
1-acetyl-3-(1-ethoxy-1-phenylmethylidene)-5,6-dimethoxy-2-indolinon-
e
[0306] 10.0 g of 1-acetyl-5,6-dimethoxy-2-indolinone, 29.2 ml of
triethyl orthobenzoate and 100 ml of acetic anhydride are stirred
for 48 hours at 120.degree. C. The solvent is eliminated and the
residue evaporated with toluene, combined with ether and the
precipitate formed (starting compound) is suction filtered. The
filtrate is concentrated by evaporation and separated through a
silica gel column with toluene, then with toluene/ethyl acetate
(10:1). The product is triturated with ether, suction filtered and
dried in vacuo at 100.degree. C.
[0307] Yield: 1.4 g (9% of theory),
[0308] R.sub.f value: 0.5 (silica gel, toluene/ethyl
acetate=5:1)
[0309] C.sub.21H.sub.21NO.sub.5
[0310] ESI mass spectrum: m/z=390 [M+Na.sup.+]
[0311] The following compounds are prepared analogously to Example
IX:
[0312] (1)
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolino-
ne
[0313] Prepared from 1-acetyl-6-methoxy-2-indolinone, triethyl
orthobenzoate and acetic anhydride
[0314] (2)
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indol-
inone
[0315] Prepared from 1-acetyl-5,6-dimethoxy-2-indolinone, triethyl
orthopropionate and acetic anhydride
[0316] (3)
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-diethoxy-2-indol-
inone
[0317] Prepared from 1-acetyl-5,6-diethoxy-2-indolinone, triethyl
orthopropionate and acetic anhydride
[0318] (4)
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinon-
e
[0319] Prepared from 6-phenyl-2-indolinone, triethyl
orthopropionate and acetic anhydride
[0320] (5)
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indoli-
none
[0321] Prepared from 6-(2-tolyl)-2-indolinone, triethyl
orthopropionate and acetic anhydride
EXAMPLE X
[0322]
1-acetyl-3-[1-hydroxy-1-(3-cyanophenyl)-methylidene]-5,6-di-methoxy-
-2-indolinone
[0323] 2.0 g of 1-acetyl-5,6-dimethoxy-2-indolinone, 1.3 g of
2-cyanobenzoic acid, 3.3 g of TBTU, 1.6 g of HOBt and 7.5 ml of
N-ethyl-diisopropylamine are dissolved in 30 ml of
dimethylformamide and stirred for two days at ambient temperature.
After this time the solution is combined with 400 ml of water and
20 ml of saturated potassium hydrogen sulphate solution. The
precipitate formed is suction filtered, washed with water, a little
methanol and a little ether and dried in vacuo at 100.degree.
C.
[0324] Yield: 2.6 g (84% of theory),
[0325] R.sub.f value: 0.8 (silica gel, methylene
chloride/methanol=5:1)
[0326] C.sub.20H.sub.16N.sub.2O.sub.5
[0327] ESI mass spectrum: m/z=363 [M-H.sup.-]
[0328] The following compound is prepared analogously to Example
X:
[0329] (1)
1-acetyl-3-(1-hydroxy-1-phenyl-methylidene)-6-trifluoromethyl-2-
-indolinone
[0330] Prepared from 1-acetyl-6-trifluoromethyl-2-indolinone and
benzoic acid
EXAMPLE XI
[0331]
1-acetyl-3-[1-chloro-1-(3-cyanophenyl)-methylidene]-5,6-dimethoxy-2-
-indolinone
[0332] 2.5 g of
1-acetyl-3-[1-chloro-1-(3-cyanophenyl)-methylidene]-5,6-di-
methoxy-2-indolinone and 1.6 g of phosphorus pentachloride are
dissolved in 30 ml of toluene and stirred for 1 hour at 80.degree.
C. The suspension is cooled, combined with 50 ml of ether and the
precipitate formed is suction filtered. After washing with ether
the residue is dried in vacuo at 50.degree. C.
[0333] Yield: 1.5 g (56% of theory),
[0334] R.sub.f value: 0.6 (silica gel, methylene
chloride/methanol=40:1)
[0335] C.sub.20H.sub.15CN.sub.12O.sub.4
[0336] ESI mass spectrum: m/z=405/407 [M+Na.sup.+]
[0337] The following compound is prepared analogously to Example
XI:
[0338] (1)
1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2--
indolinone
[0339] Prepared from
1-acetyl-3-(1-hydroxy-1-phenyl-methylidene)-6-trifluo-
romethyl-2-indoline and phosphorus pentachloride
EXAMPLE XII
[0340]
3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone
[0341] Under a nitrogen atmosphere 4.5 g of
diethyl-1-methoxybenzylphospho- nate (according to Burkhouse, D.;
Zimmer, H.; Synthesis 1984, 330) are dissolved in 40 ml of absolute
dimethylformamide and at -40.degree. C. 4.0 g of
potassium-tert-butoxide are added batchwise and stirred for 15
minutes at -10.degree. C. 3.0 g of 5,6-methylenedioxyisatin
(according to Lackey, K.; Sternbach, D. D.; Synthesis 1993, 993)
are added to the clear solution and stirred for 1 hour at ambient
temperature. After this time the mixture is poured into 20 ml of
ice-cold saturated potassium hydrogen sulphate solution and
extracted with ethyl acetate. The ethyl acetate phase is washed
with water, dried over sodium sulphate and concentrated by
evaporation. Finally the residue is separated through a silica gel
column with toluene/ethyl acetate (5:1). The product obtained can
be recrystallised from ether.
[0342] Yield: 1.6 g (35% of theory),
[0343] R.sub.f value: 0.3 (silica gel, toluene/ethyl
acetate=5:1)
[0344] C.sub.17H.sub.13NO.sub.4
[0345] ESI mass spectrum: m/z=318 [M+Na.sup.+]
EXAMPLE XIII
[0346]
1-acetoxy-3-(1-ethoxy-1-phenylmethylidene)-6-nitro-2-indolinone
[0347] 300 mg of 1-hydroxy-6-nitro-2-indolinone are dissolved in
4.0 ml of acetic anhydride and 4.0 ml of triethyl orthobenzoate,
stirred for 6 hours at 110.degree. C., concentrated by evaporation
and purified through a silica gel column with methylene chloride as
eluant.
[0348] Yield: 0.28 g (49% of theory),
[0349] R.sub.f value: 0.23 (silica gel, methylene chloride)
[0350] C.sub.19H.sub.16N.sub.2O.sub.6
[0351] Mass spectrum: m/z=368 [M.sup.+]
EXAMPLE XIV
[0352]
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}--
6-nitro-2-indolinone
[0353] 1.25 g of
1-acetoxy-3-(1-ethoxy-1-phenyl-methylidene)-6-nitro-2-ind- olinone
and 0.65 g of 4-(piperidin-1-yl-methyl)-aniline are dissolved in 10
ml of dimethylformamide and stirred for 30 minutes at ambient
temperature. After this time 46 mg of palladium on carbon (10%) are
added and carefully hydrogenated for 1 hour at ambient temperature
with 3 bar hydrogen. The catalyst is filtered off, the filtrate
concentrated by evaporation and the residue purified through a
silica gel column with methylene chloride/methanol (9:1).
[0354] Yield: 16 mg of (4% of theory),
[0355] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=9:1)
[0356] C.sub.27H.sub.26N.sub.4O.sub.3
[0357] The following compound is prepared analogously to Example
XIV:
[0358] (1)
1-acetoxy-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methyli-
dene]-6-nitro-2-indolinone
[0359] Prepared from
1-acetoxy-3-(1-ethoxy-1-phenyl-methylidene)-6-nitro-2- -indolinone
and methyl 4-aminobenzoate without subsequent hydrogenation
[0360] ESI mass spectrum: m/z=472 [M-H.sup.-]
EXAMPLE XV
[0361]
N-(2-dimethylamino-ethyl)-N-methylsulphonyl-4-nitroaniline
[0362] 38.9 g of N-methylsulphonyl-4-nitroaniline are dissolved in
2.01 of acetone, 51.9 g of 1-chloro-2-dimethylamino-ethane, 77.4 g
of potassium carbonate and 5.0 g of sodium iodide added and the
mixture is stirred for a total of 4 days at 50.degree. C., adding,
after 12 hours, a further 25.9 g of
1-chloro-2-dimethylamino-ethane, 49.8 g of potassium carbonate and
5.0 g of sodium iodide in 500 ml of acetone and, after 36 hours, a
further 26.0 g of 1-chloro-2-dimethylamino-ethane, 50.0 g of
potassium carbonate and 5.0 g of sodium iodide in 100 ml of
acetone. After this time the mixture is filtered and the filtrate
is evaporated down. The residue is stirred with ether, suction
filtered and dried at 40.degree. C.
[0363] Yield: 25.3 g (49% of theory),
[0364] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol/ammonia- =9:1:0.1)
[0365] C.sub.11H.sub.17N.sub.3O.sub.4S
[0366] ESI mass spectrum: m/z=288 [M+H.sup.+]
[0367] The following compound is prepared analogously to Example
XV:
[0368] (1) N-carboxymethyl-N-methylsulphonyl-4-nitroaniline
EXAMPLE XVI
[0369]
N-(dimethylaminocarbonyl-methyl)-N-methylsulphonyl-4-nitroaniline
[0370] 7.0 g of N-carboxymethyl-N-methylsulphonyl-4-nitroaniline,
2.5 g of dimethylamine hydrochloride, 8.1 g of TBTU and 3.9 g of
HOBT are dissolved in 125 ml of dimethylformamide and at 0.degree.
C. 17.6 ml of N-ethyl-diisopropylamine are added. The mixture is
stirred for 4 hours at ambient temperature, diluted with 11 water
and the precipitate formed is suction filtered. After washing with
water, ethanol and ether the residue is dried at 70.degree. C. in
vacuo.
[0371] Yield: 5.3 g (69% of theory),
[0372] R.sub.f value: 0.40 (silica gel, methylene
chloride/methanol=9:1)
[0373] C.sub.11H.sub.15N.sub.3O.sub.5S
[0374] ESI mass spectrum: m/z=300 [M-H.sup.-]
[0375] The following compound is prepared analogously to Example
XVI:
[0376] (1)
N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methyl-sulpho-
nyl-4-nitroaniline
EXAMPLE XVII
[0377] N-(dimethylaminomethylcarbonyl)-N-methyl-4-nitro-aniline
[0378] 1.8 g of dimethylamine hydrochloride and 5.5 g of potassium
carbonate are placed in 80 ml of acetone and 4.2 g of
N-(2-bromomethylcarbonyl)-N-methyl-4-nitroaniline (prepared
according to Chem. Ber. 119, 2430 (1986)) are added in three
batches at ambient temperature. The mixture is stirred for 12 hours
at ambient temperature. After this time the mixture is filtered and
the filtrate is concentrated by evaporation. The residue is
dissolved in ethyl acetate, washed twice with water, dried over
sodium sulphate and finally concentrated by rotary evaporation.
[0379] Yield: 2.8 g (79% of theory),
[0380] R.sub.f value: 0.5 (silica gel, ethyl
acetate/methanol=7:3)
[0381] Melting point: 121-122.degree. C.
EXAMPLE XVIII
[0382] 4-(piperidin-1-yl-methyl)-nitrobenzene
[0383] 40.0 g of 4-nitrobenzylbromide are in 500 ml of methylene
chloride dissolved, 51.5 ml of triethylamine are added and 18.3 ml
of piperidine are carefully added dropwise. After the end of the
exothermic reaction the mixture is refluxed for a further 30
minutes. After cooling it is washed with water and the organic
phase is dried over sodium sulphate. Finally, the organic phase is
evaporated down.
[0384] Yield: 36.3 g (89% of theory),
[0385] R.sub.f value: 0.6 (silica gel, methylene
chloride/methanol=9:1)
[0386] C.sub.12H.sub.16N.sub.2O.sub.2
[0387] Mass spectrum: m/z=221 [M.sup.+]
[0388] The following compounds are prepared analogously to Example
XVIII:
[0389] (1) 4-[(N-benzyl-N-methyl-amino)-methyl]-nitrobenzene
[0390] (2) 3-(dimethylaminomethyl)-nitrobenzene
[0391] (3) 4-(dimethylaminomethyl)-nitrobenzene
[0392] (4) 4-(2-dimethylamino-ethyl)-nitrobenzene
[0393] (5)
4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-nitrobenzene
[0394] (6)
4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-nitrobenzene
[0395] (7) 4-(pyrrolidin-1-yl-methyl)-nitrobenzene
EXAMPLE IXX
[0396] 4-(4-methyl-piperazin-1-yl)-nitrobenzene
[0397] 31.5 g of 4-chloro-1-nitrobenzene and 44.4 ml of
1-methyl-piperazine are combined and stirred for 18 hours at
90.degree. C. Then the solution is poured onto ice water and the
precipitate formed is suction filtered, washed with water and
recrystallised from ethanol/water (1:1). The residue is dried in
vacuo at 75.degree. C.
[0398] Yield: 44.0 g (99% of theory),
[0399] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0400] Melting point: 108-112.degree. C.
[0401] The following compounds are prepared analogously to Example
IX:
[0402] (1) N-(2-dimethylaminoethyl)-N-methyl-4-nitroaniline
[0403] Prepared from 1-fluoro-4-nitrobenzene and
1-dimethylamino-2-methyla- mino-ethane
[0404] (2) N-(3-dimethylaminopropyl)-N-methyl-4-nitroaniline
[0405] Prepared from 1-fluoro-4-nitrobenzene and
1-dimethylamino-3-methyla- mino-propane
EXAMPLE XX
[0406] 4-[N-acetyl-(2-dimethylaminoethyl)-amino]-nitrobenzene
[0407] 3.6 g of 4-(2-dimethylamino-ethylamino)-nitrobenzene
(according to Gabbay et al., J. Am. Chem. Soc. 91, 5136 (1969)) are
dissolved in 50 ml of methylene chloride and 5.0 ml of
triethylamine are added. To this mixture 1.3 ml of acetylchloride
are slowly added dropwise at ambient temperature and the mixture is
stirred for 2 hours at ambient temperature. After this time a
further 5.0 ml of triethylamine and 1.3 ml of acetylchloride are
added and the mixture is refluxed for a further 2 hours. The
solvent is eliminated in vacuo, the residue is taken up in ethyl
acetate and the organic phase is extracted twice with water. After
drying over magnesium sulphate the solvent is eliminated and the
residue is dried in vacuo.
[0408] Yield: 2.0 g (45% of theory),
[0409] R.sub.f value: 0.55 (silica gel, methylene
chloride/methanol/ammoni- a=9:1:0.1)
[0410] C.sub.12H.sub.17N.sub.3O.sub.3
[0411] ESI mass spectrum: m/z=252 [M+H.sup.+]
[0412] The following compounds are prepared analogously to Example
XX:
[0413] (1)
4-[N-acetyl-N-(3-dimethylaminopropyl)-amino]-nitrobenzene
[0414] Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene
and acetylchloride
[0415] (2)
4-[N-propionyl-N-(2-dimethylaminoethyl)-amino]-nitrobenzene
[0416] Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene
and propionylchloride
[0417] (3)
4-[N-propionyl-N-(3-dimethylaminopropyl)-amino]-nitrobenzene
[0418] Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene
and propionylchloride
EXAMPLE XXI
[0419] 4-nitro-N,N-dimethylbenzamide
[0420] 10.0 g of 4-nitrobenzoic acid, 8.4 g of dimethylamine
hydrochloride and 18.3 g of TBTU are placed in 50 ml of
dimethylformamide, 78.4 ml of N-ethyl-diisopropylamine are added at
ambient temperature and the mixture is stirred for 15 hours at
ambient temperature. After this time the mixture is combined with
water and extracted with ethyl acetate. The organic phase is again
extracted with water and with 1N hydrochloric acid, dried over
sodium sulphate and concentrated by evaporation. The product is
recrystallised from ether.
[0421] Yield: 5.6 g (48% of theory),
[0422] R.sub.f value: 0.6 (silica gel, methylene
chloride/methanol=9:1)
[0423] Melting point: 61-63.degree. C.
[0424] The following compound is prepared analogously to Example
XXI:
[0425] (1) 4-(piperidin-1-yl-carbonyl)-nitrobenzene
[0426] Prepared from 4-nitrobenzoic acid and piperidine
EXAMPLE XXII
[0427] 4-(piperidin-1-yl-methyl)-aniline
[0428] 37.0 g of 4-(piperidin-1-yl-methyl)-nitrobenzene are
dissolved in 300 ml of methanol, 8.0 g of Raney nickel are added
and the mixture is hydrogenated for 1 hour 25 minutes with 3 bar
hydrogen at ambient temperature. The catalyst is filtered off and
the filtrate is concentrated by evaporation.
[0429] Yield: 24.0 g (75% of theory),
[0430] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=9:1)
[0431] C.sub.12H.sub.18N.sub.2
[0432] ESI mass spectrum: m/z=191 [M+H.sup.+]
[0433] The following compounds are prepared analogously to Example
XXII:
[0434] (1) 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
[0435] (2)
N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
[0436] (3) 3-(dimethylaminomethyl)-aniline
[0437] (4) 4-(dimethylaminomethyl)-aniline
[0438] (5) 4-(2-dimethylamino-ethyl)-aniline
[0439] (6)
N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine
[0440] (7)
4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-aniline
[0441] (8)
N-(dimethylaminocarbonylmethyl)-N-methylsulphonyl-p-phenylenedi-
amine
[0442] (9) 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline
[0443] (10)
N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methyl-sulph-
onyl-p-phenylenediamine
[0444] (11) 4-(pyrrolidin-1-yl-methyl)-aniline
[0445] (12) 4-(4-methyl-piperazin-1-yl)-aniline
[0446] (13)
N-(2-dimethylaminoethyl)-N-methyl-p-phenylenediamine
[0447] (14)
N-(3-dimethylaminopropyl)-N-methyl-p-phenylenediamine
[0448] (15)
N-acetyl-N-(2-dimethylaminoethyl)-p-phenylenediamine
[0449] (16)
N-acetyl-N-(3-dimethylaminopropyl)-p-phenylenediamine
[0450] (17)
N-propionyl-N-(2-dimethylaminoethyl)-p-phenylenediamine
[0451] (18)
N-propionyl-N-(3-dimethylaminopropyl)-p-phenylenediamine
[0452] (19) N-methylsulphonyl-p-phenylenediamine
[0453] (20) 4-amino-N,N-dimethylbenzamide
[0454] (21) 4-(piperidin-1-yl-carbonyl)-aniline
[0455] (22) 4-tetrazol-5-yl-aniline
[0456] Preparation of the final compounds:
EXAMPLE 1
[0457]
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}--
5,6-dimethoxy-2-indolinone
[0458] 700 mg of
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-di-methoxy-
-2-indolinone and 300 mg of 4-(piperidin-1-yl-methyl)-aniline are
suspended in 3.0 ml of dimethylformamide and stirred for 2 hours at
110.degree. C. After cooling 1.0 ml of piperidine is added and the
mixture is stirred for 3 hours at ambient temperature, combined
with water and the precipitate formed is suction filtered. The
precipitate is separated through a silica gel column with methylene
chloride/methanol/ammonia (10:1:0.01), stirred with ether, suction
filtered and dried at 100.degree. C.
[0459] Yield: 300 mg of (55% of theory),
[0460] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=5:1)
[0461] C.sub.29H.sub.29N.sub.3O.sub.4
[0462] Mass spectrum: m/z=469 [M.sup.+]
[0463] The following compounds are prepared analogously to Example
1:
[0464] (1)
3-(Z)-[1-(4-methoxy-anilino)-1-phenyl-methylidene]-5,6-di-metho-
xy-2-indolinone
[0465] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and p-anisidine
[0466] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=10:1)
[0467] C.sub.24H.sub.22N.sub.2O.sub.4
[0468] Mass spectrum: m/z=402 [M.sup.+]
[0469] (2)
3-(Z)-[1-(4-chloro-anilino)-1-phenyl-methylidene]-5,6-di-methox-
y-2-indolinone
[0470] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-chloroaniline
[0471] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0472] C.sub.23H.sub.19CN.sub.12O.sub.3
[0473] Mass spectrum: m/z=406/408 [M.sub.+]
[0474] (3)
3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-pheny-
l-methylidene)-5,6-dimethoxy-2-indolinone
[0475] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
[0476] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0477] C.sub.32H.sub.31N.sub.3O.sub.3
[0478] Mass spectrum: m/z=505 [M.sup.+]
[0479] (4)
3-(Z)-(1-{4-[N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino]--
anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0480] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenyle-
nediamine
[0481] R.sub.f value: 0.5 (aluminium oxide, methylene
chloride/methanol=20:1)
[0482] C.sub.28H.sub.32N.sub.4O.sub.5S
[0483] Mass spectrum: m/z=536 [M.sup.+]
[0484] (5)
3-(Z)-{1-[3-(dimethylamino-methyl)-anilino]-1-phenyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[0485] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 3-(dimethylaminomethyl)-aniline
[0486] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=5:1)
[0487] C.sub.26H.sub.27N.sub.3O.sub.3
[0488] Mass spectrum: m/z=429 [M.sup.+]
[0489] (6)
3-(Z)-{1-(4-(dimethylaminomethyl)-anilino]-1-phenyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[0490] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-(dimethylaminomethyl)-aniline
[0491] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol/ammonia- =10:1:1)
[0492] C.sub.26H.sub.27N.sub.3O.sub.3
[0493] Mass spectrum: m/z=429 [M.sup.+]
[0494] (7)
3-(Z)-{1-[4-(2-dimethylamino-ethyl)-anilino]-1-phenyl-methylide-
ne-}-5,6-dimethoxy-2-indolinone
[0495] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-(2-dimethylamino-ethyl)-aniline
[0496] R.sub.f value: 0.6 (silica gel, methylene
chloride/methanol/ammonia- =5:1:0.01)
[0497] C.sub.27H.sub.29N.sub.3O.sub.3
[0498] Mass spectrum: m/z=443 [M.sup.+]
[0499] (8)
3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anil-
ino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone
[0500] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylened- iamine
[0501] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0502] C.sub.28H.sub.30N.sub.4O.sub.4
[0503] Mass spectrum: m/z=486 [M.sup.+]
[0504] (9)
3-(Z)-{1-[4-(1H-imidazol-4-yl)-anilino]-1-phenyl-methylidene}-5-
,6-dimethoxy-2-indolinone
[0505] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-(1H-imidazo-4-yl)-aniline (prepared
according to Chem. Pharm. bull. 38, 1803 (1990))
[0506] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0507] C.sub.26H.sub.22N.sub.4O.sub.3
[0508] ESI mass spectrum: m/z=439 [M+H.sup.+]
[0509] (10)
3-(Z)-(1-{4-[2-(4-carboxyethyl-piperidin-1-yl)-ethyl]-anilino}-
-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0510] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-aniline
[0511] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0512] C.sub.33H.sub.37N.sub.3O.sub.5
[0513] ESI mass spectrum: m/z=554 [M-H.sup.-]
[0514] (11)
3-(Z)-(1-{4-[N-(dimethylaminocarbonylmethyl)-N-methyl-sulphony-
l-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0515] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
N-(dimethylaminocarbonylmethyl)-N-methylsulphonyl-p-p-
henylenediamine
[0516] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0517] C.sub.28H.sub.30N.sub.4O.sub.6S
[0518] Mass spectrum: m/z=550 [M.sup.+]
[0519] (12)
3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylidene]-5,6--
dimethoxy-2-indolinone
[0520] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and ethyl 4-aminobenzoate
[0521] R.sub.f value: 0.5 (silica gel, methylene
chloride/ethanol=20:1)
[0522] C.sub.26H.sub.24N.sub.2O.sub.5
[0523] Mass spectrum: m/z=444 [M.sup.+]
[0524] (13)
3-(Z)-(1-{4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-anilino}-1--
phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0525] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline
[0526] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol/ammonia- =10:1:0.01)
[0527] C.sub.31H.sub.35N.sub.3O.sub.3
[0528] Mass spectrum: m/z=497 [M.sup.+]
[0529] (14)
3-(Z)-[1-(4-{N-[(2-dimethylamino-ethylamino)-carbonyl-methyl]--
N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-in-
dolinone
[0530] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-met-
hylsulphonyl-p-phenylenediamine
[0531] R.sub.f value: 0.3 (silica gel, methylene
chloride/methanol=4:1)
[0532] C.sub.30H.sub.35N.sub.5O.sub.6S
[0533] Mass spectrum: m/z=593 [M.sup.+]
[0534] (15)
3-(Z)-{1-[4-(pyrrolidin-1-yl-methyl)-anilino]-1-phenyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[0535] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-(pyrrolidin-1-yl-methyl)-aniline
[0536] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=5:1)
[0537] C.sub.28H.sub.29N.sub.3O.sub.3
[0538] Mass spectrum: m/z=455 [M.sup.+]
[0539] (16)
3-(Z)-{1-[4-(4-methyl-piperazin-1-yl)-anilino]-1-phenyl-methyl-
idene}-5,6-dimethoxy-2-indolinone
[0540] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-(4-methyl-piperazin-1-yl)-aniline
[0541] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=10:1)
[0542] C.sub.28H.sub.30N.sub.4O.sub.3
[0543] Mass spectrum: m/z=470 [M.sup.+]
[0544] (17)
3-(Z)-(1-{4-[N-acetyl-N-(2-dimethylamino-ethyl)-amino]-anilino-
}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0545] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
N-acetyl-N-(2-dimethylamino-ethyl)-p-phenylenediamine
[0546] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=9:1)
[0547] C.sub.29H.sub.32N.sub.4O.sub.4
[0548] ESI mass spectrum: m/z=499 [M-H.sup.-]
[0549] (18)
3-(Z)-(1-{4-[N-acetyl-N-(3-dimethylamino-propyl)-amino]-anilin-
o}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0550] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
N-acetyl-N-(3-dimethylamino-propyl)-p-phenylenediamin- e
[0551] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=10:1)
[0552] C.sub.30H.sub.34N.sub.4O.sub.4
[0553] ESI mass spectrum: m/z=515 [M+H.sup.+]
[0554] (19)
3-(Z)-(1-{4-[N-propionyl-N-(2-dimethylamino-ethyl)-amino]-anil-
ino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0555] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
N-propionyl-N-(2-dimethylamino-ethyl)-p-phenylenediam- ine
[0556] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=9:1)
[0557] C.sub.30H.sub.34N.sub.4O.sub.4
[0558] ESI mass spectrum: m/z=515 [M+H.sup.+]
[0559] (20)
3-(Z)-(1-{4-[N-propionyl-N-(3-dimethylamino-propyl)-amino]-ani-
lino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0560] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and
N-propionyl-N-(3-dimethylamino-propyl)-p-phenylenedia- mine
[0561] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0562] C.sub.31H.sub.36N.sub.4O.sub.4
[0563] ESI mass spectrum: m/z=529 [M+H.sup.+]
[0564] (21)
3-(Z)-[1-(4-aminocarbonyl-anilino)-1-phenyl-methylidene]-5,6-d-
imethoxy-2-indolinone
[0565] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-aminobenzamide
[0566] R.sub.f value: 0.4 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0567] C.sub.24H.sub.21N.sub.3O.sub.4
[0568] ESI mass spectrum: m/z=414 [M-H.sup.-]
[0569] (22)
3-(Z)-[1-(4-dimethylaminocarbonyl-anilino)-1-phenyl-methyliden-
e]-5,6-dimethoxy-2-indolinone
[0570] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-amino-dimethylbenzamide
[0571] R.sub.f value: 0.4 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0572] C.sub.26H.sub.25N.sub.3O.sub.4
[0573] ESI mass spectrum: m/z=442 [M-H.sup.-]
[0574] (23)
3-(Z)-{1-[4-(piperidin-1-yl-carbonyl)-anilino]-1-phenyl-methyl-
idene}-5,6-dimethoxy-2-indolinone
[0575] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-(piperidin-1-yl-carbonyl)-aniline
[0576] R.sub.f value: 0.4 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0577] C.sub.29H.sub.29N.sub.3O.sub.4
[0578] ESI mass spectrum: m/z=482 [M-H.sup.-]
[0579] (24)
3-(Z)-[1-(4-ethoxycarbonylmethyl-anilino)-1-phenyl-methylidene-
]-5,6-dimethoxy-2-indolinone
[0580] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and ethyl 4-aminophenylacetate
[0581] R.sub.f value: 0.5 (silica gel, petroleum ether/ethyl
acetate/ethanol=7:2:1)
[0582] C.sub.227H.sub.26N.sub.2O.sub.5
[0583] ESI mass spectrum: m/z=457 [M-H.sup.-]
[0584] (25)
3-(Z)-{1-[4-(tetrazol-5-yl)-anilino]-1-phenyl-methylidene}-5,6-
-dimethoxy-2-indolinone
[0585] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimeth-
oxy-2-indolinone and 4-tetrazol-5-yl-aniline
[0586] R.sub.f value: 0.4 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0587] C.sub.24H.sub.20N.sub.6O.sub.3
[0588] ESI mass spectrum: m/z=439 [M-H.sup.-]
[0589] (26)
3-(Z)-[1-anilino-1-(3-cyanophenyl)-methylidene]-5,6-di-methoxy-
-2-indolinone
[0590] Prepared from
1-acetyl-3-[1-chloro-1-(3-cyanophenyl)-methylidene]-5-
,6-dimethoxy-2-indolinone and aniline
[0591] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0592] C.sub.24H.sub.19N.sub.3O.sub.3
[0593] ESI mass spectrum: m/z=396 [M-H.sup.-]
[0594] (27)
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-ethyl-methylide-
ne}-5,6-dimethoxy-2-indolinone
[0595] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
[0596] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=5:1)
[0597] C.sub.25H.sub.31N.sub.3O.sub.3
[0598] Mass spectrum: m/z=421 [M.sup.+]
[0599] (28)
3-(Z)-{1-[4-(dimethylaminomethyl)-anilino]-1-ethyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[0600] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and 4-(dimethylaminomethyl)-aniline
[0601] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=5:1)
[0602] C.sub.22H.sub.27N.sub.3O.sub.3
[0603] Mass spectrum: m/z=381 [M.sup.+]
[0604] (29)
3-(Z)-(1-anilino-1-ethyl-methylidene)-5,6-dimethoxy-2-indolino-
ne
[0605] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and aniline
[0606] R.sub.f value: 0.3 (silica gel, methylene
chloride/methanol=20:1)
[0607] C.sub.19H.sub.20N.sub.2O.sub.3
[0608] Mass spectrum: m/z=324 [M.sup.+]
[0609] (30)
3-(Z)-(1-{4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino-
]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[0610] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and
N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylen-
ediamine
[0611] R.sub.f value: 0.4 (Alox, methylene
chloride/ethanol=20:1)
[0612] C.sub.24H.sub.32N.sub.4O.sub.5S
[0613] ESI mass spectrum: m/z=489 [M+H.sup.+]
[0614] (31)
3-(Z)-(1-{4-[N-(2-dimethylaminoethyl)-N-methyl-amino]-anilino}-
-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[0615] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and
N-(2-dimethylaminoethyl)-N-methyl-p-phenylenediamine
[0616] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=5:1)
[0617] C.sub.24H.sub.32N.sub.4O.sub.3
[0618] ESI mass spectrum: m/z=425 [M+H.sup.+]
[0619] (32)
3-(Z)-(1-{4-[N-(3-dimethylaminopropyl)-N-methyl-amino]-anilino-
}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[0620] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and
N-(3-dimethylaminopropyl)-N-methyl-p-phenylenediamine
[0621] R.sub.f value: 0.6 (silica gel, methylene
chloride/methanol/ammonia- =5:1:0.01)
[0622] C.sub.25H.sub.34N.sub.4O.sub.3
[0623] ESI mass spectrum: m/z=439 [M+H.sup.+]
[0624] (33)
3-(Z)-(1-{4-[N-acetyl-N-(3-dimethylaminopropyl)-amino]-anilino-
}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[0625] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and
N-acetyl-N-(3-dimethylamino-propyl)-p-phenylenediamine
[0626] R.sub.f value: 0.4 (Alox, methylene
chloride/ethanol=25:1)
[0627] C.sub.26H.sub.34N.sub.4O.sub.4
[0628] ESI mass spectrum: m/z=467 [M+H.sup.+]
[0629] (34)
3-(Z)-{1-[4-(N-methylsulphonylamino)-anilino]-1-ethyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[0630] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and N-methylsulphonyl-p-phenylenediamine
[0631] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0632] C.sub.21H.sub.25N.sub.3O.sub.5S
[0633] ESI mass spectrum: m/z=430 [M-H.sup.-]
[0634] (35)
3-(Z)-{1-[4-(N-acetylamino)-anilino]-1-ethyl-methylidene}-5,6--
dimethoxy-2-indolinone
[0635] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and N-acetyl-p-phenylenediamine
[0636] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=9:1)
[0637] C.sub.22H.sub.25N.sub.3O.sub.4
[0638] ESI mass spectrum: m/z=394 [M-H.sup.-]
[0639] (36)
3-(Z)-(1-{4-[N-(dimethylaminocarbonylmethyl)-N-methyl-sulphony-
l-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[0640] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and
N-(dimethylaminocarbonylmethyl)-N-methylsulphonyl-p-ph-
enylenediamine
[0641] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0642] C.sub.24H.sub.30N.sub.4O.sub.6S
[0643] Mass spectrum: m/z=502 [M.sup.+]
[0644] (37)
3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-ethyl-methylidene]-5,6-d-
imethoxy-2-indolinone
[0645] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and ethyl 4-aminobenzoate
[0646] R.sub.f value: 0.6 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0647] C.sub.22H.sub.24N.sub.2O.sub.5
[0648] ESI mass spectrum: m/z=395 [M-H.sup.-]
[0649] (38)
3-(Z)-[1-(4-aminocarbonyl-anilino)-1-ethyl-methylidene]-5,6-di-
methoxy-2-indolinone
[0650] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and 4-aminobenzamide
[0651] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=9:1)
[0652] C.sub.20H.sub.21N.sub.3O.sub.4
[0653] Mass spectrum: m/z=367 [M.sup.+]
[0654] (39)
3-(Z)-[1-(4-dimethylaminocarbonyl-anilino)-1-ethyl-methylidene-
]-5,6-dimethoxy-2-indolinone
[0655] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and 4-amino-dimethylbenzamide
[0656] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0657] C.sub.22H.sub.25N.sub.3O.sub.4
[0658] ESI mass spectrum: m/z=394 [M-H.sup.-]
[0659] (40)
3-(Z)-{1-[4-(ethoxycarbonylmethyl)-anilino]-1-ethyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[0660] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and ethyl 4-aminophenylacetate
[0661] R.sub.f value: 0.4 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0662] C.sub.23H.sub.26N.sub.2O.sub.5
[0663] Mass spectrum: m/z=410 [M.sup.+]
[0664] (41)
3-(Z)-{1-[4-(tetrazol-5-yl)-anilino]-1-ethyl-methylidene}-5,6--
dimethoxy-2-indolinone
[0665] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and 4-tetrazol-5-yl-aniline
[0666] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=9:1)
[0667] C.sub.20H.sub.20N.sub.6O.sub.3
[0668] ESI mass spectrum: m/z=391 [M-H.sup.-]
[0669] (42)
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylid-
ene}-5,6-methylenedioxy-2-indolinone
[0670] Prepared from
3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-
-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
[0671] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=5:1)
[0672] C.sub.28H.sub.27N.sub.3O.sub.3
[0673] Mass spectrum: m/z=453 [M.sup.+]
[0674] (43)
3-(Z)-{1-[4-(dimethylaminomethyl)-anilino]-1-phenyl-methyliden-
e}-5,6-methylenedioxy-2-indolinone
[0675] Prepared from
3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-
-2-indolinone and 4-(dimethylaminomethyl)-aniline
[0676] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=5:1)
[0677] C.sub.25H.sub.23N.sub.3O.sub.3
[0678] Mass spectrum: m/z=413 [M.sup.+]
[0679] (44)
3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phen-
yl-methylidene}-5,6-methylenedioxy-2-indolinone
[0680] Prepared from
3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-
-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
[0681] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=5:1)
[0682] C.sub.31H.sub.27N.sub.3O.sub.3
[0683] Mass spectrum: m/z=489 [M.sup.+]
[0684] (45)
3-(Z)-(1-{4-[N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone
[0685] Prepared from
3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-
-2-indolinone and
N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylened-
iamine
[0686] R.sub.f value: 0.6 (silica gel, methylene
chloride/methanol=5:1)
[0687] C.sub.27H.sub.28N.sub.4O.sub.5S
[0688] Mass spectrum: m/z=520 [M.sup.+]
[0689] (46)
3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-ani-
lino]-1-phenyl-methylidene}-5,6-methylenedioxy-2-indolinone
[0690] Prepared from
3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-
-2-indolinone and
N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediam- ine
[0691] R.sub.f value: 0.3 (silica gel, methylene
chloride/methanol=5:1)
[0692] C.sub.27H.sub.26N.sub.4O.sub.4
[0693] Mass spectrum: m/z=470 [M.sup.+]
[0694] (47)
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylid-
ene}-6-methoxy-2-indolinone
[0695] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-- 2-indolinone
and 4-(piperidin-1-yl-methyl)-aniline
[0696] R.sub.f value: 0.4 (aluminium oxide, toluene/ethyl
acetate/methanol=4:2:0.25)
[0697] C.sub.28H.sub.29N.sub.3O.sub.2
[0698] Mass spectrum: m/z=439 [M.sup.+]
[0699] (48)
3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phen-
yl-methylidene)-6-methoxy-2-indolinone
[0700] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-- 2-indolinone
and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
[0701] R.sub.f value: 0.5 (aluminium oxide, toluene/ethyl
acetate/ethanol=4:2:0.25)
[0702] C.sub.31H.sub.29N.sub.3O.sub.2
[0703] Mass spectrum: m/z=475 [M.sup.+]
[0704] (49)
3-(Z)-{1-[3-(dimethylaminomethyl)-anilino]-1-phenyl-methyliden-
e}-6-methoxy-2-indolinone
[0705] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-- 2-indolinone
and 3-(dimethylaminomethyl)-aniline
[0706] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=5:1)
[0707] C.sub.25H.sub.25N.sub.3O.sub.2
[0708] Mass spectrum: m/z=399 [M.sup.+]
[0709] (50)
3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-ani-
lino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone
[0710] Prepared from
1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimetho-
xy-2-indolinone and
N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenedi- amine
[0711] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=5:1)
[0712] C.sub.24H.sub.30N.sub.4O.sub.4
[0713] Mass spectrum: m/z=438 [M.sup.+]
[0714] (51)
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylid-
ene}-5,6-diethoxy-2-indolinone
[0715] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dietho-
xy-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
[0716] R.sub.f value: 0.4 (aluminium oxide, toluene/ethyl
acetate=2:1)
[0717] C.sub.31H.sub.35N.sub.3O.sub.3
[0718] ESI mass spectrum: m/z=498 [M+H.sup.+]
[0719] (52)
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylid-
ene}-6-trifluoromethyl-2-indolinone
[0720] Prepared from
1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluor-
omethyl-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
[0721] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0722] C.sub.28H.sub.26F.sub.3N.sub.3O
[0723] ESI mass spectrum: m/z=476 [M-H.sup.-]
[0724] (53)
3-(Z)-(1-{4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino-
]-anilino}-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone
[0725] Prepared from
1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluor-
omethyl-2-indolinone and
N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phe-
nylenediamine
[0726] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0727] C.sub.27H.sub.27F.sub.3N.sub.4O.sub.3S
[0728] ESI mass spectrum: m/z=543 [M-H.sup.-]
[0729] (54)
3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-ani-
lino]-1-phenyl-methylidene}-6-trifluoromethyl-2-indolinone
[0730] Prepared from
1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluor-
omethyl-2-indolinone and
N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenyl- enediamine
[0731] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=10:1)
[0732] C.sub.27H.sub.25F.sub.3N.sub.4O.sub.2
[0733] ESI mass spectrum: m/z=493 [M-H.sup.-]
[0734] (55)
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylid-
ene}-6-phenyl-2-indolinone
[0735] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2- -indolinone
and 4-(piperidin-1-yl-methyl)-aniline
[0736] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=9:1)
[0737] C.sub.33H.sub.31N.sub.3O
[0738] ESI mass spectrum: m/z=486 [M+H.sup.+]
[0739] (56)
3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phen-
yl-methylidene)-6-phenyl-2-indolinone
[0740] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2- -indolinone
and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
[0741] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=9:1)
[0742] C.sub.33H.sub.31N.sub.3O
[0743] ESI mass spectrum: m/z=486 [M+H.sup.+]
[0744] (57)
3-(Z)-(1-{4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino-
]-anilino}-1-phenyl-methylidene)-6-phenyl-2-indolinone
[0745] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2- -indolinone
and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenedia-
mine
[0746] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=9:1)
[0747] C.sub.32H.sub.32N.sub.4O.sub.3S
[0748] ESI mass spectrum: m/z=553 [M+H.sup.+]
[0749] (58)
3-(Z)-{1-[3-(dimethylaminomethyl)-anilino]-1-phenyl-methyliden-
e}-6-phenyl-2-indolinone
[0750] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2- -indolinone
and 3-(dimethylaminomethyl)-aniline
[0751] R.sub.f value: 0.55 (silica gel, methylene
chloride/methanol=10:1)
[0752] C.sub.30H.sub.27N.sub.3O
[0753] ESI mass spectrum: m/z=446 [M+H.sup.+]
[0754] (59)
3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-ani-
lino]-1-phenyl-methylidene}-6-phenyl-2-indolinone
[0755] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2- -indolinone
and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamin-
e
[0756] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=9:1)
[0757] C.sub.32H.sub.30N.sub.4O.sub.2
[0758] Mass spectrum: m/z=502 [M.sup.+]
[0759] (60)
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylid-
ene}-6-(2-tolyl)-2-indolinone
[0760] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl-
)-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
[0761] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=9:1)
[0762] C.sub.34H.sub.33N.sub.3O
[0763] ESI mass spectrum: m/z=500 [M+H.sup.+]
[0764] (61)
3-(Z)-{1-[4-(dimethylaminomethyl)-anilino]-1-phenyl-methyliden-
e}-6-(2-tolyl)-2-indolinone
[0765] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl-
)-2-indolinone and 4-(dimethylaminomethyl)-aniline
[0766] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=9:1)
[0767] C.sub.31H.sub.29N.sub.3O
[0768] Mass spectrum: m/z=459 [M.sup.+]
[0769] (62)
3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylidene]-6-(2-
-tolyl)-2-indolinone
[0770] Prepared from
1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl-
)-2-indolinone and ethyl 4-aminobenzoate
[0771] R.sub.f value: 0.5 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0772] C.sub.31H.sub.26N.sub.2O.sub.3
[0773] Mass spectrum: m/z=474 [M.sup.+]
EXAMPLE 2
[0774]
3-(Z)-(1-{4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}-1-phenyl--
methylidene)-5,6-dimethoxy-2-indolinone
[0775] 0.4 g of
3-(Z)-(1-{4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-an-
ilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone are
dissolved in 8.0 ml of ethanol and 2.0 ml of 1N sodium hydroxide
solution are added. The mixture is stirred for 1 hour at 50.degree.
C. 2.0 ml of 1N HCl are added to the clear solution and the
precipitate formed is suction filtered. The precipitate is washed
with water and ethanol and dried in vacuo at 100.degree. C.
[0776] Yield: 0.2 g (64% of theory),
[0777] R.sub.f value: 0.2 (silica gel, methylene
chloride/methanol=2:1)
[0778] C.sub.31H.sub.33N.sub.3O.sub.5
[0779] ESI mass spectrum: m/z=526 [M-H.sup.-]
[0780] The following compounds are prepared analogously to Example
2:
[0781] (1)
3-(Z)-[1-(4-carboxy-anilino)-1-phenyl-methylidene]-5,6-di-metho-
xy-2-indolinone
[0782] Prepared from
3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylid-
ene]-5,6-dimethoxy-2-indolinone
[0783] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=10:1)
[0784] C.sub.24H.sub.20N.sub.2O.sub.5
[0785] ESI mass spectrum: m/z=415 [M-H--W
[0786] (2)
3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-phenyl-methylidene}-5,6--
dimethoxy-2-indolinone
[0787] Prepared from
3-(Z)-{1-[4-(ethoxycarbonylmethyl)-anilino]-1-phenyl--
methylidene}-5,6-dimethoxy-2-indolinone
[0788] R.sub.f value: 0.1 (silica gel, petroleum ether/ethyl
acetate/ethanol=7:2:1)
[0789] C.sub.25H.sub.22N.sub.2O.sub.5
[0790] ESI mass spectrum: m/z=429 [M-H.sup.-]
[0791] (3)
3-(Z)-[1-(4-carboxy-anilino)-1-ethyl-methylidene]-5,6-di-methox-
y-2-indolinone
[0792] Prepared from
3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-ethyl-methylide-
ne]-5,6-dimethoxy-2-indolinone
[0793] R.sub.f value: 0.4 (silica gel, methylene
chloride/methanol=9:1)
[0794] C.sub.20H.sub.20N.sub.2O.sub.5
[0795] ESI mass spectrum: m/z=367 [M-H.sup.-]
[0796] (4)
3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylidene}-5,6-d-
imethoxy-2-indolinone
[0797] Prepared from
3-(Z)-{1-[4-(ethoxycarbonylmethyl)-anilino]-1-ethyl-m-
ethylidene}-5,6-dimethoxy-2-indolinone
[0798] R.sub.f value: 0.4 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0799] C.sub.21H.sub.22N.sub.2O.sub.5
[0800] ESI mass spectrum: m/z=381 [M-H.sup.-]
[0801] (5)
3-(Z)-[1-(4-carboxy-anilino)-1-phenyl-methylidene]-6-ureido-2-i-
ndolinone
[0802] Prepared from
3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methyli-
dene]-6-ureido-2-indolinone
[0803] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=4:1)
[0804] C.sub.23H.sub.18N.sub.4O.sub.4
[0805] ESI mass spectrum: m/z=413 [M-H.sup.-]
EXAMPLE 3
[0806]
3-(Z)-(1-{4-(2-{4-dimethylcarbamoyl-piperidin-1-yl)-ethyl]-anilino}-
-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0807] 0.2 g of
3-(Z)-(1-(4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}--
1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone are dissolved in
5.0 ml of dimethylformamide and 0.2 g of TBTU, 0.1 g of HOBT and
0.5 ml of triethylamine are added. Finally 0.2 g of dimethylamine
hydrochloride are added and the mixture is stirred for 2 hours at
ambient temperature. The solvent is eliminated and the residue is
stirred with water, suction filtered and washed with isopropanol
and ether. The residue is dried in vacuo at 100.degree. C.
[0808] Yield: 0.2 g (95% of theory),
[0809] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0810] C.sub.33H.sub.38N.sub.4O.sub.4
[0811] Mass spectrum: m/z=554 [M.sup.+]
[0812] The following compounds are prepared analogously to Example
3:
[0813] (1)
3-(Z)-{1-[4-(aminocarbonylmethyl)-anilino]-1-phenyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[0814] Prepared from
3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-phenyl-methyli-
dene}-5,6-dimethoxy-2-indolinone and N-hydroxy-succinimide-ammonium
salt
[0815] R.sub.f value: 0.4 (silica gel, petroleum ether/ethyl
acetate/ethanol=4:2:1)
[0816] C.sub.25H.sub.23N.sub.3O.sub.4
[0817] ESI mass spectrum: m/z=428 [M-H.sup.-]
[0818] (2)
3-(Z)-{1-[4-(dimethylaminocarbonylmethyl)-anilino]-1-phenyl-met-
hylidene}-5,6-dimethoxy-2-indolinone
[0819] Prepared from
3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-phenyl-methyli-
dene}-5,6-dimethoxy-2-indolinone and
dimethylamine-hydrochloride
[0820] R.sub.f value: 0.45 (silica gel, petroleum ether/ethyl
acetate/ethanol=4:2:1)
[0821] C.sub.27H.sub.27N.sub.3O.sub.4
[0822] ESI mass spectrum: m/z=456 [M-H.sup.-]
[0823] (3)
3-(Z)-{1-[4-(aminocarbonylmethyl)-anilino]-1-ethyl-methylidene}-
-5,6-dimethoxy-2-indolinone
[0824] Prepared from
3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylid-
ene}-5,6-dimethoxy-2-indolinone and N-hydroxy-succinimide-ammonium
salt
[0825] R.sub.f value: 0.45 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0826] C.sub.21H.sub.23N.sub.3O.sub.4
[0827] ESI mass spectrum: m/z=380 [M-H.sup.-]
[0828] (4)
3-(Z)-{1-[4-(dimethylaminocarbonylmethyl)-anilino]-1-ethyl-meth-
ylidene}-5,6-dimethoxy-2-indolinone
[0829] Prepared from
3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylid-
ene}-5,6-dimethoxy-2-indolinone and dimethylamine-hydrochloride
[0830] R.sub.f value: 0.7 (silica gel, toluene/ethyl
acetate/ethanol=4:2:1)
[0831] C.sub.23H.sub.27N.sub.3O.sub.4
[0832] ESI mass spectrum: m/z=408 [M-H.sup.-]
EXAMPLE 4
[0833]
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methy-
lidene}-2-indolinone
[0834] 11.2 g of
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-met-
hylidene}-6-nitro-2-indolinone are dissolved in 120 ml of methanol
and 60 ml of methylene chloride, 1.1 g of palladium on carbon (10%)
are added and the mixture is hydrogenated for 2 hours 45 minutes at
ambient temperature with 3 bar hydrogen. The catalyst is filtered
off, the filtrate is concentrated by evaporation and the residue is
purified through a silica gel column with methylene
chloride/methanol (4:1).
[0835] Yield: 5.2 g (52% of theory),
[0836] R.sub.f value: 0.25 (silica gel, methylene
chloride/methanol=4:1)
[0837] C.sub.27H.sub.28N.sub.4O
[0838] ESI mass spectrum: m/z=425 [M+H.sup.+]
[0839] The following compound is prepared analogously to Example
4:
[0840] (1)
6-amino-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylide-
ne]-2-indolinone
[0841] Prepared from
1-acetoxy-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phen-
yl-methylidene]-6-nitro-2-indolinone
[0842] R.sub.f value: 0.74 (silica gel, methylene
chloride/methanol=4:1)
[0843] C.sub.23H.sub.19N.sub.3O.sub.3
[0844] ESI mass spectrum: m/z=384 [M-H.sup.-]
EXAMPLE 5
[0845]
3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-6-ureido-
-2-indolinone
[0846] 560 mg of
6-amino-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-met-
hylidene]-2-indolinone, 236 mg of potassium cyanate and 3.8 ml of
glacial acetic acid are dissolved in 20 ml of ethanol and refluxed
for 1 hour. After this time the solvent is evaporated, the residue
is taken up in methylene chloride, washed with water and dried over
sodium sulphate. After evaporation, the product is dried in the
desiccator.
[0847] Yield: 280 mg of (45% of theory),
[0848] R.sub.f value: 0.25 (silica gel, ethyl
acetate/cyclohexane/methanol- =4.5:4.5:1)
[0849] C.sub.24H.sub.20N.sub.4O.sub.4
[0850] ESI mass spectrum: m/z=427 [M-H.sup.-]
EXAMPLE 6
[0851]
3-(Z)-[1-anilino-1-(3-aminomethyl-phenyl)-methylidene]-5,6-di-metho-
xy-2-indolinone
[0852] 0.8 g of
3-(Z)-[1-anilino-1-(3-cyanophenyl)-methylidene]-5,6-dimeth-
oxy-2-indolinone are dissolved in 50 ml of methanolic ammonia and
30 ml of methylene chloride are added. After the addition of 500 mg
of Raney nickel the mixture is hydrogenated for 2 hours at ambient
temperature at a pressure of 50 psi. After the end of the reaction
the catalyst is filtered off and the filtrate is concentrated by
evaporation. The residue is separated over a silica gel column with
methylene chloride/methanol (5:1) as eluant. The product is
suspended in 3 ml of dioxane, 0.4 ml of 1N hydrochloric acid are
added and the solution formed is concentrated by evaporation after
10 minutes' stirring at ambient temperature. The residue thus
obtained is triturated with ether, suction filtered and dried in
vacuo at 80.degree. C.
[0853] Yield: 0.1 g (14% of theory),
[0854] R.sub.f value: 0.7 (silica gel, methylene
chloride/methanol/ammonia- =5:1:0.01)
[0855] C.sub.24H.sub.23N.sub.3O.sub.3
[0856] ESI mass spectrum: m/z=402 [M+H.sup.+]
EXAMPLE 7
[0857]
6-benzoylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-pheny-
l-methylidene}-2-indolinone
[0858] 0.4 g of
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phe-
nyl-methylidene}-2-indolinone are dissolved in 25 ml of methylene
chloride, 12.5 ml of pyridine are added and at ambient temperature
0.1 ml of benzoylchloride are added dropwise. The reaction mixture
is stirred for 12 hours at ambient temperature, concentrated by
evaporation and purified through a silica gel column with methylene
chloride/methanol=4:1 as eluant.
[0859] Yield: 160 mg of (32% of theory),
[0860] R.sub.f value: 0.3 (silica gel, methylene
chloride/methanol=9:1)
[0861] C.sub.34H.sub.32N.sub.4O.sub.2
[0862] ESI mass spectrum: m/z=529 [M+H.sup.+]
[0863] The following compounds are prepared analogously to Example
7:
[0864] (1)
6-acetylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-ph-
enyl-methylidene}-2-indolinone
[0865] Prepared from
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]--
1-phenyl-methylidene}-2-indolinone and acetylchloride
[0866] R.sub.f value: 0.48 (silica gel, methylene
chloride/methanol=4:1)
[0867] C.sub.29H.sub.30N.sub.4O.sub.2
[0868] ESI mass spectrum: m/z=467 [M+H.sup.+]
[0869] (2)
6-(2-phenylacetylamino)-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-ani-
lino]-1-phenyl-methylidene}-2-indolinone
[0870] Prepared from
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]--
1-phenyl-methylidene}-2-indolinone and phenylacetic acid
chloride
[0871] R.sub.f value: 0.67 (silica gel, methylene
chloride/methanol=4:1)
[0872] C.sub.35H.sub.34N.sub.4O.sub.2
[0873] ESI mass spectrum: m/z=543 [M+H.sup.+]
[0874] (3)
6-methanesulphonylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-ani-
lino]-1-phenyl-methylidene}-2-indolinone
[0875] Prepared from
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]--
1-phenyl-methylidene}-2-indolinone and methanesulphonylchloride
[0876] R.sub.f value: 0.56 (silica gel, methylene
chloride/methanol=4:1)
[0877] C.sub.28H.sub.30N.sub.4O.sub.3S
[0878] ESI mass spectrum: m/z=503 [M+H.sup.+]
[0879] (4)
6-benzenesulphonylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-ani-
lino]-1-phenyl-methylidene}-2-indolinone
[0880] Prepared from
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]--
1-phenyl-methylidene}-2-indolinone and benzenesulphonyl
chloride
[0881] R.sub.f value: 0.53 (silica gel, methylene
chloride/methanol=4:1)
[0882] C.sub.33H.sub.32N.sub.4O.sub.3S
[0883] ESI mass spectrum: m/z=565 [M+H.sup.+]
[0884] (5)
3-(Z)-{1-anilino-1-[3-(acetylaminomethyl)-phenyl]-methylidene}--
5,6-dimethoxy-2-indolinone
[0885] Prepared from
3-(Z)-[1-anilino-1-(3-aminomethyl-phenyl)-methylidene-
]-5,6-dimethoxy-2-indolinone and acetic anhydride
[0886] R.sub.f value: 0.5 (silica gel, methylene
chloride/methanol=10:1)
[0887] C.sub.26H.sub.25N.sub.3O.sub.4
[0888] ESI mass spectrum: m/z=442 [M-H.sup.-]
EXAMPLE 8
[0889]
6-methylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-
-methylidene}-2-indolinone and
[0890]
6-dimethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phen-
yl-methylidene}-2-indolinone
[0891] 0.1 ml of formaldehyde solution (37%) are dissolved in 20 ml
of methanol, 0.5 g of
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-
-phenyl-methylidene}-2-indolinone are added and the mixture is
stirred for 1 hour at ambient temperature. A precipitate is formed
which is brought into solution by the addition of 5 ml of methylene
chloride. To this mixture are added 75 mg of sodium
cyanoborohydride and the mixture is stirred for 12 hours at ambient
temperature. After this time 5 ml of conc. HCl are added, the
solvent is substantially eliminated, the residue taken up in water
and made basic with sodium hydroxide solution. The aqueous phase is
extracted with methylene chloride, dried over sodium sulphate,
concentrated by evaporation and purified through a silica gel
column with methylene chloride/methanol (4:1).
[0892] Yield: 70 mg of (13% of theory)
6-methylamino-3-(Z)-{1-[4-(piperidi-
n-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone,
[0893] R.sub.f value: 0.64 (silica gel, methylene
chloride/methanol=4:1)
[0894] C.sub.28H.sub.30N.sub.4O
[0895] Mass spectrum: m/z=438 [M.sup.+]
[0896] 35 mg of (6% of theory)
6-dimethylamino-3-(Z)-{1-[4-(piperidin-1-yl-
-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone,
[0897] R.sub.f value: 0.58 (silica gel, methylene
chloride/methanol=4:1)
[0898] C.sub.29H.sub.34N.sub.4O
[0899] ESI mass spectrum: m/z=453 [M+H.sup.+]
EXAMPLE 9
[0900]
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}--
6-(pyrrol-1-yl)-2-indolinone
[0901] 0.5 g of
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phe-
nyl-methylidene}-2-indolinone are dissolved in 20 ml of glacial
acetic acid and 0.2 ml of 2,5-dimethoxytetrahydrofuran are added.
The mixture is refluxed for 1 hour, concentrated by evaporation and
the residue is taken up in 20 ml of water. After another 2 hours'
stirring the mixture is made basic with 1N sodium hydroxide
solution, the aqueous phase is extracted with methylene chloride
and the organic phase is dried over sodium sulphate. After
elimination of the solvent the residue is purified through a silica
gel column with methylene chloride/methanol (4:1) as eluant.
[0902] Yield: 200 mg of (36% of theory),
[0903] R.sub.f value: 0.73 (silica gel, methylene
chloride/methanol=4:1)
[0904] C.sub.31H.sub.30N.sub.4O
[0905] ESI mass spectrum: m/z=475 [M+H.sup.+]
EXAMPLE 10
[0906]
3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}--
6-(pyrrolidin-1-yl)-2-indolinone
[0907] 0.3 g of
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phe-
nyl-methylidene}-2-indolinone are dissolved in 10 ml of
dimethylformamide and 180 mg of potassium carbonate are added. 0.1
ml of 1,4-dibromobutane (dissolved in 1.0 ml of dimethylformamide)
is added dropwise at ambient temperature and the reaction mixture
is stirred for 12 hours at 80.degree. C. After cooling the mixture
is poured onto water and the precipitate formed is filtered
off.
[0908] Yield: 110 mg of (33.% of theory),
[0909] R.sub.f value: 0.41 (silica gel, methylene
chloride/methanol=9:1)
[0910] C.sub.31H.sub.34N.sub.4O
[0911] ESI mass spectrum: m/z=479 [M+H.sup.+]
[0912] The following compound is prepared analogously to Example
10:
[0913] (1)
6-methoxycarbonylmethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl-
)-anilino]-1-phenyl-methylidene}-2-indolinone
[0914] Prepared from
6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]--
1-phenyl-methylidene}-2-indolinone and methyl bromoacetate
[0915] Yield: 230 mg of (28% of theory),
[0916] R.sub.f value: 0.36 (silica gel, methylene
chloride/methanol=9:1)
[0917] C.sub.30H.sub.32N.sub.4O.sub.3
[0918] ESI mass spectrum: m/z=497 [M+H.sup.+]
EXAMPLE 11
[0919]
6-carboxymethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-
-phenyl-methylidene}-2-indolinone
[0920] 180 mg of
6-methoxycarbonylmethylamino-3-(Z)-{1-[4-(piperidin-1-yl--
methyl)-anilino]-1-phenyl-methylidene}-2-indolinone are placed in
10 ml of methanol, 1.0 ml of 1N sodium hydroxide solution are added
and the mixture is stirred for 1 hour at 40.degree. C. After
cooling it is neutralised with 1.0 ml of 1N hydrochloric acid and
the solvent is eliminated. The residue is dissolved in methylene
chloride and a little methanol and dried over sodium sulphate.
[0921] Yield: 76 mg of (44% of theory),
[0922] R.sub.f value: 0.05 (silica gel, methylene
chloride/methanol=9:1)
[0923] C.sub.29H.sub.30N.sub.4O.sub.3
[0924] ESI mass spectrum: m/z=483 [M+H.sup.+]
[0925] The following compounds may be prepared analogously to the
preceding Examples:
[0926] (1)
3-(Z)-(1-anilino-1-phenyl-methylidene)-5,6-dimethoxy-2-indolino-
ne
[0927] (2)
3-(Z)-[1-(4-nitro-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-
-2-indolinone
[0928] (3)
3-(Z)-1-[(4-fluoro-anilino)-1-phenyl-methylidene]-5,6-di-methox-
y-2-indolinone
[0929] (4)
3-(Z)-[1-(4-bromo-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-
-2-indolinone
[0930] (5)
3-(Z)-[1-(4-iodo-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-
-indolinone
[0931] (6)
3-(Z)-[1-(4-cyano-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-
-2-indolinone
[0932] (7)
3-(Z)-[1-(4-ethoxy-anilino)-1-phenyl-methylidene]-5,6-di-methox-
y-2-indolinone
[0933] (8)
3-(Z)-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylidene]-5,6--
dimethoxy-2-indolinone
[0934] (9)
3-(Z)-[1-(4-methyl-anilino)-1-phenyl-methylidene]-5,6-di-methox-
y-2-indolinone
[0935] (10)
3-(Z)-[1-(4-methylmercapto-anilino)-1-phenyl-methylidene]-5,6--
dimethoxy-2-indolinone
[0936] (11)
3-(Z)-[1-(4-aminomethyl-anilino)-1-phenyl-methylidene]-5,6-dim-
ethoxy-2-indolinone
[0937] (12)
3-(Z)-{1-[4-(methylaminomethyl)-anilino]-1-phenyl-methylidene}-
-5,6-dimethoxy-2-indolinone
[0938] (13)
3-(Z)-{1-[4-(isopropylaminomethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-dimethoxy-2-indolinone
[0939] (14)
3-(Z)-{1-[4-(phenylaminomethyl)-anilino]-1-phenyl-methylidene}-
-5,6-dimethoxy-2-indolinone
[0940] (15)
3-(Z)-{1-[4-(ethylaminomethyl)-anilino]-1-phenyl-methylidene}--
5,6-dimethoxy-2-indolinone
[0941] (16)
3-(Z)-{1-[4-(propylaminomethyl)-anilino]-1-phenyl-methylidene}-
-5,6-dimethoxy-2-indolinone
[0942] (17)
3-(Z)-{1-[4-(butylaminomethyl)-anilino]-1-phenyl-methylidene}--
5,6-dimethoxy-2-indolinone
[0943] (18)
3-(Z)-{1-[4-(isobutylaminomethyl)-anilino]-1-phenyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[0944] (19)
3-(Z)-{1-[4-(cyclohexylaminomethyl)-anilino]-1-phenyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[0945] (20)
3-(Z)-{1-[4-(benzylaminomethyl)-anilino]-1-phenyl-methylidene}-
-5,6-dimethoxy-2-indolinone
[0946] (21)
3-(Z)-(1-{4-[(N-ethyl-N-methyl-amino)-methyl]-anilino}-1-pheny-
l-methylidene)-5,6-dimethoxy-2-indolinone
[0947] (22)
3-(Z)-{1-[4-(diethylaminomethyl)-anilino]-1-phenyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[0948] (23)
3-(Z)-(1-{4-[(N-methyl-N-propyl-amino)-methyl]-anilino}-1-phen-
yl-methylidene)-5,6-dimethoxy-2-indolinone
[0949] (24)
3-(Z)-(1-{4-[(N-isopropyl-N-methyl-amino)-methyl]-anilino}-1-p-
henyl-methylidene)-5,6-dimethoxy-2-indolinone
[0950] (25)
3-(Z)-(1-{4-[(N-ethyl-N-propyl-amino)-methyl]-anilino}-1-pheny-
l-methylidene)-5,6-dimethoxy-2-indolinone
[0951] (26)
3-(Z)-(1-{4-[(N-ethyl-N-isopropyl-amino)-methyl]-anilino}-1-ph-
enyl-methylidene)-5,6-dimethoxy-2-indolinone
[0952] (27)
3-(Z)-{1-[4-(dipropylaminomethyl)-anilino]-1-phenyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[0953] (28)
3-(Z)-{1-[4-(diisopropylaminomethyl)-anilino]-1-phenyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[0954] (29)
3-(Z)-(1-{4-[(N-benzyl-N-ethyl-amino)-methyl]-anilino}-1-pheny-
l-methylidene)-5,6-dimethoxy-2-indolinone
[0955] (30)
3-(Z)-{1-[4-(dibenzylaminomethyl)-anilino]-1-phenyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[0956] (31)
3-(Z)-{1-[4-(3,6-dihydro-2H-pyridine-1-yl-methyl)-anilino]-1-p-
henyl-methylidene}-5,6-dimethoxy-2-indolinone
[0957] (32)
3-(Z)-{1-[4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino]-1-ph-
enyl-methylidene}-5,6-dimethoxy-2-indolinone
[0958] (33)
3-(Z)-{1-[4-(azepan-1-yl-methyl)-anilino]-1-phenyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[0959] (34)
3-(Z)-{1-[4-(piperazin-1-yl-methyl)-anilino]-1-phenyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[0960] (35)
3-(Z)-{1-[4-(morpholin-4-yl-methyl)-anilino]-1-phenyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[0961] (36)
3-(Z)-{1-[4-(thiomorpholin-4-yl-methyl)-anilino]-1-phenyl-meth-
ylidene}-5,6-dimethoxy-2-indolinone
[0962] (37)
3-(Z)-{1-[4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino]-1-pheny-
l-methylidene}-5,6-dimethoxy-2-indolinone
[0963] (38)
3-(Z)-{1-[4-(acetylamino-methyl)-anilino]-1-phenyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[0964] (39)
3-(Z)-{1-[4-(2-amino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-
-dimethoxy-2-indolinone
[0965] (40)
3-(Z)-{1-[4-(2-methylamino-ethyl)-anilino]-1-phenyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[0966] (41)
3-(Z)-{1-[4-(2-ethylamino-ethyl)-anilino]-1-phenyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[0967] (42)
3-(Z)-{1-[4-(2-diethylamino-ethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-dimethoxy-2-indolinone
[0968] (43)
3-(Z)-{1-[4-(2-piperidin-1-yl-ethyl)-anilino]-1-phenyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[0969] (44)
3-(Z)-{1-[4-(2-acetylamino-ethyl)-anilino]-1-phenyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[0970] (45)
3-(Z)-{1-[4-(3-amino-propyl)-anilino]-1-phenyl-methylidene}-5,-
6-dimethoxy-2-indolinone
[0971] (46)
3-(Z)-{1-[4-(3-dimethylamino-propyl)-anilino]-1-phenyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[0972] (47)
3-(Z)-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino]-1--
phenyl-methylidene}-5,6-dimethoxy-2-indolinone
[0973] (48)
3-(Z)-{1-[4-(N-methylaminomethylcarbonyl-N-methyl-amino)-anili-
no]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone
[0974] (49)
3-(Z)-{1-[4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anilin-
o]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone
[0975] (50)
3-(Z)-{1-[4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anil-
ino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone
[0976] (51)
3-(Z)-(1-{4-[N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0977] (52)
3-(Z)-(1-{4-[N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0978] (53)
3-(Z)-(1-{4-[N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0979] (54)
3-(Z)-(1-{4-[N-(2-amino-ethyl-carbonyl)-N-methyl-amino]-anilin-
o}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0980] (55)
3-(Z)-{1-(4-[N-(2-methylamino-ethyl-carbonyl)-N-methyl-amino]--
anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0981] (56)
3-(Z)-(1-{4-[N-(2-diethylamino-ethyl-carbonyl)-N-methyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0982] (57)
3-(Z)-(1-{4-[N-acetyl-N-(2-aminoethyl)-amino]-anilino}-1-pheny-
l-methylidene)-5,6-dimethoxy-2-indolinone
[0983] (58)
3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-ethyl)-amino]-anilino}--
1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0984] (59)
3-(Z)-(1-{4-[N-acetyl-N-(3-amino-propyl)-amino]-anilino}-1-phe-
nyl-methylidene)-5,6-dimethoxy-2-indolinone
[0985] (60)
3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-propyl)-amino]-anilino}-
-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0986] (61)
3-(Z)-(1-{4-[N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino]-anilin-
o}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0987] (62)
3-(Z)-(1-{4-[N-acetyl-N-(aminocarbonylmethyl)-amino]-anilino}--
1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0988] (63)
3-(Z)-(1-{4-[N-acetyl-N-(dimethylaminocarbonylmethyl)-amino]-a-
nilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0989] (64)
3-(Z)-(1-{4-[N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino]-
-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0990] (65)
3-(Z)-(1-{4-[N-methyl-N-(aminocarbonyl)-amino]-anilino}-1-phen-
yl-methylidene)-5,6-dimethoxy-2-indolinone
[0991] (66)
3-(Z)-(1-{4-[N-methyl-N-(methylaminocarbonyl)-amino]-anilino}--
1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0992] (67)
3-(Z)-(1-{4-[N-methyl-N-(dimethylaminocarbonyl)-amino]-anilino-
}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0993] (68)
3-(Z)-(1-{4-[N-methyl-N-(piperidin-1-yl-carbonyl)-amino]-anili-
no}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0994] (69)
3-(Z)-(1-{4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-anilino-
}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0995] (70)
3-(Z)-(1-{4-[N-(2-methylamino-ethyl)-N-methylsulphonyl-amino]--
anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0996] (71)
3-(Z)-(1-{4-[N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino]-a-
nilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0997] (72)
3-(Z)-(1-{4-[N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0998] (73)
3-(Z)-(1-{4-[N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-ami-
no]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[0999] (74)
3-(Z)-(1-{4-[N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-amin-
o]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1000] (75)
3-(Z)-(1-{4-[N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amin-
o]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1001] (76)
3-(Z)-[1-(4-{N-[2-(morpholin-4-yl)-ethyl]-N-methylsulphonyl-am-
ino}-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone
[1002] (77)
3-(Z)-(1-{4-[N-(aminocarbonylmethyl)-N-methylsulphonyl-amino]--
anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1003] (78)
3-(Z)-(1-{4-[N-(methylaminocarbonylmethyl)-N-methylsulphonyl-a-
mino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1004] (79)
3-(Z)-(1-{4-[N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-am-
ino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1005] (80)
3-(Z)-[1-(4-{N-[N-(2-dimethylamino-ethyl)-N-methyl-amino)-carb-
onylmethyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-di-
methoxy-2-indolinone
[1006] (81)
3-(Z)-(1-{4-[N-(diethylaminocarbonylmethyl)-N-methylsulphonyl--
amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1007] (82)
3-(Z)-(1-{4-[N-(pyrrolidin-1-yl-carbonylmethyl)-N-methyl-sulph-
onyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1008] (83)
3-(Z)-(1-{4-[N-(piperidin-1-yl-carbonylmethyl)-N-methyl-sulpho-
nyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1009] (84)
3-(Z)-(1-{4-[N-(piperazin-1-yl-carbonylmethyl)-N-methyl-sulpho-
nyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone
[1010] (85)
3-(Z)-[1-(4-{N-[(morpholin-4-yl)-carbonylmethyl]-N-methylsulph-
onyl-amino}-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone
[1011] (86)
3-(Z)-{1-[4-(2-dimethylamino-ethoxy)-anilino]-1-phenyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[1012] (87)
3-(Z)-{1-[4-(3-dimethylamino-propoxy)-anilino]-1-phenyl-methyl-
idene}-5,6-dimethoxy-2-indolinone
[1013] (88)
3-(Z)-{1-[4-(2-aminocarbonyl-ethyl)-anilino]-1-phenyl-methylid-
ene}-5,6-dimethoxy-2-indolinone (89)
3-(Z)-{1-[4-(pyridine-2-yl)-anilino]--
1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone
[1014] (90)
3-(Z)-{1-[4-(pyridine-3-yl)-anilino]-1-phenyl-methylidene}-5,6-
-dimethoxy-2-indolinone
[1015] (91)
3-(Z)-{1-[4-(pyridine-4-yl)-anilino]-1-phenyl-methylidene}-5,6-
-dimethoxy-2-indolinone
[1016] (92)
3-(Z)-[1-(4-nitro-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-
-2-indolinone
[1017] (93)
3-(Z)-1-[(4-fluoro-anilino)-1-ethyl-methylidene]-5,6-di-methox-
y-2-indolinone
[1018] (94)
3-(Z)-1-[(4-chloro-anilino)-1-ethyl-methylidene]-5,6-di-methox-
y-2-indolinone
[1019] (95)
3-(Z)-[1-(4-bromo-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-
-2-indolinone
[1020] (96)
3-(Z)-[1-(4-iodo-anilino)-1-ethyl-methylidene]-5,6-di-methoxy--
2-indolinone
[1021] (97)
3-(Z)-[1-(4-cyano-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-
-2-indolinone
[1022] (98)
3-(Z)-[1-(4-methoxy-anilino)-1-ethyl-methylidene]-5,6-di-metho-
xy-2-indolinone
[1023] (99)
3-(Z)-[1-(4-ethoxy-anilino)-1-ethyl-methylidene]-5,6-di-methox-
y-2-indolinone
[1024] (100)
3-(Z)-[1-(4-trifluoromethyl-anilino)-1-ethyl-methylidene]-5,6-
-dimethoxy-2-indolinone
[1025] (101)
3-(Z)-[1-(4-methyl-anilino)-1-ethyl-methylidene]-5,6-di-metho-
xy-2-indolinone
[1026] (102)
3-(Z)-[1-(4-methylmercapto-anilino)-1-ethyl-methylidene]-5,6--
dimethoxy-2-indolinone
[1027] (103)
3-(Z)-[1-(4-aminomethyl-anilino)-1-ethyl-methylidene]-5,6-dim-
ethoxy-2-indolinone
[1028] (104)
3-(Z)-{1-[4-(methylaminomethyl)-anilino]-1-ethyl-methylidene)-
-5,6-dimethoxy-2-indolinone
[1029] (105)
3-(Z)-{1-[4-(isopropylaminomethyl)-anilino]-1-ethyl-methylide-
ne}-5,6-dimethoxy-2-indolinone
[1030] (106)
3-(Z)-(1-[4-(phenylaminomethyl)-anilino]-1-ethyl-methylidene}-
-5,6-dimethoxy-2-indolinone
[1031] (107)
3-(Z)-{1-[4-(ethylaminomethyl)-anilino]-1-ethyl-methylidene}--
5,6-dimethoxy-2-indolinone
[1032] (108)
3-(Z)-{1-[4-(propylaminomethyl)-anilino]-1-ethyl-methylidene}-
-5,6-dimethoxy-2-indolinone
[1033] (109)
3-(Z)-{1-[4-(butylaminomethyl)-anilino]-1-ethyl-methylidene}--
5,6-dimethoxy-2-indolinone
[1034] (110)
3-(Z)-{1-[4-(isobutylaminomethyl)-anilino]-1-ethyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[1035] (111)
3-(Z)-{1-[4-(cyclohexylaminomethyl)-anilino]-1-ethyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[1036] (112)
3-(Z)-{1-[4-(benzylaminomethyl)-anilino]-1-ethyl-methylidene}-
-5,6-dimethoxy-2-indolinone
[1037] (113)
3-(Z)-{1-[3-(dimethylamino-methyl)-anilino]-1-ethyl-methylide-
ne}-5,6-dimethoxy-2-indolinone
[1038] (114)
3-(Z)-(1-{4-[(N-ethyl-N-methyl-amino)-methyl]-anilino}-1-ethy-
l-methylidene)-5,6-dimethoxy-2-indolinone
[1039] (115)
3-(Z)-{1-[4-(diethylaminomethyl)-anilino]-1-ethyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[1040] (116)
3-(Z)-(1-{4-[(N-methyl-N-propyl-amino)-methyl]-anilino}-1-eth-
yl-methylidene)-5,6-dimethoxy-2-indolinone
[1041] (117)
3-(Z)-(1-{4-[(N-isopropyl-N-methyl-amino)-methyl]-anilino}-1--
ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1042] (118)
3-(Z)-(1-{4-[(N-ethyl-N-propyl-amino)-methyl]-anilino}-1-ethy-
l-methylidene)-5,6-dimethoxy-2-indolinone
[1043] (119)
3-(Z)-(1-{4-[(N-ethyl-N-isopropyl-amino)-methyl]-anilino}-1-e-
thyl-methylidene)-5,6-dimethoxy-2-indolinone
[1044] (120)
3-(Z)-{1-[4-(dipropylaminomethyl)-anilino]-1-ethyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[1045] (121)
3-(Z)-{1-[4-(diisopropylaminomethyl)-anilino]-1-ethyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[1046] (122)
3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-eth-
yl-methylidene)-5,6-dimethoxy-2-indolinone
[1047] (123)
3-(Z)-(1-{4-[(N-benzyl-N-ethyl-amino)-methyl]-anilino}-1-ethy-
l-methylidene)-5,6-dimethoxy-2-indolinone
[1048] (124)
3-(Z)-{1-[4-(dibenzylaminomethyl)-anilino]-1-ethyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[1049] (125)
3-(Z)-{1-[4-(pyrrolidin-1-yl-methyl)-anilino]-1-ethyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[1050] (126)
3-(Z)-{1-[4-(3,6-dihydro-2H-pyridine-1-yl-methyl)-anilino]-1--
ethyl-methylidene}-5,6-dimethoxy-2-indolinone
[1051] (127)
3-(Z)-{1-[4-(2,6-dimethyl-piperidin-1-yl-methyl)-anilino]-1-e-
thyl-methylidene}-5,6-dimethoxy-2-indolinone
[1052] (128)
3-(Z)-{1-[4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino]-1-e-
thyl-methylidene}-5,6-dimethoxy-2-indolinone
[1053] (129)
3-(Z)-{1-[4-(azepan-1-yl-methyl)-anilino]-1-ethyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[1054] (130)
3-(Z)-{1-[4-(piperazin-1-yl-methyl)-anilino]-1-ethyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[1055] (131)
3-(Z)-{1-[4-(morpholin-4-yl-methyl)-anilino]-1-ethyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[1056] (132)
3-(Z)-{1-[4-(thiomorpholin-4-yl-methyl)-anilino]-1-ethyl-meth-
ylidene}-5,6-dimethoxy-2-indolinone
[1057] (133)
3-(Z)-{1-[4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino]-1-ethy-
l-methylidene}-5,6-dimethoxy-2-indolinone
[1058] (134)
3-(Z)-{1-[4-(acetylamino-methyl)-anilino]-1-ethyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[1059] (135)
3-(Z)-{1-[4-(2-amino-ethyl)-anilino]-1-ethyl-methylidene}-5,6-
-dimethoxy-2-indolinone
[1060]
(136)3-(Z)-{1-[4-(2-methylamino-ethyl)-anilino]-1-ethyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[1061] (137)
3-(Z)-{1-[4-(2-ethylamino-ethyl)-anilino]-1-ethyl-methylidene-
}-5,6-dimethoxy-2-indolinone
[1062] (138)
3-(Z)-{1-[4-(2-dimethylamino-ethyl)-anilino]-1-ethyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[1063] (139)
3-(Z)-{1-[4-(2-diethylamino-ethyl)-anilino]-1-ethyl-methylide-
ne}-5,6-dimethoxy-2-indolinone
[1064] (140)
3-(Z)-{1-[4-(2-piperidin-1-yl-ethyl)-anilino]-1-ethyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[1065] (141)
3-(Z)-(1-{4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-anili-
no}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1066] (142)
3-(Z)-(1-{4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}-1-e-
thyl-methylidene)-5,6-dimethoxy-2-indolinone
[1067] (143)
3-(Z)-(1-{4-[2-(4-dimethylcarbamoyl-piperidin-1-yl)-ethyl]-an-
ilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1068] (144)
3-(Z)-{1-[4-(2-acetylamino-ethyl)-anilino]-1-ethyl-methyliden-
e}-5,6-dimethoxy-2-indolinone
[1069] (145)
3-(Z)-{1-[4-(3-amino-propyl)-anilino]-1-ethyl-methylidene}-5,-
6-dimethoxy-2-indolinone
[1070] (146)
3-(Z)-{1-[4-(3-dimethylamino-propyl)-anilino]-1-ethyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[1071] (147)
3-(Z)-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino]-1-
-ethyl-methylidene}-5,6-dimethoxy-2-indolinone
[1072] (148)
3-(Z)-{1-[4-(N-methylaminomethylcarbonyl-N-methyl-amino)-anil-
ino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone
[1073] (149)
3-(Z)-{1-[4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anili-
no]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone
[1074] (150)
3-(Z)-{1-[4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-ani-
lino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone
[1075] (151)
3-(Z)-(1-{4-[N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino-
]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1076] (152)
3-(Z)-(1-{4-[N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino-
]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1077] (153)
3-(Z)-(1-{4-[N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino-
]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1078] (154)
3-(Z)-(1-{4-[N-(2-amino-ethyl-carbonyl)-N-methyl-amino]-anili-
no}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1079] (155)
3-(Z)-(1-{4-[N-(2-methylamino-ethyl-carbonyl)-N-methyl-amino]-
-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1080] (156)
3-(Z)-(1-{4-[N-(2-diethylamino-ethyl-carbonyl)-N-methyl-amino-
]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1081] (157)
3-(Z)-(1-{4-[N-acetyl-N-(2-aminoethyl)-amino]-anilino}-1-ethy-
l-methylidene)-5,6-dimethoxy-2-indolinone
[1082] (158)
3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-ethyl)-amino]-anilino}-
-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1083] (159)
3-(Z)-(1-{4-[N-acetyl-N-(2-dimethylaminoethyl)-amino]-anilino-
}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1084] (160)
3-(Z)-(1-{4-[N-acetyl-N-(3-amino-propyl)-amino]-anilino}-1-et-
hyl-methylidene)-5,6-dimethoxy-2-indolinone
[1085] (161)
3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-propyl)-amino]-anilino-
}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1086] (162)
3-(Z)-(1-{4-[N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino]-anili-
no}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1087] (163)
3-(Z)-(1-{4-[N-acetyl-N-(aminocarbonylmethyl)-amino]-anilino}-
-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1088] (164)
3-(Z)-(1-{4-[N-acetyl-N-(dimethylaminocarbonylmethyl)-amino]--
anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1089] (165)
3-(Z)-(1-{4-[N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino-
]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1090] (166)
3-(Z)-(1-{4-[N-methyl-N-(aminocarbonyl)-amino]-anilino}-1-eth-
yl-methylidene)-5,6-dimethoxy-2-indolinone
[1091] (167)
3-(Z)-(1-{4-[N-methyl-N-(methylaminocarbonyl)-amino]-anilino}-
-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1092] (168)
3-(Z)-(1-{4-[N-methyl-N-(dimethylaminocarbonyl)-amino]-anilin-
o}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1093] (169)
3-(Z)-(1-{4-[N-methyl-N-(piperidin-1-yl-carbonyl)-amino]-anil-
ino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1094] (170)
3-(Z)-(1-{4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-anilin-
o}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1095] (171)
3-(Z)-(1-{4-[N-(2-methylamino-ethyl)-N-methylsulphonyl-amino]-
-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1096] (172)
3-(Z)-(1-{4-[N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino]--
anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1097] (173)
3-(Z)-(1-{4-[N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino-
]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1098] (174)
3-(Z)-(1-{4-[N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-am-
ino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1099] (175)
3-(Z)-(1-{4-[N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-ami-
no]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1100] (176)
3-(Z)-(1-{4-[N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-ami-
no]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1101] (177)
3-(Z)-[1-(4-{N-[2-(morpholin-4-yl)-ethyl]-N-methylsulphonyl-a-
mino}-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone
[1102] (178)
3-(Z)-(1-{4-[N-(aminocarbonylmethyl)-N-methylsulphonyl-amino]-
-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1103] (179)
3-(Z)-(1-{4-[N-(methylaminocarbonylmethyl)-N-methylsulphonyl--
amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1104] (180)
3-(Z)-(1-{4-[N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-a-
mino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1105] (181)
3-(Z)-[1-(4-{N-[(2-dimethylamino-ethylamino)-carbonylmethyl]--
N-methylsulphonyl-amino}-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-ind-
olinone
[1106] (182)
3-(Z)-[1-(4-{N-[N-(2-dimethylamino-ethyl)-N-methyl-amino)-car-
bonylmethyl]-N-methylsulphonyl-amino}-anilino)-1-ethyl-methylidene]-5,6-di-
methoxy-2-indolinone
[1107] (183)
3-(Z)-(1-{4-[N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-
-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1108] (184)
3-(Z)-(1-{4-[N-(pyrrolidin-1-yl-carbonylmethyl)-N-methylsulph-
onyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1109] (185)
3-(Z)-(1-{4-[N-(piperidin-1-yl-carbonylmethyl)-N-methyl-sulph-
onyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1110] (186)
3-(Z)-(1-{4-[N-(piperazin-1-yl-carbonylmethyl)-N-methyl-sulph-
onyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone
[1111] (187)
3-(Z)-[1-[4-{N-[(morpholin-4-yl)-carbonylmethyl]-N-methylsulp-
honyl-amino}-anilino]-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone
[1112] (188)
3-(Z)-{1-[4-(2-dimethylamino-ethoxy)-anilino]-1-ethyl-methyli-
dene}-5,6-dimethoxy-2-indolinone
[1113] (189)
3-(Z)-{1-[4-(3-dimethylamino-propoxy)-anilino]1-1-ethyl-methy-
lidene}-5,6-dimethoxy-2-indolinone
[1114] (190)
3-(Z)-{1-[4-(2-aminocarbonyl-ethyl)-anilino]-1-ethyl-methylid-
ene}-5,6-dimethoxy-2-indolinone
[1115] (191)
3-(Z)-{1-[4-(1H-imidazol-4-yl)-anilino]-1-ethyl-methylidene}--
5,6-dimethoxy-2-indolinone
[1116] (192)
3-(Z)-{1-[4-(pyridine-2-yl)-anilino]-1-ethyl-methylidene}-5,6-
-dimethoxy-2-indolinone
[1117] (193)
3-(Z)-{1-[4-(pyridine-3-yl)-anilino]-1-ethyl-methylidene}-5,6-
-dimethoxy-2-indolinone
[1118] (194)
3-(Z)-{1-[4-(pyridine-4-yl)-anilino]-1-ethyl-methylidene}-5,6-
-dimethoxy-2-indolinone
[1119] (195)
3-(Z)-(1-anilino-1-phenyl-methylidene)-5,6-diethoxy-2-indolin-
one
[1120] (196)
3-(Z)-[1-(4-nitro-anilino)-1-phenyl-methylidene]-5,6-di-ethox-
y-2-indolinone
[1121] (197)
3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylidene]-5,6-
-diethoxy-2-indolinone
[1122] (198)
3-(Z)-[1-(4-carboxy-anilino)-1-phenyl-methylidene]-5,6-dietho-
xy-2-indolinone
[1123] (199)
3-(Z)-1-[(4-fluoro-anilino)-1-phenyl-methylidene]-5,6-diethox-
y-2-indolinone
[1124] (200)
3-(Z)-1-[(4-chloro-anilino)-1-phenyl-methylidene]-5,6-diethox-
y-2-indolinone
[1125] (201)
3-(Z)-[1-(4-bromo-anilino)-1-phenyl-methylidene]-5,6-di-ethox-
y-2-indolinone
[1126] (202)
3-(Z)-[1-(4-iodo-anilino)-1-phenyl-methylidene]-5,6-di-ethoxy-
-2-indolinone
[1127] (203)
3-(Z)-[1-(4-cyano-anilino)-1-phenyl-methylidene]-5,6-di-ethox-
y-2-indolinone
[1128] (204)
3-(Z)-[1-(4-methoxy-anilino)-1-phenyl-methylidene]-5,6-dietho-
xy-2-indolinone
[1129] (205)
3-(Z)-[1-(4-ethoxy-anilino)-1-phenyl-methylidene]-5,6-diethox-
y-2-indolinone
[1130] (206)
3-(Z)-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylidene]-5,-
6-diethoxy-2-indolinone
[1131] (207)
3-(Z)-[1-(4-methyl-anilino)-1-phenyl-methylidene]-5,6-diethox-
y-2-indolinone
[1132] (208)
3-(Z)-[1-(4-methylmercapto-anilino)-1-phenyl-methylidene]-5,6-
-diethoxy-2-indolinone
[1133] (209)
3-(Z)-[1-(4-aminomethyl-anilino)-1-phenyl-methylidene]-5,6-di-
ethoxy-2-indolinone
[1134] (210)
3-(Z)-{1-[4-(methylaminomethyl)-anilino]-1-phenyl-methylidene-
}-5,6-diethoxy-2-indolinone (211)
3-(Z)-{1-[4-(isopropylaminomethyl)-anili-
no]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone
[1135] (212)
3-(Z)-{1-[4-(phenylaminomethyl)-anilino]-1-phenyl-methylidene-
}-5,6-diethoxy-2-indolinone
[1136] (213)
3-(Z)-{1-[4-(ethylaminomethyl)-anilino]-1-phenyl-methylidene}-
-5,6-diethoxy-2-indolinone
[1137] (214)
3-(Z)-{1-[4-(propylaminomethyl)-anilino]-1-phenyl-methylidene-
}-5,6-diethoxy-2-indolinone
[1138] (215)
3-(Z)-{1-[4-(butylaminomethyl)-anilino]-1-phenyl-methylidene}-
-5,6-diethoxy-2-indolinone
[1139] (216)
3-(Z)-{1-[4-(isobutylaminomethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-diethoxy-2-indolinone
[1140] (217)
3-(Z)-{1-[4-(cyclohexylaminomethyl)-anilino]-1-phenyl-methyli-
dene}-5,6-diethoxy-2-indolinone
[1141] (218)
3-(Z)-{1-[4-(benzylaminomethyl)-anilino]-1-phenyl-methylidene-
}-5,6-diethoxy-2-indolinone
[1142] (219)
3-(Z)-{1-[4-(dimethylaminomethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-diethoxy-2-indolinone
[1143] (220)
3-(Z)-{1-[3-(dimethylaminomethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-diethoxy-2-indolinone
[1144] (221)
3-(Z)-(1-{4-[(N-ethyl-N-methyl-amino)-methyl]-anilino}-1-phen-
yl-methylidene)-5,6-diethoxy-2-indolinone
[1145] (222)
3-(Z)-{1-[4-(diethylaminomethyl)-anilino]-1-phenyl-methyliden-
e}-5,6-diethoxy-2-indolinone
[1146] (223)
3-(Z)-(1-{4-[(N-methyl-N-propyl-amino)-methyl]-anilino}-1-phe-
nyl-methylidene)-5,6-diethoxy-2-indolinone
[1147] (224)
3-(Z)-(1-{4-[(N-isopropyl-N-methyl-amino)-methyl]-anilino}-1--
phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1148] (225)
3-(Z)-(1-{4-[(N-ethyl-N-propyl-amino)-methyl]-anilino}-1-phen-
yl-methylidene)-5,6-diethoxy-2-indolinone
[1149] (226)
3-(Z)-(1-{4-[(N-ethyl-N-isopropyl-amino)-methyl]-anilino}-1-p-
henyl-methylidene)-5,6-diethoxy-2-indolinone
[1150] (227)
3-(Z)-{1-[4-(dipropylaminomethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-diethoxy-2-indolinone
[1151] (228)
3-(Z)-{1-[4-(diisopropylaminomethyl)-anilino]-1-phenyl-methyl-
idene}-5,6-diethoxy-2-indolinone
[1152] (229)
3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phe-
nyl-methylidene)-5,6-diethoxy-2-indolinone
[1153] (230)
3-(Z)-(1-{4-[(N-benzyl-N-ethyl-amino)-methyl]-anilino}-1-phen-
yl-methylidene)-5,6-diethoxy-2-indolinone
[1154] (231)
3-(Z)-{1-[4-(dibenzylaminomethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-diethoxy-2-indolinone
[1155] (232)
3-(Z)-{1-[4-(pyrrolidin-1-yl-methyl)-anilino]-1-phenyl-methyl-
idene}-5,6-diethoxy-2-indolinone
[1156] (233)
3-(Z)-{1-[4-(3,6-dihydro-2H-pyridine-1-yl-methyl)-anilino]-1--
phenyl-methylidene}-5,6-diethoxy-2-indolinone
[1157] (234)
3-(Z)-{1-[4-(2,6-dimethyl-piperidin-1-yl-methyl)-anilino]-1-p-
henyl-methylidene}-5,6-diethoxy-2-indolinone
[1158] (235)
3-(Z)-{1-[4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino]-1-p-
henyl-methylidene}-5,6-diethoxy-2-indolinone
[1159] (236)
3-(Z)-{1-[4-(azepan-1-yl-methyl)-anilino]-1-phenyl-methyliden-
e}-5,6-diethoxy-2-indolinone
[1160] (237)
3-(Z)-{1-[4-(piperazin-1-yl-methyl)-anilino]-1-phenyl-methyli-
dene}-5,6-diethoxy-2-indolinone
[1161] (238)
3-(Z)-{1-[4-(morpholin-4-yl-methyl)-anilino]-1-phenyl-methyli-
dene}-5,6-diethoxy-2-indolinone
[1162] (239)
3-(Z)-{1-[4-(thiomorpholin-4-yl-methyl)-anilino]-1-phenyl-met-
hylidene}-5,6-diethoxy-2-indolinone
[1163] (240)
3-(Z)-{1-[4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino]-1-phen-
yl-methylidene}-5,6-diethoxy-2-indolinone
[1164] (241)
3-(Z)-{1-[4-(acetylamino-methyl)-anilino]-1-phenyl-methyliden-
e}-5,6-diethoxy-2-indolinone
[1165] (242)
3-(Z)-{1-[4-(2-amino-ethyl)-anilino]-1-phenyl-methylidene}-5,-
6-diethoxy-2-indolinone
[1166] (243)
3-(Z)-{1-[4-(2-methylamino-ethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-diethoxy-2-indolinone
[1167] (244)
3-(Z)-{1-[4-(2-ethylamino-ethyl)-anilino]-1-phenyl-methyliden-
e}-5,6-diethoxy-2-indolinone
[1168] (245)
3-(Z)-{1-[4-(2-dimethylamino-ethyl)-anilino]-1-phenyl-methyli-
dene}-5,6-diethoxy-2-indolinone
[1169] (246)
3-(Z)-{1-[4-(2-diethylamino-ethyl)-anilino]-1-phenyl-methylid-
ene}-5,6-diethoxy-2-indolinone
[1170] (247)
3-(Z)-{1-[4-(2-piperidin-1-yl-ethyl)-anilino]-1-phenyl-methyl-
idene}-5,6-diethoxy-2-indolinone
[1171] (248)
3-(Z)-(1-{4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-anili-
no}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1172] (249)
3-(Z)-(1-{4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}-1-p-
henyl-methylidene)-5,6-diethoxy-2-indolinone
[1173] (250)
3-(Z)-(1-{4-[2-(4-dimethylcarbamoyl-piperidin-1-yl)-ethyl]-an-
ilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1174] (251)
3-(Z)-{1-[4-(2-acetylamino-ethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-diethoxy-2-indolinone
[1175] (252)
3-(Z)-{1-[4-(3-amino-propyl)-anilino]-1-phenyl-methylidene}-5-
,6-diethoxy-2-indolinone
[1176] (253)
3-(Z)-{1-[4-(3-dimethylamino-propyl)-anilino]-1-phenyl-methyl-
idene}-5,6-diethoxy-2-indolinone
[1177] (254)
3-(Z)-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino]-1-
-phenyl-methylidene}-5,6-diethoxy-2-indolinone
[1178] (255)
3-(Z)-{1-[4-(N-methylaminomethylcarbonyl-N-methyl-amino)-anil-
ino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone
[1179] (256)
3-(Z)-{1[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-ani-
lino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone
[1180] (257)
3-(Z)-{1-[4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anili-
no]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone
[1181] (258)
3-(Z)-{1-[4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-ani-
lino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone
[1182] (259)
3-(Z)-(1-{4-[N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino-
]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1183] (260)
3-(Z)-(1-{4-[N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino-
]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1184] (261)
3-(Z)-(1-{4-[N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino-
]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1185] (262)
3-(Z)-(1-{4-[N-(2-amino-ethyl-carbonyl)-N-methyl-amino]-anili-
no}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1186] (263)
3-(Z)-(1-{4-[N-(2-methylamino-ethyl-carbonyl)-N-methyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1187] (264)
3-(Z)-(1-{4-[N-(2-diethylamino-ethyl-carbonyl)-N-methyl-amino-
]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1188] (265)
3-(Z)-(1-{4-[N-acetyl-N-(2-aminoethyl)-amino]-anilino}-1-phen-
yl-methylidene)-5,6-diethoxy-2-indolinone
[1189] (266)
3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-ethyl)-amino]-anilino}-
-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1190] (267)
3-(Z)-(1-{4-[N-acetyl-N-(2-dimethylaminoethyl)-amino]-anilino-
}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1191] (268)
3-(Z)-(1-{4-[N-acetyl-N-(3-amino-propyl)-amino]-anilino}-1-ph-
enyl-methylidene)-5,6-diethoxy-2-indolinone
[1192] (269)
3-(Z)-(1-{4-[N-acetyl-N-(3-dimethylamino-propyl)-amino]-anili-
no}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1193] (270)
3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-propyl)-amino]-anilino-
}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1194] (271)
3-(Z)-(1-{4-[N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino]-anili-
no}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1195] (272)
3-(Z)-(1-{4-[N-acetyl-N-(aminocarbonylmethyl)-amino]-anilino}-
-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1196] (273)
3-(Z)-(1-{4-[N-acetyl-N-(dimethylaminocarbonylmethyl)-amino]--
anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1197] (274)
3-(Z)-(1-{4-[N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino-
]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1198] (275)
3-(Z)-(1-{4-[N-methyl-N-(aminocarbonyl)-amino]-anilino}-1-phe-
nyl-methylidene)-5,6-diethoxy-2-indolinone
[1199] (276)
3-(Z)-(1-{4-[N-methyl-N-(methylaminocarbonyl)-amino]-anilino}-
-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1200] (277)
3-(Z)-(1-{4-[N-methyl-N-(dimethylaminocarbonyl)-amino]-anilin-
o}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1201] (278)
3-(Z)-(1-{4-[N-methyl-N-(piperidin-1-yl-carbonyl)-amino]-anil-
ino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1202] (279)
3-(Z)-(1-{4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-anilin-
o}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1203] (280)
3-(Z)-(1-{4-[N-(2-methylamino-ethyl)-N-methylsulphonyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1204] (281)
3-(Z)-(1-{4-[N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino]--
anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1205] (282)
3-(Z)-(1-{4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amin-
o]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1206] (283)
3-(Z)-(1-{4-[N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino-
]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1207] (284)
3-(Z)-(1-{4-[N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-am-
ino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1208] (285)
3-(Z)-(1-{4-[N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-ami-
no]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1209] (286)
3-(Z)-(1-{4-[N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-ami-
no]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1210] (287)
3-(Z)-[1-(4-{N-[2-(morpholin-4-yl)-ethyl]-N-methylsulphonyl-a-
mino}-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone
[1211] (288)
3-(Z)-(1-{4-[N-(aminocarbonylmethyl)-N-methylsulphonyl-amino]-
-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1212] (289)
3-(Z)-(1-{4-[N-(methylaminocarbonylmethyl)-N-methylsulphonyl--
amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1213] (290)
3-(Z)-(1-{4-[N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-a-
mino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1214] (291)
3-(Z)-[1-(4-{N-[(2-dimethylamino-ethylamino)-carbonylmethyl]--
N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-ind-
olinone
[1215] (292)
3-(Z)-[1-(4-{N-[N-(2-dimethylamino-ethyl)-N-methyl-amino)-car-
bonylmethyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-d-
iethoxy-2-indolinone
[1216] (293)
3-(Z)-(1-{4-[N-(dimethylaminocarbonylmethyl)-N-methyl-sulphon-
yl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1217] (294)
3-(Z)-(1-{4-[N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-
-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1218] (295)
3-(Z)-(1-{4-[N-(pyrrolidin-1-yl-carbonylmethyl)-N-methylsulph-
onyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1219] (296)
3-(Z)-(1-{4-[N-(piperidin-1-yl-carbonylmethyl)-N-methyl-sulph-
onyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1220] (297)
3-(Z)-(1-{4-[N-(piperazin-1-yl-carbonylmethyl)-N-methyl-sulph-
onyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone
[1221] (298)
3-(Z)-[1-[4-{N-[(morpholin-4-yl)-carbonylmethyl]-N-methylsulp-
honyl-amino}-anilino]-1-phenyl-methylidene]-5,6-di-ethoxy-2-indolinone
[1222] (299)
3-(Z)-{1-[4-(2-dimethylamino-ethoxy)-anilino]-1-phenyl-methyl-
idene}-5,6-diethoxy-2-indolinone
[1223] (300)
3-(Z)-{1-[4-(3-dimethylamino-propoxy)-anilino]-1-phenyl-methy-
lidene}-5,6-diethoxy-2-indolinone
[1224] (301)
3-(Z)-{1-[4-(aminocarbonylmethyl)-anilino]-1-phenyl-methylide-
ne}-5,6-diethoxy-2-indolinone
[1225] (302)
3-(Z)-{1-[4-(2-aminocarbonyl-ethyl)-anilino]-1-phenyl-methyli-
dene}-5,6-diethoxy-2-indolinone
[1226] (303)
3-(Z)-{1-[4-(1H-imidazol-4-yl)-anilino]-1-phenyl-methylidene}-
-5,6-diethoxy-2-indolinone
[1227] (304)
3-(Z)-{1-[4-(pyridine-2-yl)-anilino]-1-phenyl-methylidene}-5,-
6-diethoxy-2-indolinone
[1228] (305)
3-(Z)-{1-[4-(pyridine-3-yl)-anilino]-1-phenyl-methylidene}-5,-
6-diethoxy-2-indolinone
[1229] (306)
3-(Z)-{1-[4-(pyridine-4-yl)-anilino]-1-phenyl-methylidene}-5,-
6-diethoxy-2-indolinone
EXAMPLE 12
[1230] Dry Ampoule Containing 75 mg of Active Substance per 10
ml
[1231] Composition:
2 Active substance 75.0 mg Mannitol 50.0 mg water for injections ad
10.0 ml
[1232] Preparation:
[1233] Active substance and mannitol are dissolved in water. After
packaging the solution is freeze-dried. To produce the solution
ready for use, the product is dissolved in water for
injections.
EXAMPLE 13
[1234] Dry Ampoule Containing 35 mg of Active Substance per 2
ml
[1235] Composition:
3 Active substance 35.0 mg Mannitol 100.0 mg water for injections
ad 2.0 ml
[1236] Preparation:
[1237] Active substance and mannitol are dissolved in water. After
packaging, the solution is freeze-dried.
[1238] To produce the solution ready for use, the product is
dissolved in water for injections.
EXAMPLE 14
[1239] Tablet Containing 50 mg of Active Substance
[1240] Composition:
4 (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch
50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0
mg 215.0 mg
[1241] Preparation:
[1242] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side. Diameter of
the tablets: 9 mm.
EXAMPLE 15
[1243] Tablet Containing 350 mg of Active Substance
[1244] Preparation:
5 (1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize
starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium
stearate 4.0 mg 600.0 mg
[1245] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side. Diameter of
the tablets: 12 mm.
EXAMPLE 16
[1246] Capsules Containing 50 mg of Active Substance
[1247] Composition:
6 (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3)
Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg
[1248] Preparation:
[1249] (1) is triturated with (3). This trituration is added to the
mixture of (2) and (4) with vigorous mixing.
[1250] This powder mixture is packed into size 3 hard gelatin
capsules in a capsule filling machine.
EXAMPLE 17
[1251] Capsules Containing 350 mg of Active Substance
[1252] Composition:
7 (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3)
Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg
[1253] Preparation:
[1254] (1) is triturated with (3). This trituration is added to the
mixture of (2) and (4) with vigorous mixing.
[1255] This powder mixture is packed into size 0 hard gelatin
capsules in a capsule filling machine.
EXAMPLE 18
[1256] Suppositories Containing 100 mg of Active Substance
[1257] 1 Suppository Contains:
8 Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg
Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan
monostearate 840.0 mg 2,000.0 mg
[1258] Preparation:
[1259] The polyethyleneglycol is melted together with polyethylene
sorbitanmonostearate. At 400.degree. C. the ground active substance
is homogeneously dispersed in the melt. It is cooled to 38.degree.
C. and poured into slightly chilled suppository moulds.
* * * * *