NEW SUBSTITUTED INDOLINONES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

INDOLINONES SUBSTITUEES, LEURS PREPARATIONS ET LEURS UTILISATIONS COMME COMPOSITIONS PHARMACEUTIQUES

English Abstract

The present invention relates to substituted indolinones
of general formula
(see formula I)
wherein
R1 to R5 and X are defined as in claim 1, the isomers
thereof and the salts thereof, particularly the
physiologically acceptable salts thereof which have
valuable pharmacological properties, particularly an
inhibitory effect on various kinases and cycline/CDK
complexes and on the proliferation of various tumour
cells, pharmaceutical compositions containing these
compounds, their use and processes for preparing them.

French Abstract

L'invention concerne des indolinones substituées de la formule générale (I) ou R1 à R5 et X sont définis comme décrit dans le revendication 1. L'invention concerne également leurs isomères et leurs sels, notamment leurs sels physiologiquement admissibles, ayant de précieuses propriétés pharmacologiques, notamment un effet inhibiteur sur différentes kinases, sur différents complexes Cycline/CDK et sur la prolifération de différentes cellules tumorales. L'invention concerne enfin des médicaments contenant ces composés, leur utilisation et leur procédé de production.

Claims

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CLAIMS:
1. A compound of the formula I
<IMG>
wherein:
X is an oxygen atom,
R1 is a hydrogen atom or a C1-4-alkoxycarbonyl
group;
R2 is a carboxy, C1-4-alkoxycarbonyl, or
aminocarbonyl group wherein the amino moiety may be
substituted by one or two C1-3-alkyl groups and the
substituents may be identical or different;
R3 is a phenyl group unsubstituted or substituted
by a fluorine, chlorine, or bromine atom, or by a methyl,
cyano, or aminomethyl group;
R4 is a hydrogen atom or a C1-3-alkyl group; and
R5 is a hydrogen atom,
a C1-5-alkyl group unsubstituted or substituted by
a carboxy or C1-3-alkoxycarbonyl group, or a benzyl group,
a C3-7-cycloalkyl group unsubstituted or
substituted by a methyl group,
an indanyl, pyridyl, oxazolyl, thiazolyl, or
imidazolyl group unsubstituted or substituted by a methyl

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group, to which a phenyl ring may additionally be fused via
two adjacent carbon atoms,
a methylphenyl group unsubstituted or substituted
by a fluorine, chlorine, or bromine atom, or by a methoxy,
carboxy, C1-3-alkyloxycarbonyl, nitro, or aminosulphonyl
group, or a dimethoxyphenyl group,
a pyrrolidinyl or piperidinyl group linked via a
carbon atom, which may be substituted at the nitrogen atom
by a C1-3-alkyl group,
a phenyl group which is substituted
by a trifluoromethoxy group, by a fluorine,
chlorine, bromine, or iodine atom, by a C1-3-alkoxy group
which may be substituted in the 2- or 3-position by an
amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, phenyl-
C1-3-alkylamino, N-(C1-3-alkyl)-phenyl-C1-3-alkylamino,
pyrrolidino, or piperidino group,
by a phenyl-C1-3-alkylamino-C1-3-alkyl group which
may be substituted in the phenyl nucleus by a fluorine,
chlorine, bromine, or iodine atom, by a C1-5-alkyl,
C1-3-alkoxy, or trifluoromethyl group and additionally at
the amine nitrogen atom by a C1-3-alkyl group wherein the
hydrogen atoms from the 2-position may be wholly or
partially replaced by fluorine atoms,
by a C1-5-alkyl, phenyl, imidazolyl,
C3-7-cycloalkyl, C1-3-alkoxy-C1-3-alkoxy, phenyl-C1-3-alkoxy,
carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy,
C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylaminocarbonyl,
N-(C1-3-alkyl)-phenyl-C1-3-alkylaminocarbonyl,
piperazinocarbonyl, N-(C1-3-alkyl)-piperazinocarbonyl, nitro,

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amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, pyrrolidino,
piperidino, morpholino, C2-4-alkanoyl-amino, N-(C1-3-alkyl)-
C2-4-alkanoylamino, benzoylamino, or N-(C1-3-alkyl)-
benzoylamino group,
by an N-(C1-3-alkyl)-C2-4-alkanoylamino group which
is additionally substituted in the alkyl moiety by a carboxy
or C1-3-alkoxycarbonyl group,
by a C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-
aminocarbonyl group wherein an alkyl moiety is additionally
substituted by a di-(C1-3-alkyl)-amino group, or
by an N-(C1-3-alkyl)-C1-3-alkylsulphonylamino or
N-(C1-3-alkyl)-phenylsulphonylamino group wherein the alkyl
moiety may additionally be substituted by a cyano, carboxy,
C1-3-alkoxycarbonyl, C1-3-alkylamino, di-(C1-3-alkyl)-amino
group, aminocarbonyl, C1-3-alkylaminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl, piperidinocarbonyl,
or 2-ethylaminocarbonyl group,
a phenyl group unsubstituted or substituted by a
C1-3-alkyl group wherein the alkyl moiety is substituted by a
hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxy-carbonyl, amino,
C1-5-alkylamino, di-(C1-5-alkyl)-amino, C2-4-alkanoylamino,
N-(C1-3-alkyl)-C2-4-alkanoylamino, pyrrolidino,
dehydropyrrolidino, piperidino, dehydropiperidino,
3-hydroxypiperidino, 4-hydroxypiperidino,
hexamethyleneimino, morpholino, thiomorpholino, piperazino,
4-(C1-3-alkyl)-piperazino, 4-phenyl-piperazino, 4-(C2-4-
alkanoyl)-piperazino, 4-benzoyl-piperazino, or imidazolyl
group, wherein the abovementioned saturated
cycloalkyleneimino rings, C1-5-alkylamino or di-(C1-5-alkyl)-
amino groups may additionally be substituted by one or two
C1-5-alkyl groups, by a C3-7-cycloalkyl, hydroxy, C1-3-alkoxy,
carboxy, C1-3-alkoxycarbonyl, aminocarbonyl,

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C1-3-alkylaminocarbonyl, or di-(C1-3-alkyl)-aminocarbonyl
group, by a phenyl-C1-3-alkyl or phenyl group optionally
mono- or disubstituted in the phenyl nucleus by fluorine,
chlorine, bromine, or iodine atoms or by C1-3-alkyl or cyano
groups, wherein the substituents may be identical or
different, or a methylene group adjacent to the nitrogen
atom in the abovementioned cycloalkyleneimino rings may be
replaced by a carbonyl or sulphonyl group, and the
abovementioned monosubstituted phenyl groups may
additionally be substituted by a fluorine, chlorine, or
bromine atom or by a methyl, amino, C1-3-alkylamino, or
di-(C1-3-alkyl)-amino group, or a phenyl ring unsubstituted
or substituted by one or two C1-3-alkoxy groups may be fused
to one of the abovementioned unsubstituted
cycloalkyleneimino rings via two adjacent carbon atoms, or a
tautomer, stereoisomer or salt thereof.
2. A compound, tautomer, stereoisomer or salt
according to claim 1, wherein:
X is an oxygen atom;
R1 is a hydrogen atom;
R2 is a carboxy, C1-4-alkoxycarbonyl or
aminocarbonyl group wherein the amino moiety may be
substituted by one or two C1-3-alkyl groups and the
substituents may be identical or different;
R3 is a phenyl group unsubstituted or substituted
by a methyl group;
R4 is a hydrogen atom or a methyl group, and
R5 is a hydrogen atom,

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a C1-3-alkyl group, a benzyl group or a methyl or
ethyl group substituted by a carboxy or C1-3-alkoxycarbonyl
group,
a C3-7-cycloalkyl group unsubstituted or
substituted by a methyl group,
an indanyl, pyridyl, oxazolyl, thiazolyl, or
imidazolyl group unsubstituted or substituted by a methyl
group, to which a phenyl ring may additionally be fused via
two adjacent carbon atoms,
a methylphenyl group unsubstituted or substituted
by a fluorine, chlorine, or bromine atom, or by a methoxy,
carboxy, C1-3-alkyloxycarbonyl, nitro, or aminosulphonyl
group, or a dimethoxyphenyl group,
a 3-pyrrolidinyl or 4-piperidinyl group which may
be substituted at the nitrogen atom by a C1-3-alkyl group,
a phenyl group which is substituted by a
trifluoromethoxy or nitro group, by a fluorine, chlorine,
bromine, or iodine atom,
by a C1-3-alkoxy group, wherein the ethoxy and n-
propoxy groups may each be terminally substituted by a
dimethylamino, diethylamino, N-ethyl-methylamino, N-benzyl-
methylamino, or piperidino group,
by a phenyl-C1-3-alkylamino-C1-3-alkyl group which
may be substituted in the phenyl nucleus by a fluorine,
chlorine, bromine, or iodine atom, by a methyl, methoxy or
trifluoromethyl group and additionally at the amine nitrogen
atom by a C1-3-alkyl or 2,2,2-trifluoroethyl group,
by a C1-4-alkyl, phenyl, imidazolyl, cyclohexyl,
carboxymethyl, C1-3-alkoxycarbonyl-methyl,

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carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-
alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-
C1-3-alkylaminocarbonyl, N-(C1-3-alkyl)-phenyl-C1-3-
alkylaminocarbonyl, piperazinocarbonyl, N-(C1-3-alkyl)-
piperazinocarbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl) -
amino, pyrrolidino, piperidino, morpholino, C2-4-alkanoyl-
amino, N-(C1-3-alkyl)-C2-4-alkanoylamino, benzoylamino, or
N-(C1-3-alkyl)-benzoylamino group,
by an N-(C1-3-alkyl)-C2-4-alkanoylamino group which
is additionally substituted in the alkyl moiety by a carboxy
or C1-3-alkoxycarbonyl group,
by a C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-
aminocarbonyl group wherein an alkyl moiety is additionally
substituted by a di-(C1-3-alkyl)-amino group, or by an
N-(C1-3-alkyl)-C1-3-alkylsulphonylamino or
N-(C1-3-alkyl)-phenylsulphonylamino group wherein the alkyl
moiety may additionally be substituted by a cyano, carboxy,
C1-3-alkoxycarbonyl, C1-3-alkylamino, di-(C1-3-alkyl)-amino
group, aminocarbonyl, C1-3-alkylaminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl, piperidinocarbonyl,
or 2-ethylaminocarbonyl group, a phenyl group unsubstituted
or substituted by a C1-3-alkyl group wherein the alkyl moiety
is substituted by a hydroxy, C1-3-alkoxy, carboxy,
C1-3-alkoxy-carbonyl, amino, C1--5-alkylamino, di-(C1-5-alkyl)-
amino, C2-4-alkanoylamino, N-(C1-3-alkyl)-C2-4-alkanoylamino,
pyrrolidino, dehydropyrrolidino, piperidino,
dehydropiperidino, 4-hydroxypiperidino, hexamethyleneimino,
morpholino, thiomorpholino, piperazino, 4-(C1-3-alkyl)-
piperazino, 4-phenyl-piperazino, 4-(C2-4-alkanoyl)-
piperazino, 4-benzoyl-piperazino, or imidazolyl group,
wherein the abovementioned saturated cycloalkyleneimino
rings may additionally be substituted by a phenyl group or
by one or two methyl groups, the abovementioned

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C1-5-alkylamino and di-(C1-5-alkyl)-amino groups may
additionally be substituted by one or two C1-3-alkyl groups,
by a cyclohexyl, hydroxy, C1-3-alkoxy, carboxy,
C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl
or di-(C1-3-alkyl)-aminocarbonyl group, by a phenyl-C1-3-alkyl
or phenyl group unsubstituted or substituted in the phenyl
nucleus by a fluorine, chlorine, bromine, or iodine atom or
by a methyl or cyano group,
or a methylene group adjacent to the nitrogen atom
in the abovementioned cycloalkyleneimino rings may be
replaced by a carbonyl or sulphonyl group, and the
abovementioned monosubstituted phenyl groups may
additionally be substituted by a fluorine, chlorine, or
bromine atom or by a methyl, amino, C1-3-alkylamino, or
di-(C1-3-alkyl)-amino group, or
a phenyl ring unsubstituted or substituted by one
or two C1-3-alkoxy groups may be fused to one of the
abovementioned unsubstituted cycloalkyleneimino rings via
two adjacent carbon atoms.
3. A compound, tautomer, stereoisomer or salt
according to claim 1 wherein:
X is an oxygen atom;
R1 is a hydrogen atom;
R2 is a carboxy or aminocarbonyl group wherein the
amino moiety may be substituted by one or two C1-3-alkyl
groups and the substituents may be identical or different;
R3 is a phenyl group unsubstituted or substituted
by a methyl group;
R4 is a hydrogen atom; and

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R5 is a hydrogen atom,
a 3-pyrrolidinyl or 4-piperidinyl group which may
be substituted at the nitrogen atom by a C1-3-alkyl group,
a phenyl group which is substituted by a
C1-3-alkoxy group, wherein the ethoxy and n-propoxy groups
may each be terminally substituted by a dimethylamino,
diethylamino, N-ethyl-methylamino, N-benzyl-methylamino, or
piperidino group,
by a phenyl-C1-3-alkylamino-C1-3-alkyl group which
may be substituted in the phenyl nucleus by a fluorine,
chlorine, bromine, or iodine atom, by a methyl, methoxy, or
trifluoromethyl group and additionally at the amine nitrogen
atom by a C1-3-alkyl or 2,2,2-trifluoroethyl group,
a phenyl group unsubstituted or substituted by a
C1-3-alkyl group wherein the alkyl moiety is substituted by a
hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxy-carbonyl, amino,
C1-5-alkylamino, di-(C1-5-alkyl)-amino, C2-4-alkanoylamino,
N-(C1-3-alkyl)-C2-4-alkanoylamino, pyrrolidino,
dehydropyrrolidino, piperidino, dehydropiperidino,
4-hydroxypiperidino, hexamethyleneimino, morpholino,
thiomorpholino, piperazino, 4-(C1-3-alkyl)-piperazino,
4-phenyl-piperazino, 4-(C2-4-alkanoyl)-piperazino, 4-benzoyl-
piperazino, or imidazolyl group, wherein the abovementioned
saturated cycloalkyleneimino rings may additionally be
substituted by a phenyl group or by one or two methyl
groups, the abovementioned C1-5-alkylamino and di-(C1-5-
alkyl)-amino groups may additionally be substituted by one
or two C1-3-alkyl groups, by a cyclohexyl, hydroxy, C1-3-
alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl,
C1-3-alkylaminocarbonyl, or di-(C1-3-alkyl)-aminocarbonyl
group, by a phenyl-C1-3-alkyl or phenyl group unsubstituted
or substituted in the phenyl nucleus by a fluorine,

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chlorine, bromine, or iodine atom or by a methyl or cyano
group,
or a methylene group adjacent to the nitrogen atom
in the abovementioned cycloalkyleneimino rings may be
replaced by a carbonyl or sulphonyl group, and the
abovementioned monosubstituted phenyl groups may
additionally be substituted by a fluorine, chlorine, or
bromine atom or by a methyl, amino, C1-3-alkylamino, or
di-(C1-3-alkyl)-amino group, or a phenyl ring unsubstituted
or substituted by one or two C1-3-alkoxy groups may be fused
to one of the abovementioned unsubstituted
cycloalkyleneimino rings via two adjacent carbon atoms.
4. A compound, tautomer, stereoisomer or salt
according to claim 1, wherein the group R2 is in
the 5-position.
5. 3-Z-[1-(4-Aminomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone; or a tautomer, stereoisomer
or salt thereof.
6. 3-Z-((1-Phenylamino)-1-phenyl-methylene)-5-amido-
2-indolinone; or a tautomer, stereoisomer or salt thereof.
7. 3-Z-[1-(4-Bromophenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone; or a tautomer, stereoisomer or salt
thereof.
8. 3-Z-[1-((4-Dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone; or a tautomer,
stereoisomer or salt thereof.
9. 3-Z-[1-(4-Pyrrolidinomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone; or a tautomer, stereoisomer
or salt thereof.

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10. 3-Z-[1-(4-Piperidinomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone; or a tautomer, stereoisomer
or salt thereof.
11. 3-Z-[1-(4-Hexamethyleneiminomethyl-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone; or a tautomer,
stereoisomer or salt thereof.
12. 3-Z-[1-((4-(4-Benzyl-piperidino)-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone; or a
tautomer, stereoisomer or salt thereof.
13. 3-Z-[1-(4-(N-Butyl-aminomethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone; or a tautomer,
stereoisomer or salt thereof.
14. 3-Z-[1-(4-(N-(Phenyl-methyl)-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone; or a
tautomer, stereoisomer or salt thereof.
15. 3-Z-[1-(4-(N-Methyl-N-benzyl-amino-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone; or a
tautomer, stereoisomer or salt thereof.
16. 3-Z-[1-(4-Piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-dimethylcarbamoyl-2-indolinone; or a tautomer,
stereoisomer or salt thereof.
17. 3-Z-[1-(4-Piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-diethylcarbamoyl-2-indolinone; or a tautomer,
stereoisomer or salt thereof.
18. 3-Z-[1-(4-(3-Diethylamino-propoxy)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone; or a tautomer,
stereoisomer or salt thereof.
19. A pharmaceutical composition comprising a
compound, tautomer, stereoisomer or salt according to any

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one of claims 1 to 18 and a pharmaceutically acceptible
carrier or diluent.
20. A pharmaceutical composition according to claim 19
for treating excessive or abnormal cell proliferation.
21. A compound, tautomer, stereoisomer or salt
according to any one of claims 1 to 18 for treating
excessive or abnormal cell proliferation.
22. A use of a compound, tautomer, stereoisomer or
salt according to any one of claims 1 to 18 for treating
excessive or abnormal cell proliferation.
23. A use of a compound, tautomer, stereoisomer or
salt according to any one of claims 1 to 18 in manufacture
of a medicament for treating excessive or abnormal cell
proliferation.
24. Process for preparing a compound according to
claim 1 wherein:
a. a compound of general formula
<IMG>
wherein
X, R2 and R3 are as defined in claim 1, R6 denotes
a hydrogen atom, a protecting group for the nitrogen atom of
the lactam group or a bond to a solid phase and

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Z1 denotes a halogen atom, a hydroxy, alkoxy or
aralkoxy group,
is reacted with an amine of general formula
<IMG>
wherein
R4 and R5 are defined as in claim 1, and
subsequently, if necessary, any protecting group used for
the nitrogen atom of the lactam group is cleaved or a
compound thus obtained is cleaved from a solid phase or
b. in order to prepare a compound of general
formula I which contains an aminomethyl group and where X
denotes an oxygen atom, a compound of general formula
<IMG>
wherein
R1 to R4 are defined as in claim 1, and R7 has the
meanings given for R5 in claim 1, with the proviso that R5
contains a cyano group, is reduced and subsequently if
desired a compound of general formula I thus obtained which
contains an alkoxycarbonyl group is converted by hydrolysis
into a corresponding carboxy compound or

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a compound of general formula I thus obtained
which contains an amino or alkylamino group is converted by
alkylation or reductive alkylation into a corresponding
alkylamino or dialkylamino compound or
a compound of general formula I thus obtained
which contains an amino or alkylamino group is converted by
acylation into a corresponding acyl compound or
a compound of general formula I thus obtained
which contains a carboxy group is converted by
esterification or amidation into a corresponding ester or
aminocarbonyl compound or
if necessary a protecting group used during the
reactions to protect reactive groups is cleaved or
subsequently if desired a compound of general
formula I thus obtained is resolved into the stereoisomers
thereof or
a compound of general formula I thus obtained is
converted into a salt thereof with an inorganic or organic
acid or base.

Description

CA 02323111 2000-09-06
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S018-546a.603
Boehringer Ingelheim Pharma KG Case 5/1238-FL
D-55216 INGELHEIM Foreign filing text
New substituted indolinones, the preparation thereof and
their use as pharmaceutical compositions
The present invention relates to new substituted
indolinones of general formula
R3
I R4
\
Ra g Rs
<)!N>
I
R1
the isomers thereof, the salts thereof, particularly the
physiologically acceptable salts thereof which have
valuable properties.
The above compounds of general formula I wherein Rl
denotes a hydrogen atom or a prodrug group have valuable
pharmacological properties, particularly an inhibiting
effect on various kinases, especially complexes of CDKs
(CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9) with
their specific cyclines (A, Bl, B2, C, D1, D2, D3, E, F,
G1, G2, H, I and K) and on viral cycline (cf. L. Mengtao
in J. Virology 71(3), 1984-1991 (1997)), and the other
compounds of the above general formula I wherein R1 does
not represent a hydrogen atom or a prodrug group are
valuable intermediate products for preparing the
abovementioned compounds.

CA 02323111 2000-09-06
- 2 -
Thus, the present invention relates to the above
compounds of general formula I (the compounds wherein Rl
denotes a hydrogen atom or a prodrug group having
valuable pharmacological properties), the pharmaceutical
compositions containing the pharmacologically active
compounds, their use and processes for preparing them.
In the above general formula I
X denotes an oxygen or sulphur atom,
R1 denotes a hydrogen atom, a C1-9-alkoxy-carbonyl or
C2_q-alkanoyl group,
R2 denotes a carboxy-, C1-9-alkoxy-carbonyl or
aminocarbonyl group wherein the amino moiety may be
substituted by one or two C1_3-alkyl groups and the
substitutents may be identical or different,
R3 denotes a phenyl or naphthyl group which may be
substituted by fluorine, chlorine or bromine atoms, by
C1_3-alkyl, C1_3-alkoxy, cyano, trifluoromethyl, nitro,
amino, C1_3-alkylamino, di- (C1_3-alkyl) -amino,
C2_4-alkanoyl-amino, N- (C1_3-alkyl) -C2_9-alkanoylamino,
N- (C1_3-alkyl) -C2_9-alkanoylamino, C1_3-alkylsulphonylamino,
amino-C1_3-alkyl, C1_3-alkylamino-C1_3-alkyl, di-
(C1-3-alkyl) -amino-C1_3-alkyl, N- (C2-9-alkanoyl) -amino-
C1_3-alkyl or N- (C2_9-alkanoyl) -C1_3-alkylamino-C1-3-alkyl
groups and the substituents may be identical or
different,
R4 denotes a hydrogen atom or a C1_3-alkyl group and
R5 denotes a hydrogen atom,
a C:_5-alkyl group optionally substituted by a phenyl,
carboxy or C1_3-alkoxy-carbonyl group,

CA 02323111 2000-09-06
- 3 -
a C3-,-cycloalkyl group optionally substituted by a
C1_3-alkyl group,
an indanyl group optionally substituted by a C1-3-alkyl
group,
a 5-membered heteroaryl group which contains an imino
group optionally substituted by a C1_3-alkyl group, an
oxygen or sulphur atom or an imino group optionally
substituted by a C1_3-alkyl group and an oxygen, sulphur
or nitrogen atom or two nitrogen atoms or a 6-membered
heteroaryl group which contains 1 to 3 nitrogen atoms,
whilst additionally a 1,3-butadienylene bridge may be
attached via two adjacent carbon atoms or via one carbon
atom and an adjacent imino group of the abovementioned
5- and 6-membered heteroaryl groups and the carbon
skeleton of the abovementioned mono- and bicyclic rings
may be mono or disubstituted by fluorine, chlorine,
bromine or iodine atoms, by C1_5-alkyl or cyano groups
and the substituents may be identical or different,
a pyrrolidinyl or piperidinyl group linked via a carbon
atom, which may be substituted at the nitrogen atom by a
C1_3-alkyl group,
a phenyl group optionally disubstituted by fluorine,
chlorine, bromine or iodine atoms, by C1_5-alkyl, C1_3-
alkoxy, carboxy, C1_3-alkoxycarbonyl, aminosulphonyl,
nitro or cyano groups, whilst the substituents may be
identical or different,
a phenyl, pyridyl, pyrimidyl or thienyl group each of
which is substituted by a trifluoromethoxy group,
by a fluorine, chlorine, bromine or iodine atom, by
a C1_3-alkoxy group which may be substituted in the 2- or
3- position by an amino, C1_3-alkylamino, di- (C1-3-
alkyl) amino, phenyl-C1_3-alkylamino, N- (C1_3-alkyl) -phenyl-

CA 02323111 2000-09-06
- 4 -
C,_3-alkylamino, pyrrolidino or piperidino group,
by a phenyl-C1_3-alkylamino-C1_3-alkyl group which may
be mono- or disubstituted in the phenyl nucleus by a
trifluoromethyl group, by fluorine, chlorine, bromine or
iodine atoms, by C;_5-alkyl or C1_3-alkoxy groups, whilst
the substituents may be identical or different, and
additionally may be replaced at the amine nitrogen atom
by a C1_3-alkyl group wherein the hydrogen atoms from
position 2 may be wholly or partially replaced by
fluorine atoms,
by a C1_5-alkyl, phenyl, imidazolyl, C3_-,-cycloalkyl,
C1_3-alkoxy-C1_3-alkoxy, phenyl-C1-3-alkoxy, carboxy-
C1_3-alkyl, C1_3-alkoxycarbonyl-C1_3-alkyl, carboxy,
C1_3-alkoxycarbonyl, aminocarbonyl, C1_3-alkylamino-
carbonyl, di-(C1_3-alkyl)-aminocarbonyl, phenyl-
Cl-3-alkylaminocarbonyl, N- (C1-3-alkyl) -phenyl-C1_3-
alkylaminocarbonyl, piperazinocarbonyl, N-(C1_3-alkyl)-
piperazinocarbonyl, nitro, amino, C1_3-alkylamino, di-
(C1_3-alkyl)-amino, pyrrolidino, piperidino, morpholino,
C2_4-alkanoyl-amino, N- (Cl_3-alkyl) -CZ_9-alkanoylamino,
benzoylamino or N-(C1_3-alkyl)-benzoylamino group,
by an N- (C1_3-alkyl) -C2_q-alkanoylamino group which is
additionally substituted in the alkyl moiety by a
carboxy or C1_3-alkoxycarbonyl group,
by a C1-3-alkylaminocarbonyl or di- (C1_3-alkyl) -
aminocarbonyl group wherein an alkyl moiety is
additionally substituted by a di-(C1-3-alkyl)-amino
group, or
by an N- (C1-3-alkyl) -C1_3-alkylsulphonylamino or
N-(C1_3-alkyl)-phenylsulphonylamino group wherein the
alkyl moiety may additionally be substituted by a cyano,
carboxy, C1_3-alkoxycarbonyl, C1-3-alkylamino, di-
(C1_3-alkyl) -amino group, aminocarbonyl, C1_3-
alkylaminocarbonyl, di-(C1_3-alkyl)-aminocarbonyl,
piperidinocarbonyl or 2-[di-(C1_3-alkylamino)]-
ethylaminocarbonyl group,

CA 02323111 2000-09-06
- 5 -
a phenyl or thienyl group substituted by a C1_3-alkyl
group wherein the alkyl moiety is substituted by a
hydroxy, C,_3-alkoxy, carboxy, C1_3-alkoxy-carbonyl, amino,
C1_5-alkylamino, di- (C1_;-alkyl) -amino, C2_4-alkanoylamino,
N- (C1_3-alkyl) -C2_q-alkanoylamino, pyrrolidino,
dehydropyrrolidino, piperidino, dehydropiperidino, 3-
hydroxypiperidino, 4-hydroxypiperidino,
hexamethyleneimino, morpholino, thiomorpholino,
piperazino, 4-(C1_3-alkyl)-piperazino, 4-phenyl-
piperazino, 4-(C2_9-alkanoyl)-piperazino, 4-benzoyl-
piperazino or imidazolyl group,
whilst the abovementioned saturated
cycloalkyleneimino rings, C1_5-alkylamino or di-
(C1_5-alkyl)-amino groups may additionally be substituted
by one or two C1-5-alkyl groups, by a C3-,-cycloalkyl,
hydroxy, C1_3-alkoxy, carboxy, C1_3-alkoxycarbonyl,
aminocarbonyl, C:_3-alkylaminocarbonyl or di- (C1-3-alkyl) -
aminocarbonyl group, by a phenyl-C1_3-alkyl or phenyl
group optionally mono- or disubstituted in the phenyl
nucleus by fluorine, chlorine, bromine or iodine atoms
or by C1-3-alkyl or cyano groups, whilst the substituents
may be identical or different,
or a methylene group adjacent to the nitrogen atom
in the abovementioned cycloalkyleneimino rings may be
replaced by a carbonyl or sulphonyl group, and the
abovementioned monosubstituted phenyl groups may
additionally be substituted by a fluorine, chlorine or
bromine atom or by a methyl, amino, C1-3-alkylamino or
di- (C1_3-alkyl) -amino group, or
a phenyl ring optionally substituted by one or two
C1-3-alkoxy groups may be fused to one of the
abovementioned unsubstituted cycloalkyleneimino rings
via two adjacent carbon atoms.
The carboxy groups mentioned in the definition of the
groups above may also be replaced by a group which can
be converted in vivo into a carboxy group and

CA 02323111 2000-09-06
- 6 -
the amino and imino groups mentioned in the definition
of the groups above may also be replaced by a group
which can be cleaved in vivo.
Moreover, the saturated alkyl and alkoxy moieties
mentioned in the above definition containing more than 2
carbon atoms also include the branched isomers thereof,
such as, for example, the isopropyl, tert.butyl,
isobutyl group, etc.
Preferred compounds of general formula I are those
wherein
X denotes an oxygen or sulphur atom,
R1 denotes a hydrogen atom, a Cl_9-alkoxy-carbonyl or
C2_4-alkanoyl group,
R2 denotes a carboxy-, C1-9-alkoxy-carbonyl or
aminocarbonyl group wherein the amino moiety may be
substituted by one or two C1_3-alkyl groups and the
substituents may be identical or different,
R3 denotes a phenyl or naphthyl group which may be
substituted by fluorine, chlorine or bromine atoms, by
C1_3-alkyl, C1_3-alkoxy, cyano, trifluoromethyl, nitro,
amino, C1_3-alkylamino, di- (C1_3-alkyl) -amino,
C2_4-alkanoyl-amino, N- (C1_3-alkyl) -C2_4-alkanoylamino,
N- (C1_3-alkyl) -C2_q-alkanoylamino, C1_3-alkylsulphonylamino,
amino-C1-3-alkyl, C1_3-alkylamino-C1_3-alkyl, di-
(C1_3-alkyl) -amino-C1_3-alkyl, N- (C2_q-alkanoyl) -amino-
C1_3-alkyl or N- (C2_9-alkanoyl) -C1_3-alkylamino-C1_3-alkyl
groups and the substituents may be identical or
different,
R4 denotes a hydrogen atom or a C1_3-alkyl group and

CA 02323111 2000-09-06
- 7 -
R. denotes a hydrogen atom,
a C1_5-alkyl group optionally substituted by a phenyl,
carboxy or C1_3-alkoxy-carbonyl group,
a C3-7-cycloalkyl group optionally substituted by a
C1_3-alkyl group,
an indanyl group optionally substituted by a C1-3-alkyl
group,
a 5-membered heteroaryl group which contains an imino
group optionally substituted by a C1_3-alkyl group, an
oxygen or sulphur atom or an imino group optionally
substituted by a C1_3-alkyl group and an oxygen, sulphur
or nitrogen atom or two nitrogen atoms or a 6-membered
heteroaryl group which contains 1 to 3 nitrogen atoms,
whilst additionally a 1,3-butadienylene bridge may be
attached via two adjacent carbon atoms or via one carbon
atom and an adjacent imino group of the abovementioned
5- and 6-membered heteroaryl groups and the carbon
skeleton of the abovementioned mono- and bicyclic rings
may be mono or disubstituted by fluorine, chlorine,
bromine or iodine atoms, by C1_5-alkyl or cyano groups
and the substituents may be identical or different,
a pyrrolidinyl or piperidinyl group linked via a carbon
atom, which may be substituted at the nitrogen atom by a
C1_3-alkyl group,
a phenyl group optionally mono- or disubstituted by
fluorine, chlorine, bromine or iodine atoms, by
C1_5-alkyl or cyano groups, whilst the substituents may
be identical or different,
a phenyl, pyridyl, pyrimidyl or thienyl group each of
which is substituted by a C3_,-cycloalkyl, C1-3-alkoxy,

CA 02323111 2000-09-06
- 8 -
phenyl-C, _3-al koxy, carboxy-C1_3-al kyl, C, _3-al koxy-
carbonyl-C1_3-alkyl, carboxy, C,__j-alkoxycarbonyl,
aminocarbonyl, C1_;-alkylaminocarbonyl, di- (C,__,-alkyl) -
aminocarbonyl, nitro, amino, C,_3-alkylamino, di-
(C1_3-alkyl) -amino, C,_4-alkanoyl-amino, N- (C,_3-alkyl) -
C2_4-alkanoylamino or N- (C1_3-alkyl ) -Cz_4-alkanoylamino
group, by a C1_3-alkylaminocarbonyl group wherein the
alkyl moiety additionally substituted by a di-
(C1_3-alkyl) -amino group, or by a N- (C1_3-alkyl) -C1_3-al-
kylsulphonylamino group wherein the alkyl moiety may
additionally be substituted by a cyano, carboxy,
C1_3-alkoxycarbonyl, C;_3-alkylamino or di- (C1-3-alkyl) -
amino group,
a phenyl or thienyl group substituted by a C1_3-alkyl
group wherein the alkyl moiety is substituted by a
hydroxy, C1_3-alkoxy, carboxy, C1_3-alkoxy-carbonyl, amino,
C1_5-alkylamino, di- (C,_5-alkyl) -amino, C2_9-alkanoylamino,
N- (C1-3-alkyl) -C2_4-alkanoylamino, pyrrolidino, piperidino,
hexamethyleneimino, morpholino, piperazino,
4- (C1-3-alkyl) -piperazino, 4- (C2-9-alkanoyl) -piperazino,
4-benzoyl-piperazino or imidazolyl group, whilst the
abovementioned cycloalkyleneimino rings, C1_5-alkylamino
or di-(C1_5-alkyl)-amino groups may additionally be
substituted by a C1_5-alkyl, C3_,-cycloalkyl, hydroxy,
C1_3-alkoxy, carboxy, C1_3-alkoxycarbonyl, aminocarbonyl,
C1_3-alkylaminocarbonyl or di- (C1_3-alkyl) -aminocarbonyl
group, by a phenyl-C1-3-alkyl or phenyl group optionally
mono or disubstituted in the phenyl nucleus by fluorine,
chlorine, bromine or iodine atoms or by C1_3-alkyl or
cyano groups, whilst the substituents may be identical
or different, or a methylene group adjacent to the
nitrogen atom in the abovementioned cycloalkyleneimino
rings may be replaced by a carbonyl or sulphonyl group,
and the abovementioned monosubstituted phenyl group may
additionally be substituted by a fluorine, chlorine or
bromine atom or by a methyl group,

CA 02323111 2000-09-06
- 9 -
particularly those compounds of general formula I
wherein
X denotes an oxygen atom,
R1 denotes a hydrogen atom or a C1_4-alkoxycarbonyl group,
R2 denotes a carboxy, C,_q-alkoxycarbonyl or aminocarbonyl
group wherein the amino moiety may be substituted by one
or two C1_3-alkyl groups and the substituents may be
identical or different,
R3 denotes a phenyl group optionally substituted by a
fluorine, chlorine or bromine atom, by a methyl, cyano
or aminomethyl group,
R4 denotes a hydrogen atom or a methyl group and
R. denotes a hydrogen atom,
a C1_5-alkyl group optionally substituted by a carboxy or
C1_3-alkoxycarbonyl group, or a benzyl group,
a C3_7-cycloalkyl group optionally substituted by a
methyl group,
an indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl
group optionally substituted by a methyl group, to which
a phenyl ring may additionally be fused via two adjacent
carbon atoms,
a methylphenyl group optionally substituted by a
fluorine, chlorine or bromine atom, or by a methoxy,
carboxy, C1_3-alkyloxycarbonyl, nitro or aminosulphonyl
group, or a dimethoxyphenyl group,

CA 02323111 2000-09-06
- 10 -
a pyrrolidinyl or piperidinyl group linked via a carbon
atom, which may be substituted at the nitrogen atom by a
C1_,-alkyl group,
a phenyl group which is substituted
by a trifluoromethoxy group, by a fluorine,
chlorine, bromine or iodine atom,
by a Cl-3-alkoxy group which may be substituted in
the 2- or 3- position by an amino, C1_3-alkylamino, di-
(C1_;-alkyl) amino, phenyl-C1_3-alkylamino, N- (C1-3-alkyl) -
phenyl-C1_3-alkylamino, pyrrolidino or piperidino group,
by a phenyl-C1_3-alkylamino-C1_3-alkyl group which may be
[substituted] in the phenyl nucleus by a fluorine,
chlorine, bromine or iodine atom, by a C1_5-alkyl, Cl_3-
alkoxy or trifluoromethyl group and additionally at the
amine nitrogen atom by a C,-3-alkyl group wherein the
hydrogen atoms from position 2 may be wholly or
partially replaced by fluorine atoms,
by a C1-5-alkyl, phenyl, imidazolyl, C3_,-cycloalkyl,
C1_3-alkoxy-C1-3-alkoxy, phenyl-C1_3-alkoxy, carboxy-
Cl-3-alkyl, C1-3-alkoxycarbonyl-C1_3-alkyl, carboxy,
C1_3-alkoxycarbonyl, aminocarbonyl, C1_3-alkylamino-
carbonyl, di-(C1_3-alkyl)-aminocarbonyl, phenyl-
C1_3-alkylaminocarbonyl, N- (C1_3-alkyl) -phenyl-C1_3-
alkylaminocarbonyl, piperazinocarbonyl, N-(C1-3-alkyl)-
piperazinocarbonyl, nitro, amino, C1_3-alkylamino, di-
(Cl_3-alkyl)-amino, pyrrolidino, piperidino, morpholino,
Cz_q-alkanoyl-amino, N- (C1-3-alkyl) -C2_4-alkanoylamino,
benzoylamino or N-(C1_3-alkyl)-benzoylamino group,
by an N- (C1-3-alkyl) -C2_4-alkanoylamino group which is
additionally substituted in the alkyl moiety by a
carboxy or C1-3-alkoxycarbonyl group,
by a C1_3-alkylaminocarbonyl or di- (C1_3-alkyl) -
aminocarbonyl group wherein an alkyl moiety is
additionally substituted by a di-(C1_3-alkyl)-amino
group, or
by an N- (C1_3-alkyl) -C,_3-alkylsulphonylamino or

CA 02323111 2000-09-06
- 11 -
N-(C,_3-alkyl)-phenylsulphonylamino group wherein the
alkyl moiety may additionally be substituted by a cyano,
carboxy, C1_3-alkoxycarbonyl, C,_3-alkylamino, di-
(C,_3-alkyl) -amino group, aminocarbonyl, C1_3-
alkylaminocarbonyl, di-(C,_3-alkyl)-aminocarbonyl,
piperidinocarbonyl or 2-[di-(C1_3-alkylamino)]-
ethylaminocarbonyl group,
a phenyl group optionally substituted by a C1_3-alkyl
group wherein the alkyl moiety is substituted by a
hydroxy, C1_3-alkoxy, carboxy, C1_3-alkoxy-carbonyl, amino,
C1_5-alkylamino, di- (C1_5-alkyl) -amino, C2_9-alkanoylamino,
N- (C1_3-alkyl) -C2_4-alkanoylamino, pyrrolidino,
dehydropyrrolidino, piperidino, dehydropiperidino, 3-
hydroxypiperidino, 4-hydroxypiperidino,
hexamethyleneimino, morpholino, thiomorpholino,
piperazino, 4-(C1_3-alkyl)-piperazino, 4-phenyl-
piperazino, 4-(C2-4-alkanoyl)-piperazino, 4-benzoyl-
piperazino or imidazolyl group,
whilst the abovementioned saturated
cycloalkyleneimino rings, C1_5-alkylamino or di-
(C1-5-alkyl)-amino groups may additionally be substituted
by one or two Cl_5-alkyl groups, by a C3_,-cycloalkyl,
hydroxy, C1_3-alkoxy, carboxy, C1_3-alkoxycarbonyl,
aminocarbonyl, C1_3-alkylaminocarbonyl or di- (C1_3-alkyl) -
aminocarbonyl group, by a phenyl-C1-3-alkyl or phenyl
group optionally mono- or disubstituted in the phenyl
nucleus by fluorine, chlorine, bromine or iodine atoms
or by C1-3-alkyl or cyano groups, whilst the substituents
may be identical or different,
or a methylene group adjacent to the nitrogen atom
in the abovementioned cycloalkyleneimino rings may be
replaced by a carbonyl or sulphonyl group, and the
abovementioned monosubstituted phenyl groups may
additionally be substituted by a fluorine, chlorine or
bromine atom or by a methyl, amino, C1_3-alkylamino or
di- (C1_3-alkyl) -amino group, or

CA 02323111 2000-09-06
- 12 -
a phenyl ring optionally substituted by one or two
C1_3-alkoxy groups may be fused to one of the above-
mentioned unsubstituted cycloalkyleneimino rings via two
adjacent carbon atoms,
the isomers and salts thereof.
Particularly preferred compounds of the above general
formula I are those wherein
X denotes an oxygen atom,
R1 denotes a hydrogen atom,
R2 denotes a carboxy, C1_9-alkoxycarbonyl or aminocarbonyl
group wherein the amino moiety may be substituted by one
or two C1_3-alkyl groups and the substituents may be
identical or different,
R3 denotes a phenyl group optionally substituted by a
methyl group,
R4 denotes a hydrogen atom or a methyl group and
R. denotes a hydrogen atom,
a C1_3-alkyl group, a benzyl group or a methyl or ethyl
group substituted by a carboxy or C1_3-alkoxycarbonyl
group,
a C3_7-cycloalkyl group optionally substituted by a
methyl group,
an indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl
group optionally substituted by a methyl group, to which
a phenyl ring may additionally be fused via two adjacent
carbon atoms,

CA 02323111 2008-06-11
25771-675
13 -
a methylphenyl group optionally substituted by a
fluorine, chlorine or bromine atom, or by a methoxy,
carboxy, C1_3-alkyloxycarbonyl, nitro or aminosulphonyl
group, or a dimethoxyphenyl group,
a 3-pyrrolidinyl or 4-piperidinyl group which may be
substituted at the nitrogen atom by a C1_3-alkyl group,
a phenyl group which is substituted
by a trifluoromethoxy, benzyloxy, cyano or nitro
group, by a fluorine, chlorine or bromine atom,
by a C1_3-alkoxy group, whilst the ethoxy and n-
propoxy groups may each be terminally substituted by a
dimethylamino, diethylamino, N-ethyl-methylamino, N-
benzyl-methylamino or piperidino group,
by a phenyl-C1_3-alkylamino-C1_3-alkyl group which may
be substituted in the phenyl nucleus by a fluorine,
chlorine, bromine or iodine atom, by a methyl, methoxy
or trifluoromethyl group and additionally at the amine
nitrogen atom by a C1_3-alkyl or 2,2,2-trifluoroethyl
group,
by a C1-4-alkyl, phenyl, imidazolyl, cyclohexyl,
methoxymethyl, carboxymethyl, C1_3-alkoxycarbonyl-methyl,
carboxy, C1_3-alkoxycarbonyl, aminocarbonyl,
C1-3-alkylaminocarbonyl, di- (C1_3-alkyl ) -aminocarbonyl,
phenyl-C1-3-alkylaminocarbonyl, N- (C1-3-alkyl) -phenyl-C1-3-
alkylaminocarbonyl, piperazinocarbonyl, N-(C1_3-alkyl)-
piperazinocarbonyl, amino, C1_3-alkylamino, di-
(C1_3-alkyl)-amino, pyrrolidino, piperidino, morpholino,
C2-4 -alkanoyl-amino, N- (C,_3-alkyl) -C2_4-alkanoylamino,
benzoylamino or N-(C1-3-alkyl)-benzoylamino group,
by an N- (C1_3-alkyl )-CZ-4-alkanoylamino group which is
additionally substituted-in the alkyl moiety by a
carboxy or C1_3-alkoxycarbonyl group,
by a C1_3-alkylaminocarbonyl or di- (C1_3-alkyl) -
aminocarbonyl group wherein an alkyl moiety is
additionaliy substituted by a di-(C1_3-alkyl)-amino

CA 02323111 2000-09-06
- 14 -
group, or
by an N- (C,_3-alkyl) -C,_3-alkylsulphonylamino or
N-(C1_3-alkyl)-phenylsulphonylamino group wherein the
alkyl moiety may additionally be substituted by a cyano,
carboxy, C1_3-alkoxycarbonyl, C7_3-alkylamino, di-
(C1_3-alkyl)-amino group, aminocarbonyl, C1_;-
alkylaminocarbonyl, di-(C1_3-alkyl)-aminocarbonyl,
piperidinocarbonyl or 2-[di-(C1_3-alkylamino)]-
ethylaminocarbonyl group,
a phenyl group optionally substituted by a C1_3-alkyl
group wherein the alkyl moiety is substituted by a
hydroxy, C1-3-alkoxy, carboxy, C1_3-alkoxy-carbonyl, amino,
C1_5-alkylamino, di- (C1_5-alkyl) -amino, C2_4-alkanoylamino,
N- (C1_3-alkyl) -C2_4-alkanoylamino, pyrrolidino,
dehydropyrrolidino, piperidino, dehydropiperidino, 4-
hydroxypiperidino, hexamethyleneimino, morpholino,
thiomorpholino, piperazino, 4-(C1_3-alkyl)-piperazino, 4-
phenyl-piperazino, 4-(C2_4-alkanoyl)-piperazino,
4-benzoyl-piperazino or imidazolyl group,
whilst the abovementioned saturated
cycloalkyleneimino rings may additionally be substituted
by a phenyl group or by one or two methyl groups,
the abovementioned C1_5-alkylamino and di- (C1_s-
alkyl)-amino groups may additionally be substituted by
one or two C1_3-alkyl groups, by a cyclohexyl, hydroxy,
C1_3-alkoxy, carboxy, C1_3-alkoxycarbonyl, aminocarbonyl,
C1_3-alkylaminocarbonyl or di-(C1_3-alkyl)-aminocarbonyl
group, by a phenyl-C1_3-alkyl or phenyl group optionally
substituted in the phenyl nucleus by a fluorine,
chlorine, bromine or iodine atom or by a methyl or cyano
group,
or a methylene group adjacent to the nitrogen atom
in the abovementioned cycloalkyleneimino rings may be
replaced by a carbonyl or sulphonyl group, and the
abovementioned monosubstituted phenyl groups may
additionally be substituted by a fluorine, chlorine or

CA 02323111 2000-09-06
- 15 -
bromine atom or by a methyl, amino, C,_3-alkylamino or
di- (C1_3-alkyl) -amino group, or
a phenyl ring optionally substituted by one or two
C1_3-alkoxy groups may be fused to one of the
abovementioned unsubstituted cycloalkyleneimino rings
via two adjacent carbon atoms,
the isomers and salts thereof.
Most particularly preferred compounds of the above
general formula I are those wherein
X denotes an oxygen atom,
R1 denotes a hydrogen atom,
R2 denotes a carboxy or aminocarbonyl group wherein the
amino moiety may be substituted by one or two C1_3-alkyl
groups and the substituents may be identical or
different,
R3 denotes a phenyl group optionally substituted by a
methyl group,
R4 denotes a hydrogen atom and
R5 denotes a hydrogen atom,
a 3-pyrrolidinyl or 4-piperidinyl group which may be
substituted at the nitrogen atom by a C1_3-alkyl group,
a phenyl group which is substituted
by a C1_3-alkoxy group, whilst the ethoxy and n-propoxy
groups may each be terminally substituted by a
dimethylamino, diethylamino, N-ethyl-methylamino, N-
benzyl-methylamino or piperidino group,
by a phenyl-C1_3-alkylamino-C1_3-alkyl group which may be

CA 02323111 2000-09-06
- 16 -
substituted in the phenyl nucleus by a fluorine,
chlorine, bromine or iodine atom, by a methyl, methoxy
or trifluoromethyl group and additionally at the amine
nitrogen atom by a C,_-alkyl or 2,2,2-trifluoroethyl
group,
a phenyl group optionally substituted by a C1_3-alkyl
group wherein the alkyl moiety is substituted by a
hydroxy, C1_3-alkoxy, carboxy, C1_3-alkoxy-carbonyl, amino,
C1_5-alkylamino, di- (C:_5-alkyl) -amino, C1-4-alkanoylamino,
N- (C1_3-alkyl) -C2_4-alkanoylamino, pyrrolidino,
dehydropyrrolidino, piperidino, dehydropiperidino, 4-
hydroxypiperidino, hexamethyleneimino, morpholino,
thiomorpholino, piperazino, 4-(C1_3-alkyl)-piperazino, 4-
phenyl-piperazino, 4-(C2_4-alkanoyl)-piperazino,
4-benzoyl-piperazino or imidazolyl group,
whilst the abovementioned saturated
cycloalkyleneimino rings may additionally be substituted
by a phenyl group or by one or two methyl groups ,
the abovementioned C1_;-alkylamino and di- (C1_5-alkyl) -
amino groups may additionally be substituted by one or
two C1_3-alkyl groups, by a cyclohexyl, hydroxy,
C1_3-alkoxy, carboxy, C1_3-alkoxycarbonyl, aminocarbonyl,
C1_3-alkylaminocarbonyl or di- (C1_3-alkyl) -aminocarbonyl
group, by a phenyl-C1__j-alkyl or phenyl group optionally
substituted in the phenyl nucleus by a fluorine,
chlorine, bromine or iodine atom or by a methyl or cyano
group,
or a methylene group adjacent to the nitrogen atom
in the abovementioned cycloalkyleneimino rings may be
replaced by a carbonyl or sulphonyl group, and the
abovementioned monosubstituted phenyl groups may
additionally be substituted by a fluorine, chlorine or
bromine atom or by a methyl, amino, C1-3-alkylamino or
di- (C1_3-alkyl) -amino group, or
a phenyl ring optionally substituted by one or two
C1_3-alkoxy groups may be fused to one of the

CA 02323111 2000-09-06
- 17 -
abovementioned unsubstituted cycloalkyleneimino rings
via two adjacent carbon atoms,
the isomers and salts thereof.
Particularly preferred are the abovementioned compounds
wherein the group R2 is in the 5-position, particularly
the following compounds:
(a) 3-Z-[1-(4-aminomethyl-phenylamino)-l-phenyl-
methylene]-5-amido-2-indolinone,
(b) 3-Z-(1-phenylamino)-1-phenyl-methylene)-5-amido-2-
indolinone,
(c) 3-Z-[l-(4-bromophenylamino)-l-phenyl-methylene]-5-
amido-2-indolinone,
(d) 3-Z-[l-(4-dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone,
(e) 3-Z-[1-(4-pyrrolidinomethyl-phenylamino)-l-phenyl-
methylene]-5-amido-2-indolinone,
(f) 3-Z-[l-(4-piperidinomethyl-phenylamino)-l-phenyl-
methylene]-5-amido-2-indolinone,
(g) 3-Z-[l-(4-hexamethyleneiminomethyl-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone,
(h) 3-Z-[l-(4-(4-benzyl-piperidino)-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone,
(i) 3-Z-[l-(4-(N-butyl-aminomethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone,
(j) 3-Z-[1-(4-(N-(phenyl-methyl)-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone,

CA 02323111 2000-09-06
- 18 -
(k) 3-Z-[1-(4-(N-methyl-N-benzyl-amino-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone,
(1) 3-Z-[l-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-dimethylcarbamoyl-2-indolinone,
(m) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-diethylcarbamoyl-2-indolinone,
(n) 3-Z-[l-(4-(3-diethylamino-propoxy)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
and the salts thereof.
According to the invention the new compounds are
obtained for example using the following methods known
in principle from the literature:
a. reacting a compound of general formula
R3
I
- zl
R X
2 N
I
wherein R6
X, R2 and R3 are as hereinbefore defined,
R. denotes a hydrogen atom, a protecting group for the
nitrogen atom of the lactam group or a bond to a solid
phase and
Z, denotes a halogen atom, a hydroxy, alkoxy or aralkoxy
group, e.g. a chlorine or bromine atom, a methoxy,
ethoxy or benzyloxy group,
with an amine of general formula
N RS
H _ \ (III),
Ra

CA 02323111 2000-09-06
- 19 -
wherein
Rq and R. are as hereinbefore defined,
and if necessary subsequently cleaving any protecting
group used for the nitrogen atom of the lactam group, or
cleaving from a solid phase.
A suitable protecting group for the nitrogen atom of the
lactam group might be for example an acetyl, benzoyl,
ethoxycarbonyl, tert.butyloxycarbonyl or
benzyloxycarbonyl group and
a suitable solid phase might be a Rink or Sieber resin.
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 C, whilst any protecting
group used can be cleaved simultaneously by
transamidation.
If Z1 in a compound of general formula II denotes a
halogen atom, the reaction is preferably carried out in
the presence of an inert base at temperatures between 20
and 120 C.
If Z1 in a compound of general formula II denotes a
hydroxy, alkoxy or aralkoxy group, the reaction is
preferably carried out at temperatures between 20 and
200 C.
If any protecting group used subsequently has to be
cleaved, this is conveniently carried out either hydro-
lytically in an aqueous or alcoholic solvent, e.g. in
methanol/water, ethanol/water, isopropanol/water,

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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 C, preferably at
temperatures between 10 and 50 C,
or advantageously by transamidation with a primary or
secondary organic base such as ammonia, methylamine,
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 C, preferably at
temperatures between 10 and 50 C.
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 C, preferably at ambient temperature.
b. In order to prepare a compound of general formula I
which contains an aminomethyl group and X denotes an
oxygen atom:
Reduction of a compound of general formula
R3
R4
N
R7
Rz p ~IV) ,
R1
wherein
R1 to Rq are as hereinbefore defined and
R7 has the meanings given for R5 hereinbefore with the
proviso that R5 contains a cyano group.

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- 21 -
The reduction is preferably carried out by catalytic
hydrogenation with hydrogen in the presence of a
catalyst such as palladium/charcoal or platinum 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 at temperatures between 0 and 50 C,
but preferably at ambient temperature, and at a hydrogen
pressure from 1 to 7 bar, but preferably from 3 to 5
bar.
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
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 or dialkylamino compound, or
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
If a compound of general formula I is obtained which
contains a carboxy group, this can be converted by
esterification or amidation into a corresponding ester
or aminocarbonyl compound.
The subsequent hydrolysis is preferably carried out in
an aqueous solvent, e.g. in 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

CA 02323111 2000-09-06
- 22 -
or potassium hydroxide at temperatures between 0 and
100 C, preferably at temperatures between 10 and 50 C.
The subsequent reductive alkylation is preferably
carried out in a suitable solvent such as methanol,
methanol/water, methanol/water/ammonia, ethanol, ether,
tetrahydrofuran, dioxane 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, lithium borohydride
or lithium aluminium hydride at temperatures between 0
and 100 C, preferably at temperatures between 20 and
80 C.
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 triethylamine, N-ethyl-
diisopropylamine or dimethylaminopyridine, preferably at
temperatures between 20 C and the boiling temperature of
the solvent used.
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 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

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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-hydroxy-
benzotriazole,. N,N'-carbonyldiimidazole or
triphenylphosphine/carbon 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 C, preferably at temperatures between 0 and
100 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 or N-methyl-morpholine at
temperatures between 0 and 150 C, preferably at
temperatures between 50 and 100 C.
The subsequent esterification or amidation is
conveniently carried out by reacting a corresponding
reactive carboxylic acid derivative with a corresponding
alcohol or amine as described hereinbefore.
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.
For example, a protecting group for a carboxyl group may
be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl

CA 02323111 2000-09-06
24 -
or tetrahydropyranyl group and
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.
Any protecting group used is optionally subsequently
cleaved for example by hydrolysis in an aqueous solvent,
e.g. in water, isopropanol/water, acetic acid/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 C, preferably at temperatures between 10 and 50 C.
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 C, but preferably at ambient
temperature, and at a hydrogen pressure of 1 to 7 bar,
but preferably 3 to 5 bar.
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 C, but preferably at
ambient temperature.

CA 02323111 2000-09-06
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A 2,4-dimethoxybenzyl group, however, is preferably
cleaved in trifluoroacetic acid in the presence of
anisol.
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, dioxan,
ethyl acetate or ether.
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 dioxan
at temperatures between 20 and 50 C.
Moreover, chiral compounds of general formula I obtained
may be resolved into their enantiomers and/or
diastereomers.
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.
The enantiomers are preferably separated by column
separation on chiral phases or by recrystallisation from
an optically active solvent or by reacting with an

CA 02323111 2000-09-06
- 26 -
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.
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.
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 phar-
maceutical use into the physiologically acceptable salts
thereof. Suitable bases for this purpose include for
example sodium hydroxide, potassium hydroxide,
cyclohexylamine, ethanolamine, diethanolamine and
triethanolamine.

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- 27 -
The compounds of general formulae I to VIII 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.
As already mentioned, the new compounds of general
formula I wherein Rl represents a hydrogen atom or a
prodrug group have valuable pharmacological properties,
particularly inhibitory effects on various kinases and
cycline/CDK-complexes, on the proliferation of
cultivated human tumour cells and, when administered
orally, on the growth of tumours in nude mice infected
with human tumour cells.
For example, the compounds listed in Table 1 were tested
for their biological properties as follows:
Test 1
Inhibition of cycline/CDK enzyme, in vitro activity
High FiveTM insect cells (BTI-TN-5B1_4) which had been
infected with a high titre of recombinant baculovirus
were used to produce active human cycline/CDK
holoenzymes. By using a baculovirus vector which
contained two promoters (polyhedrin enhancer promoter,
P10 enhancer promoter), GST-tagged cyclines (e.g.
cycline Dl or cycline D3) with the corresponding His6-
tagged CDK subunit (e.g. for CDK4 or CDK6) were
expressed in the same cell. The active holoenzyme was
isolated by affinity chromatography on glutathione
sepharose. Recombinant GST-tagged pRB (aa 379-928) was
produced in E. coli and purified by affinity
chromatography on glutathione sepharose.
The substrates used for the kinase assays depended on
the specific kinases. Histone H1 (Sigma) was used as

CA 02323111 2006-04-25
25771-675
- 28 -
the substrate for cycline E/CDK2, cycline A/CDK2,
cycline B/CDK1 and for v-cycline/CDK6. GST-tagged pRB
(aa 379-928) was used as substrate for cycline D1/CDK4,
cycline D3/CDK4, cycline D1/CDK6 and for cycline
D3/CDK6.
Lysates of the insect cells infected with recombinant
baculovirus or recombinant kinases (obtained from the
lysates by purification) were incubated together with
radiolabelled ATP in the presence of a suitable
substrate with various concentrations of the inhibitor
in a 1% DMSO solution (dimethyl sulphoxide) for 45
minutes at 30 C. The substrate proteins with associated
radioactivity were precipitated with 5% TCA
(trichloroacetic acid) in water-repellent PVDF multi-
well microtitre plates (Millipore) or with 0.5%
phosphoric acid solution on WhatmanTMP81 filters. After
the addition of scintillation liquid the radioactivity
was measured in a Wallace 1450 Microbeta Liquid
Scintillation Counter. For each concentration of the
substance double measurements were carried out; IC50
values were calculated for the enzyme inhibition.
Test 2
Inhibition of the proliferation of cultivation human
tumour cells
Cells of the Leimyosarcoma tumour cell line SK-UT-1B
(obtained from the American Type Culture Collection
(ATCC)) were cultivated in Minimum Essential Medium with
non-essential amino acids (Gibco), supplemented with
sodium pyruvate (1 mmol), glutamine (2 mmol) and 10%
foetal calf serum (Gibco) and harvested during the log-
growth phase. Then the SK-UT-1B cells were added to
Cytostar multi-well plates (Amersham) at a density of
4000 cells per well and incubated overnight in an

CA 02323111 2000-09-06
- 29 -
incubator. Various concentrations of the compounds
(dissolved in DMSO; final concentration: <1%) were added
to the cells. After 48 hours' incubation 14C-thymidine
(Amersham) was added to each well and incubation was
continued for a further 24 hours. The quantity of 14C-
thymidine incorporated into the tumour cells in the
presence of the inhibitor and representing the number of
cells in the S phase was measured in a Wallace 1450
Microbeta Liquid Scintillation Counter. IC50 values for
the inhibition of proliferation (= inhibition of
incorporated 14C-thymidine) were calculated, correcting
for the background radiation. All the measurements were
done twice.
Test 3
In vivo effects on tumour-bearina nude mice
106 cells [SK-UT-lB, or non-small cell lung tumour NCI-
H460 (obtained from ATCC)] in a volume of 0.1 ml were
injected subcutaneously into male and/or female nude mice
(NMRI nu/nu; 25-35g; N = 10-20); alternatively, small
fragments of SK-UT-1B or NCI-H460 cell clumps were
implanted subcutaneously. One to three weeks after the
injection or implantation a kinase inhibitor was
administered daily by oral route for a period of 2 to 4
weeks (by oesophageal tube). The size of the tumour was
measured three times a week using a digital sliding
gauge. The effect of a kinase inhibitor on the tumour
growth was determined as a percentage inhibition compared
with a control group treated with placebo.
Table 2 which follows contains the results obtained in in
vitro test 2:

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- 30 -
Compound Inhibition of
(Example no.) SKUT-1B-
proliferation
IC50 [um]
4( 2) 0.17
4( 14) 0.18
4( 62) 0.05
4 ( 53) 0.01
4( 54) 0.03
4( 60) 0.03
4(120) 0.04
4(122) 0.04
4( 94) 0.03
3( 3) 0.01
3( 7) 0.01
4(129) 0.04
In view of their biological properties, the new compounds
of general formula I, their isomers and physiologically
acceptable salts are suitable for the treatment of
diseases characterised by excessive or abnormal cell
proliferation.
Such diseases include (with no claim to completeness):
viral infections (e.g. HIV and Kaposi's sarcoma);
inflammation and autoimmune diseases (e.g. colitis,
arthritis, Alzheimer's disease, glomerulonephritis and
wound healing); bacterial, fungal and/or parasitic
infections; leukaemias, lymphoma and solid tumours; skin
diseases (e.g. psoriasis); bone diseases; cardiovascular
diseases (e.g. restenosis and hypertrophy). They are
also useful for protecting proliferating cells (e.g.
hair, intestinal, blood and progenitor cells) against DNA
damage caused by radiation, UV treatment and/or

CA 02323111 2000-09-06
- 31 -
cytostatic treatment.
The new compounds may be used for the short-term or long-
term treatment of the abovementioned diseases, optionally
in conjunction with other state-of-the-art compounds such
as other cytostatics.
The dosage required to achieve such an effect is
appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg
by intravenous route, and 0.1 to 100 mg/kg, preferably
0.3 to 30 mg/kg by oral route, in each case administered
1 to 4 times a day. For this purpose, the compounds of
formula I prepared according to the invention may be
formulated, optionally together with other active
substances, with one or more inert conventional 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, cetylstearyl
alcohol, carboxymethylcellulose or fatty substances such
as hard fat or suitable mixtures thereof, to produce
conventional galenic preparations such as plain or coated
tablets, capsules, powders, suspensions or suppositories.
The Examples which follow are intended to illustrate the
invention:

CA 02323111 2000-09-06
- 32 -
Example I
Methyl 1-acetyl-2-indolinone-5-carboxylate
10.5 g of methyl 2-indolinone-5-carboxylate (prepared
analogously to Ogawa et al. Chem.Pharm.Bull 36, 2253-2258
(1988)) are stirred in 30 ml of acetic anhydride for 4
hours at 140 C. Then it is allowed to cool, poured onto
ice water and the precipitate is suction filtered. The
product is again washed with water, then taken up in
methylene chloride, dried over sodium sulphate and
concentrated by evaporation.
Yield: 11 g (86 % of theory),
Rf value: 0.63 (silica gel; methylene chloride/methanol =
50:1)
Example II
Methyl 1-acetyl-3-(1-ethoxy-l-phenyl-methylene)-2-
indolinone-5-carboxylate
11 g of methyl 1-acetyl-2-indolinone-5-carboxylate are
stirred into 110 ml of acetic anhydride and 30 ml of
triethyl orthobenzoate for 2 hours at 100 C. Then the
mixture is concentrated by rotary evaporation, the
residue is washed with ether and suction filtered.
Yield: 11.5 g (67 % of theory),
Rf value: 0.55 (silica gel, methylene chloride/petroleum
ether/ethyl acetate = 4:5:1)
Example III
28.0 g of Rink resin (MBHA resin, Messrs Novobiochem) are
allowed to swell in 330 ml of dimethylformamide. Then
330 ml of 30 % piperidine in dimethylformamide are added
and the mixture is shaken for 7 minutes in order to

CA 02323111 2000-09-06
- 33 -
cleave the FMOC protecting group. The resin is then
washed several times with dimethylformamide. Finally, 7.3
g of 2-indolinone-5-carboxylic acid, 5.6 g of
hydroxybenzotriazole, 13.3 g of 0-(benzotriazol-1-yl)-
N,N,N',N'-tetramethyl-uronium-tetrafluoroborate and 5.7
ml of N-ethyl-diisopropylamine in 300 ml of
dimethylformamide are added and the mixture is shaken for
1 hour. The solution is then suction filtered and the
resin is washed five times with 300 ml of
dimethylformamide and three times with 300 ml of
methylene chloride. To dry the resin, nitrogen is blown
through it.
Yield: 28 g of charged resin
Example IV
5 g of the charged resin prepared according to Example
III are stirred with 15 ml of acetic anhydride at 80 C
for 1 hour. Then 15 ml of triethyl orthobenzoate are
added and the resulting mixture is shaken for a further 3
hours at 110 C. The resin is then suction filtered and
washed with dimethylformamide, methanol and finally with
methylene chloride.
Yield: 7 g of moist resin
Exam lp e V
4-(Ethylamino-methyl)-nitrobenzene
6 g of 4-nitrobenzylbromide are dissolved in 25 ml of
ethanol, mixed with 25 ml of 10% ethanolic ethylamine
solution and refluxed for 2 hours. Then the solution is
evaporated down, the residue is taken up in methylene
chloride and washed with dilute sodium hydroxide
solution. Finally, the organic phase is evaporated down.
Yield: 2.3 g (46 % of theory),
Rf value: 0.2 (silica gel; methylene chloride/methanol =

CA 02323111 2000-09-06
- 34 -
9:1)
The following are prepared analogously:
4- [N- (4-chlorophenyl-methyl) -amino-methyl] -nitrobenzene
4-(N-cyclohexyl-amino-methyl)-nitrobenzene
4-(N-isopropyl-amino-methyl)-nitrobenzene
4-(N-butyl-amino-methyl)-nitrobenzene
4- (N-methoxycarbonyl-methyl-amino-methyl) -nitrobenzene
4- (N- (phenyl-methyl) -amino-methyl) -nitrobenzene
4-(pyrrolidino-methyl)-nitrobenzene
4-(morpholino-methyl)-nitrobenzene
4-(piperidino-methyl)-nitrobenzene
4-(hexamethyleneimino)-nitrobenzene
4-(4-hydroxy-piperidino-methyl)-nitrobenzene
4-(4-methyl-piperidino-methyl)-nitrobenzene
4-(4-ethyl-piperidino-methyl)-nitrobenzene
4-(4-isopropyl-piperidino-methyl)-nitrobenzene
4-(4-phenyl-piperidino-methyl)-nitrobenzene
4-(4-benzyl-piperidino-methyl)-nitrobenzene
4- (4-ethoxycarbonyl-piperidino-methyl) -nitrobenzene

CA 02323111 2000-09-06
- 35 -
4-(dimethylamino-methyl)-nitrobenzene
4-(dipropylamino-methyl)-nitrobenzene
4-(4-tert.butyloxycarbonyl-piperazino-methyl)-
nitrobenzene
3-(dimethylamino-methyl)-nitrobenzene
4-(2-diethylamino-ethyl)-nitrobenzene
4-(2-morpholinyl-ethyl)-nitrobenzene
4-(2-pyrrolidinyl-ethyl)-nitrobenzene
4-(2-piperidinyl-ethyl)-nitrobenzene
4-(N-ethyl-N-benzyl-amino-methyl)-nitrobenzene
4-(N-propyl-N-benzyl-amino-methyl)-nitrobenzene
4-[N-methyl-N-(4-chlorophenylmethyl)-amino-methyl])-
nitrobenzene
4-[N-methyl-N-(4-bromophenylmethyl)-amino-methyl]-
nitrobenzene
4-[N-methyl-N-(3-chlorophenylmethyl)-amino-methyl]-
nitrobenzene
4-[N-methyl-N-(3,4-dimethoxyphenylmethyl)-amino-methyl]-
nitrobenzene
4-[N-methyl-N-(4-methoxyphenylmethyl)-amino-methyl]-
nitrobenzene

CA 02323111 2000-09-06
36 -
4-[N-2,2,2-trifluoroethyl-N-(phenylmethyl)-amino-methyl]-
nitrobenzene
4-[N-2,2,2-trifluoroethyl-N-(4-chlorophenylmethyl)-amino-
methyl]-nitrobenzene
Example VI
4-(N-ethyl-N-tert.butor>ycarbonyl-amino-methyl)-
nitrobenzene
2.2 g of 4-(ethylamino-methyl)-nitrobenzene are dissolved
in 50 ml of ethyl acetate and stirred with 2.6 g of di-
tert-butyl-dicarbonate for 30 minutes at ambient
temperature. Then the solution is washed with water and
concentrated by evaporation.
Yield: 3.4 g,
Rf value: 0.9 (silica gel, methylene chloride/methanol =
9:1)
The following are prepared analogously:
4-[N-(4-chlorophenyl-methyl)-N-tert.butoxycarbonyl-amino-
methyl)-nitrobenzene
4-(N-cyclohexyl-N-tert.butoxycarbonyl-amino-methyl)-
nitrobenzene
4-(N-isopropyl-N-tert.butoxycarbonyl-amino-methyl)-
nitrobenzene
4-(N-butyl-N-tert.butoxycarbonyl-amino-methyl)-
nitrobenzene
4-(N-methoxycarbonyl-methyl-N-tert.butoxycarbonyl-amino-
methyl)-nitrobenzene

CA 02323111 2000-09-06
- 37 -
4-(N-(phenyl-methyl)-N-tert.butoxycarbonyl-amino-methyl)-
nitrobenzene
Example VII
4-(N-ethyl-N-tert.butoxycarbonyl-amino-methyl)-aniline
6.4 g of 4-(N-ethyl-N-tert.butoxycarbonyl-amino-methyl)-
nitrobenzene are dissolved in 60 ml of methanol and
hydrogenated with 1.5 g of Raney nickel at ambient
temperature and hydrogenated under 3 bars of pressure.
Then the catalyst is filtered off and the solution is
evaporated down.
Yield: 4.78 g,
Rf value: 0.7 (silica gel, methylene chloride/methanol
50:1)
The following are prepared analogously:
4-[N-(4-chlorophenyl-methyl)-N-tert.butoxycarbonyl-amino-
methyl]-aniline
4-(N-cyclohexyl-N-tert.butoxycarbonyl-amino-methyl)-
aniline
4-(N-isopropyl-N-tert.butoxycarbonyl-amino-methyl)-
aniline
4-(N-butyl-N-tert.butoxycarbonyl-amino-methyl)-aniline
4-(N-methoxycarbonyl-methyl-N-tert.butoxycarbonyl-amino-
methyl)-aniline
4-(N-(phenyl-methyl)-N-tert.butoxycarbonyl-amino-methyl)-
aniline
4-(pyrrolidino-methyl)-aniline

CA 02323111 2000-09-06
- 38 -
4-(morpholino-methyl)-aniline
4-(piperidino-methyl)-aniline
4-(hexamethyleneimino-methyl)-aniline
4-(4-hydroxy-piperidino-methyl)-aniline
4-(4-methyl-piperidino-methyl)-aniline
4-(4-ethyl-piperidino-methyl)-aniline
4-(4-isopropyl-piperidino-methyl)-aniline
4-(4-phenyl-piperidino-methyl)-aniline
4-(4-benzyl-piperidino-methyl)-aniline
4-(4-ethoxycarbonyl-piperidino-methyl)-aniline
4-(dimethylamino-methyl)-aniline
4-(dipropylamino-methyl)-aniline
4-(4-tert.butoxycarbonyl-piperazinyl-methyl)-aniline
3-(dimethylamino-methyl)-aniline
4-(2-diethylamino-ethyl)-aniline
4-(2-morpholinyl-ethyl)-aniline
4-(2-pyrrolidinyl-ethyl)-aniline
4-(2-piperidinyl-ethyl)-aniline
4-(N-ethyl-N-benzyl-amino-methyl)-aniline

CA 02323111 2000-09-06
- 39 -
4-(N-propyl-N-benzyl-amino-methyl)-aniline
4-[N-methyl-N-(4-chlorophenylmethyl)-amino-methyl]-
aniline
4- [N-methyl-N- (4-bromophenylmethyl) -amino-methyl] -aniline
4-[N-methyl-N-(3-chlorophenylmethyl)-amino-methyl]-
aniline
4-[N-methyl-N-(3,4-dimethoxyphenylmethyl)-amino-methyl]-
aniline
4-[N-methyl-N-(4-methoxyphenylmethyl)-amino-methyl]-
aniline
4- [N-2, 2, 2-trifluoroethyl-N- (phenylmethyl) -amino-methyl] -
aniline
4- [N-2, 2, 2-trifluoroethyl-N- (4-chlorophenylmethyl) -amino-
methyl]-aniline

CA 02323111 2000-09-06
- 40 -
Preparation of the end products:
Example 1
methyl 3-Z-[1-(1-methyl-piperidin-4-yl-amino)-1-phenyl-
methylenel-2-indolinone-5-carboxylate
11.5 g of methyl 1-acetyl-3-(1-ethoxy-l-phenyl-
methylene)-2-indolinone-5-carboxylate are dissolved in
115 ml of methylene chloride and stirred with 10.8 g of
4-amino-N-methylpiperidine for 5 hours at ambient
temperature. Then 20 ml of methanolic ammonia are added
and the mixture is left to stand overnight. The solution
is evaporated down and the residue is washed with ether.
Yield: 11.9 g (97 % of theory),
Rf value: 0.20 (silica gel; methylene chloride/methanol =
9:1)
C23H25N303
Mass spectrum: m/z = 391 (M')
The.following are prepared analogously:
(1) methyl 3-Z-[l-(4-(piperidino-methyl)-phenylamino)-1-
phenyl-methylene]-2-indolinone-5-carboxylate Rf value:
0.4 (silica gel, methylene chloride/methanol = 9:1)
C29H29N303
mass spectrum: m/z = 467 (M+)
(2) methyl 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-
methyl)-phenylamino)-1-phenyl-methylene]-2-indolinone-5-
carboxylate C32H29N303
mass spectrum: m/z = 503 (M+)
(3) methyl 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-
1-phenyl-methylene]-2-indolinone-5-carboxylate C26H25N-303
mass spectrum: m/z = 427 (M')

CA 02323111 2000-09-06
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(4) methyl 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-
1-phenyl-methylene]-2-indolinone-5-carboxylate C26H25N303
mass spectrum: m/z = 427 (M')
(5) methyl 3-Z-[1-(4-chlorophenylamino)-1-phenyl-
methylene]-2-indolinone-5-carboxylate
(6) methyl 3-Z-(1-phenylamino-l-phenyl-methylene)-2-
indolinone-5-carboxylate
Example 2
3-Z-[1-(l-methyl-piperidine-4-yl-amino)-1-phenyl-
methvlenel-2-indolinone-5- arboxylic acid
11.9 g of methyl 3-Z-[1-(1-methyl-piperidin-4-yl-amino)-
1-phenyl-methylene]-2-indolinone-5-carboxylate are
refluxed in 300 ml of methanol and 150 ml of 1N sodium
hydroxide solution for 4 hours. Then the mixture is
neutralised with 150 ml of 1N hydrochloric acid and
evaporated to dryness. The residue is washed with water
several times and dried.
Yield: 86 % of theory,
Rf value: 0.17 (silica gel; methylene chloride/methanol =
4:1)
C22H23N303
Mass spectrum: m/z = 377 (M+)
The following are prepared analogously:
(1) 3-Z-[1-(4-(piperidino-methyl)-phenylamino)-1-phenyl-
methylene]-2-indolinone-5-carboxylic acidRf value: 0.15
(silica gel, methylene chloride/methanol = 9:1)
C28H27N303
mass spectrum: m/z = 453 (M+)
(2) 3-Z-[1-(4-(N-phenylmethyl-N-methylamino-methyl)-
phenylamino)-1-phenyl-methylene)-2-indolinone-5-

CA 02323111 2000-09-06
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carboxylic acid
C31H27N303
mass spectrum: m/z = 489 (M+)
(3) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-2-indolinone-5-carboxylic acidC25H23N30,
mass spectrum: m/z = 413 (M+)
(4) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene) -2-indolinone-5-carboxylic acidC25H23N303
mass spectrum: m/z = 413 (M+)
(5) 3-Z-[1-(4-chlorophenylamino)-1-phenyl-methylene]-2-
indolinone-5-carboxylic acid
(6) 3-Z-[1-phenylamino-l-phenyl-methylene)-2-indolinone-
5-carboxylic acid
Exam lp e 3
3-Z-[1-(1-methyl-piperidine-4-yl-amino)-1-phenyl-
methvlenel-5-dimethylcarbamoyl-2-indolinone
2 g of 3-Z-[1-(1-methyl-piperidin-4-yl-amino)-1-phenyl-
methylene]-2-indolinone-5-carboxylic acid are refluxed
with 5 ml of thionylchloride for 2 hours. Then the
mixture is concentrated by rotary evaporation and the
residue is washed with ether. 0.5 g of this acid chloride
are taken up in 5 ml of methylene chloride without
further purification and mixed with 0.5 ml of
dimethylamine in 5 ml of methylene chloride and stirred
overnight at ambient temperature. The product is
chromatographed over a silica gel column with methylene
chloride/methanol/ammonia (4:1:0.1).
Yield: 50 % of theory,
Rf value: 0.14 (silica gel: methylene chloride/methanol =
9:1)

CA 02323111 2000-09-06
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C2qHzBN402
Mass spectrum: m/z = 404 (M')
The following compounds are prepared analogously:
(1) 3-Z-[1-(1-methyl-piperidin-4-yl-amino)-1-phenyl-
methylene]-5-methylcarbamoyl-2-indolinone
Yield: 49 % of theory,
Rf value: 0.19 (silica gel; methylene chloride/methanol =
4:1)
C23H26N402
Mass spectrum: m/z = 390 (M+)
(2) 3-Z-[1-(1-methyl-piperidin-4-yl-amino)-1-phenyl-
methylene]-5-carbamoyl-2-indolinone
Yield: 58 % of theory,
Rf value: 0.15 (silica gel; methylene chloride/methanol =
4:1)
C22H2qNq02
Mass spectrum: m/z = 376 (M+)
(3) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-dimethylcarbamoyl-2-indolinonePrepared from
3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-2-indolinone-5-carboxylic acid and
dimethylamine or 0.64 g of Z-[1-(4-piperidino-methyl-
phenylamino)-1-phenyl-methylene]-2-indolinone-5-
carboxylic acid, 0.34 g of dimethylamine hydrochloride,
0.9 g of 0-benzotriazol-1-yl-N,N,N`,N`-tetramethyluro-
nium-tetrafluoroborate), 0.4 g of 1-hydroxy-
1H-benzotriazole and 2.9 g of diisopropylethylamine are
stirred in 20 ml of dimethylformamide for 20 hours at
ambient temperature. The mixture is then evaporated down
and the residue is suspended in water. The precipitate is
suction filtered.
Yield: 600 mg (88% of theory),
Rf value: 0.2 (silica gel, methylene chloride/ethanol =

CA 02323111 2000-09-06
- 44 -
9:1)
C30H32N402
mass spectrum: m/z = 481 (M+H)+
(4) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-methylcarbamoyl-2-indolinone
Prepared from 3-Z-[1-(4-piperidino-methyl-phenylamino)-
1-phenyl-methylene]-2-indolinone-5-carboxylic acid and
methylamine analogously to Example 3(3).
Rf value: 0.2 (silica gel, methylene chloride/ethanol =
9:1)
~- C29H30N402
mass spectrum: m/z = 467 (M+H)+
(5) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-methylethylcarbamoyl-2-indolinonePrepared
from 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-2-indolinone-5-carboxylic acid and methyl-
ethylamine analogously to Example 3(3).
Rf value: 0.55 (silica gel, methylene chloride/ethanol =
9:1)
C31H34N402
mass spectrum: m/z = 495 (M+H)'
(6) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-propylcarbamoyl-2-indolinonePrepared from 3-
Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-2-indol=inone-5-carboxylic acid and propylamine
analogously to Example 3(3).
Rf value: 0.31 (silica gel, methylene chloride/ethanol =
9:1)
C31H34N402
mass spectrum: m/z = 495 (M+H)+
(7) 3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-
methylene]-5-diethylcarbamoyl-2-indolinonePrepared from
3-Z-[1-(4-piperidino-methyl-phenylamino)-1-phenyl-

CA 02323111 2000-09-06
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methylene]-2-indolinone-5-carboxylic acid and
diethylamine analogously to Example 3(3).-
Rf value: 0.55 (silica gel, methylene chloride/ethanol =
9:1)
C32H36N402
mass spectrum: m/z = 509 (M+H)+
(8) 3-Z-[l-(4-(N-phen_ylmethyl-N-methyl-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-methylcarbamoyl-2-
indolinone
(9) 3-Z-[1-(4-(N-phenylmethyl-N-methyl-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-dimethylcarbamoyl-2-
indolinone
(10) 3-Z-[1-(4-(N-phenylmethyl-N-methyl-aminomethyl)-
phenylamino)-l-phenyl-methylene]-5-diethylcarbamoyl-2-
indolinone
(11) 3-Z-[l-(4-(N-phenylmethyl-N-methyl-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-propylcarbamoyl-2-
indolinone
(12) 3-Z-[l-(4-(N-phenylmethyl-N-methyl-aminomethyl)-
~ 25 phenylamino)-1-phenyl-methylene]-5-dipropylcarbamoyl-2-
indolinone
(13) 3-Z-[l-(4-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-methylcarbamoyl-2-indolinone
(14) 3-Z-[l-(4-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-dimethylcarbamoyl-2-indolinone
(15) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino-l-
phenyl-methylene]-5-diethylcarbamoyl-2-indolinone

CA 02323111 2000-09-06
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(16) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-propylcarbamoyl-2-indolinone
(17) 3-Z-[1-(4-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-dipropylcarbamoyl-2-indolinone
(18) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-methylcarbamoyl-2-indolinone
(19) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-dimethylcarbamoyl-2-indolinone
(20) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-diethylcarbamoyl-2-indolinone
(21) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-propylcarbamoyl-2-indolinone
(22) 3-Z-[1-(3-(dimethylamino-methyl)-phenylamino)-1-
phenyl-methylene]-5-dipropylcarbamoyl-2-indolinone
(23) 3-Z-[1-(4-chlorophenylamino)-1-phenyl-methylene]-5-
methylcarbamoyl-2-indolinone
(24) 3-Z-[1-(4-chlorophenylamino)-1-phenyl-methylene]-5-
dimethylcarbamoyl-2-indolinone
(25) 3-Z-[1-(4-chlorophenylamino-l-phenyl-methylene]-5-
diethylcarbamoyl-2-indolinone
(26) 3-Z-[1-(4-chlorophenylamino)-1-phenyl-methylene]-5-
propylcarbamoyl-2-indolinone
(27) 3-Z-[1-(4-chlorophenylamino)-1-phenyl-methylene]-5-
dipropylcarbamoyl-2-indolinone

CA 02323111 2000-09-06
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(28) 3-Z-(1-phenylamino-l-phenyl-methylene)-5-
methylcarbamoyl-2-indolinone
(29) 3-Z-(1-phenylamino-l-phenyl-methylene)-5-
dimethylcarbamoyl-2-indolinone
(30) 3-Z-(1-phenylamino-l-phenyl-methylene)-5-
diethylcarbamoyl-2-indolinone
(31) 3-Z-(1-phenylamino-l-phenyl-methylene)-5-
propylcarbamoyl-2-indolinone
(32) 3-Z-(1-phenylamino-l-phenyl-methylene)-5-
dipropylcarbamoyl-2-indolinone
Example 4
3-Z-[1-(4-amino-phenylamino)-1-phenyl-methylene]-5-amido-
2-indolinone
800 mg of resin prepared according to Example IV are
suspended in 4 ml of methylene chloride and shaken with
0.8 g of 1,4-phenylenediamine for 16 hours at ambient
temperature. The mixture is filtered and the resin is
washed several times with methylene chloride, methanol
and dimethylformamide. Then 3 ml of methanolic ammonia is
added for 2 hours in order to eliminate the acetyl group.
Finally, after further washing, 4 ml of 10%
trifluoroacetic acid in methylene chloride is added over
a period of 90 minutes, the resin is separated off and
the solution is evaporated down. The residue is taken up
in a little 1N sodium hydroxide solution and extracted
with methylene chloride. The organic phase is dried over
sodium sulphate and concentrated by rotary evaporation.
Yield: 45 mg (30 % of theory over all the steps),
Rf value: 0.26 (silica gel; methylene chloride/methanol =
9:1)

CA 02323111 2000-09-06
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CZZH18Nq02
Mass spectrum: m/z = 370 (M`)
The following compounds are prepared analogously:
(1) 3-Z-[1-(3-amino-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 24 % of theory,
Rf value: 0.44 (silica gel; methylene chloride/methanol =
9:1)
CzzHieNa02
Mass spectrum: m/z = 370 (M+)
(2) 3-Z-(1-phenylamino)-l-phenyl-methylene)-5-amido-2-
indolinone
Yield: 27 % of theory,
Rf value: 0.53 (silica gel; methylene chloride/methanol =
9:1)
C22H17N302
Mass spectrum: m/z = 355 (M+)
(3) 3-Z-[1-(4-acetylamino-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 28 % of theory,
Rf value: 0.35 (silica gel; methylene chloride/methanol =
9:1)
C2aH2oNa03
Mass spectrum: m/z = 412 (M+)
(4) 3-Z-[l-(4-acetyl-N-methyl-amino-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
Yield: 15 % of theory,
Rf value: 0.36 (silica gel; methylene chloride/methanol =
9:1)
C25H22N403
Mass spectrum: m/z = 426 (M+)

CA 02323111 2000-09-06
- 49 -
~e
(5) 3-Z-[l-(4-(2-amino-ethyl)-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 30 % of theory,
Rf value: 0.04 (silica gel; methylene chloride/methanol =
9:1)
C24H22N402
Mass spectrum: m/z = 398 (M+)
(6) 3-Z-[l-(4-methoxy-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 32 % of theory,
Rf value: 0.48 (silica gel; methylene chloride/methanol =
9:1)
C23H19N303
Mass spectrum: m/z = 385 (M+)
(7) 3-Z-[l-(4-biphenylamino)-1-phenyl-methylene]-5-amido-
2-indolinone
Yield: 22 % of theory,
Rf value: 0.51 (silica gel; methylene chloride/methanol =
9:1)
C2eH2iN302
Mass spectrum: m/z = 431 (M')
(8) 3-Z-[1-(3-pyridylamino)-1-phenyl-methylene]-5-amido-
2-indolinone
Yield: 35 % of theory,
Rf value: 0.41 (silica gel; methylene chloride/methanol =
9:1)
C21H16N402
Mass spectrum: m/z = 356 (M+)
(9) 3-Z-[1-(4-dimethylamineo-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 19 % of theory,
Rf value: 0.49 (silica gel; methylene chloride/methanol =
9:1)

CA 02323111 2000-09-06
- 50 -
C24H22N40,
Mass spectrum: m/z = 398 (M')
(10) 3-Z-[l-(4-morpholino-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 42 % of theory,
Rf value: 0.48 (silica gel; methylene chloride/methanol =
9:1)
C26H24N403
Mass spectrum: m/z = 440 (M+)
(11) 3-Z-[1-(4-tert.butyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 32 % of theory,
Rf value: 0.48 (silica gel; methylene chloride/methanol =
9:1)
C26H25N302
Mass spectrum: m/z = 411 (M+)
(12) 3-Z-[1-(2-amino-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 28 % of theory,
Rf value: 0.52 (silica gel; methylene chloride/methanol =
9:1)
C22H18N402
Mass spectrum: m/z = 370 (M+)
(13) 3-Z-[1-(4-benzyloxy-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 40 % of theory,
Rf value: 0.4 (silica gel; methylene chloride/methanol =
9:1)
C29H23N303
Mass spectrum: m/z = 461 (M+)
(14) 3-Z-[l-(4-bromophenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone

CA 02323111 2000-09-06
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Yield: 35 % of theory,
Rf value: 0.46 (silica gel; methylene chloride/methanol =
9:1)
C22H16BrN3O2
Mass spectrum: m/z = 433/435 (M+)
(15) 3-Z-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 34 % of theory,
Rf value: 0.36 (silica gel; methylene chloride/methanol =
9:1)
C2qH19N304
Mass spectrum: m/z = 413 (M+)
(16) 3-Z-[1-(3-amido-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 32 % of theory,
Rf value: 0.32 (silica gel; methylene chloride/methanol =
9:1)
C23H18N403
Mass spectrum: m/z = 398 (M+)
(17) 3-Z-[1-(3-methyl-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 12 % of theory,
Rf value: 0.5 (silica gel; methylene chloride/methanol =
9:1)
C23H19N302
Mass spectrum: m/z = 369 (M+)
(18) 3-Z-[1-(2-methyl-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 21 % of theory,
Rf value: 0.5 (silica gel; methylene chloride/methanol =
9:1)
C23Hi9N302
Mass spectrum: m/z = 369 (M+)

CA 02323111 2000-09-06
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(19) 3-Z-[1-(3-methoxy-phenylamino)-1-phenyl-methylene]-
5-amido-2-indolinone
Rf value: 0.49 (silica gel; methylene chloride/methanol =
9:1)
C23H19N303
Mass spectrum: m/z = 385 (M+)
(20) 3-Z-[1-(3-ethoxycarbonyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Rf value: 0.48 (silica gel; methylene chloride/methanol =
9:1)
C2sH2iN3Ca
Mass spectrum: m/z = 427 (M+)
(21) 3-Z-[1-(3-nitro-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 32 % of theory,
Rf value: 0.56 (silica gel; methylene chloride/methanol =
9:1)
C22H16N404
Mass spectrum: m/z = 400 (M+)
(22) 3-Z-[1-(4-amido-phenylamino)-l-phenyl-methylene]-5-
amido-2-indolinone
Yield: 26 % of theory,
Rf value: 0.47 (silica gel; methylene chloride/methanol =
9:1)
C23H18N403
Mass spectrum: m/z = 398 (M+)
(23) 3-Z-[1-(4-pyridylamino)-1-phenyl-methylene]-5-amido-
2-indolinone
Yield: 15 % of theory,
Rf value: 0.42 (silica gel; methylene chloride/methanol =
9:1)
C21H16N402
Mass spectrum: m/z = 356 (M+)

CA 02323111 2000-09-06
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(24) 3-Z-[1-(4-methyl-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 45 % of theory,
Rf value: 0.54 (silica gel; methylene chloride/methanol =
9:1)
C23H19N302
Mass spectrum: m/z = 369 (M')
(25) 3-Z-[1-(4-ethoxy-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 40 % of theory,
Rf value: 0.51 (silica gel; methylene chloride/methanol =
9:1)
C2aH2iN303
Mass spectrum: m/z = 399 (M+)
(26) 3-Z-[l-(3-bromophenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 41 % of theory,
Rf value: 0.53 (silica gel; methylene chloride/methanol =
9:1)
C22H16BrN3O2
Mass spectrum: m/z = 433/435 (M+)
(27) 3-Z-[1-(4-chlorophenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 50 % of theory,
Rf value: 0.49 (silica gel; methylene chloride/methanol =
9:1)
C22H16C1N302
Mass spectrum: m/z = 389 (M')
(28) 3-Z-[1-(4-isopropyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 48 % of theory,
Rf value: 0.65 (silica gel; methylene chloride/methanol =
9:1)

CA 02323111 2000-09-06
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C25H23N302
Mass spectrum: m/z = 397 (M+)
(29) 3-Z-[1-(2-fluorenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 43 % of theory,
Rf value: 0.58 (silica gel; methylene chloride/methanol =
9:1)
C29H21N302
Mass spectrum: m/z = 443 (M+)
(30) 3-Z-[1-(4-(2-hydroxyethyl)-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 22 % of theory,
Rf value: 0.37 (silica gel; methylene chloride/methanol =
9:1)
C2aH2iN303
Mass spectrum: m/z = 398 (M-H)
(31) 3-Z-[1-(4-(4-imidazolyl)-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 23 % of theory,
Rf value: 0.5 (silica gel; methylene chloride/methanol =
9:1)
C25H19N502
Mass spectrum: m/z = 421 (M+)
(32) 3-Z-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C26H23N304
Mass spectrum: m/z = 442 (M+H)+
(33) 3-Z-[1-(4-bromo-3-methyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C23H18BrN302
Mass spectrum: m/z = 447/449 (M')

CA 02323111 2000-09-06
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(34) 3-Z-[1-(4-cyclohexyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C28H27N302
Mass spectrum: m/z = 437 (M+)
(35) 3-Z-[1-(4-bromo-2-methyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C23H18BrN3O2
Mass spectrum: m/z = 447/449 (M+)
(36) 3-Z-(1-ainino-l-phenyl-methylene)-5-amido-2-
indolinone
Rf value: 0.3 (silica gel; methylene chloride/methanol =
9:1)
C16H13N302
Mass spectrum: m/z = 279 (M+)
(37) 3-Z-(1-cyclohexylamino-l-phenyl-methylene)-5-amido-
2-indolinone
Rf value: 0.55 (silica gel; methylene chloride/methanol =
9:1)
C22H23N302
Mass spectrum: m/z = 361 (M+)
(38) 3-Z-(1-cyclopentylamino-l-phenyl-methylene)-5-amido-
2-indolinone
Rf value: 0.53 (silica gel; methylene chloride/methanol =
9:1)
C21H21N302
Mass spectrum: m/z = 347 (M+)
(39) 3-Z-(1-methylamino-l-phenyl-methylene)-5-amido-2-
indolinone
Rf value: 0.5 (silica gel; methylene chloride/methanol =
9:1)
C17H15N302
Mass spectrum: m/z = 293 (M+)

CA 02323111 2000-09-06
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(40) 3-Z-(1-ethylamino-l-phenyl-methylene)-5-amido-2-
indolinone
Rf value: 0.52 (silica gel; methylene chloride/methanol =
9:1)
C18H17N302
Mass spectrum: m/z = 307 (M+)
(41) 3-Z-(1-isopropylamino-l-phenyl-methylene)-5-amido-2-
indolinone
Rf value: 0.44 (silica gel; methylene chloride/methanol =
9:1)
C29Hi9N302
Mass spectrum: m/z = 321 (M+)
(42) 3-Z-(1-dimethylamino-l-phenyl-methylene)-5-amido-2-
indolinone
Rf value: 0.39 (silica gel; methylene chloride/methanol =
9:1)
C18H17N302
Mass spectrum: m/z = 307 (M+)
(43) 3-Z-(1-cyclopropylamino-l-phenyl-methylene)-5-amido-
2-indolinone
Rf value: 0.47 (silica gel; methylene chloride/methanol =
9:1)
C19H17N302
Mass spectrum: m/z = 319 (M+)
(44) 3-Z-(1-cycloheptylamino-l-phenyl-methylene)-5-amido-
2-indolinone
Rf value: 0.58 (silica gel; methylene chloride/methanol =
9:1)
C23H25N302
Mass spectrum: m/z = 375 (M+)
(45) 3-Z-(1-cyclobutylamino-l-phenyl-methylene)-5-amido-
2-indolinone

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Rf value: 0.49 (silica gel; methylene chloride/methanol =
9:1)
C20H19N302
Mass spectrum: m/z = 333 (M+)
(46) 3-Z-[1-(4-methylcyclohexylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Rf value: 0.67 (silica gel; methylene chloride/methanol =
9:1)
C23H25N302
Mass spectrum: m/z = 375 (M+)
(47) 3-Z-[1-(1-(R,S)-indanylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Rf value: 0.59 (silica gel; methylene chloride/methanol =
9:1)
C25H21N302
Mass spectrum: m/z = 395 (M+)
(48) 3-Z-[1-(methoxycarbonylmethylamino)-l-phenyl-
methylene]-5-amido-2-indolinone
Rf value: 0.46 (silica gel; methylene chloride/methanol =
9:1)
C19H17N304
Mass spectrum: m/z = 351 (M+)
(49) 3-Z-[l-((2-methoxycarbonyl-ethyl)-amino)-1-phenyl-
methylene]-5-amido-2-indolinone
Rf value: 0.45 (silica gel; methylene chloride/methanol =
9:1)
C20H19N304
Mass spectrum: m/z = 365 (M+)
(50) 3-Z-[1-(4-aminomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 32 % of theory,
Rf value: 0.46 (silica gel; methylene chloride/methanol =

CA 02323111 2000-09-06
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9:1)
C23H20N402
Mass spectrum: m/z = 384 (M+)
(51) 3-Z-[1-(4-pyrrolidinomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone-trifluoroacetate
Yield: 60 % of theory,
Rf value: 0.07 (silica gel; methylene chloride/methanol =
9:1)
C27H26N402
Mass spectrum: m/z = 438 (M+)
(52) 3-Z-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 65 % of theory,
Rf value: 0.46 (silica gel; methylene chloride/methanol =
9:1)
C27H26N403
Mass spectrum: m/z = 454 (M+)
(53) 3-Z-[l-(4-piperidinomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone-trifluoroacetate
Yield: 60 % of theory,
Rf value: 0.08 (silica gel; methylene chloride/methanol =
9:1)
C28H28N402
Mass spectrum: m/z = 452 (M+)
(54) 3-Z-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C29H30N402
Mass spectrum: m/z = 466 (M+)
(55) 3-Z-[1-(4-(4-hydroxy-piperidinomethyl)-phenylamino)-
1-phenyl-methylene]-5-amido-2-indolinone
C28H28N403
Mass spectrum: m/z = 468 (M+)

CA 02323111 2000-09-06
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(56) 3-Z-[1-(4-(4-methyl-piperidinomethyl)-phenylamino)-
1-phenyl-methylene]-5-amido-2-indolinone
C29H30N402
Mass spectrum: m/z = 466 (M+)
(57) 3-Z-[1-(4-(4-ethyl-piperidinomethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C30H32N402
Mass spectrum: m/z = 480 (M+)
(58) 3-Z-[1-(4-(4-isopropyl-piperidinomethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone
C31H34N402
Mass spectrum: m/z = 494 (M')
(59) 3-Z-[1-(4-(4-phenyl-piperidinomethyl)-phenylamino)-
1-phenyl-methylene]-5-amido-2-indolinone
C34H32N4O
2
Mass spectrum: m/z = 528 (M+)
(60) 3-Z-[1-(4-(4-benzyl-piperidinomethyl)-phenylamino)-
1-phenyl-methylene]-5-amido-2-indolinone
C35H34N402
Mass spectrum: m/z 0 542 (M+)
(61) 3-Z-[1-(4-(4-ethoxycarbonyl-piperidinomethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone
C31H32N404
Mass spectrum: m/z = 524 (M+)
(62) 3-Z-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C25H24N402
Mass spectrum: m/z = 412 (M+)
(63) 3-Z-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone

CA 02323111 2000-09-06
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C29H32N402
Mass spectrum: m/z = 468 (M+)
(64) 3-Z-[1-(4-piperazinylmethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C27H27N502
Mass spectrum: m/z = 453 (M+)
(65) 3-Z-[l-(3-dimethylaminomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C25H24N402
Mass spectrum: m/z = 412 (M+)
(66) 3-Z-[l-(4-(2-diethylamino-ethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C28H30N402
Mass spectrum: m/z = 454 (M+)
(67) 3-Z-[l-(4-(2-morpholino-ethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C28H28N403
Mass spectrum: m/z = 468 (M+)
(68) 3-Z-[l-(4-(2-pyrrolidinyl-ethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C28H28N402
Mass spectrum: m/z = 452 (M+)
(69) 3-Z-[1-(4-(2-piperidinyl-ethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C29H30N402
Mass spectrum: m/z = 466 (M+)
(70) 3-Z-[1-(2-thiazolylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Yield: 30 % of theory,
Rf value: 0.48 (silica gel; methylene chloride/methanol =

CA 02323111 2000-09-06
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9:1)
C19H14Nq02S
Mass spectrum: m/z = 362 (M)
(71) 3-Z-[1-(2-benzimidazolylamino)-1-phenyl-methylene]-
5-amido-2-indolinone
Yield: 29 % of theory,
Rf value: 0.44 (silica gel; methylene chloride/methanol =
9:1)
C23H17N502
Mass spectrum.: m/z = 395 (MT)
(72) 3-Z-[1-(5-methyl-isoxazol-3-yl-amino)-1-phenyl-
methylene]-5-amido-2-indolinone
Yield: 39 % of theory,
Rf value: 0.43 (silica gel; methylene chloride/methanol =
9:1)
C21H18N403
Mass spectrum: m/z = 374 (M+)
(73) 3-Z-(1-benzylamino-l-phenyl-methylene)-5-amido-2-
indolinone
Rf value: 0.63 (silica gel; methylene chloride/methanol =
9:1)
C23H19N302
Mass spectrum: m/z = 369 (M+)
(74) 3-Z-[1-(4-(1-imidazolyl-methyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
Rf value: 0.45 (silica gel; methylene chloride/methanol =
9:1)
C26H21N502
Mass spectrum: m/z = 436 (M+H)+
(75) 3-Z-[1-(4-((2-diethylamino-ethyl)-aminocarbonyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate

CA 02323111 2000-09-06
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Yield: 27 % of theory,
Rf value: 0.05 (silica gel; methylene chloride/methanol =
9:1)
C29H31N503
Mass spectrum: m/z = 497 (M+)
(76) 3-Z-[1-(4-acetylaminomethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
Rf value: 0.4 (silica gel; methylene chloride/methanol =
9:1)
C2sH22Na03
Mass spectrum: m/z = 426 (M+)
(77) 3-Z-[1-(4-((2-dimethylaminoethyl)-N-
methanesulphonyl-amino)-phenylamino)-1-phenyl-methylene]-
5-amido-2-indolinone
Rf value: 0.1 (silica gel; methylene chloride/methanol =
9:1)
C27H29N504S
Mass spectrum: m/z = 519 (M+)
(78) 3-Z- [ 1- ( 4- ( N- ( ethoxycarbonylmethyl )-N-
methanesulphonyl-amino)-phenylamino)-1-phenyl-methylene]-
5-amido-2-indolinone
Rf value: 0.57 (silica gel; methylene chloride/methanol =
9:1)
C27H26N406
Mass spectrum: m/z = 534 (M+)
(79) 3-Z-[1-(4-(N-(cyanomethyl)-N-methanesulphonyl-
amino)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone
Rf value: 0.49 (silica gel; methylene chloride/methanol =
9:1)
C25H21N504S
Mass spectrum: m/z = 487 (M+)

CA 02323111 2000-09-06
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(80) 3-Z-[1-(4-(N-methyl-N-methanesulphonyl-amino)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone
Rf value: 0.46 (silica gel; methylene chloride/methanol =
9:1)
C24H22N404S
Mass spectrum: m/z = 462 (M+)
(81) 3-Z-[l-(4-(2-oxo-pyrrolidin-1-yl-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone
C27H24N403
Mass spectrum: m/z = 452 (M+)
(82) 3-Z-[1-(4-(2-oxo-piperidin-1-yl-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone
C28H26N403
mass spectrum: m/z = 466 (M+)
(83) 3-Z-[1-(4-(4-cyclohexyl-piperidino-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate C34H38N402
mass spectrum: m/z = 534 (M+)
(84) 3-Z-[1-(4-(2,6-dimethyl-piperidino-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C30H32N402
mass spectrum: m/z: 480 (M')
(85) 3-Z-[l-(4-(4-phenyl-4-hydroxy-piperidino-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C34H32N403
mass spectrum: m/z = 545 (M+)
Rf value: 0.66 (silica gel, methylene chloride/methanol =
4:1)

CA 02323111 2000-09-06
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(86) 3-Z-[1-(4-(2-methoxycarbonyl-pyrrolidino-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C29H28N404
mass spectrum: m/z = 497 (M+H)+
Rf value: 0.65 (silica gel, methylene chloride/methanol =
4:1)
(87) 3-Z-[1-(4-(1-oxo-thiomorpholin-4-ylmethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C27H26N403S
mass spectrum: m/z = 487 (M+H)+
Rf value: 0.68 (silica gel, methylene chloride/methanol =
4:1)
(88) 3-Z-[1-(4-(3,6-dihydro-2H-pyridin-1-ylmethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C28H26N402
mass spectrum: m/z = 451 (M+H)+
(89) 3-Z-[l-(4-(2,5-dihydro-pyrrol-1-ylmethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C27H24N402
mass spectrum: m/z = 437 (M+H)+
Rf value: 0.49 (silica gel, methylene chloride/methanol =
4:1)
(90) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)-phenylamino)-
1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
Cz,H26Nq02S
mass spectrum: m/z = 471 (M+H)+
Rf value: 0.78 (silica gel, methylene chloride/methanol =
4:1)

CA 02323111 2000-09-06
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(91) 3-Z-[1-(4-(6,7-dimethoxy-tetrahydroisoquinolin-2-
ylmethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone-trifluoroacetate
C34H32N404
mass spectrum: m/z = 561 (M+H)+
Rf value: 0.8 (silica gel, methylene chloride/methanol =
4:1)
(92) 3-Z-[1-(4-(4-phenyl-piperazin-1-ylmethyl))-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C33H31N502
mass spectrum: m/z = 530 (M+H)+
Rf value: 0.78 (silica gel, methylene chloride/methanol =
4:1)
(93) 3-Z-[1-(4-(3,5-dimethyl-piperidino-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C30H32N402
mass spectrum: m/z = 480 (M+)
Rf value: 0.54 (silica gel, methylene chloride/methanol =
4:1)
(94) 3-Z-[1-(4-(N-methyl-N-benzyl-amino-methyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C31H29N404
mass spectrum: m/z = 488 (M+)
(95) 3-Z-[1-(3,4-dimethoxy-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C24H21N304
mass spectrum: m/z = 415 (M+)
Rf value: 0.5 (silica gel, methylene chloride/methanol =
9:1)

CA 02323111 2000-09-06
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(96) 3-Z-[1-(4-trifluoromethoxy-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C23H16F3N303
mass spectrum: m/z = 439 (M+)
Rf value: 0.5 (silica gel, methylene chloride/methanol =
9:1)
(97) 3-Z-[1-(3-ethoxycarbonyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C25H21N304
mass spectrum: m/z = 427 (M+)
Rf value: 0.52 (silica gel, methylene chloride/methanol =
9:1)
(98) 3-Z-[1-(3-carboxy-phenylamino)-l-phenyl-methylene]-
5-amido-2-indolinone
C23H17N304
mass spectrum: m/z = 399 (M+)
Rf value: 0.14 (silica gel, methylene chloride/methanol =
9:1)
(99) 3-Z-[1-(3-diethylcarbamoyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C2.7H26N403
mass spectrum: m/z = 454 (M+)
Rf value: 0.48 (silica gel, methylene chloride/methanol =
9:1)
(100) 3-Z-[1-(3-ethylcarbamoyl-phenylamino)-l-phenyl-
methylene]-5-amido-2-indolinone
C25H22N403
mass spectrum: m/z = 426 (M+)
Rf value: 0.42 (silica gel, methylene chloride/methanol =
9:1)
(101) 3-Z-[1-(3-trifluoromethoxy-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone

CA 02323111 2000-09-06
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C23H16FAA
mass spectrum: m/z = 439 (M')
Rf value: 0.5 (silica gel, methylene chloride/methanol =
9:1)
(102) 3-Z-[l-(3-ethoxy-phenylamino)-1-phenyl-methylene]-
5-amido-2-indolinone
C24H21N303
mass spectrum: m/z = 399 (M+)
Rf value: 0.49 (silica gel, methylene chloride/methanol =
9:1)
(103) 3-Z-[1-(4-methoxymethyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C24H21N303
mass spectrum: m/z = 399 (M+)
Rf value: 0.4 (silica gel, methylene chloride/methanol =
4:1)
(104) 3-Z-[1-(4-ethyl-phenylamino)-l-phenyl-methylene]-5-
amido-2-indolinone
C2aH21N302
mass spectrum: m/z = 383 (M+)
Rf value: 0.52 (silica gel, methylene chloride/methanol =
4:1)
(105) 3-Z-[1-(4-methyl-3-nitro-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C23H1eNaDa
mass spectrum: m/z = 414 (M')
(106) 3-Z-[1-(4-methyl-3-methoxy-phenylamino)-l-phenyl-
methylene]-5-amido-2-indolinone
C24H21N303
mass spectrum: m/z = 399 (M+)

CA 02323111 2000-09-06
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(107) 3-Z-[1-(4-(4-aminophenyl-methyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C29H24N40z
mass spectrum: m/z = 460 (M+)
(108) 3-Z-[1-(4-methoxycarbonyl-3-methyl-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C25H21N304
mass spectrum: m/z = 427 (M+)
Rf value: 0.56 (silica gel, methylene chloride/methanol =
4:1)
(109) 3-Z-[1-(4-cyanophenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
C23H16N402
mass spectrum: m/z = 380 (M+)
Rf value: 0.65 (silica gel, methylene chloride/methanol =
9:1)
(110) 3-Z-[1-(S-methyl-pyridin-2-yl-amino)-1-phenyl-
methylene]-S-amido-2-indolinone
Rf value: 0.6 (silica gel, methylene chloride/methanol =
9:1)
C2zHieNa02
mass spectrum: m/z = 370 (M+)
(111) 3-Z-[1-(5-bromo-pyridin-2-yl-amino)-1-phenyl-
methylene]-5-amido-2-indolinone
Rf value: 0.65 (silica gel, methylene chloride/methanol =
9:1)
C21H15BrN402
mass spectrum: m/z = 434/436 (M+)
(112) 3-Z-[1-(2-chloropyridin-5-yl-amino)-1-phenyl-
methylene]-5-amido-2-indolinone
Rf value: 0.49 (silica gel, methylene chloride/methanol =
9:1)

CA 02323111 2000-09-06
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C21H15C1Nq02
mass spectrum: m/z = 390/392 (M+)
(113) 3-Z-[1-(3-cyanophenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
C23Hi6Na02
mass spectrum: m/z = 380 (M')
Rf value: 0.57 (silica gel, methylene chloride/methanol =
9:1)
(114) 3-Z-[1-(4-(N-phenyl-amino-methyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C29H2qNq02
mass spectrum: m/z = 460 (M+)
Rf value: 0.74 (silica gel, methylene chloride/methanol =
9:1)
(115) 3-Z-[1-(4-(N-methyl-N-phenyl-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone
C30H26N402
mass spectrum: m/z = 474 (M+)
Rf value: 0.75 (silica gel, methylene chloride/methanol =
9:1)
(116) 3-Z-[1-(4-(N-ethyl-aminomethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C25H24N402
mass spectrum: m/z = 412 (M+)
(117) 3-Z-[1-(4-(N-(4-chlorophenyl-methyl)-aminomethyl)-
phenyl-amino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C30H25C1N402
mass spectrum: m/z = 508/510 (M')
(118) 3-Z-[1-(4-(N-cyclohexyl-aminomethyl)-phenylamino)-
1-phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

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C2vH3oNaO2
mass spectrum: m/z = 466 (M')
(119) 3-Z-[l-(4-(N-isopropyl-aminomethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C26H26N402
mass spectrum: m/z = 426 (M')
(120) 3-Z-[1-(4-(N-butyl-aminomethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C27H28N402
mass spectrum: m/z = 440 (M')
(121) 3-Z-[1-(4-(N-methoxycarbonyl-methylamino-methyl)-
phenyl-amino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C26H24N404
mass spectrum: m/z = 456 (M+)
(122) 3-Z-[1-(4-(N-(phenyl-methyl)-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C30H26N402
mass spectrum: m/z = 464 (M+)
(123) 3-Z-[1-(4-(N-acetyl-N-ethoxycarbonylmethyl-amino)-
phenyl-amino)-1-phenyl-methylene]-5-amido-2-indolinone
C28H26N405
mass spectrum: m/z = 498 (M+)
(124) 3-Z-[1-(4-methyl-3-sulphamoyl-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone
C23H2ON909 S
mass spectrum: m/z = 448 (M+)
(125) 3-Z-[1-(4-(N-methanesulphonyl-N-
(methylcarbamoylmethyl)-amino)-phenylamino)-1-phenyl-

CA 02323111 2000-09-06
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methylene]-5-amido-2-indolinone
C26H25N505S
mass spectrum: m/z = 519 (M')
(126) 3-Z-[1-(4-(N-methanesulphonyl-N-(piperidine-
carbonyl-methyl)amino)-phenylamino)-1-phenyl-methylene]-
5-amido-2-indolinone
C30H31N505S
mass spectrum: m/z = 573 (M+)
(127) 3-Z-[1-(4-carboxy-phenylamino)-1-phenyl-methylene]-
5-amido-2-indolinone
C23H17N304
mass spectrum: m/z = 398 (M-H+)
(128) 3-Z-[1-(4-carboxy-3-methyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinone
C24H19N304
mass spectrum: m/z = 412 (M-H+)
(129) 3-Z-[1-(4-(3-diethylamino-propoxy)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C29H32N403
mass spectrum: m/z = 484 (M')
(130) 3-Z-[1-(4-(2-piperidino-ethoxy)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C29H30N403
mass spectrum: m/z = 483 (M+H)+
(131) 3-Z-[1-(4-(3-piperidino-propoxy)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C30H32N403
mass spectrum: m/z = 496 (M+)
(132) 3-Z-[1-(4-(3-dimethylamino-propoxy)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate

CA 02323111 2000-09-06
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C27H2PN4O 3
mass spectrum: m/z = 457 (M+H)+
(133) 3-Z-[1-(4-(3-N-methyl-N-benzylamino-propoxy)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone-
trifluoroacetate
C33H32N403
mass spectrum: m/z = 533 (M+H)+
(134) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone-trifluoroacetate
C26H26N403
mass spectrum: m/z = 443 (M+H)'
(135) 3-Z-[1-(4-(N-ethyl-N-benzyl-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone
(136) 3-Z-[1-(4-(N-propyl-N-benzyl-aminomethyl)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone
(137) 3-Z-[1-(4-(N-methyl-N-(4-chlorophenyl-methyl)-
aminomethyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone
(138) 3-Z-[1-(4-(N-methyl-N-(4-bromophenyl-methyl)-amino-
methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone
(139) 3-Z-[1-(4-(N-methyl-N-(3-chlorophenyl-methyl)-
amino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone
(140) 3-Z-[1-(4-(N-methyl-N-(3,4-dimethoxyphenyl-methyl)-
amino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone

CA 02323111 2000-09-06
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(141) 3-Z-[1-(4-(N-methyl-N-(4-methoxyphenyl-methyl)-
amino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone
(142) 3-Z-[1-(4-(N-trifluoroethyl-N-(phenyl-methyl)-
amino-methyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone
(143) 3-Z-[1-(4-(N-trifluoroethyl-N-(4-chlorophenyl-
methyl)-aminomethyl)-phenylamino)-1-phenyl-methylene]-5-
amido-2-indolinone
Examiple 5
3-Z-[1-(4-(4-acetyl-piperazinylmethyl)-phenylamino)-1-
phenvl-methXlenel-5-amido-2-indolinone
mg of 3-Z-[1-(4-(4-piperazinylmethyl)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinone and 0.02 g of
20 triethylamine are dissolved in 10 ml of methylene
chloride and mixed with 5 mg of acetylchloride and the
solution is stirred for 16 hours at ambient temperature.
Then it is washed with water and the organic phase is
then evaporated down.
25 Yield: 15 mg (68 % of theory),
C29H29Ns03
Mass spectrum: m/z = 495 (M+)
The following compound is prepared analogously:
(1) 3-Z-[1-(4-(4-benzoyl-piperazinylmethyl)-phenylamino)-
1-phenyl-methylene]-5-amido-2-indolinone
Prepared from 3-Z-[1-(4-(4-piperazinyl-methyl-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinone and
benzoylchloride.
Yield: 91 % of theory,

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C34H31N~,O3
Mass spectrum: m/z = 557 (M+)
Example 6
3-Z-[1-(4-diethylcarbamoyl-phenylamino-l-phenyl-
methylenel-5-amido-2-indolinone
7 g of resin from step IV are reacted analogously to
Example 4 with ethyl 4-aminobenzoate. The moist charged
resin is suspended in 30 ml of dioxane and 30 ml of
methanol and stirred with 25 ml of 1 N sodium hydroxide
solution for 40 hours. Then it is neutralised with dilute
hydrochloric acid and washed with methylene chloride,
methanol and dimethylformamide. 300 mg of the resin are
then suspended in 3 ml of dimethylformamide, and left to
stand for 60 hours at ambient temperature with 0.2 ml of
diethylamine, 0.5 g of 0-(benzotriazol-1-yl)-N,N,N',N'-
tetramethyl-uronium-tetrafluoroborate and 0.8 ml of
ethyldiisopropylamine. Finally, the product is cleaved
from the resin as described in Example 4.
Yield: 29 mg,
Rf value: 0.46 (silica gel, methylene chloride/methanol =
9:1)
C27H26N403
mass spectrum: m/z = 454 (M')
The following are prepared analogously:
(1) 3-Z-[l-(4-(piperidinocarbonyl)-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinoneRf value: 0.43 (silica
gel, methylene chloride/methanol = 9:1)
C28H26N403
mass spectrum: m/z = 466 (M+)
(2) 3-Z-[l-(4-(4-methylpiperazinocarbonyl)-phenylamino)-
1-phenyl-methylene]-5-amido-2-indolinone-

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trifluoroacetateRf value: 0.84 (silica gel, methylene
chloride/methanol = 4:1)
C2eH2iN503
mass spectrum: m/z = 481 (M')
(3) 3-Z-[l-(4-(N-(2-dimethylamino-ethyl)-N-methyl-
carbamoyl)-phenylamino)-1-phenyl-methylene]-5-amido-2-
indolinone-trifluoroacetateRf value: 0.25 (silica gel,
methylene chloride/methanol = 9:1)
C28H29N503
mass spectrum: m/z = 484 (M+H)+
(4) 3-Z-[1-(4-(N-methoxycarbonylmethyl-carbamoyl)-
phenylamino)-l-phenyl-methylene]-5-amido-2-indolinoneRf
value: 0.4 (silica gel, methylene chloride/methanol =
9:1)
C26H22N405
mass spectrum: m/z = 470 (M+)
(5) 3-Z-[1-(4-benzylcarbamoyl-phenylamino)-1-phenyl-
methylene]-5-amido-2-indolinoneRf value: 0.48 (silica
gel, methylene chloride/methanol = 9:1)
C30H24N403
mass spectrum: m/z = 488 (M+)
Example 7
3-Z-[1-(4-(N-methyl-benzoylamino)-phenylamino)-1-phenyl-
methylenel-5-amido-2-indolinone
4.5 g of resin from step IV are reacted analogously to
Example 4 with 3.4 g of 4-(9H-fluoren-9-
ylmethoxycarbonyl)-methyl-amino)-aniline in
dimethylformamide. Then the 9H-fluorene protecting group
is cleaved with 4 ml of 30% piperidine in
dimethylformamide and the resin is washed several times.
400 mg of the resin are then suspended in 4 ml of

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dimethylformamide and 0.3 ml of triethylamine and reacted
with 0.3 ml of benzoylchloride for one hour at ambient
temperature. Finally the product is cleaved from the
resin as described in Example 4.
Yield: 33 mg.
Rf value: 0.45 (silica gel, methylene chloride/methanol =
9:1)
C3oH24N403
mass spectrum: m/z = 488 (M')
The following are prepared analogously:
(1) 3-Z-[l-(4-(N-methyl-propionylamino)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinoneRf value: 0.42
(silica gel, methylene chloride/methanol = 9:1)
C26H24N403
mass spectrum: m/z = 440 (M+)
(2) 3-Z-[l-(4-(N-methyl-butyrylamino)-phenylamino)-1-
phenyl-methylene]-5-amido-2-indolinoneRf value: 0.44
(silica gel, methylene chloride/methanol = 9:1)
C27H26N403
mass spectrum: m/z = 453 (M-H')
(3) 3-Z-[1-(4-(N-methyl-ethylsulphonylamino)-
phenylamino)-l-phenyl-methylene]-5-amido-2-indolinoneRf
value: 0.42 (silica gel, methylene chloride/methanol =
9:1)
C25H24N404S
mass spectrum: m/z = 475 (M-H+)
(4) 3-Z-[1-(4-(N-methyl-propylsulphonylamino)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinoneRf
value: 0.44 (silica gel, methylene chloride/methanol =
9:1)
C25H26N90qS
mass spectrum: m/z = 491 (M+H)+

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(5) 3-Z-[1-(4-(N-methyl-phenylsulphonylamino)-
phenylamino)-1-phenyl-methylene]-5-amido-2-indolinoneRf
value: 0.53 (silica gel, methylene chloride/methanol =
9:1)
C29H24N404S
mass spectrum: m/z = 524 (M+)
Example 8
Dry ampoule containing 75 mg of active substance per 10
ml
Composition:
Active substance 75.0 mg
Mannitol 50.0 mg
water for injections ad 10.0 ml
Preparation:
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 9
Dry ampoule containing 35 mg of active substance per 2 ml
Composition:
Active substance 35.0 mg
Mannitol 100.0 mg
water for injections ad 2.0 ml
Preparation:
Active substance and mannitol are dissolved in water.

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After packaging, the solution is freeze-dried.
To produce the solution ready for use, the product is
dissolved in water for injections.
Example 10
Tablet containing 50 mg of active substance
Composition:
(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
Preparation:
(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 11
Tablet containing 350 mg of active substance
Preparation:
(1) Active substance 350.0 mg
(2) Lactose 136.0 mg
(3) Maize starch 80.0 mg

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(4) Polyvinylpyrrolidone 30.0 mg
(5) Magnesium stearate 4.0 mg
600.0 mg
(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 12
Capsules containing 50 mg of active substance
Composition:
(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
Preparation:
(1) is triturated with (3). This trituration is added to
the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 3 hard gelatin
capsules in a capsule filling machine.

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Example 13
Capsules containing 350 mg of active substance
Composition:
(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
Preparation:
(1) is triturated with (3). This trituration is added to
the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 0 hard gelatin
capsules in a capsule filling machine.
Example 14
Suppositories containing 100 mg of active substance
1 suppository contains:
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
Preparation:
The polyethyleneglycol is melted together with
polyethylene sorbitanmonostearate. At 40 C the ground
active substance is homogeneously dispersed in the melt.
It is cooled to 38 C and poured into slightly chilled
suppository moulds.

Representative Drawing