ZA200409849B - Indoline derivatives substituted in position 6, production and use thereof as medicaments - Google Patents

Indoline derivatives substituted in position 6, production and use thereof as medicaments Download PDF

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ZA200409849B
ZA200409849B ZA200409849A ZA200409849A ZA200409849B ZA 200409849 B ZA200409849 B ZA 200409849B ZA 200409849 A ZA200409849 A ZA 200409849A ZA 200409849 A ZA200409849 A ZA 200409849A ZA 200409849 B ZA200409849 B ZA 200409849B
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alkyl
group
carbonyl
amino
phenyl
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ZA200409849A
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Gerald J Roth
Armin Heckel
Joerg Kley
Thorsten Lehmann-Lintz
Frank Hilberg
Ulrike Tontsch-Grunt
Jacobus C A Van Meel
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Boehringer Ingelheim Pharma
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Description

Boehringer Ingelheim Pharma GmbH Co. KG 1-1504 foreign filing text
Indolinone derivatives, substituted in the B6-position, their preparation and their use as medicaments
The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula
R4
R3 /
N
R J ~ RS
X
Re \
R on, to their tautomers, enantiomers, diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts, which have useful pharmacological properties, to medicaments comprising these compounds to their use and to processes for their preparation.
The above compounds of the formula | have useful pharmacological properties, in particular an inhibition action on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VE GFR3, PDGFRa, PDGFR, FGFRH,
FGFRS, EGFR, HER2, c-Kit, IGF1R and HGFR, Fit-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumour cells.
Accordingly, the present invention provides the above compounds of the formula l, which have useful pharmacological properties, medicaments comprising these pharmacologically active compounds, their use and processes for their preparation.
Moreover, the present invention provi des the physiologically acceptable salts of the compounds according to the invention, medicaments comprising these compounds which in addition, if appropriate, contain one or more inert carrier materials and/or diluents, and their use for preparing a. medicament suitable in particular for treating excessive or anormal cell proliferatiors.
The present invention furthermore provides processes for preparing this medicament, characterized in particular in that the compounds according to the invention or their physiologically acceptable salts are incorporated into one or more inert carrier materials and/or diluents.
I. In the above formula I,
X is an oxygen atom,
R'is a hydrogen atom,
R? is a fluorine, chlorine or brornine atom or a cyano group,
R%is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atorm or by a Cy.3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in th e 3- or 4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a Ci.3-alkoxy or Ci.p-alkyl-carbonyl-amino group, by a cyano-Cy.3-alkyl, carboxy-Cj.a-alkyl, carboxy-Ci.s-alkoxy, carboxy-
Ci-s-alkylamino, carboxy -C.3-alkyl-N-(C.3-alkyl)-amino, C,.s-alkoxy- carbonyl-C4.z-alkyl, Cy.4-alkoxy-carbonyl-C.3-alkoxy, Ci.s-alkoxy-
carbonyl-C,.s-alkylamino, C,.4-alkoxy-carbonyl-C 1.3-alkyl-N-(C4.3-alkyl)- amino, amino-C1.3-alkyl, aminocarbony!-C4.3-alky!, (C1.2-alkylamino)- carbonyl-C1.5-alkyl, di-(C;.2-alkyl)-aminocarbonyl-C4_;-alkyl, (C1.o-alkyl- carbonyl)-amino-Ci.3-alkyl, (C14-alkoxy-carbonyl)-amino-C,_s-alkyl, (Ca. g-alkyl-carbonyl)-amino-C1.3-alkyl, (phenyl-carbonyl)-amino-C.;-alkyl, (Cas-cycloalkyl-carbonyl)-amino-C.3-alkyl, (Cae-cycloalkyl-Cy.s-alkyl- carbonyl)-amino-Ci.3-alkyl, (thiophen-2-yl-carbo nyl)-amino-C.a-alkyl, (furan-2-yl-carbonyl)-amino-C,.3-alkyl, (phenyl-C;.3-alkyl-carbonyl)- amino-C4_s-alkyl, (2-(C1.4-alkoxy)-benzoyl-carboryl)-amino-C.z-alkyl, (pyridin-2-yl-carbonyl)-amino-C1.3-alkyl, (pyridin—-3-yl-carbonyl)-amino-
Cis-alkyl-, (pyridin-4-yl-carbonyl)-amino-Ci.3-alkyl- or Cy_3-alkyl- piperazin-1-yl-carbonyl-C4.3-alkyl group, by a carboxy-C,.3;-alkenyl, aminocarbonyl-C,.3-al kenyl, (C1.3-alkyl- amino)-carbonyl-C.s-alkenyl, di-(C4.3-alkyl)-amino-carbonyl-C,.z-alkenyl or Cq.4-alkoxy-carbonyl-C,.3-alkenyl group, where the substituents may be identical or different,
R* is a phenyl group or a phenyl group which is monosubstituted by a C.s-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C1-2-alkyl)-amino-, N-{o-di-(C1.3-alkyl)-amino-C.. s-alkyl]-N-(C4.s-alkyl)-amino, N-methyl-(Cz.4-alkyl )-amino, N-(Ci.a- alkyl)-N-benzylamino, N-(C.4-alkoxycarbonyl)-armino, N-(C.4- alkoxycarbonyl)-C1.4-alkylamino, 4-(Cy.3-alkyl)-piperazin-1-yl, imidazol- 1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group, by a di-(C1.3-alkyl)-amino-(C1.s-alkyl)-sulphonyl, 2-[di-(Cs.s-alkyl)-amino]- ethoxy, 4-(C1.s-alkyl)-piperazin-1-yl-carbonyl, {®-[di-(C,.5-alkyl)-amino]- (Ca-a-alkyl)}-N-(C1.3-alkyl)-amino-carbonyl, 1-(C.z-alkyl)imidazol-2-yl, (C4-s-alkyl)-sulphonyl group, or by a grou p of the formula
Rs / —N in which
R” isa Ci-2-alkyl, Cy.s-alkyl-carbonyl, di-(Cy.2-alkyl)-amino- carbonyl-C4.z-alkyl or C.z-alkylsulphonyl group and
R® is Cy.g-alkyl, o-[di-(C1.2-alkyl)-amino]-C s-alkyl, &-[mono-(Cs.o- alkyl)-amino]-C,.3-alkyl group, or a (C.s-alkyl)-carbonyl, (Cs.6-alkyl)-carbonyl or carbonyl-(C.5- alkyl) group which is terminally substituted by a di-(C.,-alkyl)- amino, piperazin-1-yl or 4-(C,.3-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R* may also be present in quaternized forms, for example as an N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate,
R® is a hydrogen atom and
RC is a hydrogen atom, where the abovermentioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms,
where additiona lly a carboxyl, amino or imino group present may be substituted by am in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in
Vivo into a carboxyl group or in the form of a group which can be converted in 5 vivo into an imin o or amino group, their tautomers, enantiomers, diastereomers, their mixtures and their salts.
IL Particularly preferred compounds of the above formula | are those compounds in which X, R', R® and R® are as defined under I. and:
ILi. R%?and R* are as defined under I. and
Riis a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C,_s-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl gro ups may additionally be substituted in the 3- or 4-position by a fluorire, chlorine or bromine atom, by a cyano group, by a Ci.5-a Ikoxy or C,.z-alkyl-carbonyl-amino group, by a cyano-Cy.s-alkyl, carboxy-Ci.s-alkyl, carboxy-C1.4-alkoxy, carboxy-
C,.a-alkylarmino, carboxy-C.g-alkyl-N-(C,.3-alkyl)-amino, Ci.4-alkoxy- carbonyl-C 15-alkyl, Cy.4-alkoxy-carbonyi-Cy.3-alkoxy, Ci.4-alkoxy- carbonyl-C 4.3-alkylamino, C.4-alkoxy-carbonyl-Cy.s-alkyl-N-(C +.s-alkyl)- amino, ami no-Cy.s-alkyl, aminocarbonyl-C.s-alkyl, (C1..-alkyla mino)- carbonyl-C +.5-alkyl, di-(Cy.,-alkyl)-aminocarbonyl-C4.;-alkyl, (C 1-2-alkyl- carbonyl)-a mino-C,.3-alkyl, (C1-s-alkoxy-carbonyl)-amino-C4.3-alkyl, (Ca. e-alkyl-carbonyl)-amino-C.5-alkyl, (phenyl-carbonyl)-amino-C4.;-alkyl,
(Ca¢-cycloalkyi-carbonyl)-amino-Cs.;5-alkyl, (Ca.6-cycloalkyl-Cy.s-atky!- carbonyl)-amino-C;.s-alkyl, (thiophen-2-yl-carbonyl)-amino-C.s-alkyl, (furan-2-yl-carb onyl)-amino-C,.3-alkyl, (phenyl-C1.5-alkyl-carbonyl)- amino-C,s-alky, (2-(C1.4-alkoxy)-benzoyl-carbonyl)-amino-Cy.s-alkyl, (pyridin-2-yl-carbonyl)-amino-C,.3-alkyl, (pyridin-3-yl-carbonyl)-amino-
Ci.s-alkyl, (pyridin-4-yl-carbonyl)-amino-Cs.5-alkyl or C.s-alkyl-piperazin- 1-yl-carbonyl-C +.5-alkyl group, by a carboxy-C2.s-alkenyl, aminocarbonyl-C..3-alkenyl-, (C.s-alkyl- amino)-carbony-Cz.s-alkenyl-, di-(C.3-alkyl)-amino-carbonyl-C,.s- alkenyl or Cy.s-alkoxy-carbonyl-C, ;-alkenyl group, where the substituents may be identical or different;
Iii. R?and R* are as defined under I. and
R? is a phenyl group which is substituted by a Cy.2-alkyl-carbonyl-amino group, by a carboxy-C,_s-alkyl, carboxy-C1.s-alkoxy, C,.4-alkoxy-carbonyl-C.5- alkyl, Ci.4-alkoxy-carbonyl-C_s-alkoxy, aminocarbonyl-Cy.5-alkyl, (C;.,- alkylamino)-carbonyl-C,.z-alkyl, di-(C+-2-alkyl)-aminocarbonyl-C.3-alky|, (Ci-2-alkyl-carbo nyl)-amino-Cy.g-alkyl, (C+.4-alkoxy-carbonyl)-amino-Cy.s- alkyl, (phenyl-carbonyl)-amino-Cs.s-alkyl, (Cs.6-cycloalkyl-carbonyl)- amino-Ci.s-alkyl, (Cj.¢-cycloalkyl-C.3-alkyl-carbonyl)-amino-C1.s-alkyl, (thiophen-2-yl-carbonyl)-amino-C.s-alkyl, (furan-2-yl-carbonyl)-amino-
Ci.s-alkyl, (phenyl-C,.3-alkyl-carbonyl)-amino-C.s-alkyl, (2-(Cy.4- alkoxy)-benzoyl-carbonyl)-amino-C,.s-alkyl, (pyridin-2-yl-carbonyl)- amino-C.g-alkyl, (pyridin-3-yl-carbonyl)-amino-C;.s-alkyl, (pyridin-4-yl- carbonyl)-amino-C;.3-alkyl or Cy.5-alkyl-piperazin-1 -yl-carbonyl-C,_s-alkyl group,
by an aminocarbonyl-C,_a-alkenyl, (C,.3-alkylamino)-carbonyl-Cz.3- alkenyl, di-(C.3-alkyl)-amsino-carbonyl-C,.3-alkenyl or C4-alkoxy- carbonyl-C,.;-alkenyl group;
ILiii. R® and R* are as defined under I. and
R3 is a phenyl group substituted by a carboxy-Ci.z-alkyl or C;.4-alkoxy- carbonyl-C,.3-alkyl group;
ILiv. R%and R* are as defined under I. and
R? is a fluorine or chlorine atom; lv. R?and R® are as defined under |. and
R* is a phenyl group or a phenyl! group which is monosubstituted by a Ci.s-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C 1 .o-alkyl)-amino-, N-[@-di-(C.3-alkyl)-amino-C.. a-alkyl]-N-(Cy.3-alkyl)-amin o, N-methyl-(C3.4-alkyl)-amino, N-(Cj.a- alkyl)-N-benzylamino, N-(C,.4-alkoxycarbonyl)-amino, N-(C,- alkoxycarbony!)-C4.4-alkylamino, 4-(C4.3-alkyl)-piperazin-1-yl, imidazol- 1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yi, thiomorpholin-4-yl group, by a di-(C..s-alkyl)-amino-(C;.3-alkyl)-sulphonyl, 2-[di-(C,.3-alkyl)-amino}- ethoxy, 4-(C,.s-alkyl)-piperazin-1-yl-carbonyl, {w-[di-(C.3-alkyl)-amino}- (C2.3-alkyl)}-N-(C_3-alkyl)-amino-carbonyl, 1-(C;.s-alkyl)imidazol-2-yi, (C1.g-alkyl)-sulphonyl group, or by a group of the formula
Rs / —N in which
R’ is a C1.p-alkyl, C1.o-alkyl-carbonyl, di-(Cy_z-alkyl)-amino- carbonyl-C,_3-alkyl or Cy.3-alkylsulphonyl group and
R® is Cy.a-alkyl, @-[di-(C1.2-alkyl)-amino]-Ca.a-alkyl, @-[mono-(C1.o- alkyl)-amino]-C..3-alkyl group, or a (Cy.z-alkyl)-carbonyl, (Cs.s-alkyl)-carbony! or carbonyl-(C;.3- alkyl) group which is terminally substituted by a di-(C,.o-alkyl)- amino, piperazin-1-yl or 4-(Cy.s-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R* may also be present in quatemized form, for example as an N-methyl- (N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesullphonate and trifluoroacetate. li. Subgroups of particularly preferred compounds of the ab ove formula | which are to be mentioned in particular are those in which:
Li. X, R', R%, R° and R® are as defined under I., R®is as defined under Ili. and R* is as defined under Il.v.;
Li. X, R', R?, R°® and R® are as defined under I., R3is as defined under ILii. and R* is as defined under Il.v.;
Lil. X, R', R? R® and R® are as defined under I., R® is as defined under I1.iii. and R* is as defined under Il.v.;
Hiv. X, R', R® and R® are as defined under I., R?is as defined under
ILiv., R® is as defined under ILi., ILii. or ILiii. and R* is as defined under .v.
A further preferred group of compounds of the above formula | are those in which
X is an oxygen atom,
R'is a hydrogen atom,
R? is a fluorine, chlorine or bromine atom or a cyano group,
R® is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a Cy.3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a C;.3-alkoxy or C4_z-alkyl-carbonyl-amino group, by a carboxy-C.s-alkyl, aminocarbonyl-C.s-alkyl, (C+.2-alkylamino)-carbonyl-
C1.3-alkyl, di-(Ci.2-alkyl)-aminocarbonyl-C.3-alkyl, (C1.2-alkyl-carbonyl)-amino-
C,.3-alkyl or (phenyl-carbonyl)-amino-C,.3-alkyl group, where the substituents may be identical or different,
R* is a pheny! group which is substituted by a Cy.5-alkyl group terminally substituted by a di-(Cy.2-alkyl)-amino group, or by a group of the formula
R8 / —N in which
R’ is a Cy.-alkyl, C1.o-alkyl-carbonyl, di-(C1-2-alkyl)-amino-carbonyl-C.3- alkyl or C4.3-alkylsulphonyl! group and
R® is a Cy.3-alkyl or @-[di-(C1.,-alkyl)-aamino]-C,.s-alkyl group, or a Cy.z-alkyl-carbonyl group terminally substituted by a di-(C,.z-alkyl)- amino, piperazino or 4-(Cy.3-alkyl)-piperazin-1-yl group,
R® is a hydrogen atom and
Ris a hydrogen atom, where the abovementioned alkyl groups include lin-ear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical, their tautomers, enantiomers, diastereomers, their rmixtures and their salts.
The following compounds of the formula | are particularly preferred:
(a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6- chloro-2-indolinone (b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene}-6- fluoro-2-indolinone (c) 3-Z-[1-(4-dimethylaminomethylanuilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indolinone (d) 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4- (2-carboxyethyl)phenyl)methylene]-&-fluoro-2-indolinone (e) 3-Z-[1-(4-(N-(2-dimethylaminoethayl)-N-methylsulphonylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-flLoro-2-indolinone
(f) 3-Z-[1-(4-(N-(3-dimethylaminoproppyl)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-flLioro-2-indolinone (9) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-fluoro-2-indolinone (h) 3-Z-[1-(4-(N-(dimethylaminometh ylcarbonyl)-N-methylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-flLioro-2-indolinone (i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-flLioro-2-indolinone (i) 8-Z-{1-(4-(pyrrolidin-1-ylmethyl)an ilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indolinone
(k) 3-Z-[1-(4-(diethylaminomethyl)ani lino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indolinone (I) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- chloro-2-indolinone (m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- chloro-2-indolinone 40 (n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- chloro-2-indolinone (0) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)arilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- bromo-2-indolinone 45 (p) 3-Z-[1-(4-(dimethylaminomethyl)a nilino)- 1-(4-(2-carboxyethyl)phenyl)methylene]- 6-bromo-2-indolinone
(q) 3-Z-{1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo- 2-indolinone where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group, and their salts.
A group which can be converted in vivo into a carboxyl group is to be understood as meaning, for example, a hydroxymethyl group, a carboxy! group which is esterified with an alcohol in which the alcoholic moiety is preferably a Cy.¢-alkanol, a phenyl- Cis-alkanol, a Cj.g-cycloalkanol, where a Cs.g-cycloalkanol may additionally be substitituted by one or two Cs-alkyl groups, a Cs.g-cycloalkanol in which one methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a C1.s-alkyl, phenyl-C.3-alkyl, phenyl-C1.s-alkoxy- carbonyl or C.s-alkyl-carbonyl group and in which thie cycloalkanol moiety may additionally be substituted by one or two C;.3-alkyl groups, a C47-cycloalkenol, a Cs.s- alkenol, a phenyl-Cas-alkenol, a Ca.s-alkynol or a phenyl-Cs.s-alkynol, with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a Cas-cycloalkyl-C1_s-alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two Cy.3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of the formula
Ra-CO-0O-(R,CR:)-OH, in which
R. is a Cy.g-alkyl, Cs.7-cycloalkyl, phenyl or ph enyl-C,.3-alkyl group,
Ry is a hydrogen atom, a Ci.s-alkyl, Cs.7-cyclo alkyl or phenyl group, and
®
R. is a hydrogen atom or a C,.3-alkyl group, and a radical cleavable in vivo from an imino or amino group is to be understood as meaming, for example, a hydroxyl group, an acyl group, such as the benzoyl or pyridlinoyl group, or a Ci.s¢-alkylcarbonyl group, such as the formyl, acetyl, propionyl, buta noyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a Ci.ig-alkoxy- carb onyl group, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isop ropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarb-onyl group, a phenyl-
C1.s—alkoxy-carbonyl group, such as the benzyloxycarbonyl, ph.enylethoxycarbonyl or phemnylpropoxycarbonyl group, a Ci.s-alkylsulphonyl-C1.4-alkoxw-carbonyl, Cia alkoxy-Ca.4-alkoxy-Co.4-alkoxy-carbonyl or R.CO-O-(R,CR;)-O-CO- group, in which
R, is a Ci.g-alkyl, Cs.7-cycloalkyl, phenyl or phenyl-C.3-alkyl group,
Rp is a hydrogen atom, a Ci.s-alkyl, Cs.7-cycloalkyl or phenyl group and
R. is a hydrogen atom, a Cy.3-alkyl or R,CO-0O-(R,CR¢)—0- group, in which Ry to R. are as defined above, and additionally, for an amino group, the phthalimido group, w-here the ester radicals memtioned above can also be used as a group which can be converted in vivo into a carboxyl group.
Presferred prodrug radicals for a carboxyl group are a C.¢-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycawbonyl, isogpropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group, or a phenyl-C,.3-alkoxy-carbonyl group, such as the berzyloxycarbonyl group, and,
for an imino or amino group, a C1.g-alkoxy-carbonyl group, such as the me-thoxy- carbonyl, ethoxycarbon yl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxy- carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-<octyloxycarbonyl or n-nonyloxycarbonyl group, a pkenyl-C;.3- alkoxy-carbonyl group, such as the benzyloxycarbonyl group, a phenylcarbbonyl group optionally substituted by a Cy.s-alkyl group, such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl grou p, such as the nicotinoyl group, a C.s-alkylsulphorsyl-n-Ca.a- alkoxy-carbonyl or C1.3-alkoxy-C».3-alkoxy-C;.s-alkoxy-carbonyl group, such as the 2- methylsulphonylethoxycarbonyl or 2-(2-ethoxy)-ethoxycarbony! group.
According to the invention, the novel compounds are obtained, for example, by the following processes, wh ich are known in principle from the literature: a. reaction of a compound of the formula
Z!
Rs or
R2 \
RY v), in which the radicals Z' and R® may, if appropriate, change their positions,
X, R? R? and R® are as defined at the outset,
R" has the meanings mentioned at the outset for R' oris a protective group for the nitrogen atom of the lactam group, where R' may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z'is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, for examp le a chlorine or bromine atom , a methoxy, ethoxy or benzyloxy group, with an amine of the formula
R4 Rs
NT
How, in which
R* and R® are defined as mentioned at the outset, and, if required, the product is subsequently cleaved from a protective group used for the nitrogen atom of the lactam group or from a solid phase.
Suitable protective groups for the nitrogen atom of the lactam group are, for example, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl group and suitable solid phases are a resin, such as a 4-(2’,4’-dimethoxyphenylaminomethyl)- phenoxy resin, where the attachment is expediently via the amino group, or a p-benzyloxybenzyl alcohol resin, where the attachment is expediently via a spacer, such as a 2,5-dimethoxy-4-hydroxybenzyl derivative.
The reaction is expediently carried out in a solvent, such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulphoxide, methylene chloride or a mixture thereof, if appropriate in the presence of an inert base, such as triethylamine,
N-ethyldiisopropylamine or sodium bicarbonate, at temperatures between 20 and 175°C, where any protective groups used may be simultaneously removed owing to transamidation.
If, in a compound of the formula V, Z' is a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120°C.
If, in a compound of the formula V, Z' is a hydroxyl, alkoxy or arylalkoxy group, the reaction is preferably carried out at temperatures between 20 and 200°C.
The subsequent removal of a protective group used, which may be required, if appropriate, is expediently carried out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol, in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C, or, advantageously, by transamidation with an organic base, such as ammonia, 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.
Cleavage from a solid phase employed is preferably carried out using trifluoroacetic acid and water at temperatures between 0 and 35 °C, preferably at room temperature. b. To prepare a compound of the formula | in whic h R® is a phenyl or naphthyl group substituted by a carboxy-Cz.z-alkenyl, aminocarbomyl-C,.;-alkenyl, (C;.3-alkylamino)- carbonyl-C,.3-alkenyl, di-(C+.s-alkylamino)-carbonyl-C,.3-alkenyl or Cy.4-alkoxy- carbonyl-C,.3-alkenyl group, reaction of a compound of the formula
Z3
LF
/
JN
RS fC yx
R \
Rm, in which
R? R% R% Rand X are as defined at the outset,
@®
R" has the meanings mentioned at the outset for R' or is a protective group for the nitrogen atom of the lactam group, whe re R' may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and
Z% is a leaving group, for example a halogen atom or an alkyl- or arylsulphonyloxy group, such as a chlorine, bromine or iodine atom or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonylo xy or trifluoromethanesulphonyloxy group, with an alkene of the formula
O
NN x), in which
R® is an amino, (C1.3-alkylamino), di-(C.3-alkylamino) or C4.4-alkoxy group and n is the number 0 or 1.
The reaction is expediently carried out with palladium catalysis, using, for example, palladium(ll) acetate, palladium(ll) chloride, bis(triphenylphosphine)palladium(ll) acetate, bis(triphenylphosphine)palladium(ll) chloride, palladium/carbon, bis-[1,2- bis(diphenylphosphino)ethane]palladiurn(0), dichloro-(1,2-bis(diphenylphosphino)- ethane)palladium(ll), tetrakistriphenylphosphinepalladium(0), tris(dibenzylidene- acetone)dipalladium(0), 1,1’-bis(diphenylphosphino)ferrocenedichloropalladium(ll) or tris(dibenzylideneacetone)dipalladium(QO)/chloroform adduct, in the presence of a base, such as triethylamine, diisopropyl ethylamine, lithium carbonate, potassium carbonate, sodium carbonate, caesium carbonate, and a ligand, such as triphenylphosphine, tri-ortho-tolylphosphine or tri-(tert-butyl)phosphine, in solvents such as acetonitrile, N-methylpyrrolidinone, dioxane or dimethylformamide and mixtures thereof.
The cleavage of a protective group used for the nitrogen atoms of the lactam group or from a solid phase, which may be required, if appropriate, is carried out as described above under process (a).
® c. To prepare a compound of the formula | in which R3is a phenyl or naphthyl group substituted by a carboxy-C4.3-alkyl, C1.4-alkoxy-carbonyl-C4.s-alkyl, aminocarbonyl-C,.s-alkyl, (C1-5-alkylamino)-carbonyl-C,.s-alkyl or di-(C;.5-alkyl)-aminocarbonyl-C.s-alkyl group, hydrogenation of a compound of the formula "SP
LS
R¢ /
JN
RS fC ox
R \
RY (XI), in which
R?, R* R® R® and X are as defined at the outset,
R" has the meanings mentioned at the outset for R' oris a protective group for the nitrogen atom of the lactam group, where R'* m ay also, if appropriate, represent a bond, formed via a spacer, to a solid phase,
A is a Co.3-alkenyl group and
R?¥ is a hydroxyl, Cy.s-alkoxy, amino, (C1.3-alkylamino) or di-(C;.3-alkyl)amino group.
The hydrogenation is preferably carried out using catalytic hydrogenation with hydrogen in the presence of a catalyst, such as palladium/carbon or platinum, in a solvent, such as methanol, ethanol, ethyl acetat e, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid, at temperatures between 0 and 50°C, but preferably at room temperature, and at a hydrogen p ressure of 1 to 7 bar, but preferably 3 to bar.
The cleavage of a protective group used for the nitrogen atom of the lactam group or 5 from a solid phase, which may be required, if appropriate, is carried out as described under process (a).
If, according to the invention, a compound of the formula | is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxyl compound, or if a compound of the formula | is obtained which contains an amino or alkylamino group, this can be converted by reduction alkylation into a corresponding alkylamino or dialkylamino compound, or if a compound of the formula | is obtained which contains a dialkylamino group, this can be converted by alkylation into a corresponding trialkylammonium compound, or if a compound of the formula | is obtained which contains an amino or alkylamino group, this can be converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, respectively, or if a compound of the formula I is obtained vvhich contains a carboxy! group, this can be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, or if a compound of the formula | is obtained which contains a nitro group, this can be converted by reduction into a corresponding amino compound, or if a compound of the formula | is obtained which contains a cyano group, this can be converted by reduction into a corresponding aminomethyl compound, or
@® if a compound of the formula | is obtained which contains an arylalkyloxy group, this can be converted with acid into a corresponding hydroxyl compound, or if a compound of the formula | is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxyl compound, or if a compound of the formula | is obtained in which R, is a phenyl group substituted by an amino, alkylamino, aminoalky! or IN-alkylamino group, this can then be converted by reaction with a corresponding cyanate, isocyanate or carbamoyl halide into a corresponding urea compound of the formula |, or if a compound of the formula | is obtained in which R; is a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkylamino group, this can subsequently be converted by reaction with a corresponding amidino-group-transferring compound or by reaction with a corresponding nitrile into a corresponding guanidino compound of the formula I.
The subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, methanol/water, etharol/water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulphuric acid, or in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°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, meth anol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylform amide, if appropriate with addition of an acid, such as hydrochloric acid, in the presence of catalytically activated hydrogen, for example of hydrogen in the presence of Raney nickel, platinum or palladium/carbon, or in the presence of a metal hydride, such as sodium borohydride, lithium borohydride, sodium cyanoborohyrdride or lithium aluminium hydride, at
® temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.
Thee subsequent alkylation is preferably carried out in a suitable solvent, such as ether, tetrahydrofuran, dioxane, dichloromethane, acetone or acetonitrile, in the presence of alkylating agents, such as alkyl iodides, alkyl bromides, alkyl chlorides, methanesulphonic acid alkyl esters, para-toluenesulphonic acid alkyl esters or alkyl trif luoroacetates, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 60°C.
The subsequent acylation or sulphonylation is expedien tly carried out using the corresponding free acid or a corresponding reactive connpound, such as its anhydride, ester, imidazolide or halide, preferably in a solvent, such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane», acetonitrile, dimethyl sulphoxide or dimethylformamide, if appropriate in the p resence of an inorganic or a tertiary organic base, at temperatures between -20 and 200°C, preferably at temperatures between 20°C and the boiling point of the solvent used. The reaction with the free acid can, if appropriate, be carried out in the presence of an agent which activates the acid or of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chlor ide, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N’-dicy clohexylcarbodiimide,
N,NI’-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N, N'-dicyclohexyl- carbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1 -yl}-1,1,3,3- tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol -1-yl)-1,1,3,3- tetramethyluronium tetrafluoroborate/1-hydroxybenzotria zole,
N,N ’-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and, if app ropriate, with addition of a base, such as pyridine, 4-dimethylaminopyridine,
N-myethylmorpholine or triethylamine, expediently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C. The reaction with a corresponding reactive compound can, if appropriate, be carried out in the presence of a tertiary organic base, such as triethylamine, N-ethyl-diisopropylamine,
N-m ethylmorpholine or pyridine, or, if an anhydride is used, in the presence of the
® corresponding acids, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.
The subsequen t esterification or amidation is expediently carried out by reacting a reactive corresponding carboxylic acid derivative with an appropriate alcohol «or amine, as described above.
The esterificatiosn or amidation is preferably carried out in a solvent, such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20°C and the boiling point of the solvent used. Here, the reaction with a corresponding acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilaine, phosphorus trichloride, phosphorus pentoxide, N,N’-dicyclohexylcarbodiimide,
N,N’-dicyclohexyylcarbodiimide/N-hydroxysuccinimide, N,N’-dicyclohexylcarbodi- imide/1-hydroxylbenzotriazole, 2-(1H-benzotriazol-1-yl)-1, 1 ,3,3-tetramethylurorium- tetrafluoroborates, 2-(1H-benzotriazol-1-yl)-1,1 ,3,3-tetramethyluronium tetrafluoroborates/1-hydroxybenzotriazole, N,N’-carbonyldiimidazole or tripheny»I- phosphine/carban tetrachloride, and, if appropriate, with addition of a base, su ch as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, expediently 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 its anhydride, ester, imidazolide or halide, is, if appropriate, carried out in the presence of a tertiary orgamic base, such triethylamine, N-ethyldiisopropylamine or
N-methylmorphouine, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.
The subsequent reduction of a nitro group is preferably carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst, such as palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if
{ ® appropriate with addition of an acid, such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50°C, but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.
The subsequent hydrogenation of a cyano group is preferably carried out hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol, ethyl acetate, methylene chloride, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50°C, but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably of from 3 to 5 bar.
The subsequent preparation of a corresponding guanidino compound of the formula is expediently carried out by reaction with an amidino-group-transferring compound, such as 3,5-dimethylpyrazole-1-carboxamidine, preferably in a solvent, such as dimethylformamide, and, if appropriate, in the presence of a tertiary organic base, such as triethylamine, at temperatures between 0 and 50°C, preferably at room temperature.
In the reactions described above, any reactive groups present, such as carboxyl, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are removed again after the reaction.
A protective radical for a carboxyl group is, for example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and a protective group for a hydroxyl, amino, alkylamino or imino group is, for example, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, and, for the amino group, additionally the phthaly! group.
®
The subsequent removal of a protective radical used iss, if appropriate, carried out, for example, hydrolytically in an aqueous solvent, for exarmple in water, isopropanol/water, tetrahydrofuran/water or dioxane/w.ater, 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 benzyloxycarboryl radical is removed, for example, hydrogenolytically, for example using hydrog en in the presence of a catalyst, such as palladium/carbon, in a solvent such a_s methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetome or glacial acetic acid, if appropriate with addition of an acid, such as hydrochlo ric acid or glacial acetic acid, at temperatures between 0 and 50°C, but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably of from 3 to 5 bar.
A methoxybenzy! group can also be removed in the presence of an oxidizing agent, such as cerium(lV) ammonium nitrate, in a solvent, such as methylene chloride, acetonitrile or acetonitrile/water, at temperatures betwe-en 0 and 50°C, but preferably at room temperature.
However, a 2,4-dimethoxybenzyl radical is preferably removed in trifluoroacetic acid in the presence of anisole. Atert-butyl or tert-butyloxycarbonyi radical is preferably removed by treatment with an acid, such as trifluoroacetic acid or hydrochloric acid , using, if appropriate, a solvent, such as methylene chloride, dioxane, ethyl acetate or ether.
A phthalyl radical is preferably removed in the presence of hydrazine or a primary amine, such as methylamine, ethylamine or n-butylamin-e, in a solvent, such as methanol, ethanol, isopropanol, toluene/water or dioxan e, at temperatures between 20 and 50°C.
®
Furthermore, chiral compounds of the formula I obtained can be separated into their enantiomers and/or diastereomers.
Thus, for example, compounds of the formula | obtained! which occur as racemates can be separated by methods known per se (see AllingerN. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 971) into their enantiomers, and compounds of the formula | having at least 2 asymmetric carbon atoms can, owing to their physicochemical differences, be separated by methods known per se, for example by chromatography and/or fractional crystallization, into their diastereomers, which, if they are obtained in racemic for m, can then be separated into the enantiomers as mentioned above.
The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically acti ve solvent or by reaction with an optically active substance which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives obtained in this manner, for example owing to different solubilities, whereupon the free enantiomers can be released from thae pure diastereomeric salts or derivatives by action of suitable agents. Particularly cosmmon optically active acids are, for example, the D and L forms of tartaric acid, diberzoyitartaric acid, di-o- tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid,
N-acertylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. A suitable optically active alcohol is, for example, (+)- or (-)-menthol, and a suitable optically active acyl radical in amides is, for example, the (+)- or (-)-menthyloxycarbonyl radical.
Furthermore, the compounds of the formula | obtained ca n be converted into their salts, in particular, for phamaceutical use, into their physiologically acceptable salts, with inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, methanesulphonic acid,
® ethanesulphonic acid, para-toluenesulphonic acid, phenylsulpho nic acid or L-(+)- mandelic acid.
Moreover, the resulting novel compounds of the formula | can, if they contain a carboxyl group, then, if desired, be converted into their saits with inorganic or organic ba ses, in particular, for pharmaceutical use, into their physiologically acceptable sa Its. Bases suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Also suitable, for compounds of the formula | which contain 2 or rmore acidic or basic groups, are salts with 2 or more inorganic or organic bases or acids (disalts etc.).
So me of the compounds of the general formulae V to Xl used as starting materials are known from the literature or can be obtained by processes known from the lite rature or can be obtained by the processes described above and in the examples.
Compounds of the general formula 1X, for example, are described in the German patent application 198 44 003.
As already mentioned at the outset, the novel compounds of the formula (I) have useful pharmacological properties, in particular in inhibiting action on various kinases, espeecially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFRS,
PD&GFRo, PDGFRB, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular of tumour cells.
The biological properties of the novel compounds were examined by the following standard methods:
Human umbilical cord endothelial cells (HUVEC) were cultivated in IMDM (Gibco
BRL.), supplemented with 10% foetal bovine serum (FBS) (Sigma), 50 uM
B-mercaptoethanol (Fluka), standard antibiotics, 15 pg/ml of endothelial cell growth
® factor (ECGS, Collaborative Biomedical Products) and 100 ug/ml of heparin (Sigma) on gelatin-coated culture bottles (0.2 % gelatin, Sigma) at 37°C, 5% CO2, in an atmosphere saturated with water.
To examine the inhibitory activity of the compo unds according to the invention, the cells were “starved” for 16 hours, i.e. kept in cuslture medium without growth factors (ECGS + heparin). Using trypsin/EDTA, the cellls were detached from the culture bottles and washed once with serum-containing medium. 2.5 x 102 cells were then seeded in each well.
The proliferation of the cells was stimulated usi ng 5 ng/ml of VEGF165 (vascular endothelial growth factor; H. Weich, GBF Brunswick) and 10 pg/ml of heparin. Per plate, as control value, in each case 6 wells we re not stimulated.
The compounds according to the invention were dissolved in 100% dimethyl sulphoxide and, in triplicate, added to the cultures in different dilutions, the maximum dimethyl sulphoxide concentration being 0.3%.
The cells were incubated at 37°C for 76 hours, and 3H-thymidine (0.1 p Ci/well,
Amersham) was then added for a further 16 hours to determine DNA synthesis. The radioactively labelled cells were then immobilized on filter mats and the incorporated radioactivity was determined in a B counter. To determine the inhibitory activity of the compounds according to the invention, the meam value for the non-stimulated cells was subtracted from the mean value of the factor-stimulated cells (in the presence or absence of the compounds according to the invention).
The relative cell proliferation was calculated in p ercent of the control (HUVEC without inhibitor), and the concentration of active compo-und at which the proliferation of the cells is inhibited by 50% (ICso) was derived therefrom.
The compounds of the formula | according to thes invention have an ICs between 50 uM and 1 nM.
®
Owing to their inhibitory action on the proliferation of cells, in particular of endothelian
Cells and of tumour cells, the compounds of the formula | are suitable for treating diseases in which the proliferation of cells, in particular that of endothelial cells, plays arole.
Thus, for example, the proliferation of endothelial cells and the related reovascularization is a decisive step in tumour progression (Folkman J. et al., Nature 339, 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353-365, (1996)).
Furthermore, the proliferation of endothelial cells is als o of importance in hmaemangiomes, in metastasization, in rheumatoid arth ritis, in psoriasis and in ocular reeovascularization (Folkman J., Nature Med. 1, 27-31, (1995); Carmeliet P & Rakeh
J ., Nature 407, 249-257, (2000)). The therapeutic benefit of inhibitors of endothelial cell proliferation in the animal model was shown, for example, by O'Reilly et al. and
Prarangi et al. (O'Reilly M.S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc
Natl Acad Sci USA 93, 2002-2007, (1996)).
T hus, the compounds of the formula I, their tautomers, their stereoisomers or their physiologically acceptable salts are suitable, for example, for treating tumours (for example squamous epithelium carcinoma, astrocytoma, Kaposi sarcoma, glioblastoma, lung cancer, cancer of the bladder, neck carcinoma, oesophagus carcinoma, melanoma, ovarial carcinoma, prostate carcinoma, breast cancer, small- cell lung carcinoma, glioma, colorectal carcinoma, pancreas carcinoma, urogenital cancer and gastrointestinal carcinoma, and also haematological cancers, such as, for example, multiple myeloma and acute myelotic leukaemia), psoriasis, arthritis (for example rheumatoid arthritis), haemangioma, angiofibroma, disorders of the eye (for example diabetic retinopathy), neovascular glaucoma, disorders of the kidneys (for example glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplantation rejections and glomerulopathy, fibrotic disorders (for example cirrhosis of the liver), mesangial-cell- proliferative disorders, atherosclerosis, injuries of the nerve tissue and for inhibiting the reocclusion of vessels after balloon catheter treatment, in vessel prosthetics or
® after implantation of mechanical devices for keeping vessels open (for example stents) or other disorders in which cell proliferation or angiogenesis play a role.
Owing to their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumour therapy in monotherapy or in combination with other an titumor therapeutics, for example in combination with topoisomerase inhibitors (for example etoposide), mitosis inhibitors (for example vinblastine, Taxol), compounds which interact with nucleic acids (for example cisplatin, cyclophosphamide, adriarnycin), hormone antagonists (for example tamoxifen), steroids and analogues thereof (for example dexamethasone), inhibitors of metabolic processes (for example 5-FU etc.), cytokines (for example interferons), kinase inhibitors (for example EGFR ki nase inhibitoren, such as, for example, Iressa; Gleevec), allosterically acting receptor tyrosine kinase inhibitors, antibodies (for example Herceptin), COX-2 inhibitors or else in combination with radiotherapy, etc. These combinations can be administered either simu ltaneously or sequentially.
The invention is illustrated in more detail by the examples below:
3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)- methylene]-6-chloro-2-indolinone
11 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-iodophenyl)rnethylene]-6- chloro-2-indolinone
12 3-Z-[1- (4-(N-(dimethylaminomethylcarbonyl)-N-methylamiro)anilino)-1- (4-chlorophenyl)methylene]-6-chloro-2-indolinore
13 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)aniflino)-1-(4- chlorophenyl)methylene]-6-chloro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbony|)-N- 1.4 methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2- indolinone
3-2Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-
chlorophenyl)methylene]-6-chloro-2-indolinone 3-Z-(1-(4-(dimethylaminomethyl)anilino)-1-(4-chlorophenyl )methylene]- 6-chloro-2-indolinone
17 3-Z-[ 1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilimo)-1-(3,4-
dimethoxyphenyl)methylene]-6-chloro-2-indolino ne 3-Z-[1-(4-(N-(4-methylpiperazin-1-yimethylcarbony I)-N- methylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]—6-chloro-2- indolinone
9 3-Z-{1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylam ino)anilino)-
1 ~(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indol inone 110 3-Z-[ 1-(4-(dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)- methylene]-6-chloro-2-indolinone

Claims (18)

Claims
1. A compound of the formula R4 CR N R | re X R2 \ RI (1), in which Xis an oxygen atom, R'is a hydrogen atom, R? is a fluorine, chlorine or bromine atom or a cyano group, R? is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a Cy.3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a C,.3-alkoxy or Cy.p-alkyl-carbonyl-armino group,
_ by a cyano-C «.s-alkyl, carboxy-C.3-alkyl, carboxy-Ci.4-alkoxy, carboxy-C.3- alkylamino, carboxy-C1.3-alkyl-N-(C+.3-alkyl)-amino, C,4-alkoxy-carbonyl-C 1.3- alkyl, Ci.4-alkoxy-carbonyl-C;.3-alkoxy, Cj.4-alkoxy-carbonyi-C,.3-alkylamiro,
C1.4-alkoxy-caarbonyl-C1.3-alkyl-N-(C.3-alkyl)-amino, amino-C,.3-alkyl, amir o- carbonyl-C4_3—alkyl, (C1.2-alkylamino)-carbonyl-C,_s-alkyl, di-(C1.c-alkyl)-amino- carbonyl-C4_s—alkyl, (C,.2-alkyl-carbonyl)-amino-C,.3-alkyl, (C1-4-alkoxy- carbonyl)-ami no-Cj.z-alkyl, (Cs.¢-alkyl-carbonyl)-amino-C,.s-alkyl, (phenyl- carbonyl)-ami no-C1.s-alkyl, (Cs.s-cycloalkyl-carbonyl)-amino-C.z-alkyl, (C3-6- cycloalkyl-C.a-alkyl-carbonyl)-amino-C,.3-alkyl, (thiophen-2-yl-carbonyt)- amino-C4.z-allkyl, (furan-2-yl-carbonyl)-amino-C,.3-alkyl, (phenyl-C,.z-alkyl- carbonyl)-ami no-Ci.z-alkyl, (2-(C1.4-alkoxy)-benzoyl-carbonyl)-amino-C4.g-alkyl, (pyridin-2-yl-c arbonyl)-amino-C,_s-alkyl, (pyridin-3-yl-carbonyl)-amino-C.3- alkyl-, (pyridirm-4-yl-carbonyl)-amino-Ci.3-alkyl- or C4.3-alkyl-piperazin-1-yl- carbonyl-C1.3—alkyl group, by a carboxy-«C,.3-alkenyl, aminocarbonyl-C..s-alkenyl, (C1.3-alkylamino)- carbonyl-C,.3—alkenyl, di-(C,.;-alkyl)-amino-carbonyl-C,.s-alkenyl or C.4- alkoxy-carborayl-C.3-alkenyl group, where the substituents may be identical or different, R* is a phenyl group or a phenyl group which is monosubstituted by a Ci.3-alky=l group which is terminally substituted by an amino, guanidirso, mono- or di-(C.2-alkyl)-amino-, N-[w-di-(C1.5-alkyl)-amino-C..5-alkyl]-N-(C4 _3- alkyl)-amino, IN-methyl-(Cs.s-alkyl)-amino, N-(Ci.3-alkyl)-N-benzylamino, N-(C1.4-alkoxy=carbonyl)-amino, N-(Ci.4-alkoxycarbonyl)-C,.s-alkylamino, 4-(C.s-alkyl)-piperazin-1-yl, imidazol-1-yi, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-y 1, piperazin-1-yl, thiomorpholin-4-yl group, by a di-(Cs.3-a lkyl)-amino-(C,.5-alkyl)-sulphonyl, 2-[di-(C,.5-alkyl)-amino]- ethoxy, 4-(C.z-alkyl)-piperazin-1-yl-carbonyl, {w-[di-(C1.3-alkyl)-amino}-(C,. 5-
alkyl)}-IN-(C4.3-alkyl)-amino-carbonyl, 1-(C4.s-alkyl)imidazol-2-yl, (C.s-alkyl)- sulphonyl group, or by a group of the formula Rg / rR” in which R’ is a Cy.2-alkyl, Cy.2-alkyl-carbonyl, di-(C.2-alkyl)-armino-carbonyl-Cy.5- alkyl or C1.3-alkylsulphonyl group and
R& is Cy.s-alkyl, @[di-(C1.>-alkyl)-amino]-Cz.3-alky!, w-[ mono-(C;.-alkyl)- amino]-Ca.3-alkyl group, or a (Cy.3-alkyl)-carbonyl, (C4.s-alkyl)-carbonyl or carbonyi-(C4.3-alkyl) group which is terminally substituted by a di-(C4..-alkyl)-amino, piperazin-1-yl or 4-(C,.5-alkyl)-piperazin-1-yl group, where all dialkcylamino groups present in the radical R* may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-ammorium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate, R® is a hydrogen atom and
R® is a hydrogen atom, where the abovementioned alkyl groups include linear and branche d alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms,
where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be pre sent in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group, and its tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof.
2. A compound of the formula | according to Claim 1 in which X, R', R%, R*, R® and R® are as defined in Claim 1 and R? is a phenyl group which is substituted by a Cq.p-alkyl-carbonyl-amino group, by a carboxy-C1.z-alkyl, carboxy-C, _s-alkoxy, C;.4-alkoxy-carbonyl-C,z-alkyl,
C.4-alkoxy-carbonyl-C4.3-alkoxy, arminocarbonyi-C,.s-alkyl, (C,..-alkylamino)- carbonyl-C,.3-alkyl, di-(C4.o-alkyl)-arminocarbonyl-C.s-alkyl, (C1.2-alkyl- carbonyl)-amino-C1.3-alkyl, (C1.4-allkcoxy-carbonyl)-amino-Cy_s-alkyl, (phenyl- carbonyl)-amino-Ci.3-alkyl, (Cs.s-cycloalkyl-carbonyl)-amino-C,.z-alkyl, (C3.¢- cycloalkyl-C,.3-alkyl-carbonyl)-amin o-C;.s-alkyl, (thiophen-2-yl-carbonyl)- amino-C;.z-alkyl, (furan-2-yl-carbonyl)-amino-C,.3-alkyl, (phenyl-C,.z-alkyl- carbonyl)-amino-C.3-alkyl, (2-(C1.4-alkoxy)-benzoyl-carbonyl)-amino-C4.s-alkyl, (pyridin-2-yl-carbonyl)-amino-C.3-a kyl, (pyridin-3-yl-carbonyl)-amino-C_3- alkyl, (pyridin-4-yl-carbonyl}-amino- Cy_s-alkyl or C1.3-alkyl-piperazin-1-yl- carbonyl-C4.3-alkyl group, by an aminocarbonyl-Co.3-alkenyl, (C.3-alkylamino)-carbonyi-C,.3-alkenyl, di- (C1-3-alkyl}-amino-carbonyl-C,.3-alkenyl or Cy.4-alkoxy-carbonyl-C,_3-alkeny! group.
3. A compou nd of the formula | according to Claim 1 in which X, RR? R* R®and R® are as defined in Claim 1 and Ris a phenyl group su bstituted by a carboxy-C;.s-alkyl or Ci.4-alkoxy-carbonyl-C1.3- alkyl group.
4. A compou nd of the formula | according to any of Claims 1 to 3, in which X, R', R®, R*, R® and R® are as defined in any of Claims 1 to 3 and R2is a fluorine or chlorime atom.
5. A compoumd of the formula | according to Claim 1, selected from the following group: (a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6- chloro-2-indolinone (b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methwylene]-6- fluoro-2-indolinone (c) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methy/lene]-6- fluoro-2-indolinone (d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-yimethylcarbonyl)-N-methylamino)anilimo)-1-(4- (2-carboxyethyl)phenyl)rnethylene]-6-fluoro-2-indolinone (e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (f) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 40 (g) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-fluoro-2-indolinone
(h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylemnel]-6-fluoro-2-indolinone (i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylemne]-6-fluoro-2-indolinone (i) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indolinone (k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- fluoro-2-indolinone (I) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- chloro-2-indolinone (m) 3-Z-[1-(4-dimethylaminonnethylanilino)- 1-(4-(2-carboxyethyl)phenyl)methylene]-6- chloro-2-indolinone (n) 3-Z-[1-(4-(pyrrolidin-1-yimethyl)anilino)- 1-(4-(2-carboxyethyl)phenyl)methylene}-6- chloro-2-indolinone (0) 3-Z-[1-(4-(pyrrolidin-1-yImethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6- bromo-2-indolinone (p) 3-Z-[1-(4-(dimethylaminomnethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-bromo-2-indolinone (9) 3-Z-[1-(4-(diethylaminome thyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo- 2-indolinone and their salts.
6. A physiologically acceptable salt of a compound according to any of Claims 1to5.
7. A medicament, comprising a compound of the formula | according to any of Claims 1 to 5 or a physiologically acceptable salt according to Claim 6, if appropriate in addition to one or more inert carrier materials and/or diluents.
®
8. The use of a compound of the formula | according to at least one of Claims 1 to 5 or of a physiologically acceptable salt according to Claim 6 for preparing a medicament suitable for treating excessive or abnormal cell proliferation.
9. A process for preparing a medicament according to Claim 7, characterized in that, by a non-chemical route, a compound of the formula according to at least one of Claims 1 to 5 or a physiologically acceptable salt according to Claim 6 is incorporated into one or more inert carrier materials and/or diluents.
10. A process for preparing the compounds according to Claims 1 to 5, characterized in that a. a compound of the formula Zz Rs J R? \ RY Vv), in which the radicals Z' and R® may, if appropriate, cha nge their positions, X, R% R®and R°® are as defined in Claim 1, R" has the meanings mentioned at the outset for R' or is a protective group for the nitrogen atom of the lactam group, where R! may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z' is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, for example a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, is reacted with an amine of the formula
® 4 5 R _R How, in which R* and R® are defined as mentioned at the outset, and, if required, the product is subsequently cleraved from a protective group used for the nitrogen atom of the lactam group or from a solid phase,
b. for preparing a compound of the formula | in which R® is a phenyl! or naphthyl group substituted by a carboxy-C,.s-alkenyl, aminocarbonyl-C,.5-alkenyl, (C4.5-alkyl- amino)-carbonyl-C..3-alkenyl, di-(C1.3-alkylamin o)-carbonyl-C,.3-alkenyl or C.4- alkoxy-carbonyl-C,.s-alkenyl group, a compound of the formula 23 Q / IN R5 fo R \ RE x, in which R?, R* R® R° and X are as defined in Claim 1, R" has the meanings mentioned at the outset for R' or is a protective group for the nitrogen atom of the lactam group, where R" may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and 2%is a leaving group, for example a halogen atosm or an alkyl- or arylsulphonyloxy group, such as a chlorine, bromine or iodine ato m or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesuiphonyloxy or trifl uoromethanesulphonyloxy group, is reacted with an alkene of the formula
® O ANN (X), in which R® is an amino, (C1.3-alkylamino), di-(C1.s-alkylamino) or C4.4-alkoxy group and nis the numberOor1,
c. to prepare a compound of the formula I, in which R® is a phenyl or naphthyl group substituted by a carboxy-C_s-alkyl, C1.4-alkoxy- carbonyl-Cy.3-alkyl, aminocarbony|-C.5-alkyl, (C1.3-alkylamino)-carbonyl-C.5-alky! or di-(C4.s-alkyl)aminocarbonyl-C,.3-alkyl group, a compound of the formula Sp° Ul R4 / JN R® RS 3 X R \ RU x), in which R? R* R® R® and X are as defined in claim 1, R" has the meanings mentioned at the outset for R' or is a protective group for the nitrogen atom of the lactam group, where R" may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, Ais a Cy.z-alkenyl group and R® is a hydroxyl, Cy.4-alkoxy, amino, (C,.s-alkylamino) or di-(C.s-alkyl)amino group, is hydrogenated and the product is subsequently cleaved from any protective groups used for the nitrogen atom of the lactam group or from a solid phase, as described above under process (a),
and an alkoxycarbonyl group is, if appropriate, subsequently converted by hydrolysis into a corresponding carboxyl compound, or an amino or alkylamino group is converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or a dialkylamino group is converted by alkylation into a corresponding trialkylammonium compound, or an amino or alkylamino group is converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, respectively, or a carboxyl group is converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, or a nitro group is converted by reduction into a corresponding amino compound, or a cyano group is converted by reduction into a corresponding aminomethyl compound, or an arylalkyloxy group is converted with an acid into a corresponding hydroxyl compound, or an alkoxycarbonyl group is converted by hydrolysis into a corresponding carboxyl compound, or a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted by reaction with an appropriate amidino-group-transferring compound or by reaction with an appropriate nitrile into a corresponding guanidine compound of the formula I.
150a
11. A compound of the formula I according to clair |, substantially as herein described and exemplified.
12. A physiologically acceptable salt according to claim 6, substantially as herein described and exemplified.
13. A medicament according to claim 7, substantially as herein described and exemplified.
14. The use according to claim 8, substantially as herein described and exemplified.
15. A process for preparing a medicament according to claim 9, substantially as herein described and exemplified.
16. A process for preparing compounds according to claim 10, substantially as herein described and exemplified. AMENDED SHEET
150b
17. A compound of the formula 1 according to Claim 1, which is 3-Z-[1-(4- dimethylaminomethylanilino)-1-(4-(2-ethoxycarb©onylethyl)phenyl)methylene]-6- fluoro-2-indolinone.
18. The compound 1-acetyl-6-flouro-2-indolinone. AMENDED SEHEET
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