WO1999051590A1 - Substituted indolinones as kinase inhibitors - Google Patents

Substituted indolinones as kinase inhibitors Download PDF

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Publication number
WO1999051590A1
WO1999051590A1 PCT/EP1999/002186 EP9902186W WO9951590A1 WO 1999051590 A1 WO1999051590 A1 WO 1999051590A1 EP 9902186 W EP9902186 W EP 9902186W WO 9951590 A1 WO9951590 A1 WO 9951590A1
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Prior art keywords
indolinone
nitro
phenyl
methyl
imidazol
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PCT/EP1999/002186
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German (de)
French (fr)
Inventor
Wolfgang Grell
Rainer Walter
Armin Heckel
Frank Himmelsbach
Helmut Wittneben
Jacobus C. A. Van Meel
Norbert Redemann
Robert Haigh
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Boehringer Ingelheim Pharma Kg
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Priority to AU37034/99A priority Critical patent/AU3703499A/en
Publication of WO1999051590A1 publication Critical patent/WO1999051590A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • p21 mainly regulates transcription. p21 transcription is induced by the tumor suppressor gene p53, a transcriptional regulator that mediates the stopping of the cell cycle after DNA damage or in case of senescence. Basal concentrations of p21 may represent a threshold that must be exceeded before complexes can become active. Transcriptional control may also be important for pisI N K 4 B, the expression of which is greatly increased when treated with the negative growth factor TGFß. An additional effect of TGFß appears to be the release of p27, which is located in a heat-labile compartment. p27 is also likely to be involved in the effects of positive growth factors. For example, interleukin-2 stimulation appears to induce a decrease in the concentration of p27 and thereby the proliferation of T cells.
  • chromosome 9p21-22 The loss of chromosome 9p21-22 is of particular interest.
  • a gene with the name CDKN2 (MTS1, multiple tumor suppressor gene 1) is localized, which encodes a pl6 protein.
  • MTS1 multiple tumor suppressor gene 1
  • the pl6 protein binds to CDK4 and CDK6 and thereby inhibits their interaction with D-cyclins. Damage or mutations in the pl6 gene may influence the relative balance of functional pl6 and cyclin D, which leads to unregulated CDK activity and abnormal cell growth.
  • Deregulated CDK activity can therefore result from: (a) mutation or excessive expression of the kinase; (b) induced expression, overexpression or slow degradation of cyclins; (c) functional inactivation of CKIs by gene "silencing", damage or mutation; or (d) a combination of these phenomena.
  • the result of these deviations is a deregulated cell cycle with deregulated cell division that causes various diseases or contributes to their progression.
  • R ] _ is a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitro, amino, C ⁇ __ 4 alkanoylamino, (C; L_5-alkoxy) carbonylamino or benzyloxycarbonylamino group,
  • a C ⁇ _5-alkyl group by an amino, phthalimido, C ⁇ __5-alkylamino, C 3 _ 7 -cycloalkylamino-, C 3 _ 4 -alkenylamino-, benzylamino-, di- (C ⁇ _5-alkyl) -amino-, C2 -6-Alkylenimino-, di- (C 3 _ 4 ⁇ alkenyl) -amino-, N- (C ⁇ ._5-alkyl) -N- (C 3 _ 4 -alkenyl) -amino-, N- (C ⁇ __5-alkyl ) -N-benzylamino-, C 1 _ 4 -alkanoylamino-, (C ⁇ __5-alkoxy) carbonylamino-, benzyloxycarbonylamino-, N- (C ⁇ _ 4 -alkanoyl) - N ⁇
  • R a and R which may be the same or different, each represent a hydrogen atom or a methyl group
  • R c is a hydrogen atom, a (C; ⁇ _.5-alkoxy) carbonyl- C ⁇ _5-alkyl or benzyloxycarbonyl-C ⁇ _ 5 alkyl group and
  • R d is a hydrogen atom, a C 5 alkyl, C ⁇ . -Alkanoyl-, (C ⁇ _ 5 -alkoxy) carbonyl or benzyloxycarbonyl group, and
  • Het is a 5-membered heteroaromatic ring containing a nitrogen atom or a nitrogen atom and an oxygen, sulfur or nitrogen atom, the aforementioned ring also by a C ⁇ .. 5 alkyl, C 5 _ 7 -cycloalkyl -, Ph ⁇ nyl-, phenyl-C ⁇ __ 3 -alkyl-, amino-, C ⁇ . -Alkanoylamino, (C__5-alkoxy) carbonylamino or benzyloxycarbonylamino group and can also be substituted by a further C 1 -C 5 -alkyl group,
  • a 5-membered dihydrogenated heteroaromatic ring which contains a nitrogen atom or a nitrogen atom and an oxygen, sulfur or nitrogen atom, the ring mentioned above also being substituted by one or two C ⁇ _5-alkyl groups and can contain a carbonyl group and additionally on a ring nitrogen atom may be substituted by a (C ⁇ . 5 alkoxy) carbonyl or benzyloxycarbonyl,
  • a 5-membered tetrahydrated heteroaromatic ring which contains a nitrogen atom the ring mentioned above additionally by one or two C] __ 5-al yl groups a hydroxyl, carboxy, (C ⁇ __5-alkoxy) carbonyl or aminocarbonyl group can be substituted and can also contain one or two carbonyl groups,
  • R ⁇ _ is a hydrogen, fluorine, chlorine or bromine atom, a nitro, amino, C ⁇ __ 4 alkanoylamino, (C ⁇ __ 5 alkoxy) carbonylamino or benzyloxycarbonylamino group,
  • R2 is a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano, aminocarbonyl, nitro or amino group,
  • D and Het are defined as mentioned above and A represents a bond, a C ⁇ _ 3 alkylene, C ⁇ __ 3 alkylidene, C2 -3 alkenylene or C2_ 3 alkenylidene group, with a hydrogen atom, the rest of Het the carbon atom of the linking point is bonded, together with an ⁇ -hydrogen atom of the radical A can also be replaced by a further carbon-carbon bond,
  • R ⁇ is a hydrogen atom or a nitro group
  • R 2 is a hydrogen or chlorine atom, a methyl, trifluoromethyl, cyano, aminomethyl, aminoethyl or phthalimido group, a methyl or ethyl group, each represented by a methylamine, dimethylamino, ethylamino, diethylamino -, Pyrrolidino, piperidino, ⁇ -oxo-pyrrolidino, ⁇ -oxo-piperidino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, N-acetyl-N-methylamino, N-methoxycarbonyl -N-methyl-amino, N-ethoxycarbonyl-N-methyl-amino, N-benzyloxycarbonyl-N-methyl-aminomethyl, 2- (N-benzyloxycarbonyl-N-methyl-amino) -ethy
  • R 3 is 1-methyl-2-oxo-2, 3-dihydro-1H-benzimidazol-5-yl-, 1,2,3, 4-tetrahydro-isoquinolin-6-yl-, 2-acetyl-1,2 , 3, 4-tetra-hydro-isoquinolin-6-yl-, 2-acetyl-l, 2, 3, 4-tetrahydro-isochi nolin-7-yl-, 2-ethyl-1,2,3, -tetrahydro-isoquinolin-6-yl-, 2-ethyl-1, 2, 3, 4 -tetrahydro-isoquinolin-7-yl-, 4- (Imidazol-2-yl) phenyl-, 4- (1-methyl-imidazol-2-yl) -phenyl-, 4- (imidazol-4-yl) -phenyl-, 4- (l-methyl-imidazole- 4-yl) phenyl-, 4- (1-methylimidazol-5
  • R 1 is a hydrogen atom or a 5-position nitro group
  • R2 represents a hydrogen atom, a methyl or trifluoromethyl group
  • R 3 is 4- (1-methyl-imidazol-2-yl) phenyl, 4- (imidazol-4-yl) phenyl, 4- (imidazol-5-yl) phenyl, 4- (l -Methyl-imidazol-4-yl) -phenyl-, 4- (1-methyl-imidazol-5-yl) -phenyl-, 4- (2-methyl-imidazol-4-yl) -phenyl-, 4 - (2-Acetylamino-imidazol-4-yl) phenyl-, 4- [(2,4-dioxo-imidazolidin-5-ylidene) methyl] phenyl-, 4- [(1-pyrrolidinyl) methyl ] -phenyl-, 4- [2- (imidazol-4-yl) ethenyl] phenyl or 1, 2, 3, 4-tetrahydro-isoquinolin-6-yl group,
  • R ⁇ _ and R2 are defined as mentioned above, R 4 is a hydrogen atom or a protective group for the nitrogen atom of the lactam group and
  • the subsequent splitting off of a protective group that may be required is advantageously carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence of an alkali 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,
  • an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a primary or secondary organic base such as 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.
  • R2 represents one of the substituted alkenyl radicals mentioned at the beginning for R2, in the presence of a suitable noble metal-containing catalyst and, if necessary, subsequent cleavage of a protective group used for the nitrogen atom of the lactam group.
  • the Heck reaction is advantageously carried out under protective gas, for example under nitrogen or argon, if appropriate in a pressure vessel and advantageously in a solvent such as acetonitrile, dimethylformamide or N-methyl-pyrrolidin-2-one at temperatures between 20 and 180 ° C., preferably at temperatures between 80 and 150 ° C, carried out.
  • protective gas for example under nitrogen or argon
  • a solvent such as acetonitrile, dimethylformamide or N-methyl-pyrrolidin-2-one
  • the subsequent splitting off of a protective group that may be required 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 an alkali base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium acetate at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C,
  • a 1 represents a C 2 - 4 "alkenylene group, in the presence of a suitable noble metal-containing catalyst and, if necessary, subsequent cleavage of a protective group used for the nitrogen atom of the lactam group.
  • the subsequent splitting off of a protective group that may be required is advantageously carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence of an alkali base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium acetate at temperatures between 0 and 100 ° C., preferably at temperatures between 10 and 50 ° C,
  • a primary or secondary organic base such as 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 see 0 and 100 ° C, preferably carried out at temperatures between 10 and 50 ° C.
  • R 2 R 4 un ⁇ ⁇ w ⁇ e mentioned at the outset A' R l is a bond or an alkylene group, and R5 C ⁇ _ 4 is an alkyl group such as methyl or ethyl, represent
  • an ethylenediamine which can be substituted on one of the nitrogen or carbon atoms or on one of the nitrogen atoms and on one of the carbon atoms by a C ⁇ _5-alkyl group and, if necessary, subsequent removal of a protective group used for the nitrogen atom of a lactam group.
  • the reaction is advantageously carried out in a solvent such as diethyl ether, methanol or ethanol, but preferably in an excess of the ethylenediamine used at a temperature of temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • a solvent such as diethyl ether, methanol or ethanol
  • the subsequent splitting off of a protective group that may be required is advantageously carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, Dirnethylforrnamid / water, methanol or ethanol in the presence of an alkali 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,
  • an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a primary or secondary organic base such as 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.
  • a compound of the general formula I in which R2 represents a cyano, cyanoalkyl or cyanoalkenyl group this can be converted into a corresponding aminomethyl or aminoalkyl compound by means of reduction, preferably by means of catalytic hydrogenation, or a compound of the general formula I in which R 2 represents a cyano, cyanoalkyl or cyanoalkenyl group, this can be converted into a corresponding aminocarbonyl, aminocarbonylalkyl or aminocarbonylalkenyl compound by means of hydration, or
  • R 3 represents a phthalimido residue which is substituted by a (C ⁇ _ 5 -alkoxy) carbonyl-C ⁇ _5-alkyl or benzyloxycarbonyl-C ⁇ _5-alkyl group
  • this can be by means of acidolysis or hydrogenolysis in a corresponding carboxy compound can be converted, or
  • Het represents one of the aforementioned groups for Het which is substituted on a ring nitrogen atom by a (C ⁇ _ 5 alkoxy) carbonyl group or benzyloxycarbonyl group, this can by acidolysis or hydrogenolysis into a corresponding NH connection.
  • the subsequent hydrazinolysis is preferably carried out in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane, but particularly advantageously in hydrazine hydrate as the solvent, at temperatures between 20 and 120 ° C., preferably at the boiling point of the solvent used.
  • a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane, but particularly advantageously in hydrazine hydrate as the solvent, at temperatures between 20 and 120 ° C., preferably at the boiling point of the solvent used.
  • the subsequent hydrogenolysis is preferably carried out by means of catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium / carbon 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 room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon or platinum
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid
  • the subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide, optionally 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 .
  • a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide
  • the acylation with a corresponding acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, trimethyl orthoacetic acid, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorophlorochloride, phosphorus phosphorus , N '-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-dicyclohexylcarbodiimide / l-hydroxy-benzotriazole, 2- (IH-benzotriazol-l-yl) -1.1, 3, 3-tetramethyluronium tetrafluoroborate, 2- (IH-benzotriazol-l-yl) -1,1,
  • the subsequent dehalogenation is preferably carried out by means of catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium / carbon or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as glacial acetic acid or a base such as sodium umbicarbonate or triethylamine at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon or platinum
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / acetone or glacial acetic acid
  • an acid such as glacial acetic acid or a base such as sodium umbicarbonate or triethylamine at temperatures
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / 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 Room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C.
  • a methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • an oxidizing agent such as cerium (IV) ammonium nitrate
  • a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.
  • a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • chiral compounds of the general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)
  • the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives such as esters or amides, in particular acids and their activated derivatives or alcohols, with the racing compound and separating the mixture of diastereomeric salts or derivatives obtained in this way, for example on the basis of different solubilities, the free antipodes being obtained from the pure diastereomeric salts or derivatives by the action of suitable agents. tel can be released.
  • optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, calcium sulfonic acid, glutamic acid, N-acetyl-glutamic acid, aspartic acid, N-acetyl -aspartic acid or quinic acid.
  • Suitable optically active alcohols are, for example, (+) - or (-) menthol and optically active acyl radicals in amides are, for example, the (+) - or (-) menthyloxycarbonyl radicals.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of the formula I obtained in this way can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • bases which can be used here are sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I have valuable pharmacological properties, in particular inhibitory effects on various kinases and cyclin / CDK complexes, on the proliferation of cultured human tumor cells and on growth after oral administration of tumors in nude mice infected with human tumor cells.
  • the biological compounds were tested for their biological properties in the following tests, for example:
  • Tnh-ib-ie-nmg of Cyr ⁇ i n / CDK enzyme Activity in vit-.rn High Five TM insect cells (BTI-TN-5B1-4) infected with a high titer of recombinant baculovirus were used for the production of active human cyclin / CDK holoenzymes.
  • a baculovirus vector that contained two promoters (polyhedrin enhancer promoter, PlO enhancer promoter), GST-tagged cyclins (eg Cyclin Dl or Cyclin D3) with the corresponding Hisg-tagged CDK subunit ( for CDK4 or CDK6) 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 Hl Sigma was used as a substrate for Cyclin E / CDK2, Cyclin A / CDK2, Cyclin B / CDK1 and for v-Cyclin / CDK6.
  • GST-tagged pRB (aa 379-928) was used as a substrate for Cyclin D1 / CDK4, Cyclin D3 / CDK4, Cyclin D1 / CDK6 and for Cyclin D3 / CDK6.
  • Lysates of the insect cells infected with recombinant baculovirus or also recombinant kinases were combined with radioactively labeled ATP in the presence of a suitable substrate with various concentrations of the inhibitor in a 1% DMSO solution (dimethyl sulfoxide) 45 Incubated for minutes at 30 ° C.
  • the substrate proteins with associated radioactivity were multi-well mixed with 5% TCA (trichloroacetic acid) in hydrophobic PVDF Microtiter plates (Millipore) or precipitated with 0.5% phosphoric acid solution on Whatman P81 filters. After adding scintillation fluid, the radioactivity was measured in a Wallace 1450 Microbeta liquid scintillation counter. Double measurements were carried out per concentration of the substance; IC5 0 values for enzyme inhibition were calculated.
  • 14 C-thymidine (Amersham) was added to each well and incubation was continued for 24 hours.
  • the amount of 14 C-thymidine which was incorporated into the tumor cells in the presence of the inhibitor and which represents the number of cells in the S phase was measured in a Wallace 1450 Microbeta liquid scintillation counter.
  • a kinase inhibitor was administered orally daily (by gavage) for a period of 2 to 4 weeks. The tumor size was measured three times a week with a digital caliper. The effect of a kinase inhibitor on tumor growth was determined as a percent inhibition compared to a control group treated with placebo.
  • Such diseases include (without claim to completeness): viral infections (e.g. HIV and Kaposi sarcoma); Inflammation and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin disorders (e.g. psoriasis); Bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful as protection of proliferating cells (e.g. hair, intestinal, blood and progenitor cells) against DNA damage from radiation, UV treatment and / or cytostatic treatment.
  • proliferating cells e.g. hair, intestinal, blood and progenitor cells
  • the dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration, and 0.1 to 100 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day.
  • the compounds of the formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert inert carriers and / or diluents, e.g.
  • TBTU 0- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyl uronium tetrafluoroborate
  • Example B The mixture obtained in Example B consisting of 66% l-acetyl-3- ⁇ l-ethoxy-l-phenylmethylidene ⁇ -2-indolinone and 34% 1-acetyl-2-indolinone is suspended in ethanol (8 ml / g), added 2 equivalents of 4N sodium hydroxide solution and stirred at room temperature for 1.5 hours. After adding water (25 ml / g), the precipitate is filtered off, washed with water and a little ether and dried at 80 ° C.
  • Example 10 Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-2-indoline and 4-methyl-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and final cleaning by column chromatography on silica gel with CH2CI2 as the eluent.
  • Example 10 Prepared analogously to Example 10 (a) from l-acetyl-2-indolinone and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and final purification by column chromatography on silica gel with CK2Cl 2 / MeOH
  • Example 10 Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-2-indoline and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and evaporation in Vacuum.
  • a sample of the crude product obtained was purified by column chromatography on silica gel with CH 2 Cl2 / MeOH (20: 1) as the eluent.
  • Example 10 Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-indolinone and 4- (imidazol-1-yl-methyl) benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base.
  • Example 11.4 Prepared analogously to Example 11.4 (b) by reacting 1-acetyl-3- (l-hydroxy-1- [4- (imidazol-1-yl-methyl) phenyl] methylidene ⁇ - 5-nitro-2-indolinone with PCI5 in toluene and then with 4- (IH-imidazol -4-yl) aniline and triethylamine in THF.Yield: 25% of theory; melting point: 230-235 ° C; C 28 H 21 N 7 0 3 (503.53)
  • Example 10 Prepared analogously to Example 10 (a) from 1-acetyl-2-indolinone and 4-phthalimidomethylbenzoic acid (melting point: 260-262 ° C) in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, 4 hours) , Stir in dilute hydrochloric acid, extraction with CH2CI2, evaporation of the dried organic extract in vacuo, trituration of the evaporation residue with EtOAc and drying of the solid substance. Yield: 69% of theory; Melting point: 200-201 ° C; Enol reaction (with FeCl 3 solution in EtOH): positive.
  • Example 11 Prepared analogously to Example 11 (b) from the obtained under (a) enol with 2 equivalents of PC1 5 in toluene (100 ° C / l hour) and evaporated to incipient turbidity in vacuo, treated with petroleum ether, the precipitate formed, washing him with petroleum ether and dry it at 75 ° C in a vacuum.

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Abstract

The invention relates to indolinones of general formula (I), wherein R1 to R3 have the meanings given in claim 1, to their isomers and to their salts, especially their physiologically compatible salts which have valuable pharmacological properties, in particular an inhibitory effect on various kinases and cycline/CDK complexes and on the proliferation of various tumour cells. The invention also relates to medicaments containing these compounds, to their use and to a method for producing them.

Description

SUBSTITUIERTE INDOLINONE ALS INHIBITOREN VON KINASEN SUBSTITUTED INDOLINONES AS INHIBITORS OF KINASEN
Der Zellteilungs-Zyklus ist einer der fundamentalsten biologischen Prozesse, der die kontrollierte Erzeugung von Zellen mit spezialisierten Funktionen sicherstellt . Die Progression durch den eukaryotischen Zellzyklus wird kontrolliert durch die sequentielle Bildung, Aktivierung und Inaktivierung einer ganzen Reihe von Protein-Serin/Threonin-Kinasen, sogenannten Cyclin-abhängigen Kinasen (CDK's; Cyclin-dependent kinases) (siehe M. Peter et al. in Cell 22., 181-184 (1994) und G.F. Draetta in Cell Biology £, 842-846 (1994) ) . Jede CDK phospho- ryliert offenbar spezifische Substrate und koordiniert die Änderungen, die während eines bestimmten Transition Status des Zellzyklus erfolgen. Wegen der zentralen Rolle der CDK's sind große Anstrengungen unternommen worden, ihre Regulation aufzuklären und zu verstehen. Einige Mechanismen sind inzwischen identifiziert. So sind essentielle Untereinheiten (subunits) infolge der Synthese- und Abbau-Kontrolle von Cyclin nur in der entsprechenden Periode des Zellzyklus zugänglich. Außerdem werden einige CDK/Cyclin-Komplexe inhibiert durch die Bindung von kleinen Protein Inhibitoren (cyclin-dependant kinase inhibi- tors) , deren Vorhandensein ebenfalls streng kontrolliert wird. Weiterhin werden die CDK-Aktivitäten translational durch reversible Phosphorylierung ihrer katalytischen Untereinheiten reguliert (siehe C. Hutchinson and D.M. Glover (Editors) in Cell Cycle Control, IRL Press, London, 1994) .The cell division cycle is one of the most fundamental biological processes that ensures the controlled generation of cells with specialized functions. The progression through the eukaryotic cell cycle is controlled by the sequential formation, activation and inactivation of a whole series of protein serine / threonine kinases, so-called cyclin-dependent kinases (CDK's; cyclin-dependent kinases) (see M. Peter et al. In Cell 22, 181-184 (1994) and GF Draetta in Cell Biology £ 842-846 (1994)). Each CDK apparently phosphorylates specific substrates and coordinates the changes that occur during a certain transition status of the cell cycle. Because of the central role of the CDK's, great efforts have been made to elucidate and understand their regulation. Some mechanisms have now been identified. As a result of the synthesis and degradation control of cyclin, essential subunits are only accessible in the corresponding period of the cell cycle. In addition, some CDK / cyclin complexes are inhibited by binding small protein inhibitors (cyclin-dependent kinase inhibitors), the presence of which is also strictly controlled. Furthermore, CDK activities are translationally regulated by reversible phosphorylation of their catalytic subunits (see C. Hutchinson and D.M. Glover (Editors) in Cell Cycle Control, IRL Press, London, 1994).
Der primäre Regulator der CDK-Aktivität ist die assoziierte Cyclin-Untereinheit. Cycline, die ursprünglich als Proteine definiert waren, deren Konzentrationen während des Zellzyklus oszillieren, werden jetzt - genauer - als eine Familie von strukturell verwandten Proteinen definiert, die CDK-kataly- tische Untereinheiten binden und aktivieren. Zum Beispiel in- teragiert CDKl mit Cyclin B und mit Cyclin A; CDK2 mit Cyclin E und Cyclin A; CDK4 und CDK6 mit D-Cyclinen; und CDK7 mit Cyclin H. Die Cyclin Funktion wird primär kontrolliert durch Änderungen der Cyclin-Konzentrationen, die bei einem bestimmten Zell- Zustand charakteristisch ansteigen: Cyclin E in der Gl/S-Phase; Cyclin A in der S-Phase; Cyclin B in der G2/M-Phase. D-Cycline und Cyclin H sind diesbezüglich Ausnahmen, weil ihre Konzentrationen während des ganzen Zellzyklus relativ konstant sind.The primary regulator of CDK activity is the associated cyclin subunit. Cyclins, which were originally defined as proteins whose concentrations oscillate during the cell cycle, are now - more precisely - defined as a family of structurally related proteins that bind and activate CDK-catalytic subunits. For example in- interacts CDKl with cyclin B and with cyclin A; CDK2 with Cyclin E and Cyclin A; CDK4 and CDK6 with D-cyclins; and CDK7 with cyclin H. The cyclin function is primarily controlled by changes in the cyclin concentrations, which increase characteristically in a certain cell state: cyclin E in the Gl / S phase; Cyclin A in the S phase; Cyclin B in the G2 / M phase. D-Cycline and Cyclin H are exceptions to this because their concentrations are relatively constant throughout the cell cycle.
Primär verantwortlich für die Progression durch die Gl- zur S-Phase des Zellzyklus sind die D-Cycline sowie Cyclin E und Cyclin A. Wachstumshormone, Steroid-Hormone, die Aktivierung von ras, und andere mitogene Stimuli induzieren einen Anstieg der Konzentration von D-Cyclinen und/oder von Cyclin E und initiieren dadurch die Progression der Zelle durch die Gl- zur S-Phase. Ein Substrat für Cyclin D/CDK4 bzw. Cyclin D/CDK6 ist das Retinoblastoma Gen Produkt (pRB) . Das Retinoblastoma Gen seinerseits ist ein Tumor Suppressor Gen, das die Zell-Proli- feration kontrolliert. pRB - in hvpophosphorylierter Form - ist normalerweise an den Transkriptions-Faktor E2F gebunden, der in diesem Komplex inaktiv ist. Hyp≤rphosporylierung von pRB durch CDK's setzt E F frei und induziert Transkription. Eine Schlüsselrolle beim Zellwachstum spielt der Cyclin D/CDK4- bzw. /CDK6-Komplex. Es gibt zunehmend Indizien dafür, daß D-Cycline (Dl bzw. D2) offenbar stark an der Genese von Tumoren beteiligt sind (siehe L.H. Hartwell et al . in Science 2££, 1821-1828 (1994) ) . Die molekularen Mechanismen, die den proto-onkogenen Eigenschaften von Cyclin Dl zugrunde liegen, schließen chromo- somale Umlagerungen (bei Parathyroid Adenoma und B-Zell Lymphoma) sowie eine Amplifikation der chromosomalen Bande llql3 ein, die für verschiedene Krebs-Typen (inklusive Brust-, Kopf-, Nacken- und Leber-Tumoren) berichtet wurde (siehe C. Gillett et al. in Cancer Research 5A, 1812-1817 (1994) und T. Callender et al. in Cancer ü, 152-158 (1994)) . Man nimmt an, daß das Gesamt-Ergebnis dieser genetischen Veränderungen eine ektopische oder anormal erhöhte Expression des Cyclin Dl-Proteins ist, die möglicherweise zu unangemessenen Zeil-Teilungen und unreguliertem Tumor-Wachstum beiträgt.The D-cyclins as well as cyclin E and cyclin A are primarily responsible for the progression through the Gl phase to the S phase of the cell cycle. Growth hormones, steroid hormones, the activation of ras, and other mitogenic stimuli induce an increase in the concentration of D- Cyclins and / or cyclin E and thereby initiate the progression of the cell through the Gl to the S phase. A substrate for cyclin D / CDK4 or cyclin D / CDK6 is the retinoblastoma gene product (pRB). The retinoblastoma gene in turn is a tumor suppressor gene that controls cell proliferation. pRB - in hvpophosphorylated form - is normally bound to the transcription factor E 2 F, which is inactive in this complex. Hypophosphorylation of pRB by CDK's releases EF and induces transcription. The cyclin D / CDK4 or / CDK6 complex plays a key role in cell growth. There is increasing evidence that D-cyclins (Dl or D2) appear to be heavily involved in the genesis of tumors (see LH Hartwell et al. In Science 2 ££, 1821-1828 (1994)). The molecular mechanisms underlying the proto-oncogenic properties of Cyclin Dl include chromosomal rearrangements (in parathyroid adenoma and B-cell lymphoma) as well as an amplification of the chromosomal band llql3, which is necessary for different types of cancer (including breast , Head, neck and liver tumors) (see C. Gillett et al. In Cancer Research 5A, 1812-1817 (1994) and T. Callender et al. In Cancer ü, 152-158 (1994)) . The overall result of these genetic changes is believed to be ectopic or abnormally elevated expression of the cyclin Dl protein, which may contribute to inappropriate cell division and unregulated tumor growth.
An einem weiteren Hauptmechanismus der CDK-Regulation ist eine Familie verschiedener Proteine, sogenannter Cyclin-abhängiger Kinase Inhibitoren (cyclin-dependent kinase inhibitors; CKI's) beteiligt, die Cyclin/CDK-Komplexe binden und inhibieren (siehe G. Peters in Nature 371, 204-205 (1994)). Die Haupt (Säugetier) - CKI's gehören zu zwei Klassen: (1): p21 (CIP1/WAF1/-CAP20/SD1) , p27 (KIP1) und p57 (KIP2) sind verwandte Proteine mit einer Präferenz für Cyclin/CDK2- und Cyclin/CDK4-Komplexe; (2) pl6INK4/ pl5INK4B pl8INK4C und pl9INK4D sind eng verwandteAnother main mechanism of CDK regulation involves a family of different proteins, so-called cyclin-dependent kinase inhibitors (CKIs), which bind and inhibit cyclin / CDK complexes (see G. Peters in Nature 371, 204 -205 (1994)). The main (mammalian) CKIs belong to two classes: (1): p21 (CIP1 / WAF1 / -CAP20 / SD1), p27 (KIP1) and p57 (KIP2) are related proteins with a preference for cyclin / CDK2 and cyclin / CDK4 complexes; (2) pl6 INK4 / pl5 INK4B pl8 INK4C and pl9 INK4D are closely related
CKI's mit einer Spezifität für CDK4 und/oder CDK6. p21 reguliert hauptsächlich die Transkription. p21 Transkription wird durch das Tumo -Suppressor Gen p53 induziert, einen transkrip- tionalen Regulator, der das Anhalten des Zellzyklus nach einer DNA-Schädigung oder bei Senescenz vermittelt. Basal-Konzentrationen von p21 stellen möglicherweise eine Schwelle dar, die überschritten werden muß, bevor Komplexe aktiv werden können. Transkriptionale Kontrolle ist möglicherweise auch für pisINK4B wichtig, dessen Expression stark erhöht wird, wenn mit dem negativen Wachstumsfaktor TGFß behandelt wird. Ein zusätzlicher Effekt von TGFß besteht offenbar in der Freisetzung von p27, das in einem Hitze-labilen Kompartment angesiedelt ist. p27 ist wahrscheinlich auch beteiligt an den Wirkungen von positiven Wachstumsfaktoren. Zum Beispiel scheint Interleukin-2 Stimulation ein Absinken der Konzentration von p27 und dadurch die Proliferation von T-Zellen zu induzieren.CKI's with a specificity for CDK4 and / or CDK6. p21 mainly regulates transcription. p21 transcription is induced by the tumor suppressor gene p53, a transcriptional regulator that mediates the stopping of the cell cycle after DNA damage or in case of senescence. Basal concentrations of p21 may represent a threshold that must be exceeded before complexes can become active. Transcriptional control may also be important for pisI N K 4 B, the expression of which is greatly increased when treated with the negative growth factor TGFß. An additional effect of TGFß appears to be the release of p27, which is located in a heat-labile compartment. p27 is also likely to be involved in the effects of positive growth factors. For example, interleukin-2 stimulation appears to induce a decrease in the concentration of p27 and thereby the proliferation of T cells.
Neueste Studien haben häufig einen allelischen Verlust auf Chromosom 9 in einer Reihe von humanen Carcinoma (z.B. bei Melanoma, Kopf- und Nacken-Schuppenzellen-, Lungen-, pankre- atischen Adeno-, Brust- und Nasopharyngeal-Ca) gezeigt (siehe A. Kamb et al . in Science 264, 436-440 (1994); C. J. Hussussian et al. in Nature Genetics £, 15-21 (1994); C. Caldas et al . in Cancer Nature Genetics j, 27-32 (1994); T. Mori et al . in Cancer Research 5A, 3396-3397 (1994) und A. Okamato et al . in Proc. Natl. Acad. Sei. USA 3 , 11045-11049 (1994)). Von besonderem Interesse ist der Verlust von Chromosom 9p21-22. In dieser Region, in der ein Tumorsuppressor-Gen vermutet wird, ist eine Gen mit Namen CDKN2 (MTS1, Multiple Tumor Suppressor Gen 1) lokalisiert, das ein pl6-Protein kodiert. Wie oben schon erwähnt, bindet das pl6-Protein an CDK4 und CDK6 und inhibiert dadurch deren Interaktion mit D-Cyclinen. Schädigungen oder Mutationen im pl6-Gen beeinflussen möglichweise die relative Balance von funktionalem pl6 und Cyclin D, was zu unregulierter CDK-Aktivität und zu anormalem Zeil-Wachstum führt. Die neuesten Beobachtungen, daß in vielen Tumorzellen sehr häufig pl6- Schädigungen, Inaktivierung durch Gen- "Silencing" und/oder Mutationen vorkommen, weisen darauf hin, daß pl6 eine Schlüsselrolle bei der Unterdrückung der Entwicklung von verschiedenen humanen Carcinoma spielt (siehe G.I. Shapiro et al . in Cancer Research 5ü, 6200-6209 (1995)).Recent studies have often shown an allelic loss on chromosome 9 in a number of human carcinomas (e.g. melanoma, head and neck squamous cells, lung, pancreatic adeno-, breast and nasopharyngeal Ca) (see A. Kamb et al. In Science 264, 436-440 (1994); CJ Hussussian et al. In Nature Genetics £, 15-21 (1994); C. Caldas et al. In Cancer Nature Genetics j, 27-32 (1994) ; T. Mori et al. In Cancer Research 5A, 3396-3397 (1994) and A. Okamato et al. In Proc. Natl. Acad. Be. USA 3, 11045-11049 (1994)). The loss of chromosome 9p21-22 is of particular interest. In this region, in which a tumor suppressor gene is suspected, a gene with the name CDKN2 (MTS1, multiple tumor suppressor gene 1) is localized, which encodes a pl6 protein. As already mentioned above, the pl6 protein binds to CDK4 and CDK6 and thereby inhibits their interaction with D-cyclins. Damage or mutations in the pl6 gene may influence the relative balance of functional pl6 and cyclin D, which leads to unregulated CDK activity and abnormal cell growth. The latest observations that pl6 damage, inactivation by gene "silencing" and / or mutations occur very frequently in many tumor cells indicate that pl6 plays a key role in suppressing the development of various human carcinomas (see GI Shapiro et al. in Cancer Research 5ü, 6200-6209 (1995)).
Deregulierte CDK-Aktivität kann also die Folge sein von: (a) Mutation oder exzessiver Expression der Kinase; (b) induzierter Expression, Überexpression oder verlangsamtem Abbau von Cyclinen; (c) funktionaler Inaktivierung von CKI's durch Gen- "Silencing", -Schädigung oder -Mutation; oder (d) einer Kombination dieser Phänomeme. Das Ergebnis dieser Abweichungen ist ein deregulierter Zellzyklus mit deregulierter Zellteilung, die verschiedene Krankheiten verursacht oder zu ihrer Progression beiträgt .Deregulated CDK activity can therefore result from: (a) mutation or excessive expression of the kinase; (b) induced expression, overexpression or slow degradation of cyclins; (c) functional inactivation of CKIs by gene "silencing", damage or mutation; or (d) a combination of these phenomena. The result of these deviations is a deregulated cell cycle with deregulated cell division that causes various diseases or contributes to their progression.
Es wurde nun gefunden, daß die neuen substituierten Indolinone der allgemeinen FormelIt has now been found that the new substituted indolinones of the general formula
Figure imgf000006_0001
deren Isomere, deren Salze, insbesondere deren physiologisch verträgliche Salze wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine inhibierende Wirkung auf verschiedene Kinasen, vor allem auf Komplexe von CDK's (CDKl, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 und CDK9) mit ihren spezifischen Cyclinen (A, Bl, B2 , C, Dl, D2 , D3 , E, F, Gl, G2 , H, I und K) und auf virales Cyclin (siehe L. Mengtao et al . in J. Virology 21(3), 1984-1991 (1997)).
Figure imgf000006_0001
whose isomers, their salts, in particular their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory effect on various kinases, especially on complexes of CDK's (CDKl, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9) with their specific Cyclins (A, Bl, B2, C, Dl, D2, D3, E, F, Gl, G2, H, I and K) and on viral cyclin (see L. Mengtao et al. In J. Virology 21 (3) , 1984-1991 (1997)).
Gegenstand der vorliegenden Erfindung sind somit die Verbindungen der obigen allgemeinen Formel I, deren Isomere, deren Salze, insbesondere deren physiologisch verträgliche Salze, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung.The present invention thus relates to the compounds of the general formula I above, their isomers, their salts, in particular their physiologically tolerable salts, medicaments containing these compounds, their use and processes for their preparation.
In der obigen allgemeinen Formel I bedeutenIn the above general formula I mean
R]_ ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom, eine Nitro-, Amino-, Cι__4-Alkanoylamino- , (C;L_5-Alkoxy) carbonyl- amino- oder Benzyloxycarbonylaminogruppe,R ] _ is a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitro, amino, Cι__ 4 alkanoylamino, (C; L_5-alkoxy) carbonylamino or benzyloxycarbonylamino group,
R2 ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom, eine Cι_5-Alkyl-, Trifluormethyl- , Cyano-, Aminocarbonyl- , Nitro- oder Aminogruppe,R2 is a hydrogen, fluorine, chlorine, bromine or iodine atom, a Cι_5-alkyl, trifluoromethyl, cyano, aminocarbonyl, nitro or amino group,
eine Cι_5-Alkylgruppe, die durch eine Amino-, Phthalimido-, Cη__5-Alkylamino-, C3_7-Cycloalkylamino- , C3_4-Alkenylamino- , Benzylamino-, Di- (Cι_5-alkyl) -amino- , C2-6-Alkylenimino- , Di- (C3_4~alkenyl) -amino-, N- (Cτ._5-Alkyl) -N- (C3_4-alkenyl) -amino-, N- (Cι__5-Alkyl) -N-benzylamino- , C1_4-Alkanoylamino-, (Cτ__5-Alk- oxy) carbonylamino- , Benzyloxycarbonylamino- , N- (Cι_4-Alkanoyl) - N~ (Cι_5-alkyl) -amino-, α-Oxo-C^.g-alkylenimino- , N- ( (Cι_5~Alk- oxy) carbonyl) -N- (Cι__5-alkyl) -amino- , N-Benzyloxycarbonyl- N- (Ci-s-alkyl) -amino-, N- (C1_4-Alkanoyl) -N- (C2-4-alkenyl) - amino-, N- ( (C^_5-Alkoxy) carbonyl) -N- (C2_4-alkenyl) -amino-, N-Benzyloxycarbonyl-N- (C2-4-alkenyl) -amino-, N- (Cτ__4-Alkanoyl) - N-benzylamino-, N- ( (Cτ__5-Alkoxy) carbonyl) -N-benzylamino- , N-Benzyloxycarbonyl-N-benzylamino- , (C^.5-Alkoxy) carbonyl- , Benzyloxycarbonyl-, Carboxy-, Cyano-, Amidinocarbonyl- oder Imidazolylgruppe substituiert ist,a Cι_5-alkyl group by an amino, phthalimido, Cη__5-alkylamino, C 3 _ 7 -cycloalkylamino-, C 3 _ 4 -alkenylamino-, benzylamino-, di- (Cι_5-alkyl) -amino-, C2 -6-Alkylenimino-, di- (C 3 _ 4 ~ alkenyl) -amino-, N- (Cτ._5-alkyl) -N- (C 3 _ 4 -alkenyl) -amino-, N- (Cι__5-alkyl ) -N-benzylamino-, C 1 _ 4 -alkanoylamino-, (Cτ__5-alkoxy) carbonylamino-, benzyloxycarbonylamino-, N- (Cι_ 4 -alkanoyl) - N ~ (Cι_5-alkyl) -amino-, α- Oxo-C ^ .g-alkylenimino-, N- ((Cι_5 ~ alk-oxy) carbonyl) -N- (Cι__5-alkyl) -amino-, N-benzyloxycarbonyl- N- (Ci-s-alkyl) -amino- , N- (C 1 _ 4 alkanoyl) -N- (C 2-4 alkenyl) - amino, N- ((C ^ _ 5 alkoxy) carbonyl) -N- (4 C2_ alkenyl) amino -, N-Benzyloxycarbonyl-N- (C2- 4 -alkenyl) -amino-, N- (Cτ__ 4 -alkanoyl) - N-benzylamino-, N- ((Cτ__ 5 -alkoxy) carbonyl) -N-benzylamino-, N-benzyloxycarbonyl-N-benzylamino, (C ^. 5 -alkoxy) carbonyl, benzyloxycarbonyl, carboxy, cyano, amidinocarbonyl or imidazolyl group is substituted,
eine C2-5~Alkenylgruppe, die durch eine Phthalimido- , Cτ__4-Al- kanoylamino- , (Cτ_.5-Alkoxy) carbonylamino- , Benzyloxycarbonyl- amino-, N- (C^_4 -Alkanoyl) -N- (Cτ__5-alkyl) -amino-, α-Oxo- C3_g-Alkylenimino-, N- ( (C]__5-Alkoxy) carbonyl) -N- (Cτ__5-alkyl) - amino-, N-Benzyloxycarbonyl-N- (Cι_5-alkyl) -amino-, N-(Cτ__4~Al- kanoyl) -N- (C2_4-alkenyl) -amino-, N- ( (C]__5-Alkoxy) carbonyl) - N- (C2-4~alkenyl) -amino-, N-Benzyloxycarbonyl-N- (C2_4-alkenyl) - amino-, N- (Cτ__4-Alkanoyl) -N-benzylamino- , N- ( (Cτ__5-Alkoxy) - carbonyl) -N-benzylamino-, N-Benzyloxycarbonyl-N-benzylamino- , (Cη__5-Alkoxy) carbonyl- , Benzyloxycarbonyl-, Carboxy-, Cyano- oder Aminocarbonylgruppe substituiert ist, odera C 2 -5 ~ alkenyl group which is replaced by a phthalimido, Cτ__ 4 -alkanoylamino-, (Cτ_.5-alkoxy) carbonylamino-, benzyloxycarbonylamino-, N- (C ^ _ 4 -alkanoyl) -N- (Cτ__5-alkyl) -amino-, α-oxo-C 3 _g-alkylenimino-, N- ((C ] __5-alkoxy) carbonyl) -N- (Cτ__5-alkyl) - amino-, N-benzyloxycarbonyl-N- (Cι_5-alkyl) -amino-, N- (Cτ__4 ~ Al-kanoyl) -N- (C2_4-alkenyl) -amino-, N- ((C] __ 5 -alkoxy) carbonyl) - N- (C2- 4 ~ alkenyl) -amino-, N-benzyloxycarbonyl-N- (C2_ 4 -alkenyl) -amino-, N- (Cτ__ 4 -alkanoyl) -N-benzylamino-, N- ((Cτ__5-alkoxy) -carbonyl) -N -benzylamino, N-benzyloxycarbonyl-N-benzylamino, (Cη__5-alkoxy) carbonyl, benzyloxycarbonyl, carboxy, cyano or aminocarbonyl group is substituted, or
eine Allylgruppe, die in 3 -Stellung durch eine Amino-, C]__5-Alkylamino-, C3_7-Cycloalkylamino-, C3_4~Alkenylamino- , Benzyl- amino-, Di- (Cχ_5-alkyl) -amino- , C2-6-Alkylenimino- , Di- (C3_4-alkenyl) -amino-, N- (Cτ__5-Alkyl) -N- (C3_4-alkenyl) -amino- oder N- (Cι_5-Alkyl) -N-benzylaminogruppe substituiert ist, undan allyl group in the 3-position by an amino, C ] __5-alkylamino, C 3 _ 7 -cycloalkylamino-, C 3 _ 4 ~ alkenylamino-, benzylamino-, di- (Cχ_5-alkyl) -amino -, C2- 6 -alkyleneimino-, di- (C 3 _ 4 -alkenyl) -amino-, N- (Cτ__5-alkyl) -N- (C 3 _4-alkenyl) -amino- or N- (Cι_5-alkyl ) -N-benzylamino group is substituted, and
R3 eine Gruppe der FormelnR 3 is a group of the formulas
Figure imgf000008_0001
in denen
Figure imgf000008_0001
in which
A eine Bindung, eine Cτ__4-Alkylen- , Cι_4-Alkyliden-, C2_4-Alkenylen- oder C2_4~Alkenyliden-Gruppe darstellen, wobei ein Wasserstoffatom, das im Rest Het an das Kohlenstoffatom der Verknüpfungssteile gebunden ist, zusammen mit einem α-ständigen Wasserstoffatom des Restes A auch durch eine weitere Kohlenstoff-Kohlenstoff-Bindung ersetzt sein kann, D eine -CH=CH-NRa-, -CH=N-NRa-, -N=CH-NRa-, -N a-CO-NR^- , -CH2-CO-NRa-, -CO-NRc-CO-, -CH2-NRa-CH2- , -CH2-CH2-NRa- , -CH=CH-CH=N-, -CH2-CH2-CH2-NRd-, -CH=CH-N=CH- , -CH2-CE2-NRd-CH2-, -CH2-CH2-CO-NH- , -CH=CH-CO-NH- , -NRa-CO-CK=N- oder - (RaCR]-,) -CO-NRa-CO-Brücke, wobeiA represents a bond, a Cτ__ 4 -alkylene, Cι_4-alkylidene, C2_4-alkenylene or C2_4 ~ alkenylidene group, a hydrogen atom which is bonded to the carbon atom of the linking parts in the rest of Het together with an α-position Hydrogen atom of radical A can also be replaced by a further carbon-carbon bond, D a -CH = CH-NR a -, -CH = N-NR a -, -N = CH-NR a -, -N a-CO-NR ^ -, -CH 2 -CO-NR a -, - CO-NR c -CO-, -CH 2 -NR a -CH 2 -, -CH 2 -CH 2 -NR a -, -CH = CH-CH = N-, -CH 2 -CH 2 -CH 2 - NR d -, -CH = CH-N = CH-, -CH 2 -CE 2 -NR d -CH 2 -, -CH 2 -CH 2 -CO-NH-, -CH = CH-CO-NH-, -NR a -CO-CK = N- or - (R a CR] -,) -CO-NR a -CO bridge, where
Ra und R,, die gleich oder verschieden sein können, jeweils ein Wasserstoffatom oder eine Methylgruppe,R a and R ,, which may be the same or different, each represent a hydrogen atom or a methyl group,
Rc ein Wasserstoffatom, eine (C;τ_.5-Alkoxy) carbonyl- Cι_5-alkyl- oder Benzyloxycarbonyl-Cι_5-alkylgruppe undR c is a hydrogen atom, a (C; τ_.5-alkoxy) carbonyl- Cι_5-alkyl or benzyloxycarbonyl-Cι_ 5 alkyl group and
Rd ein Wasserstoffatom, eine Cι_5-Alkyl-, C^. -Alkanoyl- , (Cι_5-Alkoxy) carbonyl- oder Benzyloxycarbonylgruppe darstellen, undR d is a hydrogen atom, a C 5 alkyl, C ^. -Alkanoyl-, (Cι_ 5 -alkoxy) carbonyl or benzyloxycarbonyl group, and
Het einen 5-gliedrigen heteroaromatischen Ring, der ein Stickstoffatom oder ein Stickstoffatom und ein Sauerstoff-, Schwefel- oder Stickstoffatom enthält, wobei der vorstehend erwähnte Ring außerdem durch eine C^..5-Alkyl- , C5_7-Cyclo- alkyl-, Phεnyl-, Phenyl-Cτ__3 -alkyl- , Amino-, C^. -Alkanoyl- amino-, (C__5-Alkoxy) carbonylamino- oder Benzyloxycarbonyl- aminogruppe und außerdem noch durch eine weitere C^„5-Alkyl- gruppe substituiert sein kann,Het is a 5-membered heteroaromatic ring containing a nitrogen atom or a nitrogen atom and an oxygen, sulfur or nitrogen atom, the aforementioned ring also by a C ^ .. 5 alkyl, C 5 _ 7 -cycloalkyl -, Phεnyl-, phenyl-Cτ__ 3 -alkyl-, amino-, C ^. -Alkanoylamino, (C__5-alkoxy) carbonylamino or benzyloxycarbonylamino group and can also be substituted by a further C 1 -C 5 -alkyl group,
einen 5-gliedrigen dihydrierten heteroaromatischen Ring, der ein Stickstoffatom oder ein Stickstoffatom und ein Sauerstoff-, Schwefel- oder Stickstoffatom enthält, wobei der vorstehend erwähnte Ring außerdem durch eine oder zwei Cι_5-Alkylgruppen substituiert sein und eine Carbonylgruppe enthalten kann und zusätzlich an einem Ringstickstoffatom durch eine (C^.5-Alkoxy) carbonyl- oder Benzyloxycarbonylgruppe substituiert sein kann,a 5-membered dihydrogenated heteroaromatic ring which contains a nitrogen atom or a nitrogen atom and an oxygen, sulfur or nitrogen atom, the ring mentioned above also being substituted by one or two Cι_5-alkyl groups and can contain a carbonyl group and additionally on a ring nitrogen atom may be substituted by a (C ^. 5 alkoxy) carbonyl or benzyloxycarbonyl,
einen 5-gliedrigen tetrahydrierten heteroaromatischen Ring, der ein Stickstoffatom enthält, wobei der vorstehend erwähnte Ring zusätzlich durch eine oder zwei C]__5-Al ylgruppen, durch eine Hydroxy- , Carboxy-, (Cτ__5-Alkoxy) carbonyl- oder Aminocarbonylgruppe substituiert sein kann und außerdem eine oder zwei Carbonylgruppen enthalten kann,a 5-membered tetrahydrated heteroaromatic ring which contains a nitrogen atom, the ring mentioned above additionally by one or two C] __ 5-al yl groups a hydroxyl, carboxy, (Cτ__5-alkoxy) carbonyl or aminocarbonyl group can be substituted and can also contain one or two carbonyl groups,
einen 5-gliedrigen tetrahydrierten heteroaromatischen Ring, der ein Stickstoffatom und ein Sauerstoff-, Schwefel- oder Stickstoffatom enthält, wobei der vorstehend erwähnte Ring zusätzlich durch eine oder zwei Cη__5-Alkylgruppen substituiert sein und eine oder zwei Carbonylgruppen enthalten kann,a 5-membered tetrahydrated heteroaromatic ring which contains a nitrogen atom and an oxygen, sulfur or nitrogen atom, where the ring mentioned above can additionally be substituted by one or two Cη__5-alkyl groups and can contain one or two carbonyl groups,
eine Tetrazolyl- oder Imidazo [1, 2-a]pyrimidin-2-yl-Gruppe darstellen.represent a tetrazolyl or imidazo [1, 2-a] pyrimidin-2-yl group.
Bevorzugte Verbindungen der obigen allgemeinen Formel I sind diejenigen, in denenPreferred compounds of the above general formula I are those in which
Rτ_ ein Wasserstoff-, Fluor-, Chlor- oder Bromatom, eine Nitro-, Amino-, Cτ__4-Alkanoylamino- , (Cι__5-Alkoxy) carbonylamino- oder Benzyloxycarbonylaminogruppe,Rτ_ is a hydrogen, fluorine, chlorine or bromine atom, a nitro, amino, Cτ__ 4 alkanoylamino, (Cι__ 5 alkoxy) carbonylamino or benzyloxycarbonylamino group,
R2 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom, eine Methyl-, Trifluormethyl- , Cyano-, Aminocarbonyl- , Nitro- oder Aminogruppe,R2 is a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano, aminocarbonyl, nitro or amino group,
eine Cι_2-Alkylgruppe, die durch eine Amino-, Phthalimido- , Cι_2-Alkylamino-, Di- (C;j__2-alkyl) -amino-, C2_s-Alkylenamino-, Cι_2-Alkanoylamino-, (Cτ__5-Alkoxy) carbonylamino- , Benzyloxycarbonylamino- , N- (C]__2-Alkanoyl) -N- (Cι_2-alkyl) -amino-, N- ( (C]__5-Alkoxy) carbonyl) -N- (Cι-2~alkγl) -amino-, α-Oxo- C3_g-alkylenimino-, N-Benzyloxycarbonyl-N- (Cτ__2-alkyl) -amino-, (Cι_5-Alkoxy) carbonyl-, Benzyloxycarbonyl-, Carboxy-, Cyano-, Aminocarbonyl- oder Imidazolylgruppe substituiert ist, odera Cι_2-alkyl group by an amino, phthalimido, Cι_2-alkylamino, di- (C; j__ 2 -alkyl) -amino-, C2_s-alkylenamino-, Cι_2-alkanoylamino-, (Cτ__5-alkoxy) carbonylamino- , Benzyloxycarbonylamino-, N- (C ] __ 2 -alkanoyl) -N- (Cι_ 2 -alkyl) -amino-, N- ((C ] __5-alkoxy) carbonyl) -N- (Cι-2 ~ al kγl) -amino-, α-oxo-C 3 _g-alkylenimino-, N-benzyloxycarbonyl-N- (Cτ__2-alkyl) -amino-, (Cι_5-alkoxy) carbonyl-, benzyloxycarbonyl-, carboxy-, cyano-, aminocarbonyl- or Imidazolyl group is substituted, or
eine Allylgruppe, die in 3-Stellung durch eine C2_6-Alkylen- oder α-Oxo-C3_g-alkyleniminogruppe substituiert ist, R3 eine Gruppe der Formelnan allyl group which is substituted in the 3-position by a C 2 _ 6 -alkylene or α-oxo-C 3 _g-alkyleneimino group, R 3 is a group of the formulas
Figure imgf000011_0001
in denen
Figure imgf000011_0001
in which
D und Het wie vorstehend erwähnt definiert sind und A eine Bindung, eine Cι_3-Alkylen- , Cη__3-Alkyliden- , C2-3-Alkenylen- oder C2_3-Alkenyliden-Gruppe darstellen, wobei ein Wasserstoffatom, das im Rest Het an das Kohlenstoffatom der Verknüpfungsstelle gebunden ist, zusammen mit einem α-ständigen Wasserstoffatom des Restes A auch durch eine weitere Kohlenstoff-Kohlenstoff-Bindung ersetzt sein kann, darstellt,D and Het are defined as mentioned above and A represents a bond, a Cι_ 3 alkylene, Cη__ 3 alkylidene, C2 -3 alkenylene or C2_ 3 alkenylidene group, with a hydrogen atom, the rest of Het the carbon atom of the linking point is bonded, together with an α-hydrogen atom of the radical A can also be replaced by a further carbon-carbon bond,
bedeuten, deren Isomere und deren Salze.mean their isomers and their salts.
Besonders bevorzugte Verbindungen der obigen allgemeinen Formel I sind diejenigen, in denenParticularly preferred compounds of the general formula I above are those in which
R^ ein Wasserstoffatom oder eine Nitrogruppe,R ^ is a hydrogen atom or a nitro group,
R2 ein Wasserstoff- oder Chloratom, eine Methyl-, Trifluor- methyl-, Cyano-, Aminomethyl- , Aminoethyl- oder Phthalimido- gruppe, eine Methyl- oder Ethylgruppe, die jeweils durch eine Methylamine-, Dimethylamino- , Ethylamino-, Diethylamino- , Pyr- rolidino-, Piperidino-, α-Oxo-pyrrolidino- , α-Oxo-piperidino- , Acetylamino- , Methoxycarbonylamino- , Ethoxycarbonylamino-, Benzyloxycarbonylamino- , N-Acetyl-N-methylamino- , N-Methoxy- carbonyl-N-methyl-amino- , N-Ethoxycarbonyl-N-methyl-amino- , N-Benzyloxycarbonyl-N-methyl-aminomethyl- , 2- (N-Benzyloxycarbonyl-N-methyl-amino) -ethyl- oder Imidazolylgruppe substituiert sind,R 2 is a hydrogen or chlorine atom, a methyl, trifluoromethyl, cyano, aminomethyl, aminoethyl or phthalimido group, a methyl or ethyl group, each represented by a methylamine, dimethylamino, ethylamino, diethylamino -, Pyrrolidino, piperidino, α-oxo-pyrrolidino, α-oxo-piperidino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, N-acetyl-N-methylamino, N-methoxycarbonyl -N-methyl-amino, N-ethoxycarbonyl-N-methyl-amino, N-benzyloxycarbonyl-N-methyl-aminomethyl, 2- (N-benzyloxycarbonyl-N-methyl-amino) -ethyl or imidazolyl group ,
R3 eine l-Methyl-2-oxo-2, 3-dihydro-lH-benzimidazol-5-yl-, 1,2,3, 4-Tetrahydro-isochinolin-6-yl- , 2-Acetyl-1,2,3, 4-tetra- hydro-isochinolin-6-yl- , 2-Acetyl-l, 2, 3 , 4-tetrahydro-isochi- nolin-7-yl- , 2-Ethyl-1,2,3, -tetrahydro-isochinolin-6-yl- , 2-Ethyl-1, 2, 3 , 4 -tetrahydro-isochinolin-7-yl- , 4- (Imidazol- 2-yl) -phenyl- , 4- (1-Methyl-imidazol-2-yl) -phenyl- , 4- (Imidazol- 4-yl) -phenyl- , 4- (l-Methyl-imidazol-4-yl) -phenyl- , 4- (1-Methyl- imidazol-5-yl) -phenyl- , 4- (5-Methyl-imidazol-4-yl) -phenyl- , 4- (4-Methyl-imidazol-5-yl) -phenyl-, 4- (2-Methyl-imidazol-4-yl) - phenyl-, 4- (2-Ethyl-imidazol-4-yl) -phenyl-, 4- (2-Acetylamino- imidazol-4-yl) -phenyl-, 4- (2-Acetylamino-5-methyl-imidazol- 4-yl) -phenyl- , Imidazo [1, 2-a]pyrimidin-2-yl- , 4- [ (2, 4-Dioxo- imidazolidin-5-yl) methyl] -phenyl-, 4- [ (2 , 4-Dioxo-imidazolidin- 5-yliden) methyl] -phenyl-, 4- [ (Imidazol-4 -yl) ethyl] -phenyl-, 4- [ (Imidazol-5-yl) methyl] -phenyl- , 4- [ (1-Pyrrolidinyl) methyl] - phenyl-, 4- [2- (Imidazol- (5) -yl) ethyl] -phenyl-, 4- [2- (Imidazol- 4-yl) ethenyl] -phenyl- oder 4- [2- (Imidazol-5-yl) ethenyl] - phenylgruppe bedeuten,R 3 is 1-methyl-2-oxo-2, 3-dihydro-1H-benzimidazol-5-yl-, 1,2,3, 4-tetrahydro-isoquinolin-6-yl-, 2-acetyl-1,2 , 3, 4-tetra-hydro-isoquinolin-6-yl-, 2-acetyl-l, 2, 3, 4-tetrahydro-isochi nolin-7-yl-, 2-ethyl-1,2,3, -tetrahydro-isoquinolin-6-yl-, 2-ethyl-1, 2, 3, 4 -tetrahydro-isoquinolin-7-yl-, 4- (Imidazol-2-yl) phenyl-, 4- (1-methyl-imidazol-2-yl) -phenyl-, 4- (imidazol-4-yl) -phenyl-, 4- (l-methyl-imidazole- 4-yl) phenyl-, 4- (1-methylimidazol-5-yl) phenyl-, 4- (5-methylimidazol-4-yl) phenyl-, 4- (4-methylimidazole -5-yl) -phenyl-, 4- (2-methyl-imidazol-4-yl) -phenyl-, 4- (2-ethyl-imidazol-4-yl) -phenyl-, 4- (2-acetylamino- imidazol-4-yl) -phenyl-, 4- (2-acetylamino-5-methyl-imidazol-4-yl) -phenyl-, imidazo [1, 2-a] pyrimidin-2-yl-, 4- [( 2,4-dioxo-imidazolidin-5-yl) methyl] -phenyl-, 4- [(2,4-dioxo-imidazolidin-5-ylidene) methyl] -phenyl-, 4- [(imidazol-4-yl) ethyl] phenyl-, 4- [(imidazol-5-yl) methyl] phenyl-, 4- [(1-pyrrolidinyl) methyl] phenyl-, 4- [2- (imidazol- (5) -yl) ethyl] phenyl, 4- [2- (imidazol-4-yl) ethenyl] phenyl or 4- [2- (imidazol-5-yl) ethenyl] phenyl group,
deren Isomere und deren Salze.their isomers and their salts.
Ganz besonders bevorzugte Verbindungen der obigen allgemeinen Formel I sind"" diejenigen, in denenVery particularly preferred compounds of the above general formula I are "" are those in which
Rl ein Wasserstoffatom oder in 5-Stellung eine Nitrogruppe,R 1 is a hydrogen atom or a 5-position nitro group,
R2 ein Wasserstoffatom, eine Methyl- oder Trifluormethylgruppe,R2 represents a hydrogen atom, a methyl or trifluoromethyl group,
R3 eine 4- (1-Methyl-imidazol-2-yl) -phenyl- , 4- (Imidazol-4-yl) - phenyl-, 4- (Imidazol-5-yl) -phenyl- , 4- (l-Methyl-imidazol-4-yl) - phenyl- , 4- (1-Methyl-imidazol-5-yl) -phenyl- , 4- (2-Methyl-imi- dazol-4-yl) -phenyl-, 4- (2-Acetylamino-imidazol-4-yl) -phenyl-, 4- [ (2,4-Dioxo-imidazolidin-5-yliden)methyl] -phenyl-, 4- [ (1-Pyr- rolidinyl) -methyl] -phenyl-, 4- [2- (Imidazol-4-yl) ethenyl] -phenyl- oder 1, 2, 3, 4-Tetrahydro-isochinolin-6-yl-Gruppe bedeuten,R 3 is 4- (1-methyl-imidazol-2-yl) phenyl, 4- (imidazol-4-yl) phenyl, 4- (imidazol-5-yl) phenyl, 4- (l -Methyl-imidazol-4-yl) -phenyl-, 4- (1-methyl-imidazol-5-yl) -phenyl-, 4- (2-methyl-imidazol-4-yl) -phenyl-, 4 - (2-Acetylamino-imidazol-4-yl) phenyl-, 4- [(2,4-dioxo-imidazolidin-5-ylidene) methyl] phenyl-, 4- [(1-pyrrolidinyl) methyl ] -phenyl-, 4- [2- (imidazol-4-yl) ethenyl] phenyl or 1, 2, 3, 4-tetrahydro-isoquinolin-6-yl group,
deren Isomere und deren Salze.their isomers and their salts.
Als besonders bevorzugte Verbindungen seien beispielsweise folgende erwähnt : (a) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1-phenylmethyli- den} -2 -indolinon,The following may be mentioned as particularly preferred compounds: (a) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone,
(b) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1-phenylmethyli- den} -5-nitro-2-indolinon,(b) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(c) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-trifluorme- thyl-phenyl ) methyliden} -5-nitro-2-indolinon,(c) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-trifluoromethyl-phenyl) methylidene} -5-nitro-2-indolinone,
(d) 3-{ (Z) -1- [4- (1H- Imidazol-4-yl) anilino] -1- (4-methyl-phenyl) methyliden} -5-nitro-2-indolinon,(d) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-methylphenyl) methylidene} -5-nitro-2-indolinone,
(e) 3- { (Z) -1- [4- ( (2,4-Dioxo-imidazolidin-5-yl)methyl) anilino] 1-phenylmethyliden} -5-nitro-2-indolinon,(e) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-yl) methyl) anilino] 1-phenylmethylidene} -5-nitro-2-indolinone,
(f) 3-{ (Z) -1- [4- (2-Methyl-IH-imidazol -4-yl) anilino] -1-phenyl- methyliden} -5-nitro-2-indolinon,(f) 3- {(Z) -1- [4- (2-methyl-IH-imidazole -4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(g) 3- { (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1-phenylme- thyliden} -5-nitro-2-indolinon und(g) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone and
(h) 3-{(Z)-l- [(1,2,3 ,4-Tetrahydro-isochinolin-6 -yl) amino] - 1-phenylmethyliden} -5-nitro-2-indolinon(h) 3 - {(Z) -l- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone
sowie deren Salze.as well as their salts.
Erfindungsgemäß erhält man die neuen Verbindungen beispielsweise nach folgenden im Prinzip literaturbekannten Verfahren:According to the invention, the new compounds are obtained, for example, by the following processes which are known in principle from the literature:
a. Umsetzung einer Verbindung der allgemeinen Formel
Figure imgf000014_0001
a. Implementation of a compound of the general formula
Figure imgf000014_0001
in derin the
Rτ_ und R2 wie eingangs erwähnt definiert sind, R4 ein Wasserstoffatom oder eine Schutzgruppe für das Stickstoffatom der Lactamgruppe undRτ_ and R2 are defined as mentioned above, R 4 is a hydrogen atom or a protective group for the nitrogen atom of the lactam group and
Zη_ ein Halogenatom, eine Hydroxy-, Alkoxy- oder Aralkoxygruppe, z.B. ein Chlor- oder Bromatom, eine Methoxy- , Ethoxy- oder Benzyloxygruppe, bedeuten,Zη_ a halogen atom, a hydroxy, alkoxy or aralkoxy group, e.g. is a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,
mit einem A in der allgemeinen Formelwith an A in the general formula
H2N-R3 (III)H 2 NR 3 (III)
in derin the
R3 wie eingangs erwähnt definiert ist, und erforderlichenfalls anschließende Abspaltung einer verwendeten Schutzgruppe für das Stickstoffatom der Lactamgruppe.R 3 is defined as mentioned at the beginning, and if necessary subsequent cleavage of a protective group used for the nitrogen atom of the lactam group.
Als Schutzgruppe für das Stickstoffatom der Lactamgruppe kommt beispielsweise eine Acetyl-, Benzoyl-, Ethoxycarbonyl- oder Benzyloxycarbonylgruppe in Betracht .A protective group for the nitrogen atom of the lactam group is, for example, an acetyl, benzoyl, ethoxycarbonyl or benzyloxycarbonyl group.
Die Umsetzung wird zweckmäßigerweise in einem Lösungsmittel wie Dimethylformamid, Toluol, Acetonitril, Tetrahydrofuran, Dime- thylsulfoxid, Methylenchlorid oder deren Gemischen gegebenenfalls in Gegenwart einer inerten Base wie Triethylamin, N-Ethyl-diisopropylamin oder Natriumhydrogencarbonat bei Temperaturen zwischen 25 und 175°C durchgeführt, wobei eine verwendete Schutzgruppe infolge Umamidierung gleichzeitig abgespalten werden kann. Bedeutet Zη_ in einer Verbindung der allgemeinen Formel II ein Halogenatom, dann wird die Umsetzung vorzugsweise in Gegenwart einer inerten Base bei Temperaturen zwischen 25 und 120°C, durchgeführt .The reaction is advantageously carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyldiisopropylamine or sodium hydrogen carbonate at temperatures between 25 and 175 ° C. a protective group used can be split off simultaneously as a result of transamidation. If Zη_ in a compound of the general formula II denotes a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 25 and 120 ° C.
Bedeutet Zi in einer Verbindung der allgemeinen Formel II eine Hydroxy-, Alkoxy- oder Aralkoxygruppe, dann wird die Umsetzung vorzugsweise bei Temperaturen zwischen 80 und 150°C, durchgeführt .If Zi in a compound of the general formula II denotes a hydroxyl, alkoxy or aralkoxy group, the reaction is preferably carried out at temperatures between 80 and 150 ° C.
Die gegebenenfalls erforderliche anschließende Abspaltung einer verwendeten Schutzgruppe wird zweckmäßigerweise entweder hydrolytisch in einem wäßrigen oder alkoholischen Lösungsmittel, z.B. in Methanol/Wasser, Ethanol/Wasser, Isopropanol/Wasser, Tetrahydrofuran/Wasser, Dioxan/Wasser, Dimethylformamid/Wasser, Methanol oder Ethanol in Gegenwart einer Alkalibase wie Lithiumhydroxid, Natriumhydroxid oder Kaliumhydroxid bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C,The subsequent splitting off of a protective group that may be required is advantageously carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence of an alkali 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,
oder vorteilhafterweise durch Umamidierung mit einer primären oder sekundären organischen Base wie Methylamin, Butylamin, Dimethylamin oder Piperidin in einem Lösungsmittel wie Methanol, Ethanol, Dimethylformamid und deren Gemischen oder in einem Überschuß des eingesetzten Amins bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C, durchgeführt.or advantageously by transamidation with a primary or secondary organic base such as 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.
b. Zur Herstellung einer Verbindung der allgemeinen Formel I, in der R2 eine der für R2 eingangs erwähnten Alkenyl- oder Allylreste darstellt :b. For the preparation of a compound of the general formula I in which R2 represents one of the alkenyl or allyl radicals mentioned at the outset for R2:
Umsetzung einer Halogenphenyl-Verbindung der allgemeinen Formel
Figure imgf000016_0001
in derImplementation of a halophenyl compound of the general formula
Figure imgf000016_0001
in the
Rτ_, R3 und R4 wie eingangs erwähnt definiert sind undRτ_, R3 and R4 are defined as mentioned at the beginning and
Z2 ein Chlor-, Brom- oder Jodatom darstellt,Z2 represents a chlorine, bromine or iodine atom,
mit einem Alken der allgemeinen Formelwith an alkene of the general formula
*2' H (V),* 2 'H (V),
in derin the
R2 ' einen der für R2 eingangs erwähnten substituierten Alke- nylreste darstellt, in Gegenwart eines geeigneten Edelmetall- haltigen Katalysators und erforderlichenfalls anschließende Abspaltung einer verwendeten Schutzgruppe für das Stickstoff- atom der Lactamgruppe.R2 'represents one of the substituted alkenyl radicals mentioned at the beginning for R2, in the presence of a suitable noble metal-containing catalyst and, if necessary, subsequent cleavage of a protective group used for the nitrogen atom of the lactam group.
Als geeignete Edelmetall-Katalysatoren kommem vorzugsweise Palladium-haltige Katalysatoren wie Palladium-diacetac oder Palladium-dichlorid, insbesondere deren Komplexe mit Triphe- nylphosphin oder Tri- (o-toluol) -phosphin gegebenenfalls in Gegenwart von Aktivatoren wie Tetraphenylphosphoniu -chlorid oder -bromid und N,N-Dimethylglycin in Betracht.Suitable noble metal catalysts are preferably palladium-containing catalysts such as palladium diacetac or palladium dichloride, in particular their complexes with triphenylphosphine or tri- (o-toluene) phosphine, optionally in the presence of activators such as tetraphenylphosphonium chloride or bromide and N, N-dimethylglycine into consideration.
Die Heck-Reaktion wird zweckmäßigerweise unter Schutzgas, z.B. unter Stickstoff oder Argon, gegebenenfalls in einem Druckgefäß und zweckmäßigerweise in einem Lösungsmittel wie Acetonitril, Dimethylformamid oder N-Methyl-pyrrolidin-2-on bei Temperaturen zwischen 20 und 180°C, vorzugsweise bei Temperaturen zwischen 80 und 150°C, durchgeführt. Die gegebenenfalls erforderliche anschließende Abspaltung einer verwendeten Schutzgruppe wird zweckmäßigerweiεe entweder hydrolytisch in einem wäßrigen oder alkoholischen Lösungsmittel, z.B. in Methanol/Wasser, Ethanol/Wasser, Isopropanol/Wasser, Tetrahydrofuran/Wasser, Dioxan/Wasser, Dimethylformamid/Wasser, Methanol oder Ethanol in Gegenwart einer Alkalibase wie Lithiumhydroxid, Natriumhydroxid, Kaliumhydroxid oder Natriumacetat bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C,The Heck reaction is advantageously carried out under protective gas, for example under nitrogen or argon, if appropriate in a pressure vessel and advantageously in a solvent such as acetonitrile, dimethylformamide or N-methyl-pyrrolidin-2-one at temperatures between 20 and 180 ° C., preferably at temperatures between 80 and 150 ° C, carried out. The subsequent splitting off of a protective group that may be required 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 an alkali base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium acetate at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C,
oder vorteilhafterweise durch Umamidierung mit einer primären oder sekundären organischen Base wie Methylamin, Butylamin, Dimethylamin oder Piperidin in einem Lösungsmittel wie Methanol, Ethanol, Dimethylformamid und deren Gemischen oder in einem Überschuß des eingesetzten Amins bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C, durchgeführt.or advantageously by transamidation with a primary or secondary organic base such as 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.
c. Zur Herstellung einer Verbindung der allgemeinen Formel I, in der A eine C2_4-Alkenylengruppe darstellt:c. To prepare a compound of the general formula I in which A represents a C 2 _ 4 -alkenylene group:
Umsetzung einer Halogenphenyl-Verbindung der allgemeinen FormelImplementation of a halophenyl compound of the general formula
Figure imgf000017_0001
in der
Figure imgf000017_0001
in the
R l' R2 unα^ R 4 w^e eingangs erwähnt definiert sind und R l ' R 2 unα ^ R 4 w ^ e are initially mentioned and
Z3 ein Chlor-, Brom- oder Jodatom darstellt,Z 3 represents a chlorine, bromine or iodine atom,
mit einem Alken der allgemeinen Formelwith an alkene of the general formula
H Het (VII) , in derH Het (VII), in the
Het wie eingangs erwähnt definiert ist undHet is defined as mentioned at the beginning and
A1 eine C2-4"Alkenylengruppe darstellt, in Gegenwart eines geeigneten Edelmetall-haltigen Katalysators und erforderlichenfalls anschließende Abspaltung einer verwendeten Schutzgruppe für das Stickstoffatom der Lactamgruppe.A 1 represents a C 2 - 4 "alkenylene group, in the presence of a suitable noble metal-containing catalyst and, if necessary, subsequent cleavage of a protective group used for the nitrogen atom of the lactam group.
Als geeignete Edelmetall-Katalysatoren kommem vorzugsweise Palladium-haltige Katalysatoren wie Palladium-diacetat oder Palladium-dichlorid, insbesondere deren Komplexe mit Triphe- nylphosphin oder Tri- (o-toluol) -phosphin gegebenenfalls in Gegenwart von Aktivatoren wie Tetraphenylphosphonium-chlorid oder -bromid und N,N-Dimethylglycin in Betracht.Suitable precious metal catalysts are preferably palladium-containing catalysts such as palladium diacetate or palladium dichloride, in particular their complexes with triphenylphosphine or tri- (o-toluene) phosphine, optionally in the presence of activators such as tetraphenylphosphonium chloride or bromide and N, N-dimethylglycine into consideration.
Die Heck-Reaktion wird zweckmäßigerweise unter Schutzgas, z.B. unter Stickstoff oder Argon, gegebenenfalls in einem Druckgefäß und zweckmäßigerweise in einem Lösungsmittel wie Acetonitril, Dimethylformamid oder N-Methyl-pyrrolidin-2-on bei Temperaturen zwischen 20 und 180°C, vorzugsweise bei Temperaturen zwischen 80 und 150°C, durchgeführt.The Heck reaction is conveniently carried out under protective gas, e.g. under nitrogen or argon, if appropriate in a pressure vessel and advantageously in a solvent such as acetonitrile, dimethylformamide or N-methyl-pyrrolidin-2-one at temperatures between 20 and 180 ° C, preferably at temperatures between 80 and 150 ° C.
Die gegebenenfalls erforderliche anschließende Abspaltung einer verwendeten Schutzgruppe wird zweckmäßigerweise entweder hydrolytisch in einem wäßrigen oder alkoholischen Lösungsmittel, z.B. in Methanol/Wasser, Ethanol/Wasser, Isopropanol/Wasser, Tetrahydrofuran/Wasser, Dioxan/Wasser, Dimethylformamid/Wasser, Methanol oder Ethanol in Gegenwart einer Alkalibase wie Lithiumhydroxid, Natriumhydroxid, Kaliumhydroxid oder Natriumacetat bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C,The subsequent splitting off of a protective group that may be required is advantageously carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence of an alkali base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium acetate at temperatures between 0 and 100 ° C., preferably at temperatures between 10 and 50 ° C,
oder vorteilhafterweise durch Umamidierung mit einer primären oder sekundären organischen Base wie Methylamin, Butylamin, Dimethylamin oder Piperidin in einem Lösungsmittel wie Methanol, Ethanol, Dimethylformamid und deren Gemischen oder in einem Überschuß des eingesetzten Amins bei Temperaturen zwi- sehen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C, durchgeführt.or advantageously by transamidation with a primary or secondary organic base such as 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 see 0 and 100 ° C, preferably carried out at temperatures between 10 and 50 ° C.
d. Zur Herstellung einer Verbindung der allgemeinen Formel I, in der A eine Bindung oder eine C]__4-Alkylengruppe und Het eine der für Het eingangs erwähnten gegebenenfalls mono- oder disub- stituierten (4 , 5-Dihydro-imidazol-2-yl) -Gruppen darstellen:d. For the preparation of a compound of the general formula I in which A is a bond or a C] __ 4 -alkylene group and Het is one of the optionally mono- or disubstituted (4, 5-dihydro-imidazol-2-yl) mentioned for Het - represent groups:
Umsetzung einer Iminoether-phenyl-Verbindung der allgemeinen FormelImplementation of an iminoether-phenyl compound of the general formula
Figure imgf000019_0001
in der
Figure imgf000019_0001
in the
R l' R 2 unα^ R 4 w^e eingangs erwähnt definiert sind, A' eine Bindung oder eine Cχ_4-Alkylengruppe und R5 eine Alkylgruppe, z.B. eine Methyl- oder Ethylgruppe, darstellen,'Are as defined R 2 R 4 unα ^ w ^ e mentioned at the outset, A' R l is a bond or an alkylene group, and R5 Cχ_ 4 is an alkyl group such as methyl or ethyl, represent
mit einem Ethylendiamin, das an einem der Stickstoff- oder Kohlenstoffatome oder an einem der Stickstoffatome und an einem der Kohlenstoffatome durch eine Cι_5-Alkylgruppe substituiert sein kann und erforderlichenfalls anschließende Abspaltung einer verwendeten Schutzgruppe für das Stickstoffatom einer Lactamgruppe .with an ethylenediamine, which can be substituted on one of the nitrogen or carbon atoms or on one of the nitrogen atoms and on one of the carbon atoms by a Cι_5-alkyl group and, if necessary, subsequent removal of a protective group used for the nitrogen atom of a lactam group.
Die Umsetzung wird zweckmäßigerweise in einem Lösungsmittel wie Diethylether, Methanol oder Ethanol, vorzugsweise jedoch in einem Überschuss des eingesetzten Ethylendiamins bei Tempe- raturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C, durchgeführt.The reaction is advantageously carried out in a solvent such as diethyl ether, methanol or ethanol, but preferably in an excess of the ethylenediamine used at a temperature of temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
Die gegebenenfalls erforderliche anschließende Abspaltung einer verwendeten Schutzgruppe wird zweckmäßigerweise entweder hydrolytisch in einem wäßrigen oder alkoholischen Lösungsmittel, z.B. in Methanol/Wasser, Ethanol/Wasser, Isopropanol/Wasser, Tetrahydrofuran/Wasser, Dioxan/Wasser, Dirnethylforrnamid/Wasser, Methanol oder Ethanol in Gegenwart einer Alkalibase wie Lithiumhydroxid, Natriumhydroxid oder Kaliumhydroxid bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C,The subsequent splitting off of a protective group that may be required is advantageously carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, Dirnethylforrnamid / water, methanol or ethanol in the presence of an alkali 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,
oder vorteilhafterweise durch Umamidierung mit einer primären oder sekundären organischen Base wie Methylamin, Butylamin, Dimethylamin oder Piperidin in einem Lösungsmittel wie Methanol, Ethanol, Dimethylformamid und deren Gemischen oder in einem Überschuß des eingesetzten Amins bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C, durchgeführt .or advantageously by transamidation with a primary or secondary organic base such as 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.
Erhält man erfindungsgemäß eine Verbindung der allgemeinen Formel I, in der R3 eine (Imidazo [1, 2-a] pyrimidin-2-yl) phen- ylgruppe darstellt, so kann diese mittels Hydrazinolyse in eine entsprechende (2-Amino-imidazol-4 (5) -yl) phenylVerbindung übergeführt werden, oderIf, according to the invention, a compound of the general formula I is obtained in which R 3 represents an (imidazo [1, 2-a] pyrimidin-2-yl) phenyl group, this can be converted into a corresponding (2-amino-imidazole) by means of hydrazinolysis. 4 (5) -yl) phenyl compound are transferred, or
eine Verbindung der allgemeinen Formel I, in der R2 einen Phthalimidorest enthält, so kann diese mittels Hydrazinolyse in eine entsprechende AminoVerbindung übergeführt werden, odera compound of the general formula I in which R2 contains a phthalimido residue, this can be converted into a corresponding amino compound by means of hydrazinolysis, or
eine Verbindung der allgemeinen Formel I, in der R2 eine Cyano-, Cyanoalkyl- oder Cyanoalkenylgruppe darstellt, so kann diese mittels Reduktion, vorzugsweise mittels katalytischer Hydrierung, in eine entsprechende Aminomethyl- oder Aminoal- kylVerbindung übergeführt werden, oder eine Verbindung der allgemeinen Formel I, in der R2 eine Cyano-, Cyanoalkyl- oder Cyanoalkenylgruppe darstellt, so kann diese mittels Hydratisierung in eine entsprechende Aminocarbonyl-, Aminocarbonylalkyl- oder Aminocarbonylalkenyl-Verbindung übergeführt werden, odera compound of the general formula I in which R2 represents a cyano, cyanoalkyl or cyanoalkenyl group, this can be converted into a corresponding aminomethyl or aminoalkyl compound by means of reduction, preferably by means of catalytic hydrogenation, or a compound of the general formula I in which R 2 represents a cyano, cyanoalkyl or cyanoalkenyl group, this can be converted into a corresponding aminocarbonyl, aminocarbonylalkyl or aminocarbonylalkenyl compound by means of hydration, or
eine Verbindung der allgemeinen Formel I, in der R2 eine Al- kenylengruppe enthält, so kann diese mittels Reduktion, vorzugsweise mittels katalytischer Hydrierung in eine entsprechende Alkylenverbindung übergeführt werden, odera compound of the general formula I in which R 2 contains an alkenylene group, this can be converted into a corresponding alkylene compound by means of reduction, preferably by means of catalytic hydrogenation, or
eine Verbindung der allgemeinen Formel I, in der R3 eine Al- kenylengruppe enthält, so kann diese mittels Reduktion, vorzugsweise mittels katalytischer Hydrierung in eine entsprechende Alkylenverbindung übergeführt werden, odera compound of the general formula I in which R 3 contains an alkenylene group, this can be converted into a corresponding alkylene compound by means of reduction, preferably by means of catalytic hydrogenation, or
eine Verbindung der allgemeinen Formel I, in der R3 eine der für R3 eingangs erwähnte (Amino-imidazolyDphenylgruppe darstellt, die durch eine Alkanoyl- oder Benzyloxycarbonylgruppe substituiert ist, so kann diese mittels Hydrolyse oder Hydro- genolyse in eine entsprechende unsubstituierte Verbindung übergeführt werden, odera compound of the general formula I in which R 3 is one of the (amino-imidazolydphenyl group mentioned at the outset for R 3) which is substituted by an alkanoyl or benzyloxycarbonyl group, this can be converted into a corresponding unsubstituted compound by means of hydrolysis or hydrogenolysis , or
eine Verbindung der allgemeinen Formel I, in der R3 eine der für R3 unsubstituierten (Amino-imidazolyDphenylgruppe darstellt, so kann diese mittels Acylierung in eine entsprechende AcylVerbindung übergeführt werden, odera compound of the general formula I in which R 3 represents one of the (amino-imidazolydphenyl group unsubstituted for R3, this can be converted into a corresponding acyl compound by means of acylation, or
eine Verbindung der allgemeinen Formel I, in der R2 einen der für R2 eingangs erwähnten Reste darstellt, die eine Amino-, Alkylamino-, Alkenylamino- oder Benzylaminogruppe enthalten, so kann diese mittels Acylierung in eine entsprechende Acylverbin- dung übergeführt werden, odera compound of the general formula I in which R2 represents one of the radicals mentioned at the outset for R2 which contain an amino, alkylamino, alkenylamino or benzylamino group, this can be converted into a corresponding acyl compound by acylation, or
eine Verbindung der allgemeinen Formel I, in der RQ_ eine Ni- trogruppe darstellt, so kann diese mittels Reduktion, Vorzugs- weise mittels katalytischer Hydrierung, in eine entsprechende Aminoverbindung übergeführt werden, odera compound of the general formula I in which R Q _ represents a nitro group, this can be reduced, preferably as by means of catalytic hydrogenation, are converted into a corresponding amino compound, or
eine Verbindung der allgemeinen Formel I, in der R^ eine Aminogruppe darstellt, so kann diese mittels durch Acylierung in die entsprechende Acylverbindung übergeführt werden, odera compound of general formula I in which R ^ represents an amino group, this can be converted into the corresponding acyl compound by means of acylation, or
eine Verbindung der allgemeinen Formel I, in der A eine Alke- nylen- , Alkyliden- oder Alkenylidengruppe darstellt, so kann diese mittels katalytischer Hydrierung in eine entsprechende Alkylenverbindung übergeführt werden, odera compound of the general formula I in which A represents an alkenylene, alkylidene or alkenylidene group, this can be converted into a corresponding alkylene compound by means of catalytic hydrogenation, or
eine Verbindung der allgemeinen Formel I, in der R3 einen Phthalimidorest darstellt, der durch eine (Cι_5-Alkoxy) - carbonyl-C^_5-alkyl- oder Benzyloxycarbonyl-Cι_5-alkylgruppe substituiert ist, so kann diese mittels Acidolyse oder Hydrogenolyse in eine entsprechende Carboxyverbindung übergeführt werden, odera compound of general formula I in which R 3 represents a phthalimido residue which is substituted by a (Cι_ 5 -alkoxy) carbonyl-C ^ _5-alkyl or benzyloxycarbonyl-Cι_5-alkyl group, this can be by means of acidolysis or hydrogenolysis in a corresponding carboxy compound can be converted, or
eine Verbindung der allgemeinen Formel I , in der R2 einen Al oxycarbonyl- oder Benzyloxycarbonylrest enthält, so kann diese mittels Hydrolyse oder Hydrogenolyse in eine entsprechende Carboxyverbindung übergeführt werden, odera compound of the general formula I in which R 2 contains an Al oxycarbonyl or benzyloxycarbonyl radical, this can be converted into a corresponding carboxy compound by means of hydrolysis or hydrogenolysis, or
eine Verbindung der allgemeinen Formel I, in der R2 einen acy- lierten Aminoalkylrest darstellt, so kann diese mittels Hydrolyse oder Hydrogenolyse in eine entsprechende Aminoalkylverbin- dung übergeführt werden, odera compound of the general formula I in which R2 represents an acylated aminoalkyl radical, this can be converted into a corresponding aminoalkyl compound by means of hydrolysis or hydrogenolysis, or
eine Verbindung der allgemeinen Formel I, in der R^_ oder/und R2 ein Halogenatom darstellen, so kann diese mittels katalytischer Hydrierung in eine entsprechende dehalogenierte Verbindung übergeführt werden, odera compound of the general formula I in which R 1 and / or R 2 represent a halogen atom, this can be converted into a corresponding dehalogenated compound by means of catalytic hydrogenation, or
eine Verbindung der allgemeinen Formel I, in der R3 einen 2-Boc-, 2-Z- oder 2-Benzyl-l, 2 , 3 , 4-tetrahydroisochinolinyl-Rest darstellt, so kann diese mittels Hydrolyse oder Hydrogenolyse in eine entsprechende 1, 2, 3 , 4-Tetrahydroisochinolinyl-Verbindung übergeführt werden, odera compound of the general formula I in which R3 represents a 2-Boc, 2-Z or 2-benzyl-l, 2, 3, 4-tetrahydroisoquinolinyl radical, this can be achieved by means of hydrolysis or hydrogenolysis be converted into a corresponding 1, 2, 3, 4-tetrahydroisoquinolinyl compound, or
eine Verbindung der allgemeinen Formel I, in der R3 einen 1, 2, 3 ,4-Tetrahydro-isochinolylrest darstellt, so kann diese mittels Acylierung in eine entsprechende 2-Acyl-l, 2, 3 , 4-tetra- hydro-isochinolyl-Verbindung übergeführt werden, odera compound of the general formula I in which R 3 represents a 1, 2, 3, 4-tetrahydro-isoquinolyl radical, it can be acylated into a corresponding 2-acyl-1,2,3,4-tetra-hydro-isoquinolyl -Connection are transferred, or
eine Verbindung der allgemeinen Formel I, in der Het eine der für Het eingangs erwähnten Gruppen darstellt, die an einem Ringstickstoffatom durch eine (C^_5-Alkoxy) carbonyl- oder Benzyloxycarbonylgruppe substituiert ist, so kann diese mittels Acidolyse oder Hydrogenolyse in eine entsprechende NH-Verbin- dung übergeführt werden.a compound of general formula I in which Het represents one of the aforementioned groups for Het which is substituted on a ring nitrogen atom by a (C ^ _ 5 alkoxy) carbonyl group or benzyloxycarbonyl group, this can by acidolysis or hydrogenolysis into a corresponding NH connection.
Die anschließende Hydrazinolyse erfolgt vorzugsweise in einem Lösungsmittel wie Methanol, Ethanol, Isopropanol, Toluol/Wasser oder Dioxan, besonders vorteilhaft jedoch in Hydrazinhydrat als Lösungsmittel, bei Temperaturen zwischen 20 und 120°C, vorzugsweise bei der Siedetemperatur des verwendeten Lösungsmittel.The subsequent hydrazinolysis is preferably carried out in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane, but particularly advantageously in hydrazine hydrate as the solvent, at temperatures between 20 and 120 ° C., preferably at the boiling point of the solvent used.
Die anschließende Reduktion einer Alkenyl-, Nitro-, Cyano-, Cyanoalkyl- oder CyanoalkenylVerbindung erfolgt vorzugsweise mittels katalytischer Hydrierung mit Wasserstoff in Gegenwart eines Katalysators wie Palladium/Kohle oder Platin in einem Lösungsmittel wie Methanol, Ethanol, Essigsäureethylester, Dimethylformamid, Dirnethylformamid/Aceton oder Eisessig gegebenenfalls unter Zusatz einer Säure wie Salzsäure bei Temperaturen zwischen 0 und 50°C, vorzugsweise jedoch bei Raumtemperatur, und bei einem Wasserstoffdruck von 1 bis 7 bar, vorzugsweise jedoch von 3 bis 5 bar.The subsequent reduction of an alkenyl, nitro, cyano, cyanoalkyl or cyanoalkenyl compound is preferably carried out by means of catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium / carbon or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / 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 room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
Die anschließende Hydratisierung erfolgt vorzugsweise mittels konzentrierter Schwefelsäure oder Polyphosphorsäure bei Temperaturen zwischen 0 und 50°C, vorzugsweise jedoch bei Temperaturen zwischen 0 und 25°C. Die anschließende Hydrolyse erfolgt vorzugsweise in einem wäßrigen Lösungsmittel, z.B. in Wasser, Isopropanol/Wasser, Tetrahydrofuran/Wasser oder Dioxan/Wasser, in Gegenwart einer Säure wie Trifluoressigsäure, Salzsäure oder Schwefelsäure oder in Gegenwart einer Alkalibase wie Lithiumhydroxid, Natriumhydroxid oder Kaliumhydroxid bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C.The subsequent hydration is preferably carried out using concentrated sulfuric acid or polyphosphoric acid at temperatures between 0 and 50 ° C, but preferably at temperatures between 0 and 25 ° C. The subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali 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.
Die anschließende Hydrogenolyse erfolgt vorzugsweise mittels katalytischer Hydrierung mit Wasserstoff in Gegenwart eines Katalysators wie Palladium/Kohle oder Platin in einem Lösungsmittel wie Methanol, Ethanol, Essigsäureethylester, Dimethylformamid, Dimethylformamid/Aceton oder Eisessig gegebenenfalls unter Zusatz einer Säure wie Salzsäure bei Temperaturen zwischen 0 und 50°C, vorzugsweise jedoch bei Raumtemperatur, und bei einem Wasserstoffdruck von 1 bis 7 bar, vorzugsweise jedoch von 3 bis 5 bar.The subsequent hydrogenolysis is preferably carried out by means of catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium / carbon 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 room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
Die anschließende Acylierung wird vorzugsweise in einem Lösungsmittel wie Methylenchlorid, Diethylether, Tetrahydrofuran, Toluol, Dioxan, Acetonitril, Dimethylsulfoxid oder Dimethylformamid gegebenenfalls in Gegenwart einer anorganischen oder einer tertiären organischen Base, vorzugsweise bei Temperaturen zwischen 20°C und der Siedetemperatur des verwendeten Lösungsmittel, durchgeführt. Hierbei wird die Acylierung mit einer entsprechenden Säure vorzugsweise in Gegenwart eines wasserentziehenden Mittels, z.B. in Gegenwart von Chlorameisensäureiso- butylester, Orthokohlensäuretetraethylester, Orthoessigsäure- trimethylester, 2, 2-Dimethoxypropan, Tetramethoxysilan, Thio- nylchlorid, Trimethylchlorsilan, Phsphortrichlorid, Phosphor- pentoxid, N,N' -Dicyclohexylcarbodiimid, N,N' -Dicyclohexylcarbo- diimid/N-Hydroxysuccinimid, N,N' -Dicyclohexylcarbodiimid/l-Hy- droxy-benztriazol, 2- (IH-Benzotriazol-l-yl) -1,1,3 , 3-tetrame- thyluronium-tetrafluorborat, 2- (IH-Benzotriazol-l-yl) -1,1,3,3- tetramethyluronium-tetrafluorborat/1-Hydroxy-benztriazol, N,N' -Carbonyldiimidazol oder Triphenylphosphin/Tetrachlorkoh- lenstoff, und gegebenenfalls unter Zusatz einer Base wie Pyri- din, 4-Dimethylamino-pyridin, N-Methyl-morpholin oder Triethyl- amin zweckmäßigerweise bei Temperaturen zwischen 0 und 150°C, vorzugsweise bei Temperaturen zwischen 0 und 100°C, und die Acylierung mit einer entsprechenden reaktionsfähigen Verbindung wie deren Anhydrid, Ester, Imidazolide oder Halogenide gegebenenfalls in Gegenwart einer tertiären organischen Base wie Tri- ethylamin, N-Ethyl-diisopropylamin oder N-Methyl-morpholin bei Temperaturen zwischen 0 und 150°C, vorzugsweise bei Temperaturen zwischen 50 und 100°C, durchgeführt.The subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide, optionally 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 acylation with a corresponding acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, trimethyl orthoacetic acid, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorophlorochloride, phosphorus phosphorus , N '-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-dicyclohexylcarbodiimide / l-hydroxy-benzotriazole, 2- (IH-benzotriazol-l-yl) -1.1, 3, 3-tetramethyluronium tetrafluoroborate, 2- (IH-benzotriazol-l-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriazole, N, N '-carbonyldiimidazole or triphenylphosphine / tetrachloromethane - lenstoff, and optionally with the addition of a base such as pyridine, 4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine, advantageously at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, and Acylation with a corresponding reactive compound such as its anhydride, ester, imidazolide or halide, optionally 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 performed.
Die anschließende Acidolyse erfolgt vorzugsweise in einem wäßrigen Lösungsmittel, z.B. in Wasser, Isopropanol/Wasser, Tetrahydrofuran/Wasser oder Dioxan/Wasser, in Gegenwart einer Säure wie Trifluoressigsäure, Salzsäure oder Schwefelsäure zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C.The subsequent acidolysis 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 sulfuric acid between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
Die anschließende Dehalogenierung erfolgt vorzugsweise mittels katalytischer Hydrierung mit Wasserstoff in Gegenwart eines Katalysators wie Palladium/Kohle oder Platin in einem Lösungsmittel wie Methanol, Ethanol, Essigsäureethylester, Dimethylformamid, Dirnethylformamid/Aceton oder Eisessig gegebenenfalls unter Zusatz einer Säure wie Eisessig oder einer Base wie Natri- umbicarbonat oder Triethylamin bei Temperaturen zwischen 0 und 50°C, vorzugsweise jedoch bei Raumtemperatur, und bei einem Wasserstoffdruck von 1 bis 7 bar, vorzugsweise jedoch von 3 bis 5 bar.The subsequent dehalogenation is preferably carried out by means of catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium / carbon or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as glacial acetic acid or a base such as sodium umbicarbonate or triethylamine at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
Bei den vorstehend beschriebenen Umsetzungen können gegebenenfalls vorhandene reaktive Gruppen wie Carboxy-, Amino-, Alkylamino- oder Iminogruppen während der Umsetzung durch übliche Schutzgruppen geschützt werden, welche nach der Umsetzung wieder abgespalten werden.In the reactions described above, any reactive groups present, such as carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
Beispielsweise kommt als Schutzrest für eine Carboxylgruppe die Trimethylsilyl-, Methyl-, Ethyl-, tert.Butyl-, Benzyl- oder Tetrahydropyranylgruppe und als Schutzrest für eine Amino-, Alkylamino- oder Iminogruppe die Acetyl-, Trifluoracetyl- , Benzoyl-, Ethoxycarbonyl-, tert . Butoxycarbonyl- , Benzyloxycarbonyl- , Benzyl- , Methoxy- benzyl- oder 2, 4-Dirnethoxybenzyl-gruppe und für die Aminogruppe zusätzlich die Phthalyl-gruppe in Betracht.For example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and comes as a protective radical for a carboxyl group as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert. Butoxycarbonyl-, Benzyloxycarbonyl-, Benzyl-, Methoxy- benzyl- or 2, 4-Dirnethoxybenzyl group and for the amino group additionally the phthalyl group into consideration.
Die gegebenenfalls anschließende Abspaltung eines verwendeten Schutzrestes erfolgt beispielsweise hydrolytisch in einem wäßrigen Lösungsmittel, z.B. in Wasser, Isopropanol/Wasser, Tetrahydrofuran/Wasser oder Dioxan/Wasser, in Gegenwart einer Säure wie Trifluoressigsäure, Salzsäure oder Schwefelsäure oder in Gegenwart einer Alkalibase wie Lithiumhydroxid, Natriumhydroxid oder Kaliumhydroxid bei Temperaturen zwischen 0 und 100°C, vorzugsweise bei Temperaturen zwischen 10 und 50°C.The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically 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 sulfuric acid or in the presence of an alkali 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.
Die Abspaltung eines Benzyl--, Methoxybenzyl- oder Benzyloxy- carbonylrestes erfolgt jedoch beispielsweise hydrogenolytisch, z.B. mit Wasserstoff in Gegenwart eines Katalysators wie Palladium/Kohle in einem Lösungsmittel wie Methanol, Ethanol, Es- sigsäureethylester, Dimethylformamid, Dirnethylformamid/Aceton oder Eisessig gegebenenfalls unter Zusatz einer Säure wie Salzsäure oder Eisessig bei Temperaturen zwischen 0 und 50°C, vorzugsweise jedoch bei Raumtemperatur, und bei einem Wasserstoff- druck von 1 bis 7 bar, vorzugsweise jedoch von 3 bis 5 bar.However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / 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 Room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
Die Abspaltung einer Methoxybenzylgruppe kann auch in Gegenwart eines Oxidationsmittels wie Cer (IV) ammoniumnitrat in einem Lösungsmittel wie Methylenchlorid, Acetonitril oder Acetoni- tril/Wasser bei Temperaturen zwischen 0 und 50°C, vorzugsweise jedoch bei Raumtemperatur, erfolgen.A methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
Die Abspaltung eines 2, 4-Dimethoxybenzylrestes erfolgt jedoch vorzugsweise in Trifluoressigsäure in Gegenwart von Anisol.However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
Die Abspaltung eines tert.Butyl- oder tert .Butyloxycarbonyl- restes erfolgt vorzugsweise durch Behandlung mit einer Säure wie Trifluoressigsäure oder Salzsäure gegebenenfalls unter Verwendung eines Lösungsmittels wie Methylenchlorid, Dioxan, Essigester oder Ether.A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.
Die Abspaltung eines Phthalylrestes erfolgt vorzugsweise in Gegenwart von Hydrazin oder eines primären Amins wie Methylamin, Ethylamin oder n-Butylamin in einem Lösungsmittel wie Methanol, Ethanol, Isopropanol, Toluol/Wasser oder Dioxan bei Temperaturen zwischen 20 und 50°C.A phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
Ferner können erhaltene chirale Verbindungen der allgemeinen Formel I in ihre Enantiomeren und/oder Diastereomeren aufgetrennt werden.Furthermore, chiral compounds of the general formula I obtained can be separated into their enantiomers and / or diastereomers.
So lassen sich beispielsweise die erhaltenen Verbindungen der allgemeinen Formel I, welche in Racematen auftreten, nach an sich bekannten Methoden (siehe Allinger N. L. und Eliel E. L. in "Topics in Stereochemistry" , Vol. 6, Wiley Interscience, 1971) in ihre optischen Antipoden und Verbindungen der allgemeinen Formel I mit mindestes 2 asymmetrischen Kohlenstoffato- men auf Grund ihrer physikalisch-chemischen Unterschiede nach an sich bekannten Methoden, z.B. durch Chromatographie und/oder fraktionierte Kristallisation, in ihre Diastereomeren auftrennen, die, falls sie in racemischer Form anfallen, anschließend wie oben erwähnt in die Enantiomeren getrennt werden können.For example, the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) Compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
Die Enantiomerentrennung erfolgt vorzugsweise durch Säulentrennung an chiralen Phasen oder durch Umkristallisieren aus einem optisch aktiven Lösungsmittel oder durch Umsetzen mit einer, mit der race ischen Verbindung Salze oder Derivate wie z.B. Ester oder Amide bildenden optisch aktiven Substanz, insbesondere Säuren und ihre aktivierten Derivate oder Alkohole, und Trennen des auf diese Weise erhaltenen Gemisches diaste- reomerer Salze oder Derivate, z.B. auf Grund von verschiedenen Lδslichkeiten, wobei aus den reinen diastereomeren Salzen oder Derivaten die freien Antipoden durch Einwirkung geeigneter Mit- tel freigesetzt werden können. Besonders gebräuchliche, optisch aktive Säuren sind z.B. die D- und L-Formen von Weinsäure, Di- benzoylweinsäure, Di-o-Tolylweinsäure, Äpfelsäure, Mandelsäure, Ca phersulfonsäure, Glutaminsäure, N-Acetyl-glutaminsäure, As- paraginsäure , N-Acetyl-asparaginsäure oder Chinasäure. Als optisch aktiver Alkohol kommt beispielsweise (+) - oder (-) -Menthol und als optisch aktiver Acylrest in Amiden beispielsweise der (+) - oder (-) -Menthyloxycarbonylrest in Betracht.The enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives such as esters or amides, in particular acids and their activated derivatives or alcohols, with the racing compound and separating the mixture of diastereomeric salts or derivatives obtained in this way, for example on the basis of different solubilities, the free antipodes being obtained from the pure diastereomeric salts or derivatives by the action of suitable agents. tel can be released. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, calcium sulfonic acid, glutamic acid, N-acetyl-glutamic acid, aspartic acid, N-acetyl -aspartic acid or quinic acid. Suitable optically active alcohols are, for example, (+) - or (-) menthol and optically active acyl radicals in amides are, for example, the (+) - or (-) menthyloxycarbonyl radicals.
Desweiteren können die erhaltenen Verbindungen der Formel I in ihre Salze, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträglichen Salze mit anorganischen oder organischen Säuren, übergeführt werden. Als Säuren kommen hierfür beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Fumarsäure, Bernsteinsäure, Milchsäure, Zitronensäure, Weinsäure oder Maleinsäure in Betracht.Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Außerdem lassen sich die so erhaltenen neuen Verbindungen der Formel I, falls diese eine Carboxygruppe enthalten, gewünsch- tenfalls anschließend in ihre Salze mit anorganischen oder organischen Basen, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträglichen Salze, überführen. Als Basen kommen hierbei beispielsweise Natriumhydroxid, Kaliumhydroxid, Cyclohexylamin, Ethanolamin, Diethanolamin und Trietha- nolamin in Betracht.In addition, the new compounds of the formula I obtained in this way, if they contain a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts. Examples of bases which can be used here are sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Die als Ausgangsprodukte verwendeten Verbindungen der allgemeinen Formeln I bis VIII sind teilweise literaturbekannt oder man erhält diese nach literaturbekannten Verfahren oder werden in den Beispielen beschrieben.Some of the compounds of general formulas I to VIII used as starting products are known from the literature or can be obtained by processes known from the literature or are described in the examples.
Wie bereits eingangs erwähnt, weisen die neuen Verbindungen der allgemeinen Formel I wertvolle pharmakologische Eigenschaften auf, insbesondere inhibierende Wirkungen auf verschiedene Kinasen und Cyclin/CDK-Komplexe, auf die Proliferation kultivierter humaner Tumor-Zellen sowie nach oraler Gabe auf das Wachstum von Tumoren in Nacktmäusen, die mit humanen Tumorzellen infiziert worden waren.As already mentioned at the beginning, the new compounds of the general formula I have valuable pharmacological properties, in particular inhibitory effects on various kinases and cyclin / CDK complexes, on the proliferation of cultured human tumor cells and on growth after oral administration of tumors in nude mice infected with human tumor cells.
Die Prüfung der neuen Verbindungen auf ihre biologischen Eigenschaften wurde beispielsweise in folgenden Testen durchgeführt :The biological compounds were tested for their biological properties in the following tests, for example:
Tftflt. 1Tftflt. 1
Tnh-ib-ie-nmg von CyrΛ i n /CDK-Enzym. -Aktivität in vit-.rn High Five™ Insekten-Zellen (BTI-TN-5B1-4) , die mit einem hohen Titer an rekombinantem Baculovirus infiziert waren, wurden für die Produktion von aktiven humanen Cyclin/CDK Holoenzymen benutzt. Durch die Verwendung eines Baculovirus-Vektors, der zwei Promoter enthielt (polyhedrin enhancer promoter, PlO-en- hancer promoter), wurden GST-tagged Cycline (z.B. Cyclin Dl oder Cyclin D3) mit der entsprechenden Hisg-tagged CDK-Unter- einheit (z.B. für CDK4 oder CDK6) in derselben Zelle expri- miert . Das..aktive Holoenzym wurde durch Affinitäts-Chromatographie an Glutathion-Sepharose isoliert. Rekombinantes GST- tagged pRB (aa 379-928) wurde in E. coli produziert und durch Affinitäts-Chromatographie an Glutathion-Sepharose gereinigt.Tnh-ib-ie-nmg of CyrΛ i n / CDK enzyme. Activity in vit-.rn High Five ™ insect cells (BTI-TN-5B1-4) infected with a high titer of recombinant baculovirus were used for the production of active human cyclin / CDK holoenzymes. By using a baculovirus vector that contained two promoters (polyhedrin enhancer promoter, PlO enhancer promoter), GST-tagged cyclins (eg Cyclin Dl or Cyclin D3) with the corresponding Hisg-tagged CDK subunit ( for CDK4 or CDK6) 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.
Die Substrate, die für die Kinase-Assays verwendet wurden, hingen von den spezifischen Kinasen ab. Histone Hl (Sigma) wurde verwendet als Substrat für Cyclin E/CDK2, Cyclin A/CDK2, Cyclin B/CDK1 und für v-Cyclin/CDK6. GST-tagged pRB (aa 379- 928) wurde verwendet als Substrat für Cyclin D1/CDK4, Cyclin D3/CDK4, Cyclin D1/CDK6 und für Cyclin D3/CDK6.The substrates used for the kinase assays depended on the specific kinases. Histone Hl (Sigma) was used as a substrate for Cyclin E / CDK2, Cyclin A / CDK2, Cyclin B / CDK1 and for v-Cyclin / CDK6. GST-tagged pRB (aa 379-928) was used as a substrate for Cyclin D1 / CDK4, Cyclin D3 / CDK4, Cyclin D1 / CDK6 and for Cyclin D3 / CDK6.
Lysate der mit rekombinanten Baculovirus-infizierten Insekten- Zellen oder auch rekombinante Kinasen (erhalten aus den Lysaten durch Reinigung) wurden zusammen mit radioaktiv markiertem ATP in Gegenwart eines geeigneten Substrates mit verschiedenen Konzentrationen des Inhibitors in einer l%igen DMSO-Lösung (Dimethylsulfoxid) 45 Minuten lang bei 30°C inkubiert. Die Substrat Proteine mit assoziierter Radioaktivität wurden mit 5%iger TCA (Trichloressigsäure) in hydrophoben PVDF multi-well Mikrotiter Platten (Millipore) oder mit 0.5%iger Phosphorsäure- Lösung auf Whatman P81 Filtern ausgefällt. Nach Zugabe von Scintillations-Flüssigkeit wurde die Radioaktivität in einem Wallace 1450 Microbeta Flüssig-Scintillations-Zähler gemessen. Pro Konzentration der Substanz wurden Doppel-Messungen durchgeführt; IC50-Werte für die Enzym-Inhibition wurden berechnet.Lysates of the insect cells infected with recombinant baculovirus or also recombinant kinases (obtained from the lysates by purification) were combined with radioactively labeled ATP in the presence of a suitable substrate with various concentrations of the inhibitor in a 1% DMSO solution (dimethyl sulfoxide) 45 Incubated for minutes at 30 ° C. The substrate proteins with associated radioactivity were multi-well mixed with 5% TCA (trichloroacetic acid) in hydrophobic PVDF Microtiter plates (Millipore) or precipitated with 0.5% phosphoric acid solution on Whatman P81 filters. After adding scintillation fluid, the radioactivity was measured in a Wallace 1450 Microbeta liquid scintillation counter. Double measurements were carried out per concentration of the substance; IC5 0 values for enzyme inhibition were calculated.
TiBf. 2TiBf. 2
Inhibierung der Profileration von kultivierten humanen Tumor-Inhibition of the profiling of cultured human tumor
7i,ft1 len .7i, ft1 len.
Zellen der Leiomyosarcoma Tumorzell-Linie SK-UT-IB (erhalten von der American Type Culture Collection (ATCC) ) wurden in Minimum Essential Medium mit nicht-essentiellen Aminosäuren (Gibco) , ergänzt mit Natrium-Pyruvat (1 mMol) , Glutamin (2 mMol) und 10% fötalem Rinderserum (Gibco) kultiviert und in der log-Wachstumsphase geerntet. Anschließend wurden die SK-UT- lB-Zellen in Cytostar® multi-well Platten (Amersham) mit einer Dichte von 4000 cells per well eingebracht und über Nacht in einem Inkubator inkubiert . Verschiedene Konzentrationen der Verbindungen (gelöst in DMSO; Endkonzentration: <1%) wurden zu den Zellen zugegeben. Nach 48 Stunden Inkubation wurde 14C-Thy- midin (Amersham) zu jedem well zugesetzt, und es wurde weitere 24 Stunden inkubiert. Die Menge an 14C-Thymidin, die in Gegenwart des Inhibitors in die Tumorzellen eingebaut wurde und die die Zahl der Zellen in der S-Phase repräsentiert, wurde in einem Wallace 1450 Microbeta Flüssig Scintillations Zähler gemessen. IC50-Werte für die Inhibierung der Proliferation (= Inhibierung von eingebautem l4C-Thymidin) wurden - unter Korrektur für die Hintergrundstrahlung - berechnet . Alle Messungen wurden zweifach ausgeführt .Cells of the Leiomyosarcoma tumor cell line SK-UT-IB (obtained from the American Type Culture Collection (ATCC)) were in minimum essential medium with non-essential amino acids (Gibco), supplemented with sodium pyruvate (1 mmol), glutamine (2nd mmol) and 10% fetal bovine serum (Gibco) and harvested in the log growth phase. The SK-UT-IB cells were then introduced into Cytostar® multi-well plates (Amersham) with a density of 4000 cells per well and incubated overnight in an incubator. Different concentrations of the compounds (dissolved in DMSO; final concentration: <1%) were added to the cells. After 48 hours of incubation, 14 C-thymidine (Amersham) was added to each well and incubation was continued for 24 hours. The amount of 14 C-thymidine which was incorporated into the tumor cells in the presence of the inhibitor and which represents the number of cells in the S phase was measured in a Wallace 1450 Microbeta liquid scintillation counter. IC5 0 values for the inhibition of proliferation (= inhibition of incorporated l 4 C-thymidine) were - calculated - while correcting for background radiation. All measurements were carried out twice.
Tftsr.Tftsr.
In vivo Effekte an Tumnr-f-.ragpnrlpn NacktmäusenIn vivo effects on Tumnr-f-.ragpnrlpn nude mice
106 Zellen [SK-UT-IB, oder non-small cell Lungen-Tumor NCI-H46010 6 cells [SK-UT-IB, or non-small cell lung tumor NCI-H460
(erhalten von ATCC)] in einem Volumen von 0.1 ml wurden in männliche und/oder weibliche Nacktmäuse (NMRI nu/nu; 25-35 g; N = 10-20) subkutan injiziert; alternativ wurden kleine Stückchen von SK-UT-IB- oder NCI-H460-Zellklumpen subkutan implantiert. Eine bis drei Wochen nach Injektion bzw. Implantation wurde ein Kinase-Inhibitor täglich für die Dauer von 2 bis 4 Wochen oral (per Schlundsonde) appliziert. Die Tumor-Größe wurde dreimal pro Woche mit einer digitalen Schieblehre gemessen. Der Effekt eines Kinase-Hemmers auf das Tumor-Wachstum wurde als Prozentinhibierung im Vergleich zu einer mit Placebo behandelten Kontroll-Gruppe bestimmt.(obtained from ATCC)] in a volume of 0.1 ml were in male and / or female nude mice (NMRI nu / nu; 25-35 g; N = 10-20) injected subcutaneously; alternatively, small pieces of SK-UT-IB or NCI-H460 cell clumps were implanted subcutaneously. One to three weeks after injection or implantation, a kinase inhibitor was administered orally daily (by gavage) for a period of 2 to 4 weeks. The tumor size was measured three times a week with a digital caliper. The effect of a kinase inhibitor on tumor growth was determined as a percent inhibition compared to a control group treated with placebo.
Die nachfolgenden Tabellen 1 und 2 enthalten Ergebnisse der Teste 1 bzw. 2:Tables 1 and 2 below contain results of tests 1 and 2, respectively:
TahpllP 1 (T st 1)TahpllP 1 (T st 1)
Figure imgf000031_0001
Figure imgf000031_0001
Ta lIP. 2 fTPar ?ΛTa lip. 2 fTPar? Λ
Figure imgf000031_0002
Folgendes Ergebnis wurde im Test Nr. 3 (in vivo) erzielt:
Figure imgf000031_0002
The following result was achieved in Test No. 3 (in vivo):
Die Applikation [1 x täglich 100 mg/kg p.o. der Verbindung aus Beispiel Nr. 2.5; zwei Wochen lang] an männlichen Nacktmäusen (n = 9) ergab eine signifikante Reduktion der Tumorgröße um 65% (p < 0.05) .The application [1 x daily 100 mg / kg p.o. the compound from Example No. 2.5; for two weeks] in male nude mice (n = 9) showed a significant reduction in tumor size by 65% (p <0.05).
Auf Grund ihrer biologischen Eigenschaften eignen sich die neuen Verbindungen der allgemeinen Formel I, deren Isomere und deren physiologisch verträgliche Salze zur Behandlung von Erkrankungen an Mensch und Tier, die durch exzessive oder anomale Zeilproliferation charakterisiert sind.Due to their biological properties, the new compounds of general formula I, their isomers and their physiologically tolerable salts are suitable for the treatment of diseases in humans and animals which are characterized by excessive or abnormal cell proliferation.
Zu solchen Erkrankungen gehören (ohne Anspruch auf Vollständigkeit) : Virale Infektionen (z.B. HIV und Kaposi Sarkoma); Entzündung und Autoimmun-Erkrankungen (z.B. Colitis, Arthritis, Alzheimer Erkrankung, Glomerulonephritis und Wund-Heilung) ; bakterielle, fungale und/oder parasitäre Infektionen; Leukämien, Lymphoma und solide Tumore; Haut-Erkrankungen (z.B. Psoriasis) ; Knochen-Erkrankungen; kardiovaskuläre Erkrankungen (z.B. Restenose und Hypertrophie). Ferner sind sie nützlich als Schutz von proliferierenden Zellen (z.B. Haar-, Intestinal-, Blut- und Progenitor-Zellen) gegen DNA-Schädigung durch Strahlung, UV-Behandlung und/oder zytostatischer Behandlung.Such diseases include (without claim to completeness): viral infections (e.g. HIV and Kaposi sarcoma); Inflammation and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin disorders (e.g. psoriasis); Bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful as protection of proliferating cells (e.g. hair, intestinal, blood and progenitor cells) against DNA damage from radiation, UV treatment and / or cytostatic treatment.
Die neuen Verbindungen können zur Kurz- oder Langzeitbehandlung der vorstehend erwähnten Erkrankungen gegebenenfalls auch in Kombination mit anderen "State-of-the-art" Verbindungen verwendet werden.The new compounds can also be used in combination with other “state-of-the-art” compounds for the short-term or long-term treatment of the abovementioned diseases.
Die zur Erzielung einer entsprechenden Wirkung erforderliche Dosierung beträgt zweckmäßigerweise bei intravenöser Gabe 0 , 1 bis 30 mg/kg, vorzugsweise 0,3 bis 10 mg/kg, und bei oraler Gabe 0,1 bis 100 mg/kg, vorzugsweise 0,3 bis 30 mg/kg, jeweils 1 bis 4 x täglich. Hierzu lassen sich die erfindungsgemäß hergestellten Verbindungen der Formel I, gegebenenfalls in Kombination mit anderen Wirksubstanzen, zusammen mit einem oder meh- reren inerten üblichen Trägerstoffen und/oder Verdünnungsmitteln, z.B. mit Maisstärke, Milchzucker, Rohrzucker, mikrokristalliner Zellulose, Magnesiumstearat, Polyvinylpyrrolidon, Zitronensäure, Weinsäure, Wasser, Wasser/Ethanol, Wasser/Gly- cerin, Wasser/Sorbit, Wasser/Polyethylenglykol, Propylenglykol, Cetylstearylalkohol, Carboxymethylcellulose oder fetthaltigen Substanzen wie Hartfett oder deren geeigneten Gemischen, in übliche galenische Zubereitungen wie Tabletten, Dragees, Kapseln, Pulver, Suspensionen, Zäpfchen oder als Lösungen für Injektionen oder Infusionen einarbeiten. The dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration, and 0.1 to 100 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day. For this purpose, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances, together with one or more inert inert carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, Incorporate cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, suppositories or as solutions for injections or infusions.
Die nachfolgenden Beispiele sollen die Erfindung näher erläutern, hierbei werden folgende Abkürzungen verwendet:The following examples are intended to explain the invention in more detail, the following abbreviations being used:
Boc = tert .Butyloxycarbonyl-Boc = tert. Butyloxycarbonyl-
Bzl = BenzylBzl = benzyl
CH2CI2 = MethylenchloridCH2CI2 = methylene chloride
DBU = 1, 8-Diazabicyclo [5.4.0]undec-7-enDBU = 1,8-diazabicyclo [5.4.0] undec-7-ene
DC = DünnschichtchromatogrammDC = thin layer chromatogram
DMF = DimethylformamidDMF = dimethylformamide
DMSO = DimethylsulfoxidDMSO = dimethyl sulfoxide
EtOAc = EthylacetatEtOAc = ethyl acetate
EtOH = EthanolEtOH = ethanol
HOBT = N-Hydroxy-lH-benzotriazolHOBT = N-hydroxy-1H-benzotriazole
Hünig 's Base = N-Ethyl-N,N-diisopropyl-aminHunig's base = N-ethyl-N, N-diisopropyl-amine
MeOH = MethanolMeOH = methanol
MS = MassenspektrumMS = mass spectrum
TBTU = 0- (Benzotriazol-1-yl) -N,N,N' ,N' -tetramethyl- uronium-tetrafluorboratTBTU = 0- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyl uronium tetrafluoroborate
THF = TetrahydrofuranTHF = tetrahydrofuran
Ti = InnentemperaturTi = internal temperature
Z = BenzyloxycarbonylZ = benzyloxycarbonyl
(Z) ; (E) = Konfiguration(Z); (E) = configuration
ffprstpllπng der Αiifigang.qyprhi nrinng n :ffprstpllπng der Αiifigang.qyprhi nrinng n:
Beis iel AExample A
1-Acetyl-2-indolinon1-acetyl-2-indolinone
Hergestellt durch 3-stündiges Erhitzen von 2-Indolinon mit 1 Äquivalent Acetanhydrid in einem Bad von 170°C unter Rückfluß.Prepared by heating 2-indolinone with 1 equivalent of acetic anhydride in a bath of 170 ° C under reflux for 3 hours.
Ausbeute: 96 % der Theorie; Schmelzpunkt: 129-130°C.
Figure imgf000035_0001
Yield: 96% of theory; Melting point: 129-130 ° C.
Figure imgf000035_0001
1-Acetyl-3 - { 1-ethoxy-1-phenylmethyliden} -2-indolinon1-acetyl-3 - {1-ethoxy-1-phenylmethylidene} -2-indolinone
Hergestellt durch 22-stündiges Erhitzen von 3 Äquivalenten l-Acetyl-2-indolinon mit 6 Äquivalenten Orthobenzoesäure- triethylester und Acetanhydrid in einem Bad von 160°C unter Rückfluß. Nach Eindampfen im Vakuum wird der Rückstand mit Petrolether versetzt. Nach Stehen über Nacht filtriert man das ausgefallene Produkt ab und trocknet es bei 60°C. Ausbeute: ca. 67 % der Theorie, das Produkt enthält ca. 25 bis 34 % l-Acetyl-2-indolinon.Prepared by heating 3 equivalents of 1-acetyl-2-indolinone with 6 equivalents of triethyl orthobenzoate and acetic anhydride in a bath at 160 ° C. under reflux for 22 hours. After evaporation in vacuo, the residue is mixed with petroleum ether. After standing overnight, the precipitated product is filtered off and dried at 60 ° C. Yield: approx. 67% of theory, the product contains approx. 25 to 34% l-acetyl-2-indolinone.
Schmelzpunkt: 123-129°C (bei einem Anteil von 34 % an 1-Acetyl- 2 -indolinon) .Melting point: 123-129 ° C (with a 34% share of 1-acetyl-2-indolinone).
Aus dem obigen Gemisch wird durch Versetzen mit Ethylacetat, Ausschütteln mit verdünnter wäßriger Natriumkarbonat-Lösung, mit Wasser und durch Abfiltrieren ein ungelöster Anteil isoliert, der das reine Produkt darstellt. Schmelzpunkt: 187-189°C; C19H17N03 An undissolved portion, which is the pure product, is isolated from the above mixture by adding ethyl acetate, shaking with dilute aqueous sodium carbonate solution, with water and by filtering off. Melting point: 187-189 ° C; C 19 H 17 N0 3
Ber.: C 74.25 H 5.57 N 4.56 Gef.: 73.95 5.57 4.53Calc .: C 74.25 H 5.57 N 4.56 Found: 73.95 5.57 4.53
Beispiel CExample C
3-{l-Ethoxy-l-phenylmethyliden}-2-indolinon3- {l-ethoxy-l-phenylmethylidene} -2-indolinone
Man suspendiert das im Beispiel B erhaltene Gemisch bestehend aus 66% l-Acetyl-3-{l-ethoxy-l-phenylmethyliden}-2-indolinon und 34% 1-Acetyl-2-indolinon in Ethanol (8 ml/g) , gibt 2 Äquivalente 4N Natronlauge hinzu und rührt bei Raumtemperatur 1.5 Stunden. Nach Zugabe von Wasser (25 ml/g) wird der ausgefallene Niederschlag abfiltriert, mit Wasser und wenig Ether gewaschen und bei 80°C getrocknet.The mixture obtained in Example B consisting of 66% l-acetyl-3- {l-ethoxy-l-phenylmethylidene} -2-indolinone and 34% 1-acetyl-2-indolinone is suspended in ethanol (8 ml / g), added 2 equivalents of 4N sodium hydroxide solution and stirred at room temperature for 1.5 hours. After adding water (25 ml / g), the precipitate is filtered off, washed with water and a little ether and dried at 80 ° C.
Ausbeute: 80 % der Theorie (bezogen auf den eingesetzten Anteil an l-Acetyl-3-{l-ethoxy-l-phenylmethyliden}-2-indolinon) ; Schmelzpunkt: 168-169°C; C17H15N02 Yield: 80% of theory (based on the proportion of l-acetyl-3- {l-ethoxy-l-phenylmethylidene} -2-indolinone used); Melting point: 168-169 ° C; C 17 H 15 N0 2
Ber. : C 76. 96 H 5.70 N 5.28Ber. : C 76.96 H 5.70 N 5.28
Gef.: 76.69 5.62 5.23Found: 76.69 5.62 5.23
Beispiel DExample D
1-Acetyl-5-nitro-2-indolinon1-acetyl-5-nitro-2-indolinone
Hergestellt durch Umsetzung von 1-Acetyl-2-indolinon in konzentrierter Schwefelsäure (5.7 ml/g) bei -10 °C mit 1.1 Äquivalenten Ammoniumnitrat, das man portionsweise unter Rühren zugibt. Nach Ende der Zugabe rührt man noch 15 Minuten, gießt dann auf Eiswasser, filtriert den Niederschlag ab, wäscht ihn mit Wasser und löst ihn in Ethylacetat. Die organische Phase wird mit Wasser ausgeschüttelt, getrocknet, filtriert und im Vakuum eingedampft. Der Eindampfrückstand wird mit Petrolether verrührt. Ausbeute: 93 % der Theorie; Schmelzpunkt: 154-156°C; C10H8N2O4 Prepared by reacting 1-acetyl-2-indolinone in concentrated sulfuric acid (5.7 ml / g) at -10 ° C with 1.1 equivalents of ammonium nitrate, which is added in portions with stirring. After the addition has ended, the mixture is stirred for a further 15 minutes, then poured onto ice water, the precipitate is filtered off, washed with water and dissolved in ethyl acetate. The organic phase is shaken out with water, dried, filtered and evaporated in vacuo. The evaporation residue is stirred with petroleum ether. Yield: 93% of theory; Melting point: 154-156 ° C; C 10 H 8 N 2 O 4
Ber.: C 54.55 H 3.66 N 12.72 Gef. : 54.36 3.67 13.00Calc .: C 54.55 H 3.66 N 12.72 Found: 54.36 3.67 13.00
Beispiel EExample E
1-Acetyl-3- { 1-ethoxy-1-phenylmethyliden} -5- itro-2-indolinon1-acetyl-3- {1-ethoxy-1-phenylmethylidene} -5-itro-2-indolinone
Hergestellt durch 2.5-stündiges Erhitzen von 3 Äquivalenten l-Acetyl-5-nitro-2-indolinon mit Orthobenzoesäure-triethylester und 8 Äquivalenten Acetanhydrid in einem Bad von 100°C unter Rückfluß. Man kühlt im Eisbad, fügt Petrolether zu und rührt 1 Stunde. Die Festsubstanz wird filtriert, mit Petrolether und Ether gewaschen und bei 60°C getrocknet. Ausbeute: 77 % der Theorie;Prepared by heating 3 equivalents of l-acetyl-5-nitro-2-indolinone with triethyl orthobenzoate and 8 equivalents of acetic anhydride in a 100 ° C. bath under reflux for 2.5 hours. It is cooled in an ice bath, petroleum ether is added and the mixture is stirred for 1 hour. The solid is filtered, washed with petroleum ether and ether and dried at 60 ° C. Yield: 77% of theory;
Schmelzpunkt: 235-238°C;Melting point: 235-238 ° C;
Ci9H16N2θ5Ci9H 16 N 2 θ5
Ber. : C 64.77 H 4.58 N 7.95Ber. : C 64.77 H 4.58 N 7.95
Gef.: 64.60 4.59 7.99 Bei spiel. FFound: 64.60 4.59 7.99 For example. F
3- {l-Ethoxy-l-phenylmethyliden}-5-nitro-2-indolinon3- {l-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone
Zu einer gerührten Mischung von l-Acetyl-3- {1-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon in Methylenchlorid (11 ml/g) und EtOH (8.5 ml/g) gibt unter Eiskühlung tropfenweise 1.5 Äquivalente IN Natronlauge, so daß die Innentemperatur 14 bis 17°C nicht übersteigt. Anschließend rührt man noch 0.5 Stunden bei Raumtemperatur und entfernt das Methylenchlorid durch Eindampfen im Vakuum bei einer Badtemperatur von 30°C. Man fügt Wasser zu (11 ml/g) und rührt gut durch. Der Niederschlag wird filtriert, mit Wasser, Isopropanol und zuletzt mit Ether gewaschen und bei 100°C getrocknet. Ausbeute: 86 % der Theorie; Schmelzpunkt: 239-240°C; C17H14N2θ4 To a stirred mixture of l-acetyl-3- {1-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone in methylene chloride (11 ml / g) and EtOH (8.5 ml / g) are added dropwise with ice cooling 1.5 equivalents IN sodium hydroxide solution, so that the internal temperature does not exceed 14 to 17 ° C. The mixture is then stirred for a further 0.5 hours at room temperature and the methylene chloride is removed by evaporation in vacuo at a bath temperature of 30 ° C. Add water (11 ml / g) and stir well. The precipitate is filtered, washed with water, isopropanol and finally with ether and dried at 100 ° C. Yield: 86% of theory; Melting point: 239-240 ° C; C 17 H 14 N 2 θ 4
Ber.: C 65.80 H 4.55 N 9.03 Gef.: 65.45 4.43 8.81 Ber. : Molpeak M+ = 310 Gef.: Molpeak M+ = 310 Calc .: C 65.80 H 4.55 N 9.03 Found: 65.45 4.43 8.81 Calc. : Molpeak M + = 310 Found: Molpeak M + = 310
ff rst-pllπng He Eπ v -rh-i n ungen :ff rst-pllπng He Eπ v -rh-i n ungen:
RPI spi l 1RPI game 1
3- { (Z) -1- [ (Indol-5-yl) amino] -1-phenylmethyliden} -2-indolinon3- {(Z) -1- [(indol-5-yl) amino] -1-phenylmethylidene} -2-indolinone
Man erhitzt 0.307 g (1 mMol) l-Acetyl-3- {l-ethoxy-l-phenylme- thyliden} -2-indolinon und 0.400 mg (3 mMol) 5-Amino-indol in 10 ml Toluol 1 Stunde unter Rückfluß. Man dampft im Vakuum ein und verteilt den Eindampfrückstand zwischen EtOAc und Wasser. Aus der organischen Phase erhält man nach Trocknen, Filtrieren und Eindampfen im Vakuum ein zähes Öl, das man durch Säulenchromatographie an Kieselgel mit dem Eluens EtOAc/Petrolether (1:1) reinigt.0.307 g (1 mmol) of 1-acetyl-3- {1-ethoxy-1-phenylmethylidene} -2-indolinone and 0.400 mg (3 mmol) of 5-amino-indole in 10 ml of toluene are heated under reflux for 1 hour. It is evaporated in vacuo and the evaporation residue is distributed between EtOAc and water. After drying, filtering and evaporating in vacuo, a viscous oil is obtained from the organic phase and is purified by column chromatography on silica gel using the eluent EtOAc / petroleum ether (1: 1).
Ausbeute: 0.11 g (31 % der Theorie); Schmelzpunkt: 263-265°C;Yield: 0.11 g (31% of theory); Melting point: 263-265 ° C;
C23H17N30C 2 3H 17 N 3 0
Ber. : C 78.61 H 4.88 N 11.96Ber. : C 78.61 H 4.88 N 11.96
Gef. : 78.28 4.91 11.76Found: 78.28 4.91 11.76
Ber. : Molpeak M+ = 351Ber. : Molpeak M + = 351
Gef. : Molpeak M+ = 351Found: Molpeak M + = 351
Analog Beispiel 1 wurde folgende Verbindung erhalten:The following compound was obtained analogously to Example 1:
3-{ (Z) -1- [ (l-Methyl-benzimidazol-5-yl) amino] -1-phenylme- thyliden} -2-indolinon x 2 H2O3- {(Z) -1- [(1-methylbenzimidazol-5-yl) amino] -1-phenylmethylidene} -2-indolinone x 2 H2O
Hergestellt durch Erhitzen von l-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -2-indolinon und 2 Äquivalenten 5-Amino-l-methyl- benzimidazol vom Schmelzpunkt 158-160°C in DMF während 1.5Prepared by heating l-acetyl-3- {1-ethoxy-l-phenylmethylidene} -2-indolinone and 2 equivalents of 5-amino-l-methylbenzimidazole of melting point 158-160 ° C in DMF for 1.5
Stunden bei 120°C, anschließende Ausfällung mit Wasser undHours at 120 ° C, followed by precipitation with water and
Digerieren in MeOH.Digest in MeOH.
Ausbeute: 60 % der Theorie;Yield: 60% of theory;
Schmelzpunkt: 307-308°C;Melting point: 307-308 ° C;
C23H18N40 x 2 H20C 23 H 18 N 4 0 x 2 H 2 0
Ber.: C 68.64 H 5.51 N 13.92Calc .: C 68.64 H 5.51 N 13.92
Gef.: 68.65 5.51 13.85 Ber. : Molpeak M+ = 366 Gef.: Molpeak M+ = 366Found: 68.65 5.51 13.85 Ber. : Molpeak M + = 366 Found: Molpeak M + = 366
RPI spiel 2RPI game 2
3- { (Z) -1- [ (2-Indazol-5-yl) amino] -1-phenylmethyliden} -2-indo- linon3- {(Z) -1- [(2-indazol-5-yl) amino] -1-phenylmethylidene} -2-indoline
Man erhitzt 0.307 g (1 mMol) l-Acetyl-3- {l-ethoxy-1-phenylme- thyliden} -2 -indolinon und 0.400 mg (3 mMol) 5-Amino-indazol in 5 ml DMF 2 Stunden bei 120°C. Man verdünnt mit Wasser und extrahiert mit EtOAc. Die organische Phase wird dreimal mit Wasser ausgeschüttelt, getrocknet, filtriert und im Vakuum eingedampft. Der ölige Eindampfrückstand wird in MeOH gelöst. Man setzt unter Eiskühlung 2 ml IN Natronlauge zu und rührt 1 Stunde bei Raumtemperatur. Man dampft im Vakuum bis fast zur Trockne ein, setzt Wasser zu, filtriert die Festsubstanz ab, wäscht sie mit Wasser, und digeriert sie mit MeOH. Man reinigt sie durch Säulenchromatographie an Kieselgel mit dem Eluens EtOAc . Ausbeute: 0.15 g (42 % der Theorie); Schmelzpunkt: 287-289°C; C22H16N4O Ber. C 74.98 H 4.58 N 15.90 Gef. 74.58 4.75 15.55 Ber. Molpeak M+ = 352 Gef. Molpeak M+ = 3520.307 g (1 mmol) of 1-acetyl-3- {1-ethoxy-1-phenylmethylidene} -2-indolinone and 0.400 mg (3 mmol) of 5-amino-indazole in 5 ml of DMF are heated at 120 ° for 2 hours C. It is diluted with water and extracted with EtOAc. The organic phase is shaken three times with water, dried, filtered and evaporated in vacuo. The oily evaporation residue is dissolved in MeOH. 2 ml of 1N sodium hydroxide solution are added with ice cooling and the mixture is stirred at room temperature for 1 hour. The mixture is evaporated to dryness in vacuo, water is added, the solid is filtered off, washed with water and digested with MeOH. It is purified by column chromatography on silica gel using the EtOAc eluent. Yield: 0.15 g (42% of theory); Melting point: 287-289 ° C; C22H16N4O calc. C 74.98 H 4.58 N 15.90 Found 74.58 4.75 15.55 calc. Molpeak M + = 352 Found Molpeak M + = 352
Analog Beispiel 2 wurden folgende Verbindungen erhalten:The following compounds were obtained analogously to Example 2:
2.1 3- { (Z) -1- [ (2-Indazol-6-yl) amino] -1-phenylmethyliden} - 2 -indolinon x 0.75 H2O2.1 3- {(Z) -1- [(2-indazol-6-yl) amino] -1-phenylmethylidene} - 2 -indolinone x 0.75 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 3 Äquivalenten 6-Amino-indazol in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 42 % der Theorie; Schmelzpunkt: 307-308°C, C22H16N4° x 0.75 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 3 equivalents of 6-amino-indazole in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 42% of theory; Melting point: 307-308 ° C, C 2 2 H 16 N 4 ° x 0.75 H 2 0
Ber. C 72.21 H 4.82 N 15.31 Gef. 72.29 4.47 15.62 Ber. Molpeak M+ = 352 Gef. Molpeak M+ = 352Ber. C 72.21 H 4.82 N 15.31 Found 72.29 4.47 15.62 calc. Molpeak M + = 352 Found Molpeak M + = 352
2.2 3-{ (Z) -1- [ (2-Oxo-indolin-5-yl) amino] -1-phenylmethyliden} - 2 -indolinon x 0.2 H2O2.2 3- {(Z) -1- [(2-oxo-indolin-5-yl) amino] -1-phenylmethylidene} - 2 -indolinone x 0.2 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 3 Äquivalenten 5-Amino-2 -indolinon vom Schmelzpunkt 194-195 °C in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 54 % der Theorie; Schmelzpunkt: 288-290°C;
Figure imgf000040_0001
Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 3 equivalents of 5-amino-2-indolinone with a melting point of 194-195 ° C in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH . Yield: 54% of theory; Melting point: 288-290 ° C;
Figure imgf000040_0001
Ber. C 74.45 H 4.73 N 11.33 Gef. 74.46 4.67 11.30 Ber. Molpeak M+ = 367 Gef. Molpeak M+ = 367Ber. C 74.45 H 4.73 N 11.33 Found 74.46 4.67 11.30 calc. Molpeak M + = 367 Found Molpeak M + = 367
2.3 3- { (Z) -1- [(1,2,3 , 4-Tetrahydro-chinolin-6-yl) amino] -1-phe- nylmethyliden} -2 -indolinon x 0.5 H2O2.3 3- {(Z) -1- [(1,2,3, 4-tetrahydroquinolin-6-yl) amino] -1-phenylmethylidene} -2-indolinone x 0.5 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 3 Äquivalenten von 6-Amino-l, 2 , 3 , 4-tetrahydro-chi- nolin [hergestellt durch Hydrierung von 6-Amino-chinolin] inMade from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 3 equivalents of 6-amino-l, 2, 3, 4-tetrahydroquinoline [made by hydrogenating 6 -Amino-quinoline] in
DMF und anschließende Behandlung mit IN Natronlauge in MeOH.DMF and subsequent treatment with IN sodium hydroxide solution in MeOH.
Ausbeute: 54 % der Theorie;Yield: 54% of theory;
Schmelzpunkt: 229-230°C;Melting point: 229-230 ° C;
C24H21N3O x 0.5 H20C24H21N3O x 0.5 H 2 0
Ber.: C 76.57 H 5.89 N 11.16Calc .: C 76.57 H 5.89 N 11.16
Gef.: 76.73 5.69 10.96Found: 76.73 5.69 10.96
Ber.. Molpeak M+ = 367Calc. Molpeak M + = 367
Gef.: Molpeak M+ = 367 2-4 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1-phenylmethyliden} - 2-indolinonFound: Molpeak M + = 367 2-4 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1-phenylmethylidene} - 2-indolinone
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 1.5 Äquivalenten 4- (lH-Imidazol-4-yl) -anilin in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 68 % der Theorie;Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 1.5 equivalents of 4- (lH-imidazol-4-yl) aniline in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 68% of theory;
Schmelzpunkt: 280-285°C;Melting point: 280-285 ° C;
C24H18N4OC24H18N4O
Ber..- C 76.17 H 4.79 N 14.80Calc ..- C 76.17 H 4.79 N 14.80
Gef. : 75.83 4.83 14.62Found: 75.83 4.83 14.62
Ber. : Molpeak M+ *. 378Ber. : Molpeak M + * . 378
Gef. : Molpeak M+ = 378Found: Molpeak M + = 378
2..5 3- { (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1-phenylmethyliden} 5-nitro-2-indolinon x H 02..5 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1-phenylmethylidene} 5-nitro-2-indolinone x H 0
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro-2-indolinon und 1.5 Äquivalenten 4- (1H-Imidazol-4-yl) -anilin in DMF und anschließende Behandlung mit IN Natronlauge in MeOH.Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 1.5 equivalents of 4- (1H-imidazol-4-yl) aniline in DMF and subsequent treatment with IN Sodium hydroxide solution in MeOH.
Ausbeute: 59 % der Theorie; Schmelzpunkt: 308-311°C; C24H17N5°3 x H2°Yield: 59% of theory; Melting point: 308-311 ° C; C24 H 17 N 5 ° 3 x H 2 °
Ber. : C 65.30 H 4.34 N 15.86Ber. : C 65.30 H 4.34 N 15.86
Gef. : 65.40 4.29 15.77Found: 65.40 4.29 15.77
Ber. : Molpeak M+ = 423Ber. : Molpeak M + = 423
Gef. : Molpeak M+ = 423Found: Molpeak M + = 423
Beispiel _3_Example _3_
3-{ (Z) -1- [ (Benzimidazol-5-yl)amino] -1-phenylmethyliden} -2-in- dolinon x 0.5 H2O3- {(Z) -1- [(benzimidazol-5-yl) amino] -1-phenylmethylidene} -2-indolinone x 0.5 H 2 O
Man erhitzt 0.307 g (1 mMol) l-Acetyl-3- {1-ethoxy-l-phenyl- methyliden} -2-indolinon und 0.400 mg (3 mMol) 5-Amino-benz- imidazol vom Schmelzpunkt 169-170°C in 5 ml DMF 1.5 Stunden bei 120°C. Man verdünnt mit Wasser und extrahiert mit EtOAc. Die organische Phase wird dreimal mit Wasser ausgeschüttelt, getrocknet, filtriert und im Vakuum eingedampft. Zum öligen Eindampfrückstand gibt man 20 ml MeOH und 2 ml IN Natronlauge und rührt 1.5 Stunden bei Raumtemperatur, wobei Lösung eintritt. Man dampft im Vakuum ein und schüttelt den Eindampfrückstand mit Wasser/Methylenchlorid. Den ungelösten Teil filtriert man ab, wäscht ihn mit Wasser, digeriert ihn mit EtOAc und trocknet ihn bei 80°C.0.307 g (1 mmol) of l-acetyl-3- {1-ethoxy-1-phenylmethylidene} -2-indolinone and 0.400 mg (3 mmol) of 5-amino-benzimidazole with a melting point of 169-170 ° C. are heated in 5 ml DMF for 1.5 hours at 120 ° C. It is diluted with water and extracted with EtOAc. The organic phase is extracted three times with water, dried, filtered and evaporated in vacuo. 20 ml of MeOH and 2 ml of 1N sodium hydroxide solution are added to the oily evaporation residue and the mixture is stirred at room temperature for 1.5 hours, during which the solution occurs. It is evaporated in vacuo and the evaporation residue is shaken with water / methylene chloride. The undissolved part is filtered off, washed with water, digested with EtOAc and dried at 80 ° C.
Ausbeute: 0.19 g (54 % der Theorie); Schmelzpunkt: 287-289°C;Yield: 0.19 g (54% of theory); Melting point: 287-289 ° C;
C22H16N4O x 0.5 H20C22H16N4O x 0.5 H 2 0
Ber. C 73.10 H 4.74 N 15.50 Gef. 73.43 4.63 15.02 Ber. Molpeak M+ = 352 Gef. Molpeak M+ = 352Ber. C 73.10 H 4.74 N 15.50 Found 73.43 4.63 15.02 Calc. Molpeak M + = 352 Found Molpeak M + = 352
Analog Beispiel 3 wurden folgende Verbindungen erhalten:The following compounds were obtained analogously to Example 3:
3 -l 3-{ (Z) -1- [ (l-Methyl-2-oxo-2,3-dihydro-lH-benzimidazol- 5-yl) amino] -1-phenylmethyliden} -2 -indolinon3 -l 3- {(Z) -1- [(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) amino] -1-phenylmethylidene} -2-indolinone
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 3 Äquivalenten rohem 5-Amino-l-methyl-2-oxo-2, 3-di- hydro-lH-benzimidazol in DMF und anschließende Behandlung mitMade from 1-acetyl-3- {1-ethoxy-1-phenylmethylidene} -2-indolinone and 3 equivalents of crude 5-amino-1-methyl-2-oxo-2, 3-di-hydro-1H-benzimidazole in DMF and subsequent treatment with
IN Natronlauge in MeOH.IN caustic soda in MeOH.
Ausbeute: 63 % der Theorie;Yield: 63% of theory;
Schmelzpunkt: >340°C;Melting point:> 340 ° C;
C23H18N402 C 23 H 18 N 4 0 2
Ber. C 72.24 H 4.74 N 14.65 Gef, 71.90 4.76 14.44 Ber. Molpeak M+ = 382 Gef. Molpeak M+ = 382Ber. C 72.24 H 4.74 N 14.65 found, 71.90 4.76 14.44 calc. Molpeak M + = 382 Found Molpeak M + = 382
3.2 3-{ (Z) -1- [ (1-Methyl-benzimidazol-6 -yl) amino] -1-phenylme- thyliden} -2-indolinon3.2 3- {(Z) -1- [(1-methylbenzimidazol-6-yl) amino] -1-phenylmethylidene} -2-indolinone
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2 -indolinon und 2 Äquivalenten 6-Amino-l-methyl-benzimidazol vom - 41 -Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 2 equivalents of 6-amino-l-methyl-benzimidazole from - 41 -
Schmelzpunkt 163-165°C in DMF und anschließende Behandlung mit IN Natronlauge in MeOH.Melting point 163-165 ° C in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH.
Ausbeute : 54 % der Theorie;Yield: 54% of theory;
Schmelzpunkt: 298-300°C;Melting point: 298-300 ° C;
C23H18N4OC23H18N4O
Ber. : C 75.39 H 4.95 N 15.29Ber. : C 75.39 H 4.95 N 15.29
Gef. : 75.16 5.00 15.18Found: 75.16 5.00 15.18
Ber. : Molpeak M+ = 366Ber. : Molpeak M + = 366
Gef. : Molpeak M+ = 366Found: Molpeak M + = 366
- 3 3- { (Z) -1- [ (1-Methyl-benzimidazol-6-yl) amino] -1-phenylme- thyliden} -5-nitro-2-indolinon x 0.4 H2O- 3 3- {(Z) -1- [(1-methylbenzimidazol-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.4 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro-2-indolinon und 1.1 Äquivalenten 6 -Amino-1-methyl-benzimidazol vom Schmelzpunkt 163-165°C in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 83 % der Theorie; Schmelzpunkt: 321°C; C23H17N503 x 0.4 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 1.1 equivalents of 6-amino-1-methyl-benzimidazole, melting point 163-165 ° C in DMF and subsequent Treatment with IN sodium hydroxide solution in MeOH. Yield: 83% of theory; Melting point: 321 ° C; C 2 3H 17 N 5 0 3 x 0.4 H 2 0
Ber. C 65.98 H 4.28 N 16.73 Gef. 66.29 4,36 16.40 Ber. Molpeak M+ = 411 Gef. Molpeak M+ = 411Ber. C 65.98 H 4.28 N 16.73 Found 66.29 4.36 16.40 Calc. Molpeak M + = 411 Found Molpeak M + = 411
.4 3- { (Z) -1- [ (Chinolin-6-yl) amino] -1-phenylmethyliden} -2-in- dolinon.4 3- {(Z) -1- [(quinolin-6-yl) amino] -1-phenylmethylidene} -2-indolinone
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 3 Äquivalenten 6-Amino-chinolin in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 50 % der Theorie; Schmelzpunkt: 271-272°C; C24H17N30Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 3 equivalents of 6-amino-quinoline in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 50% of theory; Melting point: 271-272 ° C; C 24 H 17 N 3 0
Ber. C 79.32 H 4.72 N 11.56 Gef. 78.98 4.66 11.68 Ber. Molpeak M+ = 363 Gef. Molpeak M+ = 363 3.5 3-{ (Z) -1- [ (2-Oxo-l,2,3,4-tetrahydro-chinolin-6-yl) amino] - 1-phenylmethyliden} -2-indolinon x 0.2 H2OBer. C 79.32 H 4.72 N 11.56 Found 78.98 4.66 11.68 calc. Molpeak M + = 363 Found Molpeak M + = 363 3.5 3- {(Z) -1- [(2-oxo-l, 2,3,4-tetrahydroquinolin-6-yl) amino] -1-phenylmethylidene} -2-indolinone x 0.2 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon, 2.5 Äquivalenten 6-Amino-carbostyryl x HCl vom Schmelzpunkt >300°C und 5 Äquivalenten N-Ethyl-diisopropylamin in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 98 % der Theorie; Schmelzpunkt: 324-325°C; C24H19N3O2 x 0.2 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone, 2.5 equivalents of 6-amino-carbostyryl x HCl with a melting point> 300 ° C and 5 equivalents of N-ethyl-diisopropylamine in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 98% of theory; Melting point: 324-325 ° C; C24H19N3O2 x 0.2 H 2 0
Ber. C 74.86 H 5.08 N 10.91 Gef. 74.79 5.04 10.93 Ber. Molpeak M+ = 381 Gef. Molpeak M+ = 381Ber. C 74.86 H 5.08 N 10.91 Found 74.79 5.04 10.93 calc. Molpeak M + = 381 Found Molpeak M + = 381
. 3- { (Z) -1- [ (2-Oxo-l, 2 , 3 , 4-tetrahydro-chinolin-6-yl) amino] 1-phenylmethyliden}-5-nitro-2 -indolinon. 3- {(Z) -1- [(2-oxo-l, 2,3,4-tetrahydroquinolin-6-yl) amino] 1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro-2-indolinon, 1.3 Äquivalenten 6-Amino-carbostyryl x HCl vom Schmelzpunkt >300°C und 2.5 Äquivalenten N-Ethyl-diisopropylamin in DMF und anschließende Behandlung mit IN Nacronlauge in MeOH.Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone, 1.3 equivalents of 6-amino-carbostyryl x HCl with a melting point> 300 ° C and 2.5 equivalents of N-ethyl diisopropylamine in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH.
Ausbeute: 85 % der Theorie; Schmelzpunkt: 310-313 °C; C24H18N404 Yield: 85% of theory; Melting point: 310-313 ° C; C 2 4H 18 N 4 0 4
Ber. C 67.60 H 4.25 N 13.14 Gef. 67.20 4.35 12.98 Ber. Molpeak M+ = 426 Gef. Molpeak M+ = 426Ber. C 67.60 H 4.25 N 13.14 Found 67.20 4.35 12.98 calc. Molpeak M + = 426 Found Molpeak M + = 426
3.7 3-{ (Z) -1- [ (2-Oxo-l, 2-dihydro-chinoxalin-7-yl) amino] -1-phe- nylmethyliden} -2 -indolinon x 0.5 H2O3.7 3- {(Z) -1- [(2-oxo-l, 2-dihydroquinoxalin-7-yl) amino] -1-phenylmethylidene} -2-indolinone x 0.5 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 2.3 Äquivalenten 7-Amino-2-oxo-l , 2-dihydro-chinaxo- lin vom Schmelzpunkt >300°C in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 59 % der Theorie; Schmelzpunkt: 328-331°C; C23H16N4θ2 x 0.5 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 2.3 equivalents of 7-amino-2-oxo-l, 2-dihydro-quinaxo- lin of melting point> 300 ° C in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 59% of theory; Melting point: 328-331 ° C; C 2 3H 16 N 4 θ2 x 0.5 H 2 0
Ber. C 70.93 H 4.40 N 14.39 Gef. 70.91 4.48 14.35 Ber. Molpeak M+ = 380 Gef. Molpeak M+ = 380Ber. C 70.93 H 4.40 N 14.39 Found 70.91 4.48 14.35 Calc. Molpeak M + = 380 Found Molpeak M + = 380
3.8 3- { (Z) -1- [ (Isochinolin-5-yl) amino] -1-phenylmethyliden} - 2 -indolinon x 0.2 H2O3.8 3- {(Z) -1- [(isoquinolin-5-yl) amino] -1-phenylmethylidene} - 2 -indolinone x 0.2 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 3 Äquivalenten 5-Amino-isochinolin in Toluol und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 30 % der Theorie; Schmelzpunkt: 249-250°C; 24H17N3° * °-2 H2°Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 3 equivalents of 5-amino-isoquinoline in toluene and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 30% of theory; Melting point: 249-250 ° C; 24 H 17 N 3 ° * ° - 2 H 2 °
Ber. C 78.53 H 4.78 N 11.45 Gef. 78.75 4.74 11.06 Ber. Molpeak M+ = 363 Gef. Molpeak M+ = 363Ber. C 78.53 H 4.78 N 11.45 Found 78.75 4.74 11.06 calc. Molpeak M + = 363 Found Molpeak M + = 363
.9 3- { (Z) -1- [ (2-Boc-l, 2, 3, 4-tetrahydro-isochinolin-5-yl) amino] -1-phenylmethyliden} -2-indolinon x 0.2 H2O.9 3- {(Z) -1- [(2-Boc-l, 2, 3, 4-tetrahydro-isoquinolin-5-yl) amino] -1-phenylmethylidene} -2-indolinone x 0.2 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 2 Äquivalenten öligem 5-Amino-2-Boc-l,2, 3, 4-tetra- hydro-isochinolin [hergestellt aus 5-Amino-1, 2, 3 , 4-tetrahydro- chinolin-acetat vom Schmelzpunkt 143-145°C] in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 39 % der Theorie; Schmelzpunkt: 229-230°C; C29H29N3O3 x 0.2 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 2 equivalents of oily 5-amino-2-Boc-l, 2, 3, 4-tetra-hydro-isoquinoline [made from 5-amino-1, 2, 3, 4-tetrahydroquinoline acetate of melting point 143-145 ° C] in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 39% of theory; Melting point: 229-230 ° C; C29H29N3O3 x 0.2 H 2 0
Ber.: C 73.85 H 6.28 N 8.91 Gef.: 73.79 6.38 8.64 Ber. : Molpeak M+ = 467 Gef.: Molpeak M+ = 467Calc .: C 73.85 H 6.28 N 8.91 Found: 73.79 6.38 8.64 Ber. : Molpeak M + = 467 Found: Molpeak M + = 467
3.10 3-{ (Z) -1- [4- (lH-Imidazol-2-yl) anilino] -1-phenylmethyli- den} -2 -indolinon x 3 H2O3.10 3- {(Z) -1- [4- (1H-Imidazol-2-yl) anilino] -1-phenylmethylidene} -2-indolinone x 3 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 2 Äquivalenten öligem 4- (1H-Imidazol-2 -yl) -anilin [frisch hergestellt aus der entsprechenden Nitro-Verbindung vom Schmelzpunkt 310°C] in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 29 % der Theorie; Schmelzpunkt: 320°C; 24H18N4O x 3 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 2 equivalents of oily 4- (1H-imidazol-2-yl) aniline [freshly made from the corresponding nitro compound from Melting point 310 ° C] in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 29% of theory; Melting point: 320 ° C; 24H18N4O x 3 H 2 0
Ber. C 66.65 H 5.59 N 12.95 Gef. 66.39 5.24 12.72 Ber. Molpeak M+ = 378 Gef. Molpeak M+ = 378Ber. C 66.65 H 5.59 N 12.95 Found 66.39 5.24 12.72 Calc. Molpeak M + = 378 Found Molpeak M + = 378
3.11 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] -1-phenyl- methyliden} -2 -indolinon x 0.3 H2O3.11 3- {(Z) -1- [4- (l-methyl-1H-imidazol-2-yl) anilino] -1-phenylmethylidene} -2-indolinone x 0.3 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 3.2 Äquivalenten 4- (1-Methyl-IH-imidazol-2-yl) -anilin vom Schmelzpunkt 166-168 °C in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 86 % der Theorie; Schmelzpunkt: 284-286°C; C25H20N4θ x 0.3 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 3.2 equivalents of 4- (1-methyl-IH-imidazol-2-yl) aniline, melting point 166-168 ° C in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 86% of theory; Melting point: 284-286 ° C; C25 H 20 N 4θ x 0.3 H 2 0
Ber. C 75.46 H 5.22 N 14.08 Gef. 75.45 5.13 13.98 Ber. Molpeak M+ = 392 Gef. Molpeak M+ = 392 3.12 3-{ (Z) -1- [4- (1-Methyl-1H-imidazol-2-yl) anilino] -1-phenyl- methyliden} -5-nitro-2-indolinon x H2OBer. C 75.46 H 5.22 N 14.08 Found 75.45 5.13 13.98 Calc. Molpeak M + = 392 Found Molpeak M + = 392 3.12 3- {(Z) -1- [4- (1-Methyl-1H-imidazol-2-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro-2 -indolinon und 1.5 Äquivalenten 4- (1-Methyl-IH-imidazol - 2-yl) -anilin vom Schmelzpunkt 166-168°C in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 85 % der Theorie; Schmelzpunkt: 333-334°C; C25H19N5O3 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 1.5 equivalents of 4- (1-methyl-IH-imidazol-2-yl) aniline, melting point 166 -168 ° C in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 85% of theory; Melting point: 333-334 ° C; C25H19N5O3 H 2 0
Ber. C 65.93 H 4.65 N 15.38 Gef. 66.35 4.66 15.25 Ber. Molpeak M+ = 437 Gef. Molpeak M+ = 437Ber. C 65.93 H 4.65 N 15.38 Found 66.35 4.66 15.25 Calc. Molpeak M + = 437 Found Molpeak M + = 437
3.13 3-{ (Z) -1- [4- (lH-Imidazol-2-yl) anilino] -1-phenylmethyli- den}-5-nitro-2-indolinon x H2O3.13 3- {(Z) -1- [4- (1H-Imidazol-2-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethylϊden} -5-ni- tro-2- indolinon und 1.5 Äquivalenten öligem 4- (1Η-Imidazol- 2-yl) -anilin [frisch hergestellt aus der entsprechenden Nitro- Verbindung vom Schmelzpunkt 310°C] in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 87 % der Theorie; Schmelzpunkt: 195-198°C; C24H17N503 x H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylϊden} -5-nitro-2-indolinone and 1.5 equivalents of oily 4- (1Η-imidazol-2-yl) aniline [freshly prepared from the corresponding Nitro compound with a melting point of 310 ° C] in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 87% of theory; Melting point: 195-198 ° C; C 2 4H 17 N 5 0 3 x H 2 0
Ber. C 65.29 H 4.34 N 15.87 Gef. 65.15 4.53 15.46Ber. C 65.29 H 4.34 N 15.87 Found 65.15 4.53 15.46
Ber. Molpeak M+ = 423 Gef. Molpeak M+ = 423Ber. Molpeak M + = 423 Molpeak M + = 423
3.14 3-{ (Z) -1- [3- (lH-Imidazol-2-yl) anilino] -1-phenylmethyli- den} -2-indolinon x H2O3.14 3- {(Z) -1- [3- (1H-Imidazol-2-yl) anilino] -1-phenylmethylidene} -2-indolinone x H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 2 Äquivalenten rohem 3- (lH-Imidazol-2-yl) -anilin [frisch hergestellt aus der entsprechenden Nitro-Verbindung vom Schmelzpunkt 198°C] in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 40 % der Theorie; Schmelzpunkt: 288°C; C24H18N40 x H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 2 equivalents of crude 3- (1H-imidazol-2-yl) aniline [freshly made from the corresponding nitro compound from Melting point 198 ° C] in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 40% of theory; Melting point: 288 ° C; C 24 H 18 N 4 0 x H 2 0
Ber. C 72.71 H 5.08 N 14.13 Gef. 72.64 5.00 13.82 Ber. Molpeak M+ = 378 Gef. Molpeak M+ = 378Ber. C 72.71 H 5.08 N 14.13 Found 72.64 5.00 13.82 Calc. Molpeak M + = 378 Found Molpeak M + = 378
3.15 3-{ (Z) -1- [3- (lH-Imidazol-2-yl) anilino] -1-phenylmethyli- den} -5-nitro-2-indolinon x 0.5 H2O3.15 3- {(Z) -1- [3- (1H-Imidazol-2-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro-2 -indolinon und 2 Äquivalenten rohem 3- (lH-Imidazol-2-yl) - anilin [frisch hergestellt aus der entsprechenden Nitro-Ver- bindung vom Schmelzpunkt 198°C] in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 50 % der Theorie; Schmelzpunkt: 327-329°C; C24H17N5O3 x 0.5 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 2 equivalents of crude 3- (1H-imidazol-2-yl) aniline [freshly prepared from the corresponding Nitro compound with melting point 198 ° C] in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 50% of theory; Melting point: 327-329 ° C; C24H17N5O3 x 0.5 H 2 0
Ber. C 66.65 H 4.19 N 16.20Ber. C 66.65 H 4.19 N 16.20
Gef. 67.01 4.26 16.20Found 67.01 4.26 16.20
Ber. Molpeak M+ = 423Ber. Molpeak M + = 423
Gef. Molpeak M+ = 423Found Molpeak M + = 423
3.16 3-{ (Z) -1- [3- (1-Methyl- -lH-imidazc methyliden} -2 -indolinon x 0.3 H2O3.16 3- {(Z) -1- [3- (1-Methyl- -IH-imidazc methylidene} -2 -indolinone x 0.3 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon und 2 Äquivalenten rohem 3- (1-Methyl-IH-imidazol -2-yl) - anilin [frisch hergestellt aus der entsprechenden Nitro-Verbin- dung] in DMF und anschließende Behandlung mit IN Natronlauge inMade from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 2 equivalents of crude 3- (1-methyl-IH-imidazol -2-yl) aniline [freshly made from the corresponding Nitro compound] in DMF and subsequent treatment with IN sodium hydroxide solution in
MeOH.MeOH.
Ausbeute: 88 % der Theorie;Yield: 88% of theory;
Schmelzpunkt: 299-300°C; C25H2θN4θ 0.3 H20Melting point: 299-300 ° C; C 2 5 H 2 θ N 4 θ 0.3 H 2 0
Ber. C 75.46 H 5.22 N 14.08Ber. C 75.46 H 5.22 N 14.08
Gef. 75.61 5.24 14.15Found 75.61 5.24 14.15
Ber. Molpeak M+ = 392Ber. Molpeak M + = 392
Gef. Molpeak M+ = 392Found Molpeak M + = 392
3.17 3-{ (Z) -1- [3- (1-Methyl- -IH-imidazc ethyliden} -5-nitro-2-indolinon x 0.3 H2O3.17 3- {(Z) -1- [3- (1-Methyl- -IH-imidazc ethylidene} -5-nitro-2-indolinone x 0.3 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro-2 -indolinon und 2 Äquivalenten rohem 3- (1-Methyl-lH-imida- zol-2-yl) -anilin [frisch hergestellt aus der entsprechenden Ni- tro-Verbindung] in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 81 % der Theorie; Schmelzpunkt: 287-289°C; C25H19N5O3 x 0.3 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 2 equivalents of crude 3- (1-methyl-lH-imidazol-2-yl) aniline [freshly prepared from the corresponding nitro compound] in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 81% of theory; Melting point: 287-289 ° C; C25H 19 N5O 3 x 0.3 H 2 0
Ber. C 67.80 H 4.44 N 15.82Ber. C 67.80 H 4.44 N 15.82
Gef. 67.80 4.46 15.56Found 67.80 4.46 15.56
Ber. Molpeak M+ = 437Ber. Molpeak M + = 437
Gef. Molpeak M+ = 437Found Molpeak M + = 437
3.18 3-{ (Z) -1- [4- ( (Pyrrolidin-l-yl)me thyliden} -5-nitro-2-indolinon3.18 3- {(Z) -1- [4- ((Pyrrolidin-l-yl) methylidene} -5-nitro-2-indolinone
Hergestellt aus 1-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro-2-indolinon und 2 Äquivalenten 4- (1-Pyrrolidinyl-methyl) - anilin vom Schmelzpunkt 45-50°C in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 54 % der Theorie;Made from 1-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 2 equivalents of 4- (1-pyrrolidinyl-methyl) aniline, melting point 45-50 ° C in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 54% of theory;
Schmelzpunkt: 227°C;Melting point: 227 ° C;
C26H 4N4°3C26H 4 N 4 ° 3
Ber. : C 70.89 H 5.49 N 12.72Ber. : C 70.89 H 5.49 N 12.72
Gef. 70.64 5.61 12.67Found 70.64 5.61 12.67
Ber. Molpeak M+ = 440Ber. Molpeak M + = 440
Gef. Molpeak M+ = 440 3____L2. Gemisch aus 3- { (Z) -1- [ (2-Ethyl-l, 2, 3 , 4-tetrahydro-isochi- nolin-6-yl) amino] -1-phenylmethyliden} -5-nitro-2 -indolinon und 3- { (Z) -1- [ (2-Ethyl-l,2,3, -tetrahydro-isochinolin-7-yl) amino] - l-phenylmethyliden}-5-nitro-2-indolinon x 0.3 H2OFound Molpeak M + = 440 3____L2. Mixture of 3- {(Z) -1- [(2-ethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone and 3- {(Z) -1- [(2-ethyl-l, 2,3, -tetrahydro-isoquinolin-7-yl) amino] - l-phenylmethylidene} -5-nitro-2-indolinone x 0.3 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro-2-indolinon, 1.5 Äquivalenten eines Gemisches von 6- und 7-Amino-2-ethyl-l, 2, 3 , 4-tetrahydro-isochinolin x 2 HCl vom Schmelzpunkt 145-150°C und 3 Äquivalenten N-Ethyl-diisopropylamin in DMF und anschließende Behandlung mit IN Natronlauge in MeOH.Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone, 1.5 equivalents of a mixture of 6- and 7-amino-2-ethyl-l, 2, 3, 4-tetrahydro-isoquinoline x 2 HCl with a melting point of 145-150 ° C and 3 equivalents of N-ethyl-diisopropylamine in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH.
Ausbeute: 32 % der Theorie; Schmelzpunkt: 234 -236 °C;Yield: 32% of theory; Melting point: 234-236 ° C;
C26H24N4°3 x °'3 H2°C26 H 24 N 4 ° 3 x ° ' 3 H 2 °
Ber. C 70.02 H 5.56 N 12.57 Gef. 69.84 5.30 12.73 Ber. Molpeak M+ = 440 Gef. Molpeak M+ = 440Ber. C 70.02 H 5.56 N 12.57 Found 69.84 5.30 12.73 calc. Molpeak M + = 440 Found Molpeak M + = 440
.20 Gemisch von 3-{ (Z) -1- [ (2-Ethyl-l, 2, 3 , 4-tetrahydro-isochi- nolin-6-yl) amino] -1-phenylmethyliden} -2 -indolinon und 3-{ (Z) -1- [ (2-Ethyl-l,2,3,4-tetrahydro-isochinolin-7-yl) amino] - 1-phenylmethyliden} -2 -indolinon x 0.4 H2O.20 mixture of 3- {(Z) -1- [(2-ethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1-phenylmethylidene} -2-indolinone and 3 - {(Z) -1- [(2-ethyl-l, 2,3,4-tetrahydro-isoquinolin-7-yl) amino] - 1-phenylmethylidene} -2-indolinone x 0.4 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -2-in- dolinon, 1.5 Äquivalenten eines Gemisches von 6- und 7-Amino- 2-ethyl-1,2, 3, 4 -tetrahydro-isochinolin x 2 HCl vom Schmelzpunkt 145-150 °C und 3 Äquivalenten N-Ethyl-diisopropylamin in DMF und anschließende Behandlung mit IN Natronlauge in MeOH. Ausbeute: 48 % der Theorie; Schmelzpunkt: 222-223°C; C26H25N3° x °-4 H20Made from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -2-indolinone, 1.5 equivalents of a mixture of 6- and 7-amino-2-ethyl-1,2,3,4-tetrahydro- isoquinoline x 2 HCl with a melting point of 145-150 ° C and 3 equivalents of N-ethyl-diisopropylamine in DMF and subsequent treatment with IN sodium hydroxide solution in MeOH. Yield: 48% of theory; Melting point: 222-223 ° C; C26H25 N 3 ° x ° - 4 H 2 0
Ber. C 77.55 H 6.46 N 10.43 Gef. 77.70 6.32 10.29 Ber. Molpeak M+ = 395 Gef. Molpeak M+ = 395 - 49 -Ber. C 77.55 H 6.46 N 10.43 Found 77.70 6.32 10.29 Calc. Molpeak M + = 395 Found Molpeak M + = 395 - 49 -
Bei spiel 4In game 4
3-{ (Z) -1- [ (2-Ethoxycarbonylmethyl-l, 3-dioxo-isoindolin-5-yl) - amino] -1-phenylmethyliden} -2-indolinon x 0.5 H2O3- {(Z) -1- [(2-ethoxycarbonylmethyl-1,3-dioxo-isoindolin-5-yl) amino] -1-phenylmethylidene} -2-indolinone x 0.5 H2O
Man erhitzt 0.80 g (3 mMol) 3- {l-Ethoxy-1-phenylmethyliden} - 2-indolinon und 0.87 g (3.5 mMol) 5-Amino-N-ethoxycarbonylme- thyl-phthalimid vom Schmelzpunkt 172-173 °C in 10 ml DMF je zwei Stunden bei 120°C, bei 140°C und bei 150°C. Man gießt auf Eiswasser und extrahiert mit EtOAc. Die organische Phase wird mit Wasser gewaschen, getrocknet, filtriert und im Vakuum eingedampft . Der halbfeste Eindampfrückstand wird in 15 ml EtOH leicht erwärmt, wobei Kristallisation erfolgt. Das Kristallisat wird filtriert und bei 80°C getrocknet. Ausbeute: 0.39 g (28 % der Theorie); Schmelzpunkt: 263 -266°C; C27H2iN3θ5 x 0.5 H200.80 g (3 mmol) of 3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 0.87 g (3.5 mmol) of 5-amino-N-ethoxycarbonylmethyl-phthalimide, melting at 172-173 ° C. in 10, are heated ml DMF for two hours at 120 ° C, at 140 ° C and at 150 ° C. It is poured onto ice water and extracted with EtOAc. The organic phase is washed with water, dried, filtered and evaporated in vacuo. The semi-solid evaporation residue is warmed slightly in 15 ml EtOH, whereby crystallization takes place. The crystals are filtered and dried at 80 ° C. Yield: 0.39 g (28% of theory); Melting point: 263-266 ° C; C 27 H 2 iN 3 θ5 x 0.5 H 2 0
Ber. C 68.06 H 4.65 N 8.82 Gef. 68.14 4.62 9.13 Ber. Molpeak M+ = 467 Gef. Molpeak M+ = 467Ber. C 68.06 H 4.65 N 8.82 found 68.14 4.62 9.13 calc. Molpeak M + = 467 Found Molpeak M + = 467
Analog Beispiel 4 wurden folgende Verbindungen erhalten:The following compounds were obtained analogously to Example 4:
4.1 3- { (Z) -1- [ (2- (3-Ethoxycarbonyl-propyl) -1, 3-dioxo-isoin- dolin-5-yl) amino] -1-phenylmethyliden} -2-indolinon4.1 3- {(Z) -1- [(2- (3-Ethoxycarbonyl-propyl) -1, 3-dioxo-isoindolin-5-yl) amino] -1-phenylmethylidene} -2-indolinone
Hergestellt aus 3- {l-Ethoxy-l-phenylmethyliden} -2-indolinon undMade from 3- {l-ethoxy-l-phenylmethylidene} -2-indolinone and
1.2 Äquivalenten 5-Amino-N- (3 -ethoxycarbonyl-propyl) -phthalimid vom Schmelzpunkt 78-80°C in DMF durch 8-stündiges Erhitzen auf 140°C und Kristallisation aus EtOH.1.2 equivalents of 5-amino-N- (3-ethoxycarbonyl-propyl) phthalimide with a melting point of 78-80 ° C. in DMF by heating to 140 ° C. for 8 hours and crystallization from EtOH.
Ausbeute: 26 % der Theorie;Yield: 26% of theory;
Schmelzpunkt: 195-197°C;Melting point: 195-197 ° C;
C29H25N304 C29H 25 N 3 0 4
Ber. C 70.29 H 5.08 N 8.48Ber. C 70.29 H 5.08 N 8.48
Gef. 69.98 5.09 8.70Found 69.98 5.09 8.70
Ber. Molpeak M+ = 495 Gef. Molpeak M+ = 495 .2 3-{ (Z) -1- [4- (2-Amino-5-methyl-IH-imidazol-4-yl) anilino] - l-phenylmethyliden}-5-nitro-2-indolinon x 1.5 H2OBer. Molpeak M + = 495 Molpeak M + = 495 .2 3- {(Z) -1- [4- (2-amino-5-methyl-IH-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 1.5 H2O
Hergestellt aus 3- {l-Ethoxy-1-phenylmethyliden} -5-nitro-2-indolinon und 1.3 Äquivalenten 4- (2-Amino-5-methyl-IH-imidazol- 4-yl) anilin [freigesetzt aus 4- (2-Amino-5-methyl-IH-imidazol- 4-yl) anilin x H2S04 x 0.7 H20 vom Schmelzpunkt 312-315°C] in DMF durch 2-stündiges Erhitzen auf 100°C und säulenchromato- graphischer Reinigung an Kieselgel mit dem Eluens Methylenchlo- rid/MeOH/konz . Ammoniak (10:2:0.01). Ausbeute: 8.5 % der Theorie; Schmelzpunkt: 250°C; C25H2θN6θ3 x 1-5 H20Made from 3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 1.3 equivalents of 4- (2-amino-5-methyl-IH-imidazol-4-yl) aniline [released from 4- ( 2-Amino-5-methyl-IH-imidazol-4-yl) aniline x H2S0 4 x 0.7 H 2 0 from melting point 312-315 ° C] in DMF by heating for 2 hours at 100 ° C and column chromatographic purification Silica gel with the eluent methylene chloride / MeOH / conc. Ammonia (10: 2: 0.01). Yield: 8.5% of theory; Melting point: 250 ° C; C25 H 2θN6θ 3 x 1-5 H 2 0
Ber. C 62.62 H 4.83 N 17.53 Gef. 63.05 4.70 17.17 Ber. Molpeak M+ = 452 Gef. Molpeak M+ = 452Ber. C 62.62 H 4.83 N 17.53 Found 63.05 4.70 17.17 calc. Molpeak M + = 452 Found Molpeak M + = 452
4.3 3- { (Z) -1- [ (2-Acetyl-l, 2, 3 , 4-tetrahydro-isochinolin--7-yl) - amino] -1-phenylmethyliden} -2-indolinon x 0.2 H2O4.3 3- {(Z) -1- [(2-acetyl-1,2,3,4-tetrahydro-isoquinoline-7-yl) -amino] -1-phenylmethylidene} -2-indolinone x 0.2 H2O
Hergestellt aus 3- {l-Ethoxy-1-phenylmethyliden} -2 -indolinon und 1.05 Äquivalenten eines öligen Gemisches von 2-Acetyl-6-amino- 1, 2, 3 , 4-tetrahydro-isochinolin und 2 -Acetyl -7 -amino-1, 2 , 3 , -tetrahydro-isochinolin in DMF durch 7-stündiges Erhitzen auf 120°C, Eingießen in Wasser, Extraktion mit EtOAc und Kristallisation aus EtOH. Ausbeute: 24 % der Theorie; Schmelzpunkt: 252-253 °C;Made from 3- {l-ethoxy-1-phenylmethylidene} -2-indolinone and 1.05 equivalents of an oily mixture of 2-acetyl-6-amino-1, 2, 3, 4-tetrahydro-isoquinoline and 2 -acetyl -7 - amino-1, 2, 3, -tetrahydro-isoquinoline in DMF by heating at 120 ° C. for 7 hours, pouring into water, extraction with EtOAc and crystallization from EtOH. Yield: 24% of theory; Melting point: 252-253 ° C;
DC-Rf = 0.29 [Kieselgel; Methylenchlorid/MeOH/konz . Ammoniak (9:1:0.1)] ; C26H23N3°2 x 0.2 H20TLC Rf = 0.29 [silica gel; Methylene chloride / MeOH / conc. Ammonia (9: 1: 0.1)]; C 26 H 23 N 3 ° 2 x 0.2 H 2 0
Ber. C 75.59 H 5.71 N 10.17 Gef. 75.79 5.58 10.18 Ber. Molpeak M+ = 409 Gef. Molpeak M+ = 409 4.4 Gemisch aus 3- { (Z) -1- [ (2-Acetyl-l, 2, 3, 4-tetrahydro-isochi- nolin-6-yl) amino] -1-phenylmethyliden} -5-nitro-2-indolinon (ca. 40%) undBer. C 75.59 H 5.71 N 10.17 Found. 75.79 5.58 10.18 Calc. Molpeak M + = 409 Molpeak M + = 409 4.4 Mixture of 3- {(Z) -1- [(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1-phenylmethylidene} -5-nitro-2- indolinone (approx. 40%) and
3- { (Z) -1- [ (2-Acetyl-1, 2, 3 , 4 -tetrahydro-isochinolin-7-yl) amino] ■ l-phenylmethyliden}-5-nitro-2-indolinon (ca. 60%)3- {(Z) -1- [(2-acetyl-1, 2, 3, 4 -tetrahydro-isoquinolin-7-yl) amino] ■ l-phenylmethylidene} -5-nitro-2-indolinone (approx. 60 %)
Hergestellt aus 3- {l-Ethoxy-1-phenylmethyliden} -5-nitro-2-in- dolinon und 1.15 Äquivalenten eines öligen Gemisches von 2-Ac- etyl-6-amino-l, 2, 3, 4-tetrahydro-isochinolin und 2 -Acetyl-7-amino-1, 2 , 3 , 4 -tetrahydro-isochinolin in DMF durch 2.5-stündiges Erhitzen auf 100°C, Eingießen in Wasser, Extraktion mit EtOAc und Verrühren des Eindampfrückstandes mit EtOH. Ausbeute: 80 % der Theorie; Schmelzpunkt: 271-274°C;Made from 3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 1.15 equivalents of an oily mixture of 2-acetyl-6-amino-l, 2, 3, 4-tetrahydro- Isoquinoline and 2-acetyl-7-amino-1, 2, 3, 4 -tetrahydro-isoquinoline in DMF by heating to 100 ° C for 2.5 hours, pouring into water, extracting with EtOAc and stirring the evaporation residue with EtOH. Yield: 80% of theory; Melting point: 271-274 ° C;
DC-Rf = 0.34 und 0.29 [Kieselgel; Methylenchlorid/MeOH/konz . Ammoniak (9:1:0.1)] ;TLC Rf = 0.34 and 0.29 [silica gel; Methylene chloride / MeOH / conc. Ammonia (9: 1: 0.1)];
C26H22N4°4C 26 H22 N 4 ° 4
Ber.: C 68 . 69 H 4.88 N 12.32Calculated: C 68. 69 H 4.88 N 12.32
Gef.: 68.38 5.07 12.21Found: 68.38 5.07 12.21
4.5 3-{ (Z) -1- [4- (2-Amino-lH-thiazol-4-yl) anilino] -1-phenyl- methyliden}-5-nitro-2-indolinon x 0.8 Thioharnstoff4.5 3- {(Z) -1- [4- (2-Amino-1H-thiazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.8 thiourea
(a) 3-Αrrnnn-4- (4 -amino-phpnyl - t.hi37.nl(a) 3-Αrrnnn-4- (4 -amino-phpnyl - t.hi37.nl
Hergestellt durch 2-stündige Hydrierung von 2-Amino-4- (4-nitro- phenyl) -thiazol (Schmelzpunkt: 287-291°C; hergestellt aus τσ- Brom-4-nitro-acetophenon und Thioharnstoff) in DMF an Palladium/Kohle (10%) bei 20°C. Ausbeute (roh) : 100% der Theorie; Schmelzpunkt: 120°C.Prepared by hydrogenating 2-amino-4- (4-nitrophenyl) thiazole (melting point: 287-291 ° C; made from τσ-bromo-4-nitro-acetophenone and thiourea) in DMF on palladium / Coal (10%) at 20 ° C. Yield (raw): 100% of theory; Melting point: 120 ° C.
(b) 3- { (Z) -1- [4- (2-Amino-lH-thiazol-4-yl) anilino] -l-phenylme- t-byl ir~gπ}-ς-r f-rr>-?--inr!n1 i on x 0.8 Thi ohπrnstoff(b) 3- {(Z) -1- [4- (2-Amino-lH-thiazol-4-yl) anilino] -l-phenylmet-t-byl ir ~ g π } -ς-r f-rr > -? - inr! n1 i on x 0.8 thi oxygen
Hergestellt aus 3- {l-Ethoxy-1-phenylmethyliden} -5-nitro-2-in- dolinon und 2 Äquivalenten des unter (a) erhaltenen Anilin- Derivates in DMF durch 1-stündiges Erhitzen auf 110°C, Eingießen in Wasser und Waschen des Niederschlages mit MeOH und Ether. Ausbeute: 87 % der Theorie; Schmelzpunkt: 270°C; C24H17N503S x 0.8 H2N-CS-NH2 Made from 3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 2 equivalents of the aniline derivative obtained in (a) in DMF by heating at 110 ° C for 1 hour, pouring into water and washing the precipitate with MeOH and ether. Yield: 87% of theory; Melting point: 270 ° C; C 24 H 17 N 5 0 3 S x 0.8 H 2 N-CS-NH 2
Ber. C 57.68 H 3.94 N 17.91 Gef. 57.24 3.72 17.82 Ber. Molpeak M+ = 455 Gef. Molpeak M+ = 455Ber. C 57.68 H 3.94 N 17.91 Found 57.24 3.72 17.82 Calc. Molpeak M + = 455 Found Molpeak M + = 455
.6 3- { (Z) -1- [4- ( (Imidazol-1-yl) methyl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon.6 3- {(Z) -1- [4- ((imidazol-1-yl) methyl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 3- {l-Ethoxy-1-phenylmethyliden} -5-nitro-2-in- dolinon und 1.5 Äquivalenten 4- (Imidazol -1-yl) ethyl -anilin (Schmelzpunkt: 128-130°C) in DMF (120°C, 1 Stunde), Eingießen in Wasser und Waschen des Niederschlages mit MeOH und Ether. Ausbeute: 90 % der Theorie; Schmelzpunkt: 355 °C; C25H1 N5O3Made from 3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 1.5 equivalents of 4- (imidazol -1-yl) ethyl aniline (melting point: 128-130 ° C) in DMF ( 120 ° C, 1 hour), pouring into water and washing the precipitate with MeOH and ether. Yield: 90% of theory; Melting point: 355 ° C; C25H1 N5O3
Ber. C 68.64 H 4.38 N 16.01 Gef. 68.35 4.51 15.92 Ber. Molpeak M+ = 437 Gef. Molpeak M+ = 437Ber. C 68.64 H 4.38 N 16.01 Found 68.35 4.51 15.92 calc. Molpeak M + = 437 Found Molpeak M + = 437
.7 Gemisch von 3- { (Z) -1- [4- ( (2-Oxo-pyrrolidin-l-yl) methyl) - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon x 0.5 H2O (-80%) und.7 mixture of 3- {(Z) -1- [4- ((2-oxopyrrolidin-l-yl) methyl) - anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H2O ( -80%) and
3- { (Z) -1- [3- ( (2-Oxo-pyrrolidin-l-yl) methyl) anilino] -1-phe- nylmethyliden}-5-nitro-2-indolinon x 0.5 H2O (-20%)3- {(Z) -1- [3- ((2-Oxopyrrolidin-l-yl) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H2O (-20% )
(a) Gemisch aus N- (4-Nitro-benzyl) -2-pyrrolidinon (-80%) und
Figure imgf000054_0001
(a) Mixture of N- (4-nitro-benzyl) -2-pyrrolidinone (-80%) and
Figure imgf000054_0001
Hergestellt analog Beispiel D durch Reaktion von N-Benzyl- 2-pyrrolidinon mit Ammoniumnitrat in konzentrierter Schwefelsäure und abschließende Kristallisation aus Petrolether/- Ether .Prepared analogously to Example D by reaction of N-benzyl-2-pyrrolidinone with ammonium nitrate in concentrated sulfuric acid and subsequent crystallization from petroleum ether / ether.
Ausbeute: 68 % der Theorie; Schmelzpunkt: 55-75°C. (b) Gemisch aus 4- (2-Oxo-pyrrolidin-l-yl)methyl-anilin (-80%) u d 3- (2-Oxo-pyrroli -in-l -yl •.methyl -aπϊ 1 i (- 0 ^Yield: 68% of theory; Melting point: 55-75 ° C. (b) mixture of 4- (2-oxo-pyrrolidin-l-yl) methyl-aniline (-80%) ud 3- (2-oxo-pyrroli -in-l -yl • .methyl -aπϊ 1 i (- 0 ^
Hergestellt durch Hydrierung des unter (a) erhaltenen Gemisches der Nitro-Verbindungen an Rhodium/Kohle (5%) in EtOH/- Methylenchlorid (1:1) (20°C, 3.5 bar, 3 Stunden). Ausbeute: 71 % der Theorie; Schmelzpunkt: 110-115°C.Prepared by hydrogenation of the mixture of the nitro compounds on rhodium / carbon (5%) obtained in (a) in EtOH / methylene chloride (1: 1) (20 ° C., 3.5 bar, 3 hours). Yield: 71% of theory; Melting point: 110-115 ° C.
(c) Gemisch von 3- { (Z) -1- [4- ( (2-0xo-pyrrolidin-l-yl) methyl) - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon x 0.5 H2O (-80%) und(c) Mixture of 3- {(Z) -1- [4- ((2-0xo-pyrrolidin-l-yl) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H2O (-80%) and
(Z) -1- [3- ( (2-Oxo-pyrrolidin-l-yl) methyl) anilino] -1-phenylme- thyl JrJP>n}-5-n ro-?-inr1n1 innn y 0.5 H2° (~20*ϊ(Z) -1- [3- ((2-Oxopyrrolidin-l-yl) methyl) anilino] -1-phenylmethyl JrJP> n} -5-n ro -? - inr1n1 innn y 0.5 H 2 ° (~ 20 * ϊ
Hergestellt aus 3- {l-Ethoxy-1-phenylmethyliden} -5-nitro-2-in- dolinon und 1.5 Äquivalenten des unter (b) erhaltenen Gemisches der Anilin-Verbindungen in DMF (110°C, 2 Stunden) , Zugabe vonPrepared from 3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 1.5 equivalents of the mixture of the aniline compounds obtained in (b) in DMF (110 ° C., 2 hours), addition of
Wasser und Waschen des Niederschlages mit Isopropanol undWater and washing the precipitate with isopropanol and
Ether.Ether.
Ausbeute: 85 % der Theorie;Yield: 85% of theory;
Schmelzpunkt: 300-303°C;Melting point: 300-303 ° C;
C26H22 4O4 x 0.5 H20C26H22 4O4 x 0.5 H 2 0
Ber. C 67.37 H 5.00 N 12.09 Gef. 67.23 5.06 N 12.49 Ber. Molpeak M+ = 454 Gef. Molpeak M+ = 454Ber. C 67.37 H 5.00 N 12.09 Found 67.23 5.06 N 12.49 Calc. Molpeak M + = 454 Found Molpeak M + = 454
4.8 3-{ (Z) -1- [ (2-Boc-1,2, 3, 4-tetrahydro-isochinolin-6-yl) amino- 1-phenylmethyliden} -5-nitro-2-indolinon4.8 3- {(Z) -1- [(2-Boc-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino-1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 3-{l-Ethoxy-l-phenylmethyliden} -5-nitro-2-in- dolinon und 1.1 Äquivalenten eines öligen Gemisches von 2-Boc- 6-amino-l, 2, 3 , 4-tetrahydro-isochinolin [hergestellt aus 6-Ami- no-isochinolin vom Schmelzpunkt 218-220°C durch katalytische Hydrierung zum 6-Amino-l, 2 , 3 , 4-tetrahydro-isochinolin (Schmelzpunkt: 69-71°C) und anschließende Umsetzung mit 0.9 Äquivalenten Pyrokohlensäure-di-tert .butylester (=(Boc)2θ)] in DMF durch 3.5-stündiges Erhitzen auf 100°C, Eingießen in Wasser, Abfiltrieren und Waschen des Niederschlages mit Wasser und EtOH. Ausbeute: 82 % der Theorie; Schmelzpunkt: 258 -259°C; C29H28N4θ5Made from 3- {l-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone and 1.1 equivalents of an oily mixture of 2-Boc-6-amino-l, 2, 3, 4-tetrahydro-isoquinoline [ prepared from 6-amino-isoquinoline with a melting point of 218-220 ° C by catalytic hydrogenation to 6-amino-1, 2, 3, 4-tetrahydro-isoquinoline (melting point: 69-71 ° C) and subsequent reaction with 0.9 equivalents Pyrocarbonate di-tert. Butyl ester (= (Boc) 2θ)] in DMF Heating at 100 ° C for 3.5 hours, pouring into water, filtering off and washing the precipitate with water and EtOH. Yield: 82% of theory; Melting point: 258-259 ° C; C 29 H2 8 N 4 θ5
Ber. C 67.96 H 5.51 N 10.93 Gef. 68.07 5.46 N 10.96 Ber. Molpeak M+ = 512 Gef. Molpeak M+ = 512Ber. C 67.96 H 5.51 N 10.93 Found 68.07 5.46 N 10.96 Calc. Molpeak M + = 512 Found Molpeak M + = 512
4___9_ 3-{ (Z) -1- [4- (2- (Pyrrolidin-1-yl) ethyl) anilino] -1-phenyl- methyliden} -5-nitro-2-indolinon x 0.5 H204___9_ 3- {(Z) -1- [4- (2- (Pyrrolidin-1-yl) ethyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H 2 0
Hergestellt aus 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2 -indolinon und 2 Äquivalenten 4- (2- (1-Pyrrolidinyl) ethyl-anilin [Öl; hergestellt aus 2- [4-Nitro-phenyl) ethylbromid vom Schmelzpunkt 68-70°C durch Umsetzung mit Pyrrolidin und anschließende katalytische Hydrierung des öligen 1- [2- (4-Nitrophenyl) ethyl] - pyrrolidins] in DMF (2 Stunden, 100°C) Eingießen in Wasser, Abfiltrieren des- Niederschlages und Waschen mit Wasser, EtOH und Ether.Made from 3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone and 2 equivalents of 4- (2- (1-pyrrolidinyl) ethyl-aniline [oil; made from 2- [4-nitro-phenyl ) ethyl bromide of melting point 68-70 ° C by reaction with pyrrolidine and subsequent catalytic hydrogenation of the oily 1- [2- (4-nitrophenyl) ethyl] - pyrrolidine] in DMF (2 hours, 100 ° C), pouring into water, filtering off the - Precipitation and washing with water, EtOH and ether.
Ausbeute: 80 % der Theorie; Schmelzpunkt: 227-230°C; C27H26N403 x 0.5 H20Yield: 80% of theory; Melting point: 227-230 ° C; C 27 H 26 N 4 0 3 x 0.5 H 2 0
Ber. C 69.96 H 5.87 N 12.09 Gef. 70.18 5.90 N 12.55 Ber. Molpeak M+ = 454 Gef. Molpeak M+ = 454Ber. C 69.96 H 5.87 N 12.09 Found 70.18 5.90 N 12.55 calc. Molpeak M + = 454 Found Molpeak M + = 454
4.10 3-{ (Z) -1- [ (2-Methyl-4,4-dimethyl-l,3-dioxo-l,2,3,4-tetra- hydro-isochinolin-7-yl) amino] -l-phenylmethyliden}-5-nitro- 2-indolinon4.10 3- {(Z) -1- [(2-methyl-4,4-dimethyl-l, 3-dioxo-l, 2,3,4-tetra-hydro-isoquinolin-7-yl) amino] -l -phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2-in- dolinon und 1.5 Äquivalenten von 2-Methyl-7-amino-4, 4-dimethyl- 1, 3 -dioxo-1, 2, 3, 4-tetrahydro-isochinolin vom Schmelzpunkt 169-171°C in DMF durch 1-stündiges Erhitzen auf 120°C, Ein- gießen in Wasser, Abfiltrieren und Waschen des Niederschlages mit MeOH und Ether. Ausbeute: 76 % der Theorie; Schmelzpunkt: 306-310°C;Made from 3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone and 1.5 equivalents of 2-methyl-7-amino-4, 4-dimethyl-1, 3-dioxo-1, 2 , 3, 4-tetrahydro-isoquinoline from melting point 169-171 ° C in DMF by heating at 120 ° C for 1 hour, pour into water, filter and wash the precipitate with MeOH and ether. Yield: 76% of theory; Melting point: 306-310 ° C;
C27H22N4θ5C 2 7 H 22 N 4θ5
Ber.: C 67.21 H 4.60 N 11.61Calc .: C 67.21 H 4.60 N 11.61
Gef. : 66.83 4.62 N 11.51Found: 66.83 4.62 N 11.51
Ber. : Molpeak M+ = 482Ber. : Molpeak M + = 482
Gef.: Molpeak M+ = 482Found: Molpeak M + = 482
4.11 3- { (Z) -1- [4- ( (2, 5-Dioxo-pyrrolidin-l-yl) methyl) anilino] - 1-phenylmethyliden} -5-nitro-2 -indolinon4.11 3- {(Z) -1- [4- ((2,5-Dioxopyrrolidin-l-yl) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 3- (1-Ethoxy-l-phenylmethyliden) -2 -indolinon und 1.3 Äquivalenten rohem 4- (2, 5-Dioxo-pyrrolidin-1-yl) methyl) - anilin [Öl; frisch hergestellt aus der entsprechenden Nitro- Verbindung] in DMF (120°C; 1,5 Stunden) Eingießen in Wasser, Abfiltrieren und Waschen des Niederschlages mit MeOH und Ether. Ausbeute: 79 % der Theorie;Made from 3- (1-ethoxy-l-phenylmethylidene) -2-indolinone and 1.3 equivalents of crude 4- (2, 5-dioxopyrrolidin-1-yl) methyl) aniline [oil; freshly prepared from the corresponding nitro compound] in DMF (120 ° C; 1.5 hours), pouring into water, filtering off and washing the precipitate with MeOH and ether. Yield: 79% of theory;
Schmel zpunkt : 260 -265°C;Melting point: 260-265 ° C;
C26H20N4θ5C26 H 20 N 4θ5
Ber. : C 66.66 H 4.30 N 14.96Ber. : C 66.66 H 4.30 N 14.96
Gef . : 66.27 4.37 N 11.80Gef. : 66.27 4.37 N 11.80
Ber. : Molpeak M+ = 468Ber. : Molpeak M + = 468
Gef. : Molpeak M+ = 468Found: Molpeak M + = 468
4.1 2 3- -{{Z)-l-[4- ( (1 -Methyl -2, 4-dioxc den) methyl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon x H204.1 2 3- - {{Z) -l- [4- ((1-Methyl -2, 4-dioxc den) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x H 2 0
Hergestellt aus 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2-in- dolinon und 3 Äquivalenten rohem (E/Z) -4-Amino-benzyliden- (1-methyl-hydantoin [frisch hergestellt aus der entsprechenden Nitro-Verbindung (Schmelzpunkt: 210-220°C; E/Z-Gemisch) durch katalytische Hydrierung an Raney-Nickel in EtOH/Cl2Cl2 (1:1)] in DMF (120°C, 1.5 Stunden), Eingießen in Wasser, Filtrieren und Waschen des Niederschlags mit MeOH und Ether. Ausbeute: 53 % der Theorie;Made from 3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone and 3 equivalents of crude (E / Z) -4-amino-benzylidene (1-methyl-hydantoin [freshly made from the Corresponding nitro compound (melting point: 210-220 ° C; E / Z mixture) by catalytic hydrogenation on Raney nickel in EtOH / Cl 2 Cl 2 (1: 1)] in DMF (120 ° C, 1.5 hours), Pour in water, filter and wash the precipitate with MeOH and ether. Yield: 53% of theory;
Schmelzpunkt: 390°C;Melting point: 390 ° C;
DC-Rf = 0.58 und 0.52 (Kieselgel; EtOAc)DC-Rf = 0.58 and 0.52 (silica gel; EtOAc)
C 6H19N5θ5 x H20C 6 H 19 N 5θ 5 x H 2 0
Ber. : C 62.52 H 4.24 N 14.02Ber. : C 62.52 H 4.24 N 14.02
Gef. 62.22 4.25 N 13.66Found 62.22 4.25 N 13.66
Ber. Molpeak M+ = 481Ber. Molpeak M + = 481
Gef.. Molpeak M+ = 481Found. Molpeak M + = 481
4.13 3-{ (Z) -1- [4- (1,2,4-Triazol-l-yl) methyliden} -5-nitro-2-indolinon4.13 3- {(Z) -1- [4- (1,2,4-Triazol-l-yl) methylidene} -5-nitro-2-indolinone
Hergestellt aus 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2-in- dolinon und 3 Äquivalenten rohem 4- [ (1, 2, 4-Triazol-l-yl)me- thyl] -anilin [frisch hergestellt aus der entsprechenden Nitro-Verbindung (Schmelzpunkt: 100-103°C) durch katalytische Hydrierung an Raney-Nickel in EtOH] in DMF (120 °C, 2 Stunden) , Eingießen in Wasser, Filtrieren und Waschen des Niederschlags mit Isopropanol und Ether. Ausbeute: 84 % der Theorie; Schmelzpunkt: 289-294°C; C24Hι8N603 Made from 3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone and 3 equivalents of crude 4- [(1, 2, 4-triazol-l-yl) methyl] aniline [ freshly prepared from the corresponding nitro compound (melting point: 100-103 ° C) by catalytic hydrogenation on Raney nickel in EtOH] in DMF (120 ° C, 2 hours), pouring into water, filtering and washing the precipitate with isopropanol and Ether. Yield: 84% of theory; Melting point: 289-294 ° C; C 2 4Hι 8 N 6 0 3
Ber. : Molpeak M+ = 438 Gef.: Molpeak M+ = 438Ber. : Molpeak M + = 438 Found: Molpeak M + = 438
4.14 3-{ (Z) -1- [4- (2-Butyl-lH-imidazol-4-yl) anilino] -l-phenyl- methyliden} -5-nitro-2-indolinon4.14 3- {(Z) -1- [4- (2-Butyl-1H-imidazol-4-yl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 4- (2-Butyl-lH-imidazol-4-yl) anilin und 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2 -indolinon in DMF. Ausbeute: 58 % der Theorie; Schmelzpunkt: 175-180°C; 28H25N5°3Made from 4- (2-butyl-lH-imidazol-4-yl) aniline and 3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone in DMF. Yield: 58% of theory; Melting point: 175-180 ° C; 28 H 25 N 5 ° 3
Ber. : Molpeak M+ = 479Ber. : Molpeak M + = 479
Gef.: Molpeak M+ = 479 C28H25N5°3 X 0.3 H20 (484.94) Ber.: C 69.34 H 5.32 N 14.44 Gef.: 69.60 5.52 13.94 4.15 3-{(Z)-l-[4- (2-Pentyl-lH-imidazol-4-yl) anilino] -1-phenyl- methyliden} -5-nitro-2-indolinonFound: Molpeak M + = 479 C 28 H 25 N 5 ° 3 X 0.3 H 2 0 (484.94) Calc .: C 69.34 H 5.32 N 14.44 Found: 69.60 5.52 13.94 4.15 3 - {(Z) -l- [4- (2-Pentyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 4- (2-Pentyl-IH-imidazol-4-yl) anilin undMade from 4- (2-pentyl-IH-imidazol-4-yl) aniline and
3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2 -indolinon in DMF.3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone in DMF.
Ausbeute: 50 % der Theorie;Yield: 50% of theory;
Schmelzpunkt: 170-175°C; 29H27 5O3 (493.57)Melting point: 170-175 ° C; 29H27 5O3 (493.57)
Ber..- Molpeak M+ = 493Calculation ..- Molpeak M + = 493
Gef.: Molpeak M+ = 493Found: Molpeak M + = 493
C29H27N5θ3 X 0.3 H20 (498.96)C 2 9H 27 N 5 θ3 X 0.3 H 2 0 (498.96)
Ber.: C 69.80 H 5.58 N 14.04Calc .: C 69.80 H 5.58 N 14.04
Gef.: 69.75 5.98 13.80Found: 69.75 5.98 13.80
4.16 3- { (Z) -1- [4- (2-Cyclohexyl-lH-imidazol-4-yl) anilino] -1-phe- nylmethyliden} -5-nitro-2-indolinon4.16 3- {(Z) -1- [4- (2-Cyclohexyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 4- (2-Cyclohexyl-iH-imidazol-4-yl) anilin undMade from 4- (2-cyclohexyl-iH-imidazol-4-yl) aniline and
3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2-indolinon in DMF.3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone in DMF.
Ausbeute: 90 % der Theorie;Yield: 90% of theory;
Schmelzpunkt: 290-295°C;Melting point: 290-295 ° C;
C3oH27N5θ3 (505.58)C 3 oH2 7 N 5 θ3 (505.58)
Ber.: Molpeak (M+H) + = 506Calc .: Molpeak (M + H) + = 506
Gef.: Molpeak (M+H) + = 506Found: Molpeak (M + H) + = 506
C29H27N5θ3 X 1.0 DMF (578.7)C29H 27 N 5 θ3 X 1.0 DMF (578.7)
Ber.: C 68.50 H 5.92 N 14.52Calc .: C 68.50 H 5.92 N 14.52
Gef.: 68.50 4.29 14.52Found: 68.50 4.29 14.52
4.17 3-{ (Z) -1- [4- (2-Phenyl-IH-imidazol-4-yl) anilino] -1-phenyl- methyliden} -5-nitro-2-indolinon4.17 3- {(Z) -1- [4- (2-Phenyl-IH-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 4- (2-Phenyl-lH-imidazol-4-yl) anilin und 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2-indolinon in DMF. Ausbeute: 98 % der Theorie; Schmelzpunkt: 230-235°C; C3θH21 N5θ3 99.53)Made from 4- (2-phenyl-lH-imidazol-4-yl) aniline and 3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone in DMF. Yield: 98% of theory; Melting point: 230-235 ° C; C3 θ H2 1 N 5θ 3 99.53)
Ber. : Molpeak M+ = 499Ber. : Molpeak M + = 499
Gef.: Molpeak M+ = 499 30 H 21 N5°3 X 1-0 H20 (517.53) Found: Molpeak M + = 499 30 H 21 N 5 ° 3 X 1-0 H 2 0 (517.53 )
Ber.: C 69.62 H 4.48 N 13.53Calc .: C 69.62 H 4.48 N 13.53
Gef. : 69.26 4.85 14.43Found: 69.26 4.85 14.43
4.18 3-{(Z)-l-[4- (2-Phenylmethyl-IH-imidazol-4-yl) anilino] - 1-phenylmethyliden} -5-nitro-2-indolinon4.18 3 - {(Z) -l- [4- (2-Phenylmethyl-IH-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 4- (2-Phenylmethyl-IH-imidazol-4-yl) anilin undMade from 4- (2-phenylmethyl-IH-imidazol-4-yl) aniline and
3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2-indolinon in DMF.3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone in DMF.
Ausbeute: 38 % der Theorie;Yield: 38% of theory;
Schmelzpunkt: 2Q0-205°C;Melting point: 2Q0-205 ° C;
C3lH23 N5θ3 (513.56)C 3l H 23 N 5θ 3 (513.56)
Ber.: Molpeak (M+H) + = 514Calc .: Molpeak (M + H) + = 514
Gef.: Molpeak (M+H)+ = 514Found: Molpeak (M + H) + = 514
DC-Rf = 0.6 (Kieselgel; Methylenchlorid/Methanol 10:1)TLC Rf = 0.6 (silica gel; methylene chloride / methanol 10: 1)
4.19 3- { (Z) -1- [4- (2, 5-Dihydro-pyrrol-l-yl-methyl) anilino] - 1-phenylmethyliden} -5-nitro-2-indolinon4.19 3- {(Z) -1- [4- (2,5-dihydro-pyrrol-1-yl-methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 4- (2, 5-Dihydro-pyrrol-l-yl-methyl) anilin und 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2-indolinon in DMF. Ausbeute: 41 % der Theorie; Schmelzpunkt: 205-207°C; C26H22N4O3 38.49) Made from 4- (2, 5-dihydro-pyrrol-l-yl-methyl) aniline and 3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone in DMF. Yield: 41% of theory; Melting point: 205-207 ° C; C2 6 H22N4O 3 38.49 )
Ber. Molpeak M+ = 438Ber. Molpeak M + = 438
Gef. Molpeak M+ = 438Found Molpeak M + = 438
Ber. C 71.22 H 5.06 N 12.78Ber. C 71.22 H 5.06 N 12.78
Gef. 70.62 5.26 12.52Found 70.62 5.26 12.52
4.20 3-{ (Z) -1- [4- (3-Hydroxyr jyrrolidir4.20 3- {(Z) -1- [4- (3-Hydroxyr jyrrolidir
1-phenylmethyliden}-5-nitro-2-indolinon1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 4- (3 -Hydroxypyrrolidin-1-yl-methyl) anilin und 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2-indolinon in DMF. Ausbeute: 34 % der Theorie; Schmelzpunkt: 120-125°C; C26 24N4°4 ( 56.51) Ber. : Molpeak M+ = 456 Gef.: Molpeak M+ = 456 26H24N4°4 H2° (474.52)Made from 4- (3-hydroxypyrrolidin-1-yl-methyl) aniline and 3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone in DMF. Yield: 34% of theory; Melting point: 120-125 ° C; C 26 24 N 4 ° 4 ( 56.51 ) calc. : Molpeak M + = 456 Found: Molpeak M + = 456 26 H 24 N 4 ° 4 H 2 ° ( 4 74.52)
Ber.: C 65.81 H 5.52 N 11.81Calc .: C 65.81 H 5.52 N 11.81
Gef.: 66.16 5.61 11.59Found: 66.16 5.61 11.59
4.21 3-{ (Z) -1- [4- (2-Methoxycarbonyl-pyrrolidin-1-yl-methyl) - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon4.21 3- {(Z) -1- [4- (2-methoxycarbonylpyrrolidin-1-ylmethyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 4- ( -Methoxycarbonyl-pyrrolidin-1-yl-methyl) - anilin und 3- (1-Ethoxy-l-phenylmethyliden) -5-nitro-2 -indolinon in DMF.Made from 4- (-Methoxycarbonyl-pyrrolidin-1-yl-methyl) aniline and 3- (1-Ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone in DMF.
Ausbeute: 49 % der Theorie;Yield: 49% of theory;
Schmelzpunkt: 189-191°C; c28H26N4-θ5 ( 98.54) Melting point: 189-191 ° C; c 28 H 26 N 4-θ5 ( 98.54 )
Ber. : Molpeak M+ = 498Ber. : Molpeak M + = 498
Gef. : Molpeak M" = 498Found: Molpeak M " = 498
Ber.: C 67.46 H 5.26 N 11.24Calc .: C 67.46 H 5.26 N 11.24
Gef. : 67.39 5.35 11.13Found: 67.39 5.35 11.13
. 2 3-{ (Z) -1- [4- ( (2-Hydroxycarbonyl)pyrrolidin-l-yl-methyl) - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon. 2 3- {(Z) -1- [4- ((2-Hydroxycarbonyl) pyrrolidin-1-ylmethyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
Eine Lösung von 299 mg (0.60 mMol) 4- [ (2-Methoxycarbonyl) pyrro- lidin-1-yl-methyl] anilin und 1.2 ml IN Natronlauge in 10 ml Methanol wird 13 Stunden bei 60°C gerührt. Danach wird das Lösungsmittel im Vakuum entfernt. Der Rückstand wird in Wasser aufgenommen und einmal mit Essigester gewaschen. Dann wird 1.2 ml IN Salzsäure zugesetzt und 2 Stunden bei Raumtemperatur gerührt. Der Niederschlag wird abgesaugt und im Vakuum getrocknet.A solution of 299 mg (0.60 mmol) of 4- [(2-methoxycarbonyl) pyrrolidin-1-yl-methyl] aniline and 1.2 ml of 1N sodium hydroxide solution in 10 ml of methanol is stirred at 60 ° C. for 13 hours. The solvent is then removed in vacuo. The residue is taken up in water and washed once with ethyl acetate. Then 1.2 ml IN hydrochloric acid is added and the mixture is stirred for 2 hours at room temperature. The precipitate is filtered off and dried in vacuo.
Ausbeute: 72 % der Theorie; Schmelzpunkt: 265-266°C; C27H2 N405 (484.52)Yield: 72% of theory; Melting point: 265-266 ° C; C 27 H 2 N 4 0 5 (484.52)
Ber.: Molpeak (M+Na) + = 507Calc .: Molpeak (M + Na) + = 507
Gef.: Molpeak (M+Na) + = 507Found: Molpeak (M + Na) + = 507
C27H24N4°5 x H2° (502.53) C 27 H 24 N 4 ° 5 x H 2 ° ( 502.53)
Ber.: C 64.53 H 5.21 N 11.15Calc .: C 64.53 H 5.21 N 11.15
Gef.: 64.23 5.53 11.15Found: 64.23 5.53 11.15
Bei πp l 5.At πp l 5.
3- { (Z) -1- [3- (1H-Imidazol-4-yl) anilino] -1-phenylmethyliden}- 2-indolinon x 0.5 H2O3- {(Z) -1- [3- (1H-Imidazol-4-yl) anilino] -1-phenylmethylidene} - 2-indolinone x 0.5 H2O
Man erhitzt 1.02 g von 60%igem l-Acetyl-3- {l-ethoxy-l-phenyl- methyliden} -2-indolinon (2.2 mMol), 0.70 g (3.0 mMol) 3-(lH- Imidazol-4-yl) -anilin x 2 HCl (Schmelzpunkt: 296°C) und 0.91 ml (6.5 mMol) Triethylamin in 8 ml DMF 2 Stunden bei 100°C. Nach Abkühlen auf Raumtemperatur versetzt man mit 1.0 ml (10 mMol) Piperidin und rührt über Nacht. Man gießt auf Wasser. Der ausgefallene Niederschlag wird durch Säulenchromatographie an Kieselgel mit dem Eluens Methylenchlorid/MeOH (20:1) gereinigt. Ausbeute: 0.67 g (89 % der Theorie); Schmelzpunkt: 215-218°C (aus Ether); C24H18N40 x 0.5 H201.02 g of 60% l-acetyl-3- {l-ethoxy-l-phenylmethylidene} -2-indolinone (2.2 mmol), 0.70 g (3.0 mmol) of 3- (1H-imidazol-4-yl) are heated ) -aniline x 2 HCl (melting point: 296 ° C) and 0.91 ml (6.5 mmol) triethylamine in 8 ml DMF for 2 hours at 100 ° C. After cooling to room temperature, 1.0 ml (10 mmol) of piperidine are added and the mixture is stirred overnight. You pour on water. The precipitate is purified by column chromatography on silica gel using the eluent methylene chloride / MeOH (20: 1). Yield: 0.67 g (89% of theory); Melting point: 215-218 ° C (from ether); C 24 H 18 N 4 0 x 0.5 H 2 0
Ber. C 74 . 40 H 4 . 94 N 14 . 46 Gef. 74 . 18 H 5 . 35 14 . 02 Ber. Molpeak M+ = 378 Gef. Molpeak M+ - 378Ber. C 74. 40 H 4. 94 N 14. 46 found 74. 18 H 5. 35 14. 02 Ber. Molpeak M + = 378 Molpeak M + - 378
Analog Beispiel 5 wurden folgende Verbindungen erhalten:The following compounds were obtained analogously to Example 5:
5 ■ 1 3- { (Z) -1- [2- (1H-Imidazol-4-yl) anilino] -1-phenylmethyliden} - 5-nitro-2-indolinon x 0.3 H2O5 ■ 1 3- {(Z) -1- [2- (1H-Imidazol-4-yl) anilino] -1-phenylmethylidene} - 5-nitro-2-indolinone x 0.3 H2O
Hergestellt aus l-Acetyl-3- {l-ethoxy-l-phenylmethyliden}-5-ni- tro-2-indolinon und 1.5 Äquivalenten 2- (lH-Imidazol-4-yl) -anilin (Öl) in DMF (2 Stunden bei 100°C) , anschließende Behandlung mit Piperidin und säulenchromatographische Reinigung an AI2O3 (Aktivitätsstufe II-II) mit dem Eluens Methylenchlorid/EtOHMade from l-acetyl-3- {l-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone and 1.5 equivalents of 2- (lH-imidazol-4-yl) aniline (oil) in DMF (2nd Hours at 100 ° C), subsequent treatment with piperidine and column chromatographic purification on AI2O3 (Activity level II-II) with the eluent methylene chloride / EtOH
(20:1) .(20: 1).
Ausbeute: 24.6 % der Theorie; Schmelzpunkt: 240-245°C; C24H17 5O3 x 0.3 H20Yield: 24.6% of theory; Melting point: 240-245 ° C; C24H17 5O3 x 0.3 H 2 0
Ber. C 67.21 H 4.14 N 16.33 Gef. 67.26 4.33 15.92 Ber. Molpeak M+ = 423 Gef. Molpeak M+ = 423Ber. C 67.21 H 4.14 N 16.33 Found 67.26 4.33 15.92 calc. Molpeak M + = 423 Molpeak M + = 423
5.2 3- { (Z) -1- [4- (2-Amino-lH-imidazol-4-yl) anilino] -1-phenylme- thyliden}-5-nitro-2-indolinon x 0.7 H20 x 0.7 EtOH5.2 3- {(Z) -1- [4- (2-Amino-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.7 H 2 0 x 0.7 EtOH
Hergestellt aus l-Acetyl-3- {l-ethoxy-1-phenylmethyliden} -5-ni- tro- 2 -indolinon und 1.0 Äquivalent rohem 4- (2-Amino-lH-imida- zol-4-yl) -anilin [frisch hergestellt aus 2-Amino-4- (4-nitro- phenyl) -IH-imidazol] in DMF (2 Stunden bei 100°C) , anschließende Behandlung mit Piperidin und säulenchromatographische Reinigung an AI2O3 (Aktivitätsstufe II -II) . Ausbeute: 29.3 % der Theorie; Schmelzpunkt: 220-225°C; 24 H 18 N 6°3 x 0.7 H20 x 0.7 EtOHMade from l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 1.0 equivalent of crude 4- (2-amino-lH-imidazol-4-yl) aniline [freshly prepared from 2-amino-4- (4-nitro-phenyl) -IH-imidazole] in DMF (2 hours at 100 ° C), subsequent treatment with piperidine and column chromatographic purification on AI2O 3 (activity level II -II). Yield: 29.3% of theory; Melting point: 220-225 ° C; 2 4 H 18 N 6 ° 3 x 0.7 H 2 0 x 0.7 EtOH
Ber. C 63.12 H 4.92 N 17.39 Gef. 63.19 4.96 17.03 Ber. Molpeak M+ = 438 Gef. Molpeak M+ = 438Ber. C 63.12 H 4.92 N 17.39 Found 63.19 4.96 17.03 Ber. Molpeak M + = 438 Found Molpeak M + = 438
5 - 3 Gemisch von 3- { (Z) -1- [4- ( (l-Boc-imidazolin-2-yl) methyl) - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon (75 %)und 3-{ (Z) -1- [3- ( (1-Boc-imidazolin-2-yl) methyl) anilino] -1-phe- nylmethyliden}-5-nitro-2-indolinon (25 %)5 - 3 mixture of 3- {(Z) -1- [4- ((l-Boc-imidazolin-2-yl) methyl) - anilino] -1-phenylmethylidene} -5-nitro-2-indolinone (75% ) and 3- {(Z) -1- [3- ((1-Boc-imidazolin-2-yl) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone (25%)
Hergestellt aus l-Acetyl-3- (1-ethoxy-l-phenylmethyliden) -5-ni- tro-2 -indolinon und 1.5 Äquivalenten eines rohen Gemisches von 4- [ (l-Boc-imidazolin-2-yl) methyl] anilin und 3- [ (1-Boc-imidazo- lin-2-yl) methyl] anilin [hergestellt aus 2 -Benzyl -imidazolin x hydrochlorid durch Umsetzung mit Ammoniumnitrat in konzentrierter Schwefelsäure, Acylierung des erhaltenen (70 : 30) -Gemisches von 2- (4-Nitrobenzyl) - und 2- (3-Nitro-benzyl) -imidazolin mit Pyrokohlensäure-di-tert .butylester und anschließende kataly- tische Hydrierung] in DMF (120°C, 1 Stunde) , Behandlung mit Piperidin und abschließende säulenchromatographische Reinigung an Kieselgel mit Toluol/EtOAc/EtOH (4:2:1) als Eluens. Ausbeute: 56 % der Theorie; Schmelzpunkt: 200°C;Made from l-acetyl-3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone and 1.5 equivalents of a crude mixture of 4- [(l-Boc-imidazolin-2-yl) methyl] aniline and 3- [(1-Boc-imidazoline-2-yl) methyl] aniline [prepared from 2-benzylimidazoline x hydrochloride by reaction with ammonium nitrate in concentrated sulfuric acid, acylation of the (70:30) mixture obtained of 2- (4-nitrobenzyl) - and 2- (3-nitro-benzyl) imidazoline with pyrocarbonate di-tert. butyl ester and subsequent catalytic hydrogenation] in DMF (120 ° C., 1 hour), treatment with piperidine and final purification by column chromatography on silica gel with toluene / EtOAc / EtOH (4: 2: 1) as the eluent. Yield: 56% of theory; Melting point: 200 ° C;
C30H29N5O5 C 30H29N5 O 5
Ber..- C 66.02 H 5.54 N 13.27Calc ..- C 66.02 H 5.54 N 13.27
Gef. : 66.44 5.38 12.91Found: 66.44 5.38 12.91
Ber. : Molpeak M+ = 539Ber. : Molpeak M + = 539
Gef. : Molpeak M+ = 539Found: Molpeak M + = 539
Beispiel _£Example _ £
3-{ (Z) -1- [4- ( (2, -Dioxo-imidazolidin-5-yl) methyl) anilino] - 1-phenylmethyliden} -5-nitro-2-indolinon x 0.3 H20 (I) und 3- { (Z) -1- [4- ( (2 , 4-Dioxo-imidazolidin-5-yliden) methyl) anilino] - 1-phenylmethyliden}-5-nitro-2-indolinon x H20 (II)3- {(Z) -1- [4- ((2, -Dioxo-imidazolidin-5-yl) methyl) anilino] - 1-phenylmethylidene} -5-nitro-2-indolinone x 0.3 H 2 0 (I) and 3- {(Z) -1- [4- ((2,4-dioxo-imidazolidin-5-ylidene) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x H 2 0 (II )
(a) 4-Amino-benzyliden-hydantoin (A) und 4-Amino-benzyl-hydan- oin (n ) (a) 4-amino-benzylidene-hydantoin (A) and 4-amino-benzyl-hydanoin ( n )
Rohes 4-Nitro-benzyliden-hydantoin vom Schmelzpunkt 310°CCrude 4-nitro-benzylidene hydantoin with a melting point of 310 ° C
(hergestellt durch 8-stündiges Erhitzen von 4-Nitro-benzaldehyd mit Hydantoin in Eisessig in Gegenwart von Natriumacetat auf 155°C unter Rückfluß) wird in DMF an Palladium/Kohle (10%) bei 20°C und 3.5 bar hydriert. Man erhält nach Eindampfen im Vakuum und Digerieren mit CH2Cl2/MeOH (7:1) ein Produkt vom Schmelzpunkt 185-190°C, das laut DC (Kieselgel; CH2Cl2/MeOH (5:1)) und MS aus (A) (Rf » 0.60; M+ = 203), viel (B) (Rf = 0.52; M+ = 205) und einer unbekannten dritten Substanz (C) (Rf = 0.39) besteht .(prepared by heating 8-nitro-benzaldehyde with hydantoin in glacial acetic acid in the presence of sodium acetate at 155 ° C. under reflux for 8 hours) is hydrogenated in DMF over palladium / carbon (10%) at 20 ° C. and 3.5 bar. After evaporation in vacuo and digesting with CH 2 Cl 2 / MeOH (7: 1), a product of melting point 185-190 ° C. is obtained which, according to TLC (silica gel; CH 2 Cl 2 / MeOH (5: 1)) and MS consists of (A) (Rf »0.60; M + = 203), much (B) (Rf = 0.52; M + = 205) and an unknown third substance (C) (Rf = 0.39).
(b) m und (TTΪ(b) m and (TTΪ
Man erhitzt 0.70 g (2 mMol) l-Acetyl-3- { 1-ethoxy-l-phenylme- thyliden}-5-nitro-2-indolinon und 0.61 g (~3 mMol) des unter (a) erhaltenen Produktes vom Schmelzpunkt 185-190°C in 6 ml DMF 1 Stunde bei 120°C. Nach Abkühlen auf 20°C versetzt man mit 1 ml Piperidin und rührt 1 Stunde . Man gibt Wasser und festes Natriumchlorid zu, filtriert vom ausgefallenen Niederschlag ab und reinigt diesen durch Säulenchromatographie an Kieselgel mit dem Eluens CH2Cl2/MeOH (10:1).0.70 g (2 mmol) of l-acetyl-3- {1-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 0.61 g (~ 3 mmol) of the product obtained under (a), of melting point, are heated 185-190 ° C in 6 ml DMF 1 hour at 120 ° C. After cooling to 20 ° C., 1 ml of piperidine is added and the mixture is stirred for 1 hour. Water and solid sodium chloride are added, the precipitate which has separated out is filtered off and this is purified by column chromatography on silica gel using the eluent CH 2 Cl 2 / MeOH (10: 1).
Zuerst wird (I) eluiert (Rf = 0.68) :First (I) is eluted (Rf = 0.68):
3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yl) methyl) anilino] - 1 -phenylmethyl iden}- -ni tro-2- indol non x 0.3 H2Q (T)3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-yl) methyl) anilino] -1-phenylmethylidene} - -niotro-2-indole non x 0.3 H 2 Q (T)
Ausbeute: 0.105 g (11.2 % der Theorie); Schmelzpunkt: 310-315 °C; C25H19N5θ5 x 0.3 H20Yield: 0.105 g (11.2% of theory); Melting point: 310-315 ° C; C 25 H 19 N5θ5 x 0.3 H 2 0
Ber. C 63.23 H 4.16 N 14.75 Gef. 63.18 4.26 14.72 Ber. Molpeak M+ = 469 Gef. Molpeak M+ = 469Ber. C 63.23 H 4.16 N 14.75 Found 63.18 4.26 14.72 Calc. Molpeak M + = 469 Found Molpeak M + = 469
Danach wird (II) eluiert (Rf = 0.55) :Then (II) is eluted (Rf = 0.55):
3- { (Z) -1- [4- ( (2,4-Dioxo-imidazolidin-5-yliden)methyl) anilino]3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino]
1 -phenylmethyl iden}- -ni ro-2-indol inon x H2Q (TT)1 -phenylmethyl iden} - -ni ro-2-indole inon x H 2 Q (TT)
Ausbeute: 0.045 g (4.8 % der Theorie); Schmelzpunkt: 280-285°C; 25H17N5°5 x H2° Ber. C 61.85 H 3.94 N 14.43Yield: 0.045 g (4.8% of theory); Melting point: 280-285 ° C; 25 H 17 N 5 ° 5 x H 2 ° calc. C 61.85 H 3.94 N 14.43
Gef. 61.56 4.16 14.32Found 61.56 4.16 14.32
Ber. Molpeak M+ = 467Ber. Molpeak M + = 467
Gef. Molpeak M+ = 467Found Molpeak M + = 467
Beispiel 7Example 7
3-{ (Z) -1- [4- ( (2, 4 -Dioxo-imidazolidin-5-yliden) methyl) anilino] - l-phenylmethyliden}-5-nitro-2-indolinon x 0.2 H2O3- {(Z) -1- [4- ((2,4 -Dioxo-imidazolidin-5-ylidene) methyl) anilino] - l-phenylmethylidene} -5-nitro-2-indolinone x 0.2 H2O
(a) 4-Amino-benτ:y1 i den-hydπntni n (Al(a) 4-Amino-benτ: y1 i den-hydπntni n (Al
Zu 3 g (12.9 mMol) rohem 4-Nitro-benzyliden-hydantoin vom Schmelzpunkt 300°C (hergestellt wie im Beispiel 6 unter (a) beschrieben) in 50 ml 80%iger Essigsäure gibt man bei 100 °C 3 g Eisenpulver. Nach 30 Minuten filtriert man über Kieselgur und dampft das Filtrat im Vakuum ein. Der Eindampfrückstand wird zwischen EtOAc und verdünnter wäßriger Ammoniak-Lösung verteilt; vor Trennung der Phasen filtriert man nochmals über Kieselgur. Die organische Phase wird mit Wasser gewaschen, getrocknet, filtriert und im Vakuum eingedampft. Der erhaltene gelbe Schaum (0.80 g; 30.6% der Theorie) enthält laut DC (Kieselgel; Toluol/EtOAc/EtOH (4:2:1)) ganz überwiegend 4-Amino- benzyliden-hydantoin (A) (Rf = 0.55), jedoch kein 4-Amino-ben- zyl-hydantoin (B) (Rf = 0.48).3 g at 100 ° C. are added to 3 g (12.9 mmol) of crude 4-nitro-benzylidene hydantoin having a melting point of 300 ° C. (prepared as described in Example 6 under (a)) in 50 ml of 80% acetic acid Iron powder. After 30 minutes, filter through kieselguhr and evaporate the filtrate in vacuo. The evaporation residue is distributed between EtOAc and dilute aqueous ammonia solution; before separating the phases, filter again through diatomaceous earth. The organic phase is washed with water, dried, filtered and evaporated in vacuo. The yellow foam obtained (0.80 g; 30.6% of theory) contains, according to TLC (silica gel; toluene / EtOAc / EtOH (4: 2: 1)), predominantly 4-aminobenzylidene hydantoin (A) (Rf = 0.55), however, no 4-amino-benzyl-hydantoin (B) (Rf = 0.48).
(b) 3-{ (Z) -1- [4- ( (2,4-Dioxo-imidazolidin-5-yliden)methyl) anilino] -1 -phenylmethyliden} - -nitro- 2-indo non x 0.2 H2Ω(b) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1 -phenylmethylidene} - nitro-2-indo non x 0.2 H 2 Ω
Man erhitzt 0.92 g (2.6 mMol) l-Acetyl-3- {l-ethoxy-1-phenylme- thyliden}-5-nitro-2-indolinon und 0.80 g (3.9 mMol) des unter0.92 g (2.6 mmol) of l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone and 0.80 g (3.9 mmol) of the under are heated
(a) erhaltenen 4-Amino-benzyliden-hydantoins in 8 ml DMF 2 Stunden bei 120°C. Nach Abkühlen auf 20 °C versetzt man mit 1 ml Piperidin und rührt 1 Stunde. Der ausgefallene gelbe Niederschlag wird abfiltriert, mit MeOH und Ether gewaschen und bei 80°C getrocknet.(a) 4-Amino-benzylidene hydantoins obtained in 8 ml of DMF at 120 ° C. for 2 hours. After cooling to 20 ° C., 1 ml of piperidine is added and the mixture is stirred for 1 hour. The precipitated yellow precipitate is filtered off, washed with MeOH and ether and dried at 80 ° C.
Ausbeute: 0.54 g (44.3 % der Theorie); Schmelzpunkt: 370°C;Yield: 0.54 g (44.3% of theory); Melting point: 370 ° C;
DC-Rf = 0.52 (Kieselgel; Methylenchlorid/ Methanol (10:1)) C25H17 5O5 x 0.2 H20TLC Rf = 0.52 (silica gel; methylene chloride / methanol (10: 1)) C25H17 5O5 x 0.2 H 2 0
Ber C 63.69 H 3.72 N 14.86 Gef 63.70 4.05 14.69 Ber Molpeak M+ = 467 Gef Molpeak M+ = 467Ber C 63.69 H 3.72 N 14.86 Gef 63.70 4.05 14.69 Ber Molpeak M + = 467 Gef Molpeak M + = 467
Analog Beispiel 7 wurde erhalten:The following was obtained analogously to Example 7:
3-{ (Z) -1- [3- ( (2, 4-Dioxo-imidazolidin-5-yliden) ethyl) anilino] - 1-phenylmethyliden}-5-nitro-2 -indolinon x 0.25 H203- {(Z) -1- [3- ((2,4-Dioxo-imidazolidin-5-ylidene) ethyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.25 H 2 0
(a) 3-Αm no-ben7:y1 i den-hydantoin—[Al(a) 3-Αm no-ben7: y1 i den-hydantoin— [Al
Man hydriert 2.3 g (10 mMol) rohes 3-Nitro-benzyliden-hydantoin vom Schmelzpunkt 280-284 °C (hergestellt wie im Beispiel 6 unter (a) beschrieben) in 60 ml DMF und 40 ml EtOH an 2 g Raney- Nickel 36 Stunden bei 20°C und 3.5 bar. Man filtriert über Kieselgur und dampft das Filtrat im Vakuum ein. Der Eindampf- rückstand wird mit Ether kristallisiert.2.3 g (10 mmol) of crude 3-nitro-benzylidene-hydantoin with a melting point of 280-284 ° C. (prepared as in Example 6 under) are hydrogenated (a) described) in 60 ml DMF and 40 ml EtOH over 2 g Raney nickel for 36 hours at 20 ° C and 3.5 bar. It is filtered through diatomaceous earth and the filtrate is evaporated in vacuo. The evaporation residue is crystallized with ether.
Ausbeute: 1.5 g (74 % der Theorie); Schmelzpunkt: 225-230°C.Yield: 1.5 g (74% of theory); Melting point: 225-230 ° C.
(b) 3-{(Z)-l-[3-( (2,4-Dioxo-imidazolidin-5-yliden)methyl)ani-(b) 3 - {(Z) -l- [3- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) ani-
1 inol -1 -phenylmethyl i den|-5-ni ro-2- indol i on x 0.2 N2n1 inol -1 -phenylmethyl i den | -5-ni ro-2-indol i on x 0.2 N 2 n
Hergestellt aus 3- (l-Ethoxy-l-phenylmethyliden}-5-nitro-2-in- dolinon und 1 Äquivalent des unter (a) erhaltenen 3-Amino- benzyliden-hydantoins in DMF (1 Stunde, 120°C) . Nach Abkühlen im Eisbad versetzt man mit Wasser, filtriert vom Niederschlag ab und wäscht ihn mit Wasser, MeOH und Ether.Prepared from 3- (l-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone and 1 equivalent of the 3-aminobenzylidene hydantoin obtained under (a) in DMF (1 hour, 120 ° C). After cooling in an ice bath, water is added, the precipitate is filtered off and washed with water, MeOH and ether.
Ausbeute: 80 % der Theorie; Schmelzpunkt: 361°C; C25H17N5°5 x 0-25 H2°Yield: 80% of theory; Melting point: 361 ° C; C 25 H 17 N 5 ° 5 x 0- 25 H 2 °
Ber. : C 63.62 H 3.74 N 14.84Ber. : C 63.62 H 3.74 N 14.84
Gef. : 63.62 3.78 14.86Found: 63.62 3.78 14.86
Ber. : Molpeak M+ = 467Ber. : Molpeak M + = 467
Gef. : Molpeak M+ = 467Found: Molpeak M + = 467
R^i s l _aR ^ i s l _a
3- { (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -1-phenylmethy- liden} -2-indolinon x H2O3- {(Z) -1- [4- (1-Methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone x H2O
(a) 4- 4-N-i tro-phenyl ) - idazol(a) 4- 4-N-i-trophenyl) idazole
Hergestellt durch Nitrierung von 4 -Phenyl-imidazol in konzentrierter Schwefelsäure mit Ammoniumnitrat analog Beispiel DManufactured by nitrating 4-phenyl-imidazole in concentrated sulfuric acid with ammonium nitrate analogously to Example D.
(64 % der Theorie; Schmelzpunkt: 220°C) oder durch Erhitzen von τσ-Brom-acetophenon in Formamid (160°C, 2.5 Stunden) (53 % der Theorie; Schmelzpunkt: 220-222°C) . (b) 1 -Methyl -4- (4-nit.rn-phenyl) -imidazol(64% of theory; melting point: 220 ° C) or by heating τσ-bromo-acetophenone in formamide (160 ° C, 2.5 hours) (53% of theory; melting point: 220-222 ° C). (b) 1-Methyl -4- (4-nit.rn-phenyl) imidazole
Hergestellt durch Umsetzung von 4- (4-Nitro-phenyl) -imidazol inManufactured by converting 4- (4-nitro-phenyl) imidazole into
DMSO mit Kalium-tert .butylat bei 0°C und dann mit Methyljodid bei 20-25°C.DMSO with potassium tert-butoxide at 0 ° C and then with methyl iodide at 20-25 ° C.
Ausbeute : 76 % der Theorie ;Yield: 76% of theory;
Schmelzpunkt : 176 - 178 °C .Melting point: 176 - 178 ° C.
( c) 4 - ( 4 -Amino-phenyl ) - 1 -methyl - i midazo](c) 4 - (4-Amino-phenyl) -1-methyl-i midazo]
Hergestellt durch Hydrierung von l-Methyl -4 - (4 -nitro-phenyl ) - imidazol in MeOH an Palladium/Kohle (10 %) bei 20 ° C undManufactured by hydrogenation of l-methyl -4 - (4 -nitro-phenyl) - imidazole in MeOH on palladium / carbon (10%) at 20 ° C and
3 . 5 bar .3rd 5 bar.
Ausbeute: 93 % der Theorie;Yield: 93% of theory;
Schmelzpunkt: 167-170°C.Melting point: 167-170 ° C.
(d) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -1-phenyl- methyl iden} -2-indol non x H20(d) 3- {(Z) -1- [4- (l-methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indole non x H 2 0
Hergestellt durch Umsetzung von l-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -2-indolinon mit 1.5 Äquivalenten 4- (4-Amino-phe- nyl) -1-methyl-imidazol in DMF (120°C, 2 Stunden) , anschließende Behandlung mit 3 Äquivalenten von IN Natronlauge in MeOH (20°C, 1 Stunde) und Ausfällen mit Wasser. Ausbeute: 81 % der Theorie; Schmelzpunkt: 275-278°C; C25H20N4O x H20Prepared by reacting l-acetyl-3- {1-ethoxy-l-phenyl-methylidene} -2-indolinone with 1.5 equivalents of 4- (4-amino-phenyl) -1-methyl-imidazole in DMF (120 ° C, 2 hours), subsequent treatment with 3 equivalents of IN sodium hydroxide solution in MeOH (20 ° C., 1 hour) and precipitation with water. Yield: 81% of theory; Melting point: 275-278 ° C; C 25 H 20 N 4 O x H 2 0
Ber. C 73.15 H 5.40 N 13.65 Gef. 73.55 5.42 13.75 Ber. Molpeak M+ = 392 Gef. Molpeak M+ = 392Ber. C 73.15 H 5.40 N 13.65 Found 73.55 5.42 13.75 Calc. Molpeak M + = 392 Found Molpeak M + = 392
Analog Beispiel 8 wurden folgende Verbindungen erhalten:The following compounds were obtained analogously to Example 8:
8.1 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -1-phe- nylmethyliden} -5-nitro-2-indolinon x 0.5 H208.1 3- {(Z) -1- [4- (l-methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H 2 0
Hergestellt durch Umsetzung von l-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.5 Äquivalenten 4- ( -Ami- no-phenyl) - 1 -methyl -imidazol in DMF und anschließende Behandlung mit Natronlauge in MeOH . Ausbeute : 92 % der Theorie ; Schmelzpunkt : 302 -305 °C ; 25H19N5°3 x ° - 5 H20Prepared by reacting l-acetyl-3- {1-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.5 equivalents of 4- (-ami- no-phenyl) - 1-methyl-imidazole in DMF and subsequent treatment with sodium hydroxide solution in MeOH. Yield: 92% of theory; Melting point: 302-305 ° C; 25 H 19 N 5 ° 3 x ° - 5 H 2 0
Ber. C 67.26 H 4.52 N 15.69 Gef. 67.41 4.47 15.78 Ber. Molpeak M+ = 437 Gef. Molpeak M+ = 437Ber. C 67.26 H 4.52 N 15.69 Found 67.41 4.47 15.78 Calc. Molpeak M + = 437 Found Molpeak M + = 437
8.2 3- { (Z) -1- [4- (Imidazo [1, 2-a] pyrimidin-2-yl) anilino] -1-phe- nylmethyliden} -5-nitro-2-indolinon x H208.2 3- {(Z) -1- [4- (imidazo [1, 2-a] pyrimidin-2-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x H 2 0
Hergestellt durch Umsetzung von 1-Acetyl-3- { l-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.3 Äquivalenten 4- (Imidazo [1, 2-a] pyrimidin-2-yl) -anilin x HBr (Schmelzpunkt: 240-250°C) und 1.7 Äquivalenten Triethylamin in DMF und anschließende Behandlung mit Natronlauge in MeOH. Ausbeute: 91 % der Theorie; Schmelzpunkt: 350-354°C; C27H18N603 x H20Prepared by reacting 1-acetyl-3- {l-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.3 equivalents of 4- (imidazo [1, 2-a] pyrimidin-2-yl) - aniline x HBr (melting point: 240-250 ° C) and 1.7 equivalents of triethylamine in DMF and subsequent treatment with sodium hydroxide solution in MeOH. Yield: 91% of theory; Melting point: 350-354 ° C; C 27 H 18 N 6 0 3 x H 2 0
Ber. C 65.85 H 4.09 N 17.06 Gef. 66.08 3.81 17.06 Ber. Molpeak M+ = 474 Gef. Molpeak M+ = 474Ber. C 65.85 H 4.09 N 17.06 Found 66.08 3.81 17.06 Calc. Molpeak M + = 474 Found Molpeak M + = 474
8.3 3-{ (Z) -1- [4- (Imidazo [1, 2-a] pyrimidin-2-yl) anilino] -1-phe- nylmethyliden} -2 -indolinon x 0.5 H 08.3 3- {(Z) -1- [4- (imidazo [1, 2-a] pyrimidin-2-yl) anilino] -1-phenylmethylidene} -2-indolinone x 0.5 H 0
Hergestellt durch Umsetzung von l-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -2-indolinon mit 1.3 Äquivalenten 4- (Imidazo [1, 2-a] pyrimidin-2-yl) -anilin x HBr (Schmelzpunkt: 245-250°C) und 1.7 Äquivalenten Triethylamin in DMF und anschließende Behandlung mit Natronlauge in MeOH. Ausbeute: 58 % der Theorie; Schmelzpunkt: 300-302 °C; C27H19N5° x 0.5 H20Prepared by reacting l-acetyl-3- {1-ethoxy-l-phenylmethylidene} -2-indolinone with 1.3 equivalents of 4- (imidazo [1, 2-a] pyrimidin-2-yl) aniline x HBr ( Melting point: 245-250 ° C) and 1.7 equivalents of triethylamine in DMF and subsequent treatment with sodium hydroxide solution in MeOH. Yield: 58% of theory; Melting point: 300-302 ° C; C 27 H 19 N 5 ° x 0.5 H 2 0
Ber. : C 73.96 H 4.60 N 15.97Ber. : C 73.96 H 4.60 N 15.97
Gef. : 74.27 4.64 15.72Found: 74.27 4.64 15.72
Ber. : Molpeak M+ = 429Ber. : Molpeak M + = 429
Gef. : Molpeak M+ = 429Found: Molpeak M + = 429
Beispiel _aExample _a
3- { (Z) -1- [4- (5-Methyl-IH-imidazol-4-yl) anilino] -1-phenylmethy- liden} -2 -indolinon x 0.25 H203- {(Z) -1- [4- (5-Methyl-IH-imidazol-4-yl) anilino] -1-phenylmethylidene} -2 -indolinone x 0.25 H 2 0
(a) 5 -Methyl -4- (4-ni tτ-o-pheny1 ) -imidazol(a) 5-Methyl -4- (4-ni tτ-o-pheny1) imidazole
Hergestellt durch Nitrierung von 5-Methyl-4 -phenyl-imidazol (Schmelzpunkt: 185-188°C) in konzentrierter Schwefelsäure mit Ammoniumnitrat analog Beispiel D. Ausbeute: 78 % der Theorie; Schmelzpunkt: 206-210°C.Prepared by nitration of 5-methyl-4-phenyl-imidazole (melting point: 185-188 ° C.) in concentrated sulfuric acid with ammonium nitrate analogously to Example D. Yield: 78% of theory; Melting point: 206-210 ° C.
(b) 4- (4-Αmi o-phenyl ) - -methyl -imi daτ:o1(b) 4- (4-Αmi o-phenyl) - -methyl -imi daτ: o1
Hergestellt durch Hydrierung von 5-Methyl-4- (4-nitro-phenyl) - imidazol in MeOH an Palladium/Kohle (10%) bei 20°C und 3.5 bar. Ausbeute (roh) : 100 % der Theorie; Schmelzpunkt: 195-198°C.Manufactured by hydrogenation of 5-methyl-4- (4-nitro-phenyl) imidazole in MeOH on palladium / carbon (10%) at 20 ° C and 3.5 bar. Yield (raw): 100% of theory; Melting point: 195-198 ° C.
(c) 3-{ (Z) -1- [4- (5-Methyl-lH-imidazol-4-yl) anilino] -1-phenyl- methyliden} -2-indolinon x 0.25 H2Q(c) 3- {(Z) -1- [4- (5-Methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone x 0.25 H2Q
Hergestellt durch Umsetzung von l-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -2 -indolinon mit 1.5 Äquivalenten 4- (4-Amino-phe- nyl) -5-methyl-imidazol in DMF (100°C, 2 Stunden), anschließende Behandlung mit 6.7 Äquivalenten Piperidin (20°C, 0.5 Stunden) und Ausfällen mit Wasser.Prepared by reacting l-acetyl-3- {1-ethoxy-l-phenyl-methylidene} -2-indolinone with 1.5 equivalents of 4- (4-amino-phenyl) -5-methyl-imidazole in DMF (100 ° C, 2 hours), subsequent treatment with 6.7 equivalents of piperidine (20 ° C, 0.5 hours) and precipitation with water.
Ausbeute: 77 % der Theorie;Yield: 77% of theory;
Schmelzpunkt: 300-305°C;Melting point: 300-305 ° C;
C25H20N4° x 0.25 H20 C 25 H 20 N 4 ° x 0.25 H 2 0
Ber.: C 75.64 H 5.20 N 14.11Calc .: C 75.64 H 5.20 N 14.11
Gef. : 75.81 5.27 14.04 Ber. : Molpeak M+ = 392 Gef.: Molpeak M+ = 392Found: 75.81 5.27 April 14 Ber. : Molpeak M + = 392 Found: Molpeak M + = 392
Analog Beispiel 9 wurden folgende Verbindungen erhalten:The following compounds were obtained analogously to Example 9:
9-1 3-{ (Z) -1- [4- (5-Methyl-lH-imidazol-4-yl) anilino] -1-phenyl- methyliden} -5-nitro-2-indolinon x 0.5 H209-1 3- {(Z) -1- [4- (5-Methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H 2 0
Hergestellt durch Umsetzung von 1-Acetyl-3 -{ l-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.5 Äquivalenten 4-(4-Ami- no-phenyl) -5-methyl-imidazol in DMF und anschließende Behandlung mit 6.7 Äquivalenten Piperidin. Ausbeute: 88 % der Theorie; Schmelzpunkt: 340-345°C; C25H19N5θ3 x 0.5 H20Prepared by reacting 1-acetyl-3 - {l-ethoxy-l-phenyl-methylidene} -5-nitro-2-indolinone with 1.5 equivalents of 4- (4-amino-phenyl) -5-methyl-imidazole in DMF and subsequent treatment with 6.7 equivalents of piperidine. Yield: 88% of theory; Melting point: 340-345 ° C; C 25 H 19 N 5 θ3 x 0.5 H 2 0
Ber. C 67.25 H 4.52 N 15.69 Gef. 67.29 4.46 15.81 Ber. Molpeak M+ = 437 Gef. Molpeak M+ = 437Ber. C 67.25 H 4.52 N 15.69 Found 67.29 4.46 15.81 calc. Molpeak M + = 437 Found Molpeak M + = 437
9-2 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -1-phenyl- methyliden} -5 -nitro-2-indolinon x H209-2 3- {(Z) -1- [4- (2-Methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x H 2 0
(a) -Methyl -4- (4 -ni ro-phenyl ) -imidazol(a) -Methyl -4- (4-ni ro-phenyl) imidazole
Hergestellt durch Nitrierung von 2 -Methyl-4 -phenyl-imidazol (Schmelzpunkt: 154-156°C)) in konzentrierter Schwefelsäure mit Ammoniumnitrat analog Beispiel D. Ausbeute: 34 % der Theorie; Schmelzpunkt: 216-219°C.Prepared by nitration of 2-methyl-4-phenyl-imidazole (melting point: 154-156 ° C)) in concentrated sulfuric acid with ammonium nitrate analogously to Example D. Yield: 34% of theory; Melting point: 216-219 ° C.
(b) 4 - (4 - Ami nn-phenyl ) - -methyl - i mi Ha ol(b) 4 - (4 - Amino-phenyl) - -methyl - i mi Ha ol
Hergestellt durch Hydrierung von 2 -Methyl-4- (4 -nitro-phenyl) - imidazol in MeOH an Palladium/Kohle (10 %) bei 20°C undManufactured by hydrogenation of 2-methyl-4- (4-nitro-phenyl) imidazole in MeOH on palladium / carbon (10%) at 20 ° C and
3.5 bar.3.5 bar.
Ausbeute (roh, Schaum) : 100 % der Theorie; (c) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -1-phenyl- met-hyl iden} -5-ni tro-2-i ndol inon x H20Yield (raw, foam): 100% of theory; (c) 3- {(Z) -1- [4- (2-Methyl-1H-imidazol-4-yl) anilino] -1-phenyl-methyl-iden} -5-nitro-2-indol inon x H 2 0
Hergestellt durch Umsetzung von 1-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.5 Äquivalenten 4- (4-Ami- no-phenyl) -2-methyl-imidazol in DMF (100°C, 0.5 Stunden), anschließende Behandlung mit 6.7 Äquivalenten Piperidin (20°C, 0.5 Stunden) und Ausfällen mit Wasser. Ausbeute: 75 % der Theorie; Schmelzpunkt: 338-340°C; C 5H19N5°3 x H20Prepared by reacting 1-acetyl-3- {1-ethoxy-l-phenyl-methylidene} -5-nitro-2-indolinone with 1.5 equivalents of 4- (4-amino-phenyl) -2-methyl-imidazole in DMF (100 ° C, 0.5 hours), subsequent treatment with 6.7 equivalents of piperidine (20 ° C, 0.5 hours) and precipitation with water. Yield: 75% of theory; Melting point: 338-340 ° C; C 5 H 19 N 5 ° 3 x H 2 0
Ber. C 65.93 H 4.65 N 15.38 Gef. 66.19 4.68 15.26 Ber. Molpeak M+ = 437 Gef. Molpeak M+ = 437Ber. C 65.93 H 4.65 N 15.38 Found 66.19 4.68 15.26 calc. Molpeak M + = 437 Found Molpeak M + = 437
9.3 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-5-yl) anilino] -1-phenyl- methyliden}-5-nitro-2-indolinon x 0.4 H209.3 3- {(Z) -1- [4- (1-Methyl-1H-imidazol-5-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.4 H 2 0
(a) 1 -Methyl -5- (4- i tτ-o-pheny1 -imidazol(a) 1 -Methyl -5- (4- i tτ-o-pheny1 imidazole
Hergestellt durch Erhitzen von 3.8 g (20 mMol) 4-(4-Nitro- phenyl) -imidazol (Schmelzpunkt: 220-222°C) , 2.5 ml (25 mMol) Acetanhydrid und 1.9 ml (30 mMol) Methyljodid in 50 ml Ace- tonitril in einer Glasampulle (80°C, 24 Stunden) . Mari dampft im Vakuum ein, gibt zum Eindampfrückstand EtOAc und IN Salzsäure, stellt dann mit verdünntem wäßrigem Ammoniak alkalisch und trennt die Phasen. Die organische Phase wird mit Wasser gewaschen, getrocknet und im Vakuum eingedampft. Der Eindampfrückstand (3.4 g) wird durch Säulenchromatographie an Kieselgel mit dem Eluens CH2Cl2/MeOH (10:1) gereinigt, wobei zuerst 1-Methyl- 4-phenyl-imidazol (Rf = 0.75), dann das gewünschte 1-Methyl- 5-phenyl-imidazol (Rf = 0.57) und danach viel 4- (4-Nitro-phe- nyl) -imidazol (Rf = 0.42) eluiert wird. Ausbeute: 0.40 g (9.8 % der Theorie); Schmelzpunkt: 167-170°C. (b) 5- (4 -Amino-phenyl ) -1 -methyl -imidazolPrepared by heating 3.8 g (20 mmol) of 4- (4-nitrophenyl) imidazole (melting point: 220-222 ° C.), 2.5 ml (25 mmol) of acetic anhydride and 1.9 ml (30 mmol) of methyl iodide in 50 ml of Ace - Tonitrile in a glass ampoule (80 ° C, 24 hours). Mari evaporates in a vacuum, adds EtOAc and IN hydrochloric acid to the evaporation residue, then makes alkaline with dilute aqueous ammonia and separates the phases. The organic phase is washed with water, dried and evaporated in vacuo. The evaporation residue (3.4 g) is purified by column chromatography on silica gel using the eluent CH 2 Cl 2 / MeOH (10: 1), first using 1-methyl-4-phenyl-imidazole (R f = 0.75), then the desired 1- Methyl- 5-phenyl-imidazole (R f = 0.57) and then a lot of 4- (4-nitro-phenyl) imidazole (R f = 0.42) is eluted. Yield: 0.40 g (9.8% of theory); Melting point: 167-170 ° C. (b) 5- (4-Amino-phenyl) -1-methyl-imidazole
Hergestellt durch Hydrierung von l-Methyl-5 - (4 -nitro-phenyl ) - imidazol in MeOH an Palladium/Kohle (10 %) bei 20 °C undManufactured by hydrogenation of l-methyl-5 - (4-nitro-phenyl) imidazole in MeOH on palladium / carbon (10%) at 20 ° C and
3 . 5 bar .3rd 5 bar.
Ausbeute (roh) : 90 % der Theorie;Yield (raw): 90% of theory;
Schmelzpunkt: 130°C.Melting point: 130 ° C.
(c) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-5-yl) anilino] -1-phenyl- methyliden} -5-ni tro-2-indolinon x 0.4 H2Q(c) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-5-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.4 H 2 Q
Hergestellt durch Umsetzung von 1 -Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.3 Äquivalenten 4- (4-Ami- no-phenyl) -2 -methyl-imidazol in DMF (120°C, 1 Stunde), anschließende Behandlung mit 4.2 Äquivalenten von Piperidin (20°C, 1 Stunde) und Ausfällen mit Wasser. Ausbeute: 95 % der Theorie; Schmelzpunkt: 365-368°C; 25H19N503 x 0.4 H20Prepared by reacting 1-acetyl-3- {1-ethoxy-l-phenyl-methylidene} -5-nitro-2-indolinone with 1.3 equivalents of 4- (4-amino-phenyl) -2-methyl-imidazole in DMF (120 ° C, 1 hour), followed by treatment with 4.2 equivalents of piperidine (20 ° C, 1 hour) and precipitation with water. Yield: 95% of theory; Melting point: 365-368 ° C; 25 H 19N 5 0 3 x 0.4 H 2 0
Ber. C 67.53 H 4.49 N 15.75Ber. C 67.53 H 4.49 N 15.75
Gef. 67.65 4.65 16.00Found 67.65 4.65 16.00
Ber. Molpeak M+ = 437Ber. Molpeak M + = 437
Gef. Molpeak M+ = 437Found Molpeak M + = 437
9.4 :■ 5- { (Z) -1- [4- (2 -Acetylamino-IH-imi nylmethyliden} -5-nitro-2-indolinon x 1.5 H209.4: ■ 5- {(Z) -1- [4- (2 -acetylamino-IH-iminylmethylidene} -5-nitro-2-indolinone x 1.5 H 2 0
(a) 2-Acetyl aππno-4- (4-nitro-pheny] ) -imidazol(a) 2-acetyl aππno-4- (4-nitro-pheny]) imidazole
Hergestellt durch Umstzung von τσ-Brom-4-nitro-acetophenon mit 3 Äquivalenten 1-Acetyl -guanidin in DMF (Raumtemperatur, 5 Tage) und abschließende Reinigung durch Säulenchromatographie an Kieselgel mit dem Eluens CH Cl2/MeOH (20:1). Ausbeute: 35 % der Theorie (Schaum).Prepared by reaction of τσ-bromo-4-nitro-acetophenone with 3 equivalents of 1-acetyl-guanidine in DMF (room temperature, 5 days) and final purification by column chromatography on silica gel with the eluent CH Cl 2 / MeOH (20: 1). Yield: 35% of theory (foam).
(b) 2 -A etylami no-4 - ( -aτπi no-phenyl ) - i mi dazol(b) 2 -A etylami no-4 - (-aτπi no-phenyl) - i mi dazol
Hergestellt durch katalytische Hydrierung der unter (a) erhaltenen Nitro-Verbindung in MeOH/CH2Cl2 (1:1) an Palladium/Kohle (10 %) bei Raumtemperatur und 3.5 bar für 2 Stunden. Ausbeute (roh) : 100 % der Theorie (Schaum) . (c) 3-{ (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] 1 -phenylmethyliden}- -nit-ro-2-indo1 inon x 1.5 W OPrepared by catalytic hydrogenation of the nitro compound obtained under (a) in MeOH / CH2Cl2 (1: 1) on palladium / carbon (10%) at room temperature and 3.5 bar for 2 hours. Yield (raw): 100% of theory (foam). (c) 3- {(Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] 1 -phenylmethylidene} - nit-ro-2-indo1 inone x 1.5 WO
Hergestellt durch Umsetzung von l-Acetyl-3- {l-ethoxy-1-phe- nylmethyliden} -5-nitro-2-indolinon mit 2 Äquivalenten rohemPrepared by reacting l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone with 2 equivalents of crude
2-Acetylamino-4- (4-amino-phenyl) -imidazol in DMF (120°C,2-acetylamino-4- (4-aminophenyl) imidazole in DMF (120 ° C,
2 Stunden) , anschließende Behandlung mit 3.8 Äquivalenten von2 hours), followed by treatment with 3.8 equivalents of
Piperidin (20°C, 1 Stunde) und Ausfällen mit Wasser.Piperidine (20 ° C, 1 hour) and precipitation with water.
Ausbeute: 56 % der Theorie;Yield: 56% of theory;
Schmelzpunkt: 275°C;Melting point: 275 ° C;
C26H20N6θ6 x 1-5 H20C26 H 20 N 6θ6 x 1-5 H 2 0
Ber . : C 61 . 53 H 4 . 57 N 16 . 56Ber. : C 61. 53 H 4. 57 N 16. 56
Gef . : 61 .41 4 . 70 17 . 10Gef. : 61 .41 4. 70 17. 10
Ber. : Molpeak M+ = 480Ber. : Molpeak M + = 480
Gef.: Molpeak M+ = 480Found: Molpeak M + = 480
9 - 5 3- { (Z) -1- [4- (2-Acetylamino-5-methyl-lH-imidazol-4-yl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon x H20 x 0.1 DMF9 - 5 3- {(Z) -1- [4- (2-Acetylamino-5-methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x H 2 0 x 0.1 DMF
(a) -Acetyl a i no- 5 -methyl - -phenyl - imi dazol(a) -Acetyl a i no- 5 -methyl - -phenyl - imi dazol
Hergestellt durch Umsetzung von 2-Brom-propiophenon mit 3 Äquivalenten 1-Acetyl-guanidin in DMF (Raumtemperatur, 3 Tage) . Ausbeute: 49 % der Theorie; Schmelzpunkt: 188-191°C.Prepared by reacting 2-bromo-propiophenone with 3 equivalents of 1-acetyl-guanidine in DMF (room temperature, 3 days). Yield: 49% of theory; Melting point: 188-191 ° C.
(b) 2 -Acetylami o- 5-methyl -4- (4-ni tτ-o-phenyl ) --imidazol Hergestellt analog Beispiel D durch Umsetzung von 2-Acetyl- amino-5-methyl-4-phenyl-imidazol mit Ammoniumnitrat in konzentrierter Schwefelsäure.(b) 2-Acetylami o- 5-methyl -4- (4-ni tτ-o-phenyl ) --imidazole Prepared analogously to Example D by reacting 2-acetylamino-5-methyl-4-phenylimidazole with Ammonium nitrate in concentrated sulfuric acid.
Ausbeute: 87 % der Theorie; Schmelzpunkt: 265-270°C.Yield: 87% of theory; Melting point: 265-270 ° C.
(c)
Figure imgf000074_0001
Hergestellt durch katalytische Hydrierung der unter (b) erhaltenen Nitro-Verbindung in MeOH/CH2Cl2 (1:1) an Palladium/Kohle(C)
Figure imgf000074_0001
Prepared by catalytic hydrogenation of the nitro compound obtained under (b) in MeOH / CH 2 Cl 2 (1: 1) on palladium / carbon
(10 %) bei Raumtemperatur und 3.5 bar für 2 Stunden. Ausbeute : 92 % der Theorie; Schmelzpunkt: 230-235°C.(10%) at room temperature and 3.5 bar for 2 hours. Yield: 92% of theory; Melting point: 230-235 ° C.
(d) 3-{ (Z) -1- [4- (2-Acetylamino-5-methyl-IH-imidazol-4-yl)ani- 1 inol - -phenylmethyl i e } -5-nitro-2- dol inon x T ) x 0-1 DMF(d) 3- {(Z) -1- [4- (2-Acetylamino-5-methyl-IH-imidazol-4-yl) ani- 1 inol - -phenylmethyl ie} -5-nitro-2-dol inone x T) x 0-1 DMF
Hergestellt durch Umsetzung von l-Acetyl-3- {1-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.5 Äquivalenten 2-Ace- tylamino-5-methyl-4- (4-amino-phenyl) -imidazol in DMF (100°C, 1 Stunde) , anschließende Behandlung mit 5 Äquivalenten von Piperidin (20°C, 0.5 Stunden) und Ausfällen mit Wasser. Ausbeute: 69 % der Theorie; Schmelzpunkt: 300-305°C; C27H22N6°4 x H2° x 0.1 DMFPrepared by reacting l-acetyl-3- {1-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.5 equivalents of 2-acetylamino-5-methyl-4- (4-aminophenyl ) -imidazole in DMF (100 ° C, 1 hour), subsequent treatment with 5 equivalents of piperidine (20 ° C, 0.5 hour) and precipitation with water. Yield: 69% of theory; Melting point: 300-305 ° C; C 27 H 22 N 6 ° 4 x H 2 ° x 0.1 DMF
Ber. C 63.01 H 4.72 N 16.44 Gef. 63.21 4.66 16.97 Ber. Molpeak M+ = 494 Gef. Molpeak M+ = 494Ber. C 63.01 H 4.72 N 16.44 Found 63.21 4.66 16.97 calc. Molpeak M + = 494 Found Molpeak M + = 494
.6 3-{ (Z) -1- [3- (lH-Imidazol-4-yl) anilino] -1-phenylmethyliden} 5-nitro-2-indolinon.6 3- {(Z) -1- [3- (1H-Imidazol-4-yl) anilino] -1-phenylmethylidene} 5-nitro-2-indolinone
(a) 4 - (3 -Ni tro-phenyl ) - i dazol(a) 4 - (3 -Ni tro-phenyl) - i dazol
Hergestellt durch Erhitzen von α-Brom-3-nitro-acetophenon inMade by heating α-bromo-3-nitro-acetophenone in
Formamid (160°C, 2.5 Stunden).Formamide (160 ° C, 2.5 hours).
Ausbeute: 86 % der Theorie;Yield: 86% of theory;
Schmelzpunkt: 210-212°C (Lit . Schmelzpunkt: 224°C) .Melting point: 210-212 ° C (lit.Melting point: 224 ° C).
(b) 4 - (3 -Ami no-phenyl ) - i mi da zol x 2 HCl(b) 4 - (3-Amino no-phenyl) - i mi da zol x 2 HCl
Hergestellt durch katalytische Hydrierung der unter (a) erhaltenen Nitro-Verbindung in MeOH an Palladium/Kohle (10%) bei Raumtemperatur und 3.5 bar für 2 Stunden und anschließende Zugabe von ethanolischer Salzsäure. Ausbeute: 85 % der Theorie; Schmelzpunkt: 296°C. (c) 3- { (Z) -1- [3- (lH-Imidazol-4-yl) anilino] -1-phenylmethylidfin}^Prepared by catalytic hydrogenation of the nitro compound obtained under (a) in MeOH on palladium / carbon (10%) at room temperature and 3.5 bar for 2 hours and subsequent addition of ethanolic hydrochloric acid. Yield: 85% of theory; Melting point: 296 ° C. (c) 3- {(Z) -1- [3- (1H-Imidazol-4-yl) anilino] -1-phenylmethylide f in} ^
5-ni tro-2-indol non5-nitro-2-indole non
Hergestellt durch Umsetzung von l-Acetyl-3- {l-ethoxy-1-phe- nylmethyliden} -5-nitro-2-indolinon mit 1.5 Äquivalenten 4- (3 -Amino-phenyl) -imidazol x 2 HCl und 3.25 Äquivalenten Triethylamin in DMF (100°C, 1.5 Stunden), anschließende Behandlung mit 5 Äquivalenten Piperidin (20°C, 1 Stunde) und Ausfällen mit Wasser.Prepared by reacting l-acetyl-3- {l-ethoxy-1-phenylmethylidene} -5-nitro-2-indolinone with 1.5 equivalents of 4- (3-amino-phenyl) -imidazole x 2 HCl and 3.25 equivalents of triethylamine in DMF (100 ° C, 1.5 hours), subsequent treatment with 5 equivalents of piperidine (20 ° C, 1 hour) and precipitation with water.
Ausbeute: 95 % der Theorie; Schmelzpunkt: 365°C; C24H17N503 Yield: 95% of theory; Melting point: 365 ° C; C 24 H 17 N 5 0 3
Ber. C 68.08 H 4.05 N 16.54 Gef. 67.68 4.3ß 16.25 Ber. Molpeak M+ = 423 Gef. Molpeak M+ = 423Ber. C 68.08 H 4.05 N 16.54 Found 67.68 4.3ß 16.25 calc. Molpeak M + = 423 Molpeak M + = 423
9.7 3-{ (Z) -1- [4- (lH-Tetrazol-5-yl) anilino] -1-phenylmethyliden} - 5-nitro-2-indolinon9.7 3- {(Z) -1- [4- (1H-Tetrazol-5-yl) anilino] -1-phenylmethylidene} - 5-nitro-2-indolinone
(a) 5- (4 -Amino-phenyl ) -IH-tetrazol(a) 5- (4-Amino-phenyl) -IH-tetrazole
Hergestellt durch katalytische Hydrierung von 5- (4-Nitro-phenyl) -IH-tetrazol in MeOH an Platindioxid (Raumtemperatur, 3.5 bar, 40 Minuten). Ausbeute: 87 % der Theorie; Schmelzpunkt: 264-268°C.Manufactured by catalytic hydrogenation of 5- (4-nitro-phenyl) -IH-tetrazole in MeOH on platinum dioxide (room temperature, 3.5 bar, 40 minutes). Yield: 87% of theory; Melting point: 264-268 ° C.
(b) 3-{ (Z) -1- [4- (lH-Tetrazol-5-yl) anilino] -1-phenyl methyl i en}-(b) 3- {(Z) -1- [4- (1H-tetrazol-5-yl) anilino] -1-phenyl methyl i en} -
5-nitro-2-inrio1 inon5-nitro-2-inrio1 inon
Hergestellt durch Umsetzung von l-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.3 Äquivalenten 5- (4-Ami- no-phenyl) -IH-tetrazol in DMF (125°C, 2 Stunden), anschließende Behandlung mit 6.7 Äquivalenten von Piperidin (20°C, 1 Stunde) und Ausfällen mit Wasser.Prepared by reacting l-acetyl-3- {1-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.3 equivalents of 5- (4-amino-phenyl) -IH-tetrazole in DMF ( 125 ° C, 2 hours), subsequent treatment with 6.7 equivalents of piperidine (20 ° C, 1 hour) and precipitation with water.
Ausbeute: 40 % der Theorie; Schmelzpunkt: >400°C; C22Hi5N7θ3 Yield: 40% of theory; Melting point:> 400 ° C; C 22 Hi5N 7 θ 3
Ber. : Molpeak M+ = 425Ber. : Molpeak M + = 425
Gef.: Molpeak M+ = 425Found: Molpeak M + = 425
9 - 8 3- { (Z) -1- [4- ( (Imidazol-4-yl)methyl) anilino] -1-phenylme- thyliden} -5-nitro-2-indolinon9 - 8 3- {(Z) -1- [4- ((Imidazol-4-yl) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
(a) l-Triphenylmethyl-4- [ (1-hydroxy-1-phenyl) methyl] -lH-imida-(a) l-triphenylmethyl-4- [(1-hydroxy-1-phenyl) methyl] -lH-imida-
ZΩ2ZΩ2
Hergestellt durch Umstzung von 4-Formyl-l-triphenylmethyl-lH- imidazol (Schmelzpunkt: 202-205°C; hergestellt durch Oxidation der entsprechenden 4-Hydroxymethyl-Verbindung mit Mangandioxid in Dioxan) mit Phenylmagnesiumbromid in trockenem THF. Ausbeute: 94 % der Theorie;Prepared by reacting 4-formyl-1-triphenylmethyl-1H-imidazole (melting point: 202-205 ° C; prepared by oxidizing the corresponding 4-hydroxymethyl compound with manganese dioxide in dioxane) with phenylmagnesium bromide in dry THF. Yield: 94% of theory;
Schmelzpunkt: 187-191°C.Melting point: 187-191 ° C.
(b) 4τBenzy] -IH-imidazol(b) 4τBenzy] -IH-imidazole
Hergestellt entsprechend Arch. Pharm. 1975, 308, 755-759 durch katalytische Hydrierung der unter (a) erhaltenen Verbindung in MeOH an Palladium/Kohle (10 %) (50°C, 3.5 bar, 7 Stunden). Ausbeute: 44 % der Theorie; Schmelzpunkt: 82-84°C (Lit. Schmelzpunkt: 85-86°C) .Prepared according to Arch. Pharm. 1975, 308, 755-759 by catalytic hydrogenation of the compound obtained under (a) in MeOH on palladium / carbon (10%) (50 ° C., 3.5 bar, 7 hours). Yield: 44% of theory; Melting point: 82-84 ° C (lit.Melting point: 85-86 ° C).
( c) 4 - U -Ni t-ro-benzyl ) - I H- i i dazol(c) 4 - U -Ni t-ro-benzyl) - I H- i i dazol
Hergestellt entsprechend Arch. Pharm. 1975, 308, 755-759 durch Umsetzung von 4-Benzyl-lH-imidazol in rauchender 100%iger Salpetersäure bei -10 bis -5°C (30 Minuten) . Ausbeute: 63 % der Theorie; Schmelzpunkt: 162-164°C (Lit. Schmelzpunkt: 161-162°C) .Prepared according to Arch. Pharm. 1975, 308, 755-759 by reacting 4-benzyl-lH-imidazole in smoking 100% nitric acid at -10 to -5 ° C (30 minutes). Yield: 63% of theory; Melting point: 162-164 ° C (lit.Melting point: 161-162 ° C).
(d) 4 - - Ami no-henzyl ) - I H- i i a zol(d) 4 - - Amino no-henzyl) - I H- i i a zol
Hergestellt durch katalytische Hydrierung von 4- (4-Nitro-ben- zyl) -IH-imidazol in EtOH an Palladium/Kohle (10%) (20°C, 3.5 bar, 45 Minuten). Ausbeute: 95 % der Theorie; Schmelzpunkt: 98-100°C. (e) 3- { (Z) -1- [4- ( (Imidazol-4-yl) methyl) anilino] -1-phenylmethy-Prepared by catalytic hydrogenation of 4- (4-nitro-benzyl) -IH-imidazole in EtOH on palladium / carbon (10%) (20 ° C, 3.5 bar, 45 minutes). Yield: 95% of theory; Melting point: 98-100 ° C. (e) 3- {(Z) -1- [4- ((Imidazol-4-yl) methyl) anilino] -1-phenylmethy-
1 i den} -5-nitro- - i dol i on1 i den} -5-nitro- - i dol i on
Hergestellt durch Umsetzung von l-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -5-nitro-2 -indolinon mit 1.45 Äquivalenten 4-(4-Ami- no-benzyl) -IH-imidazol in DMF (100°C, 2 Stunden), anschließende Behandlung mit 5 Äquivalenten Piperidin (20°C, 1 Stunde) und Ausfällen mit Wasser. Ausbeute: 91 % der Theorie; Schmelzpunkt: 322-325°C;Prepared by reacting l-acetyl-3- {1-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.45 equivalents of 4- (4-amino-benzyl) -IH-imidazole in DMF ( 100 ° C, 2 hours), subsequent treatment with 5 equivalents of piperidine (20 ° C, 1 hour) and precipitation with water. Yield: 91% of theory; Melting point: 322-325 ° C;
C25H19N5O3C25H19N5O3
Ber. C 68.64 H 4.38 N 16.01 Gef. 68.30 4.38 15.83 Ber. Molpeak M+ = 437 Gef. Molpeak M+ = 437Ber. C 68.64 H 4.38 N 16.01 Found 68.30 4.38 15.83 calc. Molpeak M + = 437 Found Molpeak M + = 437
.9 3- { (Z) -1- [4- (2- (Imidazol-4-yl) ethyl) anilino] -1-phenylme- thyliden} -5-nitro-2-indolinon x 0.5 H2O.9 3- {(Z) -1- [4- (2- (imidazol-4-yl) ethyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H2O
(a) 4- [2- (4 -Nitro-phenyl) -ethenyl] -1-triphenylmethyl-l-H-imi- dazol(a) 4- [2- (4-Nitro-phenyl) -ethenyl] -1-triphenylmethyl-1-H-imidazole
Hergestellt durch Umsetzung von 4-Nitro-benzaldehyd mitManufactured by reacting with 4-nitro-benzaldehyde
1.2 Äquivalenten (l-Triphenylmethyl-lH-imidazol-4-yl) methyl- triphenylphosponium-chlorid (Schmelzpunkt: 240-245°C) und 2 Äquivalenten DBU in THF/EtOH (1:1) (20°C, 2 Stunden) und Ausfällen mit Wasser.1.2 equivalents (l-triphenylmethyl-lH-imidazol-4-yl) methyl triphenylphosphonium chloride (melting point: 240-245 ° C) and 2 equivalents DBU in THF / EtOH (1: 1) (20 ° C, 2 hours) and water failures.
Ausbeute an (E) -Isomer (mit Spur des etwas polareren (Z) -Isomeren) : 50 % der Theorie; Schmelzpunkt: 280-285°C.Yield of (E) -isomer (with trace of the somewhat more polar (Z) -isomer): 50% of theory; Melting point: 280-285 ° C.
Aus der Mutterlauge des (E) -Isomeren wurde durch Säulenchromatographie an Kieselgel mit CH2Cl2 als Eluens noch ein Gemisch der (E/Z) -Isomeren (-3:4) gewonnen: Ausbeute: 43 % der Theorie (Schaum) .A mixture of the (E / Z) isomers (-3: 4) was obtained from the mother liquor of the (E) isomer by column chromatography on silica gel with CH2Cl 2 as eluent: Yield: 43% of theory (foam).
(b) 4- T2- (4- i τ-o-phenyl ) - (V. /7Λ -ethenyl 1 -1 -H- i mi dazol Hergestellt durch Erhitzen des unter (a) erhaltenen Gemisches der (E/Z) -Isomeren (-3/4) in IN Salzsäure auf Rückfluß (4 Stun- den) und Säulenchromatographie an Kieselgel mit CH2Cl2/MeOH(b) 4- T2- (4- i τ-o-phenyl) - (V. / 7Λ -ethenyl 1 -1 -H- i mi dazol Prepared by heating the mixture of (E / Z) obtained under (a) Isomers (-3/4) in IN hydrochloric acid at reflux (4 hours den) and column chromatography on silica gel with CH 2 Cl 2 / MeOH
(10:1) als Eluens. Ausbeute an (E/Z) -Isomeren (-3 :4) -Gemisch: 96 % der Theorie(10: 1) as Eluens. Yield of (E / Z) isomers (-3: 4) mixture: 96% of theory
(Schaum) .(Foam) .
(c) 4 - T2 - U -Ami no-phenyl ) -ethyl 1 - 1 -H- i mi da zol(c) 4 - T2 - U -Ami no-phenyl) -ethyl 1 - 1 -H- i mi da zol
Hergestellt durch katalytische Hydrierung des unter (b) erhaltenen Gemisches der (E/Z) -Isomeren (-3/4) in EtOH an Palladium/Kohle (10 %) (20°C, 3.5 bar, 1 Stunde). Ausbeute: 98 % der Theorie; Schmelzpunkt: 165-167°C.Prepared by catalytic hydrogenation of the mixture of (E / Z) isomers (-3/4) obtained in (b) in EtOH on palladium / carbon (10%) (20 ° C, 3.5 bar, 1 hour). Yield: 98% of theory; Melting point: 165-167 ° C.
(d) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) ethyl) anilino] -1-phenylme- hyl iden}- -nitτ-o-2-indo1 non x 0.5 H2 n (d) 3- {(Z) -1- [4- (2- (imidazol-4-yl) ethyl) anilino] -1-phenylmethyl iden} - -nitτ-o-2-indo1 non x 0.5 H 2 n
Hergestellt durch Umsetzung von l-Acetyl-3- { 1-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.3 ÄquivalentenPrepared by reacting l-acetyl-3- {1-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.3 equivalents
4- [2- (4-Amino-phenyl) -ethyl] -1-H-imidazol in DMF (120°C,4- [2- (4-aminophenyl) ethyl] -1-H-imidazole in DMF (120 ° C,
0.5 Stunden), anschließende Behandlung mit 4.2 Äquivalenten0.5 hours), followed by treatment with 4.2 equivalents
Piperidin (20°C, 1 Stunde) und Ausfällen mit Wasser.Piperidine (20 ° C, 1 hour) and precipitation with water.
Ausbeute: 72 % der Theorie;Yield: 72% of theory;
Schmelzpunkt: 305-307°C;Melting point: 305-307 ° C;
C26H21N5O3 x 0.5 H20C26H21N5O3 x 0.5 H 2 0
Ber. C 67.82 H 4.82 N 15.21 Gef. 68.07 4.75 14.74 Ber. Molpeak M+ = 451 Gef. Molpeak M+ = 451Ber. C 67.82 H 4.82 N 15.21 Found 68.07 4.75 14.74 calc. Molpeak M + = 451 Found Molpeak M + = 451
Q.m 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - l-phenylmethyliden}-5-nitro-2-indolinon x 0.5 H20Qm 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] - l-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H 2 0
(a) 4- [2- (4-Nj tro-phenyl ) - (V.) -ethenyl 1 -1 -H- imidazol Hergestellt durch Erhitzen des im Beispiel 9.9 unter (a) erhaltenen 4- [2- (4-Nitro-phenyl) - (E) -ethenyl] -1-triphenylmethyl- 1-H-imidazols (Schmelzpunkt: 280-285°C) in IN Salzsäure auf Rückfluß (4 Stunden) und Säulenchromatographie an Kieselgel mit CH2Cl2/MeOH (10:1) als Eluens. Ausbeute: 97 % der Theorie; Schmelzpunkt: 185-188°C.(a) 4- [2- (4-Nj tro-phenyl) - (V.) -ethenyl 1 -1 -H-imidazole Prepared by heating the 4- [2- (4- Nitro-phenyl) - (E) -ethenyl] -1-triphenylmethyl-1-H-imidazole (melting point: 280-285 ° C) in 1N hydrochloric acid at reflux (4 hours) and column chromatography on silica gel with CH 2 Cl 2 / MeOH (10: 1) as Eluens. Yield: 97% of theory; Melting point: 185-188 ° C.
(b) 4- \ 2 ~ (4 -Amino-phenyl ) - CFΛ -ethenyl 1 -1 -H- imid ol Hergestellt durch Behandeln der unter (a) erhaltenen Nitro- Verbindung in 80%iger Essigsäure mit Eisen-Pulver bei 70°C. Ausbeute: 71 % der Theorie;(b) 4- \ 2 ~ (4 -Amino-phenyl) - CFΛ -ethenyl 1 -1 -H- imid ol prepared by treating the nitro compound obtained under (a) in 80% acetic acid with iron powder at 70 ° C. Yield: 71% of theory;
Schmelzpunkt: 228-230°C.Melting point: 228-230 ° C.
(c) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) nilino] - 1 -phenylmethyl de } -5-ni tro-2-i dol i on x 0.5 H2Q(c) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) nilino] -1-phenylmethyl de} -5-nitro-2-i dol i on x 0.5 H 2 Q
Hergestellt durch Umsetzung von l-Acetyl-3- {l-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.5 Äquivalenten 4- [2- (4-Amino-phenyl) - (E) -ethenyl] -1-H-imidazol in DMF (110°C, 1.5 Stunden), anschließende Behandlung mit 3 Äquivalenten Piperidin (20°C, 0.5 Stunden) und Ausfällen mit Wasser. Ausbeute: 89 % der Theorie; Schmelzpunkt: 338-342°C; C26H19N5O3 x °-5 H2°Prepared by reacting l-acetyl-3- {l-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.5 equivalents of 4- [2- (4-aminophenyl) - (E) -ethenyl ] -1-H-imidazole in DMF (110 ° C, 1.5 hours), subsequent treatment with 3 equivalents of piperidine (20 ° C, 0.5 hours) and precipitation with water. Yield: 89% of theory; Melting point: 338-342 ° C; C 26H19N5O3 x ° - 5 H 2 °
Ber. C 68.11 H 4.40 N 15.28Ber. C 68.11 H 4.40 N 15.28
Gef. 68.15 4.27 15.21Found 68.15 4.27 15.21
Ber. Molpeak M+ = 449Ber. Molpeak M + = 449
Gef. Molpeak M+ = 449Found Molpeak M + = 449
9.11 3-{(Z)-l-[4- ( (2,4-Dioxo-thiazoli lino] -l-phenylmethyliden}-5-nitro-2-indolinon x 0.5 H209.11 3 - {(Z) -l- [4- ((2,4-Dioxothiazolino] -l-phenylmethylidene} -5-nitro-2-indolinone x 0.5 H 2 0
(a) - -Am no-henzyl iden) -th azol i di n-2.4-di on Hergestellt durch katalytische Hydrierung von 5- (4-Nitro-ben- zyliden) -thiazolidin-2,4-dion [Schmelzpunkt: 265-270°C; erhalten durch Erhitzen von 4-Nitro-benzaldehyd und 2 Äquivalenten von Thiazolidin-2,4-dion in Gegenwart von Piperidin in Toluol am Wasserabscheider] in Eisessig an Palladium/Kohle (10%)(a) - -Am no-henzyl iden) -th azole i di n-2.4-di on Manufactured by catalytic hydrogenation of 5- (4-nitro-benzylidene) thiazolidine-2,4-dione [melting point: 265 -270 ° C; obtained by heating 4-nitro-benzaldehyde and 2 equivalents of thiazolidine-2,4-dione in the presence of piperidine in toluene on a water separator] in glacial acetic acid on palladium / carbon (10%)
(50°C, 3.5 bar, 0.5 Stunden). Ausbeute: 62 % der Theorie; Schmelzpunkt: 256-260°C. (b) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-thiazolidin-5-yliden) methyl) ani- 1 inol -1 -pheny1methyliden}-5-nitro-2-indo1 inon x 0.5 H2Q(50 ° C, 3.5 bar, 0.5 hours). Yield: 62% of theory; Melting point: 256-260 ° C. (b) 3- {(Z) -1- [4- ((2,4-Dioxothiazolidin-5-ylidene) methyl) ani- 1 inol -1-phenylmethylidene} -5-nitro-2-indo1 inone x 0.5 H 2 Q
Hergestellt durch Umsetzung von l-Acetyl-3- { l-ethoxy-l-phenyl- methyliden} -5-nitro-2-indolinon mit 1.5 Äquivalenten 5-(4-Ami- no-benzyliden) -thiazolidin-2,4-dion in DMF (120°C, 2 Stunden), anschließende Behandlung mit 6 Äquivalenten von Piperidin (20°C, 0.5 Stunden), Eindampfen im Vakuum und Verreiben mit EtOH.Prepared by reacting l-acetyl-3- {l-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.5 equivalents of 5- (4-amino-benzylidene) thiazolidine-2,4- dione in DMF (120 ° C, 2 hours), then treated with 6 equivalents of piperidine (20 ° C, 0.5 hours), evaporated in vacuo and triturated with EtOH.
Ausbeute: 27 % der Theorie; Schmelzpunkt: 328-333°C; C25Hi6 405S x 0.5 H20Yield: 27% of theory; Melting point: 328-333 ° C; C 25 Hi6 4 0 5 S x 0.5 H 2 0
Ber. C 60.84 H 3.47 N 11.35 Gef. 60.46 3.83 11.23 Ber. Molpeak M+ = 484 Gef. Molpeak M+ = 484Ber. C 60.84 H 3.47 N 11.35 Found 60.46 3.83 11.23 Calc. Molpeak M + = 484 Found Molpeak M + = 484
9-1 3- { (Z) -1- [4- ( (2,4-Dioxo-thiazolidin-5-yl)methyl) nilino] 1-phenylmethyliden} -5-nitro-2-indolinon9-1 3- {(Z) -1- [4- ((2,4-Dioxothiazolidin-5-yl) methyl) nilino] 1-phenylmethylidene} -5-nitro-2-indolinone
(a) q- -Ami no-benzyl ) -t i azol idi n - 2 , 4 -di on(a) q- -Ami no-benzyl) -t i azole idi n - 2, 4 -di on
Hergestellt durch katalytische Hydrierung von 5- (4-Amino-ben- zyliden) -thiazolidin-2 , 4-dion in Eisessig an Palladium/Kohle (10%) (50°C, 3.5 bar, 6 Stunden). Ausbeute: 42 % der Theorie; Schmelzpunkt: 135-140°C.Prepared by catalytic hydrogenation of 5- (4-amino-benzylidene) thiazolidin-2, 4-dione in glacial acetic acid over palladium / carbon (10%) (50 ° C, 3.5 bar, 6 hours). Yield: 42% of theory; Melting point: 135-140 ° C.
(b) 3- { (Z) -1- [4- ( (2,4-Dioxo-thiazolidin-5-yl)methyl) anilino] -(b) 3- {(Z) -1- [4- ((2,4-Dioxothiazolidin-5-yl) methyl) anilino] -
1-phenylmethyl i en} -5-nitro-2 - indol i non1-phenylmethyl i en} -5-nitro-2-indole i non
Hergestellt durch Umsetzung von l-Acetyl-3- ( 1-ethoxy-l-phenyl- methyliden} -5-nitro-2 -indolinon mit 1.2 Äquivalenten 5-(4-Ami- no-benzyl) -thiazolidin-2, 4-dion in DMF (120°C, 1 Stunde), anschließende Behandlung mit 6.7 Äquivalenten Piperidin (20°C,Prepared by reacting l-acetyl-3- (1-ethoxy-l-phenylmethylidene} -5-nitro-2-indolinone with 1.2 equivalents of 5- (4-amino-benzyl) thiazolidine-2,4- dione in DMF (120 ° C, 1 hour), subsequent treatment with 6.7 equivalents of piperidine (20 ° C,
1 Stunde) , Eindampfen im Vakuum und Verreiben mit EtOH/Wasser (1:1) .1 hour), evaporation in vacuo and trituration with EtOH / water (1: 1).
Ausbeute: 96% der Theorie; Schmelzpunkt: 265-270°C; C25H18N405SYield: 96% of theory; Melting point: 265-270 ° C; C25 H 18N 4 0 5 p
Ber. C 61.72 H 3.73 N 11.52 Gef. 61.83 3.90 11.28 Ber. Molpeak M+ = 486 Gef. Molpeak M+ = 486Ber. C 61.72 H 3.73 N 11.52 Found 61.83 3.90 11.28 calc. Molpeak M + = 486 Found Molpeak M + = 486
Q-13 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -1-phenyl- methyliden}-5-nitro-2-indolinon x 0.6 H20Q-13 3- {(Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x 0.6 H 2 0
Hergestellt durch Umsetzung von 3- {l-Ethoxy-1-phenyl-methyliden} -5-nitro-2 -indolinon mit 1.3 Äquivalenten 4-(4-Amino- phenyl) -2-ethyl-imidazol in DMF (120°C, 1,5 Stunden) und Ausfällen mit Wasser. Ausbeute: 81 % der Theorie; Schmelzpunkt: 254-256°C. C26H2lN5θ3 x 0.6 x H20Prepared by reacting 3- {l-ethoxy-1-phenyl-methylidene} -5-nitro-2-indolinone with 1.3 equivalents of 4- (4-aminophenyl) -2-ethyl-imidazole in DMF (120 ° C, 1.5 hours) and water failures. Yield: 81% of theory; Melting point: 254-256 ° C. C26 H 2lN5θ3 x 0.6 x H 2 0
Ber. C 67.55 H 4.84 N 15.15 Gef. 67.49 5.07 15.23 Ber. Molpeak M+ = 451 Gef. Molpeak M+ = 451Ber. C 67.55 H 4.84 N 15.15 Found 67.49 5.07 15.23 calc. Molpeak M + = 451 Found Molpeak M + = 451
q -14 3-{ (Z) -1- [4- (2-n-Propyl-IH-imidazol-4-yl) anilino] -1-phe- nyl-methyliden} -5-nitro-2-indolinon x H20 q -14 3- {(Z) -1- [4- (2-n-propyl-IH-imidazol-4-yl) anilino] -1-phenyl-methylidene} -5-nitro-2-indolinone x H 2 0
Hergestellt durch Umsetzung von 3- {l-Ethoxy-1-phenyl-methyliden} -5-nitro-2-indolinon mit 1.3 Äquivalenten 4- (4-Amino-phenyl) -2-n-propyl-imidazol in DMF (120°C, 1 Stunde) und Ausfällen mit Wasser.Prepared by reacting 3- {l-ethoxy-1-phenyl-methylidene} -5-nitro-2-indolinone with 1.3 equivalents of 4- (4-aminophenyl) -2-n-propyl-imidazole in DMF (120 ° C, 1 hour) and precipitation with water.
Ausbeute: 67 % der Theorie; Schmelzpunkt: 180°C.Yield: 67% of theory; Melting point: 180 ° C.
C27H23N5°3 x H2°C27 H 23 N 5 ° 3 x H 2 °
Ber. C 67.07 H 5.21 N 14.48 Gef. 67.08 5.33 14.48 Ber. Molpeak M+ = 465 Gef. Molpeak M+ = 465 9-15 3-{ (Z) -1- [4- (2-Isopropyl-lH-imidazol-4-yl) anilino] -1-phe- nyl-methyliden}-5-nitro-2-indolinon x H20Ber. C 67.07 H 5.21 N 14.48 Found 67.08 5.33 14.48 calc. Molpeak M + = 465 Found Molpeak M + = 465 9-15 3- {(Z) -1- [4- (2-Isopropyl-1H-imidazol-4-yl) anilino] -1-phenyl-methylidene} -5-nitro-2-indolinone x H 2 0
Hergestellt durch Umsetzung von 3- {l-Ethoxy-1-phenyl-methy- liden} -5-nitro-2-indolinon mit 1.3 Äquivalenten 4-(4-Amino- phenyl) -2-isopropyl-imidazol in DMF (120°C, 1 Stunde) und Ausfällen mit Wasser. Ausbeute: 75 % der Theorie; Schmelzpunkt: 202-202°C.Prepared by reacting 3- {l-ethoxy-1-phenyl-methylidene} -5-nitro-2-indolinone with 1.3 equivalents of 4- (4-aminophenyl) -2-isopropyl-imidazole in DMF (120 ° C, 1 hour) and precipitation with water. Yield: 75% of theory; Melting point: 202-202 ° C.
C27H23N5°3 x H2° C 27 H 23 N 5 ° 3 x H 2 °
Ber. : C 67.07 H 5.21 N 14.48Ber. : C 67.07 H 5.21 N 14.48
Gef . : 67.20 5.29 14.45Gef. : 67.20 5.29 14.45
Ber. : Molpeak M+ = 465Ber. : Molpeak M + = 465
Gef. : Molpeak M+ = 465Found: Molpeak M + = 465
Belspä el 10Belspä el 10
3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-trifluormethyl- phenyl) methyliden} -5-nitro-2-indolinon3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-trifluoromethylphenyl) methylidene} -5-nitro-2-indolinone
(a) l-Acetyl-3- [1-hydroxy-l- (4 -trifluormethyl-phenyl) methyliden} -5-nit.rΩ-2-indQlinQn(a) l-Acetyl-3- [1-hydroxy-1- (4-trifluoromethyl-phenyl) methylidene} -5-nit.rΩ-2-indQlinQn
Hergestellt durch Reaktion von l-Acetyl-5-nitro-2-indolinon mit einem Äquivalent 4-Trifluormethyl-benzoesaure in trockenem DMF in Gegenwart von je 1 Äquivalent TBTU und HOBT sowie vonPrepared by reaction of l-acetyl-5-nitro-2-indolinone with one equivalent of 4-trifluoromethyl-benzoic acid in dry DMF in the presence of 1 equivalent each of TBTU and HOBT and of
5 Äquivalenten Hünig 's Base (20°C, 4 Stunden), Einrühren in verdünnter Salzsäure, Filtration des Niederschlages, Lösen des5 equivalents of Hünig 's base (20 ° C, 4 hours), stirring in dilute hydrochloric acid, filtration of the precipitate, dissolving the
Niederschlages in EtOAc, Trocknen der organischen Phase undPrecipitation in EtOAc, drying of the organic phase and
Eindampfen im Vakuum und Reinigung des Eindampfrückstandes durch Säulenchromatographie an Kieselgel mit CH Cl2/MeOH (10:1) als Eluens .Evaporation in vacuo and purification of the evaporation residue by column chromatography on silica gel with CH Cl 2 / MeOH (10: 1) as the eluent.
Ausbeute: 86 % der Theorie;Yield: 86% of theory;
Schmelzpunkt: 177°C;Melting point: 177 ° C;
Enol-Reaktion (mit FeCl3-Lösung in EtOH) : positiv. (b) 3- [1-Brom-l- (4-trifluormethyl-phenyl) methyliden} -5-nitro-Enol reaction (with FeCl 3 solution in EtOH): positive. (b) 3- [1-bromo-1- (4-trifluoromethylphenyl) methylidene} -5-nitro-
?- ndo1 i on? - ndo1 i on
Hergestellt durch Reaktion der unter (a) erhaltenen Verbindung mit 1.2 Äquivalenten Triphenylphosphin und 1.1 Äquivalenten von Tetrabrom-methan in CH2Cl2 (1 Stunde bei 0 °C, über Nacht bei Raumtemperatur) , Zugabe von 2 Äquivalenten Piperidin und Rühren bei Raumtemperatur für 1.5 Stunden, sowie Eindampfen im Vakuum und Reinigung des Eindampfrückstandes durch Säulenchromatographie an Kieselgel mit Cyclohexan/EtOAc (1:1) als Eluens. Ausbeute: 5.6 % der Theorie;Prepared by reaction of the compound obtained under (a) with 1.2 equivalents of triphenylphosphine and 1.1 equivalents of tetrabromomethane in CH 2 Cl2 (1 hour at 0 ° C, overnight at room temperature), addition of 2 equivalents of piperidine and stirring at room temperature for 1.5 Hours, as well as evaporation in vacuo and purification of the evaporation residue by column chromatography on silica gel with cyclohexane / EtOAc (1: 1) as the eluent. Yield: 5.6% of theory;
Schmelzpunkt: 222-225°C;Melting point: 222-225 ° C;
C16H8BrF3N2θ3C 16 H 8 BrF 3 N 2 θ3
Ber. : Molpeak M+ = 412/414 (1 Br)Ber. : Molpeak M + = 412/414 (1 Br)
Gef.: Molpeak M+ = 412/414 (1 Br)Found: Molpeak M + = 412/414 (1 Br)
(c) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-trifluormethyl- henyl ) ethyl iden} -5-n τo-2-i ndol non(c) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-trifluoromethylhenyl) ethyl iden} -5-n τo-2-indole non
Hergestellt durch Reaktion der unter (b) erhaltenen Brom-Verbindung mit 2 Äquivalenten 4- (lH-Imidazol-4-yl) anilin x 2 HClPrepared by reacting the bromine compound obtained under (b) with 2 equivalents of 4- (1H-imidazol-4-yl) aniline x 2 HCl
(Schmelzpunkt: 350°C) und 3.9 Äquivalenten Triethylamin in To- luol/DMF (2:1) für 2 Stunden bei 40°C, Eingießen in verdünntem Ammoniak und Reinigung des erhaltenen Niederschlages durch Säulenchromatographie an Kieselgel mit CH2Cl2/MeOH/konz . Ammoniak(Melting point: 350 ° C.) and 3.9 equivalents of triethylamine in toluene / DMF (2: 1) for 2 hours at 40 ° C., pouring into dilute ammonia and purifying the precipitate obtained by column chromatography on silica gel with CH2Cl2 / MeOH / conc. ammonia
(10:1:0.1) als Eluens. Ausbeute: 17.4 % der Theorie; Schmelzpunkt : 358°C;(10: 1: 0.1) as eluent. Yield: 17.4% of theory; Melting point: 358 ° C;
C25H16F3N5O3C25H16F3N5O3
Ber. : Molpeak M+ = 491Ber. : Molpeak M + = 491
Gef.: Molpeak M+ = 491Found: Molpeak M + = 491
Analog Beispiel 10 wurde folgende Verbindung erhalten: 10-1 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (3 -cyano-phe- nyl) methyliden} -2-indolinonThe following compound was obtained analogously to Example 10: 10-1 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (3 -cyano-phenyl) methylidene} -2-indolinone
(a) l-Acetyl-3- [1-hydroxy-l- (3 -cyano-phenyl) methyliden] -2-in- dol inon(a) l-Acetyl-3- [1-hydroxy-1- (3-cyano-phenyl) methylidene] -2-indole inone
Hergestellt aus 1-Acetyl-2 -indolinon und 3-Cyano-benzoesäure in trockenem DMF in Gegenwart von TBTU, HOBT sowie Hünig's BaseMade from 1-acetyl-2-indolinone and 3-cyano-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base
(35 °C, 2 Stunden) und abschließende Reinigung durch Säulenchromatographie an Kieselgel mit CH2Cl /MeOH (10:1) als Eluens. Ausbeute: 62 % der Theorie;(35 ° C, 2 hours) and final purification by column chromatography on silica gel with CH 2 Cl / MeOH (10: 1) as the eluent. Yield: 62% of theory;
Schmelzpunkt: 173-175C;Melting point: 173-175C;
Enol-Reaktion (mit FeCl3 -Lösung in EtOH) : positiv.Enol reaction (with FeCl3 solution in EtOH): positive.
(b) 3- [1 -R-rom-1 - (3 -cyano-phenyl ) methyliden! -2-indol -inon Hergestellt durch Reaktion der unter (a) erhaltenen Verbindung mit Triphenylphosphin und Tetrabrom-methan in CH2Cl2 unc^ a^~ schließende Reinigung durch Säulenchromatographie an Kieselgel mit Cyclohexan/EtOAc (1:1) als Eluens.(b) 3- [1 -R-rom-1 - (3 -cyano-phenyl) methylidene! -2-indole -inone Prepared by reaction of the compound obtained under (a) with triphenylphosphine and tetrabromomethane in CH 2 Cl2 unc ^ a ^ ~ final purification by column chromatography on silica gel with cyclohexane / EtOAc (1: 1) as eluent.
Ausbeute: 14 % der Theorie;Yield: 14% of theory;
Schmelzpunkt: 218°C;Melting point: 218 ° C;
CigHgBr^OCigHgBr ^ O
Ber.: Molpeak M+ = 324/326 (1 Br)Calc .: Molpeak M + = 324/326 (1 Br)
Gef.: Molpeak M+ = 324/326 (1 Br)Found: Molpeak M + = 324/326 (1 Br)
(c) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (3 -cyano-phenyl) - methyl i den } -2-i dol i non(c) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (3 -cyano-phenyl) - methyl i den} -2-i dol i non
Hergestellt durch Reaktion der unter (b) erhaltenen Brom-Verbindung mit 4 Äquivalenten 4- (1H-Imidazol-4-yl) anilin x 2 HClPrepared by reacting the bromine compound obtained under (b) with 4 equivalents of 4- (1H-imidazol-4-yl) aniline x 2 HCl
(Schmelzpunkt: 350°C) und 6 Äquivalenten Triethylamin in To- luol/DMF (3:2) (60°C, 4 Stunden), Eingießen in verdünnten Ammoniak, Abtrennen der organischen Phase und deren Reinigung durch Säulenchromatographie an Kieselgel mit CH2Cl2/MeOH/konz . Ammoniak (10:1:0.15) als Eluens. Ausbeute : 3.3 % der Theorie ; Schmelzpunkt : 76°C; DC-Rf = 0.43 [Kieselgel; CH2Cl2/MeOH/konz . Ammoniak (100:10:1)] 25H17N5O(Melting point: 350 ° C.) and 6 equivalents of triethylamine in toluene / DMF (3: 2) (60 ° C., 4 hours), pouring into dilute ammonia, separating off the organic phase and purifying it by column chromatography on silica gel with CH 2 Cl 2 / MeOH / conc. Ammonia (10: 1: 0.15) as eluent. Yield: 3.3% of theory; Melting point: 76 ° C; TLC Rf = 0.43 [silica gel; CH 2 Cl 2 / MeOH / conc. Ammonia (100: 10: 1)] 25H17N5O
Ber. : Molpeak M+ = 403Ber. : Molpeak M + = 403
Gef.: Molpeak M+ = 403Found: Molpeak M + = 403
Beispiel 11Example 11
3- ( (Z) -1- [4- (1H- Imidazol-4-yl) anilino] -1- (4-methyl-phenyl) methyliden} -5-nitro-2-indolinon3- ((Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-methylphenyl) methylidene} -5-nitro-2-indolinone
(a) l-Acetyl-3- [1-hydroxy-1- (4-methyl-phenyl) methyliden] -5-ni- t-τo-2- indol inon(a) l-Acetyl-3- [1-hydroxy-1- (4-methylphenyl) methylidene] -5-nit-τo-2-indole inone
Hergestellt analog Beispiel 10 (a) aus l-Acetyl-5-nitro-2-indo- linon und 4-Methyl-benzoesäure in trockenem DMF in Gegenwart von TBTU, HOBT sowie Hünig's Base (20°C, über Nacht) und abschließende Reinigung durch Säulenchromatographie an Kieselgel mit CH2CI2 als Eluens.Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-2-indoline and 4-methyl-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and final cleaning by column chromatography on silica gel with CH2CI2 as the eluent.
Ausbeute: 53 % der Theorie;Yield: 53% of theory;
Schmelzpunkt: 175°C;Melting point: 175 ° C;
Enol-Reaktion (mit FeCl3 -Lösung in EtOH) : positiv.Enol reaction (with FeCl3 solution in EtOH): positive.
(b) l-Acetyl-3- [1-chlor-l- (4-methyl-phenyl) methyliden] -5-nitro- -indol inon(b) l-Acetyl-3- [1-chloro-l- (4-methylphenyl) methylidene] -5-nitro- indole inone
Man erhitzt 3.55 g (10.5 mMol) l-Acetyl-3- [1-hydroxy-l- (4-me- thyl-phenyl) methyliden} -5-nitro-2-indolinon und 2.40 g3.55 g (10.5 mmol) of l-acetyl-3- [1-hydroxy-1- (4-methylphenyl) methylidene} -5-nitro-2-indolinone and 2.40 g are heated
(11.5 mMol) PCI5 in 60 ml Toluol 2 Stunden bei 80°C. Man dampft im Vakuum ein, gibt frisches Toluol zum Eindampfrückstand, dampft erneut ein und wiederholt diese Prozedur ein weiteres Mal. Der Eindampfrückstand wird in wenig Toluol in der Hitze gelöst. Bei langsamen Abkühlen kristallisiert ein Isomer, wahrscheinlich das (Z) -Isomere, aus. Aus der Mutterlauge erhält man durch Säulenchromatographie an Kieselgel mit CH2CI2 noch ein Gemisch der (Z) - und (E) -Isomeren.(11.5 mmol) PCI5 in 60 ml of toluene for 2 hours at 80 ° C. Evaporate in vacuo, add fresh toluene to the evaporation residue, evaporate again and repeat this procedure again. The evaporation residue is dissolved in a little toluene in the heat. With slow cooling, an isomer, probably the (Z) isomer, crystallizes out. A mixture of the (Z) and (E) isomers is obtained from the mother liquor by column chromatography on silica gel with CH2Cl2.
(7Λ -Tπomer :(7Λ tomer:
Ausbeute: 46 % der Theorie; Schmelzpunkt: 201-202°C; DC-Rf = 0.54 [Kieselgel; CH2Cl2/Toluol (5:2)]; Cι8H13ClN204 Yield: 46% of theory; Melting point: 201-202 ° C; TLC Rf = 0.54 [silica gel; CH 2 Cl 2 / toluene (5: 2)]; Cι 8 H 13 ClN 2 0 4
Ber.: Molpeak M+ = 356/358 (1 Cl) Gef.: Molpeak M+ = 356/358 (1 Cl) ( 7, /V. ) - Isomeren -Gemi RPII- Ausbeute: 37 % der Theorie; Schmelzpunkt: 168-170C;Calculated: Molpeak M + = 356/358 (1 Cl) Found: Molpeak M + = 356/358 (1 Cl) (7, / V.) - Isomers -Gemi RPII- Yield: 37% of theory; Melting point: 168-170C;
DC-Rf = 0.54 und 0.49 [Kieselgel; CH2C12/Toluol (5:2)]; Beide DC-Flecke geben den Molpeak M+ = 356/358 (1 Cl) .TLC-Rf = 0.54 and 0.49 [silica gel; CH 2 C1 2 / toluene (5: 2)]; Both DC spots give the Molpeak M + = 356/358 (1 Cl).
(c) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-methyl-phe- yl ) methyl i en } -5-n τo- - i ndol inon(c) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-methyl-phe-yl) methyl i en} -5-n τo- - i ndol inon
Hergestellt durch Reaktion des unter (b) erhaltenen (Z) -IsomersPrepared by reaction of the (Z) isomer obtained in (b)
(Schmelzpunkt: 201-202°C) mit 1.1 Äquivalent 4- (1H-Imidazol- 4-yl) anilin x 2 HCl (Schmelzpunkt: 350°C) und 3.3 Äquivalenten NaHCθ3 in DMF (50°C, 1 Stunde) , Eingießen in verdünntem Ammoniak, Extraktion mit EtOAc, Abtrennen der organischen Phase und deren Reinigung durch Säulenchromatographie an Kieselgel mit CH2Cl2/MeOH/konz . Ammoniak (10:1:0.1) als Eluens. Ausbeute : 4.6 % der Theorie; Schmelzpunkt : 297°C; C25H19N5O3 (Melting point: 201-202 ° C) with 1.1 equivalent of 4- (1H-imidazol-4-yl) aniline x 2 HCl (melting point: 350 ° C) and 3.3 equivalents of NaHCO 3 in DMF (50 ° C, 1 hour), Pour in dilute ammonia, extract with EtOAc, separate the organic phase and purify it by column chromatography on silica gel with CH2Cl2 / MeOH / conc. Ammonia (10: 1: 0.1) as eluent. Yield: 4.6% of theory; Melting point: 297 ° C; C25H 19 N5O 3
Ber.: Molpeak (M+H) + = 438 Gef.: Molpeak (M+H) + = 438Calc .: Molpeak (M + H) + = 438 Found: Molpeak (M + H) + = 438
Analog Beispiel 11 wurden folgende Verbindungen erhalten:The following compounds were obtained analogously to Example 11:
ii-i 3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-brom-phen- yl) methyliden} -2-indolinonii-i 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-bromo-phen-yl) methylidene} -2-indolinone
(a) l-Acetyl-3- [1-hydroxy-l- (4-brom-phenyl) methyliden] -2-indolinon(a) l-Acetyl-3- [1-hydroxy-1- (4-bromophenyl) methylidene] -2-indolinone
Hergestellt analog Beispiel 10 (a) aus l-Acetyl-2-indolinon und 4-Brom-benzoesäure in trockenem DMF in Gegenwart von TBTU, HOBT sowie Hünig's Base (20°C, über Nacht) und abschließende Reinigung durch Säulenchromatographie an Kieselgel mit CK2Cl2/MeOHPrepared analogously to Example 10 (a) from l-acetyl-2-indolinone and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and final purification by column chromatography on silica gel with CK2Cl 2 / MeOH
(20:1) als Eluens. Ausbeute: 81 % der Theorie; Schmelzpunkt: 140-142°C;(20: 1) as Eluens. Yield: 81% of theory; Melting point: 140-142 ° C;
Enol-Reaktion (mit FeCl3~Lösung in EtOH) : positiv.Enol reaction (with FeCl3 ~ solution in EtOH): positive.
(b) l-Acetyl-3- [1-chlor-l- (4 -brom-phenyl) methyliden] -2-indo- linon(b) l-Acetyl-3- [1-chloro-l- (4-bromo-phenyl) methylidene] -2-indoline
Man erhitzt l-Acetyl-3- [1-hydroxy-l- (4-brom-phenyl) methyliden} - 2 -indolinon und 2 Äquivalente PCI5 in Toluol 1 Stunde bei1-Acetyl-3- [1-hydroxy-1- (4-bromophenyl) methylidene} -2-indolinone and 2 equivalents of PCI5 are heated in toluene for 1 hour
100 °C. Man filtriert, dampft im Vakuum ein und gibt Petrolether zum öligen Eindampfrückstand.100 ° C. It is filtered, evaporated in vacuo and petroleum ether is added to the oily evaporation residue.
Ausbeute: 46 % der Theorie;Yield: 46% of theory;
Schmelzpunkt: 177-178°C;Melting point: 177-178 ° C;
C17HnBrClN02 C 17 HnBrClN0 2
Ber. : Molpeak M+ = 375/377/379 (1 Br, 1 Cl)Ber. : Molpeak M + = 375/377/379 (1 Br, 1 Cl)
Gef.: Molpeak M+ = 375/377/379 (1 Br, 1 Cl)Found: Molpeak M + = 375/377/379 (1 Br, 1 Cl)
(c) 3- rch or-1 - (4-brom-phenyl ) methyli en! -2- indol non Hergestellt aus der unter (b) erhaltenen Verbindung durch Reaktion mit 1 Äquivalent Piperidin in MeOH (5 Stunden, 40°C) Ausbeute: 46 % der Theorie;(c) 3- rch or-1 - (4-bromophenyl) methyli en! -2- indole non Prepared from the compound obtained under (b) by reaction with 1 equivalent of piperidine in MeOH (5 hours, 40 ° C.) Yield: 46% of theory;
Schmelzpunkt: 260-262°C;Melting point: 260-262 ° C;
C15H9BrClNOC 15 H9BrClNO
Ber. : Molpeak M+ = 333/335/337 (Br, Cl)Ber. : Molpeak M + = 333/335/337 (Br, Cl)
Gef.: Molpeak M+ = 333/335/337 (Br, Cl)Found: Molpeak M + = 333/335/337 (Br, Cl)
(d) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4 -brom-phenyl) - methyl den } -2- i ndol inon(d) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-bromo-phenyl) -methyl den} -2- i ndol inone
Hergestellt durch Reaktion der unter (c) erhaltenen Verbindung mit 1.2 Äquivalenten 4- (lH-Imidazol-4-yl) anilin x 2 HClPrepared by reaction of the compound obtained under (c) with 1.2 equivalents of 4- (1H-imidazol-4-yl) aniline x 2 HCl
(Schmelzpunkt: 350°C) und 6 Äquivalenten Hünig's Base in DMF (80°C, 6 Stunden; 100°C, 2 Stunden) , Eingießen in Wasser, Extraktion mit EtOAc, Abtrennen der organischen Phase und deren Reinigung durch Säulenchromatographie an Kieselgel mit CH2Cl2/MeOH (10:1) als Eluens. Ausbeute: 8.2 % der Theorie; Schmelzpunkt: 332-336°C; C24H1 BrN40(Melting point: 350 ° C) and 6 equivalents of Hünig's base in DMF (80 ° C, 6 hours; 100 ° C, 2 hours), pouring into water, extraction with EtOAc, separation of the organic phase and its purification by column chromatography on silica gel with CH 2 Cl 2 / MeOH (10: 1) as eluent. Yield: 8.2% of theory; Melting point: 332-336 ° C; C 24 H 1 BrN 4 0
Ber. : Molpeak M+ = 456/458 (1 Br)Ber. : Molpeak M + = 456/458 (1 Br)
Gef.: Molpeak M+ = 456/458 (1 Br)Found: Molpeak M + = 456/458 (1 Br)
ιi-2 3-{ (Z) -1- [4- ( (2-Oxo-pyrrolidin-l-yl) -methyl) anilino] - 1- (4 -brom-phenyl) methyliden} -5-nitro-2-indolinonιi-2 3- {(Z) -1- [4- ((2-Oxopyrrolidin-l-yl) methyl) anilino] - 1- (4-bromophenyl) methylidene} -5-nitro-2 -indolinone
(a) l-Acetyl-3- [1-hydroxy-l- (4 -brom-phenyl) methyliden] -5-nitro- - n ol inon(a) l-Acetyl-3- [1-hydroxy-1- (4-bromo-phenyl) methylidene] -5-nitro- - n ol inone
Hergestellt analog Beispiel 10 (a) aus l-Acetyl-5-nitro-2-indo- linon und 4-Brom-benzoesäure in trockenem DMF in Gegenwart von TBTU, HOBT sowie Hünig's Base (20°C, über Nacht) und Eindampfen im Vakuum. Eine Probe des erhaltenen Rohprodukts wurde durch Säulenchromatographie an Kieselgel mit CH2Cl2/MeOH (20:1) als Eluens gereinigt .Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-2-indoline and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and evaporation in Vacuum. A sample of the crude product obtained was purified by column chromatography on silica gel with CH 2 Cl2 / MeOH (20: 1) as the eluent.
Schmelzpunkt: 313 °C;Melting point: 313 ° C;
Enol-Reaktion (mit FeCl3 -Lösung in EtOH) : positiv. c17HllBrN2°Enol reaction (with FeCl3 solution in EtOH): positive. c 17 H ll BrN 2 °
Ber. : Molpeak M+ = 402/404 (Br)Ber. : Molpeak M + = 402/404 (Br)
Gef.: Molpeak M+ = 402/404 (Br)Found: Molpeak M + = 402/404 (Br)
(b) l-Acetyl-3- [1-chlor-l- (4 -brom-phenyl) methyliden] -5-nitro-(b) l-acetyl-3- [1-chloro-l- (4-bromophenyl) methylidene] -5-nitro-
2-i ndol i non2-i ndol i non
Hergestellt aus dem unter (a) erhaltenen Rohprodukt durch Erhitzen mit 2 Äquivalenten PCI5 in trockenem Toluol (3 Stunden, 80 °C) , Eindampfen im Vakuum und Verreiben mit Ether. Ausbeute: 59 % der Theorie;Prepared from the crude product obtained under (a) by heating with 2 equivalents of PCI5 in dry toluene (3 hours, 80 ° C.), evaporating in vacuo and triturating with ether. Yield: 59% of theory;
Schmelzpunkt: 202-205°C;Melting point: 202-205 ° C;
C17H10BrClN2O4 C 17 H 10 BrClN 2 O 4
Ber.: Molpeak M+ = 420/422/424 (Br, Cl)Calc .: Molpeak M + = 420/422/424 (Br, Cl)
Gef.: Molpeak M+ = 420/422/424 (Br, Cl)Found: Molpeak M + = 420/422/424 (Br, Cl)
( ) 3- n -rhlor-1 - U-hrom-phenyl ) methyl idenl -5-nitro-2- i ndol inon Hergestellt aus der unter (b) erhaltenen Verbindung durch Zu- tropfen von soviel einer verdünnten Lösung von Natriummethylat in MeOH bei Raumtemperatur, bis laut DC-Kontrolle keine Ausgangsverbindung mehr nachweisbar ist. Ausbeute: 88 % der Theorie;() 3- n -Rhlor-1 - U-hrom-phenyl) methyl idenl -5-nitro-2-indole inone Prepared from the compound obtained under (b) by dropwise addition of as much dilute solution of sodium methylate in MeOH at room temperature until, according to the DC control, no further output connection can be detected. Yield: 88% of theory;
Schmelzpunkt: 263-265°C;Melting point: 263-265 ° C;
C17H8BrClN203 C 17 H 8 BrClN 2 0 3
Ber. : Molpeak M+ = 378/380/382 (Br, Cl)Ber. : Molpeak M + = 378/380/382 (Br, Cl)
Gef.: Molpeak M+ = 378/380/382 (Br, Cl)Found: Molpeak M + = 378/380/382 (Br, Cl)
(d) 3-{ (Z) -1- (4- (2-Oxo-pyrrolidin-l-yl) -methyl) anilino] -(d) 3- {(Z) -1- (4- (2-Oxo-pyrrolidin-l-yl) methyl) anilino] -
1 - ( Δ -brom-phenyl) ethyl i en} -5-nitro-2-i ndol inon1 - (Δ-Bromophenyl) ethyl i en} -5-nitro-2-indol inone
Hergestellt durch Reaktion der unter (c) erhaltenen Verbindung mit 1 Äquivalent 4- ( (2-0xo-pyrrolidin-l-yl) -methyl) anilin undPrepared by reaction of the compound obtained under (c) with 1 equivalent of 4- ((2-0xo-pyrrolidin-l-yl) methyl) aniline and
2 Äquivalenten Hünig's Base in DMF (120°C, 0.75 Stunden), Eingießen in Wasser, Extraktion mit EtOAc, Abtrennen der organischen Phase und deren Reinigung durch Säulenchromatographie an Kieselgel mit CH2Cl /MeOH (15:1) als Eluens.2 equivalents of Hünig's base in DMF (120 ° C, 0.75 hours), pouring into water, extraction with EtOAc, separation of the organic phase and purification by column chromatography on silica gel with CH 2 Cl / MeOH (15: 1) as the eluent.
Ausbeute: 53 % der Theorie; Schmelzpunkt: 285-287°C;Yield: 53% of theory; Melting point: 285-287 ° C;
C26H21BrN4θ4 C 26H21 BrN 4 θ 4
Ber. : Molpeak MH+ = 532/534 (Br)Ber. : Molpeak MH + = 532/534 (Br)
Gef.: Molpeak MH+ = 532/534 (Br)Found: Molpeak MH + = 532/534 (Br)
11.3 3- { (Z) -1- [4- (Pyrrolidin-1-yl-methyl) anilino] -1- (4-brom- phenyl) methyliden} -5-nitro-indolinon11.3 3- {(Z) -1- [4- (Pyrrolidin-1-yl-methyl) anilino] -1- (4-bromophenyl) methylidene} -5-nitro-indolinone
Hergestellt durch Reaktion von 3- [1-Chlor-l- (4 -brom-phenyl) - methyliden] -5-nitro-2-indolinon mit 1 Äquivalent 4- (Pyrrolidin- 1-yl-methyl) anilin und 2 Äquivalenten Hünig's Base in DMF (1 Stunden, 120°C) , Eingießen in Wasser, Extraktion mit EtOAc, Abtrennen der organischen Phase und deren Reinigung durch Säulenchromatographie an Si02 mit CH Cl /MeOH (15:1) als Eluens. Ausbeute: 37.6 % der Theorie; Schmelzpunkt: 300-304°C; C26H23BrN403 Prepared by reaction of 3- [1-chloro-l- (4-bromo-phenyl) methylidene] -5-nitro-2-indolinone with 1 equivalent of 4- (pyrrolidin-1-yl-methyl) aniline and 2 equivalents of Hünig's Base in DMF (1 hour, 120 ° C), pouring into water, extraction with EtOAc, separating the organic phase and purifying it by column chromatography on Si0 2 with CH Cl / MeOH (15: 1) as the eluent. Yield: 37.6% of theory; Melting point: 300-304 ° C; C 26 H 23 BrN 4 0 3
Ber. : Molpeak M+ = 518/520 (Br) Gef.: Molpeak M+ = 518/420 (Br) n -4 3-{ (Z) -1- [4- (Pyrrolidin-1-yl-methyl) anilino] -1- [4- (imidazol-1-yl-methyl) -phenylmethyliden] } -5-nitro-2-indolinonBer. : Molpeak M + = 518/520 (Br) Found: Molpeak M + = 518/420 (Br) n -4 3- {(Z) -1- [4- (pyrrolidin-1-yl-methyl) anilino] -1- [4- (imidazol-1-yl-methyl) -phenylmethylidene]} -5-nitro- 2-indolinone
(a) l-Acetyl-3- {l-hydroxy-1- [4- (imidazol-1-yl-methyl) phenyl] - methyl iden} -5-nitro-2- i dol inon(a) l-Acetyl-3- {l-hydroxy-1- [4- (imidazol-1-ylmethyl) phenyl] methyl iden} -5-nitro-2-i dol inone
Hergestellt analog Beispiel 10 (a) aus l-Acetyl-5-nitro-indoli- non und 4- (Imidazol-1-yl-methyl)benzoesäure in trockenem DMF in Gegenwart von TBTU, HOBT und Hünig's Base.Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-indolinone and 4- (imidazol-1-yl-methyl) benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base.
Ausbeute: 89 % der Theorie; Schmelzpunkt: 235-237°C; 21H16N4°5 (404.39) Ber.: Molpeak (M-H) " = 403 Gef.: Molpeak (M-H)" = 403Yield: 89% of theory; Melting point: 235-237 ° C; 21 H 16 N 4 ° 5 ( 404.39 ) Calc .: Molpeak (MH) "= 403 Found: Molpeak (MH)" = 403
(b) 3-{ (Z) -1- [4- (Pyrrolidin-1-yl-methyl) anilino] -1- [4- (imidazo] -1-yl -methyl ^ phenyl 1 methyl i den } -5-nitm- -indolinon(b) 3- {(Z) -1- [4- (pyrrolidin-1-ylmethyl) anilino] -1- [4- (imidazo] -1-ylmethyl ^ phenyl 1 methyl i den} -5 -nitm- -indolinone
Hergestellt durch Umsetzung der unter (a) erhaltenen Verbindung mit PCI5 in Toluol analog Beispiel 11 (b) und anschließend mit 4- (Pyrrolidin-1-yl-methyl) anilin und Triethylamin in THF analog Beispiel 11. Id.Prepared by reacting the compound obtained under (a) with PCI5 in toluene analogously to Example 11 (b) and then with 4- (pyrrolidin-1-yl-methyl) aniline and triethylamine in THF analogously to Example 11. Id.
Ausbeute: 16 % der Theorie;Yield: 16% of theory;
Schmelzpunkt: 202 -204 °C;Melting point: 202-204 ° C;
C30H28N6O3 (520.60)C3 0 H28N6O3 (520.60)
Ber.: Molpeak (M+H) + = 521Calc .: Molpeak (M + H) + = 521
Gef.: Molpeak (M+H) + = 521Found: Molpeak (M + H) + = 521
DC-Rf = 0.7 (Kieselgel; Dichlormethan/Methanol/NH OH 5:1:0.01TLC Rf = 0.7 (silica gel; dichloromethane / methanol / NH OH 5: 1: 0.01
11.5 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- [4- (imidazol- η -yl -mp-hyl pheny11 methyl i den} -5-ni tro- -i ndol inon11.5 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- [4- (imidazole- η -yl-mp-methyl pheny11 methyl i den} -5-nitro - -i ndol inon
Hergestellt analog Beispiel 11.4 (b) durch Umsetzung von 1-Ace- tyl-3-(l-hydroxy-l- [4- (imidazol-1-yl-methyl) phenyl] methyliden} - 5-nitro-2-indolinon mit PCI5 in Toluol und anschließend mit 4- (IH-imidazol -4-yl) anilin und Triethylamin in THF. Ausbeute: 25 % der Theorie ; Schmelzpunkt: 230-235°C; C28H21N703 (503.53)Prepared analogously to Example 11.4 (b) by reacting 1-acetyl-3- (l-hydroxy-1- [4- (imidazol-1-yl-methyl) phenyl] methylidene} - 5-nitro-2-indolinone with PCI5 in toluene and then with 4- (IH-imidazol -4-yl) aniline and triethylamine in THF.Yield: 25% of theory; melting point: 230-235 ° C; C 28 H 21 N 7 0 3 (503.53)
Ber.: Molpeak (M+H)+ = 504Calc .: Molpeak (M + H) + = 504
Gef.: Molpeak (M+H) + = 504Found: Molpeak (M + H) + = 504
C27H24N 05 X H20 (521.54)C 27 H 24 N 0 5 XH 2 0 (521.54)
Ber.: C 64.45 H 4.40 N 18.57Calc .: C 64.45 H 4.40 N 18.57
Gef.: 64.30 4.40 18.57Found: 64.30 4.40 18.57
Figure imgf000092_0001
Figure imgf000092_0001
3-{ (Z) -l-[3- (lH-Imidazolin-2-yl) anilino] -1-phenylmethyliden} - 2-indolinon x 0.4 H203- {(Z) -l- [3- (1H-Imidazolin-2-yl) anilino] -1-phenylmethylidene} -2-indolinone x 0.4 H 2 0
Man gibt l-Benzoyl-3- (l- [3 -cyano-anilino] -1-phenylmethyliden} - 2-indolinon (Schmelzpunkt: 245-248°C) in eine kalte (-10°C) gesättigte Lösung von HCl-Gas in MeOH. Nach Rühren über Nacht bei Raumtemperatur dampft man bei 30°C im Vakuum ein, versetzt den Eindampfrückstand mit Ether und trocknet ihn bei 20°C im Vakuum. Das erhaltene rohe Imino-methylether-Hydrochlorid (Schmelzpunkt: 233-237°C) rührt man zusammen mit 5 Äquivalenten Ethylendiamin über Nacht bei Raumtemperatur. Nach Eindampfen im Vakuum versetzt man mit Ether und reinigt den erhaltenen Niederschlag durch Säulenchromatographie an Kieselgel mit MeOH/EtOAc/konz . Ammoniak (9:1:0.5) als Eluens . Ausbeute: 25 % der Theorie; Schmelzpunkt: 262-267°C; C24H20N4° x 0.4 H201-Benzoyl-3- (l- [3-cyano-anilino] -1-phenylmethylidene} - 2-indolinone (melting point: 245-248 ° C.) is added to a cold (-10 ° C.) saturated solution of HCl- Gas in MeOH After stirring overnight at room temperature, the mixture is evaporated in vacuo at 30 ° C., the evaporation residue is mixed with ether and dried in vacuo at 20 ° C. The crude iminomethyl ether hydrochloride obtained (melting point: 233-237 ° C) is stirred together with 5 equivalents of ethylenediamine overnight at room temperature, after evaporation in vacuo, ether is added and the precipitate obtained is purified by column chromatography on silica gel using MeOH / EtOAc / concentrated ammonia (9: 1: 0.5) as the eluent : 25% of theory; melting point: 262-267 ° C; C24H 2 0 N 4 ° x 0.4 H 2 0
Ber. C 74.35 H 5.41 N 14.45 Gef. 74.64 5.55 14.23 Ber. Molpeak M+ = 380 Gef. Molpeak M+ = 380Ber. C 74.35 H 5.41 N 14.45 Found 74.64 5.55 14.23 Calc. Molpeak M + = 380 Found Molpeak M + = 380
Analog Beispiel 12 wurde folgende Verbindung erhalten:The following compound was obtained analogously to Example 12:
1 .1 3-{ (Z) -1- [4- ( (Imidazolin-2-yl) methyl) -anilino] -1-phenyl■ methyliden}-5-nitro-2 -indolinon1 .1 3- {(Z) -1- [4- ((imidazolin-2-yl) methyl) anilino] -1-phenyl ■ methylidene} -5-nitro-2 -indolinon
Hergestellt aus 3-{ (Z) -1- [4-Cyanomethyl-anilino] -1-phenylme- thyliden}-5-nitro-2 -indolinon (Schmelzpunkt: 329°C) durch Be- handeln zuerst mit gesättigter HCl/MeOH-Lösung bei -10°C und danach mit Ethylendiamin, Abtrennen von 3-{ (Z) -1- [4-Methoxycar- bonylmethyl-anilino] -1-phenylmethyliden}-5-nitro-2-indolinon (43 % der Theorie, Schmelzpunkt: 238-240°C) durch Extraktion aus 2N-essigsaurer Lösung mit Methylenchlorid und Ausfällen der Titelverbindung durch Zugabe von konz . Ammoniak zur wäßrigen Lösung .Made from 3- {(Z) -1- [4-cyanomethyl-anilino] -1-phenylmethylidene} -5-nitro-2-indolinone (melting point: 329 ° C) by loading act first with saturated HCl / MeOH solution at -10 ° C and then with ethylenediamine, separation of 3- {(Z) -1- [4-methoxycarbonylmethyl anilino] -1-phenylmethylidene} -5-nitro-2 -Indolinone (43% of theory, melting point: 238-240 ° C) by extraction from 2N acetic acid solution with methylene chloride and precipitation of the title compound by adding conc. Ammonia to the aqueous solution.
Ausbeute: 14.5 % der Theorie; Schmelzpunkt: 329-330°CYield: 14.5% of theory; Melting point: 329-330 ° C
C25H21N5O3C25H21N5O3
Ber. : Molpeak M+ = 439Ber. : Molpeak M + = 439
Gef.: Molpeak M+ = 439Found: Molpeak M + = 439
Beispiel 13.Example 13.
3- { (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1-phenylmethyliden} - 5-nitro-2 -indolinon Hydrochlorid x 0.5 H20 x 0.8 Dioxan3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1-phenylmethylidene} - 5-nitro-2-indolinone hydrochloride x 0.5 H 2 0 x 0.8 dioxane
Hergestellt aus 3- { (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1-phe- nylmethyliden}-5-nitro-2-indolinon in Dioxan mit 1.09 Äquivalenten IN Salzsäure und Eindampfen im Vakuum. Ausbeute: 81 % der Theorie; Schmelzpunkt: >400°C; 24H17N5°3 H 1 x -5 H2° x 0.8 DioxanMade from 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone in dioxane with 1.09 equivalents of IN hydrochloric acid and evaporation in Vacuum. Yield: 81% of theory; Melting point:> 400 ° C; 24 H 17 N 5 ° 3 H 1 x - 5 H 2 ° x 0.8 dioxane
Ber. : C 60.48 H 4.75 N 13.01Ber. : C 60.48 H 4.75 N 13.01
Gef. : 60.62 4.72 12.93Found: 60.62 4.72 12.93
Ber. : Molpeak M+ = 423Ber. : Molpeak M + = 423
Gef. : Molpeak M+ = 423Found: Molpeak M + = 423
Beispiel 14Example 14
3- { (Z) -1- [4- (1,2,3 , 4-Tetrahydro-isochinolin- (5) -yl) amino] - l-phenylmethyliden}-2-indolinon-hydrochlorid x H2O3- {(Z) -1- [4- (1,2,3, 4-tetrahydro-isoquinoline- (5) -yl) amino] - l-phenylmethylidene} -2-indolinone hydrochloride x H 2 O
Hergestellt aus 3- { (Z) -1- [4- (2-Boc-l, 2, 3 , 4-tetrahydro-isochinolin- (5) -yl) amino] -1-phenylmethyliden} -2-indolinon in CH2CI2 mit Salzsäure/EtOAc (20°C, 2 Stunden) . Ausbeute: 83 % der Theorie; Schmelzpunkt : ~290 ° C ; C24H21N30 x HCl x H20Made from 3- {(Z) -1- [4- (2-Boc-l, 2, 3, 4-tetrahydro-isoquinoline- (5) -yl) amino] -1-phenylmethylidene} -2-indolinone in CH2CI2 with hydrochloric acid / EtOAc (20 ° C, 2 hours). Yield: 83% of theory; Melting point: ~ 290 ° C; C 24 H 21 N 3 0 x HCl x H 2 0
Ber. C 68.32 H 5.73 N 9.96 Gef. 68.71 5.76 10.13 Ber. Molpeak M+ = 367 Gef. Molpeak M+ = 367Ber. C 68.32 H 5.73 N 9.96 Found 68.71 5.76 10.13 calc. Molpeak M + = 367 Found Molpeak M + = 367
Analog Beispiel 14 wurden erhalten:The following were obtained as in Example 14:
14.1 3-{ (Z) -1- [ (l,2,3,4-Tetrahydro-isochinolin-6-yl) amino] - 1-phenylmethyliden} -5-nitro-2-indolinon x HCl x H2014.1 3- {(Z) -1- [(l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] - 1-phenylmethylidene} -5-nitro-2-indolinone x HCl x H 2 0
Hergestellt aus 3- { (Z) -1- [ (2-Boc-l, 2, 3 , 4-tetrahydro-isochino- lin-6-yl) amino-1-phenylmethyliden} -5-nitro-2-indolinon mittels Chlorwasserstoff in EtOAc. Ausbeute: 86 % der Theorie; Schmelzpunkt: 299-300°C; 24H20N4°3 x HC1 x H2°Made from 3- {(Z) -1- [(2-Boc-l, 2, 3, 4-tetrahydro-isoquinoline-6-yl) amino-1-phenylmethylidene} -5-nitro-2-indolinone Hydrogen chloride in EtOAc. Yield: 86% of theory; Melting point: 299-300 ° C; 24 H 20 N 4 ° 3 x HC1 x H 2 °
Ber. C 61.74 H 4.96 N 12.00 Gef, 62.11 4.70 12.05 Ber. Molpeak M+ = 412 Gef. Molpeak M+ = 412Ber. C 61.74 H 4.96 N 12.00 Gef, 62.11 4.70 12.05 Ber. Molpeak M + = 412 Found Molpeak M + = 412
14.2 Gemisch von 3- { (Z) -1- [4- ( (Imidazolin-2-yl) methyl) anilino] - l-phenylmethyliden}-5-nitro-2 -indolinon x CF3COOH (75 %) und 3- { (Z) -1- [3- ( (Imidazolin-2-yl) methyl) anilino] -1-phenylmethyli- den}-5-nitro-2-indolinon x CF3COOH (25 %)14.2 Mixture of 3- {(Z) -1- [4- ((imidazolin-2-yl) methyl) anilino] - l-phenylmethylidene} -5-nitro-2-indolinone x CF3COOH (75%) and 3- { (Z) -1- [3- ((imidazolin-2-yl) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone x CF3COOH (25%)
Hergestellt aus dem Gemisch von 3- { (Z) -1- [4- ( (l-Boc-imidazolin-Made from the mixture of 3- {(Z) -1- [4- ((l-Boc-imidazolin-
2-yl) methyl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon2-yl) methyl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
(75 %)und 3-{ (Z) -1- [3- ( (l-Boc-imidazolin-2-yl) methyl) anilino] -(75%) and 3- {(Z) -1- [3- ((l-Boc-imidazolin-2-yl) methyl) anilino] -
1-phenylmethyliden} -5-nitro-2 -indolinon (25 %) mit1-phenylmethylidene} -5-nitro-2-indolinone (25%) with
Trifluoressigsäure in Methylenchlorid.Trifluoroacetic acid in methylene chloride.
Ausbeute: 75 % der Theorie;Yield: 75% of theory;
Schmelzpunkt: 238-241°C;Melting point: 238-241 ° C;
C25H21 5O3 CF3COOHC25H21 5O3 CF3COOH
Ber.: C 58.59 H 4.01 N 12.65Calc .: C 58.59 H 4.01 N 12.65
Gef.: 58.45 3.99 12.62 Ber. : Molpeak M+ = 439 Gef.: Molpeak M+ = 439Found: 58.45 3.99 12.62 Ber. : Molpeak M + = 439 Found: Molpeak M + = 439
Beispiel 15Example 15
3- { (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (3 -aminomethyl-phenyl) methyliden} -2 -indolinon3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (3-aminomethylphenyl) methylidene} -2-indolinone
Hergestellt aus 3- { (Z) -1- [4- (1H-Imidazol-4-yl) anilino] - 1- (3 -cyano-phenyl) methyliden} -2-indolinon durch katalytische Hydrierung an Raney-Nickel in gesättigtem methanolischem Ammoniak (20°C, 3.5 bar, 3 Stunden), Eindampfen im Vakuum und Verreiben mit Ether. Ausbeute: 83 % der Theorie; Schmelzpunkt: ab 101°C (Zers.);Made from 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] - 1- (3 -cyano-phenyl) methylidene} -2-indolinone by catalytic hydrogenation on Raney nickel in saturated methanolic ammonia (20 ° C, 3.5 bar, 3 hours), evaporation in vacuo and trituration with ether. Yield: 83% of theory; Melting point: from 101 ° C (dec.);
DC-Rf = 0.32 [Kieselgel; Methylenchlorid/Methanol/konz . Ammoniak (100:10:1)] C25H21N50TLC Rf = 0.32 [silica gel; Methylene chloride / methanol / conc. Ammonia (100: 10: 1)] C 2 5H 21 N 5 0
Ber. : Molpeak M+ = 407 Gef.: Molpeak M+ = 407Ber. : Molpeak M + = 407 Found: Molpeak M + = 407
•Rei spiel 16 • Rei game 16
3- { (Z) -1- [4- (2-Amino-lH-imidazol-4-yl) anilino] -1-phenylmethy- 1iden} -2-indolinon x H 03- {(Z) -1- [4- (2-Amino-1H-imidazol-4-yl) anilino] -1-phenylmethy-1idene} -2-indolinone x H 0
Hergestellt aus 3- { (Z) -1- [4- (Imidazo [1, 2-a] pyrimidin-2-yl) anilino] -1-phenylmethyliden} -2 -indolinon x 0.5 H20 und 13 Äquivalenten Hydrazi -hydrat in EtOH durch Erhitzen unter Rückfluß (72 Stunden) , Eindampfen im Vakuum und Reinigung durch Säulenchromatographie an AI2O3 mit CH2Cl2/MeOH (10:1) als Eluens. Ausbeute: 21.8 % der Theorie; Schmelzpunkt: 250-255 °C; 24H19N5° x H2°Made from 3- {(Z) -1- [4- (Imidazo [1, 2-a] pyrimidin-2-yl) anilino] -1-phenylmethylidene} -2 -indolinone x 0.5 H 2 0 and 13 equivalents of hydrazi - hydrate in EtOH by heating under reflux (72 hours), evaporating in vacuo and purifying by column chromatography on Al2O3 with CH 2 Cl 2 / MeOH (10: 1) as the eluent. Yield: 21.8% of theory; Melting point: 250-255 ° C; 24 H 19 N 5 ° x H 2 °
Ber.: C 70.06 H 5.14 N 17.02Calc .: C 70.06 H 5.14 N 17.02
Gef.: 70.11 5.17 17.17Found: 70.11 5.17 17.17
Ber.: Molpeak M+ = 393Calc .: Molpeak M + = 393
Gef.: Molpeak M+ = 393 Beispi l 17Found: Molpeak M + = 393 Example 17
3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4 -aminomethyl-phenyl) methyliden} -5-nitro-2-indolinon x H203- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-aminomethylphenyl) methylidene} -5-nitro-2-indolinone x H 2 0
(a) l-Acetyl-3- [1-hydroxy-l- (4 -phthalimidornethyl -phenyl )methy-(a) l-acetyl-3- [1-hydroxy-l- (4-phthalimidomethylphenyl) methyl
1 i den} -5 -nitro-2- indol inon1 i the} -5-nitro-2-indole inone
Hergestellt analog Beispiel 10 aus l-Acetyl-5-nitro-2 -indolinon und 4-Phthalimidomethyl-benzoesäure (Schmelzpunkt: 260-262°C; erhalten aus dem entsprechenden tert .Butylester vom Schmelzpunkt 142-145 °C mit TFA) in trockenem DMF in Gegenwart von TBTU, HOBT sowie Hünig's Base (20°C, 2 Stunden), Einrühren in verdünnter Salzsäure, Digerieren des erhaltenen Niederschlages in EtOAc und Trocknen der FestSubstanz bei 100 °C im Vakuum. Ausbeute: 85 % der Theorie;Prepared analogously to Example 10 from l-acetyl-5-nitro-2-indolinone and 4-phthalimidomethyl-benzoic acid (melting point: 260-262 ° C; obtained from the corresponding tert-butyl ester of melting point 142-145 ° C with TFA) in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, 2 hours), stirring in dilute hydrochloric acid, digesting the precipitate obtained in EtOAc and drying the solid at 100 ° C in vacuo. Yield: 85% of theory;
Schmelzpunkt: 241-242°C;Melting point: 241-242 ° C;
Enol-Reaktion (mit FeCl3 -Lösung in EtOH) .- positiv.Enol reaction (with FeCl3 solution in EtOH) .- positive.
(b) l-Acetyl-3- [1-chlor-l- (4 -phthalimidomethyl -phenyl) methyliden} -5-ni t,rQ-2-inrio] Inon(b) l-Acetyl-3- [1-chloro-l- (4-phthalimidomethylphenyl) methylidene} -5-nit, rQ-2-inrio] inon
Man erhitzt analog Beispiel 11 (b) das oben unter (a) erhaltene Enol mit 2 Äquivalenten von PCI5 in Toluol (90°C/6 Stunden und 110°C/6 Stunden) , isoliert den beim Abkühlen entstehenden Niederschlag, wäscht ihn mit Toluol und trocknet ihn bei 75 °C im Vakuum.The enol obtained under (a) above is heated in analogy to Example 11 (b) with 2 equivalents of PCI5 in toluene (90 ° C./6 hours and 110 ° C./6 hours), the precipitate formed on cooling is isolated and washed with toluene and dry it at 75 ° C in a vacuum.
Ausbeute: 65 % der Theorie; Schmelzpunkt: 234-236°C; C25H20N6°3 x H20Yield: 65% of theory; Melting point: 234-236 ° C; C25 H 20 N 6 ° 3 x H 2 0
Ber. C 62.22 H 3.21 N 8.37 Cl 7.06 Gef. 62.25 3.31 8.27 7.20 Ber. Molpeak M+ = 501/503 (1 Cl) Gef. Molpeak M+ = 501/503 (1 Cl) (c) l-Acetyl-3 - { (Z) -1- [4 - (lH-imidazol-4-yl) anilino] -Ber. C 62.22 H 3.21 N 8.37 Cl 7.06 Found 62.25 3.31 8.27 7.20 calc. Molpeak M + = 501/503 (1 Cl) Found Molpeak M + = 501/503 (1 Cl) (c) l-acetyl-3 - {(Z) -1- [4 - (lH-imidazol-4-yl) anilino] -
1 - (4-phthal midomethyl -phenyl )methy1 i den } - -nitro-2-i ndo inon Man gibt eine Lösung von 0.50 g (1 mMol) der unter (b) erhaltenen Chlor-Verbindung in 20 ml CH2C12 zu einer kalten (Tj_ =1 - (4-phthal midomethyl-phenyl) methy1 i den} - -nitro-2-i ndo inon A solution of 0.50 g (1 mmol) of the chlorine compound obtained under (b) in 20 ml CH 2 C1 2 is added to a cold (T j _ =
-60 °C) gerührten Suspension von 0.35 g (1.5 mMol) 4-(lH-Imida- zol-4-yl) anilin x 2 HCl (Schmelzpunkt: 350°C) und 0.77 ml-60 ° C) stirred suspension of 0.35 g (1.5 mmol) of 4- (1H-imidazol-4-yl) aniline x 2 HCl (melting point: 350 ° C) and 0.77 ml
(4.5 mMol) Hünig's Base in 20 ml CH2C1 und rührt über Nacht bei Raumtemperatur. Nach Eindampfen im Vakuum und zwei Eindampfen mit Toluol im Vakuum verreibt man den erhaltenen Rückstand mit EtOH.(4.5 mmol) of Hünig's base in 20 ml CH 2 C1 and stirred overnight at room temperature. After evaporation in vacuo and two evaporation with toluene in vacuo, the residue obtained is triturated with EtOH.
Ausbeute (roh): 0.47 g (75 % der Theorie); Schmelzpunkt: 200 °C; C35H24N606 Yield (crude): 0.47 g (75% of theory); Melting point: 200 ° C; C 35 H2 4 N 6 0 6
Ber. : Molpeak M+ = 624 Gef.: Molpeak M+ = 624Ber. : Molpeak M + = 624 Found: Molpeak M + = 624
(d) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4 -aminomethyl - heny] .) ethyliden }-5-n.i ro-2- indolinon H2Ω(d) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-aminomethyl-heny].) ethylidene} -5-ni ro-2-indolinone H 2 Ω
Man erhitzt 0.45 g (0.72 mMol) der unter (c) erhaltenen Verbindung zusammen mit 0.1 ml 80%igem Hydrazin-hydrat (1.6 mMol) in 20 ml CH2Cl2/EtOH (1:1) 6 Stunden bei 50 °C. Man dampft im Vakuum ein und reinigt den Eindampfrückstand durch Säulenchromatographie an Kieselgel mit CH2Cl /EtOH/ konz . Ammoniak0.45 g (0.72 mmol) of the compound obtained under (c) is heated together with 0.1 ml of 80% hydrazine hydrate (1.6 mmol) in 20 ml of CH 2 Cl 2 / EtOH (1: 1) for 6 hours at 50 ° C. It is evaporated in vacuo and the evaporation residue is purified by column chromatography on silica gel with CH 2 Cl / EtOH / conc. ammonia
(5:2:0.05) als Eluens.(5: 2: 0.05) as eluent.
Ausbeute: 0.10 g (30.7 % der Theorie); Schmelzpunkt: 270-275°C; C25H20N6O3 x H20Yield: 0.10 g (30.7% of theory); Melting point: 270-275 ° C; C 25 H 20 N 6 O 3 x H 2 0
Ber. C 63.82 H 4.71 N 17.86 Gef. 64.26 5.13 17.20 Ber. Molpeak M+ = 452 Gef. Molpeak M+ = 452Ber. C 63.82 H 4.71 N 17.86 Found 64.26 5.13 17.20 Calc. Molpeak M + = 452 Found Molpeak M + = 452
Analog Beispiel 17 wurde folgende Verbindung erhalten: 17.1 3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-aminomethyl- phenyl) methyliden} -2-indolinonThe following compound was obtained analogously to Example 17: 17.1 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-aminomethylphenyl) methylidene} -2-indolinone
(a) l-Acetyl-3- [1-hydroxy-l- (4-phthalimidomethyl-phenyl) methy- 1 i de } -2 - i ndol i non(a) l-Acetyl-3- [1-hydroxy-l- (4-phthalimidomethylphenyl) methy-1i de} -2 - indol i non
Hergestellt analog Beispiel 10 (a) aus 1-Acetyl-2-indolinon und 4-Phthalimidomethyl-benzoesäure (Schmelzpunkt: 260-262°C) in trockenem DMF in Gegenwart von TBTU, HOBT sowie Hünig's Base (20°C, 4 Stunden) , Einrühren in verdünnter Salzsäure, Extraktion mit CH2CI2, Eindampfen des getrockneten organischen Extraktes im Vakuum, Verreiben des Eindampfrückstandes mit EtOAc und Trocknen der Festsubstanz . Ausbeute: 69 % der Theorie; Schmelzpunkt: 200-201°C; Enol-Reaktion (mit FeCl3 -Lösung in EtOH) : positiv.Prepared analogously to Example 10 (a) from 1-acetyl-2-indolinone and 4-phthalimidomethylbenzoic acid (melting point: 260-262 ° C) in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, 4 hours) , Stir in dilute hydrochloric acid, extraction with CH2CI2, evaporation of the dried organic extract in vacuo, trituration of the evaporation residue with EtOAc and drying of the solid substance. Yield: 69% of theory; Melting point: 200-201 ° C; Enol reaction (with FeCl 3 solution in EtOH): positive.
(b) l-Acetyl-3- [1-chlor-l- (4-phthalimidomethyl-phenyl) methyli- en} -2 -indol inon(b) l-Acetyl-3- [1-chloro-l- (4-phthalimidomethyl-phenyl) methyl-ene} -2-indole inone
Hergestellt analog Beispiel 11 (b) aus dem unter (a) erhaltenen Enol mit 2 Äquivalenten PC15 in Toluol (100°C/l Stunde) , dampft bis zur beginnenden Trübung im Vakuum ein, versetzt mit Petrolether, isoliert den entstandenen Niederschlag, wäscht ihn mit Petrolether und trocknet ihn bei 75°C im Vakuum.Prepared analogously to Example 11 (b) from the obtained under (a) enol with 2 equivalents of PC1 5 in toluene (100 ° C / l hour) and evaporated to incipient turbidity in vacuo, treated with petroleum ether, the precipitate formed, washing him with petroleum ether and dry it at 75 ° C in a vacuum.
Ausbeute: 85 % der Theorie;Yield: 85% of theory;
Schmelzpunkt: 207-208°C;Melting point: 207-208 ° C;
C26Hι7ClN204 C 26 Hi 7 ClN 2 0 4
Ber. : Molpeak M+ = 456/458 (1 Cl)Ber. : Molpeak M + = 456/458 (1 Cl)
Gef.: Molpeak M+ = 456/458 (1 Cl)Found: Molpeak M + = 456/458 (1 Cl)
(c) l-Acetyl-3- { (Z) -1- [4- (lH-imidazol-4-yl) anilino] -(c) l-acetyl-3- {(Z) -1- [4- (lH-imidazol-4-yl) anilino] -
1 - (4-phthal i i omethyl -phenyl ethyl iden } -2 -indol i on1 - (4-phthal i i omethyl-phenyl ethyl iden} -2-indol i on
Hergestellt aus der unter (b) erhaltenen Chlor-Verbindung und zwei Äquivalenten 4- (1H-Imidazol-4-yl) anilin x 2 HCl (Schmelzpunkt: 350°C) und 3 Äquivalenten von Hünig's Base in DMF (80°C, 1 Stunde) , Zugabe von EtOAc und Waschen mit Wasser, Eindampfen der organischen Phase im Vakuum und Reinigung des Eindampfrück- Standes durch Säulenchromatographie an Kieselgel mit CH2CI2/- EtOH/konz. Ammoniak (15:1:0.1) als Eluens. Ausbeute: 26 % der Theorie (Schaum) ; Schmelzpunkt: 200°C;Prepared from the chlorine compound obtained under (b) and two equivalents of 4- (1H-imidazol-4-yl) aniline x 2 HCl (melting point: 350 ° C) and 3 equivalents of Hünig's base in DMF (80 ° C, 1 Hour), adding EtOAc and washing with water, evaporating the organic phase in vacuo and cleaning the evaporation back Stand by column chromatography on silica gel with CH2CI2 / - EtOH / conc. Ammonia (15: 1: 0.1) as eluent. Yield: 26% of theory (foam); Melting point: 200 ° C;
C35H25N6θ 4 C35 H 25 N 6 θ 4
Ber. : Molpeak M+ = 579Ber. : Molpeak M + = 579
Gef.: Molpeak M+ = 579Found: Molpeak M + = 579
(d) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-aminomethyl- phenyl ) methyl iden } -2- i ndol i on(d) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-aminomethylphenyl) methyl iden} -2- indol ion
Hergestellt aus der unter (c) erhaltenen Verbindung zusammen mit 3 Äquivalenten Hydrazin-hydrat in EtOH (70°C/4 Stunden) , Eindampfen im Vakuum und abschließende Reinigung durch Säulenchromatographie an Kieselgel mit CH2Cl2/EtOH/konz . AmmoniakPrepared from the compound obtained under (c) together with 3 equivalents of hydrazine hydrate in EtOH (70 ° C / 4 hours), evaporation in vacuo and final purification by column chromatography on silica gel with CH 2 Cl 2 / EtOH / conc. ammonia
(4:1:0.1) als Eluens. Ausbeute: 50 % der Theorie; Schmelzpunkt: 22 -225°C; C25H21N50(4: 1: 0.1) as eluent. Yield: 50% of theory; Melting point: 22-225 ° C; C 25 H 21 N 5 0
Ber. : Molpeak M+ = 407 Gef.: Molpeak M+ = 407Ber. : Molpeak M + = 407 Found: Molpeak M + = 407
Beispiel 18Example 18
3- { (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-acetylaminomethyl- phenyl) methyliden} -5-nitro-2-indolinon3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-acetylaminomethylphenyl) methylidene} -5-nitro-2-indolinone
Man rührt 3- { (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-aminome- thyl-phenyl) methyliden} -5-nitro-2-indolinon x H2O in trockenem3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-aminomethyl-phenyl) methylidene} -5-nitro-2-indolinone x H2O is stirred in dry
Dioxan zusammen mit 1.2 Äquivalenten Acetanhydrid und einigenDioxane along with 1.2 equivalents of acetic anhydride and some
Tropfen Eisessig über Nacht bei Raumtemperatur. Man dampft imDrop glacial acetic acid overnight at room temperature. You steam in
Vakuum ein und verreibt den Eindampfrückstand mit Ether.Vacuum and rubs the evaporation residue with ether.
Ausbeute: 83 % der Theorie;Yield: 83% of theory;
Schmelzpunkt: 170°C;Melting point: 170 ° C;
C27H22N6θ4 C 27 H 22 N6θ 4
Ber. : Molpeak M+ = 494Ber. : Molpeak M + = 494
Gef.: Molpeak M+ = 494 Analog Beispiel 18 wurden folgende Verbindungen erhalten:Found: Molpeak M + = 494 The following compounds were obtained analogously to Example 18:
18-1 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-N-acetylami- nomethyl-phenyl) methyliden} -2-indolinon18-1 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-N-acetylaminomethyl-phenyl) methylidene} -2-indolinone
Hergestellt aus 3- { (Z) -1- [4- (lH-Imidazol-4-yl) anilino] - 1- (4-aminomethyl-phenyl) methyliden} -2-indolinon in trockenem Dioxan mit Acetanhydrid und etwas Eisessig (Raumtemperatur, 24 Stunden) , Eindampfen im Vakuum ein und Verreiben des Eindampfrückstandes mit Ether. Ausbeute: 88 % der Theorie; Schmelzpunkt: 186-188°C; C-27H23N5°2Made from 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] - 1- (4-aminomethylphenyl) methylidene} -2-indolinone in dry dioxane with acetic anhydride and some glacial acetic acid ( Room temperature, 24 hours), evaporate in vacuo and triturate the evaporation residue with ether. Yield: 88% of theory; Melting point: 186-188 ° C; C-27 H 23 N 5 ° 2
Ber. : Molpeak M+ = 449 Gef.: Molpeak M+ = 449Ber. : Molpeak M + = 449 Found: Molpeak M + = 449
lfl-2 3-( (Z) -1- [ (2-Acetyl-1, 2,3, 4 -tetrahydro-isochinolin-6-yl) - amino] -1-phenylmethyliden} -5-nitro-2-indolinonIfl-2 3- ((Z) -1- [(2-acetyl-1, 2,3, 4-tetrahydro-isoquinolin-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone
Hergestellt aus 3-( (Z) -1- [ (1, 2, 3 , 4-Tetrahydro-isochinolin- 6-yl) amino] -1-phenylmethyliden} -5-nitro-2-indolinon x HCl x H20 in Eisessig mit Acetanhydrid in Gegenwart von Hünig's Base. Ausbeute: 83 % der Theorie; Schmelzpunkt: 285-286°C;Made from 3- ((Z) -1- [(1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone x HCl x H 2 0 in glacial acetic acid with acetic anhydride in the presence of Hünig's base, yield: 83% of theory, melting point: 285-286 ° C .;
C26H22N4θ4 C 2 6H22 N 4θ 4
Ber. C 68.69 H 4.88 N 12,32 Gef. 68.34 4.81 12.27 Ber. Molpeak M+ = 454 Gef. Molpeak M+ = 454 Ber. C 68.69 H 4.88 N 12.32 Found 68.34 4.81 12.27 Calc. Molpeak M + = 454 Found Molpeak M + = 454
Beispiel 19Example 19
3- { (Z) -1- [4- (3- (rac-4-Aminocarbonyl-2-oxo-pyrrolidin-l-yl) - (Z) - 1-propen-l-yl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon3- {(Z) -1- [4- (3- (rac-4-aminocarbonyl-2-oxopyrrolidin-l-yl) - (Z) - 1-propen-l-yl) anilino] -1- phenylmethylidene} -5-nitro-2-indolinone
(I) und(I) and
3- { (Z) -1- [4- (3- (rac-4-Aminocarbonyl-2-oxo-pyrrolidin-l-yl) - (Ξ) -3- {(Z) -1- [4- (3- (rac-4-aminocarbonyl-2-oxopyrrolidin-l-yl) - (Ξ) -
1-propen-l-yl ) anilino] - 1 -phenylmethyliden} -5 -nitro-2 -indolinon1-propen-l-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone
( II)(II)
(a) 3- [ (Z) -1- (4-Brom-anilino) -1-phenylmethyliden] -5-nitro-(a) 3- [(Z) -1- (4-bromoanilino) -1-phenylmethylidene] -5-nitro-
' -indol inon ' -indole inon
Hergestellt durch Umsetzung von l-Acetyl-3- (1-ethoxy-l-phenyl- methyliden) -5-nitro-2-indolinon mit 1.5 Äquivalenten 4-Brom- anilin in DMF (110°C, 2 Stunden) , anschließende Behandlung mit Piperidin (20°C, 0.5 Stunden) und Ausfällen mit Wasser. Ausbeute: 92 % der Theorie; Schmelzpunkt: 300-305°C; C2ιH14BrN303 Ber. C 57.82 H 3.23 N 9.63 Br 18.32Prepared by reacting l-acetyl-3- (1-ethoxy-l-phenylmethylidene) -5-nitro-2-indolinone with 1.5 equivalents of 4-bromoaniline in DMF (110 ° C., 2 hours), followed by treatment with piperidine (20 ° C, 0.5 hours) and precipitation with water. Yield: 92% of theory; Melting point: 300-305 ° C; C 2 ιH 14 BrN 3 0 3 Ber. C 57.82 H 3.23 N 9.63 Br 18.32
Gef. 57.81 3.20 9.65 18.22 Ber. Molpeak M+ = 435/437 1 (Br) Gef. Molpeak M+ = 435/437 (1 Br)Found 57.81 3.20 9.65 18.22 calc. Molpeak M + = 435/437 1 (Br) Found Molpeak M + = 435/437 (1 Br)
(b) (T) und (TT) Man rührt 440 mg (1.0 mMol) der unter (a) erhaltenen 4-3rom- phenyl-Verbindung, 21 mg (0.069 mMol) Tri-o-tolyl-phosphin,(b) (T) and (TT) 440 mg (1.0 mmol) of the 4-3rom-phenyl compound obtained under (a), 21 mg (0.069 mmol) of tri-o-tolyl-phosphine are stirred,
5 mg (0.023 mMol) Palladium-diacetat, 185 mg (1.1 mMol) rac- l-Allyl-4-aminocarbonyl-2-oxo-pyrrolidin (Schmelzpunkt; : 69-5 mg (0.023 mmol) palladium diacetate, 185 mg (1.1 mmol) rac-l-allyl-4-aminocarbonyl-2-oxopyrrolidine (melting point;: 69-
70°C) und 0.35 ml (2.0 mMol) Hüning's Base in 20 ml DMF70 ° C) and 0.35 ml (2.0 mmol) of Hüning's base in 20 ml of DMF
15 Stunden bei 100°C, filtriert über Kieselgur, gießt auf15 hours at 100 ° C, filtered through diatomaceous earth, poured on
Wasser filtriert vom Niederschlag und reinigt ihn εäulenchroma- tographisch an Kieselgel mit CH Cl2/MeOH (10:1) als Eluens.Water filters the precipitate and purifies it by column chromatography on silica gel with CH Cl 2 / MeOH (10: 1) as the eluent.
Zuerst wird das (Z) -Isomer (I) eluiert (Rf = 0.50), das mitFirst the (Z) -isomer (I) is eluted (Rf = 0.50), that with
Ether kristallisiert:Ether crystallizes:
3- { (Z) -1- [4- (3- (rac-4-Aminocarbonyl-2-oxo-pyrrolidin-l-yl) - (Z) -3- {(Z) -1- [4- (3- (rac-4-aminocarbonyl-2-oxopyrrolidin-l-yl) - (Z) -
1-propen-l-yl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon.1-propen-l-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone.
Ausbeute: 131 mg (91 % der Theorie);Yield: 131 mg (91% of theory);
Schmelzpunkt: 170°C (Schaum); C29H25N505 Melting point: 170 ° C (foam); C 2 9 H 25N 5 0 5
Ber. : Molpeak M+ = 523Ber. : Molpeak M + = 523
Gef.: Molpeak M+ = 523Found: Molpeak M + = 523
Dann wird das (E) -Isomer (II) eluiert (Rf = 0.43), das in MeOH (+ Ether) kristallisiert.Then the (E) isomer (II) is eluted (Rf = 0.43), which crystallizes in MeOH (+ ether).
3- { (Z) -1- [4- (3- (rac-4-Aminocarbonyl-2-oxo-pyrrolidin-l-yl) - (E) - 1-propen-l-yl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon. Ausbeute: 147 mg (14 % der Theorie); Schmelzpunkt: 220-225°C;3- {(Z) -1- [4- (3- (rac-4-aminocarbonyl-2-oxopyrrolidin-l-yl) - (E) - 1-propen-l-yl) anilino] -1- phenylmethylidene} -5-nitro-2-indolinone. Yield: 147 mg (14% of theory); Melting point: 220-225 ° C;
C29H25N5θ5C 29 H25 N 5θ5
Ber. : Molpeak M+ = 523Ber. : Molpeak M + = 523
Gef.: Molpeak M+ = 523Found: Molpeak M + = 523
Analog Beispiel 19 wurden folgende Verbindungen erhalten:The following compounds were obtained analogously to Example 19:
1 .1 3-{ (Z) -1- [4- (3- (2-Oxo-pyrrolidin-l-yl) - (Z) -1-propen-l-yl) - anilino] -I-phenylmethyliden} -5-nitro-2-indolinon (I) und 3- { (Z) -1- [4- (3- (2-Oxo-pyrrolidin-l-yl) - (E) -1-propen-l-yl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon (II)1 .1 3- {(Z) -1- [4- (3- (2-Oxo-pyrrolidin-l-yl) - (Z) -1-propen-l-yl) - anilino] -I-phenylmethylidene} -5-nitro-2-indolinone (I) and 3- {(Z) -1- [4- (3- (2-Oxopyrrolidin-l-yl) - (E) -1-propen-l-yl ) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone (II)
Hergestellt durch Umsetzung von 3- [ (Z) -1- (4- (4-Brom-anilino) - 1-phenylmethyliden] -5-nitro-2-indolinon mit 1.1 Äquivalenten N-Allyl-pyrrolidin-2-on, 0,07 Äquivalenten Tri- (o-tolyl) - phosphin, 0.02 Äquivalenten Palladium-diacetat und 2 Äquivalenten Hünig's Base in DMF (3 Stunden, 100°C; unter Stickstoff) , Filtration über Kieselgur, Versetzen mit Wasser und Reinigung des erhaltenen Niederschlages durch Säulenchromatographie an Kieselgel mit EtOAc/EtOH (10:1) als Eluens.Prepared by reacting 3- [(Z) -1- (4- (4-bromoanilino) -1-phenylmethylidene] -5-nitro-2-indolinone with 1.1 equivalents of N-allyl-pyrrolidin-2-one, 0 , 07 equivalents of tri (o-tolyl) phosphine, 0.02 equivalents of palladium diacetate and 2 equivalents of Hünig's base in DMF (3 hours, 100 ° C; under nitrogen), filtration over diatomaceous earth, adding water and purification of the precipitate obtained Column chromatography on silica gel with EtOAc / EtOH (10: 1) as the eluent.
Zuerst wird das (Z) -Isomer (I) eluiert (Rf = 0.63):First the (Z) -isomer (I) is eluted (Rf = 0.63):
3-{ (Z) -1- [4- (3- (2-Oxo-pyrrolidin-l-yl) - (Z) -1-propen-l-yl) - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon.3- {(Z) -1- [4- (3- (2-Oxo-pyrrolidin-l-yl) - (Z) -1-propen-l-yl) - anilino] -1-phenylmethylidene} -5- nitro-2-indolinone.
Ausbeute: 22 % der Theorie;Yield: 22% of theory;
Schmelzpunkt: 262-263°C; C28H24N4°4 Ber. C 69.99 H 5.03 N 11.66Melting point: 262-263 ° C; C 28 H24 N 4 ° 4 calc. C 69.99 H 5.03 N 11.66
Gef. 69.50 5.30 11.45Found 69.50 5.30 11.45
Ber. Molpeak (M-H) ~ = 479Ber. Molpeak (MH) ~ = 479
Gef. Molpeak (M-H) " = 479Found Molpeak (MH) " = 479
Dann wird das (E) -Isomer (II) eluiert (Rf = 0.41) :Then the (E) isomer (II) is eluted (Rf = 0.41):
3-{ (Z) -1- [4- (3- (2-Oxo-pyrrolidin-l-yl) - (E) -1-propen-l-yl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon.3- {(Z) -1- [4- (3- (2-Oxopyrrolidin-l-yl) - (E) -1-propen-l-yl) anilino] -1-phenylmethylidene} -5-nitro -2-indolinone.
Ausbeute: 19 % der Theorie;Yield: 19% of theory;
Schmelzpunkt: 278-280°C;Melting point: 278-280 ° C;
C28H24N404 C 28 H 24 N 4 0 4
Ber. C 69.99 H 5.03 N 11.66Ber. C 69.99 H 5.03 N 11.66
Gef. 69.78 5.24 11.49Found 69.78 5.24 11.49
Ber. Molpeak (M-H) ~ = 479Ber. Molpeak (MH) ~ = 479
Gef. Molpeak (M-H) " = 479Found Molpeak (MH) " = 479
IS .. Gemisch von 3- { (Z) -1- [4- (2- (2-Oxo-pyrrolidin-l-yl) - (Z) - ethen-1-yl) anilino] -1-phenylmethyliden} -5 -nitro-2-indolinon (I) undIS .. mixture of 3- {(Z) -1- [4- (2- (2-oxopyrrolidin-l-yl) - (Z) - ethen-1-yl) anilino] -1-phenylmethylidene} - 5-nitro-2-indolinone (I) and
3-{ (Z) -1- [4- (2- (2-Oxo-pyrrolidin-l-yl) - (E) -ethen-1-yl) anilino] -3- {(Z) -1- [4- (2- (2-Oxo-pyrrolidin-l-yl) - (E) -ethen-1-yl) anilino] -
1-phenylmethyliden} -5-nitro-2 -indolinon (II)1-phenylmethylidene} -5-nitro-2-indolinone (II)
Hergestellt durch Umsetzung von 3- [ (Z) -1- (4- (4-3rcm-anilino) - 1-phenylmethyliden] -5-nitro mit 1.5 Äquivalenten N-Vinyl- pyrrolidon-2-in, 0,07 Äquivalenten Tri- (o-tolyi)phosphin, 0.02 Äquivalenten Palladium-diacetat und 2 Äquivalenten Hünig's Base in DMF (2 Stunden, 100 °C) , Filtration über Kieselgur, Versetzen mit Wasser und Reinigung des erhaltenen Niederschlages durch Säulenchromatographie an Kieselgel mit Tcluol/EtOAc/EtOH (4:2:1) als Eluens.Prepared by reacting 3- [(Z) -1- (4- (4-3rcm-anilino) -1-phenylmethylidene] -5-nitro with 1.5 equivalents of N-vinylpyrrolidon-2-yne, 0.07 equivalents of tri - (o-tolyi) phosphine, 0.02 equivalents of palladium diacetate and 2 equivalents of Hünig's base in DMF (2 hours, 100 ° C), filtration over diatomaceous earth, adding water and purification of the precipitate obtained by column chromatography on silica gel with Tcluol / EtOAc / EtOH (4: 2: 1) as eluent.
Man erhält ein (Z/E) -Isomeren-Gemisch (Rf = 0.48 und 0.40): Ausbeute: 54.9 % der Theorie; Schmelzpunkt: 260-265°C; C27H22N 0 x 0.3 H20A (Z / E) isomer mixture is obtained (Rf = 0.48 and 0.40): Yield: 54.9% of theory; Melting point: 260-265 ° C; C 27 H 2 2N 0 x 0.3 H 2 0
Ber.: C 68.71 H 4.83 N 11.87 Gef.: 68.72 5.10 11.68 Ber. : Molpeak M+ = 466 Gef.: Molpeak M+ = 466Calc .: C 68.71 H 4.83 N 11.87 Found: 68.72 5.10 11.68 Ber. : Molpeak M + = 466 Found: Molpeak M + = 466
Analog den vorstehenden Beispielen können folgende Verbindungen hergestellt werden:The following compounds can be prepared analogously to the examples above:
(1) 3-{ (Z) -1- [ ( Indol-5-yl) amino] -1-phenylmethyliden} -5-nitro- 2 -indolinon,(1) 3- {(Z) -1- [(indol-5-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(2) 3- { (Z) -1- [ (1-Methyl-benzimidazol-5-yl) amino] -1-phenylmethy- liden} -5-nitro-2-indolinon,(2) 3- {(Z) -1- [(1-methylbenzimidazol-5-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(3) 3-{ (Z) -1- [ (2-Indazol-5-yl) amino] -1-phenylmethyliden} -5-nitro-2-indolinon,(3) 3- {(Z) -1- [(2-indazol-5-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(4) 3- { (Z) -1- [ (2-Indazol-6-yl) amino] -1-phenylmethyliden} -5-ni- tro-2-indolinon,(4) 3- {(Z) -1- [(2-indazol-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(5) 3-{ (Z) -1- [ (2-Oxo-indolin-5-yl) amino] -1-phenylmethyliden} -5- nitro-2 -indolinon,(5) 3- {(Z) -1- [(2-oxo-indolin-5-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(6) 3- { (Z) -1- [(1,2,3 , 4-Tetrahydro-chinolin-6-yl) amino] -1-phen- ylmethyliden} -5-nitro-2-indolinon,(6) 3- {(Z) -1- [(1,2,3,4-tetrahydroquinolin-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(7) 3- { (Z) -1- [ (Benzimidazol-5-yl) amino] -1-phenylmethyliden} - 5-nitro-2-indolinon,(7) 3- {(Z) -1- [(benzimidazol-5-yl) amino] -1-phenylmethylidene} - 5-nitro-2-indolinone,
(8) 3-{ (Z) -1- [ (l-Methyl-2-oxo-2, 3-dihydro-lH-benzimidazol- 5-yl) amino] -1-phenylmethyliden}-5-nitro-2-indolinon,(8) 3- {(Z) -1- [(1-methyl-2-oxo-2, 3-dihydro-1H-benzimidazol-5-yl) amino] -1-phenylmethylidene} -5-nitro-2- indolinone,
(9) 3- { (Z) -1- [ (Chinolin-6-yl) amino] -1-phenylmethyliden} -5-ni- tro-2-indolinon,(9) 3- {(Z) -1- [(quinolin-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(10) 3- { (Z) -1- [ (2-Oxo-l, 2-dihydro-pyrazin-7-yl) amino] -1-phen- ylmethyliden}-5-nitro-2-indolinon, (11) 3- { (Z) -1- [ (Isochinolin-5-yl) amino] -1-phenylmethyliden} - 5-nitro-2-indolinon,(10) 3- {(Z) -1- [(2-oxo-l, 2-dihydro-pyrazin-7-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone, (11) 3- {(Z) -1- [(isoquinolin-5-yl) amino] -1-phenylmethylidene} - 5-nitro-2-indolinone,
(12) 3-{ (Z) -1- [ (2-Boc-1,2, 3, 4-tetrahydro-isochinolin-5-yl) amino] -1-phenylmethyliden} -5-nitro-2-indolinon,(12) 3- {(Z) -1- [(2-Boc-1,2,3,4-tetrahydro-isoquinolin-5-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(13) 3- { (Z) -1- [ (2-Ethoxycarbonylmethyl-l, 3-dioxo-isoindolin- 5-yl) amino] -1-phenylmethyliden} -5-nitro-2-indolinon,(13) 3- {(Z) -1- [(2-ethoxycarbonylmethyl-1,3-dioxo-isoindolin-5-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(14) 3-{ (Z) -1- [ (2- (3-Ethoxycarbonyl-propyl) -1, 3 -dioxo-isoin- dolin-5-yl) amino] -1-phenylmethyliden} -5-nitro-2-indolinon(14) 3- {(Z) -1- [(2- (3-ethoxycarbonyl-propyl) -1, 3 -dioxo-isoindolin-5-yl) amino] -1-phenylmethylidene} -5-nitro- 2-indolinone
(15) 3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (3 -cyano-phenyl) methyliden} -5-nitro-2-indolinon(15) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (3-cyano-phenyl) methylidene} -5-nitro-2-indolinone
(16) 3-{ (Z) -1- [3- (lH-Imidazolin-2-yl) anilino] -1-phenylmethyli- den}-5-nitro-2-indolinon,(16) 3- {(Z) -1- [3- (1H-imidazolin-2-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(17) 3-{ (Z) -1- [4- (1,2,3,4-Tetrahydro-isochinolin- (5) -yl) amino] ■ 1-phenylmethyliden} -5-nitro-2-indolinon-hydrochlorid,(17) 3- {(Z) -1- [4- (1,2,3,4-tetrahydro-isoquinoline- (5) -yl) amino] ■ 1-phenylmethylidene} -5-nitro-2-indolinone- hydrochloride,
(18) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (3 -aminomethyl- phenyl) methyliden} -5-nitro-2-indolinon(18) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (3-aminomethylphenyl) methylidene} -5-nitro-2-indolinone
(19) 3- { (Z) -1- [4- (2-Amino-lH-imidazol-4-yl) anilino] -1-phenyl- methyliden} -5-nitro-2-indolinon,(19) 3- {(Z) -1- [4- (2-amino-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(20) 3-{ (Z)-l- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1-phenyl- methyliden} -2-indolinon,(20) 3- {(Z) -l- [4- ((pyrrolidin-1-yl) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(21) 3-{ (Z) -1- [4- (2-Amino-5-methyl-lH-imidazol-4-yl) anilino] - 1-phenylmethyliden} -2-indolinon,(21) 3- {(Z) -1- [4- (2-amino-5-methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone,
(22) 3-{ (Z) -1- [4- (2-Amino-lH-thiazol-4-yl) anilino] -1-phenyl- methyliden} -2-indolinon, (23) 3-{ (Z) -1- [4- ( (Imidazol-1-yl) methyl) anilino] -1-phenylme- thyliden} -2-indolinon,(22) 3- {(Z) -1- [4- (2-amino-1H-thiazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone, (23) 3- {(Z) -1- [4- ((imidazol-1-yl) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(24) 3-{ (Z) -1- [4- ( (2-Oxo-pyrrolidin-l-yl) methyl) anilino] -1-phe- nylmethyliden} -2-indolinon,(24) 3- {(Z) -1- [4- ((2-oxopyrrolidin-l-yl) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(25) 3-{ (Z) -1- [3- ( (2-Oxo-pyrrolidin-1-yl) methyl) anilino] -1-phe- nylmethyliden} -2-indolinon,(25) 3- {(Z) -1- [3- ((2-oxopyrrolidin-1-yl) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(26) 3-{ (Z) -1- [2- (lH-Imidazol-4-yl) anilino] -1-phenylmethyli- den} -2-indolinon,(26) 3- {(Z) -1- [2- (1H-Imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone,
(27) 3- { (Z) -1- [4- (2-Amino-lH-imidazol-4-yl) anilino] -1-phenyl- methyliden} -2-indolinon,(27) 3- {(Z) -1- [4- (2-amino-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone,
(28) 3- ( (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yl) methyl) anilino] - 1-phenylmethyliden} -2-indolinon,(28) 3- ((Z) -1- [4- ((2,4-dioxo-imidazolidin-5-yl) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(29) 3-{(Z)-l-[4-( (2,4-Dioxo-imidazolidin-5-yliden)methyl) anilino] -1-phenylmethyliden} -2-indolinon,(29) 3 - {(Z) -l- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(30) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -1-phenyl- methyliden} -2-indolinon,(30) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone,
(31) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-5-yl) anilino] -1-phenyl- methyliden} -2-indolinon,(31) 3- {(Z) -1- [4- (l-methyl-1H-imidazol-5-yl) anilino] -1-phenylmethylidene} -2-indolinone,
(32) 3- { (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] - 1-phenylmethyliden} -2-indolinon,(32) 3- {(Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone,
(33) 3- { (Z) -1- [4- (2-Acetylamino-5-methyl-lH-imidazol-4-yl) anilino] -1-phenylmethyliden} -2-indolinon,(33) 3- {(Z) -1- [4- (2-acetylamino-5-methyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -2-indolinone,
(34) 3-{ (Z) -1- [4- (lH-Tetrazol-5-yl) anilino] -1-phenylmethyliden} -2-indolinon, (35) 3- { (Z) -1- [4- ( (Imidazol-4-yl) methyl) anilino] -1-phenylme- thyliden} -2-indolinon,(34) 3- {(Z) -1- [4- (1H-tetrazol-5-yl) anilino] -1-phenylmethylidene} -2-indolinone, (35) 3- {(Z) -1- [4- ((imidazol-4-yl) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(36) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) ethyl) anilino] -1-phenylme- thyliden} -2-indolinon,(36) 3- {(Z) -1- [4- (2- (imidazol-4-yl) ethyl) anilino] -1-phenylmethylidene} -2-indolinone,
(37) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -1-phe- nylmethyliden} -2-indolinon,(37) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -1-phenylmethylidene} -2-indolinone,
(38) 3- { (Z) -1- [4- ( (2,4-Dioxo-thiazolidin-5-yliden)methyl) anilino] -1-phenylmethyliden} -2-indolinon,(38) 3- {(Z) -1- [4- ((2,4-Dioxothiazolidin-5-ylidene) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(39) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-thiazolidin-5-yl) methyl) anilino] - 1-phenylmethyliden} -2-indolinon,(39) 3- {(Z) -1- [4- ((2,4-Dioxothiazolidin-5-yl) methyl) anilino] -1-phenylmethylidene} -2-indolinone,
(40) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) nilino] -1- (4-trifluormethyl-phenyl) methyliden} -2-indolinon,(40) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) nilino] -1- (4-trifluoromethylphenyl) methylidene} -2-indolinone,
(41) 3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4 -methyl-phe- yDphethyliden} -2-indolinon,(41) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4 -methyl-phe-yDphethylidene} -2-indolinone,
(42) 3-{ (Z) -1- [4- (2-Isobutyl-lH-imidazol-4-yl) anilino] -1-phe- nylmethyliden} -5-nitro-2 -indolinon,(42) 3- {(Z) -1- [4- (2-isobutyl-1H-imidazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(43) 3- { (Z) -1- [4- [ (l-Boc-imidazolin-2-yl) methyl] anilino] -1-phe- nylmethyliden} -5-nitro-2-indolinon,(43) 3- {(Z) -1- [4- [(1-Boc-imidazolin-2-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(44) 3-{ (Z) -1- [4- [ (Imidazolin-2-yl) methyl] anilino] -1-phenylme- thyliden} -5-nitro-2-indolinon,(44) 3- {(Z) -1- [4- [(imidazolin-2-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(45) 3-{ (Z) -1- [4- [ (Imidazolin-1-yl) methyl] anilino] -1-phenylme- thyliden} -5-nitro-2-indolinon,(45) 3- {(Z) -1- [4- [(imidazolin-1-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(46) 3- ( (Z) -1- [4- [ (5-Methoxycarbonyl-2-oxo-pyrrolidin-l-yl) - methyl] anilino] -1-phenylmethyliden} -5-nitro-2-indolinon, (47) 3-{ (Z) -1- [4- [ (5-Carboxy-2-oxo-pyrrolidin-l-yl) methyl] - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon,(46) 3- ((Z) -1- [4- [(5-methoxycarbonyl-2-oxopyrrolidin-l-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone, (47) 3- {(Z) -1- [4- [(5-carboxy-2-oxopyrrolidin-l-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(48) 3- { (Z) -1- [4- [ (Pyrrol-1-yl) methyl] anilino] -1-phenylmethy- liden} -5-nitro-2-indolinon,(48) 3- {(Z) -1- [4- [(pyrrol-1-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(49) 3-{ (Z) -1- [4- [ (2, 5-Dihydro-2,5-dioxo-pyrrol-l-yl) methyl] - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon,(49) 3- {(Z) -1- [4- [(2,5-dihydro-2,5-dioxopyrrol-l-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro- 2-indolinone,
(50) 3- { (Z) -1- [4- [ (2, 5-Dioxo-pyrrolidin-1-yl) methyl] anilino] - 1-phenylmethyliden}-5-nitro-2-indolinon,(50) 3- {(Z) -1- [4- [(2,5-dioxopyrrolidin-1-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(51) 3- ( (Z) -1- [4- [ (3 -Oxo-pyrrolidin-1-yl) methyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(51) 3- ((Z) -1- [4- [(3 -oxo-pyrrolidin-1-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(52) 3- { (Z) -1- [4- (Imidazol-1-yl) anilino] -1-phenylmethyliden} - 5-nitro-2-indolinon,(52) 3- {(Z) -1- [4- (imidazol-1-yl) anilino] -1-phenylmethylidene} - 5-nitro-2-indolinone,
(53) 3-{ (Z) -1- [4- (3, 5-Dioxo-tetrahydro-1, 2, 4-triazol-4-yl) anilino] -1-phenylmethyliden} -5-nitro-2-indolinon,(53) 3- {(Z) -1- [4- (3,5-dioxo-tetrahydro-1,2,4-triazol-4-yl) anilino] -1-phenylmethylidene} -5-nitro-2- indolinone,
(54) 3-{(Z)-l-[4- (2,4-Dioxo-imidazolin-5-yl) anilino] -1-phenyl- methyliden} -5-nitro-2-indolinon,(54) 3 - {(Z) -l- [4- (2,4-dioxo-imidazolin-5-yl) anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(55) 3-{ (Z) -1- [4- [(3-Methyl-2,4-dioxo-imidazolin-5-yliden) - methyl] anilino] -1-phenylmethyliden} -5-nitro-2-indolinon,(55) 3- {(Z) -1- [4- [(3-Methyl-2,4-dioxoimidazolin-5-ylidene) methyl] anilino] -1-phenylmethylidene} -5-nitro-2- indolinone,
(56) 3-{(Z)-l-[4-[(l, 3-Dimethyl-2,4-dioxo-imidazolin-5-yliden) - methyl] anilino] -1-phenylmethyliden} -5-nitro-2-indolinon,(56) 3 - {(Z) -l- [4 - [(1,3-dimethyl-2,4-dioxo-imidazolin-5-ylidene) methyl] anilino] -1-phenylmethylidene} -5-nitro- 2-indolinone,
(57) 3-{ (Z) -1- [4- [ (l-Methyl-2,4-dioxo-imidazolin-5-yl) methyl] - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon,(57) 3- {(Z) -1- [4- [(l-Methyl-2,4-dioxo-imidazolin-5-yl) methyl] - anilino] -1-phenylmethylidene} -5-nitro-2- indolinone,
(58) 3-{ (Z) -1- [4- [ (3-Methyl-2,4-dioxo-imidazolin-5-yl)methyl] - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon, (59) 3-{ (Z) -1- [4- [ (1, 3 -Dimethyl-2,4-dioxo-imidazolin-5-yl) methyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(58) 3- {(Z) -1- [4- [(3-Methyl-2,4-dioxo-imidazolin-5-yl) methyl] - anilino] -1-phenylmethylidene} -5-nitro-2- indolinone, (59) 3- {(Z) -1- [4- [(1,3-dimethyl-2,4-dioxo-imidazolin-5-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2 -indolinone,
(60) 3-{ (Z) -1- [4- [1- (Imidazol-4-yl)ethen-l-yl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(60) 3- {(Z) -1- [4- [1- (imidazol-4-yl) ethen-l-yl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(61) 3-{ (Z) -1- [4- [1- (Imidazol-4-yl) ethyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(61) 3- {(Z) -1- [4- [1- (imidazol-4-yl) ethyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(62) 3-{ (Z) -1- [3- [1- (Imidazol-4-yl) -3-propen-1-yl] anilino] - l-phenylmethyliden}-5-nitro-2-indolinon,(62) 3- {(Z) -1- [3- [1- (imidazol-4-yl) -3-propen-1-yl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(63) 3-{ (Z) -1- [3- [1- (Imidazol-4-yl) -1-propen-l-yl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(63) 3- {(Z) -1- [3- [1- (imidazol-4-yl) -1-propen-l-yl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(64) 3-{ (Z) -1- [3- [1- (Imidazol-4-yDpropyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(64) 3- {(Z) -1- [3- [1- (imidazol-4-yDpropyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(65) 3- { (Z) -1- [4- [3- (5-Aminocarbonyl-2-oxo-pyrrolidin-l-yl) - 1-propen-l-yl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(65) 3- {(Z) -1- [4- [3- (5-aminocarbonyl-2-oxopyrrolidin-l-yl) -1-propen-l-yl] anilino] -l-phenylmethylidene} - 5-nitro-2-indolinone,
( 66 ) 3-{ (Z) -1- [4- [3- (5-Aminocarbonyl-2-oxo-pyrrolidin-1-yl) - propyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(66) 3- {(Z) -1- [4- [3- (5-aminocarbonyl-2-oxopyrrolidin-1-yl) propyl] anilino] -l-phenylmethylidene} -5-nitro-2- indolinone,
(67) 3-{ (Z) -1- [4- [3- (Pyrrolidin-1-yl) -1-propen-l-yl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(67) 3- {(Z) -1- [4- [3- (pyrrolidin-1-yl) -1-propen-l-yl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(68) 3-{ (Z) -1- [4- [3- (Pyrrolidin-1-yl) -propyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(68) 3- {(Z) -1- [4- [3- (pyrrolidin-1-yl) propyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(69) 3- { (Z) -1- [4- [ (2-Oxo-pyrrolidin-1-yl) -1-propen-l-yl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(69) 3- {(Z) -1- [4- [(2-oxopyrrolidin-1-yl) -1-propen-l-yl] anilino] -l-phenylmethylidene} -5-nitro-2- indolinone,
(70) 3-( (Z) -1- [4- [ (2-Oxo-pyrrolidin-l-yl) -propyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon, (71) 3-{ (Z) -1- [3- (l-Methyl-lH-imidazol-4-yl) anilino] -l-phenylmethyliden} -2 -indolinon,(70) 3- ((Z) -1- [4- [(2-oxopyrrolidin-l-yl) propyl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone, (71) 3- {(Z) -1- [3- (l-methyl-1H-imidazol-4-yl) anilino] -l-phenylmethylidene} -2-indolinone,
(72) 3-{ (Z) -1- [3- (lH-Imidazol-4-yl) anilino] -1- (4-trifluormethyl-phenyl) methyliden} -5-nitro-2-indolinon,(72) 3- {(Z) -1- [3- (1H-Imidazol-4-yl) anilino] -1- (4-trifluoromethylphenyl) methylidene} -5-nitro-2-indolinone,
(73) 3-{ (Z) -1- [3- (lH-Imidazol-4-yl) anilino] -1- (4 -methyl-phenyl) methyliden} -5-nitro-2-indolinon,(73) 3- {(Z) -1- [3- (1H-Imidazol-4-yl) anilino] -1- (4-methylphenyl) methylidene} -5-nitro-2-indolinone,
(74) 3- { (Z) -1- [3- (2-Acetylamino-lH-imidazol-4-yl) anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(74) 3- {(Z) -1- [3- (2-acetylamino-1H-imidazol-4-yl) anilino] - 1-phenylmethylidene} -5-nitro-2-indolinone,
(75) 3-{ (Z) -1- [3- (2-Methyl-lH-imidazol-4-yl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(75) 3- {(Z) -1- [3- (2-methyl-1H-imidazol-4-yl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(76) 3- { (Z) -1- [3- ( (Pyrrolidin-1-yl) methyl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(76) 3- {(Z) -1- [3- ((Pyrrolidin-1-yl) methyl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(77) 3-( (Z) -1- [3- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(77) 3- ((Z) -1- [3- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(78) 3-{ (Z) -1- [3- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) -yl- iden) methyl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(78) 3- {(Z) -1- [3- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) -ylidene) methyl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(79) 3-{ (Z) -1- [3- (2-Ethyl-lH-imidazol-4-yl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(79) 3- {(Z) -1- [3- (2-ethyl-1H-imidazol-4-yl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(80) 3-{ (Z) -1- [4- [2- (2-Oxo-pyrrolidin-l-yl)ethen-l-yl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(80) 3- {(Z) -1- [4- [2- (2-Oxopyrrolidin-l-yl) ethen-l-yl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone ,
(81) 3-{ (Z) -1- [4- [2- (2-Oxo-pyrrolidin-1-yl) ethyl] anilino] - 1-phenylmethyliden} -5-nitro-2-indolinon,(81) 3- {(Z) -1- [4- [2- (2-oxopyrrolidin-1-yl) ethyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(82) 3-{ (Z) -1- [4- [1- (Pyrrolidin-1-yl) ethyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon, (83) 3-{ (Z) -1- [4- [1- (2-Oxo-pyrrolidin-l-yl) ethyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(82) 3- {(Z) -1- [4- [1- (pyrrolidin-1-yl) ethyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone, (83) 3- {(Z) -1- [4- [1- (2-oxopyrrolidin-l-yl) ethyl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(84) 3-{ (Z) -1- [4- [ (2-Methyl-pyrrolidin-1-yl) methyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(84) 3- {(Z) -1- [4- [(2-methyl-pyrrolidin-1-yl) methyl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(85) 3-{ (Z) -1- [4- [ (3-Methyl-pyrrolidin-l-yl) methyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(85) 3- {(Z) -1- [4- [(3-methyl-pyrrolidin-l-yl) methyl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
( 86 ) 3-{ (Z) -1- [4- [ (Pyrrolidin-2-yl) methyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(86) 3- {(Z) -1- [4- [(pyrrolidin-2-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(87) 3- { (Z) -1- [4- [ (l-Methyl-pyrrolidin-2-yl)methyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(87) 3- {(Z) -1- [4- [(l-methyl-pyrrolidin-2-yl) methyl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(88) 3-{ (Z) -1- [4- [ (l-Acetyl-pyrrolidin-2-yl) methyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(88) 3- {(Z) -1- [4- [(l-acetyl-pyrrolidin-2-yl) methyl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(89) 3-{(Z)-l-[4-[ (Pyrrolidin-3-yl) methyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(89) 3 - {(Z) -l- [4- [(pyrrolidin-3-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(90) 3- { (Z) -1- [4- [ (1-Methyl-pyrrolidin-3-yl) methyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(90) 3- {(Z) -1- [4- [(1-methyl-pyrrolidin-3-yl) methyl] anilino] - 1-phenylmethylidene} -5-nitro-2-indolinone,
(91) 3-{ (Z) -1- [4- [ (1-Acetyl-pyrrolidin-3-yl) methyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(91) 3- {(Z) -1- [4- [(1-acetyl-pyrrolidin-3-yl) methyl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(92) 3-{ (Z) -1- [4- [ (2-Oxo-pyrrolidin-5-yl) methyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(92) 3- {(Z) -1- [4- [(2-oxopyrrolidin-5-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(93) 3- ( (Z) -1- [4- [ (2-Oxo-pyrrolidin-3 -yl) methyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(93) 3- ((Z) -1- [4- [(2-oxopyrrolidin-3-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(94) 3-{ (Z) -1- [4- [ (2-0xo-pyrrolidin-4-yl) methyl] anilino] -l-phenylmethyliden-5-nitro-2-indolinon, (95) 3-{ (Z) -1- [4- [ (2, 5-Dioxo-pyrrolidin-3-yl) methyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(94) 3- {(Z) -1- [4- [(2-0xo-pyrrolidin-4-yl) methyl] anilino] -l-phenylmethylidene-5-nitro-2-indolinone, (95) 3- {(Z) -1- [4- [(2,5-dioxopyrrolidin-3-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro-2-indolinone,
(96) 3-{ (Z) -1- [4- [ (2, 5-Dioxo-2,5-dihydro-pyrrol-3-yl) methyl] - anilino] -1-phenylmethyliden} -5-nitro-2-indolinon,(96) 3- {(Z) -1- [4- [(2,5-Dioxo-2,5-dihydro-pyrrol-3-yl) methyl] anilino] -1-phenylmethylidene} -5-nitro- 2-indolinone,
(97) 3-{(Z)-l-[4-[ (2-Hydroxymethyl-pyrrolidin-1-yl) methyl] - anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(97) 3 - {(Z) -l- [4- [(2-hydroxymethyl-pyrrolidin-1-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(98) 3-{(Z)-l-[4-[ (2-Methoxymethyl-pyrrolidin-1-yl) methyl] - anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(98) 3 - {(Z) -l- [4- [(2-methoxymethyl-pyrrolidin-1-yl) methyl] - anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(99) 3-{(Z)-l-[4-[ (2-Ethoxycarbonyl-pyrrolidin-1-yl) methyl] - anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(99) 3 - {(Z) -l- [4- [(2-ethoxycarbonyl-pyrrolidin-1-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(100) 3-{ (Z) -1- [4- [ (Pyrazol-1-yl) methyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(100) 3- {(Z) -1- [4- [(pyrazol-1-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(101) 3-{ (Z) -1- [4- [ (3-Oxo-2, 3 -dihydro-pyrazol-1-yl) methyl] anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(101) 3- {(Z) -1- [4- [(3-Oxo-2, 3 -dihydro-pyrazol-1-yl) methyl] anilino] -l-phenylmethylidene} -5-nitro-2-indolinone ,
(102) 3-{ (Z) -1- [4- [ (2-0xo-imidazolidin-l-yl) methyl] anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(102) 3- {(Z) -1- [4- [(2-0xo-imidazolidin-l-yl) methyl] anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(103) 3-{ (Z) -1- [4- [ (2-Oxo-2, 3-dihydro-imidazol-1-yl) methyl] - anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(103) 3- {(Z) -1- [4- [(2-Oxo-2, 3-dihydro-imidazol-1-yl) methyl] - anilino] -l-phenylmethylidene} -5-nitro-2- indolinone,
(104) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- ( -aminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(104) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (-aminomethylphenyl) methylidene} -5-nitro-2-indolinone ,
(105) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -1- (4-ami- nomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(105) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] -1- (4-aminomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(106) 3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-aminomethyl- phenyl) -methyliden} -2-indolinon, (107) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-aminomethyl- phenyl) -methyliden} -5-nitro-2-indolinon,(106) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-aminomethylphenyl) methylidene} -2-indolinone, (107) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-aminomethylphenyl) methylidene} -5-nitro-2-indolinone,
(108) 3-{ (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] - 1- (4-aminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(108) 3- {(Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] - 1- (4-aminomethylphenyl) methylidene} -5-nitro-2- indolinone,
(109) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -1- (4-ami- nomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(109) 3- {(Z) -1- [4- (2-Methyl-1H-imidazol-4-yl) anilino] -1- (4-aminomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(110) 3-( (Z) -1- [ (1,2,3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4-aminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(110) 3- ((Z) -1- [(1,2,3, 4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4-aminomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(111) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4-aminomethyl-phenyl) -methyliden} -5-nitro-2-indoli- non,(111) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4-aminomethylphenyl) methylidene} -5-nitro-2-indolinone,
(112) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4-aminomethyl-phenyl) -methyliden} -5-nitro-2-in- dolinon,(112) 3- {(Z) -1- [4- ((2, 4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4-aminomethylphenyl) methylidene} -5- nitro-2-indolinone,
(113) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-ami- nomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(113) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -1- (4-aminomethylphenyl) methylidene} -5-nitro-2-indolinone ,
(114) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - 1- ( -aminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(114) 3- {(Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (-aminomethylphenyl) methylidene} -5-nitro -2-indolinone,
(115) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4-aminomethyl-phenyl) -methyliden} - 5-nitro-2-indolinon,(115) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4-aminomethyl -phenyl) -methylidene} - 5-nitro-2-indolinone,
(116) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -1- (4-ami- nomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(116) 3- {(Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -1- (4-aminomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(117) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) nilino] -1- (4-ace- tylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon, (118) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4-ace- tylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(117) 3- {(Z) -1- [4- (1-methyl-IH-imidazol-2-yl) nilino] -1- (4-acetylaminomethylphenyl) methylidene} -5-nitro- 2-indolinone, (118) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4-acetylaminomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(119) 3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-acetylaminomethyl-phenyl) -methyliden} -2-indolinon,(119) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-acetylaminomethylphenyl) methylidene} -2-indolinone,
(120) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4 -acetylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(120) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4 -acetylaminomethylphenyl) methylidene} -5-nitro-2-indolinone,
(121) 3-{ (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] -(121) 3- {(Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] -
1- (4-acetylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,1- (4-acetylaminomethylphenyl) methylidene} -5-nitro-2-indolinone,
(122) 3-( (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -1- (4-ace- tylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(122) 3- ((Z) -1- [4- (2-Methyl-1H-imidazol-4-yl) anilino] -1- (4-acetylaminomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(123) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] -(123) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -
1- (4-acetylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,1- (4-acetylaminomethylphenyl) methylidene} -5-nitro-2-indolinone,
(124) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4-acetylaminomethyl-phenyl) -methyliden} -5-nitro-2 -indolinon,(124) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4-acetylaminomethylphenyl) methylidene} -5-nitro-2-indolinone,
(125) 3- { (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) anilino] -1- (4-acetylaminomethyl-phenyl) -methyliden} -5-nitro-2-in- dolinon,(125) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4-acetylaminomethylphenyl) methylidene} -5-nitro -2-indolinone,
(126) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-ace- tylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(126) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -1- (4-acetylaminomethylphenyl) methylidene} -5-nitro-2-indolinone ,
(127) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(127) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4-acetylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,1- (4-acetylaminomethylphenyl) methylidene} -5-nitro-2-indolinone,
(128) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) -yl- iden) methyl) anilino] -1- (4-acetylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon, (129) 3- { (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -1- (4-ace- tylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(128) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) -ylidene) methyl) anilino] -1- (4th -acetylaminomethyl-phenyl) -methylidene} -5-nitro-2-indolinone, (129) 3- {(Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -1- (4-acetylaminomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(130) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4-pyr- rolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(130) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(131) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4-pyr- rolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(131) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(132) 3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4 -pyrrolidinomethyl-phenyl) -methyliden} -2-indolinon,(132) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-pyrrolidinomethylphenyl) methylidene} -2-indolinone,
(133) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-pyrrolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(133) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro-2-indolinone,
(134) 3-{ (Z) -1- [4- (2-Pyrrolidino-lH-imidazol-4-yl) anilino] -(134) 3- {(Z) -1- [4- (2-pyrrolidino-lH-imidazol-4-yl) anilino] -
1- (4-pyrrolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro-2-indolinone,
(135) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) nilino] -1- (4-pyr- rolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(135) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) nilino] -1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(136) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] -(136) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -
1- (4-pyrrolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro-2-indolinone,
(137) 3-{ (Z) -1- [ (2-Acetyl-1,2, 3, 4-tetrahydro-isochinolin-6-yl) - amino] -1- (4-pyrrolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(137) 3- {(Z) -1- [(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro-2-indolinone,
(138) 3- { (Z) -1- [4- ( (2,4-Dioxo-imidazolidin-5-yliden)methyl) anilino] -1- (4-pyrrolidinomethyl-phenyl) -methyliden} -5-nitro-2-in- dolinon,(138) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro -2-indolinone,
(139) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-pyr- rolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(139) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro-2-indolinone ,
(140) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(140) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4-pyrrolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon, (141) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) -yl- iden) methyl) anilino] -1- (4-acetylaminomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro-2-indolinone, (141) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) -ylidene) methyl) anilino] -1- (4th -acetylaminomethyl-phenyl) -methylidene} -5-nitro-2-indolinone,
(142) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -1- (4-pyr- rolidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(142) 3- {(Z) -1- [4- (2-ethyl-lH-imidazol-4-yl) anilino] -1- (4-pyrrolidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(143) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] -1- (4-pi- peridinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(143) 3- {(Z) -1- [4- (l-methyl-1H-imidazol-2-yl) anilino] -1- (4-piperidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(144) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -1- (4-pi- peridinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(144) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] -1- (4-piperidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(145) 3-{ (Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-piperidino- methyl-phenyl) -methyliden} -2-indolinon,(145) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-piperidino-methylphenyl) methylidene} -2-indolinone,
(146) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-piperidino- methyl-phenyl) -methyliden} -5-nitro-2-indolinon,(146) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -1- (4-piperidino-methylphenyl) methylidene} -5-nitro-2-indolinone,
(147) 3-{ (Z) -1- [4- (2-Pyrrolidino-lH-imidazol-4-yl) anilino] -(147) 3- {(Z) -1- [4- (2-pyrrolidino-lH-imidazol-4-yl) anilino] -
1- (4-piperidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,1- (4-piperidinomethylphenyl) methylidene} -5-nitro-2-indolinone,
(148) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -1- (4-pi- peridinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(148) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -1- (4-piperidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(149) 3-{ (Z) -1- [ (l,2,3,4-Tetrahydro-isochinolin-6-yl)amino] - 1- (4-piperidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(149) 3- {(Z) -1- [(l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4-piperidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(150) 3-{ (Z) -1- [ (2-Acetyl-l,2, 3 , 4-tetrahydro-isochinolin-6-yl) - amino] -1- (4-piperidinomethyl-phenyl) -methyliden} -5-nitro-2-in- dolinon,(150) 3- {(Z) -1- [(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4-piperidinomethylphenyl) methylidene} -5-nitro-2-indolinone,
(151) 3-{(Z)-l-[4-( (2,4-Dioxo-imidazolidin-5-yliden)methyl) anilino] -1- (4-piperidinomethyl-phenyl) -methyliden} -5-nitro-2-in- dolinon, (152) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-pi- peridinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(151) 3 - {(Z) -l- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4-piperidinomethylphenyl) methylidene} -5-nitro -2-indolinone, (152) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -1- (4-piperidinomethylphenyl) methylidene} -5-nitro-2-indolinone ,
(153) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(153) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4-piperidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,1- (4-piperidinomethylphenyl) methylidene} -5-nitro-2-indolinone,
(154) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4-piperidinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(154) 3- {(Z) -1- [4- ((1-Methyl-2,4-dioxoimidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4-piperidinomethyl -phenyl) methylidene} -5-nitro-2-indolinone,
(155) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -1- (4-pipe- ridinomethyl-phenyl) -methyliden} -5-nitro-2-indolinon,(155) 3- {(Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -1- (4-pipidinomethylphenyl) methylidene} -5-nitro- 2-indolinone,
(156) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) nilino] -(156) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) nilino] -
1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-oxopyrrolidinomethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(157) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) nilino] -(157) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) nilino] -
1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-oxopyrrolidinomethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(158) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-oxo-pyrro- lidino-methyl) -phenyl) -methyliden} -2-indolinon,(158) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-oxo-pyrrolidino-methyl) phenyl) methylidene} - 2-indolinone,
(159) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2-oxo-pyrro- lidino-methyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(159) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2-oxo-pyrrolidino-methyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(160) 3-{ (Z) -1- [4- (2-Pyrrolidino-lH-imidazol-4-yl) anilino] - 1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(160) 3- {(Z) -1- [4- (2-Pyrrolidino-1H-imidazol-4-yl) anilino] -1- (4- (2-oxopyrrolidino-methyl) phenyl) methylidene } -5-nitro- 2-indolinone,
(161) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(161) 3- {(Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -
1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon, (162) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-oxopyrrolidinomethyl) phenyl) methylidene} -5-nitro-2-indolinone, (162) 3- {(Z) -1- [(1,2, 3,4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- (2-oxopyrrolidinomethyl) phenyl) -methylidene} -5-nitro- 2-indolinone,
(163) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) amino] -1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -(163) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-oxopyrrolidino-methyl) ) -phenyl) -methylidene} -
5-nitro-2-indolinon,5-nitro-2-indolinone,
(164) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} - 5-nitro-2-indolinon,(164) 3- {(Z) -1- [4- ((2, 4-Dioxo-imidazolidin-5-ylidene) methyl) - anilino] -1- (4- (2-oxopyrrolidino-methyl) - phenyl) methylidene} - 5-nitro-2-indolinone,
(165) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(165) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-oxopyrrolidinomethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(166) 3-{ (Z)-l- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilinoj - _1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -.5-nitro- 2-indolinon,(166) 3- {(Z) -l- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilinoj - _1- (4- (2-oxopyrrolidino-methyl) -phenyl ) -methylidene} -.5-nitro- 2-indolinone,
(167) 3-( (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) - methyliden} -5-nitro-2-indolinon,(167) 3- ((Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 2-oxo-pyrrolidino-methyl) phenyl) methylidene} -5-nitro-2-indolinone,
(168) 3- { (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(168) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- (2-oxo-pyrrolidino-methyl) -phenyl) -methyliden} -5-nitro- 2 -indol inon,1- (4- (2-oxopyrrolidinomethyl) phenyl) methylidene} -5-nitro-2-indole inone,
(169) 3 - { (Z) -1- [4 - (l-Methyl-lH-imidazol-2-yl) anilino] -(169) 3 - {(Z) -1- [4 - (l-methyl-lH-imidazol-2-yl) anilino] -
1- (4- (2-oxo-piperidino-methyl ) -phenyl ) -methyliden} -5-nitro- 2 -indolinon,1- (4- (2-oxo-piperidino-methyl) phenyl) methylidene} -5-nitro-2-indolinone,
(170) 3- ( (Z) -1- [4 - (l-Methyl-lH-imidazol-4 -yl ) anilino] -(170) 3- ((Z) -1- [4 - (l-methyl-lH-imidazol-4 -yl) anilino] -
1- (4- (2-oxo-piperidino-methyl ) -phenyl ) -methyliden} -5 -nitro- 2 -indol inon, (171) 3- { (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-oxo-pipe- ridino-methyl) -phenyl) -methyliden} -2-indolinon,1- (4- (2-oxopiperidino-methyl) phenyl) methylidene} -5-nitro-2-indole inone, (171) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-oxo-pipe-ridino-methyl) phenyl) methylidene} - 2-indolinone,
(172) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-oxo-pipe- ridino-methyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(172) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-oxo-pipe-ridino-methyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(173) 3-{ (Z) -1- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] - 1- (4- (2-oxo-piperidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(173) 3- {(Z) -1- [4- (2-piperidino-1H-imidazol-4-yl) anilino] -1- (4- (2-oxo-piperidino-methyl) phenyl) methylidene } -5-nitro- 2-indolinone,
(174) 3-{ (Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] -(174) 3- {(Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] -
1- (4- (2-oxo-piperidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-oxopiperidino-methyl) phenyl) methylidene} -5-nitro-2-indolinone,
(175) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (2-oxo-piperidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(175) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-oxopiperidino-methyl) phenyl) -methylidene} -5-nitro- 2-indolinone,
(176) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- (2-oxo-piperidino-methyl) -phenyl) -methyliden} -5-ni- tro-2-indolinon,(176) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4- (2-oxopiperidino- methyl) phenyl) methylidene} -5-nitro-2-indolinone,
(177) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) anilino] -1- (4- (2-oxo-piperidino-methyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(177) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- (2-oxopiperidino-methyl) phenyl ) -methylidene} -5-nitro-2-indolinone,
(178) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(178) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (2-oxo-piperidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-oxopiperidino-methyl) phenyl) methylidene} -5-nitro-2-indolinone,
(179) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (2-oxo-piperidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(179) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (2-oxo-piperidino-methyl) - phenyl) methylidene} -5-nitro- 2-indolinone,
(180) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -l- (4- (2-oxo-piperidino-methyl) -phenyl) - methyliden} -5-nitro-2-indolinon, (181) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(180) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -l- (4- ( 2-oxo-piperidino-methyl) -phenyl) methylidene} -5-nitro-2-indolinone, (181) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- (2-oxo-piperidino-methyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-oxopiperidino-methyl) phenyl) methylidene} -5-nitro-2-indolinone,
(182) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] -(182) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-2-yl) anilino] -
1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (2-aminoethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(183) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -(183) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] -
1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (2-aminoethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(184) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-amino- ethyl) -phenyl) -methyliden} -2-indolinon,(184) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-aminoethyl) phenyl) methylidene} -2-indolinone,
(185) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-amino- ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(185) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-aminoethyl) phenyl) methylidene} -5-nitro- 2-indolinone,
(186) 3- { (Z) -1- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] -(186) 3- {(Z) -1- [4- (2-piperidino-1H-imidazol-4-yl) anilino] -
1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (2-aminoethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(187) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(187) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (2-aminoethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(188) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(188) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-aminoethyl) phenyl) methylidene } -5-nitro-2-indolinone,
(189) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) amino] -1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(189) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-amino-ethyl) - phenyl) methylidene} -5-nitro-2-indolinone,
(190) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-(190) 3- {(Z) -1- [4- ((2,4-dioxoimidazolidin-5-ylidene) methyl) anilino] -1- (4- (2-aminoethyl) phenyl) -methylidene} -5-nitro-
2-indolinon,2-indolinone,
(191) 3-{(Z)-l-[4-( (Pyrrolidin-1-yl) methyl) anilino] -(191) 3 - {(Z) -l- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon, (192) 3-{ (Z)-l- [4- (2- (Imidazol-4-yl)- (E) -ethenyl) anilino] -1- (4- (2-aminoethyl) phenyl) methylidene} -5-nitro-2-indolinone, (192) 3- {(Z) -l- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (2-aminoethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(193) 3-{ (Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(193) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 2-amino-ethyl) -phenyl) -methylidene} -5-nitro-2-indolinone,
(194) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(194) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- (2-amino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (2-aminoethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(195) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] - 1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(195) 3- {(Z) -1- [4- (l-methyl-1H-imidazol-2-yl) anilino] - 1- (4- (2-acetylamino-ethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(196) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] - 1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(196) 3- {(Z) -1- [4- (1-Methyl-1H-imidazol-4-yl) anilino] - 1- (4- (2-acetylaminoethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(197) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2-ace- tylamino-ethyl) -phenyl) -methyliden} -2-indolinon,(197) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2-acetylaminoethyl) phenyl) methylidene} -2- indolinone,
(198) 3-{ (Z)-l- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(198) 3- {(Z) -l- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-acetylamino-ethyl) phenyl) methylidene} -5-nitro- 2-indolinone,
(199) 3-{ (Z) -1- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] - 1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro-(199) 3- {(Z) -1- [4- (2-Piperidino-1H-imidazol-4-yl) anilino] - 1- (4- (2-acetylaminoethyl) phenyl) methylidene} - 5-nitro
2-indolinon,2-indolinone,
(200) 3-{ (Z)-l- [4- (2-Methyl-lH-imidazol-4-yl) anilino] - 1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(200) 3- {(Z) -l- [4- (2-methyl-1H-imidazol-4-yl) anilino] - 1- (4- (2-acetylaminoethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(201) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon, (202) 3-{ (Z) -1- [(2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) amino] -1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(201) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-acetylaminoethyl) phenyl) methylidene } -5-nitro-2-indolinone, (202) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-acetylamino-ethyl) - phenyl) methylidene} -5-nitro- 2-indolinone,
(203) 3- { (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-ni- tro-2-indolinon,(203) 3- {(Z) -1- [4- ((2, 4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- (2-acetylamino-ethyl) -phenyl) -methylidene} -5-nitro-2-indolinone,
(204) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(204) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-acetylaminoethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(205) 3- { (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro-(205) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (2-acetylamino-ethyl) -phenyl) -methylidene} -5-nitro-
2-indolinon,2-indolinone,
(206) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- (2-acetylamino-ethyl) -phenyl) - methyliden} -5-nitro-2-indolinon,(206) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 2-acetylamino-ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(207) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] - 1- (4- (2-acetylamino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(207) 3- {(Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] - 1- (4- (2-acetylaminoethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(208) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(208) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-2-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(209) 3-{ (Z)-l- [4- (l-Methyl-lH-imidazol-4-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(209) 3- {(Z) -l- [4- (l-methyl-1H-imidazol-4-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(210) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-pyrroli- dino-ethyl) -phenyl) -methyliden} -2-indolinon,(210) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-pyrrolidino-ethyl) phenyl) methylidene} -2- indolinone,
(211) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-pyrro- lidino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon, (212) 3- { (Z) -1- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro-(211) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-pyridylino-ethyl) phenyl) methylidene} -5- nitro-2-indolinone, (212) 3- {(Z) -1- [4- (2-piperidino-1H-imidazol-4-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) phenyl) methylidene} - 5-nitro
2-indolinon,2-indolinone,
(213) 3-{ (Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(213) 3- {(Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] - 1- (4- (2-pyrrolidinoethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(214) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(214) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-pyrrolidinoethyl) phenyl) methylidene } -5-nitro-2-indolinone,
(215) 3-{(Z)-l-[ (2-Acetyl-1,2, 3, 4-tetrahydro-isochinolin-6-yl) amino] -1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(215) 3 - {(Z) -l- [(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-pyrrolidino-ethyl) - phenyl) methylidene} -5-nitro- 2-indolinone,
(216) 3-{(Z)-l-[4-( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(216) 3 - {(Z) -l- [4- ((2,4-dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- (2-pyrrolidino-ethyl) phenyl) -methylidene} -5-nitro-2-indolinone,
(217) 3-( (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(217) 3- ((Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2-pyrrolidino-ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(218) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro-(218) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (2-pyrrolidino-ethyl) -phenyl) -methylidene} -5-nitro-
2-indolinon,2-indolinone,
(219) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- (2-pyrrolidino-ethyl) -phenyl) - methyliden}-5-nitro-2-indolinon,(219) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 2-pyrrolidino-ethyl) -phenyl) methylidene} -5-nitro-2-indolinone,
(220) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon, (221) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] - 1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(220) 3- {(Z) -1- [4- (2-ethyl-IH-imidazol-4-yl) anilino] - 1- (4- (2-pyrrolidino-ethyl) phenyl) methylidene} - 5-nitro-2-indolinone, (221) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-2-yl) anilino] - 1- (4- (2-piperidino-ethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(222) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] - 1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(222) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] - 1- (4- (2-piperidino-ethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(223) 3- { (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2-piperi- dino-ethyl) -phenyl) -methyliden} -2-indolinon,(223) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2-piperidino-ethyl) phenyl) methylidene} -2- indolinone,
(224) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2-piperi- dino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(224) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2-piperidino-ethyl) phenyl) methylidene} -5- nitro-2-indolinone,
(225) 3- { (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] - 1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(225) 3- {(Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] - 1- (4- (2-piperidino-ethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(226) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] - 1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(226) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] - 1- (4- (2-piperidino-ethyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(227) 3-{(Z)-l-[(l, 2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(227) 3 - {(Z) -l - [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- (2-piperidinoethyl) phenyl) methylidene } -5-nitro-2-indolinone,
(228) 3-{ (Z) -1- [ (2-Acetyl-1,2, 3, 4-tetrahydro-isochinolin- 6-yl) amino] -1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} - 5-nitro-2-indolinon,(228) 3- {(Z) -1- [(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2-piperidino-ethyl) - phenyl) methylidene} - 5-nitro-2-indolinone,
(229) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(229) 3- {(Z) -1- [4- ((2, 4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- (2-piperidino-ethyl) phenyl) -methylidene} -5-nitro- 2-indolinone,
(230) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4- (2-pi- peridino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon, (231) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(230) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -1- (4- (2-piperidinoethyl) phenyl) methylidene} -5 -nitro-2-indolinone, (231) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (2-piperidino-ethyl) -phenyl) -methylidene} -5-nitro-2-indolinone,
(232) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) -yliden) methyl) anilino] -1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(232) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) -ylidene) methyl) anilino] -1- (4- ( 2-piperidino-ethyl) -phenyl) -methylidene} -5-nitro-2-indolinone,
(233) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -(233) 3- {(Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -
1- (4- (2-piperidino-ethyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,1- (4- (2-piperidino-ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(234) 3- { (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] -(234) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-2-yl) anilino] -
1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(235) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -(235) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(236) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2- (2-oxo- pyrrolidino) -ethyl) -phenyl) -methyliden} -2-indolinon,(236) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene } -2-indolinone,
(237) 3-{ (Z) -1- [4- (lH-Irnidazol-4-yl) anilino] -1- (4- (2- (2-oxo- pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(237) 3- {(Z) -1- [4- (1H-Irnidazol-4-yl) anilino] -1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene } -5-nitro-2-indolinone,
(238) 3- { (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] -(238) 3- {(Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(239) 3-{ (Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] -(239) 3- {(Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(240) 3- { (Z) -1- [(1,2,3 , 4-Tetrahydro-isochinolin-6-yl) amino] -(240) 3- {(Z) -1- [(1,2,3, 4-tetrahydro-isoquinolin-6-yl) amino] -
1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon, (241) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) ■ amino] -1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} - 5-nitro-2-indolinon,1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone, (241) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) ■ amino] -1- (4- (2- (2-oxo -pyrrolidino) -ethyl) -phenyl) -methylidene} - 5-nitro-2-indolinone,
(242) 3- { (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(242) 3- {(Z) -1- [4- ((2,4-dioxoimidazolidin-5-ylidene) methyl) anilino] -1- (4- (2- (2-oxopyrrolidino) -ethyl) -phenyl) -methylidene} -5-nitro-2-indolinone,
(243) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl)methyl) anilino] -(243) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(244) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) nilino] -(244) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) nilino] -
1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(245) 3-{ (Z) -1- [4- ( (1-Methyl-2, 4-dioxo-imidazolidin-5- (E/Z) -yliden) methyl) anilino] -1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(245) 3- {(Z) -1- [4- ((1-Methyl-2, 4-dioxo-imidazolidin-5- (E / Z) -ylidene) methyl) anilino] -1- (4- ( 2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(246) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(246) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-pyrrolidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopyrrolidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(247) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] -(247) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-2-yl) anilino] -
1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopiperidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(248) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -(248) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopiperidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(249) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2- (2-oxo- piperidino) -ethyl) -phenyl) -methyliden} -2-indolinon, (250) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (2- (2-oxo-pi- peridino) -ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(249) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (2- (2-oxopiperidino) ethyl) phenyl) methylidene } -2-indolinone, (250) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (2- (2-oxo-piperidino) ethyl) phenyl) -methylidene} -5-nitro-2-indolinone,
(251) 3-{ (Z) -1- [4- (2-Acetylamino-IH-imidazol-4-yl) anilino] -(251) 3- {(Z) -1- [4- (2-acetylamino-IH-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopiperidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(252) 3-{ (Z)-l- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(252) 3- {(Z) -l- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopiperidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(253) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro- -indolinon,(253) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2- (2-oxopiperidino) ethyl) ) -phenyl) -methylidene} -5-nitro- indolinone,
(254) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -(254) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (2- (2-oxo -piperidino) -ethyl) -phenyl) -methylidene} -
5-nitro-2-indolinon,5-nitro-2-indolinone,
(255) 3-{{Z)-l-[4-( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} - 5-nitro-2-indolinon,(255) 3 - {{Z) -l- [4- ((2, 4-Dioxo-imidazolidin-5-ylidene) methyl) - anilino] -1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methylidene} - 5-nitro-2-indolinone,
(256) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(256) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxopiperidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(257) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(257) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxo-piperidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(258) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro-2-indolinon, (259) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(258) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 2- (2-oxopiperidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone, (259) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-pipridino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxo-pipridino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(260) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -(260) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -
1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3-aminopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(261) 3- { (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -(261) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] -
1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3-aminopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(262) 3- { (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (3-amino-pro- pyl) -phenyl) -methyliden} -2-indolinon,(262) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (3-amino-propyl) phenyl) methylidene} -2- indolinone,
(263) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3-amino-pro- pyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(263) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3-amino-propyl) phenyl) methylidene} -5- nitro-2-indolinone,
(264) 3- { (Z) -1- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] -(264) 3- {(Z) -1- [4- (2-piperidino-1H-imidazol-4-yl) anilino] -
1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3-aminopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(265) 3- { (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(265) 3- {(Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -
1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3-aminopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(266) 3-{(Z)-l-[(l,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(266) 3 - {(Z) -l - [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- (3-aminopropyl) phenyl) methylidene } -5-nitro-2-indolinone,
(267) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(267) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4- (3-aminopropyl) -phenyl) methylidene} -5-nitro-2-indolinone,
(268) 3-{ (Z) -1- [4- ( (2,4-Dioxo-imidazolidin-5-yliden)methyl) anilino] -1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indo- linon,(268) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- (3-aminopropyl) phenyl) - methylidene} -5-nitro-2-indoline,
(269) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(269) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon, (270) 3-{ (Z)-l- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -1- (4- (3-aminopropyl) phenyl) methylidene} -5-nitro-2-indolinone, (270) 3- {(Z) -l- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3-aminopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(271) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(271) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 3-aminopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(272) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -(272) 3- {(Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -
1- (4- (3-amino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3-aminopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(273) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] -(273) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-2-yl) anilino] -
1- (4- (3-acetylamino-propyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,1- (4- (3-acetylamino-propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(274) 3-( (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -1- (4- (3- acetylamino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(274) 3- ((Z) -1- [4- (l-methyl-1H-imidazol-4-yl) anilino] -1- (4- (3-acetylamino-propyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(275) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (3-acetylami- no-propyl) -phenyl) -methyliden} -2-indolinon,(275) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (3-acetylaminopropyl) phenyl) methylidene} -2- indolinone,
(276) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (3-acetylami- no-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(276) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (3-acetylaminopropyl) phenyl) methylidene} -5- nitro-2-indolinone,
(277) 3- ( (Z) -1- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] - 1- (4- (3-acetylamino-propyl) -phenyl) -methyliden} -5-nitro-(277) 3- ((Z) -1- [4- (2-piperidino-lH-imidazol-4-yl) anilino] - 1- (4- (3-acetylamino-propyl) phenyl) methylidene} - 5-nitro
2-indolinon,2-indolinone,
(278) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -1- (4- (3- acetylamino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(278) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -1- (4- (3-acetylamino-propyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(279) 3-{(Z)-l-[(l,2, 3 , 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (3-acetylamino-propyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(279) 3 - {(Z) -l - [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- (3-acetylamino-propyl) phenyl) methylidene } -5-nitro-2-indolinone,
(280) 3-{ (Z) -1- [ (2-Acetyl-1,2, 3, 4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- (3-acetylamino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon, (281) 3 - { (Z) -1- [4- ( (2 , 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4 - (3 -acetylamino-propyl) -phenyl) -methyliden} -5-ni - t ro - 2 - indol inon ,(280) 3- {(Z) -1- [(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (3-acetylamino-propyl) -phenyl) methylidene} -5-nitro- 2-indolinone, (281) 3 - {(Z) -1- [4- ((2, 4-Dioxo-imidazolidin-5-ylidene) methyl) - anilino] -1- (4 - (3-acetylamino-propyl) -phenyl) -methylidene} -5-ni - t ro - 2 - indole inon,
(282 ) 3 - { (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4 - (3 - acetylamino -propyl) -phenyl ) -methyliden} -5 -nitro- 2 -indolinon,(282) 3 - {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -1- (4 - (3 - acetylamino-propyl) phenyl) methylidene} -5-nitro - 2-indolinone,
(283 ) 3 - { (Z) - 1- [4- (2- ( Imidazol-4 -yl) - (E) -ethenyl ) anilino] - 1- (4- (3 -acetylamino -propyl) -phenyl) -methyliden} -5-nitro-(283) 3 - {(Z) - 1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (3-acetylamino-propyl) -phenyl) -methylidene} -5-nitro-
2 -indol inon,2-indole inon,
(284) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- (3-acetylamino-propyl) -phenyl) - methyliden} -5-nitro-2-indolinon,(284) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 3-acetylamino-propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(285) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -1- (4- (3- acetylamino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(285) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -1- (4- (3-acetylamino-propyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(286) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] - 1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(286) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] - 1- (4- (3-pyrrolidinopropyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(287) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] - 1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(287) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] - 1- (4- (3-pyrrolidinopropyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(288) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3-pyrroli- dino-propyl) -phenyl) -methyliden} -2-indolinon,(288) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3-pyrrolidino-propyl) phenyl) methylidene} -2- indolinone,
(289) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3-pyrroli- dino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(289) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3-pyrrolidino-propyl) phenyl) methylidene} -5- nitro-2-indolinone,
(290) 3-{ (Z)-l- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] - 1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro-(290) 3- {(Z) -l- [4- (2-piperidino-1H-imidazol-4-yl) anilino] - 1- (4- (3-pyrrolidinopropyl) phenyl) methylidene} - 5-nitro
2-indolinon, (291) 3-{ (Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] - 1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,2-indolinone, (291) 3- {(Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] - 1- (4- (3-pyrrolidinopropyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(292) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(292) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (3-pyrrolidinopropyl) phenyl) methylidene } -5-nitro-2-indolinone,
(293) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(293) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (3-pyrrolidinopropyl) -phenyl) methylidene} -5-nitro- 2-indolinone,
(294) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) anilino] -1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(294) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- (3-pyrrolidinopropyl) phenyl) - methylidene} -5-nitro- 2-indolinone,
(295) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(295) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3-pyrrolidinopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(296) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro-(296) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] - 1- (4- (3-pyrrolidinopropyl) phenyl) -methylidene} -5-nitro-
2-indolinon,2-indolinone,
(297) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden)methyl) anilino] -1- (4- (3-pyrrolidino-propyl) -phenyl) - methyliden} -5-nitro-2-indolinon,(297) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 3-pyrrolidinopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(298) 3-( (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl)anilino] -(298) 3- ((Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- (3-pyrrolidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3-pyrrolidinopropyl) phenyl) methylidene} -5-nitro-2-indolinone,
(299) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] - 1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon, (300) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] - 1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,(299) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] - 1- (4- (3-piperidino-propyl) phenyl) methylidene} - 5-nitro-2-indolinone, (300) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] - 1- (4- (3-piperidino-propyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(301) 3-( (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (3-pi- peridino-propyl) -phenyl) -methyliden} -2-indolinon,(301) 3- ((Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (3-piperidino-propyl) phenyl) methylidene} -2- indolinone,
(302) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (3-piperi- dino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(302) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (3-piperidino-propyl) phenyl) methylidene} -5- nitro-2-indolinone,
(303) 3-((Z)-l-[4- (2-Acetylamino-IH-imidazol-4-yl) anilino] - 1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(303) 3 - ((Z) -l- [4- (2-acetylamino-IH-imidazol-4-yl) anilino] - 1- (4- (3-piperidino-propyl) phenyl) methylidene} - 5-nitro-2-indolinone,
(304) 3-( (Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] - 1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro- -indolinon,(304) 3- ((Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] - 1- (4- (3-piperidino-propyl) phenyl) methylidene} - 5-nitro-indolinone,
(305) 3- { (Z) -1- [(1,2,3 , 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,(305) 3- {(Z) -1- [(1,2,3, 4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- (3-piperidino-propyl) phenyl) methylidene } -5-nitro-2-indolinone,
(306) 3-( (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) • amino] -1- (4- (3 -piperidino-propyl) -phenyl.) -methyliden} -5-nitro- 2-indolinon,(306) 3- ((Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) • amino] -1- (4- (3-piperidino-propyl) -phenyl.) -methylidene} -5-nitro- 2-indolinone,
(307) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(307) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- (3-piperidino-propyl) phenyl) -methylidene} -5-nitro-2-indolinone,
(308) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4- (3-pi- peridino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(308) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -1- (4- (3-piperidino-propyl) phenyl) methylidene} -5 -nitro-2-indolinone,
(309) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(309) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro-2-indo- linon, (310) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3-piperidino-propyl) phenyl) methylidene} -5-nitro-2-indoline, (310) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 3-piperidino-propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(311) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -(311) 3- {(Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -
1- (4- (3-piperidino-propyl) -phenyl) -methyliden} -5-nitro-2-in- dolinon,1- (4- (3-piperidino-propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(312) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -(312) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -
1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3- (2-oxopyrrolidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(313) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -(313) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -
1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3- (2-oxopyrrolidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(314) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3- (2-oxo- pyrrolidino) -propyl) -phenyl) -methyliden} -2-indolinon,(314) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3- (2-oxopyrrolidino) propyl) phenyl) methylidene } -2-indolinone,
(315) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (3- (2-oxo- pyrrolidino) -propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(315) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (3- (2-oxopyrrolidino) propyl) phenyl) methylidene } -5-nitro-2-indolinone,
(316) 3- { (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] - 1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(316) 3- {(Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] - 1- (4- (3- (2-oxopyrrolidino) propyl) - phenyl) methylidene} -5-nitro-2-indolinone,
(317) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(317) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- (3- (2-oxopyrrolidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(318) 3-{(Z)-l-[(l, 2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} -5-ni- tro-2-indolinon,(318) 3 - {(Z) -l - [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- (3- (2-oxopyrrolidino) propyl ) -phenyl) -methylidene} -5-nitro-2-indolinone,
(319) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) amino] -1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} 5-nitro-2-indolinon, (320) 3-{(Z)-l-[4-( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(319) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1- (4- (3- (2-oxo- pyrrolidino) propyl) phenyl) methylidene} 5-nitro-2-indolinone, (320) 3 - {(Z) -l- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) - anilino] -1- (4- (3- (2-oxopyrrolidino) -propyl) -phenyl) -methylidene} -5-nitro-2-indolinone,
(321) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(321) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} -5-ni- tro-2-indolinon,1- (4- (3- (2-oxopyrrolidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(322) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(322) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- (3- (2-oxo-pyrrolidino) -propyl) -phenyl) -methyliden} -5-ni- tro-2-indolinon,1- (4- (3- (2-oxopyrrolidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(323) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden)methyl) anilino] -1- (4- (3- (2-oxo-pyrrolidino) -propyl) - phenyl) -methyliden} -5-nitro-2-indolinon,(323) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 3- (2-oxopyrrolidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(324) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -(324) 3- {(Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -
1- (4- (3- (2-oxo-pyrrolidino) -propyl) --phenyl) -methyliden} -5-ni- tro-2-indolinon,1- (4- (3- (2-oxopyrrolidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(325) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] -(325) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-2-yl) anilino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(326) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -(326) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(327) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- (3- (2-oxo-pi- peridino) -propyl) -phenyl) -methyliden} -2-indolinon,(327) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- (3- (2-oxo-piperidino) propyl) phenyl) -methylidene} -2-indolinone,
(328) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3- (2-oxo-pi- peridino) -propyl) -phenyl) -methyliden} -5-nitro-2-indolinon, (329) 3- { (Z) -1- [4- (2-Acetylamino-IH-imidazol-4-yl) anilino] -(328) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- (3- (2-oxo-piperidino) propyl) phenyl) -methylidene} -5-nitro-2-indolinone, (329) 3- {(Z) -1- [4- (2-acetylamino-IH-imidazol-4-yl) anilino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(330) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(330) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(331) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] -(331) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(332) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} - 5-nitro-2-indolinon,(332) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4- (3- (2-oxo -piperidino) -propyl) -phenyl) -methylidene} - 5-nitro-2-indolinone,
(333) 3-((Z)-l-[4-( (2, 4-Dioxo-imidazolidin-5-yliden) ethyl) anilino] -1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -(333) 3 - ((Z) -l- [4- ((2,4-dioxo-imidazolidin-5-ylidene) ethyl) anilino] -1- (4- (3- (2-oxo-piperidino) - propyl) phenyl) methylidene} -
5-nitro-2-indolinon,5-nitro-2-indolinone,
(334) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(334) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(335) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(335) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(336) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden)methyl) anilino] -1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro-2-indolinon,(336) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( 3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone,
(337) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -(337) 3- {(Z) -1- [4- (2-ethyl-IH-imidazol-4-yl) anilino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon, - 134 -1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone, - 134 -
(338) 3-{ (Z)-l- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4- ( (3- amino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(338) 3- {(Z) -l- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4- ((3-amino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(339) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4- ( (3- amino-1-propen-1-yl)phenyl) -methyliden} -5-nitro-2-indolinon,(339) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4- ((3-amino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(340) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3-amino- 1-propen-1-yl) phenyl) -methyliden} -2-indolinon,(340) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3-amino-1-propen-1-yl) phenyl) methylidene } -2-indolinone,
(341) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- ( (3-amino- 1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(341) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- ((3-amino-1-propen-1-yl) phenyl) methylidene } -5-nitro-2-indolinone,
(342) 3-{ (Z) -1- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] -(342) 3- {(Z) -1- [4- (2-piperidino-1H-imidazol-4-yl) anilino] -
1- (4- ( (3 -amino-1-propen-l-yl) phenyl) -methyliden} -5-nitro-2-in- dolinon,1- (4- ((3-amino-1-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(343) 3-{ (Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] -(343) 3- {(Z) -1- [4- (2-Methyl-IH-imidazol-4-yl) anilino] -
1- (4- ( (3 -amino-1-propen-l-yl) phenyl) -methyliden} -5-nitro-2-in- dolinon,1- (4- ((3-amino-1-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(344) 3- { (Z) -1- [(1,2,3 , 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- ( (3 -amino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(344) 3- {(Z) -1- [(1,2,3, 4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- ((3-amino-1-propene-1- yl) phenyl) methylidene} -5-nitro-2-indolinone,
(345) 3-( (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- ( (3-amino-1-propen-1-yl) phenyl) -methyliden} -5-ni- tro-2-indolinon,(345) 3- ((Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4- ((3-amino-1 propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(346) 3-{(Z)-l-[4-( (2, 4-Dioxo-imidazolidin-5-yliden) ethyl) - anilino] -1- (4- ( (3-amino-l-propen-l-yl) phenyl) -methyliden} -5-ni- tro-2-indolinon,(346) 3 - {(Z) -l- [4- ((2,4-dioxo-imidazolidin-5-ylidene) ethyl) anilino] -1- (4- ((3-amino-l-propene l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(347) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) ethyl) anilino] -(347) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) ethyl) anilino] -
1- (4- ( (3-amino-l-propen-l-yl) phenyl) -methyliden} -5-nitro-2-in- dolinon, (348) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -1- (4- ((3-amino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone, (348) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- ( (3-amino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-in- dolinon,1- (4- ((3-amino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(349) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- ( (3 -amino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(349) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( (3-amino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(350) 3-{ (Z) -1- [4- (2-Ethyl-IH-imidazol-4-yl) anilino] -(350) 3- {(Z) -1- [4- (2-ethyl-IH-imidazol-4-yl) anilino] -
1- (4- ( (3-amino-1-propen-l-yl) phenyl) -methyliden} -5-nitro-2-in- dolinon,1- (4- ((3-amino-1-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(351) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-2-yl) anilino] -1- (4- ( (3- acetylamino-l-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(351) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-2-yl) anilino] -1- (4- ((3-acetylamino-l-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(352) 3-{ (Z)-l- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4- ( (3- acetylamino-1-propen-l-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(352) 3- {(Z) -l- [4- (1-methyl-IH-imidazol-4-yl) anilino] -1- (4- ((3-acetylamino-1-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(353) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3 -acetylamino-1-propen-1-yl) phenyl) -methyliden} -2-indolinon,(353) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3-acetylamino-1-propen-1-yl) phenyl) methylidene } -2-indolinone,
(354) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3 -acetylamino-1-propen-1-yl)phenyl) -methyliden} -5-nitro-2-indolinon,(354) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3-acetylamino-1-propen-1-yl) phenyl) methylidene } -5-nitro-2-indolinone,
(355 ) 3 - { (Z) -1- [4 - (2 -Piperidino-lH- imidazol-4 -yl ) anilino] -(355) 3 - {(Z) -1- [4 - (2 -piperidino-1H-imidazol-4-yl) anilino] -
1- (4 - ( (3 -acetylamino- 1 -propen- 1-yl ) phenyl ) -methyliden} - 5-nitro- 2 - indol inon,1- (4 - ((3-acetylamino-1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indole inone,
(356) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(356) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3-acetylamino-l-propen-l-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-acetylamino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(357) 3-{ (Z) -1- [ (1,2, 3, -Tetrahydro-isochinolin-6-yl) amino] -(357) 3- {(Z) -1- [(1,2,3, -Tetrahydro-isoquinolin-6-yl) amino] -
1- (4- ( (3-acetylamino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon, (358) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) • amino] -1- (4- ( (3 -acetylamino-1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon,1- (4- ((3-acetylamino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone, (358) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) • amino] -1- (4- ((3-acetylamino-1 -propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone,
(359) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- ( (3-acetylamino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(359) 3- {(Z) -1- [4- ((2,4-dioxoimidazolidin-5-ylidene) methyl) anilino] -1- (4- ((3-acetylamino-1-propene 1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(360) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(360) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- ( (3-acetylamino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-acetylamino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(361) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(361) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- ( (3-acetylamino-l-propen-l-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-acetylamino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(362) 3-{,(Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- ( (3-acetylamino-l-propen-l-yl)phe- nyl) -methyliden} -5-nitro-2-indolinon,(362) 3 - {, (Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ((3-acetylamino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(363) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(363) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3-acetylamino-l-propen-l-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-acetylamino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(364) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4- ( (3- pyrrolidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(364) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4- ((3-pyrrolidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(365) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -1- (4- ( (3- pyrrolidino-1-propen-1-yl)phenyl) -methyliden} -5-nitro-2-indolinon,(365) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] -1- (4- ((3-pyrrolidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(366) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4- ( (3-pyrroli- dino-1-propen-1-yl)phenyl) -methyliden} -2-indolinon, (367) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3-pyrroli- dino-1-propen-l-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(366) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4- ((3-pyrrolidino-1-propen-1-yl) phenyl) -methylidene} -2-indolinone, (367) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3-pyrrolidino-1-propen-l-yl) phenyl) -methylidene} -5-nitro-2-indolinone,
(368) 3-{ (Z) -1- [4- (2-Piperidino-lH-imidazol-4-yl) anilino] -(368) 3- {(Z) -1- [4- (2-piperidino-1H-imidazol-4-yl) anilino] -
1- (4- ( (3-pyrrolidino-l-propen-l-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-pyrrolidino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(369) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(369) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3-pyrrolidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-pyrrolidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(370) 3- { (Z) -1- [ (1, 2, 3,4-Tetrahydro-isochinolin-6-yl) amino] -(370) 3- {(Z) -1- [(1, 2, 3,4-tetrahydro-isoquinolin-6-yl) amino] -
1- (4- ( (3-pyrrolidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-pyrrolidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(371) 3-{ (Z) -1- [ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- ( (3-pyrrolidino-1-propen-l-yl)phenyl) -methyliden} - 5-nitro-2-indolinon,(371) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4- ((3-pyrrolidino-1 -propen-l-yl) phenyl) methylidene} - 5-nitro-2-indolinone,
(372) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- ( (3-pyrrolidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(372) 3- {(Z) -1- [4- ((2,4-dioxoimidazolidin-5-ylidene) methyl) anilino] -1- (4- ((3-pyrrolidino-1-propene 1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(373) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(373) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- ( (3-pyrrolidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-pyrrolidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(374) 3-{ (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] -(374) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- ( (3-pyrrolidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-pyrrolidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(375) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- ( (3-pyrrolidino-l-propen-l-yl)phe- nyl) -methyliden} -5-nitro-2-indolinon, (376) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(375) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( (3-pyrrolidino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone, (376) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3-pyrrolidino-1-propen-l-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-pyrrolidino-1-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(377) 3-{ (Z)-l- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4- ( (3- piperidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(377) 3- {(Z) -l- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4- ((3-piperidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(378) 3-{ (Z) -1- [4- (l-Methyl-lH-imidazol-4-yl) anilino] -1- (4- ( (3- piperidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(378) 3- {(Z) -1- [4- (l-methyl-lH-imidazol-4-yl) anilino] -1- (4- ((3-piperidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(379) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3-piperi- dino-1-propen-1-yl)phenyl) -methyliden} -2-indolinon,(379) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3-piperidino-1-propen-1-yl) phenyl) -methylidene} -2-indolinone,
(380) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3-piperi- dino-1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(380) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3-piperidino-1-propen-1-yl) phenyl) -methylidene} -5-nitro-2-indolinone,
(381) 3-{ (Z) -1- [4- (2-Acetylamino-IH-imidazol-4-yl) anilino] -(381) 3- {(Z) -1- [4- (2-acetylamino-IH-imidazol-4-yl) anilino] -
1- (4- ( (3-piperidino-l-propen-l-yl)phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-piperidino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(382) 3- ( (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(382) 3- ((Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3-piperidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-piperidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(383) 3- { (Z) -1- [(1,2,3 , 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- ( (3 -piperidino-1-propen-l-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,(383) 3- {(Z) -1- [(1,2,3, 4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- ((3 -piperidino-1-propene-l- yl) phenyl) methylidene} -5-nitro- 2-indolinone,
(384) 3-{(Z)-l-[ (2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- ( (3-piperidino-1-propen-1-yl) phenyl) -methyliden} -(384) 3 - {(Z) -l- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4- ((3-piperidino-1 -propen-1-yl) phenyl) methylidene} -
5-nitro-2-indolinon,5-nitro-2-indolinone,
(385) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -l- (4- ( (3-piperidino-1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon, (386) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(385) 3- {(Z) -1- [4- ((2, 4-Dioxo-imidazolidin-5-ylidene) methyl) - anilino] -l- (4- ((3-piperidino-1-propene 1-yl) phenyl) methylidene} - 5-nitro-2-indolinone, (386) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- ( (3-piperidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-piperidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(387) 3-{ (Z)-l- [4- (2-(Imidazol-4-yl)- (E) -ethenyl) anilino] -(387) 3- {(Z) -l- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- ( (3-piperidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-piperidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(388) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) -yliden) methyl) anilino] -1- (4- ( (3-piperidino-l-propen-l-yl)phenyl) - methyliden} -5-nitro-2-indolinon,(388) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) -ylidene) methyl) anilino] -1- (4- ( (3-piperidino-l-propen-l-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(389) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(389) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3-piperidino-1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- ((3-piperidino-1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(390) 3- ( (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} -5-nitro- 2-indolinon,(390) 3- ((Z) -1- [4- (1-methyl-IH-imidazol-2-yl) anilino] -1- (4- ((3- (2-oxopyrrolidino) -1- propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(391) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} -5-nitro-(391) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4- ((3- (2-oxopyrrolidino) -1- propen-1-yl) phenyl) methylidene} -5-nitro-
2-indolinon,2-indolinone,
(392) 3-{ (Z)-l- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3- (2-oxo- pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} -2-indolinon,(392) 3- {(Z) -l- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3- (2-oxopyrrolidino) -1-propen-1- yl) phenyl) methylidene} -2-indolinone,
(393) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3- (2-oxo- pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-in- dolinon,(393) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3- (2-oxopyrrolidino) -1-propen-1- yl) phenyl) methylidene} -5-nitro-2-indolinone,
(394) 3-( (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] -(394) 3- ((Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] -
1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon, (395) 3-{ (Z)-l- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -1- (4- ((3- (2-oxopyrrolidino) -1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone, (395) 3- {(Z) -l- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} 5-nitro-2-indolinon,1- (4- ((3- (2-oxopyrrolidino) -1-propen-1-yl) phenyl) methylidene} 5-nitro-2-indolinone,
(396) 3-{ (Z) -1- [ (l,2,3,4-Tetrahydro-isochinolin-6-yl)amino] - 1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} 5-nitro-2-indolinon,(396) 3- {(Z) -1- [(1,3,4,4-Tetrahydro-isoquinolin-6-yl) amino] - 1- (4- ((3- (2-oxopyrrolidino) - 1-propen-1-yl) phenyl) methylidene} 5-nitro-2-indolinone,
(397) 3-{ (Z) -1- [ (2-Acetyl-1,2, 3, 4-tetrahydro-isochinolin-6-yl) ■ amino] -1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(397) 3- {(Z) -1- [(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-6-yl) ■ amino] -1- (4- ((3- (2- oxo-pyrrolidino) -1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(398) 3-{ (Z) -1- [4- ( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) - anilino] -1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl)phenyl) - methyliden} -5-nitro-2-indolinon,(398) 3- {(Z) -1- [4- ((2,4-Dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- ((3- (2-oxopyrrolidino ) -1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(399) 3-{ (Z)-l- [4- ((Pyrrolidin-1-yl) ethyl) anilino] -(399) 3- {(Z) -l- [4- ((Pyrrolidin-1-yl) ethyl) anilino] -
1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon,1- (4- ((3- (2-oxopyrrolidino) -1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone,
(400) 3- { (Z) -1- [4- (2- (Imidazol-4-yl) - (E) -ethenyl) anilino] - l-(4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon,(400) 3- {(Z) -1- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] - l- (4- ((3- (2-oxopyrrolidino ) -1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone,
(401) 3-{ (Z)-l- [4- ( (1-Methyl-2, 4-dioxo-imidazolidin-5- (E/Z) - yliden) ethyl) anilino] -1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen- 1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(401) 3- {(Z) -l- [4- ((1-Methyl-2,4-dioxoimidazolidin-5- (E / Z) - ylidene) ethyl) anilino] -1- (4- ( (3- (2-oxopyrrolidino) -1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(402) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(402) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3- (2-oxo-pyrrolidino) -1-propen-1-yl) -phenyl) -methyliden} -5-nitro-2-indolinon,1- (4- ((3- (2-oxopyrrolidino) -1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(403) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -(403) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-2-yl) anilino] -
1- (4- (3- (2-oxo-piperidino) -propyl) -phenyl) -methyliden} -5-nitro- 2-indolinon, (404) 3-{ (Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4- ( (3 - (2-oxo-piperidino) -1-propen-1-yl) phenyl) -methyliden} -5-nitro-1- (4- (3- (2-oxopiperidino) propyl) phenyl) methylidene} -5-nitro-2-indolinone, (404) 3- {(Z) -1- [4- (1-Methyl-IH-imidazol-4-yl) anilino] -1- (4- ((3 - (2-oxo-piperidino) -1- propen-1-yl) phenyl) methylidene} -5-nitro-
2-indolinon,2-indolinone,
(405) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3- (2-oxo- piperidino) -1-propen-1-yl) phenyl) -methyliden} -2-indolinon,(405) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3- (2-oxopiperidino) -1-propen-1- yl) phenyl) methylidene} -2-indolinone,
(406) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ( (3- (2-oxo- piperidino) -1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(406) 3- {(Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4- ((3- (2-oxopiperidino) -1-propen-1- yl) phenyl) methylidene} -5-nitro-2-indolinone,
(407) 3- { (Z) -1- [4- (2-Acetylamino-lH-imidazol-4-yl) anilino] -(407) 3- {(Z) -1- [4- (2-acetylamino-1H-imidazol-4-yl) anilino] -
1- (4- ( (3- (2-oxo-piperidino) -1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon,1- (4- ((3- (2-oxopiperidino) -1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone,
(408) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -(408) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -
1- (4- ( (3- (2-oxo-piperidino) -1-propen-1-yl)phenyl) -methyliden} - 5-nitro-2-indolinon,1- (4- ((3- (2-oxopiperidino) -1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone,
(409) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - 1- (4- ( (3- (2-oxo-piperidino) -1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon,(409) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] - 1- (4- ((3- (2-oxopiperidino) - 1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone,
(410) 3-{ (Z) -1- [(2-Acetyl-l,2,3,4-tetrahydro-isochinolin-6-yl) - amino] -1- (4- ( (3- (2-oxo-piperidino) -1-propen-1-yl)phenyl) -methyliden} -5-nitro-2-indolinon,(410) 3- {(Z) -1- [(2-acetyl-l, 2,3,4-tetrahydro-isoquinolin-6-yl) - amino] -1- (4- ((3- (2- oxo-piperidino) -1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(411) 3-{(Z)-l-[4-( (2, 4-Dioxo-imidazolidin-5-yliden) methyl) anilino] -1- (4- ( (3- (2-oxo-piperidino) -1-propen-1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(411) 3 - {(Z) -l- [4- ((2,4-dioxo-imidazolidin-5-ylidene) methyl) anilino] -1- (4- ((3- (2-oxo-piperidino) -1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(412) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -(412) 3- {(Z) -1- [4- ((Pyrrolidin-1-yl) methyl) anilino] -
1- (4- ( (3-'(2-oxo-piperidino) -1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon, (413) 3-( (Z)-l- [4- (2- (Imidazol-4-yl)- (E) -ethenyl) anilino] -1- (4- ((3- ' (2-oxo-piperidino) -1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone, (413) 3- ((Z) -l- [4- (2- (imidazol-4-yl) - (E) -ethenyl) anilino] -
1- (4- ( (3- (2-oxo-piperidino) -1-propen-1-yl) phenyl) -methyliden} - 5-nitro-2-indolinon,1- (4- ((3- (2-oxopiperidino) -1-propen-1-yl) phenyl) methylidene} - 5-nitro-2-indolinone,
(414) 3-{ (Z) -1- [4- ( (l-Methyl-2,4-dioxo-imidazolidin-5- (E/Z) - yliden) methyl) anilino] -1- (4- ( (3- (2-oxo-piperidino) -1-propen- 1-yl) phenyl) -methyliden} -5-nitro-2-indolinon,(414) 3- {(Z) -1- [4- ((l-Methyl-2,4-dioxo-imidazolidin-5- (E / Z) - ylidene) methyl) anilino] -1- (4- ( (3- (2-oxopiperidino) -1-propen-1-yl) phenyl) methylidene} -5-nitro-2-indolinone,
(415) 3-{ (Z) -1- [4- (2-Ethyl-lH-imidazol-4-yl) anilino] -(415) 3- {(Z) -1- [4- (2-ethyl-1H-imidazol-4-yl) anilino] -
1- (4- (2- (2-oxo-piperidino) -ethyl) -phenyl) -methyliden} -5-nitro- 2-indolinon,1- (4- (2- (2-oxo-piperidino) ethyl) phenyl) methylidene} -5-nitro-2-indolinone,
(416) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-me- thyl-phenyl) methyliden} -5-nitro-2-indolinon,(416) 3- {(Z) -1- [4- ((pyrrolidin-1-yl) methyl) anilino] -1- (4-methylphenyl) methylidene} -5-nitro-2-indolinone,
(417) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-meth- oxy-phenyl) ethyliden} -5-nitro-2-indolinon,(417) 3- {(Z) -1- [4- ((pyrrolidin-1-yl) methyl) anilino] -1- (4-methoxyphenyl) ethylidene} -5-nitro-2-indolinone,
(418) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-fluor- phenyl) methyliden} -5-nitro-2-indolinon,(418) 3- {(Z) -1- [4- ((pyrrolidin-1-yl) methyl) anilino] -1- (4-fluorophenyl) methylidene} -5-nitro-2-indolinone,
(419) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-chlor- phenyl) methyliden} -5-nitro-2-indolinon,(419) 3- {(Z) -1- [4- ((pyrrolidin-1-yl) methyl) anilino] -1- (4-chlorophenyl) methylidene} -5-nitro-2-indolinone,
(420) 3-{ (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -1- (4-brom- phenyl)methyliden} -5-nitro-2-indolinon,(420) 3- {(Z) -1- [4- ((pyrrolidin-1-yl) methyl) anilino] -1- (4-bromophenyl) methylidene} -5-nitro-2-indolinone,
(421) 3-{ (Z) -1- [4- (Imidazol-4-yl) anilino] -1- (4-methyl-phenyl) - methyliden} -5-nitro-2-indolinon,(421) 3- {(Z) -1- [4- (imidazol-4-yl) anilino] -1- (4-methylphenyl) methylidene} -5-nitro-2-indolinone,
(422) 3-{ (Z) -1- [4- (Imidazol-4-yl) anilino] -1- (4-methoxy-phenyl) - methyliden} -5-nitro-2-indolinon,(422) 3- {(Z) -1- [4- (imidazol-4-yl) anilino] -1- (4-methoxyphenyl) methylidene} -5-nitro-2-indolinone,
(423) 3-{ (Z) -1- [4- (Imidazol-4-yl) anilino] -1- (4-fluor-phenyl) - methyliden} -5-nitro-2-indolinon, (424) 3-{ (Z) -1- [4- (Imidazol-4-yl) anilino] -1- (4-chlor-phenyl) - methyliden} -5-nitro-2-indolinon,(423) 3- {(Z) -1- [4- (imidazol-4-yl) anilino] -1- (4-fluorophenyl) methylidene} -5-nitro-2-indolinone, (424) 3- {(Z) -1- [4- (imidazol-4-yl) anilino] -1- (4-chlorophenyl) methylidene} -5-nitro-2-indolinone,
(425) 3-{ (Z) -1- [4- (Imidazol-4-yl) anilino] -1- (4-brom-phenyl) - methyliden} -5-nitro-2-indolinon,(425) 3- {(Z) -1- [4- (imidazol-4-yl) anilino] -1- (4-bromophenyl) methylidene} -5-nitro-2-indolinone,
(426) 3-{ (Z) -1- [ (4,4-Dimethyl-l,3-dioxo-l,2,3,4-tetrahydro- isochinolin-6-yl) -amino] -l-phenylmethyliden-5-nitro-2-indolinon,(426) 3- {(Z) -1- [(4,4-dimethyl-l, 3-dioxo-l, 2,3,4-tetrahydro-isoquinolin-6-yl) amino] -l-phenylmethylidene- 5-nitro-2-indolinone,
(427) 3-{ (Z) -1- [ (4,4-Dimethyl-l,3-dioxo-l,2,3,4-tetrahydro-iso- chinolin-7-yl) -amino] -l-phenylmethyliden-5-nitro-2-indolinon,(427) 3- {(Z) -1- [(4,4-dimethyl-l, 3-dioxo-l, 2,3,4-tetrahydro-isoquinolin-7-yl) amino] -l- phenylmethylidene-5-nitro-2-indolinone,
Rfiff iel 20Riff iel 20
Trockenampulle mit 75 mg Wirkstoff pro 10 mlDry ampoule with 75 mg of active ingredient per 10 ml
Zusammensetzung:Composition:
Wirkstoff 75,0 mgActive ingredient 75.0 mg
Mannitol 50,0 mgMannitol 50.0 mg
Wasser für Injektionszwecke ad 10,0 mlWater for injections ad 10.0 ml
Herstellung:Manufacturing:
Wirkstoff und Mannitol werden in Wasser gelöst . Nach Abfüllung wird gefriergetrocknet. Die Auflösung zur gebrauchsfertigen Lösung erfolgt mit Wasser für Injektionszwecke.Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
Beispiel 21Example 21
Trockenampulle mit 35 mg Wirkstoff pro 2 mlDry ampoule with 35 mg of active ingredient per 2 ml
Zusammensetzung:Composition:
Wirkstoff 35,0 mg Mannitol 100,0 mgActive ingredient 35.0 mg Mannitol 100.0 mg
Wasser für Injektionszwecke ad 2,0 mlWater for injections ad 2.0 ml
Herstellung:Manufacturing:
Wirkstoff und Mannitol werden in Wasser gelöst. Nach Abfüllung wird gefriergetrocknet .Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.
Die Auflösung zur gebrauchsfertigen Lösung erfolgt mit Wasser für Injektionszwecke.The ready-to-use solution is dissolved with water for injections.
Beispiel 22Example 22
Tablette mit 50 mg WirkstoffTablet with 50 mg of active ingredient
Zusammensetzung :Composition:
(1) Wirkstoff 50,0 mg(1) Active ingredient 50.0 mg
(2) Milchzucker 98,0 mg(2) milk sugar 98.0 mg
(3) Maisstärke 50,0 mg(3) corn starch 50.0 mg
(4) Polyvinylpyrrolidon 15,0 mg(4) Polyvinylpyrrolidone 15.0 mg
(5) Magnesiumstearat , 0 mg(5) Magnesium stearate, 0 mg
215,0 mg215.0 mg
Herstellung:Manufacturing:
(1) , (2) und (3) werden gemischt und mit einer wäßrigen Lösung von (4) granuliert. Dem getrockneten Granulat wird (5) zugemischt. Aus dieser Mischung werden Tabletten gepreßt, biplan mit beidseitiger Facette und einseitiger Teilkerbe. Durchmesser der Tabletten: 9 mm. Wp ι .cs -i e1 23(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 9 mm. Wp ι .cs -i e1 23
Tablette mit 350 mg WirkstoffTablet with 350 mg of active ingredient
Zusammensetzung :Composition:
(1) Wirkstoff 350,0 mg(1) Active ingredient 350.0 mg
(2) Milchzucker 136,0 mg(2) milk sugar 136.0 mg
(3) Maisstärke 80,0 mg(3) corn starch 80.0 mg
(4) Polyvinylpyrrolidon 30,0 mg(4) polyvinyl pyrrolidone 30.0 mg
(5) Magnesiumstearat 4,0 πig(5) Magnesium stearate 4.0πig
600, 0 mg600.0 mg
Herstellung:Manufacturing:
(1) , (2) und (3) werden gemischt und mit einer wäßrigen Lösung von (4) granuliert. Dem getrockneten Granulat wird (5) zugemischt. Aus dieser Mischung werden Tabletten gepreßt, biplan mit beidseitiger Facette und einseitiger Teilkerbe. Durchmesser der Tabletten: 12 mm.(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with facets on both sides and partial notch on one side. Tablet diameter: 12 mm.
Beispiel , 24Example, 24
Kapseln mit 50 mg WirkstoffCapsules with 50 mg of active ingredient
Zusammensetzung :Composition:
(1) Wirkstoff 50,0 mg(1) Active ingredient 50.0 mg
(2) Maisstärke getrocknet 58,0 mg(2) Corn starch dried 58.0 mg
(3) Milchzucker pulverisiert 50,0 mg(3) Milk sugar powdered 50.0 mg
(4) Magnesiumstearat ,0 mg(4) Magnesium stearate, 0 mg
160,0 mg Herstellung:160.0 mg Manufacturing:
(1) wird mit (3) verrieben. Diese Verreibung wird der Mischung aus (2) und (4) unter intensiver Mischung zugegeben.(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
Diese Pulvermischung wird auf einer Kapselabfüllmaschine in Hartgelatine-Steckkapseln Größe 3 abgefüllt.This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.
Rffig -i »] 25.Rffig -i »] 25.
Kapseln mit 350 mg WirkstoffCapsules with 350 mg of active ingredient
Zusammensetzung :Composition:
(1) Wirkstoff 350,0 mg(1) Active ingredient 350.0 mg
(2) Maisstärke getrocknet 46,0 mg(2) Corn starch dried 46.0 mg
(3) Milchzucker pulverisiert 30,0 mg(3) Milk sugar powdered 30.0 mg
(4) Magnesiumstearat 4,(1 mg(4) Magnesium stearate 4, (1 mg
430, 0 mg430.0 mg
Herstellung :Manufacturing:
(1) wird mit (3) verrieben. Diese Verreibung wird der Mischung aus (2) und (4) unter intensiver Mischung zugegeben.(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
Diese Pulvermischung wird auf einer Kapselabfüllmaschine in Hartgelatine-Steckkapseln Größe 0 abgefüllt.This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.
Beispiel 26Example 26
Suppositorien mit 100 mg WirkstoffSuppositories with 100 mg of active ingredient
1 Zäpfchen enthält :1 suppository contains:
Wirkstoff 100,0 mgActive ingredient 100.0 mg
Polyethylenglykol (M.G. 1500) 600,0 mg Polyethylenglykol (M.G. 6000) 460,0 mg Polyethylensorbitanmonostearat 8 0 fn mgPolyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MW 6000) 460.0 mg polyethylene sorbitan monostearate 8 0 f n mg
2 000,0 mg2,000.0 mg
Hfirstel l ng:Hfirstel l ng:
Das Polyethylenglykol wird zusammen mit Polyethylensorbitanmonostearat geschmolzen. Bei 40°C wird die gemahlene Wirksubstanz in der Schmelze homogen dispergiert. Es wird auf 38°C abgekühlt und in schwach vorgekühlte Suppositorienformen ausgegossen. The polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40 ° C, the ground active substance is homogeneously dispersed in the melt. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

Claims

Patent an.qprήπhq Patent to.qprήπhq
1 . Substituierte Indolinone der allgemeinen Formel1 . Substituted indolinones of the general formula
Figure imgf000150_0001
in der
Figure imgf000150_0001
in the
Rl ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom, eine Nitro-, Amino-, ^-Δ-Alkanoylamino- , (C]__5-Alkoxy) carbonyl- amino- oder Benzyloxycarbonylaminogruppe,R l is a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitro, amino, ^ -Δ-alkanoylamino, (C] __ 5 -alkoxy) carbonylamino or benzyloxycarbonylamino group,
R.2 ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom, eine Cι_5-Alkyl-, Trifluormethyl-, Cyano-, Aminocarbonyl-, Nitro- oder Aminogruppe,R.2 is a hydrogen, fluorine, chlorine, bromine or iodine atom, a Cι_5-alkyl, trifluoromethyl, cyano, aminocarbonyl, nitro or amino group,
eine C]__5-Alkylgruppe, die durch eine Amino-, Phthalimido- , Cι_5-Alkylamino-, C3_7-Cycloalkylamino- , C3. -Alkenylamino- , Benzylamino-, Di- (Cι_5-alkyl) -amino- , C2_6~Alkylenimino- , Di- (C3_4-alkenyl) -amino-, N- (Cι_5-Alkyl) -N- (C3_4~alkenyl) -amino-, N- (Cι_5~Alkyl) -N-benzylamino-, Cι_4-Alkanoylamino-, (Cι_5~Alk- oxy) carbonylamino- , Benzyloxycarbonylamino- , N- (C^-4-Alkanoyl) N- (Cι_5~alkyl) -amino-, α-Oxo-C3_g-alkylenimino- , N- ( (Cι_5~Alk- oxy) carbonyl) -N- (Cι_5-alkyl) -amino-, N-Benzyloxycarbonyl- N- (C^s-alkyl) -amino- , N- (C-±.4-Alkanoyl) -N- (C2_4-alkenyl) - amino-, N- (
Figure imgf000150_0002
carbonyl) -N- (C2_4-alkenyl) -amino-, N-Benzyloxycarbonyl-N- (C2-4~alkenyl) -amino-, N- (C^_4-Alkanoyl) N-benzylamino- , N- ( (C]__5-Alkoxy) carbonyl) -N-benzylamino- , N-Benzyloxycarbonyl-N-benzylamino- , (Cι_5~Alkoxy) carbonyl- , Benzyloxycarbonyl-, Carboxy-, Cyano-, Amidinocarbonyl- oder Imidazolylgruppe substituiert ist,a C ] __5-alkyl group which is replaced by an amino, phthalimido, Cι_5-alkylamino, C 3 _7-cycloalkylamino, C 3 . -Alkenylamino-, benzylamino-, di- (Cι_5-alkyl) -amino-, C2_6 ~ A lkylenimino-, di- (C 3 _4-alkenyl) -amino-, N- (Cι_ 5- alkyl) -N- (C 3 _ 4 ~ alkenyl) amino-, N- (Cι_5 ~ alkyl) -N-benzylamino-, Cι_4-alkanoylamino-, (Cι_5 ~ alkoxy) carbonylamino-, benzyloxycarbonylamino-, N- (C ^ - 4- alkanoyl ) N- (Cι_ 5 ~ alkyl) -amino-, α-oxo-C 3 _g-alkylenimino-, N- ((Cι_5 ~ alk-oxy) carbonyl) -N- (Cι_5-alkyl) -amino-, N- Benzyloxycarbonyl- N- (C ^ s-alkyl) -amino-, N- (C- ± .4-alkanoyl) -N- (C 2 _4-alkenyl) - amino-, N- (
Figure imgf000150_0002
carbonyl) -N- (4 C2_ alkenyl) amino, N-benzyloxycarbonyl-N- (C2-4 ~ alkenyl) amino, N- (C ^ _4-alkanoyl) N-benzylamino, N- (( C] __ 5-alkoxy) carbonyl) -N-benzylamino-, N-benzyloxycarbonyl-N-benzylamino-, (Cι_5 ~ alkoxy) carbonyl-, Benzyloxycarbonyl, carboxy, cyano, amidinocarbonyl or imidazolyl group is substituted,
eine C2-5-Alkenylgruppe, die durch eine Phthalimido- , Cι_4~Al- kanoylamino- , (C _5-Alkoxy) carbonylamino-, Benzyloxycarbonyl- amino-, N- (C^-4-Alkanoyl) -N- (C]__5-alkyl) -amino- , oc-Oxo- C3_6-alkylenimino-, N- ( (Cι_5-Alkoxy) carbonyl) -N- (Cι_5-alkyl) - amino-, N-Benzyloxycarbonyl-N- (Cχ_5-alkyl) -amino- , N- (C^_4-Al- kanoyl) -N- (C2_4-alkenyl) -amino-, N- ( (Cι_5-Alkoxy) carbonyl) - N- (C2_4-alkenyl) -amino-, N-Benzyloxycarbonyl-N- (C2_4-alkenyl) - amino-, N- 1 -4-Alkanoyl) -N-benzylamino- , N- ( (C^.5-Alkoxy) - carbonyl) -N-benzylamino- , N-Benzyloxycarbonyl-N-benzylamino- , (C]__5-Alkoxy) carbonyl- , Benzyloxycarbonyl- , Carboxy- , Cyano- oder Aminocarbonylgruppe substituiert ist, odera C2-5-alkenyl group which is replaced by a phthalimido, Cι_4 ~ al-kanoylamino, (C _5-alkoxy) carbonylamino, benzyloxycarbonylamino, N- (C ^ - 4- alkanoyl) -N- (C] __5-alkyl) -amino, oc-oxo-6 C3_ -alkylenimino-, N- ((Cι_5 alkoxy) carbonyl) -N- (Cι_5-alkyl) - amino, N-benzyloxycarbonyl-N- (5 Cχ_ - alkyl) amino, N- (C ^ _4-Al kanoyl) -N- (C2_4-alkenyl) amino, N- ((Cι_5 alkoxy) carbonyl) - N- (4 C2_ alkenyl) amino -, N-Benzyloxycarbonyl-N- (C 2 _ 4 -alkenyl) - amino-, N- 1 - 4 -alkanoyl) -N-benzylamino-, N- ((C ^ .5-alkoxy) - carbonyl) -N -benzylamino, N-benzyloxycarbonyl-N-benzylamino, (C ] __5-alkoxy) carbonyl, benzyloxycarbonyl, carboxy, cyano or aminocarbonyl group is substituted, or
eine Allylgruppe, die in 3-Stellung durch eine Amino-, Cι_5-Al- kylamino-, C3_7-Cycloalkylamino- , C3-.4-Alkenylamino- , Benzyl- amino-, Di- (Cι_5-alkyl) -amino- , C2-6-Alkylenimino- , Di- (C3_4~alkenyl) -amino-, N- (^.5-Alkyl) -N- (C3_4~alkenyl) -amino- oder N- (Cι_5-Alkyl) -N-benzylaminogruppe substituiert ist, undan allyl group in the 3-position by an amino, Cι_ 5 -alkylamino-, C 3 _7-cycloalkylamino, C 3 -. 4- alkenylamino-, benzylamino-, di- (Cι_5-alkyl) -amino-, C2- 6 -alkyleneimino-, di- (C 3 _ 4 ~ alkenyl) -amino-, N- (^. 5 alkyl) ) -N- (C 3 _ 4 ~ alkenyl) amino or N- (Cι_ 5 alkyl) -N-benzylamino group is substituted, and
R3 eine Gruppe der FormelnR 3 is a group of the formulas
Figure imgf000151_0001
in denen
Figure imgf000151_0001
in which
A eine Bindung, eine C^_4-Alkylen- , Cι_4~Alkyliden- , C2_4-Alkenylen- oder C2-4-Alkenyliden-Gruppe darstellen, wobei ein Wasserstoffatom, das im Rest Het an das Kohlenstoffatom der Verknüpfungsstelle gebunden ist, zusammen mit einem α-ständigen Wasserstoffatom des Restes A auch durch eine weitere Kohlenstoff-Kohlenstoff-Bindung ersetzt sein kann, D eine -CH=CH-NRa-, -CH=N-NRa-, -N=CH-NRa-, -NRa-CO-NRh-- , -CH2-CO-N a-, -CO-NRc-CO-, -CH2-NRa-CH2- , -CH2-CH2-NRa- , -CK=CK-CK=N-, -CH2-CH2-CH2-NRd-, -CH=CH-N=CH- , -CZ2-C≡2 -'t*Rά-C 2 - > -CH2-CH2-CO-NH-, -CH=CH-CO-NH- , -NRa-CO-CK=N- oder - (RaCRh) -CO-NRa-CO-Brücke, wobeiA represents a bond, a C ^ _ 4 -alkylene, Cι_ 4 ~ alkylidene, C 2 _4-alkenylene or C2- 4 alkenylidene group, a hydrogen atom which is bonded in the rest of Het to the carbon atom of the linking point together with an α-hydrogen atom of the radical A can also be replaced by a further carbon-carbon bond, D a -CH = CH-NR a -, -CH = N-NR a -, -N = CH-NR a -, -NR a -CO-NR h -, -CH 2 -CO-N a -, -CO-NR c -CO-, -CH 2 -NR a -CH 2 -, -CH 2 -CH 2 -NR a -, -CK = CK-CK = N-, -CH2-CH 2 -CH2-NR d -, -CH = CH-N = CH-, -CZ 2 -C≡ 2 - 't * R ά- C 2 -> -CH 2 -CH 2 -CO-NH-, -CH = CH-CO- NH-, -NR a -CO-CK = N- or - (R a CR h ) -CO-NR a -CO bridge, where
Ra und R>j, die gleich oder verschieden sein können, jeweils ein Wasserstoffatom oder eine Methylgruppe,R a and R> j , which may be the same or different, each represent a hydrogen atom or a methyl group,
Rc ein Wasserstoffatom, eine (C^_5-Alkoxy) carbonyl-C]__5-alkyl- oder Benzyloxycarbonyl-C]__5-alkylgruppe undR c is a hydrogen atom, a (C ^ _ 5 -alkoxy) carbonyl-C ] __5-alkyl or benzyloxycarbonyl-C] __ 5-alkyl group and
d ein Wasserstoffatom, eine Cι_5-Alkyl-, Ci.4-Alkanoyl- , (Cι_-5-Alkoxy) carbonyl- oder Benzyloxycarbonylgruppe darstellen, undd represents a hydrogen atom, a Cι_5-alkyl, Ci.4-alkanoyl, (Cι_- 5 alkoxy) carbonyl or benzyloxycarbonyl group, and
Het einen 5-gliedrigen heteroaromatischen Ring, der ein Stickstoffatom oder ein Stickstoffatom und ein Sauerstoff-, Schwefel- oder Stickstoffatom enthält, wobei der vorstehend erwähnte Ring außerdem durch eine Cι_5-Alkyl-, C5_7~Cyclo- alkyl-, Phenyl-, Phenyl-C]__3-alkyl- , Amino-, C^.4-Alkanoyl- amino-, (Cτ__5-Alkoxy) carbonylamino- oder Benzyloxycarbonyl- aminogruppe und außerdem noch durch eine weitere C^.5-Alkyl- gruppe substituiert sein kann,Het a 5-membered heteroaromatic ring which contains a nitrogen atom or a nitrogen atom and an oxygen, sulfur or nitrogen atom, wherein the above-mentioned ring is furthermore by a Cι_5-alkyl, C5_7 ~ cycloalkyl, phenyl, phenyl C] __ 3-alkyl, amino, C ^ .4-alkanoyl-amino, (Cτ__5-alkoxy) carbonylamino or benzyloxycarbonyl-amino group and can also be substituted by a further C ^ .5-alkyl group,
einen 5-giiedrigen dihydrierten heteroaromatischen Ring, der ein Stickstoffatom oder ein Stickstoffatom und ein Sauerstoff-, Schwefel- oder Stickstoffatom enthält, wobei der vorstehend erwähnte Ring außerdem durch eine oder zwei Cι_5-Alkylgruppen substituiert sein und eine Carbonylgruppe enthalten kann und zusätzlich an einem Ringstickstoffatom durch eine (C^-5-Alkoxy) carbonyl- oder Benzyloxycarbonylgruppe substituiert sein kann,a 5-membered dihydrogenated heteroaromatic ring which contains a nitrogen atom or a nitrogen atom and an oxygen, sulfur or nitrogen atom, the ring mentioned above also being substituted by one or two Cι_ 5 alkyl groups and may contain a carbonyl group and additionally on one Ring nitrogen atom can be substituted by a (C ^ -5-alkoxy) carbonyl or benzyloxycarbonyl group,
einen 5-gliedrigen tetrahydrierten heteroaromatischen Ring, der ein Stickstoffatom enthält, wobei der vorstehend erwähnte Ring zusätzlich durch eine oder zwei Cι_5-Alkylgruppen, durch eine Hydroxy-, Carboxy-, (C^.5-Alkoxy) carbonyl- oder Aminocarbonylgruppe substituiert sein kann und außerdem eine oder zwei Carbonylgruppen enthalten kann,a 5-membered tetrahydrated heteroaromatic ring which contains a nitrogen atom, the ring mentioned above additionally by one or two Cι_5-alkyl groups a hydroxy, carboxy, (C ^ .5-alkoxy) carbonyl or aminocarbonyl group can be substituted and can also contain one or two carbonyl groups,
einen 5-gliedrigen tetrahydrierten heteroaromatischen Ring, der ein Stickstoffatom und ein Sauerstoff-, Schwefel- oder Stickstoffatom enthält, wobei der vorstehend erwähnte Ring zusätzlich durch eine oder zwei C]__5-Alkylgruppen substituiert sein und eine oder zwei Carbonylgruppen enthalten kann,a 5-membered tetrahydrated heteroaromatic ring which contains a nitrogen atom and an oxygen, sulfur or nitrogen atom, where the ring mentioned above may additionally be substituted by one or two C] __ 5-alkyl groups and can contain one or two carbonyl groups,
eine Tetrazolyl- oder Imidazo [1, 2-a] yrimidin-2-yl-Gruppe darstellen,represent a tetrazolyl or imidazo [1, 2-a] yrimidin-2-yl group,
bedeuten, deren Isomere und deren Salze.mean their isomers and their salts.
2. Substituierte Indolinone der allgemeinen Formel I gemäß Anspruch 1, in der2. Substituted indolinones of general formula I according to claim 1, in which
R]_ ein Wasserstoff-, Fluor-, Chlor- oder Bromatom, eine Nitro-, Amino-, Cx_ ~Alkanoylamino- , (C^..5-Alkoxy) carbonylamino- oder Benzyloxycarbonylaminogruppe,R ] _ is a hydrogen, fluorine, chlorine or bromine atom, a nitro, amino, Cx_ ~ alkanoylamino, (C ^ .. 5-alkoxy) carbonylamino or benzyloxycarbonylamino group,
R2 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom, eine Methyl-, Trifluormethyl- , Cyano-, Aminocarbonyl-, Nitro- oder Aminogruppe,R2 is a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano, aminocarbonyl, nitro or amino group,
eine Cι_2-Alkylgruppe, die durch eine Amino-, Phthalimido- , Cι_2-Alkylamino-, Di- (Cι_2-alkyl) -amino- , C2-6-Alkylenamino- , Cι_2-Alkanoylamino-, (C^_5-Alkoxy) carbonylamino- , Benzyloxycarbonylamino- , N- (C]__2-Alkanoyl) -N- (Cι_2-alkyl) -amino-, N- ( (Ci.s-Alkoxy) carbonyl) -N- (C1_2-alkyl) -amino-, α-Oxo- C3_g-alkylenimino- , N-Benzyloxycarbonyl-N- (Cι_2-alkyl) -amino- , (C]__5-Alkoxy) carbonyl- , Benzyloxycarbonyl-, Carboxy-, Cyano-, Aminocarbonyl- oder Imidazolylgruppe substituiert ist, oder eine Allylgruppe, die in 3-Stellung durch eine C2-g-Alkylen- oder α-Oxo-C3_g-alkyleniminogruppe substituiert ist,a Cι_2-alkyl group, which by an amino, phthalimido, Cι_ 2 alkylamino, di (Cι_ 2 alkyl) amino, C2- 6 alkylene amino, Cι_ 2 alkanoylamino, (C ^ _ 5 -Alkoxy) carbonylamino-, benzyloxycarbonylamino-, N- (C] __ 2 -alkanoyl) -N- (Cι_2-alkyl) -amino-, N- ((Ci.s-alkoxy) carbonyl) -N- (C 1 _2 -alkyl) -amino-, α-oxo-C 3 _g-alkylenimino-, N-benzyloxycarbonyl-N- (Cι_2-alkyl) -amino-, (C] __ 5-alkoxy) carbonyl-, benzyloxycarbonyl-, carboxy-, cyano -, Aminocarbonyl- or imidazolyl group is substituted, or an allyl group which is substituted in the 3-position by a C 2 -g-alkylene or α-oxo-C 3 -g-alkyleneimino group,
R3 eine Gruppe der FormelnR 3 is a group of the formulas
Figure imgf000154_0001
in denen
Figure imgf000154_0001
in which
D und Het wie vorstehend erwähnt definiert sind und A eine Bindung, eine Cι_3-Alkylen- , C]__3-Alkyliden- , C2_3-Alkenylen- oder C2_3-Alkenyliden-Gruppe darstellen, wobei ein Wasserstoffatom, das im Rest Het an das Kohlenstoffatom der Verknüpfungsstelle gebunden ist, zusammen mit einem α-ständigen Wasserstoffatom des Restes A auch durch eine weitere Kohlenstoff-Kohlenstoff-Bindung ersetzt sein kann, darstellt,D and Het are defined as mentioned above and A is a bond, a Cι_ 3 alkylene, C] __ 3 alkylidene, C 2 _ 3 alkenylene or C2_ 3 alkenylidene group, a hydrogen atom, which is in Radical Het is bonded to the carbon atom of the linking point, together with an α-hydrogen atom of radical A can also be replaced by a further carbon-carbon bond,
bedeuten, deren Isomere und deren Salze.mean their isomers and their salts.
3. Substituierte Indolinone der allgemeinen Formel I gemäß Anspruch 1, in der3. Substituted indolinones of general formula I according to claim 1, in which
RQ_ ein Wasserstoffatom oder eine Nitrogruppe,R Q _ is a hydrogen atom or a nitro group,
R2 ein Wasserstoff- oder Chloratom, eine Methyl-, Trifluormethyl-, Cyano-, Aminomethyl-, Aminoethyl- oder Phthalimido- gruppe, eine Methyl- oder Ethylgruppe, die jeweils durch eine Methylamino-, Dimethylamino- , Ethylamino-, Diethylamino- , Pyrrolidino-, Piperidino-, α-Oxo-pyrrolidino- , α-Oxo-piperidino- , Acetylamino-, Methoxycarbonylamino- , Ethoxycarbonylamino- , Benzyloxycarbonylamino- , N-Acetyl-N-methylamino- , N-Methoxy- carbonyl-N-methyl-amino- , N-Ethoxycarbonyl-N-methyl-amino- , N-Benzyloxycarbonyl-N-methyl-aminomethyl- , 2- (N-Benzyloxycarbonyl-N-methyl-amino) -ethyl- oder Imidazolylgruppe substituiert sind, R3 eine l-Methyl-2-oxo-2,3-dihydro-lH-benzimidazol-5-yl- , 1,2,3 ,4-Tetrahydro-isochinolin-6-yl-, 2-Acetyl-1,2, 3, 4-tetrahydro-isochinolin-6-yl- , 2-Acetyl-1,2,3, -tetrahydro-isochinolin-7-yl- , 2-Ethyl-1, 2, 3 , 4-tetrahydro-isochinolin-6-yl- , 2-Ethyl-1, 2, 3, 4-tetrahydro-isochinolin-7-yl-, 4- (Imidazol- 2-yl) -phenyl-, 4- (l-Methyl-imidazol-2-yl) -phenyl- , 4- (Imidazol- 4-yl) -phenyl-, 4- (1-Methyl-imidazol-4-yl) -phenyl-, 4- (1-Methyl- imidazol-5-yl) -phenyl-, 4- (5-Methyl-imidazol-4-yl) -phenyl-, 4- (4-Methyl-imidazol-5-yl) -phenyl-, 4- (2-Methyl-imidazol-4-yl) - phenyl-, 4- (2-Ethyl-imidazol-4-yl) -phenyl-, 4- (2-Acetylamino- imidazol-4-yl) -phenyl-, 4- (2-Acetylamino-5-methyl-imidazol- 4-yl) -phenyl-, Imidazo [1,2-a]pyrimidin-2-yl-, 4- [ (2,4-Dioxo- imidazolidin-5-yl) methyl] -phenyl-, 4- [ (2, 4-Dioxo-imidazolidin- 5-yliden) methyl] -phenyl-, 4- [ (Imidazol-4-yl) methyl] -phenyl-, 4- [ (Imidazol-5-yl) methyl] -phenyl-, 4- [ (1-Pyrrolidinyl) methyl] - phenyl-, 4- [2- (Imidazol-4 (5) -yl) ethyl] -phenyl- , 4- [2- (Imidazol- 4-yl) ethenyl] -phenyl- oder 4- [2- (Imidazol-5-yl) ethenyl] -phenyl- gruppe bedeuten,R2 represents a hydrogen or chlorine atom, a methyl, trifluoromethyl, cyano, aminomethyl, aminoethyl or phthalimido group, a methyl or ethyl group, each represented by a methylamino, dimethylamino, ethylamino, diethylamino, pyrrolidino -, piperidino, α-oxo-pyrrolidino, α-oxo-piperidino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, N-acetyl-N-methylamino, N-methoxycarbonylamino-N-methyl amino, N-ethoxycarbonyl-N-methyl-amino, N-benzyloxycarbonyl-N-methyl-aminomethyl, 2- (N-benzyloxycarbonyl-N-methyl-amino) -ethyl or imidazolyl group, R3 is l-methyl-2-oxo-2,3-dihydro-lH-benzimidazol-5-yl-, 1,2,3,4-tetrahydro-isoquinolin-6-yl-, 2-acetyl-1,2, 3, 4-tetrahydro-isoquinolin-6-yl-, 2-acetyl-1,2,3, -tetrahydro-isoquinolin-7-yl-, 2-ethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6 -yl-, 2-ethyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl-, 4- (imidazol-2-yl) -phenyl-, 4- (l-methyl-imidazol-2-yl ) -phenyl-, 4- (imidazol-4-yl) -phenyl-, 4- (1-methyl-imidazol-4-yl) -phenyl-, 4- (1-methyl-imidazol-5-yl) -phenyl -, 4- (5-Methyl-imidazol-4-yl) -phenyl-, 4- (4-methyl-imidazol-5-yl) -phenyl-, 4- (2-methyl-imidazol-4-yl) - phenyl-, 4- (2-ethyl-imidazol-4-yl) -phenyl-, 4- (2-acetylamino-imidazol-4-yl) -phenyl-, 4- (2-acetylamino-5-methyl-imidazole- 4-yl) -phenyl-, imidazo [1,2-a] pyrimidin-2-yl-, 4- [(2,4-dioxo-imidazolidin-5-yl) methyl] -phenyl-, 4- [(2nd , 4-Dioxo-imidazolidin- 5-ylidene) methyl] -phenyl-, 4- [(imidazol-4-yl) methyl] -phenyl-, 4- [(imidazol-5-yl) methyl] -phenyl-, 4 - [(1-pyrrolidinyl) methyl] phenyl-, 4- [2- (imidazo 1-4 (5) -yl) ethyl] phenyl-, 4- [2- (imidazol-4-yl) ethenyl] phenyl- or 4- [2- (imidazol-5-yl) ethenyl] phenyl- group mean,
deren Isomere und deren Salze.their isomers and their salts.
4. Substituierte Indolinone der allgemeinen Formel I gemäß Anspruch 1, in der4. Substituted indolinones of general formula I according to claim 1, in which
Rl ein Wasserstoffatom oder in 5-Stellung eine Nitrogruppe,R 1 is a hydrogen atom or a 5-position nitro group,
R2 ein Wasserstoffatom, eine Methyl- oder Trifluormethylgruppe,R2 represents a hydrogen atom, a methyl or trifluoromethyl group,
R3 eine 4- (1-Methyl-imidazol-2-yl) -phenyl- , 4- (Imidazol-4-yl) - phenyl-, 4- (Imidazol-5-yl) -phenyl- , 4- (1-Methyl-imidazol-4-yl) - phenyl-, 4- (1-Methyl-imidazol-5-yl) -phenyl- , 4- (2-Methyl-imi- dazol-4-yl) -phenyl-, 4- (2-Acetylamino-imidazol-4-yl) -phenyl-, 4- [ (2, 4-Dioxo-imidazolidin-5-yliden) methyl] -phenyl-, 4- [ (1-Pyr- rolidinyl) -methyl] -phenyl-, 4- [2- (Imidazol-4-yl) ethenyl] -phenyl- oder 1, 2, 3, 4-Tetrahydro-isochinolin-6-yl-Gruppe bedeuten,R 3 is 4- (1-methyl-imidazol-2-yl) phenyl, 4- (imidazol-4-yl) phenyl, 4- (imidazol-5-yl) phenyl, 4- (1 -Methyl-imidazol-4-yl) -phenyl-, 4- (1-methyl-imidazol-5-yl) -phenyl-, 4- (2-methyl-imidazol-4-yl) -phenyl-, 4 - (2-Acetylamino-imidazol-4-yl) phenyl-, 4- [(2, 4-dioxo-imidazolidin-5-ylidene) methyl] phenyl-, 4- [(1-pyrrolidinyl) methyl ] -phenyl-, 4- [2- (imidazol-4-yl) ethenyl] phenyl or 1, 2, 3, 4-tetrahydro-isoquinolin-6-yl group,
deren Isomere und deren Salze. their isomers and their salts.
5. Folgende substituierte Indolinone der allgemeinen Formel I gemäß Anspruch 1 :5. The following substituted indolinones of the general formula I according to claim 1:
(a) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -l-phenylmethyliden} -2-indolinon,(a) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -l-phenylmethylidene} -2-indolinone,
(b) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(b) 3- {(Z) -1- [4- (1H-imidazol-4-yl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(c) 3-{ (Z) -1- [4- (lH-Imidazol-4-yl) anilino] -1- (4-trifluor-me- thyl-phenyl) methyliden} -5-nitro-2-indolinon,(c) 3- {(Z) -1- [4- (1H-Imidazol-4-yl) anilino] -1- (4-trifluoro-methyl-phenyl) methylidene} -5-nitro-2-indolinone ,
(d) 3-{ (Z) -1- [4- (IH-Imidazol-4-yl) anilino] -1- (4-methyl-phenyl) methyliden} -5-nitro-2-indolinon,(d) 3- {(Z) -1- [4- (IH-imidazol-4-yl) anilino] -1- (4-methylphenyl) methylidene} -5-nitro-2-indolinone,
(e) 3-{(Z)-l-[4-( (2, 4-Dioxo-imidazolidin-5-yl) methyl) anilino] - l-phenylmethyliden} -5-nitro-2-indolinon,(e) 3 - {(Z) -l- [4- ((2,4-dioxo-imidazolidin-5-yl) methyl) anilino] - l-phenylmethylidene} -5-nitro-2-indolinone,
(f) 3-{ (Z) -1- [4- (2-Methyl-lH-imidazol-4-yl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(f) 3- {(Z) -1- [4- (2-methyl-1H-imidazol-4-yl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(g) 3- { (Z) -1- [4- ( (Pyrrolidin-1-yl) methyl) anilino] -l-phenylmethyliden} -5-nitro-2-indolinon,(g) 3- {(Z) -1- [4- ((pyrrolidin-1-yl) methyl) anilino] -l-phenylmethylidene} -5-nitro-2-indolinone,
(h) 3-{ (Z) -1- [ (1,2, 3, 4-Tetrahydro-isochinolin-6-yl) amino] - l-phenylmethyliden} -5-nitro-2-indolinon(h) 3- {(Z) -1- [(1,2,3,4-tetrahydro-isoquinolin-6-yl) amino] -1-phenylmethylidene} -5-nitro-2-indolinone
und deren Salze.and their salts.
6. Physiologisch verträgliche Salze der Verbindungen gemäß den Ansprüchen 1 bis 5.6. Physiologically acceptable salts of the compounds according to claims 1 to 5.
7. Arzneimittel, enthaltend eine Verbindung nach mindestens einem der Ansprüche 1 bis 5 oder ein Salz gemäß Anspruch 6 neben gegebenenfalls einem oder mehreren inerten Trägerstoffen und/oder Verdünnungsmitteln. 7. Medicament containing a compound according to at least one of claims 1 to 5 or a salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents.
8. Verwendung einer Verbindung nach mindestens einem der Ansprüche 1 bis 5 oder ein Salz gemäß Anspruch 6 zur Herstellung eines Arzneimittels, welches zur Behandlung von exzessiven oder anomalen Zellproliferationen geeignet ist.8. Use of a compound according to at least one of claims 1 to 5 or a salt according to claim 6 for the manufacture of a medicament which is suitable for the treatment of excessive or abnormal cell proliferation.
9. Verfahren zur Herstellung eines Arzneimittels gemäß Anspruch 7, dadurch gekennzeichnet, daß auf nichtchemischem Wege eine Verbindung nach mindestens einem der Ansprüche 1 bis 5 oder ein Salz gemäß Anspruch 6 in einen oder mehrere inerte Trägerstoffe und/oder Verdünnungsmittel eingearbeitet wird.9. A process for the preparation of a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 5 or a salt according to claim 6 is incorporated in one or more inert carriers and / or diluents in a non-chemical way.
10. Verfahren zur Herstellung der Verbindungen gemäß den Ansprüchen 1 bis 6, dadurch gekennzeichnet, daß10. A process for the preparation of the compounds according to claims 1 to 6, characterized in that
a. eine Verbindung der allgemeinen Formela. a compound of the general formula
Figure imgf000157_0001
in der
Figure imgf000157_0001
in the
Rl und R2 wie in den Ansprüchen 1 bis 5 erwähnt definiert sind, R4 ein Wasserstoffatom oder eine Schutzgruppe für das Stickstoffatom der Lactamgruppe undR 1 and R2 are as defined in claims 1 to 5, R 4 is a hydrogen atom or a protective group for the nitrogen atom of the lactam group and
Z]_ ein Halogenatom, eine Hydroxy- , Alkoxy- oder Aralkoxygruppe bedeuten,Z] _ represents a halogen atom, a hydroxyl, alkoxy or aralkoxy group,
mit einem Amin der allgemeinen Formelwith an amine of the general formula
H2N-R3 (III), in derH 2 NR 3 (III), in the
R3 wie in den Ansprüchen 1 bis 5 erwähnt definiert ist, umgesetzt und erforderlichenfalls anschließend eine verwendete Schutzgruppe für das Stickstoffatom der Lactamgruppe abgespalten wird, oderR 3 is as defined in claims 1 to 5, implemented and, if necessary, a protective group used for the nitrogen atom of the lactam group is subsequently split off, or
b. zur Herstellung einer Verbindung der allgemeinen Formel I, in der R2 eine der für R2 in den Ansprüchen 1 bis 5 erwähnten Alkenyl- oder Allylreste darstellt,b. for the preparation of a compound of the general formula I in which R2 represents one of the alkenyl or allyl radicals mentioned for R2 in claims 1 to 5,
eine Halogenphenyl-Verbindung der allgemeinen Formela halophenyl compound of the general formula
Figure imgf000158_0001
in der
Figure imgf000158_0001
in the
R^, R3 und R4 wie in den Ansprüchen 1 bis 5 erwähnt definiert sind undR ^, R 3 and R 4 are as defined in claims 1 to 5 and
Z2 ein Chlor-, Brom- oder Jodatom darstellt,Z2 represents a chlorine, bromine or iodine atom,
mit einem Alken der allgemeinen Formelwith an alkene of the general formula
R2' - H (V),R 2 '- H (V),
in derin the
R2 ' einen der für R2 in den Ansprüchen 1 bis 5 erwähnten substituierten Alkenylreste darstellt, in Gegenwart eines geeigneten Edelmetallhaltigen Katalysators umgesetzt und erforderlichenfalls anschließend eine verwendete Schutzgruppe für das Stickstoffatom der Lactamgruppe abgespalten wird, oder c. zur Herstellung einer Verbindung der allgemeinen Formel I, in der A eine C2-4-Alkenylengruppe darstellt,R2 'represents one of the substituted alkenyl radicals mentioned for R 2 in claims 1 to 5, is reacted in the presence of a suitable noble metal-containing catalyst and, if necessary, a protective group used for the nitrogen atom of the lactam group is subsequently cleaved off, or c. for the preparation of a compound of the general formula I in which A represents a C2-4-alkenylene group,
eine Halogenphenyl-Verbindung der allgemeinen Formela halophenyl compound of the general formula
Figure imgf000159_0001
in der
Figure imgf000159_0001
in the
R l' R2 unc R4 wie in den Ansprüchen 1 bis 5 erwähnt definiert sind und R 1 ' R 2 and R 4 are as defined in claims 1 to 5 and
Z3 ein Chlor-, Brom- oder Jodatom darstellt,Z3 represents a chlorine, bromine or iodine atom,
mit einem Alken der allgemeinen Formelwith an alkene of the general formula
H - A1 Het (VII) ,H - A 1 Het (VII),
in derin the
Het wie in den Ansprüchen 1 bis 5 erwähnt definiert ist und A' eine C2_4-Alkenylengruppe darstellt, in Gegenwart eines geeigneten Edelmetall-haltigen Katalysators umgesetzt und erforderlichenfalls anschließend eine verwendete Schutzgruppe für das Stickstoffatom der Lactamgruppe abgespalten wird, oderHet is as defined in claims 1 to 5 and A 'represents a C2_4-alkenylene group, reacted in the presence of a suitable noble metal-containing catalyst and, if necessary, a protective group used for the nitrogen atom of the lactam group is subsequently cleaved off, or
d. zur Herstellung einer Verbindung der allgemeinen Formel I, in der A eine Bindung oder eine C]__4-Alkylengruppe und Het eine der für Het in den Ansprüchen 1 bis 5 erwähnten gegebenenfalls mono- oder disubstituierten (4, 5-Dihydro-imidazol-2-yl) -Gruppen darstellen, eine Iminoether-phenyl-Verbindung der allgemeinen Formeld. for the preparation of a compound of the general formula I in which A is a bond or a C ] __ 4 -alkylene group and Het is one of the optionally mono- or disubstituted (4, 5-dihydro-imidazole-2 represent -yl) groups, an iminoether-phenyl compound of the general formula
Figure imgf000160_0001
in der
Figure imgf000160_0001
in the
R l' R 2 unα^ R 4 wie ^n den Ansprüchen 1 bis 5 erwähnt definiert sind, R 1 ' R 2 and α ^ R 4 w i e ^ n are defined in claims 1 to 5,
A' eine Bindung oder eine Cχ_4-Alkylengruppe undA 'is a bond or a Cχ_4 alkylene group and
R5 eine Alkylgruppe darstellen,R5 represent an alkyl group,
mit einem Ethylendiamin, das an einem der Stickstoff- oder Kohlenstoffatome oder an einem der Stickstoffatome und an einem der Kohlenstoffatome durch eine C^„5-Alkylgruppe substituiert sein kann, umgesetzt und erforderlichenfalls anschließend eine verwendete Schutzgruppe für das Stickstoffatom einer Lactamgruppe abgespalten wird undis reacted with an ethylenediamine which can be substituted on one of the nitrogen or carbon atoms or on one of the nitrogen atoms and on one of the carbon atoms by a C 1-5 alkyl group and, if necessary, subsequently a protective group used for the nitrogen atom of a lactam group is removed and
gewünschtenfalls anschließend eine so erhaltene Verbindung der allgemeinen Formel I, in der R3 eine (Imidazo [1, 2-a] pyrimidin- 2-yl)phenylgruppe darstellt, mittels Hydrazinolyse in eine entsprechende (2-Amino-imidazol-4 (5) -yl)phenyl erbindung übergeführt wird, oderif desired, a compound of the general formula I obtained in this way, in which R 3 represents an (imidazo [1, 2-a] pyrimidin-2-yl) phenyl group, by means of hydrazinolysis into a corresponding (2-amino-imidazole-4 (5) -yl) phenyl compound is transferred, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R2 einen Phthalimidorest enthält, mittels Hydrazinolyse in eine entsprechende Aminoverbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R2 contains a phthalimido residue, is converted into a corresponding amino compound by means of hydrazinolysis, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R2 eine Cyano-, Cyanoalkyl- oder Cyanoalkenylgruppe darstellt, mittels Reduktion in eine entsprechende Aminomethyl- oder Ami- noalkylverbindung übergeführt wird, odera compound of the general formula I obtained in this way, in which R 2 represents a cyano, cyanoalkyl or cyanoalkenyl group, is converted into a corresponding aminomethyl or aminoalkyl compound by reduction, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R2 eine Cyano-, Cyanoalkyl- oder Cyanoalkenylgruppe darstellt, mittels Hydratisierung in eine entsprechende Aminocarbonyl-, Aminocarbonylalkyl- oder Ammocarbonylalkenyl-Verbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R2 represents a cyano, cyanoalkyl or cyanoalkenyl group, is converted into a corresponding aminocarbonyl, aminocarbonylalkyl or ammocarbonylalkenyl compound by means of hydration, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R2 eine Alkenylengruppe enthält, mittels Reduktion in eine entsprechende Alkylenverbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R2 contains an alkenylene group, is converted into a corresponding alkylene compound by reduction, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R3 eine Alkenylengruppe enthält, mittels Reduktion in eine entsprechende Alkylenverbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R 3 contains an alkenylene group, is converted into a corresponding alkylene compound by reduction, or
e±ne so erhaltene Verbindung der allgemeinen Formel I, in der R3 eine der für R3 in den Ansprüchen 1 bis 5 erwähnte (Amino- imidazolyl) phenylgruppe darstellt, die durch eine Alkanoyl- oder Benzyloxycarbonylgruppe substituiert ist, mittels Hydrolyse oder Hydrogenolyse in eine entsprechende unsubstituierte Verbindung übergeführt wird, odere ± ne compound of the general formula I thus obtained, in which R 3 represents one of the (aminoimidazolyl) phenyl groups mentioned for R3 in claims 1 to 5, which is substituted by an alkanoyl or benzyloxycarbonyl group, by means of hydrolysis or hydrogenolysis into one corresponding unsubstituted compound is transferred, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R3 eine der für R3 in den Ansprüchen 1 bis 5 erwähnte unsub- stituierten (Amino-imidazolyDphenylgruppe darstellt, mittels Acylierung in eine entsprechende Acylverbindung übergeführt wird, odera compound of the general formula I obtained in this way, in which R 3 is one of the unsubstituted (aminoimidazolydphenyl group mentioned for R 3 in claims 1 to 5) is converted into a corresponding acyl compound by acylation, or
eine so erhaltene Verbindung der allgemeinen Formel I , in der R2 einen der für R2 in den Ansprüchen 1 bis 5 erwähnten Reste darstellt, die eine Amino-, Alkylamino-, Alkenylamino- oder Benzylaminogruppe enthalten, mittels Acylierung in eine entsprechende Acylverbindung übergeführt wird, oder eine so erhaltene Verbindung der allgemeinen Formel I, in der R-|_ eine Nitrogruppe darstellt, mittels Reduktion in eine entsprechende Aminoverbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R 2 represents one of the radicals mentioned for R 2 in claims 1 to 5, which contain an amino, alkylamino, alkenylamino or benzylamino group, is converted into a corresponding acyl compound by acylation , or a compound of the general formula I thus obtained, in which R - represents a nitro group, is converted into a corresponding amino compound by reduction, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R^ eine Aminogruppe darstellt, mittels durch Acylierung in die entsprechende Acylverbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R ^ represents an amino group, is converted into the corresponding acyl compound by means of acylation, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der A eine Alkenylen-, Alkyliden- oder Alkenylidengruppe darstellt, mittels katalytischer Hydrierung in eine entsprechende Alkylen- verbindung übergeführt wird, odera compound of the general formula I obtained in this way, in which A represents an alkenylene, alkylidene or alkenylidene group, is converted into a corresponding alkylene compound by means of catalytic hydrogenation, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R3 einen Phthalimidorest darstellt, der durch eine (Cι_5-Alk- oxy) carbonyl-C^_5-alkyl- oder Benzyloxycarbonyl-Ci_5-alkyl- gruppe substituiert ist, mittels Acidolyse oder Hydrogenolyse in eine entsprechende Carboxyverbindung übergeführt wird, odera compound of the general formula I obtained in this way, in which R 3 represents a phthalimido residue which is substituted by a (Cι_5-alkoxy) carbonyl-C ^ _5-alkyl or benzyloxycarbonyl-Ci_5-alkyl group, by means of acidolysis or hydrogenolysis is converted into a corresponding carboxy compound, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R2 einen Alkoxycarbonyl- oder Benzyloxycarbonylrest enthält, mittels Hydrolyse oder Hydrogenolyse in eine entsprechende Carboxyverbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R2 contains an alkoxycarbonyl or benzyloxycarbonyl radical, is converted into a corresponding carboxy compound by means of hydrolysis or hydrogenolysis, or
eine so erhaltene Verbindung der allgemeinen Formel I , in der R2 einen acylierten Aminoalkylrest darstellt, mittels Hydrolyse oder Hydrogenolyse in eine entsprechende Aminoalkylverbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R 2 represents an acylated aminoalkyl radical, is converted into a corresponding aminoalkyl compound by means of hydrolysis or hydrogenolysis, or
eine so erhaltene Verbindung der allgemeinen Formel I , in der Rl oder/und R2 ein Halogenatom darstellen, mittels katalytischer Hydrierung in eine entsprechende dehalogenierte Verbindung übergeführt werden, odera compound of the general formula I thus obtained, in which R 1 or / and R 2 represent a halogen atom, are converted into a corresponding dehalogenated compound by means of catalytic hydrogenation, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R3 einen 2-Boc-, 2-Z- oder 2-Benzyl-l, 2, 3 , 4-tetrahydroiso- chinolinyl-Rest darstellt, mittels Hydrolyse oder Hydrogenolyse in eine entsprechende 1, 2, 3 ,4-Tetrahydroisochinolinyl-Verbindung übergeführt wird, odera compound of the general formula I obtained in this way, in which R3 represents a 2-Boc, 2-Z or 2-benzyl-l, 2, 3, 4-tetrahydroisoquinolinyl radical, by means of hydrolysis or hydrogenolysis is converted into a corresponding 1, 2, 3, 4-tetrahydroisoquinolinyl compound, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der R3 einen 1, 2, 3, 4-Tetrahydro-isochinolylrest darstellt, mittels Acylierung in eine entsprechende 2-Acyl-l, 2, 3, 4-tetrahydro- isochinolyl-Verbindung übergeführt wird, odera compound of the general formula I thus obtained, in which R 3 represents a 1, 2, 3, 4-tetrahydro-isoquinolyl radical, is converted into a corresponding 2-acyl-1, 2, 3, 4-tetrahydro-isoquinolyl compound by means of acylation will, or
eine so erhaltene Verbindung der allgemeinen Formel I, in der Het eine der für Het in den Ansprüchen 1 bis 5 erwähnten Gruppen darstellt, die an einem Ringstickstoffatom durch eine (Cι_5-Alkoxy) carbonyl- oder Benzyloxycarbonylgruppe substituiert ist, mittels Acidolyse oder Hydrogenolyse in eine entsprechende NH-Verbindung übergeführt wird, unda compound of the general formula I thus obtained, in which Het is one of the groups mentioned for Het in claims 1 to 5, which is substituted on a ring nitrogen atom by a (Cι_5-alkoxy) carbonyl or benzyloxycarbonyl group, by means of acidolysis or hydrogenolysis in one corresponding NH compound is transferred, and
erforderlichenfalls ein während den Umsetzungen zum Schütze von reaktiven Gruppen verwendeter Schutzrest abgespalten wird, oderif necessary, a protective residue used during the reactions to protect reactive groups is split off, or
gewünschtenfalls anschließend eine so erhaltene Verbindung der allgemeinen Formel I in ihre Stereoisomere aufgetrennt wird, oderif desired, a compound of the general formula I thus obtained is subsequently separated into its stereoisomers, or
eine so erhaltene Verbindung der allgemeinen Formel I in ihre Salze, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträglichen Salze mit einer anorganischen oder organischen Säure oder Base, übergeführt wird. a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid or base.
PCT/EP1999/002186 1998-04-03 1999-03-30 Substituted indolinones as kinase inhibitors WO1999051590A1 (en)

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO2000064872A1 (en) * 1999-04-23 2000-11-02 Vertex Pharmaceuticals Incorporated INHIBITORS OF c-JUN N-TERMINAL KINASES (JNK)
EP1103552A1 (en) * 1998-08-07 2001-05-30 Takeda Chemical Industries, Ltd. Benzothiepin derivatives, process for the preparation of the same and uses thereof
US6818632B2 (en) 1999-03-04 2004-11-16 Smithkline Beecham Corporation 3-(anilinomethylene)oxindoles
WO2006114371A1 (en) * 2005-04-28 2006-11-02 Boehringer Ingelheim International Gmbh Novel compounds for treating inflammatory diseases
US7612065B2 (en) 2000-04-21 2009-11-03 Vertex Pharmaceuticals Incorporated Inhibitors of c-JUN N-terminal kinases (JNK)
CN111269192A (en) * 2020-02-25 2020-06-12 成都睿智化学研究有限公司 Synthesis method of 5-hydroxymethyl tetrazole and derivatives thereof
CN115703758A (en) * 2021-08-12 2023-02-17 中国医学科学院药物研究所 Compound used as kinase inhibitor and preparation method and application thereof

Families Citing this family (6)

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US6624171B1 (en) 1999-03-04 2003-09-23 Smithkline Beecham Corporation Substituted aza-oxindole derivatives
AU6998000A (en) 1999-08-27 2001-03-26 Boehringer Ingelheim Pharma Kg Substituted indolinones as tyrosine kinase inhibitors
US6762180B1 (en) 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
DE19949209A1 (en) * 1999-10-13 2001-04-19 Boehringer Ingelheim Pharma 5-substituted indolinones, their preparation and their use as pharmaceuticals
UA75054C2 (en) * 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Substituted in position 6 indolinones, producing and use thereof as medicament
PE20060777A1 (en) 2004-12-24 2006-10-06 Boehringer Ingelheim Int INDOLINONE DERIVATIVES FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001349A1 (en) * 1993-07-01 1995-01-12 Pharmacia S.P.A. Arylidene and heteroarylidene oxindole derivatives as tyrosine kinase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001349A1 (en) * 1993-07-01 1995-01-12 Pharmacia S.P.A. Arylidene and heteroarylidene oxindole derivatives as tyrosine kinase inhibitors

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EP1103552A1 (en) * 1998-08-07 2001-05-30 Takeda Chemical Industries, Ltd. Benzothiepin derivatives, process for the preparation of the same and uses thereof
EP1103552A4 (en) * 1998-08-07 2003-01-15 Takeda Chemical Industries Ltd Benzothiepin derivatives, process for the preparation of the same and uses thereof
US6818632B2 (en) 1999-03-04 2004-11-16 Smithkline Beecham Corporation 3-(anilinomethylene)oxindoles
US7129253B2 (en) 1999-03-04 2006-10-31 Smithkline Beecham Corporation Compounds
WO2000064872A1 (en) * 1999-04-23 2000-11-02 Vertex Pharmaceuticals Incorporated INHIBITORS OF c-JUN N-TERMINAL KINASES (JNK)
US7612065B2 (en) 2000-04-21 2009-11-03 Vertex Pharmaceuticals Incorporated Inhibitors of c-JUN N-terminal kinases (JNK)
WO2006114371A1 (en) * 2005-04-28 2006-11-02 Boehringer Ingelheim International Gmbh Novel compounds for treating inflammatory diseases
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US7723381B2 (en) 2005-04-28 2010-05-25 Boehringer Ingelheim International Gmbh Compounds for the treatment of inflammatory diseases
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CN111269192A (en) * 2020-02-25 2020-06-12 成都睿智化学研究有限公司 Synthesis method of 5-hydroxymethyl tetrazole and derivatives thereof
CN115703758A (en) * 2021-08-12 2023-02-17 中国医学科学院药物研究所 Compound used as kinase inhibitor and preparation method and application thereof
CN115703758B (en) * 2021-08-12 2024-03-26 中国医学科学院药物研究所 Compounds used as kinase inhibitors, preparation method and application thereof

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