[go: up one dir, main page]

US20010014690A1 - Substituted N-benzylindol-3-ylglyoxylic acid derivatives having antitumor action - Google Patents

Substituted N-benzylindol-3-ylglyoxylic acid derivatives having antitumor action Download PDF

Info

Publication number
US20010014690A1
US20010014690A1 US09/736,431 US73643100A US2001014690A1 US 20010014690 A1 US20010014690 A1 US 20010014690A1 US 73643100 A US73643100 A US 73643100A US 2001014690 A1 US2001014690 A1 US 2001014690A1
Authority
US
United States
Prior art keywords
group
cooh
radical
acid
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US09/736,431
Other versions
US6432987B2 (en
Inventor
Eckhard Gunter
Peter Emig
Dietmar Reichert
Guillaume Le Baut
Bernd Nickel
Gerald Bacher
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aeterna Zentaris GmbH
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Assigned to ASTA MEDICA AG reassignment ASTA MEDICA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BACHER, GERALD, EMIG, PETER, GUNTER, ECKHARD, REICHERT, DIETMAR, LE BAUT, GUILLAUME, NICKEL, BERND
Publication of US20010014690A1 publication Critical patent/US20010014690A1/en
Assigned to ZENTARIS AG reassignment ZENTARIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ASTA MEDICA GMBH
Application granted granted Critical
Publication of US6432987B2 publication Critical patent/US6432987B2/en
Assigned to ZENTARIS GMBH reassignment ZENTARIS GMBH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: ZENTARIS AG
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the aim of the present invention is to make available novel compounds from the indol-3-ylglyoxylic acid series of the general formula 1 which have a good antitumor action and can be employed for the preparation of antitumor agents;
  • R nitro, amino, mono- or di(C 1 -C 6 )-alkylamino, mono- or di(C 1 -C 6 )-cycloalkylamino, (C 1 -C 6 ) -acylamino, phenyl (C 1 -C 6 )-alkylamino, aroylamino, heteroaroylamino, (C 1 -C 6 )-alkylsulfonamido, aryl-sulfonamido, maleimido, succinimido, phthalimido, benzyloxycarbonylamino (Z-amino), tert-butoxy-carbonylamino (BOC-amino), 9-fluorenylmethoxy-carbonylamino (Fmoc-amino), triphenylmethylamino (Tr-amino), 2-(4′-pyridyl)ethoxycarbonylamino (Pyoc-
  • R 1 hydrogen, (C 1 -C 6 )-alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring for its part can be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C 1 -C 6 -alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C 1 -C 6 )-alkyl groups, halogen atoms or trifluoromethyl groups,
  • R 1 is further the benzyloxycarbonyl group (Z group) and the tertiary-butoxycarbonyl radical (Boc radical), furthermore the acetyl group.
  • R 2 can be the phenyl ring, which is mono- or polysubstituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C 1 -C 6 ) -alkylamino, (C 1 -C 6 )-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with C 1 -C 6 -alkanols, or can be a pyridine structure of the formula 2
  • the radicals R 5 and R 6 can be identical or different and have the meaning (C 1 -C 6 )-alkyl and the meaning (C 3 -C 7 ) -cycloalkyl, (C 1 -C 6 )-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl and further are the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
  • R 2 can further be a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore can be the 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolyl structure substituted by (C 1 -C 6 )-alkyl, halogen, the nitro group, the amino group and the (C 1 -C 6 )-alkylamino radical, can be a 2-, 3- and [sic] 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, nitro, amino and (C 1 -C 6 )-alkoxycarbonylamino.
  • R 2 in the case in which R 1 are [sic] hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group can furthermore be the acid radical of a natural or unnatural amino acid, e.g.
  • the amino groups of the respective amino acids can be present unprotected or can be protected.
  • a possible protective group of the amino function is the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group.
  • the second, unbonded carboxyl group is present as a free carboxyl group or in the form of a carboxyl group esterified with C 1 -C 6 -alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.
  • R 2 can be the allylaminocarbonyl-2-methylprop-1-yl group.
  • R 1 and R 2 can further form, together with the nitrogen atom to which they are bonded, a piperazine ring of the formula 3 or a homopiperazine ring, provided R 2 is an aminoalkylene group, in which
  • R 7 is an alkyl radical, is a phenyl ring which can be mono- or polysubstituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, halogen, the nitro group, the amino function and by the (C 1 -C 6 )-alkylamino group.
  • R 7 is furthermore the benzhydryl group and the bis-p-fluorobenzhydryl group.
  • R 3 and R 4 can be identical or different and are hydrogen, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, (C 1 -C 6 )-alkanoyl, (C 1 -C 6 )-alkoxy, halogen and benzyloxy.
  • R 3 and R 4 can furthermore be the nitro group, the amino group, the (C 1 -C 4 )-mono- or dialkyl-substituted amino group, and the (C 1 -C 6 )-alkoxycarbonylamino function or (C 1 -C 6 )-alkoxycarbonylamino-(C 1 -C 6 )-alkyl function.
  • Z is O and S.
  • alkyl, alkanol, alkoxy or alkylamino group for the radicals R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 is normally understood as meaning both “straight-chain” and “branched” alkyl groups, where “straight-chain alkyl groups” can be, for example, radicals such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and “branched alkyl groups” designate, for example, radicals such as isopropyl or tert-butyl.
  • Cycloalkyl is understood as meaning radicals such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the designation “halogen” represents fluorine, chlorine, bromine or iodine.
  • alkoxy group represents radicals such as, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.
  • acyl of the acylamino radicals is to be understood as meaning the groups formyl, acetyl, propionyl, butyryl, valeryl and isovaleryl.
  • aroyl of the aroylamino groups represents benzoyl, naphthoyl, toluoyl, phthaloyl and the group heteroaroyl of the heteroaroylamino radicals represents nicotinoyl, isonicotinoyl, thenoyl and furoyl.
  • the designation aryl of the arylsulfonamido group is understood as meaning phenyl, tolyl and naphthyl.
  • the compounds can also be employed as acid addition salts, for example as salts of mineral acids, such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids, such as, for example, acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxyethanesulfonic acid, nicotinic acid and p-toluenesulfonic acid.
  • Both the compounds of the formula 1 and their salts are biologically active.
  • the compounds of the formula 1 can be administered in free form or as salts with physiologically tolerable acids. Administration can be performed orally, parenterally, intravenously, transdermally or by inhalation.
  • the invention furthermore relates to pharmaceutical preparations which contain at least one of the compounds of the formula 1 or their salts with physiologically tolerable inorganic or organic acids and, if appropriate, pharmaceutically utilizable excipients and/or diluents or auxiliaries.
  • Suitable administration forms are, for example, tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments.
  • the indole derivative which can be unsubstituted or monosubstituted or polysubstituted on C-2 or in the phenyl structure, is dissolved in a protic, dipolar aprotic or nonpolar organic solvent, such as, for example, isopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dioxane, toluene or methylene chloride and added dropwise to a suspension of a base prepared in a three-necked flask under an N 2 atmosphere or employed in a molar amount or in excess, such as, for example, sodium hydride, powdered potassium hydroxide, potassium tert-butoxide, dimethylaminopyridine or sodium amide, in a suitable solvent.
  • a protic, dipolar aprotic or nonpolar organic solvent such as, for example, isopropanol, tetrahydro
  • the desired alkyl, aralkyl or heteroaralkyl halide for example, is added, if appropriate with addition of a catalyst, such as, for example, copper and the mixture is allowed to react for some time, for example for 30 minutes to 12 hours, and the temperature is maintained within a range from 0° C. to 120° C., preferably between 30° C. to [sic] 80° C., particularly between 50° C. and 65° C.
  • the reaction mixture is added to water, the solution is extracted, e.g.
  • the organic phase is concentrated in vacuo, the residue which remains is crystallized by trituration or the oily residue is purified by recrystallization, distillation or by column or flash chromatography on silica gel or alumina.
  • the eluent used is, for example, a mixture of dichloromethane and diethyl ether in the ratio 8:2 (vol/vol) or a mixture of dichloromethane and ethanol in the ratio 9:1 (vol/vol).
  • the N-substituted indole obtained according to the above procedure of the 1st stage is dissolved under a nitrogen atmosphere in an aprotic or nonpolar organic solvent, such as, for example, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride or chloroform and added to a solution prepared under a nitrogen atmosphere of a monomolar up to 60% excess amount of oxalyl chloride in an aprotic or nonpolar solvent, such as, for example, in diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride, the temperature being kept between ⁇ 5° C.
  • an aprotic or nonpolar organic solvent such as, for example, diethyl ether, methyl tert-butyl ether,
  • reaction solution is then heated at a temperature between 10° C. and 130° C., preferably between 20° C. and 80° C., particularly between 30° C. and 50° C., for a period of 30 minutes to 5 hours and the solvent is then evaporated.
  • the residue of the “indolyl-3-glyoxyloyl chloride” formed in this manner which remains is dissolved in an aprotic solvent such as, for example, tetrahydrofuran, dioxane, diethyl ether, toluene or alternatively in a dipolar aprotic solvent, such as, for example, dimethylformamide, dimethylacetamide or dimethyl sulfoxide, cooled to a temperature between 10° C.
  • aprotic solvent such as, for example, tetrahydrofuran, dioxane, diethyl ether, toluene
  • a dipolar aprotic solvent such as, for example, dimethylformamide, dimethylacetamide or
  • Acid scavengers used are triethylamine, pyridine, dimethylaminopyridine, basic ion exchanger, sodium carbonate, potassium carbonate, powdered potassium hydroxide and excess primary or secondary amine employed for the reaction.
  • the reaction takes place at a temperature from 0° C. to 120° C., preferably at 20-80° C., particularly between 40° C.
  • the hydrochloride of the acid scavenger is filtered, the filtrate is concentrated in vacuo and the residue is recrystallized from an organic solvent or purified by column chromatography on silica gel or alumina.
  • the eluent used is, for example, a mixture of dichloromethane and ethanol (95:5, vol/vol).
  • N-nitrobenzyl-substituted “indoleglyoxylamide” obtained according to the above procedure (2nd stage) is dissolved in a protic solvent, such as, for example, methanol, ethanol, propanol, isopropanol or butanol or in a nonpolar solvent, such as, for example, tetrahydrofuran, dioxane or glycol dimethyl ether or in a dipolar aprotic solvent, such as, for example, dimethyl sulfoxide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone and the solution is treated with a hydrogenation catalyst such as, for example, Raney nickel, palladium/carbon or platinum under a nitrogen atmosphere and with stirring.
  • a protic solvent such as, for example, methanol, ethanol, propanol, isopropanol or butanol
  • a nonpolar solvent such as, for example, tetrahydrofuran, dioxane or glycol
  • Hydrogen is passed into the suspension with moderate shaking at a gas pressure of 1-15 bar, preferably 2-10 bar, particularly at 4-6 bar and the temperature is raised to about 20°-80° C., preferably 30°-60° C., particularly to 45°-55° C. If appropriate, after about 1 hour a further amount of catalyst is added and the hydrogenation is continued. The hydrogenation was complete after a reaction time of 4-10 hours.
  • the catalyst was filtered off under a nitrogen atmosphere, the solvent was concentrated to dryness in vacuo and the colorless to yellowish residue was dried in vacuo at 40° C.
  • a mixture of 5.28 g of sodium hydride (0.22 mol, mineral oil suspension) in 200 ml of dimethyl sulfoxide is treated with a solution of 23.4 g (0.2 mol) of indole in 100 ml of dimethyl sulfoxide. It is heated at 65° C. for 1 hour, then allowed to cool and 37.7 g (0.22 mol) of 4-nitrobenzyl chloride are then added dropwise. The solution is heated to 60° C., kept at room temperature for 14 hours and then poured into 700 ml of water with stirring.
  • the mixture is extracted in portions with a total of 300 ml of methylene chloride, the organic phase is dried using anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo.
  • the residue is purified on a silica gel column (silica gel 60, Merck AG, Darmstadt; eluent methylene chloride/ethanol 9:1, v/v).
  • a solution of 4.50 ml of oxalyl chloride in 50 ml of ether is treated dropwise with a solution of 10.09 g (0.04 mol) of 1-(4-nitrobenzyl)indole in 50 ml of ether at 0° C. [sic] and under a nitrogen atmosphere.
  • the mixture is heated at reflux temperature for 2 hours and the solvent is then evaporated.
  • 100 ml of tetrahydrofuran are added to the residue, it is cooled to ⁇ 5° C. and a solution of of [sic] 9.32 g (0.099 mol) of 4-aminopyridine in 400 ml of tetrahydrofuran is added dropwise.
  • the mixture is heated to reflux for 3 hours and allowed to stand at room temperature overnight.
  • the 4-aminopyridine hydrochloride is filtered off with suction, the precipitate is washed with tetrahydrofuran, the filtrate is concentrated in vacuo and the residue is recrystallized from ethyl acetate.
  • a mixture of 200 mg of Raney nickel in 50 ml of dioxane is treated with a suspension of 320 mg (0.8 mmol) of N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide in a solvent mixture of 150 ml of dioxane and 20 ml of isopropanol. Hydrogen is passed into this suspension with shaking at a gas pressure of 5 bar and the temperature is kept at 30-35° C. After about 3 hours, a further 400 mg of Raney nickel are added and the hydrogenation is continued at 35° C. and 5 bar for a further 8 hours with vigorous shaking. The catalyst is filtered off under an N 2 atmosphere, the filtrate is concentrated to dryness in vacuo and the residue is dried in vacuo at 40° C.
  • a solution of 10 g (85.3 mmol) of indole in 100 ml of ether is added dropwise at 0° C. to a solution of 9 ml of oxalyl chloride in 100 ml of anhydrous ether.
  • the mixture is kept under reflux for 3 hours.
  • a suspension of 12 g (127.9 mmol) of 4-aminopyridine in 500 ml of tetrahydrofuran is then added dropwise at ⁇ 5° C., the reaction mixture is heated to reflux temperature with stirring for 3 hours and allowed to stand overnight at room temperature. It is filtered, the precipitate is treated with water and the dried compound is purified on a silica gel column (silica gel 60, Merck AG, Darmstadt) using the eluent methylene chloride/ethanol (10:1, v/v).
  • N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]-glyoxylamide obtained according to the 2nd Stage (Scheme 2) is catalytically hydrogenated according to the “hydrogenation procedure” (page 7) and the compound N-(pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide obtained is isolated.
  • the indole derivative which can be unsubstituted or substituted on C-2 or in the phenyl ring, dissolved in a solvent, as, for example, indicated above for oxalyl chloride, is added dropwise at a temperature between ⁇ 5° C. and +5° C. to a solution prepared under a nitrogen atmosphere of a monomolar up to 60% excess amount of oxalyl chloride in an aprotic or nonpolar solvent, such as, for example, in diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane or alternatively dichloromethane.
  • the reaction solution is then heated for 1 to 5 hours to a temperature between 10° C.
  • Acid scavengers used are triethylamine, pyridine, dimethylaminopyridine, basic ion exchanger, sodium carbonate, potassium carbonate, powdered potassium hydroxide and excess primary or secondary amine employed for the reaction.
  • the reaction takes place at a temperature from 0° C. to 120° C., preferably at 20-80° C., particularly between 40° C. and 60° C.
  • the mixture is filtered, the precipitate is digested with water, filtered off with suction and dried in vacuo.
  • the desired compound is purified by recrystallization in an organic solvent or by column chromatography on silica gel or alumina.
  • the eluent used is, for example, a mixture of dichloromethane and ethanol (10:1, vol/vol).
  • the “indol-3-ylglyoxylamide” obtained according to the above procedure of the 1st Stage is dissolved in a protic, dipoplar aprotic or nonpolar organic solvent, such as, for example, in isopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dioxane, toluene or methylene chloride and added dropwise to a suspension of a base prepared in a three-necked flask under an N 2 atmosphere or employed in a molar amount or in excess, such as, for example, sodium hydride, powdered potassium hydroxide, potassium tert-butoxide, dimethylaminopyridine or sodium amide, in a suitable solvent.
  • a protic, dipoplar aprotic or nonpolar organic solvent such as, for example, in isopropanol, tetrahydrofuran, dimethyl s
  • the desired alkyl, aralkyl or heteroaralkyl halide is then added either undiluted or in a diluent, which was also used, for example, for dissolving the “indol-3-ylglyoxylamide”, if appropriate with addition of a catalyst, such as, for example, copper and the mixture is allowed to react for some time, e.g. for 30 minutes to 12 hours, and the temperature is kept within a range between 0° C. and 120° C., preferably between 30° C. and 80° C., particularly between 50° C. and 70° C.
  • a catalyst such as, for example, copper
  • the reaction mixture is added to water, the solution is extracted, for example, with diethyl ether, dichloromethane, chloroform, methyl tert-butyl ether, tetrahydrofuran or n-butanol and the organic phase obtained in each case is dried using anhydrous sodium sulfate.
  • the organic phase is concentrated in vacua, the residue which remains is crystallized by trituration or the oily residue is purified by distillation or by column or flash chromatography on silica gel or alumina.
  • the eluent used is, for example, a mixture of methylene chloride and diethyl ether in the ratio 8:2 (vol/vol) or a mixture of methylene chloride and ethanol in the ratio 9:1 (v/v).
  • N-nitrobenzyl-substituted “indoleglyoxylamide obtained according to the above procedure (2nd stage) is dissolved in a protic solvent, such as, for example, methanol, ethanol, propanol or butanol or in a nonpolar solvent, such as, for example, tetrahydrofuran, dioxane or glycol dimethyl ether or in a dipolar aprotic solvent, such as, for example, dimethyl sulfoxide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone and the solution is treated with a hydrogenation catalyst such as, for example, Raney nickel, palladium/carbon or platinum under a nitrogen atmosphere and with stirring.
  • a protic solvent such as, for example, methanol, ethanol, propanol or butanol
  • a nonpolar solvent such as, for example, tetrahydrofuran, dioxane or glycol dimethyl ether
  • a dipolar aprotic solvent
  • Hydrogen is passed into the suspension with moderate shaking at a gas pressure of 1-15 bar, preferably 2-10 bar, particularly at 4-6 bar and the temperature is raised to about 20°-80° C., preferably 30°-60° C., particularly to 45°-55° C. If appropriate, after about 1 hour a further amount of catalyst is added and the hydrogenation is continued. The hydrogenation was complete after a reaction time of 4-6 hours.
  • the catalyst was filtered off under a nitrogen atmosphere, the solvent was concentrated to dryness and the colorless to yellowish residue was dried in vacuo at 40° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Indole Compounds (AREA)

Abstract

The invention relates to novel, substituted N-benzyl-indol-3-ylglyoxylic acid derivatives of the following formula and their use for the treatment of oncoses
Figure US20010014690A1-20010816-C00001
The invention further relates to their physiologically tolerable acid addition salts and if possible their N-oxides. In addition, the invention relates to pharmaceutical preparations containing at least one of the compounds of the abovementioned formula or their salts or N-oxides with physiologically tolerable inorganic or organic acids and, if appropriate, pharmaceutically utilizable vehicles and/or diluents or excipients and also administration forms of the compounds of the abovementioned formula containing at least one of the compounds of this formula or their salts in the form of tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments

Description

  • The aim of the present invention is to make available novel compounds from the indol-3-ylglyoxylic acid series of the general formula 1 which have a good antitumor action and can be employed for the preparation of antitumor agents; [0001]
    Figure US20010014690A1-20010816-C00002
  • Where the radicals R, R[0002] 1, R2, R3, R4 and Z have the following meaning
  • R=nitro, amino, mono- or di(C[0003] 1-C6)-alkylamino, mono- or di(C1-C6)-cycloalkylamino, (C1-C6) -acylamino, phenyl (C1-C6)-alkylamino, aroylamino, heteroaroylamino, (C1-C6)-alkylsulfonamido, aryl-sulfonamido, maleimido, succinimido, phthalimido, benzyloxycarbonylamino (Z-amino), tert-butoxy-carbonylamino (BOC-amino), 9-fluorenylmethoxy-carbonylamino (Fmoc-amino), triphenylmethylamino (Tr-amino), 2-(4′-pyridyl)ethoxycarbonylamino (Pyoc-amino), diphenylmethylsilylamino (DPMS-amino), where the radicals for R can alternatively be substituted on the C atoms 2, 3 and 4 of the phenyl ring,
  • R can furthermore be, in the case in which R[0004] 1=hydrogen, the methyl or phenylmethyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, the following radicals:
  • —NH—CH[0005] 2—COOH; —NH—CH(CH3)—COOH; (CH3)2CH—CH2—CH2—CH(NH)—COOH; H3C—CH2—CH(CH3)—CH(NH)—COOH; HOH2C—CH(NH)—COOH; phenyl—CH2—CH(NH)—COOH; (4-imidazoyl)—CH2—CH(NH)—COOH; HN═C(NH2)—NH—(CH2)3—CH(NH)—COOH; H2N—(CH2)4—CH(NH)—COOH; H2N—CO—CH2—CH(NH)—COOH; HOOC—(CH2)2—CH(NH)—COOH
  • R[0006] 1=hydrogen, (C1-C6)-alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring for its part can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6)-alkyl groups, halogen atoms or trifluoromethyl groups,
  • R[0007] 1 is further the benzyloxycarbonyl group (Z group) and the tertiary-butoxycarbonyl radical (Boc radical), furthermore the acetyl group.
  • R[0008] 2 can be the phenyl ring, which is mono- or polysubstituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6) -alkylamino, (C1-C6)-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with C1-C6-alkanols, or can be a pyridine structure of the formula 2
    Figure US20010014690A1-20010816-C00003
  • and its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substituents R[0009] 5 and R6. The radicals R5 and R6 can be identical or different and have the meaning (C1-C6)-alkyl and the meaning (C3-C7) -cycloalkyl, (C1-C6)-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl and further are the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
  • R[0010] 2 can further be a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore can be the 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolyl structure substituted by (C1-C6)-alkyl, halogen, the nitro group, the amino group and the (C1-C6)-alkylamino radical, can be a 2-, 3- and [sic] 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, amino and (C1-C6)-alkoxycarbonylamino.
  • R[0011] 2 in the case in which R1=hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group can furthermore be the following radicals:
  • —CH[0012] 2COOH; —CH(CH3)—COOH; (CH3)2CH—(CH2)2—CH(COOH)—; H3C—H2C—CH(CH3)—CH(COOH)—; [HO—H2C—CH(COOH)—-; phenyl—CH2—-CH(COOH)—; (4-imidazolyl)—CH2—CH(COOH)—; [HN═C(NH2)—NH—(CH2)3—CH(COOH)—; H2N—(CH2)4—CH (COOH)—; H2N—CO—CH2—CH—(COOH)—; HOOC—(CH2)2—CH(COOH)—;
  • R[0013] 2 in the case in which R1 are [sic] hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group can furthermore be the acid radical of a natural or unnatural amino acid, e.g. the α-glycyl, the α-sarcosyl, the α-alanyl, the α-leucyl, the α-isoleucyl, the α-seryl, the α-phenylalanyl, the α-histidyl, the α-prolyl, the α-arginyl, the α-lysyl, the α-asparagyl and the α-glutamyl radical, where the amino groups of the respective amino acids can be present unprotected or can be protected. A possible protective group of the amino function is the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R2, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of a carboxyl group esterified with C1-C6-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester. Furthermore, R2 can be the allylaminocarbonyl-2-methylprop-1-yl group. R1 and R2 can further form, together with the nitrogen atom to which they are bonded, a piperazine ring of the formula 3 or a homopiperazine ring, provided R2 is an aminoalkylene group, in which
    Figure US20010014690A1-20010816-C00004
  • R[0014] 7 is an alkyl radical, is a phenyl ring which can be mono- or polysubstituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, the nitro group, the amino function and by the (C1-C6)-alkylamino group. R7 is furthermore the benzhydryl group and the bis-p-fluorobenzhydryl group.
  • R[0015] 3 and R4 can be identical or different and are hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen and benzyloxy. R3 and R4 can furthermore be the nitro group, the amino group, the (C1-C4)-mono- or dialkyl-substituted amino group, and the (C1-C6)-alkoxycarbonylamino function or (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl function.
  • Z is O and S. [0016]
  • The designation alkyl, alkanol, alkoxy or alkylamino group for the radicals R, R[0017] 1, R2, R3, R4, R5, R6, R7 is normally understood as meaning both “straight-chain” and “branched” alkyl groups, where “straight-chain alkyl groups” can be, for example, radicals such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and “branched alkyl groups” designate, for example, radicals such as isopropyl or tert-butyl. “Cycloalkyl” is understood as meaning radicals such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The designation “halogen” represents fluorine, chlorine, bromine or iodine. The designation “alkoxy group” represents radicals such as, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy. The designation acyl of the acylamino radicals is to be understood as meaning the groups formyl, acetyl, propionyl, butyryl, valeryl and isovaleryl. The designation aroyl of the aroylamino groups represents benzoyl, naphthoyl, toluoyl, phthaloyl and the group heteroaroyl of the heteroaroylamino radicals represents nicotinoyl, isonicotinoyl, thenoyl and furoyl. The designation aryl of the arylsulfonamido group is understood as meaning phenyl, tolyl and naphthyl.
  • The compounds can also be employed as acid addition salts, for example as salts of mineral acids, such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids, such as, for example, acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxyethanesulfonic acid, nicotinic acid and p-toluenesulfonic acid. Both the compounds of the formula 1 and their salts are biologically active. The compounds of the formula 1 can be administered in free form or as salts with physiologically tolerable acids. Administration can be performed orally, parenterally, intravenously, transdermally or by inhalation. [0018]
  • The invention furthermore relates to pharmaceutical preparations which contain at least one of the compounds of the formula 1 or their salts with physiologically tolerable inorganic or organic acids and, if appropriate, pharmaceutically utilizable excipients and/or diluents or auxiliaries. [0019]
  • Suitable administration forms are, for example, tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments. [0020]
  • The processes for the preparation of the compounds according to the invention are described in the following reaction schemes 1 and 2 (Stages 1-3) and in general procedures. All compounds can be prepared as described or analogously. [0021]
  • The compounds of the general formula 1 with Z═O, R═NO[0022] 2 and NH2 and R2=aryl, aralkyl and heteroaryl are obtainable according to the following Scheme 1:
    Figure US20010014690A1-20010816-C00005
  • The indole derivative, which can be unsubstituted or monosubstituted or polysubstituted on C-2 or in the phenyl structure, is dissolved in a protic, dipolar aprotic or nonpolar organic solvent, such as, for example, isopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dioxane, toluene or methylene chloride and added dropwise to a suspension of a base prepared in a three-necked flask under an N[0023] 2 atmosphere or employed in a molar amount or in excess, such as, for example, sodium hydride, powdered potassium hydroxide, potassium tert-butoxide, dimethylaminopyridine or sodium amide, in a suitable solvent. Then the desired alkyl, aralkyl or heteroaralkyl halide, for example, is added, if appropriate with addition of a catalyst, such as, for example, copper and the mixture is allowed to react for some time, for example for 30 minutes to 12 hours, and the temperature is maintained within a range from 0° C. to 120° C., preferably between 30° C. to [sic] 80° C., particularly between 50° C. and 65° C. After completion of the reaction, the reaction mixture is added to water, the solution is extracted, e.g. with diethyl ether, dichloromethane, chloroform, methyl tert-butyl ether or tetrahydrofuran, and the organic phase obtained in each case is dried with anhydrous sodium sulfate. The organic phase is concentrated in vacuo, the residue which remains is crystallized by trituration or the oily residue is purified by recrystallization, distillation or by column or flash chromatography on silica gel or alumina. The eluent used is, for example, a mixture of dichloromethane and diethyl ether in the ratio 8:2 (vol/vol) or a mixture of dichloromethane and ethanol in the ratio 9:1 (vol/vol).
  • 2nd stage [0024]
  • The N-substituted indole obtained according to the above procedure of the 1st stage is dissolved under a nitrogen atmosphere in an aprotic or nonpolar organic solvent, such as, for example, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride or chloroform and added to a solution prepared under a nitrogen atmosphere of a monomolar up to 60% excess amount of oxalyl chloride in an aprotic or nonpolar solvent, such as, for example, in diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride, the temperature being kept between −5° C. and 20° C. The reaction solution is then heated at a temperature between 10° C. and 130° C., preferably between 20° C. and 80° C., particularly between 30° C. and 50° C., for a period of 30 minutes to 5 hours and the solvent is then evaporated. The residue of the “indolyl-3-glyoxyloyl chloride” formed in this manner which remains is dissolved in an aprotic solvent such as, for example, tetrahydrofuran, dioxane, diethyl ether, toluene or alternatively in a dipolar aprotic solvent, such as, for example, dimethylformamide, dimethylacetamide or dimethyl sulfoxide, cooled to a temperature between 10° C. and −15° C., preferably between −5° C. and 0° C., and treated in the presence of an acid scavenger with a solution of the primary or secondary amine in a diluent. Possible diluents are the solvents used above for dissolving the indolyl-3-glyoxyloyl chloride. Acid scavengers used are triethylamine, pyridine, dimethylaminopyridine, basic ion exchanger, sodium carbonate, potassium carbonate, powdered potassium hydroxide and excess primary or secondary amine employed for the reaction. The reaction takes place at a temperature from 0° C. to 120° C., preferably at 20-80° C., particularly between 40° C. and 60° C. After a reaction time of 1-3 hours and standing at room temperature for 24 hours, the hydrochloride of the acid scavenger is filtered, the filtrate is concentrated in vacuo and the residue is recrystallized from an organic solvent or purified by column chromatography on silica gel or alumina. The eluent used is, for example, a mixture of dichloromethane and ethanol (95:5, vol/vol). [0025]
  • 3rd stage [0026]
  • The N-nitrobenzyl-substituted “indoleglyoxylamide” obtained according to the above procedure (2nd stage) is dissolved in a protic solvent, such as, for example, methanol, ethanol, propanol, isopropanol or butanol or in a nonpolar solvent, such as, for example, tetrahydrofuran, dioxane or glycol dimethyl ether or in a dipolar aprotic solvent, such as, for example, dimethyl sulfoxide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone and the solution is treated with a hydrogenation catalyst such as, for example, Raney nickel, palladium/carbon or platinum under a nitrogen atmosphere and with stirring. Hydrogen is passed into the suspension with moderate shaking at a gas pressure of 1-15 bar, preferably 2-10 bar, particularly at 4-6 bar and the temperature is raised to about 20°-80° C., preferably 30°-60° C., particularly to 45°-55° C. If appropriate, after about 1 hour a further amount of catalyst is added and the hydrogenation is continued. The hydrogenation was complete after a reaction time of 4-10 hours. The catalyst was filtered off under a nitrogen atmosphere, the solvent was concentrated to dryness in vacuo and the colorless to yellowish residue was dried in vacuo at 40° C. [0027]
    • WORKING EXAMPLES
  • According to this general procedure for stages 1-3, on which synthesis scheme 1 is based, the following compounds were synthesized which are evident from the following tabulated list [sic] detailing the respective chemical name. [0028]
    • Example 1 N-(Pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide (D-68838)
  • 1st stage [0029]
  • 1-(4-Nitrobenzyl)indole [0030]
  • A mixture of 5.28 g of sodium hydride (0.22 mol, mineral oil suspension) in 200 ml of dimethyl sulfoxide is treated with a solution of 23.4 g (0.2 mol) of indole in 100 ml of dimethyl sulfoxide. It is heated at 65° C. for 1 hour, then allowed to cool and 37.7 g (0.22 mol) of 4-nitrobenzyl chloride are then added dropwise. The solution is heated to 60° C., kept at room temperature for 14 hours and then poured into 700 ml of water with stirring. The mixture is extracted in portions with a total of 300 ml of methylene chloride, the organic phase is dried using anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is purified on a silica gel column (silica gel 60, Merck AG, Darmstadt; eluent methylene chloride/ethanol 9:1, v/v). [0031]
  • Yield: 43.9 g (87% of theory) MS: m/e 253 (M+H) [0032]
  • 2nd stage [0033]
  • N-(Pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide (D-68836) [0034]
  • A solution of 4.50 ml of oxalyl chloride in 50 ml of ether is treated dropwise with a solution of 10.09 g (0.04 mol) of 1-(4-nitrobenzyl)indole in 50 ml of ether at 0° C. [sic] and under a nitrogen atmosphere. The mixture is heated at reflux temperature for 2 hours and the solvent is then evaporated. 100 ml of tetrahydrofuran are added to the residue, it is cooled to −5° C. and a solution of of [sic] 9.32 g (0.099 mol) of 4-aminopyridine in 400 ml of tetrahydrofuran is added dropwise. The mixture is heated to reflux for 3 hours and allowed to stand at room temperature overnight. The 4-aminopyridine hydrochloride is filtered off with suction, the precipitate is washed with tetrahydrofuran, the filtrate is concentrated in vacuo and the residue is recrystallized from ethyl acetate. [0035]
  • Yield: 13.5 g (84% of theory) MS: m/e 401 (M+H) [0036]
  • 3rd stage [0037]
  • N-(Pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide (D-68838) [0038]
  • A mixture of 200 mg of Raney nickel in 50 ml of dioxane is treated with a suspension of 320 mg (0.8 mmol) of N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide in a solvent mixture of 150 ml of dioxane and 20 ml of isopropanol. Hydrogen is passed into this suspension with shaking at a gas pressure of 5 bar and the temperature is kept at 30-35° C. After about 3 hours, a further 400 mg of Raney nickel are added and the hydrogenation is continued at 35° C. and 5 bar for a further 8 hours with vigorous shaking. The catalyst is filtered off under an N[0039] 2 atmosphere, the filtrate is concentrated to dryness in vacuo and the residue is dried in vacuo at 40° C.
  • Yield: 273 mg (92% of theory) MS: m/e 371 (M+H) [0040]
  • Furthermore, the compounds of the general formula 1 with Z═O, R═NO[0041] 2 and NH2 and R2=aryl, aralkyl, heteroaryl, heteroaralkyl and the allylaminocarbonyl-2-methylprop-1-yl group can also be synthesized according to the synthesis route of Scheme 2:
    Figure US20010014690A1-20010816-C00006
  • 1 st stage [0042]
  • N-(Pyridin-4-yl)-(indol-3-yl)glyoxylamide [0043]
  • A solution of 10 g (85.3 mmol) of indole in 100 ml of ether is added dropwise at 0° C. to a solution of 9 ml of oxalyl chloride in 100 ml of anhydrous ether. The mixture is kept under reflux for 3 hours. A suspension of 12 g (127.9 mmol) of 4-aminopyridine in 500 ml of tetrahydrofuran is then added dropwise at −5° C., the reaction mixture is heated to reflux temperature with stirring for 3 hours and allowed to stand overnight at room temperature. It is filtered, the precipitate is treated with water and the dried compound is purified on a silica gel column (silica gel 60, Merck AG, Darmstadt) using the eluent methylene chloride/ethanol (10:1, v/v). [0044]
  • Yield: 9.8 g (43.3% of theory) MS: m/e 266 (M+H) [0045]
  • 2nd stage [0046]
  • N-(Pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide (D-68836) [0047]
  • The N-(pyridin-4-yl)-(indol-3-yl)glyoxylamide obtained according to the 1st Stage (Scheme 2) is reacted with 4-nitrobenzyl chloride according to the “benzylation procedure” (page 5) and the compound N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide obtained is isolated. [0048]
  • Yield: 64% of theory MS: m/e 401 (M+H) [0049]
  • N-(Pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide (D-68838) [0050]
  • The N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]-glyoxylamide obtained according to the 2nd Stage (Scheme 2) is catalytically hydrogenated according to the “hydrogenation procedure” (page 7) and the compound N-(pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide obtained is isolated. [0051]
  • Yield: 94% of theory MS: m/e 371 (M+H) [0052]
  • General procedure for the preparation of the compounds of the general formula 1 according to Scheme 2 [0053]
  • 1st stage: [0054]
  • The indole derivative, which can be unsubstituted or substituted on C-2 or in the phenyl ring, dissolved in a solvent, as, for example, indicated above for oxalyl chloride, is added dropwise at a temperature between −5° C. and +5° C. to a solution prepared under a nitrogen atmosphere of a monomolar up to 60% excess amount of oxalyl chloride in an aprotic or nonpolar solvent, such as, for example, in diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane or alternatively dichloromethane. The reaction solution is then heated for 1 to 5 hours to a temperature between 10° C. and 120° C., preferably between 20° C. and 80° C., particularly between 30° C. and 60° C., and the solvent is then evaporated. The residue of the (indol-3-yl)glyoxyloyl chloride which remains is dissolved or suspended in an aprotic solvent, such as, for example, tetrahydrofuran, dioxane, diethyl ether, toluene or alternatively in a dipolar aprotic solvent, such as, for example, dimethylformamide, dimethylacetamide or dimethyl sulfoxide, cooled to a temperature between −10° C. and +10° C., preferably to −5° C. to 0° C., and treated in the presence of an acid scavenger with a solution of the primary or secondary amine in a diluent. Possible diluents are the solvents used for dissolving the “indolyl-3-glyoxyloyl chloride”. Acid scavengers used are triethylamine, pyridine, dimethylaminopyridine, basic ion exchanger, sodium carbonate, potassium carbonate, powdered potassium hydroxide and excess primary or secondary amine employed for the reaction. The reaction takes place at a temperature from 0° C. to 120° C., preferably at 20-80° C., particularly between 40° C. and 60° C. After a reaction time of 1-4 hours and standing at room temperature for 24 hours, the mixture is filtered, the precipitate is digested with water, filtered off with suction and dried in vacuo. The desired compound is purified by recrystallization in an organic solvent or by column chromatography on silica gel or alumina. The eluent used is, for example, a mixture of dichloromethane and ethanol (10:1, vol/vol). [0055]
  • 2nd Stage [0056]
  • The “indol-3-ylglyoxylamide” obtained according to the above procedure of the 1st Stage is dissolved in a protic, dipoplar aprotic or nonpolar organic solvent, such as, for example, in isopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dioxane, toluene or methylene chloride and added dropwise to a suspension of a base prepared in a three-necked flask under an N[0057] 2 atmosphere or employed in a molar amount or in excess, such as, for example, sodium hydride, powdered potassium hydroxide, potassium tert-butoxide, dimethylaminopyridine or sodium amide, in a suitable solvent. The desired alkyl, aralkyl or heteroaralkyl halide is then added either undiluted or in a diluent, which was also used, for example, for dissolving the “indol-3-ylglyoxylamide”, if appropriate with addition of a catalyst, such as, for example, copper and the mixture is allowed to react for some time, e.g. for 30 minutes to 12 hours, and the temperature is kept within a range between 0° C. and 120° C., preferably between 30° C. and 80° C., particularly between 50° C. and 70° C. After completion of the reaction, the reaction mixture is added to water, the solution is extracted, for example, with diethyl ether, dichloromethane, chloroform, methyl tert-butyl ether, tetrahydrofuran or n-butanol and the organic phase obtained in each case is dried using anhydrous sodium sulfate. The organic phase is concentrated in vacua, the residue which remains is crystallized by trituration or the oily residue is purified by distillation or by column or flash chromatography on silica gel or alumina. The eluent used is, for example, a mixture of methylene chloride and diethyl ether in the ratio 8:2 (vol/vol) or a mixture of methylene chloride and ethanol in the ratio 9:1 (v/v).
  • 3rd stage [0058]
  • The N-nitrobenzyl-substituted “indoleglyoxylamide obtained according to the above procedure (2nd stage) is dissolved in a protic solvent, such as, for example, methanol, ethanol, propanol or butanol or in a nonpolar solvent, such as, for example, tetrahydrofuran, dioxane or glycol dimethyl ether or in a dipolar aprotic solvent, such as, for example, dimethyl sulfoxide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone and the solution is treated with a hydrogenation catalyst such as, for example, Raney nickel, palladium/carbon or platinum under a nitrogen atmosphere and with stirring. Hydrogen is passed into the suspension with moderate shaking at a gas pressure of 1-15 bar, preferably 2-10 bar, particularly at 4-6 bar and the temperature is raised to about 20°-80° C., preferably 30°-60° C., particularly to 45°-55° C. If appropriate, after about 1 hour a further amount of catalyst is added and the hydrogenation is continued. The hydrogenation was complete after a reaction time of 4-6 hours. The catalyst was filtered off under a nitrogen atmosphere, the solvent was concentrated to dryness and the colorless to yellowish residue was dried in vacuo at 40° C. [0059]
  • According to this general procedure for stages 1-3, on which the synthesis scheme 2 is based, the compounds D-68836 and D-68838 were synthesized, which have also already been prepared according to the synthesis procedure of reaction scheme 1. [0060]
  • It was possible to show the activity of the present compounds in a tubulin polymerization assay. In particular, proof was provided that D-68838 inhibits the polymerization of tubulin and thus exerts a destabilizing effect on microtubuli or the mitotic spindles. [0061]

Claims (8)

1. Novel, substituted N-benzylindol-3-ylglyoxylic acid derivatives having antitumor action of the general formula 1
Figure US20010014690A1-20010816-C00007
Where the radicals R, R1, R2, R3, R4 and Z have the following meaning:
R=nitro, amino, mono- or di(C1-C6)-alkylamino, mono- or di(C1-C6)-cycloalkylamino, (C1-C6)-acylamino, phenyl (C1-C6)-alkylamino, aroylamino, heteroaroylamino, (C1-C6) -alkylsulfonamido, arylsulfonamido, maleimido, succinimido, phthalimido, benzyloxycarbonylamino (z-amino), tert-butoxycarbonylamino (boc-amino), 9-fluorenylmethoxy-carbonylamino (Fmoc-amino), triphenylmethylamino (Tr-amino), 2-(4′-pyridyl)ethoxycarbonylamino (Pyoc-amino), diphenylmethylsilylamino (DPMS-amino), where the radicals for R can alternatively be substituted on the C atoms 2, 3 and 4 of the phenyl ring,
R can furthermore be, in the case in which R1=hydrogen, the methyl or phenylmethyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, the following radicals:
—NH—CH2—COOH; —NH—CH(CH3)—COOH; (CH3)2CH—CH2—CH2—CH(NH)—COOH; H3C—CH2—CH(CH3)—CH(NH)—COOH; HOH2C—CH(NH)—COOH; phenyl—CH2—CH(NH)—COOH; (4-imidazoyl)—CH2—CH(NH)—COOH; HN═C(NH2)—NH—(CH2)3—CH(NH)—COOH; H2N—(CH2)4—CH(NH)—COOH; H2N—CO—CH2—CH(NH)—COOH; HOOC—(CH2)2—CH(NH)—COOH
R1=hydrogen, (C1-C6)-alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring for its part can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6)-alkyl groups, halogen atoms or trifluoromethyl groups,
R1 is further the benzyloxycarbonyl group (Z group) and the tertiary-butoxycarbonyl radical (Boc radical), furthermore the acetyl group
R2 can be the phenyl ring, which is mono- or polysubstituted by (C1-C6)-alkyl, (C1-C6) -alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-alkylamino, (C1-C6)-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with C1-C6-alkanols, or can be a pyridine structure of the formula 2 and their N-oxide [sic]
Figure US20010014690A1-20010816-C00008
and its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substituents R5 and R6 [R5 and R6 in formula 2 can be identical or different and have the meaning (C1-C6)-alkyl and the meaning (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl and further are the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
R2 can further be a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore can be the 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolyl structure substituted by (C1-C6)-alkyl, halogen, the nitro group, the amino group and the (C1-C6)-alkylamino radical, can be a 2-, 3- and [sic] 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, amino and (C1-C6) -alkoxycarbonylamino,
R2 in the case in which R1=hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group can furthermore be the following radicals:
—CH2COOH; —CH(CH3)—COOH; (CH3)2CH—(CH2)2—CH(COOH)—; H3C—H2C—CH(CH3)—CH(COOH)—; [HO—H2C—CH(COOH)—; phenyl—CH2—CH(COOH)—; (4-imidazolyl)—CH2—CH(COOH)—; HN═C(NH2)—NH—(CH2)3—CH(COOH)—; H2N—(CH2)4—CH(COOH)—; H2N—CO—CH2—CH(COOH)—; HOOC—(CH2)2—CH(COOH)—;
R2 in the case in which R1 are [sic] hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group can furthermore be the acid radical of a natural or unnatural amino acid, e.g. the α-glycyl, the α-sarcosyl, the αalanyl, the α-leucyl, the α-isoleucyl, the α-seryl, the α-phenylalanyl, the α-histidyl, the α-prolyl, the α-arginyl, the α-lysyl, the (α-asparagyl and the α-glutamyl radical, where the amino groups of the respective amino acids can be present unprotected or can be protected. A possible protective group of the amino function is the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R2, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of a carboxyl group esterified with C1-C6-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester; furthermore, R2 can be the allylaminocarbonyl-2-methylprop-1-yl group; [R1 and R2 can further form, together with the nitrogen atom to which they are bonded, a piperazine ring of the formula 3 or a homopiperazine ring, provided R2 is an aminoalkylene group, in which
Figure US20010014690A1-20010816-C00009
R7 is an alkyl radical, is a phenyl ring which can be mono- or polysubstituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, the nitro group, the amino function and by the (C1-C6)-alkylamino group; R7 is furthermore the benzhydryl group and the bis-p-fluorobenzhydryl group.
R3 and R4 can be identical or different and are hydrogen, (C1-C6) -alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen and benzyloxy; R3 and R4 can furthermore be the nitro group, the amino group, the (C1-C4)-mono- or dialkyl-substituted amino group, and the (C1-C6)-alkoxycarbonylamino function or the (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl function,
Z is 0 and S.
2. N-(Pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]-glyoxylamide (D-68838)
3. N-(Pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]-glyoxylamide (D-68836)
4. Acid addition salts of the compounds according to claims 1-4 of the general formula 1 as salts of mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids, in particular acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxy-ethanesulfonic acid, nicotinic acid and p-toluene-sulfonic acid.
5. Pharmaceutical preparations of the compounds according to claims 1-4 of the general formula 1 containing at least one of the compounds of the formula 1 or their salts according to
claim 3
 with physiologically tolerable inorganic or organic acids and, if appropriate, pharmaceutically utilizable vehicles and/or diluents or excipients.
6. Application forms of the compounds according to claims 1-4 of the general formula 1 containing at least one of the compounds of the formula 1 or their salts according to
claim 3
 in the form of tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can he employed by inhalation, suspensions, creams and ointments
7. Use of the compounds according to claims 1-4 of the general formula 1 for the production of antitumor compositions.
8. Use of compounds according to claims 1-4 of the general formula 1 for the treatment of oncoses.
US09/736,431 1999-12-23 2000-12-15 Substituted N-benzylindol-3-ylglyoxylic acid derivatives having antitumor action Expired - Fee Related US6432987B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19962300A DE19962300A1 (en) 1999-12-23 1999-12-23 New N-benzylindolyl glyoxylic acid derivatives are useful as antitumor agents
DE19962300 1999-12-23
DE19962300.7 1999-12-23

Publications (2)

Publication Number Publication Date
US20010014690A1 true US20010014690A1 (en) 2001-08-16
US6432987B2 US6432987B2 (en) 2002-08-13

Family

ID=7934006

Family Applications (1)

Application Number Title Priority Date Filing Date
US09/736,431 Expired - Fee Related US6432987B2 (en) 1999-12-23 2000-12-15 Substituted N-benzylindol-3-ylglyoxylic acid derivatives having antitumor action

Country Status (31)

Country Link
US (1) US6432987B2 (en)
EP (1) EP1240157B1 (en)
JP (1) JP2003519137A (en)
KR (1) KR100747425B1 (en)
CN (1) CN1283637C (en)
AR (1) AR027098A1 (en)
AT (1) ATE259364T1 (en)
AU (1) AU772745B2 (en)
BG (1) BG106924A (en)
BR (1) BR0016712A (en)
CA (1) CA2395259A1 (en)
CO (1) CO5251472A1 (en)
CZ (1) CZ20022094A3 (en)
DE (2) DE19962300A1 (en)
DK (1) DK1240157T3 (en)
ES (1) ES2215768T3 (en)
HK (1) HK1054038B (en)
HU (1) HUP0203716A3 (en)
IL (1) IL150235A0 (en)
MX (1) MXPA02006229A (en)
NO (1) NO324750B1 (en)
NZ (2) NZ519977A (en)
PL (1) PL195014B1 (en)
PT (1) PT1240157E (en)
RU (1) RU2266280C2 (en)
SK (1) SK8752002A3 (en)
TR (1) TR200400601T4 (en)
TW (1) TWI284128B (en)
UA (1) UA75060C2 (en)
WO (1) WO2001047913A2 (en)
ZA (1) ZA200204896B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006099256A3 (en) * 2005-03-11 2006-12-07 Vertex Pharma Modulators of atp-binding cassette transporters
US9782407B2 (en) 2004-12-31 2017-10-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19946301A1 (en) * 1998-04-02 2001-04-19 Asta Medica Ag Antitumor agents and angiogenesis inhibitors having low neurotoxicity, comprise indole-3-glyoxylamide derivatives, are effective against resistant and metastasis-forming carcinomas
DE19814838C2 (en) * 1998-04-02 2001-01-18 Asta Medica Ag Indolyl-3-glyoxylic acid derivatives with anti-tumor effects
DE10037310A1 (en) * 2000-07-28 2002-02-07 Asta Medica Ag New indole derivatives and their use as medicines
DE10318609A1 (en) * 2003-04-24 2004-11-11 Elbion Ag 5-hydroxyindoles with N-oxide groups and their use as therapeutic agents
DE10318611A1 (en) * 2003-04-24 2004-11-11 Elbion Ag 4-, 6- or 7-hydroxyindoles with N-oxide groups and their use as therapeutic agents
JP4878285B2 (en) * 2003-06-05 2012-02-15 エテルナ ツェンタリス ゲゼルシャフト ミット ベシュレンクテル ハフツング Indole derivatives with apoptosis-inducing action
US7211588B2 (en) * 2003-07-25 2007-05-01 Zentaris Gmbh N-substituted indolyl-3-glyoxylamides, their use as medicaments and process for their preparation
WO2005023761A2 (en) 2003-09-11 2005-03-17 Kemia, Inc. Cytokine inhibitors
US7268159B2 (en) * 2003-09-25 2007-09-11 Wyeth Substituted indoles
DE102004031538A1 (en) * 2004-06-29 2006-02-09 Baxter International Inc., Deerfield Presentation form (obtainable by dissolving indibulin in or with a highly concentrated organic acid), useful to orally administer poorly soluble active compound indibulin, comprises a poorly soluble active compound indibulin
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
WO2008019357A2 (en) * 2006-08-07 2008-02-14 Ironwood Pharmaceuticals, Inc. Indole compounds
CA2670778A1 (en) * 2006-11-28 2008-06-05 Ziopharm Oncology, Inc. Use of indolyl-3-glyoxylic acid derivatives including indibulin, alone or in combination with further agents for treating cancer
MX2011011517A (en) 2009-04-29 2012-06-19 Amarin Corp Plc Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same.
AR084433A1 (en) 2010-12-22 2013-05-15 Ironwood Pharmaceuticals Inc FAAH INHIBITORS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
IN2014CN02290A (en) 2011-09-27 2015-06-19 Reddys Lab Ltd Dr

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1028812A (en) * 1962-08-28 1966-05-11 Ici Ltd Indole derivatives
KR950701317A (en) * 1992-05-08 1995-03-23 오오쓰까 아끼히꼬 Indole Derivative
IL109311A0 (en) * 1993-04-16 1994-07-31 Lilly Co Eli 1H-indole-3-acetamide sPla2 inhibitors
FI963272A0 (en) * 1994-02-22 1996-08-21 Merrell Pharma Inc New indole derivatives useful in the treatment of estrogen-associated tumors and diseases
RU2128169C1 (en) * 1994-04-01 1999-03-27 Эли Лилли Энд Компани 1h-indole-3-glyoxylamides inhibiting -mediated fatty acids releasing, a pharmaceutical composition
DE19636150A1 (en) * 1996-09-06 1998-03-12 Asta Medica Ag N-substituted indole-3-glyoxylamides with antiasthmatic, antiallergic and immunosuppressive / immunomodulating effects
WO1998037069A1 (en) * 1997-02-20 1998-08-27 Shionogi & Co., Ltd. Indole dicarboxylic acid derivatives
US5972988A (en) * 1997-03-26 1999-10-26 Eli Lilly And Company Method for treatment of chronic bronchitis using indole compounds
WO1998047507A1 (en) * 1997-04-24 1998-10-29 Shionogi & Co., Ltd. Method for the treatment of stroke using n-heterocyclic glyoxylamide compounds
TW455581B (en) * 1997-06-26 2001-09-21 Lilly Co Eli Process for preparing 4-substituted-1H-indole-3-glyoxamides
US6610728B2 (en) * 1997-08-28 2003-08-26 Eli Lilly And Company Method for treatment of non-rheumatoid arthritis
WO1999016453A1 (en) * 1997-09-26 1999-04-08 Eli Lilly And Company Method for the treatment of cystic fibrosis
AU1279899A (en) * 1997-10-27 1999-05-17 Eli Lilly And Company N,n-diethylglycolamido ester prodrugs of indole spla2 inhibitors
WO1999021545A1 (en) * 1997-10-27 1999-05-06 Eli Lilly And Company ISOPROPYL ESTER PRODRUGS OF INDOLE sPLA2 INHIBITORS
DE69830335T2 (en) * 1997-10-27 2006-02-02 Eli Lilly And Co., Indianapolis MORPHOLINO-N-ETHYL ESTER PRODUCTS BY INDOL sPLA 2 HEMMER
WO1999024033A1 (en) * 1997-11-12 1999-05-20 Shionogi & Co., Ltd. Method for the treatment of disorders associated with apoptosis using n-heterocyclic glyoxylamide compounds
CA2310249A1 (en) * 1997-11-14 1999-05-27 August Masaru Watanabe Treatment for alzheimer's disease
CA2322162A1 (en) * 1998-02-25 1999-09-02 Genetics Institute, Llc Inhibitors of phospholipase enzymes
DE19814838C2 (en) * 1998-04-02 2001-01-18 Asta Medica Ag Indolyl-3-glyoxylic acid derivatives with anti-tumor effects
DZ2770A1 (en) * 1998-04-17 2003-12-01 Lilly Co Eli Process for the preparation of 1h-indol-3 glyoxamides substituted in position 4.
DE19818964A1 (en) * 1998-04-28 1999-11-04 Dresden Arzneimittel New hydroxy-indole derivatives useful in treatment of degenerative joint disease, viral and parasitic infections, bronchial, dermatological, neurodegenerative and prostate disorders, etc.
TR200003130T2 (en) * 1998-04-28 2001-01-22 Arzneimittelwerk Dresden Gmbh Novel hydroxyindoles, processes for their use and preparation as phosphodiesterase 4 inhibitors
JP2002513783A (en) * 1998-05-01 2002-05-14 イーライ・リリー・アンド・カンパニー SPLA2 inhibitory compounds for treating diseases
KR20010071197A (en) * 1998-05-01 2001-07-28 피터 지. 스트링거 sPLA2 inhibitor ester
AU4834200A (en) * 1999-05-10 2000-11-21 Protarga, Inc. Fatty acid-n-substituted indol-3-glyoxyl-amide compositions and uses thereof
TWI269654B (en) * 1999-09-28 2007-01-01 Baxter Healthcare Sa N-substituted indole-3-glyoxylamide compounds having anti-tumor action

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9782407B2 (en) 2004-12-31 2017-10-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
WO2006099256A3 (en) * 2005-03-11 2006-12-07 Vertex Pharma Modulators of atp-binding cassette transporters
US20070264196A1 (en) * 2005-03-11 2007-11-15 Ruah Sara H Modulators of ATP-binding cassette transporters
EP2363128A3 (en) * 2005-03-11 2011-09-21 Vertex Pharmaceuticals Incorporated Indole modulators of ATP-binding cassette transporters
US8242149B2 (en) 2005-03-11 2012-08-14 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters

Also Published As

Publication number Publication date
EP1240157B1 (en) 2004-02-11
ATE259364T1 (en) 2004-02-15
RU2002120462A (en) 2004-01-10
NZ519977A (en) 2004-08-27
AU2011901A (en) 2001-07-09
DE50005284D1 (en) 2004-03-18
TR200400601T4 (en) 2004-04-21
EP1240157A2 (en) 2002-09-18
TWI284128B (en) 2007-07-21
CN1420880A (en) 2003-05-28
ES2215768T3 (en) 2004-10-16
BR0016712A (en) 2002-09-03
HUP0203716A3 (en) 2004-05-28
MXPA02006229A (en) 2003-01-28
SK8752002A3 (en) 2003-01-09
US6432987B2 (en) 2002-08-13
KR20020063245A (en) 2002-08-01
RU2266280C2 (en) 2005-12-20
HK1054038B (en) 2007-04-13
NO324750B1 (en) 2007-12-03
WO2001047913A3 (en) 2002-04-25
HUP0203716A2 (en) 2003-03-28
DE19962300A1 (en) 2001-06-28
DK1240157T3 (en) 2004-06-14
AR027098A1 (en) 2003-03-12
PL195014B1 (en) 2007-07-31
AU772745B2 (en) 2004-05-06
PT1240157E (en) 2004-06-30
NO20023039D0 (en) 2002-06-21
BG106924A (en) 2003-04-30
IL150235A0 (en) 2002-12-01
NO20023039L (en) 2002-08-09
CO5251472A1 (en) 2003-02-28
NZ533731A (en) 2005-03-24
CZ20022094A3 (en) 2002-10-16
CA2395259A1 (en) 2001-07-05
PL355684A1 (en) 2004-05-17
WO2001047913A2 (en) 2001-07-05
KR100747425B1 (en) 2007-08-09
UA75060C2 (en) 2006-03-15
JP2003519137A (en) 2003-06-17
ZA200204896B (en) 2002-12-20
HK1054038A1 (en) 2003-11-14
CN1283637C (en) 2006-11-08

Similar Documents

Publication Publication Date Title
US20010014690A1 (en) Substituted N-benzylindol-3-ylglyoxylic acid derivatives having antitumor action
US6344467B1 (en) N-substituted indole-3-glyoxylamides having anti-asthmatic, antiallergic and immunosuppressant/immuno-modulating action
US6232327B1 (en) Indolyl-3-glyoxylic acid derivatives having antitumor action
CZ20003483A3 (en) Derivatives of indolyl-3-glyoxylic acid exhibiting antitumor activity
MXPA00009646A (en) Indolyl-3-glyoxylic acid derivatives with antitumoral activity

Legal Events

Date Code Title Description
AS Assignment

Owner name: ASTA MEDICA AG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GUNTER, ECKHARD;EMIG, PETER;REICHERT, DIETMAR;AND OTHERS;REEL/FRAME:011640/0252;SIGNING DATES FROM 20010122 TO 20010314

AS Assignment

Owner name: ZENTARIS AG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ASTA MEDICA GMBH;REEL/FRAME:012752/0016

Effective date: 20020319

AS Assignment

Owner name: ZENTARIS GMBH, GERMAN DEMOCRATIC REPUBLIC

Free format text: CHANGE OF NAME;ASSIGNOR:ZENTARIS AG;REEL/FRAME:015452/0886

Effective date: 20021204

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20100813