Indolyl-3-glyoxylic acid derivatives having antitumor action
First Claim
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1. A method of using an N-substituted indole-3-glyoxylamide of formula 1 as an antitumor agent, where the radicals R, R1, R2, R3, R4 and Z have the following meanings:
- R=hydrogen, (C1-C6)-alkyl, where the alkyl group is optionally mono- or polysubstituted by a phenyl ring and this phenyl ring for its part is optionally 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 or by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6)-alkyl groups, halogen atoms or trifluoromethyl groups, or R is a benzyloxycarbonyl group or a tertiary-butoxycarbonyl radical (BOC radical), or an acetyl group, R1 is a pyridine structure of formula 2
or its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and is optionally substituted by the substituents R5 and R6;
R5 and R6 are identical or different and signify (C1-C6)-alky, (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino radical and a carboxyalkyloxy group in which the alkyl group has 1-4 C atoms;
R2 is hydrogen or a (C1-C6)-alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part is optionally mono or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6 -alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups, the (C1-C6)-alkyl group is optionally substituted by the 2-quinolyl group and the 2-, 3- and 4-pyridyl structure, which are optionally in each case mono- or polysubstituted by halogen, (C1-C4)-alkyl groups or (C1-C4)-alkoxy groups, or R2 is an aroyl radical, where the aryl moiety on which the radical is based is a phenyl ring, which is optionally mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups;
R3 and R4 are identical or different and are hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen and benzyloxy, or a nitro group, an amino group, a (C1-C4)- mono or dialkyl-substituted amino group, or a (C1-C6) alkoxycarbonylamino function or (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl function; and
Z is O or S;
said method comprising administering said N-substituted indole-3-glyoxylamide or an acid addition salt or N-oxide thereof to a subject in need of antitumor treatment.
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Abstract
The invention relates to the use of N-substituted indole-3-glyoxylamides of the general formula I as antitumor agents
and to a pharmaceutical composition having antitumor action, characterized in that it contains at least one of the compounds of the general formula 1, if appropriate also in the form of the physiologically tolerable acid addition salts or N-oxides. Furthermore, the invention also includes antitumor agents comprising as active compound one or more N-substituted indole-3-glyoxylamides according to the general formula 1 and, if appropriate, their physiologically tolerable acid addition salts and, if possible, N-oxides and a pharmaceutically utilizable carrier and/or diluent or auxiliary substance 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.
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Citations
5 Claims
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1. A method of using an N-substituted indole-3-glyoxylamide of formula 1 as an antitumor agent,
where the radicals R, R1, R2, R3, R4 and Z have the following meanings: -
R=hydrogen, (C1-C6)-alkyl, where the alkyl group is optionally mono- or polysubstituted by a phenyl ring and this phenyl ring for its part is optionally 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 or by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6)-alkyl groups, halogen atoms or trifluoromethyl groups, or R is a benzyloxycarbonyl group or a tertiary-butoxycarbonyl radical (BOC radical), or an acetyl group, R1 is a pyridine structure of formula 2 or its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and is optionally substituted by the substituents R5 and R6;
R5 and R6 are identical or different and signify (C1-C6)-alky, (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino radical and a carboxyalkyloxy group in which the alkyl group has 1-4 C atoms;
R2 is hydrogen or a (C1-C6)-alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part is optionally mono or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6 -alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups, the (C1-C6)-alkyl group is optionally substituted by the 2-quinolyl group and the 2-, 3- and 4-pyridyl structure, which are optionally in each case mono- or polysubstituted by halogen, (C1-C4)-alkyl groups or (C1-C4)-alkoxy groups, or R2 is an aroyl radical, where the aryl moiety on which the radical is based is a phenyl ring, which is optionally mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups;
R3 and R4 are identical or different and are hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen and benzyloxy, or a nitro group, an amino group, a (C1-C4)- mono or dialkyl-substituted amino group, or a (C1-C6) alkoxycarbonylamino function or (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl function; and
Z is O or S;
said method comprising administering said N-substituted indole-3-glyoxylamide or an acid addition salt or N-oxide thereof to a subject in need of antitumor treatment. - View Dependent Claims (2, 3, 4)
where the radicals R=hydrogen R1=4 pyridyl, R2=benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl R3 and R=hydrogen and Z is oxygen. -
3. The method of claim 1 wherein an acid addition salt is administered which is the salt of a mineral acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a salt of an organic acid, or N-oxide thereof.
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4. The method of claim 3, wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, malonic acid, maleic acid, lumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid and 2-hydropoxyethanesulfonic acid.
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5. Method of using N-substituted indole-3-glyoxylamides of the general formula 1
where the radicals R, R1, R2, R3, R4 and Z have the following meanings: -
R=hydrogen, (C1-C6)-alkyl, where the alkyl group is optionally mono- or polysubstituted by a phenyl ring and this phenyl ring for its part is optionally 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 or by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6)-alkyl groups, halogen atoms or trifluoromethyl groups, or R is a benzyloxycarbonyl group or a tertiary-butoxycarbonyl radical (BOC radical), or an acetyl group, R1 is a pyridine structure of formula 2 or its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and is optionally substituted by the substituents R5 and R6;
R5 and R6 are identical or different and signify (C1-C6)-alkyl, (C3-C7)-cycloalkyl , (C1-C6) -alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino radical, and a carboxylkyloxy group in which the alkyl group has 1-4 C atoms;
R2 is hydrogen or a (C1-C6)-alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part is optionally mono or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups, the (C1-C6)-alkyl group is optionally substituted by the 2-quinolyl group and the 2-, 3- and 4pyriddyl structure, which are optionally in each case mono- or polysubstituted by halogen, (C1-C4)-alkyl groups or (C1-C4)-alkoxy groups, or R2 is an aroyl radical, where the aryl moiety on which the radical is based is a phenyl ring, which is optionally mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, epoxy groups or benzyloxy groups;
R3 and R4 are identical or different and are hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen and benzyloxy, or a nitro group, an amino group, a (C1-C4)-mono or diaklyl-substituted amino group, or a (C1-C6) alkoxycarbonylamino function or (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl function; and
Z is O or S;
and their physiologically tolerable acid addition salts for the treatment of tumors or oncoses, said method comprising administering at least one of the following compounds or a physiologically acceptable acid addition salt or N-oxide thereof; N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide;
N-(pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamide;
N-(4-fluorophenyl)-[1-(3-pyridylmethyl)-indol-3-yl]glyoxylamide;
N-(pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylamide; and
N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide hydrochloride salt;
a subject in need of such treatment.
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Specification
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Current AssigneeZiopharm Oncology, Inc.
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Original AssigneeAsta Medica Aktiengesellschaft (Rag-Stiftung)
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InventorsSchmidt, Jürgen, Günther, Eckhard, Reichert, Dietmar, Emig, Peter, Nickel, Bernd, Szelenyi, Istvan, Brune, Kay
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Primary Examiner(s)Rotman, Alan L.
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Assistant Examiner(s)DESAI, RITA J
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Application NumberUS09/285,058Time in Patent Office774 DaysField of Search514/337, 546/278.1, 546/256US Class Current514/337CPC Class CodesA61K 31/404 Indoles, e.g. pindololA61K 31/4178 not condensed 1,3-diazoles ...A61K 31/4439 containing a five-membered ...A61K 31/444 containing a six-membered r...A61K 31/4709 Non-condensed quinolines an...A61K 31/496 Non-condensed piperazines c...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 35/04 specific for metastasisC07D 209/14 Radicals substituted by nit...C07D 401/12 linked by a chain containin...C07D 401/14 containing three or more he...C07D 403/12 linked by a chain containin...
