RU2002111866A - Derivatives of N-substituted indole-3-glyoxylamide - an antitumor drug and an agent that suppresses angiogenesis (options), a pharmaceutical composition and an antitumor drug (options) - Google Patents

Claims (13)

1. The use of N-substituted indole-3-glyoxylamides of the general formula 1 as an antitumor drug for the treatment of tumors, especially in the event of drug resistance and metastatic carcinoma, and / or as an agent that suppresses angiogenesis and has significantly less side effects, in particular, significantly less neurotoxicity

Formula 1 where R, R ₁ , R ₂ , R ₃ , R ₄ and Z have the following meanings: R is hydrogen, (C ₁ -C ₆ ) alkyl, wherein the alkyl group may contain at least one phenyl ring as a substituent, which in turn may have at least one substituent selected from the group containing halogen, ( C ₁ -C ₆ ) alkyl and (C ₃ -C ₇ ) cycloalkyl, carboxyl groups, esters of carboxyl groups with (C ₁ -C ₆ ) alkanols, trifluoromethyl, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, as well as benzyl groups, containing at least one substituent in the phenyl residue selected ny from (C ₁ -C ₆₎ alkyl, halogen or trifluoromethyl, in addition, R is benzyloxycarbonyl (Z-group) and tert.-butoxycarbonyl residue (Boc group) and an acetyl group; R ₁ may mean a phenyl ring containing at least one substituent selected from the group consisting of (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 a carboxyl group, as well as esters of a carboxyl group with (C ₁ -C ₆ ) alkanols, or the pyridine residue of formula 2 and its N-oxide

Formula 2 or its N-oxide, in which the pyridine residue is optionally bound to cyclic carbon atoms 2, 3, and 4 and may contain substituents R ₅ and R ₆ ; residues R ₅ and R ₆ may be the same or different and mean (C ₁ -C ₆ ) alkyl, as well as (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy, nitro, amino, hydroxy, halogen and trifluoromethyl, as well as an ethoxycarbonylamino group and a carboxyalkyloxy group in which the alkyl group may contain 1-4 carbon atoms, in addition, R ₁ may be a 2- or 4-pyrimidinyl heterocycle, and the 2-pyrimidinyl ring may be substituted by at least one methyl group, as well as mean residue 2-, 3-, 4- and 8-quinolyl, containing as substituent (C ₁ -C ₆₎ alkyl, n ogen, nitro, amino, (C ₁ -C ₆₎ alkylamino, wherein R ₁ may denote a 2-, 3- and 4-hinolilmetilnuyu group wherein the carbon atoms in the cyclic moiety pirimidilmetilnom hinolilgruppy and hinolilmetilnye groups may have substituents such as (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, nitro, amino and (C ₁ -C ₆ ) alkoxycarbonylamino, in addition, if R is hydrogen, methyl or benzyl, as well as benzyloxycarbonyl (Z -group), tert-butoxycarbonyl (Boc group) and acetyl group, then R ₁ means the following residues: —CH ₂ COOH, —CH (CH ₃ ) COOH, - (CH ₃ ) ₂ —CH— (CH ₂ ) ₂ -CH-COO-, H ₃ C-H ₂ C-CH (CH ₃ ) -CH (COOH) -, HO-H ₂ C-CH (COOH) -, phenyl-CH ₂ -CH- (COOH) -, (4-imidazolyl) -CH ₂ -CH (COOH) -, HN = C (NH ₂ ) -NH- (CH ₂ ) ₃ -CH (COOH) -, H ₂ N- (CH ₂ ) ₄ -CH (COOH) -, H ₂ N-CO-CH ₂ -CH- (COOH) -, HOOC- (CH ₂ ) ₂ -CH (COOH) - in addition, in case R represents hydrogen, Z-group , A BOC group and an acetyl or benzyl group, then R ₁ may mean an acid residue of a natural or unnatural amino acid, such as, for example, α-glycyl, α-sarcosyl, α-alanyl, α-leucyl, α-isoleucyl, α-serial α-phenylalanyl, α-histidyl, α-prolyl, α-arginyl, α-lysyl, α-asparagil and α-glutamyl, with amino groups respectively of the existing amino acids may be protected or not protected, and the benzyloxycarbonyl (Z-group), tert-butoxycarbonyl group (BOC-group) and acetyl group are used as the protective group of amino groups, moreover, in the case of using aspartic and glutamic acid residues as R ₁ , second, unrelated carboxyl group is present as a free carboxyl group or an ester with C ₁ -C ₆ alkanols such as for example methyl, ethyl or tert-butyl, furthermore, R ₁ can mean llilaminokarbonil-2-methylprop-1-yl, furthermore, R and R ₁ may be combined with the nitrogen atom to which they are attached to form a piperazine ring of the formula 3 or a homopiperazine ring if R ₁ is aminoalkylene group,

Formula 3 in which R ₇ means an alkyl group, a phenyl ring, which may contain at least one substituent selected from the group consisting of (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halogen, nitro, amino or ( C ₁ -C ₆ ) alkylamino, in addition, R ₇ means a benzhydryl group and a bis-p-fluorobenzylhydryl group; R ₂ may be hydrogen or (C ₁ -C ₆ ) alkyl, wherein the alkyl group may contain at least one substituent selected from halogen and phenyl, in which at least one substituent selected from the group may be present containing halogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, carboxyl groups, esters of carboxyl groups with C ₁ -C ₆ alkanols, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy; in addition, the alkyl group used as R ₂ (C ₁ -C ₆ ) may contain substituents, such as a 2-quinolyl group and a 2-, 3- and 4-pyridyl radical, both of which may contain at least one substituent, selected from halogen, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy; in addition, R ₂ means an aroyl residue, wherein the aryl moiety constituting it is a phenyl ring, which may contain at least one substituent selected from the group consisting of halogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) icloalkyl, carboxyl groups and esters of carboxyl groups with (C ₁ -C ₆ ) alkanols, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy groups; R ₃ and R ₄ may be the same or different and mean hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, halogen and benzyloxy; in addition, R ₃ and R ₄ may mean a nitro, amino, amino group containing mono- or di- (C ₁ -C ₄ ) alkyl substituents, (C ₁ -C ₆ ) alkoxycarbonylamino or (C ₁ -C ₆ ) alkoxycarbonylamino A (C ₁ -C ₆ ) alkyl group; a Z means O or S. 2. The use of N-substituted indole-3-glyoxylamides of the general formula 1a for the treatment of tumors, in particular in cases of drug resistance and metastatic carcinoma, as a means of suppressing angiogenesis and having less side effects, in particular, significantly less neurotoxicity

Formula 1a where R is hydrogen; R ₁ is 4-pyridyl, 4-fluorophenyl; R ₂ is benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl; R ₃ and R _{4 are} hydrogen; Z is oxygen. 3. A pharmaceutical composition for treating tumors, in particular in cases of drug resistance and metastatic carcinoma, as well as an agent that suppresses angiogenesis and has less side effects, in particular, significantly less neurotoxicity, characterized in that it contains at least one a compound of general formula 1 or 1a, optionally in the form of its acid addition salts, for example salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, salts with organic acids such as acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid and 2-hydroxyethane sulfonic acid, and also, if possible, in the form of N-oxides. 4. The use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically acceptable acid additive salts for the preparation of antitumor drugs, used in particular for drug resistance and metastatic carcinomas, as well as for inhibiting angiogenesis and having significantly less side effects, in particular, significantly less neurotoxicity, especially of the following compounds or their salts with physiologically acceptable acids or, if possible, their N-oxides: D-24241 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide, D-24843 N- (pyridin-4-yl) (1-benzylindol-3-yl) glyoxylamide, D-24850 N- (4-fluorophenyl) [1- (3-pyridylmethyl) indol-3-yl] glyoxylamide, D-24851 N- (pyridin-4-yl) [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide, D-25505 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide HCl. 5. An antitumor drug for use in particular with drug resistance and metastatic carcinoma, inhibiting angiogenesis and having significantly less side effects, in particular significantly less neurotoxicity, characterized in that it contains at least one N-substituted indole as an active agent -3-glyoxylamide of the general formula 1 or 1a and, if necessary, its physiologically acceptable acid addition salts, in particular at least one compound according to claim 4. 6. An antitumor drug for the treatment of tumors, especially with drug resistance and metastatic carcinoma, which suppresses angiogenesis and has less side effects, in particular, significantly less neurotoxicity, characterized in that it is specific, especially when it contains as an active agent D 24241 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide or its hydrochloride. 7. An antitumor drug for the treatment of tumors, especially with drug resistance and metastatic carcinoma, which suppresses angiogenesis and has significantly less side effects, in particular, significantly less neurotoxicity, characterized in that it is specific, especially when it contains as active Agent D 24843 N- (pyridin-4-yl) (1-benzylindol-3-yl) glyoxylamide. 8. An antitumor drug for the treatment of tumors, especially with drug resistance and metastatic carcinoma, which inhibits angiogenesis and has significantly less side effects, in particular, significantly less neurotoxicity, characterized in that it is specific, especially when it contains as active Agent D 24850 N- (4-fluorophenyl) [1- (3-pyridylmethyl) indol-3-yl] glyoxylamide. 9. An antitumor drug for the treatment of tumors, especially with drug resistance and metastatic carcinoma, which suppresses angiogenesis and has significantly less side effects, in particular, significantly less neurotoxicity, characterized in that it is specific, especially when it contains as active Agent D 24851 N- (pyridin-4-yl) [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide. 10. An antitumor drug for the treatment of tumors, especially with drug resistance and metastatic carcinoma, which suppresses angiogenesis and has significantly less side effects, in particular, significantly less neurotoxicity, characterized in that it contains at least one N as an active agent -substituted indole-3-glyoxylamide of the general formula 1 or 1a, if necessary, its physiologically acceptable acid addition salts, and, if possible, N-oxides, in particular at least about the bottom of the compound according to any one of claims 4, 6-8, and pharmaceutically acceptable carriers and / or diluents or excipients, and is presented in the form of tablets, dragees, capsules, infusion solutions or ampoules, suppositories, plasters, inhalation powders, suspensions, creams and ointments. 11. The use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically acceptable acid addition salts as agents for suppressing angiogenesis, especially the following compounds or their salts with physiologically tolerated acids and, if possible, their N- oxides: D-24241 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide, D-24843 N- (pyridin-4-yl) (1-benzylindol-3-yl) glyoxylamide, D-24850 N- (4-fluorophenyl) [1- (3-pyridylmethyl) indol-3-yl] glyoxylamide, D-24851 N- (pyridin-4-yl) [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide, D-25505 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide HCl. 12. The use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically acceptable acid addition salts, especially with drug resistance, as a substitute for an antitumor agent that is no longer active due to drug resistance, especially the following compounds: D-24241 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide, D-24843 N- (pyridin-4-yl) (1-benzylindol-3-yl) glyoxylamide, D-24850 N- (4-fluorophenyl) [1- (3-pyridylmethyl) indol-3-yl] glyoxylamide, D-24851 N- (pyridin-4-yl) [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide, D-25505 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide HCl. 13. The use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically acceptable acid addition salts, especially with drug resistance, as a substitute for an antitumor agent that is no longer active due to drug resistance, in fixed or arbitrary combination with known antitumor agents, especially the following compounds: D-24241 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide, D-24843 N- (pyridin-4-yl) (1-benzylindol-3-yl) glyoxylamide, D-24850 N- (4-fluorophenyl) [1- (3-pyridylmethyl) indol-3-yl] glyoxylamide, D-24851 N- (pyridin-4-yl) [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide, D-25505 N- (pyridin-4-yl) [1- (4-fluorobenzyl) indol-3-yl] glyoxylamide HCl.