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WO2009006839A1 - Dérivés d'indol-3-yl oxalylpodophyllotoxine substitués, leurs sels et leur application - Google Patents

Dérivés d'indol-3-yl oxalylpodophyllotoxine substitués, leurs sels et leur application Download PDF

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Publication number
WO2009006839A1
WO2009006839A1 PCT/CN2008/071573 CN2008071573W WO2009006839A1 WO 2009006839 A1 WO2009006839 A1 WO 2009006839A1 CN 2008071573 W CN2008071573 W CN 2008071573W WO 2009006839 A1 WO2009006839 A1 WO 2009006839A1
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Prior art keywords
group
substituted
acid
ring
carbon atoms
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Ceased
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PCT/CN2008/071573
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English (en)
Chinese (zh)
Inventor
Hong Chen
Zhiyong Lei
Pengfei Yu
Maosheng Cheng
Bo Cao
Shufang Bai
Min Feng
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MEDICAL COLLEGE OF CHINESE PEOPLE`S ARMED POLICE FORCE
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MEDICAL COLLEGE OF CHINESE PEOPLE`S ARMED POLICE FORCE
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Publication of WO2009006839A1 publication Critical patent/WO2009006839A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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 present invention relates to a substituted indole-3-yloxalyl glycoside derivative, an inorganic acid salt thereof and an organic acid salt, and to use in the preparation of an antitumor drug.
  • ⁇ -3-Glyceramide has a variety of biological activities and has been demonstrated by considerable literature and published patent records.
  • the indole-3-oxalic acid amide derivative is a class of compounds having anti-inflammatory, antipyretic and analgesic activities.
  • an indole-3-yloxacin derivative as an analgesic, anticonvulsant and ⁇ -adrenergic compound is described.
  • G. Domschke et al. (Ber. 94, 2353 (196 1)) describe indole-3-yloxacin derivatives having certain pharmacological properties.
  • E. Walson, J. Med. Chem., 11 , 1252 (1968) describes indole-3-yl oxalic acid amide derivatives which have an inhibitory effect on glycerophosphate dehydrogenase and lactate dehydrogenase.
  • a second object of the present invention is to provide an inorganic or organic salt which replaces the indole-3-yloxalyl glycoside derivative.
  • a third object of the present invention is to provide a use of a substituted indole-3-yloxalyl glycoside derivative for the preparation of an antitumor drug.
  • a fourth object of the present invention is to provide an inorganic salt or an organic salt of a substituted indolin-3-yloxalyl glycoside derivative for use in the preparation of an antitumor drug.
  • R represents hydrogen or methyl
  • ⁇ represents hydrogen, an alkyl group, C 3 ⁇ (: 7 cycloalkyl, ( ⁇ (: 6 aralkyl, ⁇ (: 6 alkylsulfonyl, haloacyl, halosulfonyl, ethoxy) a carbonyl group, an alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, an alkoxysulfonyl group having an alkyl moiety of 1 to 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrimidine ring a substituted pyrimidine ring, a quinoline ring, a substituted quinoline ring, a benzyl group, a substituted benzyl group, a benzoyl group, a substituted benzoyl group, a cinnamyl group, a substituted al
  • ⁇ represents a substituted benzyl group represented by the formula ( ⁇ ):
  • substitution sites H of the benzene ring in the substituted benzyl group represented by the formula ( ⁇ ) are substituted by the same or different substituents of ( ⁇ (: 6 alkyl group, C 3 to C 7 Cycloalkyl, ( ⁇ (: 6 alkoxy, ( ⁇ (: 6 alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, alkane Alkoxycarbonyl group having 1 to 18 carbon atoms in the base portion and alkoxysulfonyl group having 1 to 18 carbon atoms in the alkyl moiety;
  • R 4 , R 6 , and R 7 of the above formula (I) are the same or different, and R 4 , R 6 , and R 7 represent hydrogen, ( ⁇ (: 6 alkyl group, C 3 ⁇ C) 7 cycloalkyl, ( ⁇ (: 6 alkoxy, ( ⁇ (: 6 alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl)
  • X is an oxygen or an imino group.
  • R represents a methyl group
  • ⁇ represents p-chlorobenzyl
  • X represents oxygen
  • R represents a methyl group, which represents a 3,4-dichlorobenzyl group
  • X represents oxygen
  • the chemical name is: 4-[1 -(3,4-Dichlorobenzyl)indol-3-yl]oxalyl epipodophyllotoxin (YB-F1EP0).
  • R represents a methyl group, which represents a 3,4-methylenedioxybenzyl group
  • X represents oxygen
  • the chemical name is: 4 -[1-(3,4-Methylenedioxybenzyl)indol-3-yl]oxalyl epipodophyllotoxin (YB-L1EP0).
  • R represents a methyl group
  • ! ⁇ represents p-chlorobenzyl
  • X represents an imino group
  • R represents a methyl group, and represents a 3,4-methylenedioxybenzyl group
  • X represents an imino group
  • the chemical name is: 4-[1-(3,4-Methylenedioxybenzyl)indol-3-yl]oxalylamino-4-deoxyepidetoxin (YB-L1EPN).
  • R represents a methyl group, represents a bromine, represents hydrogen, and X represents an imino group, and the chemical name is: 4-(5-bromoindol-3-yl)oxalylamino-4-deoxyepidetoxin ( YB-XB1EPN).
  • R represents a methyl group, represents a methoxy group, represents hydrogen, and X represents an imino group, and the chemical name is: 4-(5-methoxyindol-3-yl)oxalylamino-4-deoxy table ghost white toxin (YB-X31EPN).
  • R represents a methyl group, represents a methyl group, represents hydrogen, and X represents an imino group, and the chemical name is: 4-[2-methylindol-3-yl]oxalylamino-4-deoxyepide White toxin (YB-V81EPN).
  • R represents a methyl group
  • R 6 represents a fluorine
  • X represents an imino group
  • the chemical name is: 4-(6-fluoroindol-3-yl)oxalylamino-4-deoxyepide White toxin (YB-Y11EPN).
  • R represents a methyl group
  • R 6 represents a methoxy group
  • X represents an imino group
  • the chemical name is: 4-(6-methoxyindol-3-yl)oxalylamino-4 - Deoxyepoxyphoratoxin (YB-Y31EPN).
  • R represents hydrogen
  • X represents an imino group
  • the chemical name is: 4 ⁇ -(( ⁇ -3-yl)oxalylamino)-4-deoxy-demethylepipodophyllotoxin (FM- PN5).
  • any one of the above substituted inorganic or organic acid salts of an indole-3-yloxalyl glycoside derivative the inorganic acid being hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid being acetic acid, lactic acid or C Diacid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, pamoic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxyethanesulfonic acid, nicotinic acid or p-toluene acid.
  • the invention utilizes the existing natural resource ghost white toxin in our country to synthesize a series of compounds with anti-tumor activity, in order to find anti-tumor drugs with high anti-tumor activity and effective against multi-drug resistant tumors.
  • the structural modification of the natural product, ghost white toxin is expected to make the newly synthesized compound effective against multiple drug-resistant tumors while retaining its anti-tumor activity.
  • Figure 1 is a nuclear magnetic resonance spectrum of 4-[1-(p-chlorobenzyl)indol-3-yl]oxalylpodophyllotoxin (YB-B1EP0);
  • Figure 2 is a nuclear magnetic resonance spectrum of 4-[l-(3,4-dichlorobenzyl)indol-3-yl]oxalylpodophyllotoxin (YB-F1EP0);
  • Figure 3 is 4-[1-( Nuclear magnetic resonance spectrum of 3,4-methylenedioxybenzyl)indol-3-yl]oxalylpodophyllotoxin (YB-L1EP0);
  • Figure 4 is a nuclear magnetic resonance spectrum of 4-[1-(p-chlorobenzyl)indol-3-yl]oxalylamino-4-deoxyepidetoxin (YB-B1EPN);
  • Figure 5 is a nuclear magnetic resonance spectrum of 4-[1-(3,4-methylenedioxybenzyl)indol-3-yl]oxalylamino-4-deoxyepipodophyllotoxin (YB-L1EPN);
  • Figure 6 is a nuclear magnetic resonance spectrum of 4-(5-bromoindol-3-yl)oxalylamino-4-deoxyepipodophyllotoxin (YB-XB1EPN);
  • Figure 7 is 4-(5-methoxyindole) Nuclear magnetic resonance spectrum of -3-yl) oxalylamino-4-deoxyepipodophyllotoxin (YB-X31EPN);
  • Figure 8 is a nuclear magnetic resonance spectrum of 4-[2-methylindol-3-yl]oxalylamino-4-deoxyepipodophyllotoxin (YB-V81EPN);
  • Figure 9 is 4-(6-fluoroindole- Nuclear magnetic resonance spectrum of 3-yl) oxalylamino-4-deoxyepipodophyllotoxin (YB-Y11EPN);
  • Figure 10 is 4-(6-methoxyindol-3-yl)oxalylamino-4-deoxy Nuclear magnetic resonance spectrum of epipodophyllotoxin ( ⁇ 13 315? ⁇ ).
  • Figure 11 is a nuclear magnetic resonance spectrum of 4?-((1-(4-cyanobenzyl)-indol-3-yl)-oxalylamino)-epipodophyllotoxin (FM-PN1).
  • Figure 12 is a nuclear magnetic resonance spectrum of 4 ⁇ -(indol-3-acetyl)-epipodophyllotoxin (FM-PN2).
  • Figure 13 is a nuclear magnetic resonance spectrum of 4?-((1-benzyl-indol-3-yl)-oxalylamino)-epipodophyllotoxin (FM-PN3).
  • Figure 14 is a nuclear magnetic resonance spectrum (FM-PN4) of 4?-((1-(3-cyanobenzyl)-indol-3-yl)-oxalylamino)-epenophorin.
  • Figure 15 is a nuclear magnetic resonance spectrum of 4 ⁇ -(( ⁇ -3-yl)-oxalylamino)-4-deoxydemethylepipodophyllotoxin (FM-PN5).
  • Figure 16 is a nuclear magnetic resonance spectrum of 4?-((1-benzyl-indol-3-yl)-oxalylamino)-4-deoxydemethylepipodophyllotoxin (FM-PN6).
  • Figure 17 is a nuclear magnetic resonance spectrum of 4-(6-methoxyindol-3-yl)oxalylamino-4-deoxydemethylepipodophyllotoxin (FM-PN7).
  • the synthetic process of the invention is:
  • reaction mixture is added to water, and the obtained aqueous solution is extracted with diethyl ether (an organic solvent such as dichloromethane, chloroform, methyl t-butyl ether or tetrahydrofuran); the organic phase is combined, and then anhydrous sodium sulfate is used.
  • diethyl ether an organic solvent such as dichloromethane, chloroform, methyl t-butyl ether or tetrahydrofuran
  • the organic phase is concentrated under reduced pressure, and the remaining residue or oily residue is crystallized by trituration or recrystallization, distillation or purification by silica gel or alumina column chromatography or flash column chromatography to give intermediate III, eluent used A mixture of acetone:ethyl ether having a volume ratio of 8:2 or acetone:ethanol mixture having a volume ratio of 9:1;
  • the intermediate product III is dissolved in toluene under nitrogen protection (other than a toluene solvent, other aprotic or non-polar organic solvents such as xylene, dichloromethane, diethyl ether, tert-butyl methyl ether) may be used.
  • a toluene solvent other aprotic or non-polar organic solvents such as xylene, dichloromethane, diethyl ether, tert-butyl methyl ether
  • tetrahydrofuran, dioxane Ring or chloroform tetrahydrofuran, dioxane Ring or chloroform
  • reaction temperature and reaction time can also be: 0 ° C-4 (TC, reaction 1 _ 3 hours, 60 ° C - 8 (TC, reaction for 1 hour, at 20 ° C - 30 ° C, allowed to stand for 24 hours, filtered, the filtrate was concentrated in vacuo, the residue was recrystallized from organic solvent, or silica gel column chromatography or alumina Chromatographic purification affords a fine formula I, using a mixture of acetone:ethyl ether in a volume ratio of 8:2 or a mixture of acetone:ethanol in a volume ratio of 9:1.
  • R represents hydrogen or methyl
  • ⁇ represents hydrogen, an alkyl group, C 3 ⁇ (: 7 cycloalkyl, ( ⁇ (: 6 aralkyl, ⁇ (: 6 alkylsulfonyl, haloacyl, halosulfonyl, ethoxy) a carbonyl group, an alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, an alkoxysulfonyl group having an alkyl moiety of 1 to 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrimidine ring a substituted pyrimidine ring, a quinoline ring, a substituted quinoline ring, a benzyl group, a substituted benzyl group, a benzoyl group, a substituted benzoyl group, a cinnamyl group, a substituted al
  • substitution sites H of the benzene ring in the substituted benzyl group represented by the formula ( ⁇ ) are substituted by the same or different substituents of ( ⁇ (: 6 alkyl group, C 3 to C 7 Cycloalkyl, ( ⁇ (: 6 alkoxy, ( ⁇ (: 6 alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, alkane a base having an alkoxycarbonyl group of 1 to 18 carbon atoms, An alkoxysulfonyl group having an alkyl moiety of 1 18 carbon atoms;
  • R 4 R 5 R 6 R 7 of the formula (I) is the same or different, and R 4 R 5 R 6 R 7 represents hydrogen, ⁇ CM alkyl, C 3 C 7 cycloalkyl, ( ⁇ ⁇ (: 6 alkoxy, ( ⁇ (: 6 alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, alkyl moiety having 1 18 An alkoxycarbonyl group of a carbon atom, an alkoxysulfonyl group having an alkyl moiety of 1 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrimidine ring, a substituted pyrimidine ring, a quinoline ring, a substituted quinoline a ring, a benzyloxy group, a substituted benzyloxy group
  • Table 1 shows the structure and physical properties of derivatives of several substituted indole-3-yloxalyl glycoside derivatives
  • the above compound is used to prepare a mineral acid salt or an organic acid salt, which is hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is acetic acid, lactic acid, malonic acid, horse Acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, pamoic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxyethanesulfonic acid, nicotinic acid or p-toluenesulfonic acid to increase Its solubility in water.
  • the organic acid is acetic acid, lactic acid, malonic acid, horse Acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, pamoic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxyethanesulfonic acid, nicotinic acid or p-toluenesul
  • Anti-tumor activity study In vitro anti-tumor activity screening The cells in logarithmic growth phase were diluted to lx 10 4 C ell/ml, immediately seeded in 96-well culture plates, 0.1 ml/well, and then cultured with different concentrations in the experimental wells.

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

Abstract

L'invention porte sur des dérivés d'indol-3-yl oxalylpodophyllotoxine substitués et sur leurs sels, qui sont représentés par la formule (I) générale suivante. Ces composés sont efficaces contre de nombreuses tumeurs résistantes aux médicaments.
PCT/CN2008/071573 2007-07-11 2008-07-08 Dérivés d'indol-3-yl oxalylpodophyllotoxine substitués, leurs sels et leur application Ceased WO2009006839A1 (fr)

Applications Claiming Priority (2)

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CNA2007100578990A CN101085779A (zh) 2007-07-11 2007-07-11 取代吲哚－3－基草酰表鬼臼毒素衍生物及其盐及其用途
CN200710057899.0 2007-07-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
WO2025082431A1 (fr) * 2023-10-18 2025-04-24 正大天晴药业集团股份有限公司 Utilisation d'un dérivé d'indole dans le traitement d'une tumeur de la tête et du cou

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101085779A (zh) * 2007-07-11 2007-12-12 中国人民武装警察部队医学院 取代吲哚－3－基草酰表鬼臼毒素衍生物及其盐及其用途
CN105250265B (zh) * 2015-08-27 2017-10-03 遵义医学院 鬼臼毒素靛红类衍生物在抗白血病药物中的应用及制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1299280A (zh) * 1998-04-02 2001-06-13 Asta药物股份公司 具有抗肿瘤作用的吲哚基－3－乙醛酸衍生物
WO2004000859A2 (fr) * 2002-06-21 2003-12-31 University Of North Carolina At Chapel Hill Analogues d'etoposide et leurs methodes d'utilisation
CN101085779A (zh) * 2007-07-11 2007-12-12 中国人民武装警察部队医学院 取代吲哚－3－基草酰表鬼臼毒素衍生物及其盐及其用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1299280A (zh) * 1998-04-02 2001-06-13 Asta药物股份公司 具有抗肿瘤作用的吲哚基－3－乙醛酸衍生物
WO2004000859A2 (fr) * 2002-06-21 2003-12-31 University Of North Carolina At Chapel Hill Analogues d'etoposide et leurs methodes d'utilisation
CN101085779A (zh) * 2007-07-11 2007-12-12 中国人民武装警察部队医学院 取代吲哚－3－基草酰表鬼臼毒素衍生物及其盐及其用途

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
WO2025082431A1 (fr) * 2023-10-18 2025-04-24 正大天晴药业集团股份有限公司 Utilisation d'un dérivé d'indole dans le traitement d'une tumeur de la tête et du cou

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