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WO2005063760A1 - Hybrides acridone/acridine de pyrrolo[2,1-c][1,4]benzodiazepine a liaison c-8 - Google Patents

Hybrides acridone/acridine de pyrrolo[2,1-c][1,4]benzodiazepine a liaison c-8 Download PDF

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Publication number
WO2005063760A1
WO2005063760A1 PCT/IN2003/000464 IN0300464W WO2005063760A1 WO 2005063760 A1 WO2005063760 A1 WO 2005063760A1 IN 0300464 W IN0300464 W IN 0300464W WO 2005063760 A1 WO2005063760 A1 WO 2005063760A1
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WIPO (PCT)
Prior art keywords
formula
compound
methoxy
oxy
hybrid
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Ceased
Application number
PCT/IN2003/000464
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English (en)
Inventor
Ahmed Kamal
Olepu Srinivas
Poddutoori Ramulu
Gujjar Ramesh
Pogula Praveen Kumar
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Council of Scientific and Industrial Research CSIR
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Council of Scientific and Industrial Research CSIR
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Priority to PCT/IN2003/000464 priority Critical patent/WO2005063760A1/fr
Priority to AU2003300720A priority patent/AU2003300720A1/en
Priority to GB0614754A priority patent/GB2424884B/en
Priority to JP2005512763A priority patent/JP4718328B2/ja
Publication of WO2005063760A1 publication Critical patent/WO2005063760A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention provides novel pyrrolo-[2,l-c][l,4]benzodiazepine hybrids useful as anti-tumour agents.
  • the present invention also provides a process for the preparation of new pyrrolo[2,l-c][l,4]benzodiazepine hybrids as antitumour agents.
  • the present invention provides a process for the preparation of 7-methoxy-8-[n'- (4"-acridonylcarboxamido)alkyl]-oxy-( 11 aS) ⁇ 1,2,3,11 a-tetraydro-5H- ⁇ yrrolo [2, 1 -c] [l,4]benzodiazepin-5-one and 7-methoxy-8-[n'-(4"-acridinylcarboxamido)-alkyl]-oxy- (llaS)-l,2,3,lla-tetraydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one with aliphatic chain length variation of these compounds and it also describes the DNA binding, anticancer (antitumour) activity.
  • the structural formula of the novel pyrrolo[2,l-c]-[l,4]benzodiazepines of the invention is given below:
  • PBD dimers have been developed that comprises two C2-exo-methylene substituted DC-81 subunits tethered through their C ⁇ 8 position via an inert propanedioxy linker (Gregson, S. I; Howard, P. W.; Hartely, J. A.; Brooks, N. A.; Adams, L. I; Jenkins, T. C; Kelland, L. R. and Thurston, D. E. J. Med. Chem. 2001, 44, 737). Recently, a noncross- linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent antitumour activitiy.
  • Naturally occurring pyrrolo[2,l-c][l,4]benzodiazepines belong to a group of antitumour antibiotics derived from Streptomyces species. Recently, there is much impetus for the PBD systems as they can recognize and bind to specific sequence of DNA.
  • the main object of the present invention is to provide new pyrrolo[2,l-c][l,4]- benzodiazepine hybrids useful as antitumour agents.
  • the compound of the invention is selected from the group consisting .of 7-Methoxy-8-[2'-(4"-acridonylcarboxamido)ethyl]-oxy-
  • Formula VII the process comprising reacting an acridone or an acridine acid with (2S)-N-[4-(n'- aminoalkyloxy)-5-methoxy-2-nitrobenzoyl]-pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I
  • Formula V isolating the compound of formula Il/formula V and then reducing the compounds of formula Il/formula V with SnCl 2 .2H 2 O in presence of an organic solvent up to a reflux temperature, isolating the (2S)-N- ⁇ 4-[n'-(4"-acridonylcarboxamido)-alkyl]-oxy-5-methoxy-2- aminobenzoyl ⁇ pyrroU-dine-2-carboxaldehydediethylthioacetal of formula III/(2S)-N- ⁇ 4-[n'- (4"-acridinylcarbox-arm ⁇ o)-alkyl]-oxy-5-methoxy-2-aminobenzoyl ⁇ pyrroUdine-2- carboxaldehyde diethyl thioacetal of formula VI where n is 2-3 by known methods,
  • Formula HI Formula VI reacting compound of formula Ill/formula VI with a known deprotecting agents in a conventional manner to give novel pyrrolo[2,l-c][l,4]benzodiazepine hybrids of formula IV/formula VII wherein n and R are as stated above.
  • the organic solvent used for the reaction of the acridone/acridine acid with compound of formula I comprises dimethyl furan.
  • the compound of formula Il/formula V is isolated by washing with saturated NaHCO 3 , brine, drying and evaporation of the solvent.
  • the organic solvent used during the reduction of compound of formula Il/formula V comprises methanol.
  • the compound of formula Ill/formula V is isolated by adjusting the pH of the reaction mixture to about pH 8 with a saturated NaHCO 3 solution, diluting with ethyl acetate, filtering through ceUte and extracted an organic phase and drying the organic phase over Na 2 SO 4 .
  • the deprotecting agent used for obtaining the compound of formula IV/formula Nil comprises HgCl 2 and CaCO 3 in MeC ⁇ -water (4:1).
  • the process of the invention comprises reacting, an acridone or an acridine acid with (2S)- ⁇ -[4-(n'-ammoalkyloxy)-5-methoxy-2-nitrobenzoyl]-pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I
  • the organic solvent used for the reaction of the acridone/acridine acid with compound of formula I comprises dimethyl furan and the compound of formula Il/formula V is isolated by washing with saturated NaHCO 3 , brine, drying and evaporation of the solvent.
  • the organic solvent used during the reduction of compound of formula Il/formula V comprises methanol and the compound of formula Ill/formula V is isolated by adjusting the pH of the reaction mixture to about pH 8 with a saturated NaHCO 3 solution, diluting with ethyl acetate, filtering through celite and extracted an organic phase and drying the organic phase over Na 2 SO 4 .
  • the deprotecting agent used for obtaining the compound of formula IV/formula VII comprises HgCl 2 and CaCO 3 in MeCN-water (4: 1).
  • the precursors acridone acid (AtweU, G. J.; Cain, B. F.; Baguley, B. C; Finlay, G. J.; Denny, W. A. J. Med. Chem. 1984, 27, 1481), acridine acid (AtweU, G. J.; Rewcastle, G. W.; Baguley, B. C; Denny, W. A. J. Med Chem.
  • Example 2 Compound acridone acid (0.239 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203g, 1.5 mmol) and HOBt(0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(2'- aminoethyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethylthioacetal of formula I (0.459 g, 1 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight.
  • Example 4 Compound acridone acid (0.239 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203 g, 1.5 mmol)and HOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(3'- aminopropyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I (0.473 g, 5 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight.
  • Example 6 Compound acridine acid (0.223 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203- g, 1.5 mmol)and HOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(2'- aminoethyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I (0.459 g, 1 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight.
  • Example 7 Compound acridine acid (0.223 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203 g, 1.5 mmol)and ⁇ OBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (2S)-N-[4-(3'-amino-propyl)oxy- 5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I (0.457 g, 1 mmol) in DMF was added to it at same temperature and the solution was stirred at room-temperature for overnight.
  • IV 0 0 10 a One dose of IV at 10 molar concentration
  • formula IV has shown to possess ⁇ 10 nano molar potency (at the LC 50 level) against one melanoma cancer (UACC-62) and 0.1 micro molar potency against colon cancer (HCC- 2998), CNS cancer (SNB-75), breast cancer (MDA-MB-435) and also have ⁇ 10 micro molar potency against two melanoma cancer cell lines (LOXIMVI, M14) and one renal cancer (SN12C).
  • Table 2. logio GI50 logio TGI and logio LC50 mean graphs midpoints(MGJV ⁇ D) of in vitro cytotoxicity data for the compound IV against human tumour cell lines.
  • Each cancer type represents the average of six to nine different cancer ceU lines. 333NF/03 MEAN GRAPH

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  • 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)
  • Hematology (AREA)
  • Oncology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux hybrides de pyrrolo-[2,1-c][1,4]benzodiazépine représentés par la formule ci-dessous dans laquelle R est H ou OH et n est 2-3, et utilisés comme agents anti-tumoraux, ainsi qu'un procédé de préparation de ceux-ci.
PCT/IN2003/000464 2003-12-31 2003-12-31 Hybrides acridone/acridine de pyrrolo[2,1-c][1,4]benzodiazepine a liaison c-8 Ceased WO2005063760A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/IN2003/000464 WO2005063760A1 (fr) 2003-12-31 2003-12-31 Hybrides acridone/acridine de pyrrolo[2,1-c][1,4]benzodiazepine a liaison c-8
AU2003300720A AU2003300720A1 (en) 2003-12-31 2003-12-31 C-8 linked pyrrolo(2,1-c)(1,4)benzodiazepine-acridone/acridine hybrids
GB0614754A GB2424884B (en) 2003-12-31 2003-12-31 C-8 linked pyrrolo[2,1-c][1,4]benzodiazepine-acridone/acridine hybrids
JP2005512763A JP4718328B2 (ja) 2003-12-31 2003-12-31 Ｃ８連結したピロロ［２，１−ｃ］［１，４］ベンゾジアゼピン−アクリドン／アクリジン・ハイブリッド

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PCT/IN2003/000464 WO2005063760A1 (fr) 2003-12-31 2003-12-31 Hybrides acridone/acridine de pyrrolo[2,1-c][1,4]benzodiazepine a liaison c-8

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009016647A1 (fr) * 2007-08-01 2009-02-05 Council Of Scientific & Industrial Research Promédicaments pyrrolo [2,1-c][1,4] benzodiazépine-glycosides utiles comme agent anti-tumoral sélectif
JP2009515870A (ja) * 2005-11-10 2009-04-16 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ 新規なピロロ［２，１−ｃ］［１，４］ベンゾジアゼピンハイブリッドおよびその調製のための方法
US11583590B2 (en) 2017-09-29 2023-02-21 Daiichi Sankyo Company, Limited Antibody-pyrrolobenzodiazepine derivative conjugate and method of use thereof for treating a tumor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0098098A2 (fr) * 1982-06-25 1984-01-11 Development Finance Corporation Of New Zealand Composés acridinecarboxamidiques
WO2000012508A2 (fr) * 1998-08-27 2000-03-09 Spirogen Limited Composes

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Publication number Priority date Publication date Assignee Title
GB9621795D0 (en) * 1996-10-18 1996-12-11 Xenova Ltd Pharmaceutical compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0098098A2 (fr) * 1982-06-25 1984-01-11 Development Finance Corporation Of New Zealand Composés acridinecarboxamidiques
WO2000012508A2 (fr) * 1998-08-27 2000-03-09 Spirogen Limited Composes

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
GAMAGE S W ET AL: "A NEW SYNTHESIS OF SUBSTITUTED ACRIDINE-4CARBOXYLIC ACIDS AND THE ANTICANCER DRUG N-U2-(DIMETHYLAMINO)ETHYLACRIDINE-4-CARBOXAMIDE", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 38, no. 4, 27 January 1997 (1997-01-27), pages 699 - 702, XP002051605, ISSN: 0040-4039 *
KAMAL A ET AL: "Design, Synthesis, and Evaluation of New Non-Crosslinking Pyrrolobenzodiazepine Dimers with Efficient DNA Binding Ability and Potent Antitumor Activity", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 45, 2002, pages 4679 - 4688, XP002249808, ISSN: 0022-2623 *
SCHOFIELD P C ET AL: "Metabolism of N-(2-(dimethylamino)ethyl)acridine-4-carboxamide in cancer patients undergoing a phase I clinical trial", CANCER CHEMOTHERAPY AND PHARMACOLOGY, SPRINGER VERLAG, BERLIN, DE, vol. 44, no. 1, July 1999 (1999-07-01), pages 51 - 58, XP002238691, ISSN: 0344-5704 *
THURSTON D E ET AL: "SYNTHESIS OF DNA-INTERACTIVE PYRROLO2,1-C1,4BENZODIAZEPINES", CHEMICAL REVIEWS, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 94, 1994, pages 433 - 465, XP001026336, ISSN: 0009-2665 *
THURSTON D E ET AL: "Synthesis of Sequence-Selective C8-Linked Pyrrolo(2,1-c)(1,4)benzodia zepine DNA Interstrand Cross-Linking Agents", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 61, no. 23, 1996, pages 8141 - 8147, XP002272010, ISSN: 0022-3263 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009515870A (ja) * 2005-11-10 2009-04-16 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ 新規なピロロ［２，１−ｃ］［１，４］ベンゾジアゼピンハイブリッドおよびその調製のための方法
WO2009016647A1 (fr) * 2007-08-01 2009-02-05 Council Of Scientific & Industrial Research Promédicaments pyrrolo [2,1-c][1,4] benzodiazépine-glycosides utiles comme agent anti-tumoral sélectif
US11583590B2 (en) 2017-09-29 2023-02-21 Daiichi Sankyo Company, Limited Antibody-pyrrolobenzodiazepine derivative conjugate and method of use thereof for treating a tumor
US11628223B2 (en) 2017-09-29 2023-04-18 Daiichi Sankyo Company, Limited Antibody-drug conjugates comprising substituted benzo[e]pyrrolo[1,2-α][1,4]diazepines
US12246196B2 (en) 2017-09-29 2025-03-11 Daiichi Sankyo Company, Limited Antibody-drug conjugates comprising substituted benzo[e]pyrrolo[1,2-a][1,4]diazepines
US12350344B2 (en) 2017-09-29 2025-07-08 Daiichi Sankyo Company, Limited Methods of treating a tumor by administering a claudin-6 (CLDN6) or CLDN9 antibody-pyrrolobenzodiazepine derivative conjugate

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Publication number Publication date
JP2007528344A (ja) 2007-10-11
GB2424884B (en) 2008-06-11
JP4718328B2 (ja) 2011-07-06
AU2003300720A1 (en) 2005-07-21
GB2424884A (en) 2006-10-11
GB0614754D0 (en) 2006-09-06

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