WO2009118749A1 - Hybrides de pyrrolo[2,1-c][1,4]benzodiazépine liés à la benzophénone-pipérazine en tant qu'agents anti-cancéreux potentiels et procédé d'obtention des ces hybrides - Google Patents

Hybrides de pyrrolo[2,1-c][1,4]benzodiazépine liés à la benzophénone-pipérazine en tant qu'agents anti-cancéreux potentiels et procédé d'obtention des ces hybrides Download PDF

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WO2009118749A1
WO2009118749A1 PCT/IN2008/000714 IN2008000714W WO2009118749A1 WO 2009118749 A1 WO2009118749 A1 WO 2009118749A1 IN 2008000714 W IN2008000714 W IN 2008000714W WO 2009118749 A1 WO2009118749 A1 WO 2009118749A1
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benzodiazepine
pyrrolo
benzophenone
methoxy
chloro
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PCT/IN2008/000714
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English (en)
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Ahmed Kamal
Bandari Rajendra Prasad
Adla Malla Reddy
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Council Of Scientific & Industrial Research
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Priority to EP08873530A priority Critical patent/EP2262809A1/fr
Priority to JP2011501342A priority patent/JP2011515459A/ja
Publication of WO2009118749A1 publication Critical patent/WO2009118749A1/fr

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    • 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

Definitions

  • the present invention relates to benzophenone-piperazine linked pyrrolo[2,1- c][1 , ⁇ benzodiazepine hybrids and a process for the preparation there of. More particularly It relates to 7-Methoxy-8-[n- ⁇ /1 -[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-piperazino-acetamide] alkyloxy ⁇ -(11 aS)-1 ,2,3, 11 a-tetrahydro-5H-pyrrolo[2, 1 -c][1 ,4] benzodiazepine-5-one with aliphatic chain length variations useful as anticancer (antitumour) agent.
  • the structural formula of these benzophenone-piperazine linked pyrrolo[2,1-c][1,4]benzodiazepines hybrids is given below.
  • Pyrrolo[2,1-c][1 ,4]benzodiazepine antitumour antibiotics are commonly known as anthramycin class of compounds.
  • PBDs pyrrolo [2, 1-c][1 ⁇ benzodiazepines
  • antibiotics react covalently with DNA to form an N2-guanine adduct that lies within the minor groove of duplex DNA via an acid-labile aminal bond to the electrophilic imine at the N10-C11 position
  • PBD dimers have been developed that comprise of two C2-exo-methylene substituted DC-81 subunits tethered through their C-8 position via an inert propanedioxy linker (Gregson, S. J.; Howard, P. W.; Hartely, J. A.; Brooks, N. A.; Adams, L. J.; Jenkins, T. C; Kelland, L R. and Thurston, D. E. J. Med. Chem. 2001, 44, 737).
  • a non-cross-linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent antitumour activity (Kamal, A.; Ramesh, G.
  • Naturally occurring pyrrolo[2,1-c][1 , ⁇ 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. Examples of naturally occurring PBDs include anthramycin, DC-81 , tomaymycin, sibiromycin and neothramycin.
  • the main objective of the present invention is to provide novel benzophenone - piperazine linked pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrids, useful as antitumour agents.
  • Yet another object of this invention is to provide a process for the preparation of novel benzophenone-piperazine linked pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrids.
  • the present invention provides a novel benzophenone-piperazine linked pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrid of general formula 5
  • n 3, 4, 5, 6, 8
  • novel benzophenone-piperazine linked pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrid according to claim 1 is represented by the group of the following compounds:
  • novel benzophenone-piperazine linked pyrrolo [2,1- c][1 ,4]benzodiazepine hybrid exhibits an in vitro anticancer/antitumour activity against human cancer cell lines selected from the group consisting of lung (Hop-62), cervix (SiHa), breast (MCF7, Zr-75-1), colon (Colo205), prostate (DU 145, PC3) and oral (DWD, HT1080) cell lines.
  • the concentration of benzophenone linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrid used for in vitro activity against Colo205 for IC50 is in the range of 13 to 80 ⁇ m, at an exposure period of at least 48 hrs.
  • the concentration of benzophenone linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrids used for in vitro activity against DU145 for IC50 is in the range of 12 to 80 ⁇ m, at an exposure period of at least 48 hrs.
  • the concentration of benzophenone linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrids used for in vitro activity against DWD for IC50 is in the range of 8 to 80 ⁇ m, at an exposure period of at least 48 hrs. In yet another embodiment the concentration of benzophenone linked pyrrolo[2,1- c][1 , ⁇ benzodiazepine hybrids used for in vitro activity against HoP62 for IC50 is in the range of 11 to 48 ⁇ m, at an exposure period of at least 48 hrs.
  • the concentration of benzophenone linked pyrrolo[2,1- c][1,4]benzodiazepine hybrids used for in vitro activity against HT1080 for IC50 is in the range of 14 to 36 ⁇ m, at an exposure period of at least 48 hrs.
  • the concentration of benzophenone linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrids used for in vitro activity against MCF7 for IC50 is in the range of 22 to about 80 ⁇ m, at an exposure period of at least 48 hrs.
  • the concentration of benzophenone linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrids used for in vitro activity against PC3 for IC50 is in the range of 28 to about 80 ⁇ m, at an exposure period of at least 48 hrs.
  • the concentration of benzophenone linked pyrrolo[2,1- c][1,4]benzodiazepine hybrids used for in vitro activity against SiHa for IC50 is in the range of 36 to about 80 ⁇ m, at an exposure period of at least 48 hrs.
  • the concentration of benzophenone linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrids used for in vitro activity against Zr-75-1 for IC50 is in the range of 29 to about 80 ⁇ m, at an exposure period of at least 48 hrs.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising benzophenone linked pyrrolo[2,1-c][1 ,4]benzodiazepine hybrid, its derivatives, analogues, salts or mixture thereof optionally with pharmaceutically acceptable carriers, adjuvants and additives.
  • benzophenone-piperazine linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrid used is represented by a general formula 5,
  • n 3, 4, 5, 6, 8 and the said process comprising the steps of: a) reacting (2S)-N-[(n-bromoalkyloxy)-3-methoxy-2-nitrobenzoyl)]pyrrolidine-2- carboxaldehyde diethylthioacetal of formula 1
  • n 3, 4, 5, 6, 8 4a-e c) reacting the above said amino compound of formula 4 obtained in step (b) with a deprotecting agent of the kind of mercuric chloride by known method to obtain the desired compound of formula 5
  • the mild inorganic base used in steps (a) is potassium carbonate.
  • aprotic organic solvent used in step (a) is acetone and acetonitrile
  • organic solvent used in step (c) is acetonitrile and acetone
  • the alcohol used in step (b) is selected from methanol and ethanol.
  • the compounds of formula 5a-e obtained are represented by a group of the following compounds:
  • the benzophenone-piperazine linked pyrrolo[2,1- c][1 ,4]benzodiazepine hybrid of formula 5a-e exhibits an in vitro anticancer/antitumour activity against human cancer cell lines selected from the group consisting of lung, cervix, breast, colon, prostate and oral cell lines.
  • Reagents and conditions (i) K 2 CO 3 , acetone,18 h, refllux, 90-92%; (ii) SnCI 2 .2H 2 O, MeOH, 2 h, reflux, 8! 87%; (iii) HgCI 2 -CaCO 3 , CH 3 CN-H 2 O (4:1), 12 h, rt, 68-71 %.
  • This compound was prepared according to the method described for the compound 3 a by employing 2S- ⁇ /-[4-(4-bromobutoxy)-5-methoxy-2-nitrobenzoyl] pyrrolidine-2- carboxaldehyde (1b) diethylthioacetal (535 mg, 1.0 mmol) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and ⁇ /1-4-chloro-2-(2-chlorobenzoyl)phenyl]-2- piperazinoacetamide 2 (392 mg, 1.0 mmol) to obtain the pure product 3b (710 mg, 84% yield).
  • This compound was prepared according to the method described for the compound 4a by reducing 2S- ⁇ /- ⁇ 4-[4- ⁇ /1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-piperazinoacetamide] butyl)oxy-5-methoxy-2-nitrobenzoyl ⁇ pyrrolidine-2-carboxaldehyde diethylthioacetal 3b (846 mg, 1.0 mmol) using SnCI 2 .2H 2 O (1.12 g, 5.0 mmol). The amino compound 4b obtained was (795 mg, 97% yield).
  • This compound was prepared according to the method described for the compound 5a employing 2S- ⁇ /-4- ⁇ /1 -[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-piperazinoacetamide]butyl) oxy-5-methoxy-2-aminobenzoyl ⁇ pyrrolidine-2-carboxaldehyde diethylthioacetal 4b (816 mg, 1.0 mmol) and HgCI 2 (582 mg, 2.26 mmol), CaCO 3 (230 mg, 2.46 mmol) in acetonitrile-water (4: 1) to obtain the pure product 5b (330 mg, 58% yield).).
  • This compound was prepared according to the method described for the compound 3a by employing 2S- ⁇ /-[4-(5-bromopenyloxy)-5-methoxy-2-nitrobenzoyl] pyrrolidine-2- carboxaldehyde diethylthioacetal (1c) (549 mg, 1.0 mmol) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and ⁇ /1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2- piperazinoacetamide 2 (392 mg, 1.0 mmol) to obtain the pure product 3c (740 mg, 87% yield).
  • This compound was prepared according to the method described for the compound 5a employing 2S- ⁇ /-[5- ⁇ /1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-piperazinoacetamide] pentyl)oxy-5-methoxy-2-aminobenzoyl ⁇ pyrrolidine-2-carboxaldehyde diethylthioacetal 4c (830 mg, 1.0 mmol) and HgCI 2 (590 mg, 2.26 mmol), CaCO 3 (244 mg, 2.46 mmol) in acetonitrile-water (4:1) to obtain the pure product 5c (330 mg, 58% yield).
  • This compound was prepared according to the method described for the compound 3a by employing 2S- ⁇ /-[4-(6-bromohexyloxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2- carboxaldehyde diethylthioacetal 1d (563 mg, 1.0 mmol) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and ⁇ /1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2- piperazinoacetamide 2 (392 mg,1.0 mmol) to obtain the pure product (3d) (775 mg, 88% yield).
  • This compound was prepared according to the method described for the compound 4a by reducing 2S- ⁇ // ' 4-/6- ⁇ /1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-piperazinoacetamide] hexyl)oxy-5-methoxy-2-nitrobenzoyl ⁇ pyrrolidine-2-carboxaldehyde diethyl thioacetal 3d (874 mg, 1.0 mmol) using SnCI 2 .2H 2 O (1.12 g, 5.0 mol). The amino compound 4d obtained was (842 mg, 97% yield).
  • the C8-linked benzophenone-piperazine-PBD hybrids have been tested against sixty human tumour cell lines derived from nine cancer types (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer) as per NCI protocol.
  • dose response curves for individual cell lines have been measured at a minimum of five concentrations at 10 fold dilutions.
  • a protocol of 48 h continuous drug exposure has been used, and a sulforhodamine B (SRB) protein assay was used to estimate cell viability or growth.
  • the concentration for 50% cell growth inhibition (Gl 50 ), total cell growth inhibition (TGI, 0% growth) and 50% cell death (LC 50 , 50% growth) compared with the control has been calculated (Figure-2).
  • Compounds 5b and 5d have been evaluated for their in vitro cytotoxicity in eleven cell lines from nine human cancer cell lines of colon (Colo205), lung (Hop-62), cervix (SiHa), prostate (DU145, PC3), oral (DWD, HT1080), and breast (MCF7, Zr-75-1) origin. The results are expressed as percent of cell growth determined relative to that of untreated control cells (Table 1). The representative compounds 5b and 5d have shown significant cytotoxicity against some cancer cell lines.
  • Each cancer type represents the average of six to eight different cancer cell lines.
  • 5b-d exhibits a wide spectrum of activity against fifty six cell lines in nine cell panels, with Gl 50 value of ⁇ 20 nM.
  • the growth of HOP-62, NCI-H23 cell lines were affected by compound 5b with Gl 50 values as 20.1 , 24.2 and 27.1 nM respectively.
  • the Gl 50 values of compound 5d against colon cancer HCC-2988, HCT-116 and KM12 cell lines are 21.3, 21.8 and 23.7 nM respectively.
  • the Gl 50 values for compound 5b against CNS SF-295, SF-539, SNB-19 and SNB-75 cell lines are in a range of 14.1-33.5 nM.
  • Compound 5b exhibits activity against fifty-six cell lines in nine cancer cell panels with Gl 50 values of ⁇ 10 ⁇ M.
  • Compound 5d exhibits activity against fifty-seven cell lines in nine cancer cell panels, Gl 50 values of ⁇ 10 ⁇ M.
  • In vitro cytotoxicity of compounds 5b and 5d in selected cancer cell lines has been illustrated in Table 2.
  • the average Gl 50 values for each cancer panel of compounds 5b and 5d have been illustrated in Table 3.
  • the mean graph mid point values of Iog 10 TGI and log 10 LC 50 as well as log 10 Gl 50 for 5b and 5d are listed in Table-1. As demonstrated by mean graph pattern, compounds 5b and 5d exhibit an interesting profile of activity and selectivity for various cell lines.
  • the mean graph mid points of log-io TGI and log 10 LCg 0 have shown similar pattern to the logTM Gl 50 mean graph mid points.
  • Table-3. log 10 Gl 50 , logioTGI and log 10 LC 50 mean graphs midpoints(MG_MID) of in vitro cytotoxicity data for the compounds 5b and 5d against human tumour cell lines.
  • Thermal denaturation studies Compounds have been subjected to thermal denaturation studies with duplex-form calf thymus DNA (CT-DNA) using a modification of a reported procedure.
  • Working solutions in aqueous buffer (10 mM NaH 2 PO 4 ZNa 2 HPO 4 , 1 mM Na 2 EDTA, pH 7.00 + 0.01) containing CT-DNA (100 nm in phosphate) and the PBD (20nm) have been prepared by addition of concentrated PBD solutions in DMSO to obtain a fixed [PBD]/[DNA] molar ratio of 1:5.
  • the DNA-PBD solutions have been incubated at 37 0 C for 0 and 18 h prior to analysis.
  • the present invention provides novel pyrrolo[2,1-c][1 , ⁇ benzodiazepine hybrids useful as antitumour agents. ;
  • novel C8-linked benzophenone-piperazine-PBD hybrids that have been synthesized exhibited significant DNA-binding ability and showed cytotoxic activity against sixty human tumour cell lines. Some of these hybrids exhibited promising DNA-binding among these hybrids the compound 5c show high DNA-binding ability (9.6 0 C).

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Abstract

Hybrides de pyrrolo[2,1-c][1,4]benzodiazépine liés à la benzophénone-pipérazine représentés par la formule générale 5a-e, convenant comme agents anti-tumeurs potentiels contre des lignées de cellules cancéreuses humaines. Est décrit un procédé de fabrication de d'hybrides de pyrrolo[2,1-c][1, 4]benzodiazépine représentés par les formules (5a-e).
PCT/IN2008/000714 2008-03-26 2008-10-31 Hybrides de pyrrolo[2,1-c][1,4]benzodiazépine liés à la benzophénone-pipérazine en tant qu'agents anti-cancéreux potentiels et procédé d'obtention des ces hybrides WO2009118749A1 (fr)

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EP08873530A EP2262809A1 (fr) 2008-03-26 2008-10-31 Hybrides de pyrrolo[2,1-c][1,4]benzodiazépine liés à la benzophénone-pipérazine en tant qu'agents anti-cancéreux potentiels et procédé d'obtention des ces hybrides
JP2011501342A JP2011515459A (ja) 2008-03-26 2008-10-31 抗癌剤候補としてのベンゾフェノンピペラジン結合ピロロ［２，１−ｃ］［１，４］ベンゾジアゼピンハイブリッド及びその調製方法

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087716A1 (fr) * 2003-03-31 2004-10-14 Council Of Scientific And Industrial Research Dimeres de pyrrolo(2,1-c) (1,4) benzodiazepine en tant qu'agents antitumoraux et procede correspondant
WO2006003670A1 (fr) * 2004-06-30 2006-01-12 Council Of Scientific And Industrial Research Conjugues de pyrrolo[2,1-c][1,4]benzodiazepine-napthalimide lies par une fraction piperazine et leurs procedes de preparation
WO2007054954A1 (fr) * 2005-11-10 2007-05-18 Council Of Scientific & Industrial Research NOUVEL HYBRIDE DE PYRROLO[2,1-c][1,4]BENZODIAZÉPINE ET PROCÉDÉ POUR LA PRÉPARATION DE CELUI-CI
WO2008020455A2 (fr) * 2006-08-14 2008-02-21 Council Of Scientific & Industrial Research Hybrides pyrrolo[2,1-c][1,4]benzodiazépine et leur procédé de préparation
WO2008120235A1 (fr) * 2007-03-30 2008-10-09 Council Of Scientific & Industrial Research Nouveaux hybrides de benzophénone utilisés comme agents anticancéreux potentiels et procédé de préparation de ceux-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087716A1 (fr) * 2003-03-31 2004-10-14 Council Of Scientific And Industrial Research Dimeres de pyrrolo(2,1-c) (1,4) benzodiazepine en tant qu'agents antitumoraux et procede correspondant
WO2006003670A1 (fr) * 2004-06-30 2006-01-12 Council Of Scientific And Industrial Research Conjugues de pyrrolo[2,1-c][1,4]benzodiazepine-napthalimide lies par une fraction piperazine et leurs procedes de preparation
WO2007054954A1 (fr) * 2005-11-10 2007-05-18 Council Of Scientific & Industrial Research NOUVEL HYBRIDE DE PYRROLO[2,1-c][1,4]BENZODIAZÉPINE ET PROCÉDÉ POUR LA PRÉPARATION DE CELUI-CI
WO2008020455A2 (fr) * 2006-08-14 2008-02-21 Council Of Scientific & Industrial Research Hybrides pyrrolo[2,1-c][1,4]benzodiazépine et leur procédé de préparation
WO2008120235A1 (fr) * 2007-03-30 2008-10-09 Council Of Scientific & Industrial Research Nouveaux hybrides de benzophénone utilisés comme agents anticancéreux potentiels et procédé de préparation de ceux-ci

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JP2011515459A (ja) 2011-05-19

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