WO2010058414A1 - Nouveaux dérivés de pyrrolo[2,1-c][1,4]benzodiazépine possédant des chaînes latérales dithiocarbamate et leur procédé de préparation - Google Patents

Nouveaux dérivés de pyrrolo[2,1-c][1,4]benzodiazépine possédant des chaînes latérales dithiocarbamate et leur procédé de préparation Download PDF

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Publication number
WO2010058414A1
WO2010058414A1 PCT/IN2009/000193 IN2009000193W WO2010058414A1 WO 2010058414 A1 WO2010058414 A1 WO 2010058414A1 IN 2009000193 W IN2009000193 W IN 2009000193W WO 2010058414 A1 WO2010058414 A1 WO 2010058414A1
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WO
WIPO (PCT)
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formula
tetrahydro
methyl
methyloxy
ethylsulfanyl
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PCT/IN2009/000193
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English (en)
Inventor
Kamal Ahmed
Sreekanth Kokkonda
Praveen Kumar Pogula
Balakishan Gorre
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Council Of Scientific & Industrial Research
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Application filed by Council Of Scientific & Industrial Research filed Critical Council Of Scientific & Industrial Research
Priority to US13/129,935 priority Critical patent/US8592407B2/en
Priority to EP09787581.9A priority patent/EP2358719B1/fr
Publication of WO2010058414A1 publication Critical patent/WO2010058414A1/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
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to synthesis and in vitro anticancer activity of new pyrrolo[2,l- c][l, ⁇ benzodiazepine derivatives with dithiocarbamate side chains.
  • the present invention also relates to a process for the preparation of new pyrrolo[2,l-c][l, ⁇ benzodiazepine derivatives with dithiocarbamate side chains of general formula A.
  • n 1 - ⁇
  • the present invention relates to new pyrrolo[2,l-c] [l,4]benzodiazepine derivatives with dithiocarbamate side chains of general formula A.
  • the structural formulae of these pyrrolo[2,l-c][l,4]benzodiazepine derivatives with dithiocarbamate side chains is given below and is represented by the compounds of formula 12 a-i, 13a-i and 14a-i.
  • the present invention also relates to a process for the preparation of 3-cyano-3,3- diphenylpropyl4-(n-[(l laS)-7-(methyloxy)-5-oxo-2,3,5,l la-tetrahydro-lH-benzo[e] pyrrolo[l,2- ⁇ ][l,4]diazepin-8-yl]oxyalkyl)hexahydro-l-pyrazine carbodithioate / n-[(l laS)- 7-(methyloxy)-5-oxo-2,3,5,l la-tetrahydro-lH-benzo[e]pyrrolo[l,2- ⁇ ][l,4] diazepin-8- yl]oxyalkyl4-[3-( 1 ,3-dioxo-2,3-dihydro- lH-benzo[i/e]isoquinolin-2-yl)propyl] hexahydro- 1 - pyra
  • Naturally occurring pyrrolo[2,l-c][l,4]benzodiazepuies 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.
  • Pyrrolo[2,l-c][l,4]benzodiazepine antitumour antibiotics are commonly known as anthramycin class of compounds.
  • PBDs pyrrolo[2,l-c][l,4]benzodiazepine
  • 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 NlO-CI l position
  • Dithiocarbamic acid esters are a common class of organic molecules. These simple molecules have shown remarkable antitumour properties, whose mode of action is thought to result from their derivatives in view of potent phase II enzyme inducers which could be used as cancer chemo preventive agents (Gerhauser, C; You, M.; Pezzuto, J. M. Cancer Res. 1997, 57, 272; Li, R. T.; Cheng, T. M.; Cui, J. R. C. N. Patent 01118399.3, 2004. X.; Wang, R. Q.; Cui, J.R.; Li, R. T.; Cheng, T. M.; Ge, Z. M. Chin. J. Clin. Pharmacol. Ther. 2004, 9, 59).
  • the new PBD hybrids have been designed and synthesized by linking 3-cyano-3,3-diphenylpropyl hexahydro-1- pyrazinecarbodithioate at C8-position of pyrrolo[2,l-c] [l,4]benzodiazepine with varying alkane spacers, similarly 2-(3-hexahydro-l-pyrazinylpropyl)-2,3-dihydro-lH-benzo[-/e] isoquinoline-l,3-dione and 1-methylhexahydropyrazine moieties linked at C8-position of pyrrolo[2,l-c][l,4]benzodiazepine with varying dithiocarbamate side chains.
  • the main objective of the present invention is to provide synthesis and in vitro anticancer activity of new pyrrolo[2,l-c][l,4]benzodiazepine derivatives with dithiocarbamate side chains.
  • Yet another object of the present invention is to provide a process for the preparation of new pyrrolo[2,l-c][l, ⁇ benzodiazepine derivatives with dithiocarbamate side chains.
  • the present invention provides a process for the preparation of a new pyrrolo[2,l-c][l,4]benzodiazepine derivatives with dithiocarbamate side chains of general formula A.
  • the new pyrrolo[2,l-c][l,4]benzodiazepine derivatives with dithiocarbamate side chains of general formula A is represented by the formulae 12a-i, 13a-i and 14a-i.
  • the present invention provides a process for preparation of a new pyrrolo[2,l- c ][l ⁇ benzodiazepine derivatives with dithiocarbamate side chains of formula 12a-i, 13a-i and 14a-i which comprises of a) Reacting (25)-2-[di(ethylsulfanyl)methyl]tetrahydro-lH-l-pyrrolyl[4-hydroxy -5- (methyloxy)-2-nitrophenyl]methanone of formula 1
  • Me-N NH S isolating 3 -cyano-3 ,3 -diphenylpropyl4-(n-[4-((25)-2-[di(ethylsulfanyl)methyl] tetrahydro- IH-I -pyrrolylcarbon-yl)-2-(methyloxy)-5-nitrophenyl]oxyalkyl)hexa hydro- 1 - pyrazinecarbodithioate of formula 6a-i,
  • step (b) Reacting the above said amino compounds of formula 9a-i, 10a-i and lla-i obtained in step (b) with known deprotecting agents in a conventional manner to give novel pyrrolo[2,l- c][l, ⁇ benzodiazepine hybrids of formula 12a-i, 13a-i and 14a-i.
  • 1,3-dione 4 (323 mg, 1 mmol) in dry acetone (10 mL) was added carbon disulfide 10 drops (-2.5 mmol) and anhydrous K 3 PO 4 (425 mg, 2 mmol). The mixture was stirred ⁇ 10°C for 1 h. Than the [4-[(4-bromobutyl)oxy]-5-(methyloxy)-2-nitrophenyl](25)-2- [di(ethylsulfanyl)methyl]- tetrahydro-lH-1-pyrrolylmethanone 2b (535 mg, 1 mmol). The reaction mixture was stirred at room temperature for 12 h. TLC using ethylacetate as a solvent system monitored the reaction.
  • CT-DNA duplex-form calf thymus DNA
  • DNA helixDcoil transition temperatures (r m ) have been obtained from the maxima in the d(A ⁇ o)ldT derivative plots.
  • the fixed [PBD]/[DNA] ratio used has not resulted in binding saturation of the host DNA duplex for any compound examined.
  • Anticancer activity In vitro anticancer activity studies for the compounds 12b-c were carried out at the National Cancer Institute (USA). The compounds 12b-c were evaluated for in vitro anticancer activity against sixty human tumour cells derived from nine cancer types (leukemia, non- small-cell lung, colon, CNS, melanoma, ovarian, prostate, and breast cancer) as per NCI protocol. For each compound, dose response curves for each cell line were measured at a minimum of five concentrations at 10 fold dilutions. A protocol of 48 h continuous drug exposure was used and a sulforhodamine B (SRB) protein assay was used to estimate cell viability or growth. The concentration causing 50% cell growth inhibition (GI50), total cell growth inhibition (TGI 0%growth) and 50% cell death (LC50, -50% growth) compared with the control was calculated.
  • GI50 50% cell growth inhibition
  • TGI 0%growth total cell growth inhibition
  • LC50 50% cell death
  • Compound 12b has been evaluated for in vitro cytotoxicity in sixty cell lines from nine human cancer types of leukemia (MOLT-4, SR), lung (Hop-62, NCI-H522), colon (HCT- 116, SW-620), CNS (SF268), melanoma (LOX IMVI, MALME-3M), ovarian (IGROVl, OVCAR-3, OVCAR-8), renal (CAKI-I, RXF 393), prostate (DU-145), breast (MCF-7, MD A-MB-468) origin.
  • MOLT-4 leukemia
  • SR lung
  • Hop-62, NCI-H522 lung
  • HCT- 116 colon
  • CNS CNS
  • SF268 melanoma
  • LOX IMVI, MALME-3M melanoma
  • ovarian IGROVl, OVCAR-3, OVCAR-8
  • renal CAKI-I, RXF 393
  • prostate DU-145
  • breast M
  • Compound 12c has been evaluated for in vitro cytotoxicity in sixty cell lines from nine human cancer types of leukemia (HL-60 (TB), SR), lung (Hop-62, HOP-92, NCI-H522), colon (HCT-116, HT-29, SW-620), CNS (U251), melanoma (LOX IMVI, SK-MEL-2), ovarian (IGROVl), renal (RXF 393, UO-31), prostate (PC3), breast (MCF-7, MDA-MB- 468) origin.
  • the results are expressed as percent of cell growth determined relative to that of untreated control cells (Table 3).
  • the representative compound 12b has shown significant cytotoxicity against some cancer cell lines.
  • each cancer type represents the average of six to eight different cancer cell lines.
  • the compound 12b exhibits a wide spectrum of activity against sixty cell lines in nine cell panels, with GI 50 value of ⁇ 2.69 ⁇ m.
  • GI 50 value 0.21 and 0.17 ⁇ m respectively.
  • the GI 50 values of compound 12b against colon cancer HCT-116 and SW-620 cell lines are 0.38 and 0.51 ⁇ m respectively.
  • the GI 50 values for compound 12b against leukemia MOLT-4 and SR cell lines are 0.22, 0.18 ⁇ m respectively.
  • the GI 50 values for compound 12b against CNS SF268 cell line is 0.28 ⁇ m
  • the GI50 values for compound 12b against melanoma LOX IMVI and MALME-3M cell lines are 0.60, and 0.93 ⁇ m respectively.
  • the GI 50 values for compound 12b against ovarian IGROVl, OVCAR-3 and OVCAR-8 cell lines are 0.30, 0.28 and 0.99 ⁇ m
  • the GI 50 values for compound 12b against renal CAKI-I and RXF 393 cell lines are 0.30 and 0.19 ⁇ M.
  • the GI 50 value for compound 12b against prostate DU- 145 cell line is 0.26 ⁇ m
  • the GI50 values for compound 12b against breast MCF-7 and MDA-MB-468 cell lines are 0.33 and 0.28 ⁇ m respectively.
  • Compounds 12b and 12c exhibit activity against sixty cell lines in nine cancer cell panels with GI 50 values of ⁇ 2.69 and ⁇ 3.29 DM respectively. Compare 12b and 12c, the compound 12b showing higher activity than 12c, In vitro cytotoxicity of compounds 12b and 12c in selected cancer cell lines have been illustrated in Table 3. The average GI50 values for each cancer panel of compounds 12b and 12c have been illustrated in Table 2 Table 3. In vitro cytotoxicity of compounds 12b and 12c in selected cancer cell lines
  • the mean graph mid point values of logio TGI and logio LC 50 as well as logio GI 50 for 12b and 12c are listed in Table-5. As demonstrated by mean graph pattern, compounds 12b and 12c exhibit an interesting profile of activity and selectivity for various cell lines.
  • the mean graph mid points of logio TGI and logto LC 5 0 have shown similar pattern to the logio GI50 mean graph mid points.
  • LogioGI5Q logioTGI and log ⁇ oLC50 mean graphs midpoints (MG_MID) of in vitro cytotoxicity data for the representative compounds against human tumour cell lines
  • Table 5 Preliminary in vitro cytotoxicity data for the compounds 12c and 14c-d at concentration (mg/ml) lxl0 "5 M, Adriamycin at concentration (mg/ml) 1x10 "6 M
  • the new pyrrolo[2,l-c][l,4]benzodiazepine derivatives with dithiocarbamate side chains that have been synthesized exhibited significant DNA-binding ability and showed cytotoxic activity against sixty human tumour cell lines.
  • the present invention provides a new pyr ⁇ olo[2,l-c][l,4]benzodiazepine derivatives with dithiocarbamate side chains useful as antitumour agents. It also provides a process for the preparation of novel pyrrolo[2,l-c] [1, ⁇ benzodiazepine hybrids.

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  • Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention porte sur la synthèse et l'activité anticancéreuse in vitro de nouveaux dérivés de pyrrolo[2,1-c][1,4]benzodiazépine possédant des chaînes latérales dithiocarbamate. La présente invention porte également sur un procédé pour la préparation de nouveaux dérivés de pyrrolo[2,1-c][1,4]benzodiazépine possédant des chaînes latérales dithiocarbamate représentés par la formule générale (A) et sur un procédé pour leur préparation.
PCT/IN2009/000193 2008-11-19 2009-03-24 Nouveaux dérivés de pyrrolo[2,1-c][1,4]benzodiazépine possédant des chaînes latérales dithiocarbamate et leur procédé de préparation WO2010058414A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US13/129,935 US8592407B2 (en) 2008-11-19 2009-03-24 Pyrrolo[2,1-c][1,4] benzodiazepine derivatives with dithiocarbamate side chains and process for the preparation thereof
EP09787581.9A EP2358719B1 (fr) 2008-11-19 2009-03-24 Nouveaux dérivés de pyrrolo[2,1-c][1,4]benzodiazépine possédant des chaînes latérales dithiocarbamate et leur procédé de préparation

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IN2600/DEL/2008 2008-11-19
IN2600DE2008 2008-11-19

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063759A1 (fr) * 2003-12-31 2005-07-14 Council Of Scientific And Industrial Research Procede servant a preparer des hybrides de pyrrolo[2, 1-c] [1, 4] benzodiazepine
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063759A1 (fr) * 2003-12-31 2005-07-14 Council Of Scientific And Industrial Research Procede servant a preparer des hybrides de pyrrolo[2, 1-c] [1, 4] benzodiazepine
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

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US8592407B2 (en) 2013-11-26
US20120101270A1 (en) 2012-04-26
EP2358719A1 (fr) 2011-08-24
EP2358719B1 (fr) 2014-10-01

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