WO2004087711A1 - Pyrene-linked pyrrolo (2,1-c) (1,4) benzodiazepine derivatives useful as anticancer agents - Google Patents
Pyrene-linked pyrrolo (2,1-c) (1,4) benzodiazepine derivatives useful as anticancer agents Download PDFInfo
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- the present invention relates to a process for the preparation of novel pyrrolo [2,1- c][l,4]benzodiazepine hybrids useful as potential antitumour agents.
- This invention also relates to a process for the preparation of new pyrrolo[2,l-c][l,4]benzodiazepine hybrids as potential antitumour agents.
- 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 comprises two C2-exo-methylene substituted DC-81 subunits tethered through their C-8 position via an inert propanedioxy linker (Gregson, S. L; Howard, P. W.; Hartely, 1 A.; Brooks, N. A; Adams, L. L; Jenkins, T. C; Kelland, L. R. and Thurston, D. E. J. Med.
- the main object of the present invention is to provide new pyrrolo[2,l-c][l,4]- benzodiazepine hybrids useful as antitumour agents.
- Another objective of the present invention is to provide a process for the preparation of novel ⁇ yrrolo[2,l-c][l,4]-benzodiaze ⁇ ine hybrids useful as antitumour agents. Summary of the invention
- the present process provides a process for preparation of pyrrolo[2,l- c][l,4]benzodiazepine hybrids of formula V
- Example 2 Compound (4R)-hydroxy-(2S)-N-[4-[(l '-carboxy methyl)oxy]-5-methoxy-2-nitro- benzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula II (2.37 g, 5 mmol) was taken in dry CH2CI 2 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2CI 2 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 min.
- Example 8 Compound (4R)-hydroxy-(2o>N- ⁇ 4-[(3'-carboxy butyl)oxy]-5-methoxy-2- nitrobenzoyl ⁇ pyrrolidine-2-car-boxaldehyde diethyl thioacetal of formula II (2.58 g, 5 mmol) was taken in. dry CH 2 C1 2 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2CI2 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 rnin.
- Compounds Ve and Vg were evaluated the primary anti-cancer activity (Table 1) and further Ve have been evaluated in vitro against sixty human tumour cells derived from nine cancer types (leukemia, non-small-cell lung, colon, CNS, melanoma, ovarian, prostate, and breast cancer). 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.
- SRB sulforhodamine B
- the novel pyrrolobenzodiazepine hybrid formula Vila has shown to possess 10 nano molar potency (at the LC 5 Q level) against one non-small cell lung cancer (NCI-H226) and one colon cancer (HCC-2998). and 0.1 micro molar potency against leukemia cancer (SR), melanoma cancer (M14), renal cancer (A498) and CNS cancer (SF-539) and also have 10 micro molar potency against two CNS cancer cell lines (SF539, SNB75) and one prostate cancer (DU-145).
- log 10 GI50 logio TGI and log 10 LC50 mean graphs midpoints(MGjV__D) of in vitro cytotoxicity data for the compound Ve against human tumour cell lines.
- Each cancer type represents the average of six to nine different cancer cell lines.
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Abstract
The present invention relates to pyrrolo [2,1-c][1,4]benzodiazepine hybrids useful as potential antitumour agents. This invention also relates to a process for the preparation of new pyrrolo[2,1-c][1,4]benzodiazepine hybrids as potential antitumour agents. More particularly, it provides 7-methoxy-8-[N-(1″-pyrenyl)-alkane-3′-carboxamide]-oxy-(11aS)-1,2,3,11a-tetraydro 5H-pyrrolo[2,1-c][1,4]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 this novel pyrrolo[2,1-c][1,4]benzodiazepine is given below, formula (I):
Description
PYRENE-LINKED PYRROLO (2 , 1-C) ( 1 , 4 ) BENZODIAZEPINE DERIVATIVES USEFUL AS
ANTICANCER AGENTS
Field of the invention The present invention relates to a process for the preparation of novel pyrrolo [2,1- c][l,4]benzodiazepine hybrids useful as potential antitumour agents. This invention also relates to a process for the preparation of new pyrrolo[2,l-c][l,4]benzodiazepine hybrids as potential antitumour agents. More particularly, it provides a process for the preparation of 7- methoxy-8-[N-(l"-pyrenyl)-alkane-3'-carboxamide]-oxy-(l laiS)-l,2,3,l la-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 this novel pyrrolo [2, 1-c] [l,4]benzodiazepine is given below:
Background of the invention Pyrrolo[2,l-c][l,4]benzodiazepine antitumour antibiotics are commonly known as anthramycin class of compounds. In the last few years, a growing interest has been shown in the development of new pyrrolo[2,l-c][l,4]benzodiazepines (PBDs). These 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 (Kunimoto, S.; Masuda, T.; Kanbayashi, N.; Hamada, M.; Naganawa, H.; Miyamoto, M.; Takeuchi, T.; and Unezawa, H. J. Antibiot., 1980, 33, 665.; Kohn, K. W. and Speous, C. L. J. Mol Biol, 1970, 51, 551.; Hurley, L. H.; Gairpla, C. and Zmijewski, M. Biochem. Biophys. Ada., 1977, 475, 521.; Kaplan, D. J. and Hurley, L. H. Biochmesiry, 1981, 20, 7572). The molecules have a right-handed twist, which allows them to follow the curvature of the minor groove of B-form double-stranded DNA spanning three base pairs. Recently, 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. L; Howard, P. W.; Hartely, 1 A.; Brooks, N. A; Adams, L. L; Jenkins, T. C; Kelland, L. R. and Thurston, D. E. J. Med. Chem. 2001, 44, 131). A recent development has been the linking of two PBD units through their C-8 positions to give bisfunctional
alkylating agents capable of cross-linking DNA (Thurston, D. E.; Bose, D. S.; Thomson, A. S.; Howard, P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C; Neidle, S. and Hurley, L. H. J. Org. Chem., 1996, 61, 8141).
Recently, a noncross-linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent anti tumour activitiy. (Kamal, A.; Ramesh, G.; Laxman, N.; Ramulu, P.; Srinivas, O.; Neelima, K.; Kondapi, A. K.; Srinu, V. B.; Nagarajaram, H. M. /. Med. Chem. 2002, 45, 4679).
DC-81 dimers (n = 3-5); DSB-120 (n = 3)
The main object of the present invention is to provide new pyrrolo[2,l-c][l,4]- benzodiazepine hybrids useful as antitumour agents.
Another objective of the present invention is to provide a process for the preparation of novel ρyrrolo[2,l-c][l,4]-benzodiazeρine hybrids useful as antitumour agents. Summary of the invention
Accordingly the present invention provides a process for the preparation of a novel pyrrolo[2,l-c][l,4]benzodiazepine hybrids of formula V wherein R = H, OH and n is 1-4
FORMULA V
Accordingly the present process provides a process for preparation of pyrrolo[2,l- c][l,4]benzodiazepine hybrids of formula V
FORMULA V which comprises reacting pyrene amine of formula I
III reducing the above nitro compounds of formula III with SnCl2.2H2O in presence of organic solvent up to a reflux temperature, isolating the (2S)-N-{4-[N-(l"-pyrenyl)-alkane-3'- carboxamide]-oxy--5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV where n is 1-4 and R is as stated above by known methods,
Chem. 2001, 9, 593) and (2S)-N-{4-[(3'-carboxy alkyl)oxy]-5-methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula II (Baraldi, P. G.; Balboni, G.;
Cacciari, B.; Guiotto, A.; Manfredini, S.; Romagnoli, R.; Spalluto, G.; Thurston, D. E.;
Howard, P. W.; Bianchi, N.; Rutigiiano, C; Mischiati, C. and Gambari, R. J. Med. Chem. 1999, 42, 5131.; Reddy, B. S. P.; Damayanthi, Y.; Reddy, B. S. N.; Lown, W. J. Anti-Cancer
Drug Design 2000, 15, 225) have been prepared by literature methods.
These new analogues of pyrrolo[2,l-c][l,4]benzodiazepine hybrids linked at C-8 position have shown promising DNA binding activity and efficient anticancer activity in various cell lines. The molecules synthesized are of immense biological significance with
potential sequence selective DNA-binding property. This resulted in design and synthesis of new congeners as illustrated in Scheme-1, which comprise:
1. The ether linkage at C-8 position of DC-81 intermediates with pyrene ring moiety.
2. Refluxing the reaction mixture for 24-48 h.
3. Synthesis of C-8 linked PBD antitumour antibiotic hybrid imines.
4. Purification by column chromatography using different solvents like ethyl acetate, hexane, dichloromethane and methanol.
SCHEME I
Some representative compounds of formula V present invention are given below
7-Methoxy-8-[N-( 1 "-pyrenyl)-methane- 1 '-carboxamide]-oxy-(l 1 aS) 1 ,2,3, 11 a tetrahydro-5i -pyrrolo[2, l-e][ l,4]benzodiazepin-5-one
2. 7-Methoxy-8-[N-(l"-pyrenyl)-methane-l'-carboxamide]-oxy-(4R)-hydroxy (l laS)
1,2,3,1 la tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one
3. 7-Methoxy-8-[N-(l"-pyrenyl)-ethane-2'-carboxamide]-oxy-(l laS)l,2,3,l la tetrahydro-5H-pyrrolo[2,l-c][l54]benzodiazepin-5-one
4. 7-Methoxy-8-[N-(l "-pyrenyl)-ethane-2'-carboxamide]-oxy-(4R)-hydroxy (UaS) 1,2,3,1 la tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one 5. 7-Methoxy-8-[N-(l''-ρyrenyl)-propane-3'-carboxamide]-oxy-(l laS)-l,2 A la tetxa-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one
6. 7-Methoxy-8-[N-(r'-pyrenyl)-propane-3'-carboxamide]-oxy-(4R)-hydroxy (1 laS)-
1,2,3,1 la-tetra-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one
7. 7-Methoxy-8-pS[-(r'-pyrenyl)-butane-4'-carboxamide]-oxy-(l laS)-l, 2,3,1 la-tetra- hydro-5H-pyrrolo[2, l-c][l,4]benzodiazepin-5-one
8. 7-Methoxy-8-[N-( '-pyrenyl)-butane-4'-carboxamide]-oxy-(4R)-hydroxy (1 laS)- 1,2,3, 1 la-tetra-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one
The process for the preparation of new pyrrolo[2,l-e][l,4]benzodiazepine hydrids is disclosed and claimed in our copending copatent application no. The following examples are given by way of illustration and therefore should not be construed to the present limit of the scope of invention. Example 1
Compound (2S)-N-[4-[(l'-carboxy methyl)oxy]-5-methoxy-2-mtrobenzoyl] pyrro- lidine-2-carboxaldehyde diethyl thioacetal of formula II (2.29 g, 5 mmol) was taken in dry CH2C12 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2CI2 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 min. A solution of 1 -amino pyrene of formula I (251 mg, 5 mmol) in CH2CI2 was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (2S)-N-{4-[N-(l"- pyrenyl)-methane-3'-carboxamide]-oxy~5-methoxy-2-nitro-benzoyl}pyrrolidine-2- carboxaldehyde diethyl thioacetal of formula III as a yellow liquid.
The (2S)-N- {4-[N-( 1 "-pyrenyl)-methane- 1 '-carboxamide]-oxy~5 -methoxy-2-nitro benzoyl}pyrrolidinβ-2-carboxaldehyde diethyl thioacetal of formula III (0.657 g, 1 mmol) was dissolved in ethyl acetate (15 mL) and added SnCl2.2H20 (1.12 g, 5 mmol) was refluxed for 3 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHC03 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2S0 ϊ and
evaporated under vacuum to afford the crude (2S)-N-{4-[N-(l"-pyrenyl)-methane-l'- carboxamide]-oxy--5-me oxy-2-aminobenzoyl}pyrrolidirιe-2-carboxaldehyde diethyl thioacetal of formula IV.
A solution of (2iS)-N-{4-[N-(l"-pyrenyl)-methane-r-carboxamide]-oxy~5-methoxy- 2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (627 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaC03 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-Methoxy-8-[N-(l"-pyrenyl)-propane-3'-carboxamide]-oxy-(l laS)-l,2,3,l la tetra-hydro-5H-pyrrolo[2,l-c][l,4]benzo-diazepin-5-one as pale yellow oil. Example 2 Compound (4R)-hydroxy-(2S)-N-[4-[(l '-carboxy methyl)oxy]-5-methoxy-2-nitro- benzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula II (2.37 g, 5 mmol) was taken in dry CH2CI2 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2CI2 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 min. A solution of 1 -amino pyrene formula I (251 mg, 5 mmol) in CH2CI2 was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (2S)-N-{4-[N-(l"-pyrenyl)-methane- -carboxamide]-oxy~5-methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III as a yellow liquid.
The (4R)-hydroxy-(2S)-N-{4-[N-(l "-pyrenyl)-methane-l'-carboxamide]-oxy-5- methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III (0.673 g, 1 mmol) was dissolved in ethyl acetate (15 mL) and added SnCl2.2H20 (1.12 g, 5 mmol) was refluxed for 3 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO , and evaporated under vacuum to afford the crude (4R)-hydroxy-(2S)-N- {4_[^.(l' pyrenyl)-methane- -carboxamide]-oxy--5-methoxy-2-amino-benzoyl}pyrrolidine- 2-carboxaldehyde diethyl thioacetal of formula IV.
A solution of (4R)-hydroxy-(26)-N-{4-[N-(l"-pyrenyl)-methane-l '-carboxamide]-oxy- -5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (643 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN- water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-methoxy-8-[N-(l "-pyrenyl)-methane-l '-carboxamide]-oxy-(4i?)-hydroxy- (l laS)-l,2,3,llatetra-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one as pale yellow oil. Example 3
Compound (2S)-N-[4-[(2'-carboxy ethyl)oxy]-5-methoxy-2-nitrobenzoyl] pyrrolidine- 2-carboxaldehyde diethyl thioacetal of formula JJ (2.36 g, 5 mmol) was taken in dry CH2CI2 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2CI2 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 min. A solution of 1 -amino pyrene of formula I (251 mg, 5 mmol) in CH2CI2 was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (2S)-N-{4-[N-(l"-pyrenyl)- ethane-2'-carboxamide]-oxy~5-methoxy-2-nitro-benzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula III as a yellow liquid.
The (2S)-N-{4-[N-(l''-pyrenyl)-ethane-2'-carboxamide]-oxy--5-methoxy-2-nitro benzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III (0.671 g, 1 mmol) was dissolved in ethyl acetate (15 mL) and added SnCl2.2H2O (1.12 g, 5 mmol) was refluxed for 3 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2S04, and evaporated under vacuum to afford the crude (2S)-N-{4-[N-(l"-pyrenyl)-ethane-2'- carboxamide]-oxy~5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV.
A solution of (2ιS)-N-{4-[N-(l"-pyrenyl)-ethane-2'-carboxamide]-oxy~5-methoxy-2- aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (641 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaC03 (246 mg, 2.46 mmol) in MeCN-water (4: 1)
_ _ __ IN2003/000102
was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-Methoxy-8-[N-(l"-pyrenyl)-ethane-2'-carboxamide]-oxy-(l laS)-l,2,3,l latetra- hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one as pale yellow oil. Example 4
Compound (4R)-hydroxy-(2»S)-N-[4-[(2'-carboxy ethyl)oxy]-5-methoxy-2- nitrobenzoyl] pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula II (2.44 g, 5 mmol) was taken in dry CH2CI2 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2CI2 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 min. A solution of 1-amino pyrene of formula I (251 mg, 5 mmol) in CH2CI2 was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (4R)-hydroxy-(2S)-N-{4-[N-(l"-pyrenyl)-ethane-2'-carboxamide]-oxy~5-methoxy-2- nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III as a yellow liquid.
The(4R)-hydroxy-(2S)-N-{4-[N-(l"-pyrenyl)-ethane-2'-carboxamide]-oxy-5-methoxy -2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III (0.687 g, 1 mmol) was dissolved in ethyl acetate (15 mL) and added SnCl2.2H2O (1.12 g, 5 mmol) was refluxed for 3 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2S04, and evaporated under vacuum to afford the crude (4R)-hydroxy-(2S)-N-{4-[N-(l"- pyrenyl)-ethane-2'-carboxamide]-oxy~5-methoxy-2-amino-benzoyl}pyrrolidine-2- carboxaldehyde diethyl thioacetal of formula IV. A solution of (4R)-hydroxy-(2.S)-N-{4-[N-(l"-pyrenyl)-ethane-2'-carboxamide]-oxy~
5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (657 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN- water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through
a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-Methoxy-8-[N-(l "-pyrenyl)-ethane-2'-carboxamide]-oxy-(4R)-hydroxy- (1 la_)-l,2,3,l latetra-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one as pale yellow oil. Example 5
Compound (2S)-N-[4-[(3 '-carboxy propyl)oxy]-5-methoxy-2-nitrobenzoyl] pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula II (2.43 g, 5 mmol) was taken in dry CH2C12 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0- 5°C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2C12 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 min. A solution of 1 -amino pyrene formula I (251 mg, 5 mmol) in CH2CI2 was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (2S)-N-{4-[N-(l"- pyrenyl)-propane-3'-carboxamide]-oxy~5-methoxy-2-nitrobenzoyl}pyrrolidine-2- carboxaldehyde diethyl thioacetal of formula III as a yellow liquid (1.92 g, 56%). 1H NMR (CDC13) δ 1.10-1.40 (m, 6H), 1.40-2.40 (m, 6H), 2.50-2.90 (m, 4H), 3.10-3.25 (m, 2H), 3.60 (s, 3H), 4.0-4.20(m, 2H), 4.55-4.85 (m, 2H), 6.70 (s, 1H), 7.62 (s, lH), 7.70-8.40 (m, 9H), 8.60-8.90 (m, 1H); MS (FAB) 686 [M + H]+'.
The (2S)-N-{4-[N-(l "-pyrenyl)-propane-3 '-carboxamide]-oxy~5-methoxy-2-nitro benzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III (0.685 g, 1 mmol) was dissolved in ethyl acetate (15 mL) and added SnCl2.2H2O (1.12 g, 5 mmol) was refluxed for 3 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2S04, and evaporated under vacuum to afford the crude (2S)-N-{4-[N-(l"-pyrenyl)-propane-3'- carboxamide]-oxy-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (458 mg, 70%). 1H NMR (CDC13) δ 1.10-1.40 (m, 6H), 1.50-2.30 (m, 8H), 2.40-2.80 (m, 4H), 3.40 (s, 3H), 3.45-3.60 (m, 2H), 4.05-4.15 (m, 2H), 4.50-4.70 (m, 2H), 6.25 (s, 1H), 6.70 (s, 1H), 7.65- 8.30 (m, 9H), 9.10-9.25 (m, 1H).
A solution of (2S)-N-{4- -(l"-pyrenyl)-propane-3'-carboxamide]-oxy~5-methoxy-2- aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (655 mg, 1
mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-Methoxy-8-[N-(l "-pyrenyl)-propane-3 '-carboxamide]-oxy-(l 1 aS)-
1,2,3,1 latetra-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one as pale yellow oil of formula V (285 mg, 54%). 1H NMR (CDC13) δ 1.40-2.40 (m, 10H), 2.60-2.90 (m, 2H), 3.40-4.05 (m, 4H), 4.10-4.40 (m, 2H), 6.85 (s, 1H), 7.40 (s, 1H), 7.65 (d, 1H), 7.75-8.20 (m, 8H), 8.20-8.40 (m, 1H), 9.0-9.10 (m, 1H); MS (FAB) 530 [M + H]+'. Example 6
Compound (4R)-hydroxy-(2S)-N-[4-[(3 '-carboxy propyl)oxy]-5-methoxy-2- nitrobenzoyl] pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula II (2.51 g, 5 mmol) was taken in dry CH2C12 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2CI2 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 min. A solution of 1 -amino pyrene of formula I (251 mg, 5 mmol) in CH2C12 was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHC03 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (4R)-hydroxy-(2S)-N-{4-[N-(l "-pyrenyl)-propane-3 '-carboxamide]-oxy~5-methoxy-2- nitrobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula III as a yellow liquid.
The (4R)-hydroxy-(2»S)-N- {4-[N-(l "-pyrenyl)-proρane-3 '-carboxamide]-oxy~5- methoxy-2-nitrobenzoyl}pyrrolidine~2-carboxaldehyde diethyl thioacetal of formula III (0.701 g, 1 mmol) was dissolved in ethyl acetate (15 mL) and added SnCl2.2H20 (1.12 g, 5 mmol) was refluxed for 3 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHC03 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2S04, and evaporated under vacuum to afford the crude (4R)-hydroxy-(2S)-N- {4-[N-(l"-pyrenyl)-propane-3'-carboxamide]-oxy~5-methoxy-2-aminobenzoyl}pyrrolidine- 2-carboxaldehyde diethyl thioacetal of formula IV.
A solution of (4R)-hydroxy-(2S)-N-{4-[N-(l"-pyrenyl)-propane-3'-carboxamide]-oxy- -5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (671 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN- water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-Methoxy-8-[N-(l"-pyrenyl)-propane-3'-carboxamide]-oxy-(4R) hydroxy- (lla_)-l,2,3,llatetra-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one as pale yellow oil of formula V. Example 7
Compound (2S)-N-{4-[(3'-carboxy butyl)oxy]-5-methoxy-2-mtrobenzoyl}pyrrolidine -2-car-boxaldehyde diethyl thioacetal of formula II (2.50 g, 5 mmol) was taken in dry CH2C12 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2C12 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 min. A solution of 1 -amino pyrene of formula I (251 mg, 5 mmol) in CH2C12 was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (2S)-N-{4-[N-(l"-pyrenyl)- butane-3'-carboxamide]-oxy-5-methoxy-2-nitrobe-nzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III as a yellow liquid (1.92 g, 55%). 1H NMR (CDC13) δ 1.10-1.40 (m, 6H), 1.40-2.40 (m, 8H), 2.50-2.90 (m, 4H), 3.10-3.25 (m, 2H), 3.60 (s, 3H), 4.0-4.20 (m, 2H), 4.55-4.85 (m, 2H), 6.70 (s, IH), 7.62 (s, IH), 7.70-8.40 (m, 9H), 8.60-8.90 (m, IH); MS (FAB) 700 [M + H]+\
The nitro diethyl thioacetal (2S)-N-{4-[N-(l"-pyrenyl)-butane-3'-carboxamide]-oxy- 5-methoxy-2-nitrobenzo-yl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III (0.699 g, 1 mmol) was dissolved in ethyl acetate (15 mL) and added SnCl2.2H 0 (1.12 g, 5 mmol) was refluxed for 3 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude amino diethyl thioacetal
(26^-N-{4-[N-( '-pyrenyl)-butane-3'-carboxamide]-oxy-5-methoxy-2-aminobenzoyl} ρyrroUdine-2-carboxaldehyde diethyl thioacetal of formula IV (482 mg, 72%). 1H NMR (CDC13) δ 1.10-1.40 (m, 6H), 1.50-2.30 (m, 10H), 2.40-2.80 (m, 6H), 3.40 (s, 3H), 3.45-3.60 (m, 2H), 4.05-4.15 (m, 2H), 4.50-4.70 (m, 2H), 6.25 (s, IH), 6.70 (s, IH), 7.65- 8.30 (m, 9H), 9.10-9.25 (m, IH).
A solution of (25)-N-{4-[N-(l"-pyrenyl)-butane-3'-carboxamide]-oxy-5-methoxy-2- aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (669 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. Reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and combined organic phase is dried (Na2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH Cl2-MeOH) to give compound 7- Methoxy-8-[N-( 1 "-pyrenyl)-butne-4'-carboxamide]-oxy-(l 1 aS)- 1 ,2,3, 11 a-tetra-hydro-5H- pyrrolo[2, l-c][l,4]benzodiazepin-5-one of formula V as pale yellow oil (266 mg, 49%).
1HNMR (CDC13) δ 1.40-2.40 (m, 12H), 2.60-2.90 (m, 2H), 3.40-4.05 (m, 4H), 4.10-4.40 (m, 2H), 6.85 (s, IH), 7.40 (s, IH), 7.65 (d, IH), 7.75-8.20 (m, 8H), 8.20-8.40 (m, IH), 9.0-9.10 (m, IH); MS (FAB) 544 [M + H]+'. Example 8 Compound (4R)-hydroxy-(2o>N-{4-[(3'-carboxy butyl)oxy]-5-methoxy-2- nitrobenzoyl}pyrrolidine-2-car-boxaldehyde diethyl thioacetal of formula II (2.58 g, 5 mmol) was taken in. dry CH2C12 (20 mL), TEA (707 mg, 7 mmol) was added and the mixture was cooled at 0-5 °C. Isobutyl chloroformate (819 mg, 6 mmol) in dry CH2CI2 (10 mL) was added dropwise and the mixture was kept at 0-5 °C for 15 rnin. A solution of 1 -amino pyrene of formula I (251 mg, 5 mmol) in CH2C12 was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (4R)-hydroxy-(2S)-N-{4-[N-(l"-pyrenyl)-butane-3'-carboxamide]-oxy-5-methoxy-2-nitrobe- nzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III as a yellow liquid.
The nitro diethyl thioacetal (4R)-hydroxy-(2S)-N-{4-[N-(l"-pyrenyl)-butane-3'- carboxamide]-oxy-5-metlιoxy-2-nitrobenzo-yl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula III (0.715 g, 1 mmol) was dissolved in ethyl acetate (15 mL) and added SnCl2.2H20 (1.12 g, 5 mmol) was refluxed for 3 h or until the TLC indicated that reaction
was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHC03 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude amino diethyl thioacetal ((4R)-hydroxy-(2-S)-N-{4-[N-(l"-pyrenyl)-butane-3'- carboxarm^e]-oxy-5-methθ5_y-2-ammobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV.
A solution of (4R)-hydroxy-(2S)-N-{4-[N-(l"-pyrenyl)-butane-3'-carboxamide]-oxy- 5-memoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV (685 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN- water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CHzCfe-MeOH) to give compound 7-Methoxy-8-[N-(l"-pyrenyl)-butne-4'-carboxamide]-oxy-(4R)-hydroxy- (l la5)-l,2,3,lla-tetra-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one of formula V as pale yellow oil. Biological Activity:
In vitro biological activity studies were carried out at National Cancer Institute (USA).
Cytotoxicity:
Compounds Ve and Vg were evaluated the primary anti-cancer activity (Table 1) and further Ve have been evaluated in vitro against sixty human tumour cells derived from nine cancer types (leukemia, non-small-cell lung, colon, CNS, melanoma, ovarian, prostate, and breast cancer). 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. The mean graph midpoint values of logioTGI and logioLC50 as well as logio GΪ50 for Ve are listed in Table 2. As demonstrated by mean graph pattern, compound Ve exhibits an interesting profile of activity and selectivity for various cell lines. The mean graph mid point of log10 TGI and log10 LC50 showed similar pattern to the logι0 GI50 mean graph mid points.
Table 1. In vitro one dose primary anticancer assayapyrene linked PBD hybrid of formula Ve and Vg
PBD hybrids Growth percentages
(Lung) (Breast) (CNS) NCI-H460 MCF7 SF-268
Ye 11 31 70 106 72 131 aOne dose of Ve and Vg at 10-4 molar concentration The novel pyrrolobenzodiazepine hybrid formula Vila has shown to possess 10 nano molar potency (at the LC5Q level) against one non-small cell lung cancer (NCI-H226) and one colon cancer (HCC-2998). and 0.1 micro molar potency against leukemia cancer (SR), melanoma cancer (M14), renal cancer (A498) and CNS cancer (SF-539) and also have 10 micro molar potency against two CNS cancer cell lines (SF539, SNB75) and one prostate cancer (DU-145). The LC50 values of nine cancers (average of six to nine cancer cell lines) of compound Vila listed in Table 3
Table 2. log10 GI50 logio TGI and log10 LC50 mean graphs midpoints(MGjV__D) of in vitro cytotoxicity data for the compound Ve against human tumour cell lines.
Compound LogιoGI50 LogioTGI Log10LC50
~ e -7/75 6\89 ^ /74
Table 3. Log LC50 (concentration in mol/L causing 50% lethahty) Values for Compounds Ve
Cancer Compound
Ve
Leukemia -4.65
Non-small-cell lung -4.67
Colon -5.00
CNS -5.23
Melanoma -5.62
Ovarian > -4.00
Renal -5.05
Prostate -5.30
Breast > -4.00
Each cancer type represents the average of six to nine different cancer cell lines.
Claims
We Claim:
1 Pyrrolo[2, l-c][l,4]benzodiazepine hybrid of formula V wherein R is H, OH and n is 1-4.
FORMULA V 2 A pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structural formula
3 A pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structural formula
4 A pyrrolobenzodiazepine as claimed in claim 1 of the structural formula
5 A pyrrolobenzodiazepine as claimed in claim 1 of the structural formula
7 A pyrrolobenzodiazepine as claimed in claim 1 of the structural formula
8 A pyrrolobenzodiazepine as claimed in claim 1 of the structural formula
9 A pyrrolobenzodiazepine as claimed in claim 1 of the structural formula
10. A process for preparing a pyrrolo[2,l-c][l,4]benzodiazepine hybrid of formula V
FORMULA V which comprises reacting pyrene amine of formula I
with (2)S)-N-{4-[(3'-carboxy alkyl)oxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2- carboxaldehyde diethyl thioacetal of formula JJ where R is as stated above
II up to refluxing for a period of 24 h isolating (2S)-N-{4-[N-(l"-pyrenyl)-alkane-3'- carboxamide]-oxy--5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III where n is 1-4 and R is as stated above,
III reducing the nitro compounds of formula JJI with SnCl2.2H2O in presence of an organic solvent up to a reflux temperature, isolating the (2S)-N-{4-[N-(l"-pyrenyl)-alkane-3'- carboxamide]-oxy~5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV where n is 1-4 and R is as stated above,
IV reacting the amino compound of formula IV with a deprotecting agent to give pyrrolo [2,l--][l,4]benzodiazepine hybrids of formula V wherein n and R are as stated above. 11. A process as claimed in claim 10 wherein the reaction between the compound of formula I and the compound of formula II carried out in in the presence of isobutyl chloroformate and in the presence of a base selected from the group consisting of triethyl amine and
DBU; and in the presence of an organic solvent selected from the group consistin of ethyl acetate, hexance and dichloromethane.
12. A process as claimed in claim 10 wherein the organic solvent used for the, reduction of the nitro compound of formula III comprises ethyl acetate.
13. Use of pyrrolo[2,l-c][l,4]benzodiazepine hybrid of formula V wherein R is H, OH and n is 1-4.
FORMULA V for the treatment of cancer in a subject suffering therefrom.
14. Use as claimed in claim 13 wherein the cancer comprises any one from the group consisting of leukemia, non-small-cell lung, colon, CNS, melanoma, ovarian, prostate, and breast cancer.
15. Method for the treatment of cancer comprising administering to a subject suffering therefrom, a therapeutically effective amount of a PyrroIo[2,l-c][l,4]be__-odiazepine hybrid of formula V wherein R is H; OH and n is 1-4.
FORMULA V
16. Method as claimed in claim 15 wherein the cancer comprises any one from,, the group consisting of leukemia, non-small-cell lung, colon, CNS, melanoma, ovarian, prostate, and breast cancer.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002520901A CA2520901C (en) | 2003-03-31 | 2003-03-31 | Pyrene-linked pyrrolo (2,1-c) (1,4) benzodiazepine derivatives useful as anticancer agents |
| DE60332874T DE60332874D1 (en) | 2003-03-31 | 2003-03-31 | PYRENE-PYRROLO (2,1-C) (1,4) BENZODIAZEPINE DERIVATIVES FOR USE AS ANTICROBIAL AGENTS |
| PCT/IN2003/000102 WO2004087711A1 (en) | 2003-03-31 | 2003-03-31 | Pyrene-linked pyrrolo (2,1-c) (1,4) benzodiazepine derivatives useful as anticancer agents |
| AT03719078T ATE469904T1 (en) | 2003-03-31 | 2003-03-31 | PYRENE-BONDED PYRROLO(2,1-C)(1,4)BENZODIAZEPINE DERIVATIVES FOR USE AS ANTICANCER AGENTS |
| AU2003223107A AU2003223107A1 (en) | 2003-03-31 | 2003-03-31 | Pyrene-linked pyrrolo (2,1-c) (1,4) benzodiazepine derivatives useful as anticancer agents |
| EP03719078A EP1608650B1 (en) | 2003-03-31 | 2003-03-31 | Pyrene-linked pyrrolo(2,1-c)(1,4)benzodiazepine derivatives useful as anticancer agents |
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| PCT/IN2003/000102 WO2004087711A1 (en) | 2003-03-31 | 2003-03-31 | Pyrene-linked pyrrolo (2,1-c) (1,4) benzodiazepine derivatives useful as anticancer agents |
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| EP (1) | EP1608650B1 (en) |
| AT (1) | ATE469904T1 (en) |
| AU (1) | AU2003223107A1 (en) |
| CA (1) | CA2520901C (en) |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015166289A1 (en) | 2014-05-02 | 2015-11-05 | Femtogenix Limited | Pyrrolobenzodiazepine compounds |
| WO2020157491A1 (en) | 2019-01-29 | 2020-08-06 | Femtogenix Limited | G-a crosslinking cytotoxic agents |
| EP4086251A1 (en) | 2015-08-21 | 2022-11-09 | Femtogenix Limited | Piperidinobenzodiazepine compounds with anti proliferative activity |
| 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 |
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| GB201510010D0 (en) | 2015-06-09 | 2015-07-22 | King S College London | PDD and BPD compounds |
| US20180339985A1 (en) | 2015-08-21 | 2018-11-29 | Femtogenix Limited | Pdd compounds |
-
2003
- 2003-03-31 WO PCT/IN2003/000102 patent/WO2004087711A1/en not_active Application Discontinuation
- 2003-03-31 AT AT03719078T patent/ATE469904T1/en not_active IP Right Cessation
- 2003-03-31 EP EP03719078A patent/EP1608650B1/en not_active Expired - Lifetime
- 2003-03-31 CA CA002520901A patent/CA2520901C/en not_active Expired - Lifetime
- 2003-03-31 DE DE60332874T patent/DE60332874D1/en not_active Expired - Lifetime
- 2003-03-31 AU AU2003223107A patent/AU2003223107A1/en not_active Abandoned
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015166289A1 (en) | 2014-05-02 | 2015-11-05 | Femtogenix Limited | Pyrrolobenzodiazepine compounds |
| EP4086251A1 (en) | 2015-08-21 | 2022-11-09 | Femtogenix Limited | Piperidinobenzodiazepine compounds with anti proliferative activity |
| 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 |
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| WO2020157491A1 (en) | 2019-01-29 | 2020-08-06 | Femtogenix Limited | G-a crosslinking cytotoxic agents |
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|---|---|
| EP1608650B1 (en) | 2010-06-02 |
| AU2003223107A1 (en) | 2004-10-25 |
| ATE469904T1 (en) | 2010-06-15 |
| CA2520901A1 (en) | 2004-10-14 |
| DE60332874D1 (en) | 2010-07-15 |
| CA2520901C (en) | 2009-09-08 |
| EP1608650A1 (en) | 2005-12-28 |
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