Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-03-25
2004-10-05
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S496000
Reexamination Certificate
active
06800622
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of novel 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 a process for the preparation of 7-methoxy-8-[N-(1″-pyrenyl)-alkane-3′-carboxamide]-oxy-(11aS)-1,2,3,11a-tetraydro 5H-pyrrolo[2,1-c][1,4]benzodiazepine-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:
BACKGROUND OF THE INVENTION
Pyrrolo[2,1-c][1,4]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[2,1-c][1,4]benzodiazepine 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. Acta
., 1977, 475, 521.; Kaplan, D. J. and Hurley, L. H.
Biochmestry
, 1951, 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. 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 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 activity. (Kamal, A.; Ramesh, G.; Laxman, N.; Ramulu, P.; Srinivas, O.; Neelima, K.; Kondapi, A. K.; Srinu, V. B.; Nagarajaram, H. M.
J. Med. Chem
. 2002, 45, 4679).
Naturally occurring pyrrolo[2,1-c][1,4]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. Examples of naturally occurring PBD's include anthramycin, DC-81, tomaymycin, sibiromycin and neothramycin. However, the clinical efficacy for these antibiotics is hindered by several limitations, such as poor water solubility, cardiotoxicity, development of drug resistance and metabolic inactivation.
OBJECTS IF THE INVENTION
The main object of the present invention is to provide new pyrrolo[2,1-c][1,4]-benzodiazepine hybrids useful as antitumour agents.
Another objective of the present invention is to provide a process for the preparation of novel pyrrolo[2,1-c][1,4]-benzodiazepine hybrids useful as antitumour agents.
SUMMARY OF THE INVENTION
Accordingly the present invention provides a process for the preparation of a novel pyrrolo[2,1-c][1,4]benzodiazepine hybrids of formula V wherein R=H, OH and n is 1-4
Accordingly the present process provides a process for preparation of pyrrolo[2,1-c][1,4]benzodiazepine hybrids of formula V
which comprise reacting pyrene amine of formula I
with (2S)-N-{4-[(3′-carboxyalkyl)oxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula II where R is as stated above
in the presence of isobutyl chloroformate, bases like triethyl amine, DBU in presence of organic solvents up to refluxing for a period of 24 h isolating (2S)-N-{4-[N-(1″-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 by conventional methods,
reducing the above nitro compounds of formula III with SnCl
2
.2H
2
O in presence of organic solvent up to a reflux temperature, isolating the (2S)-N-{4-[N-(1″-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,
reacting the above said amino compound of formula IV with known deprotecting agents in a conventional manner to give novel pyrrolo[2,1-c][1,4]benzodiazepine hybrids of formula V wherein n and R are as stated above.
REFERENCES:
Zhou et al. (J. Am. Chem. Soc. 2001, 123, 4865-4866).
Gujjar Ramesh
Kamal Ahmed
Olepu Srinivas
Poddutoori Ramulu
Council of Scientific and Industrial Research
Kifle Bruck
Ladas & Parry
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