Process for the preparation of antitumor agents

Details Process for the preparation of antitumor agents Process for the preparation of antitumor agents

2001-03-30

2002-03-26

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06362331

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for the preparation of antitumour agents The present invention particularly relates to a process for the preparation of novel pyrrolo[2,1-c][1,4]benzodiazepines useful as potential antitumour agents. More particularly, the present invention relates to a process for the preparation of 8-methoxy-7-(3-[7-methoxy-5-oxo(11aS)-2,3,4,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4][benzodiazepine-8-yloxyalkyloxy)-(11aR)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione, with aliphatic chain length variations and their 2-hydroxy and 2-acetyloxy derivatives.
2. Description of Related Art
In the past few years, a growing interest has been shown in the development of new pyrrolo[2,1-c][1,4]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 animal bond to the electrophilic imine at the N
10
-C
11
position. (Ref. Kunimoto, S., Masuda. T., Kanbayshi, 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.,
Biocheim. Biophys Acta.,
1977, 475, 521.; Kaplan D. J. and Hurley, L. H.
Biochmestry,
1981, 20, 7572). The molecules have a right-handed twist allowing them to follow the curvature of the minor groove of B-form double-stranded DNA spanning three base pairs. 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 (Ref. 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, 8141-8147).
Naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines belong to a group of antitumour antibiotics derived from Streptomyces species. Recently, emphasis has been given to PBD systems as they can recognize and bind to a specific sequence of DNA. Examples of naturally occurring PBD's include anthramycin, tomaymycin, sibiromycin and neothramycin.
In the last decade a number of PBD's, particularly C-8 linked PBD dimers, have been designed and synthesized to explore their effectiveness as DNA-sequence selective agents (Ref: Bose, D. S., Thomson, A. S., Ching, J. A., Hartley, J. A., Berardini. M. D., Jenkins. T. C., Neidle, S., Hurley, L. H. and Thurston. D. E.,
J. Am. Chem. Soc.
1992, 114, 4939).
Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones are a class of compounds that bind to DNA by non-covalent interactions such as hydrophobic, Vanderwalls interactions and hydrogen bonding between ring substituents and DNA, and are also responsible for influencing sequence selectivity. Some dilactams such as (7-methoxy-2-methylcarbonyloxy-5,11-dioxo-(2S)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]-benzodiazepine-5,11-dione-8-yl acetate is reported to possess significant in vivo antitumour activity in P388 rat model. (Ref.: Kaneko, T., Wong, H., Doyle, T. W., Rose, W. C and Bradner. W. T.,
J. Med Chem.
1985, 28, 388)
The main object of present invention is to provide a new class of C-8 linked PBD dimers, wherein one PBD has an imine functionality while the other has an amide group. It has been envisaged that such a mixed dimer could offer more insight not only for the covalent binding but also the role played by non-covalent interactions with DNA bases.
Another object of the invention is to provide a process for the preparation of novel Pyrrolo[2,1-c][1,4]benzodiazepines useful as antitumour agents.
BRIEF SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of a Pyrrolo[2,1-c][1,4]benzodiazepine of formula VI wherein R is H, OH, OAc; R
1
, is H; and n is 3 to 5.
The process comprises:
reacting (2S)-N-[4-hydroxy-5-methoxy-2-nitrobenzyl]-pyrrolidine-2-carboxy-carbaldehyde diethyl thioacetal of formula I wherein R
1
is H
with a dibromoalkane in an aprotic water miscible organic solvent in the presence of a mild inorganic base with a refluxing temperature for a period upto 48 hours; isolating (2S)-N [4-(3-bromoalkoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxy carbaldehyde diethyl thioacetal of formula II wherein R
1
is H;
reacting the compound of formula II with a dilactam of formula III wherein R is H, OH or OAc
in the presence of a mild inorganic base in the presence of an aprotic water miscible organic solvent with a refluxing temperature for a period upto 48 hours;
isolating 8-([(2S)-N-5-methoxy-2-nitrobenzoyl]pyrrolidin-2-carbaldehyde diethylthioacetal)-alkoxy-7-methoxy-2,3,5,10,11,11a-hydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione of formula IV wherein R is H, OH or OAc; R
1
is H; and n is 3 to 5;
reducing the above nitro compound of formula IV with SnCl
2
2H
2
O in the presence of an organic solvent with a reflux temperature, isolating the 8-([(2S)-N-5-methoxy-2-aminobenzoyl]pyrrolidin-2-carbaldehyde diethylthioacetal)-alkoxy-7-methoxy-2,3,5,10,11,11a-hydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione of formula V, wherein R is H, OH or OAc; R
1
, is H; and n is 3 to 5; and
reacting the amino compound of formula V with a deprotecting agent to obtain the pyrrolo[2,1-c][1,4]benzodiazepines of formula VI wherein R, R
1
and n are as stated above.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the invention, the aprotic water miscible organic solvent used is selected from the group consisting of acetone, tetrahydrofuran (THF) and dimethylformamide (DMF).
In another embodiment of the invention the mild inorganic base used for the reaction of compound of formula I is selected from the group consisting of K
2
CO
3
, BaCO
3
, Na
2
CO
3
, and mixtures thereof, and the reaction is refluxed at a temperature for a period in the range of 24 to 48 hours.
In another embodiment of the invention, the compound of formula II comprises (2S)-N[4-(3-bromopropoxy)-5-methoxy-2-nitrobenzyol]pyrrolidine-2-carboxy carbaldehyde diethyl thioacetal, (2S)-N-[4-(4-bromobutoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxy carbaldehyde diethyl thioacetal and/or (2s)-N-[4-(5-bromopentyloxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxy carbaldehyde diethyl thioacetal wherein R
1
is H.
In another embodiment of the invention, the aprotic water miscible organic solvent used when reacting the compound of formula II with the debenzylated dilactam of formula III is selected from acetone, THF and DMF. (Ref: I. Kaneko, E.: Wang, H.; Doyle T. W.
The J. Antibiotics.
1984, 3, 300).
In yet another embodiment of the invention, the compound of formula IV comprises 8-([(2S)-N-5-methoxy-2-nitrobenzoyl]pyrrolidin-2-carbaldehyde diethylthioacetal)-propoxy-7-methoxy-2,3,5,10,11,11a -hydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione, 8-([(2S)-N-5-methoxy-2-nitrobenzoyl]pyrrolidin-2-carbaldehyde diethylthioacetal)-butoxy-7-methoxy-2,3,5,10,11,11a-hydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione, and/or 8-[[(2S)-N-5-methoxy-2-nitrobenzoyl]pyrrolidin-2-carbaldehyde diethylthioacetal]-pentyloxy-7-methoxy-2,3,5,10,11,11a-hydro-1H-pyrrolo[2,1,-c][1,4]benzodiazepine-5,11-dione, wherein R is H, OH or OAc and R
1
is H.
In another embodiment of the invention, the organic solvent used in the reduction of the nitrothioacetal compounds of the formula IV with SnCI
2
.2H
2
O is selected from the group consisting of MeOH, DMF, 1,4-dioxane, and mixtures thereof.
In a further embodiment of the invention, the compound of formula V obtained by the reduction of compound of formula IV comprise

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