Pyrrolobenzodiazepines

Details Pyrrolobenzodiazepines Pyrrolobenzodiazepines

2001-02-26

2003-05-13

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S219000, C514S220000, C540S486000, C540S494000, C540S496000

Reexamination Certificate

active

06562806

ABSTRACT:

The present invention relates to pyrrolobenzodiazepines (PBDs), and is particularly concerned with the use of these compounds as prodrugs for antibody-directed enzyme-prodrug therapy (ADEPT), gene-directed enzyme-prodrug therapy (GDEPT), photodynamic therapy (PDT) and naturally present enzyme-prodrug therapy (NPEPT).
BACKGROUND TO THE INVENTION
Pyrrolobenzodiazepines (PBDs) have the ability to recognise and bond to specific sequences of DNA; the most preferred sequence is PuGPu (Purine-Guanine-Purine). The first PBD antitumour antibiotic, anthramycin, was discovered in 1965 (Leimgruber et al., 1965
J. Am. Chem. Soc.,
87, 5793-5795; Leimgruber et al., 1965
J. Am. Chem. Soc.,
87, 5791-5793). Since then, a number of naturally occurring PBDs have been reported, and over 10 synthetic routes have been developed to a variety of analogues (Thurston et al., 1994
Chem. Rev.
1994, 433-465). Family members include abbeymycin (Hochlowski et al., 1987
J. Antibiotics,
40, 145-148), chicamycin (Konishi et al., 1984
J. Antibiotics,
37, 200-206), DC-81 (Japanese Patent 58-180 487; Thurston et al., 1990,
Chem. Brit.,
26, 767-772; Bose et al., 1992
Tetrahedron,
48, 751-758), mazethramycin (Kuminoto et al., 1980
J. Antibiotics,
33, 665-667), neothramycins A and B (Takeuchi et al., 1976
J. Antibiotics,
29, 93-96), porothramycin (Tsunakawa et al., 1988
J. Antibiotics,
41, 1366-1373), prothracarcin (Shimizu et al, 1982
J. Antibiotics,
29, 2492-2503; Langley and Thurston, 1987
J. Org. Chem.,
52, 91-97), sibanomicin (DC-102)(Hara et al., 1988
J. Antibiotics,
41, 702-704; Itoh et al., 1988
J. Antibiotics,
41, 1281-1284), sibiromycin (Leber et al., 1988
J. Am. Chem. Soc.,
110, 2992-2993) and tomamycin (Arima et al., 1972
J. Antibiotics,
25, 437-444). PBDs are of the general structure:
They differ in the number, type and position of substituents, in both their aromatic A rings and pyrrolo C rings, and in the degree of saturation of the C ring. In the B-ring there is either an imine (N═C), a carbinolamine (NH—CH(OH)) or a carbinolamine methyl ether (NH—CH(OMe))at the N10-C11 position which is the electrophilic centre responsible for alkylating DNA. All of the known natural products have an (S)-configuration at the chiral C11a position which provides them with a right-handed twist when viewed from the C ring towards the A ring. This gives them the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site (Kohn, 1975 In
Antibiotics III.
Springer-Verlag, New York, pp. 3-11; Hurley and Needham-VanDevanter, 1986
Acc. Chem. Res.,
19, 230-237). Their ability to form an adduct in the minor groove enables them to interfere with DNA processing, hence their use as antitumour agents.
The use of prodrugs represents a very valuable clinical concept in cancer therapy. For example, a prodrug may be converted into an antitumour agent under the influence of an enzyme that is linked to a monoclonal antibody so that it can bind to a tumour associated antigen. The combination of such a prodrug with such an enzyme monoclonal antibody conjugate represents a very powerful therapeutic strategy. This approach to cancer therapy, often referred to as “antibody directed enzyme/prodrug therapy” (ADEPT) is disclosed in WO88/07378.
A further therapeutic approach termed “virus-directed enzyme prodrug therapy” (VDEPT) has been proposed as a method for treating tumour cells in patients using prodrugs. Tumour cells are targeted with a viral vector carrying a gene encoding an enzyme capable of activating a prodrug. The gene may be transcriptionally regulated by tissue specific promoter or enhancer sequences. The viral vector enters tumour cells and expresses the enzyme, thereby converting the prodrug into the active drug within the tumour cells (Huber et al.,
Proc. Natl. Acad. Sci. USA
(1991) 88, 8039). Alternatively, non-viral methods for the delivery of genes have been used. Such methods include calcium phosphate co-precipitation, microinjection, liposomes, direct DNA uptake, and receptor-mediated DNA transfer. These are reviewed in Morgan & French, Annu. Rev. Biochem., 1993, 62;191. The term “GDEPT” (gene-directed enzyme prodrug therapy) is used to include both viral and non-viral delivery systems.
Photodynamic therapy (PDT) provides another method which uses prodrugs to deliver desired drugs to specific sites in the human body. Advances in the field of light delivery to internal areas of the body allow delivery to organs and other areas without the need for any extensive surgical procedures. The activation process can be extremely site specific, as the direction of a laser beam can be controlled with great precision, and the beam diameter can be reduced far below that of a single cell, minimising any possible damage to other neighbouring tissue from unwanted activation of the drug. The high energy of ultra-violet light (e.g. 350 nm equivalent to 340 kJ/mol) is sufficient to break a range of chemical bonds, since the bond energy spectrum of the majority of organic molecules lies between 250 and 420 kJ/mol. For example, there has been wide application of the photochemical deprotection of amino acids, peptides and polysaccharides from their o-nitrobenzyl carbamate, CBZ, and 4,5-dimethoxy-2-nitrobenzyl carbamate forms at wavelengths longer than 350 nm.
A further class of prodrugs is those where the protecting group is removed by an enzyme naturally present at the desired site of action. These enzymes include dopa-decarboxylase, L-&ggr;-glutamyl transpeptidase, and mixed function oxidases and reductase (e.g. DT-diaphrase). This is method termed “naturally present enzyme-prodrug therapy (NPEPT) in this application. One enzyme of particular interest is glutathione transferase (GST), which forms part of a major cellular defence mechanism based on the use of the tripeptide, glutathione, as a scavenger of toxic electrophiles. GST acts as a catalyst in the reaction between glutathione and its target electrophiles. A consequence of this defence mechanism is the inactivation of electrophilic therapeutic agents. Many human tumour cells exhibit elevated GST levels compared to normal cells and the association of GST with resistance to DNA alkylating agents has been demonstrated by Lewis et al. (Carcinogenesis 1988, 9, 1283-1287), Kuzmich et al. (Journal of Biochemistry 1992, 281, 219-224), and Tew et al. (Glutathione-S-transferase and anti-cancer drug resistance, in Mechanism of Drug Resistance in Neoplastic Cells; Wooley, P. V., Tew, Kr. D., Eds.; Academic Press: Orlando, Fla., 1987; pp141-159). Chemotherapeutic agents that take advantage of this intrinsic property of cancer cells may prove highly useful in treating refractory cancers.
Prodrugs which make use of this elevated GST level have been made (Satyam et al., Med. Chem. 1996, 39, 1736-1747). They have a glutathione molecule linked via a 2-sulphonylethyloxycarbonyl linker to a phosphorodiamidate mustard. An alternative type of prodrug has made use of the closely related 2-phenylsulphonylethyloxycarbonyl (Psec) group (Nicolaou et al., Science, 1992, 256, 1172-1178). Such prodrugs showed selectivity between healthy human bone marrow cells and promeocytic and T cell leukemia tumour lines.
BRIEF SUMMARY OF THE INVENTION
A first aspect of the present invention provides a compound with the formula I:
wherein:
R
10
is a therapeutically removable nitrogen protecting group;
R
2
and R
3
are independently selected from: H, R, OH, OR, ═O, ═CH—R, ═CH
2
, CH
2
—CO
2
R, CH
2
—CO
2
H, CH
2
—SO
2
R, O—SO
2
—R, CO
2
R, COR and CN;
R
6
, R
7
and R
9
are independently selected from H, R, OH, OR, halo, amino, nitro, Me
3
Sn; or R, and R, together form a group —O—(CH
2
)
p
—O—, where p is 1 or 2;
X is S, O or NH;
R
11
is either H or R;
where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group (i.e. an alkyl group with one or more aryl substituents), preferably of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon-carbon doubl

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