Collections of compounds

Details Collections of compounds Collections of compounds

2001-02-26

2004-06-08

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

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

Reexamination Certificate

active

06747144

ABSTRACT:

BACKGROUND TO THE INVENTION
Compounds having biological activity can be identified by screening diverse collections of compounds (i.e. libraries of compounds) produced through synthetic chemical techniques. Such screening methods include methods wherein the library comprises a plurality of compounds synthesized at specific locations on the surface of a solid support whereby a receptor is appropriately labelled to bind to and identify a compound, e.g., fluorescent or radioactive labels. Correlation of the labelled receptor bound to the support and its location on the support identifies the binding compound (U.S. Pat. No. 5,143,854).
Central to these methods is the screening of a multiplicity of compounds in the library and the ability to identify the structures of the compounds which have a requisite biological activity. In order to facilitate synthesis and identification, the compounds in the library are typically formed on solid supports. Usually each such compound is covalently attached to the support via a cleavable or non-cleavable linking arm. The libraries of compounds can be screened either on the solid support or as cleaved products to identify compounds having good biological activity.
A particular class of compounds which would be useful for inclusion in screening libraries are pyrrolobenzodiazepines (PBDs). 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. 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.
DISCLOSURE OF THE INVENTION
A first aspect of the present invention relates to compounds of formula (I):
wherein:
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, and there is optionally a double bond between C1 and C2 or C2 and C3;
R
6
, R
7
, R
8
, and R
9
, are independently selected from H, R, OH, OR, halo, nitro, amino, Me
3
Sn; or R
7
and R
8
together from a group —O—(CH
2
)
p
—O—, where p is 1 or 2;
R
11
, is either H or R;
Q is S, O or NH;
L is a linking group, or less preferably a single bond;
O is a solid support;
where R is a lower alkyl group having 1 to 10 carbon atoms, or an alkaryl 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 system, or an aryl group, preferably of up to 12 carbon atoms; and is optionally substituted by one or more halo, hydroxy, amino, or nitro groups, and optionally contains one or more hetero atoms, which may form part of, or be, a functional group; and
where one or more of R
2
, R
3
, R
6
, R
7
and R
8
may alternatively be independently X—Y—A—, where X is selected from —COZ′, NHZ, SH, or OH, where Z is either H or a nitrogen protecting group, Z′ is either OH or an acid protecting group, Y is a divalent group such that HY-R, and A is O, S, NH, or a single bond.
If R is an aryl group and contains a hetero atom, then R is a heterocyclic group. If R is an alkyl chain, and contains a hetero atom, the hetero atom may be located anywhere in the alkyl chain, e.g. —O—C
2
H
5
, —CH
2
—S—CH
3
, or may form part of, or be, a functional group, e.g. carbonyl, hydroxy, cyano, ester.
R and HY groups are preferably independently selected from a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group, preferably of up to 12 carbon atoms, or an aryl group, preferably of up to 12 carbon atoms, optionally substituted by one or more halo, hydroxy, amino, or nitro groups. It is more preferred that R and HY groups are independently selected from a lower alkyl group having 1 to 10 carbon atoms optionally substituted by one or more halo, hydroxy, amino, or nitro groups. It is particularly preferred that R or HY are unsubstituted straight or branched chain alkyl groups, having 1 to 10, preferably 1 to 6, and more preferably 1 to 4, carbon atoms, e.g. methyl, ethyl, propyl, butyl. R may be selected only from methyl and ethyl.
Alternatively, R
6
, R
7
, R
8
and R
9
may preferably be independently selected from R groups with the following structural characteristics:
(i) an optionally substituted phenyl group;
(ii) an optionally substituted ethenyl group;
(iii) an ethenyl group conjugated to an electron sink.
The term ‘electron sink’ means a moiety-covalently attached to a compound which is capable of reducing electron density in other parts of the compound. Examples of electron sinks include cyano, carbonyl and ester groups.
The term ‘nitrogen protecting group’ has the meaning usual in synthetic chemistry, particularly synthetic peptide chemistry. It means any group which may be covalently bound to the nitrogen atom of any grouping of the molecule, particularly of the amine grouping, and permits reactions to be carried out upon the molecule containing this protected grouping without its removal. Nevertheless, it is able to be removed from the nitrogen atom without affecting the remainder of the molecule. Suitable amine protecting groups for the present invention include Fmoc (9-fluorenylmethoxycarbonyl), Nvoc (6-nitroveratryloxycarbonyl), Teoc (2-trimethylsilylethyloxycarbonyl), Troc (2,2,2-trichloroethyloxycarbonyl), Boc (t-butyloxycarbonyl), CBZ (benzyloxycarbonyl), Alloc (allyloxycarbonyl) and Psec (2(-phenylsulphonyl)ethyloxycarbonyl). Other suitable groups are described in Protective Groups in Organic Synthesis, T Green and P Wuts, published by Wiley, 1991 which is incorporated herein by reference.
The term ‘acid protecting group’ has the meaning usual in synthetic chemistry. It means any group which may be reacted with any carboxylic acid moiety of the molecule, and permits reactions to be carried out upon the molecule containing this protected grouping without its removal. Nevertheless, the carboxylic acid mo

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