Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,... – Conjugated via claimed linking group – bond – chelating agent,...
Reexamination Certificate
2001-03-06
2003-02-11
Ceperley, Mary E. (Department: 1641)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
Conjugated via claimed linking group, bond, chelating agent,...
C424S178100, C424S093200, C514S237200, C514S397000, C514S183000, C544S111000, C548S314700, C548S968000
Reexamination Certificate
active
06517836
ABSTRACT:
The present invention relates to novel nitrophenylaziridines, and is particularly concerned with the use of these compounds as anti-cancer agents, as well as prodrugs for antibody-directed enzyme-prodrug therapy (ADEPT) and gene-directed enzyme-prodrug therapy (GDEPT), in conjunction with nitroreductase enzymes.
BACKGROUND OF THE INVENTION
The use of prodrugs represents a clinically very valuable concept in cancer therapy since, particularly where the prodrug is to be converted to an anti-tumour agent under the influence of an enzyme that is linkable to a monoclonal antibody that will bind to a tumour associated antigen, the combination of such a prodrug with such an is enzyme monoclonal/antibody conjugate represents a very powerful clinical agent. 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, in order that a prodrug is converted to an 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.
A number of nitrophenylaziridines have been reported as antitumour agents (Cobb et al., Biochem. Pharmacol., 1969, 18, 1519-1527; Khan and Ross, Chem.-Biol. Int., 1971, 4, 11-22; Workman et al., Cancer Chemother. Pharmacol., 1986, 16, 9-14; Roberts et al., WO 89/07592). One example [CB 1954: 5-(aziridin-1-yl)-2,4-dinitrobenzamide] has also been reported to be a substrate for both DT diaphorase (Knox et al., Biochem. Pharmacol., 1988, 37, 4661-4669 and 4671-4677) and the aerobic nitroreductase (NR) isolated from
E. coli
B (Boland et al., Biochem. Pharmacol. 1991, 41, 867-875; Anlezark et al., Biochem. Pharmacol, 1992, 44, 2289-2295). This compound has also been used as a prodrug in both ADEPT (Knox et al., Biochem. Pharmacol., 1995, 49, 1641-1647) and GDEPT (Bridgewater et al., Eur. J. Cancer, 1995, 31A, 2362-2370; Bailey et al., Gene Ther., 1996, 3, 1143-1150; Bailey and Hart, Gene Ther., 1997, 4, 80-81; Green et al., Cancer Gene Ther., 1997, 4, 229-238) applications.
DISCLOSURE OF THE INVENTION
In a first aspect, the present invention relates to the use of a class compounds represented by the general formula (I) for the manufacture of a medicament for treatment of neoplastic disease in combination with a nitroreductase enzyme:
wherein:
X represents CO or SO
2
;
Y represents H, or a lower alkyl group being optionally substituted with one or more of the following groups: hydroxy, alkoxy, halo, N-oxy, amino, alkylamino, dialkylamino, imidazolyl, alkylpiperazinyl and morpholino, thio and thioether; and
R
1
represents at any available aromatic ring position, H, halo, NO
2
, N
3
, CN, SOCH
2
Y, SO
2
CH
2
Y, COCH
2
Y, SONHY, SO
2
NHY, CONHY, CO
2
Y or a lower alkyl group being optionally substituted with one or more of the following groups: hydroxy, alkoxy, halo, N-oxy, amino, alkylamino, dialkylamino, imidazolyl, alkylpiperazinyl, morpholino, thio and thioether;
or R
1
may represent the replacement of one —CH═ group in the aromatic ring by an —N═ (aza) group;
the aziridine may be at any available aromatic ring position;
R
2
represents the optional presence at either or both aziridine ring positions independently one or more substituents independently selected from methyl or ethyl;
provided that when X is CO, R
1
is an NO
2
group, the two NO
2
groups being in the 2 and 4 positions on the ring, and the aziridine is in the 5 position, and there are no substituents on the aziridine ring, then Y is not H.
The nitroreductase enzyme is generally present in the patient to be treated, preferably at the site of the tumour. Delivery of the enzyme to the tumour may be achieved by linking it to a monoclonal antibody which will bind to a tumour associated antigen, or by targeting the tumour cells with a viral vector carrying a gene encoding of the enzyme.
A second aspect of the present invention relates to compounds of formula (I):
wherein:
X represents CO or SO
2
;
Y represents H, or a lower alkyl group being optionally substituted with one or more of the following groups: hydroxy, alkoxy, halo, N-oxy, amino, alkylamino, dialkylamino, imidazolyl, alkylpiperazinyl and morpholino, thio and thioether; and
R
1
represents at any available aromatic ring position, H, halo, NO
2
, N
3
, CN, SOCH
2
Y, SO
2
CH
2
Y, COCH
2
Y, SONHY, SO
2
NHY, CONHY, CO
2
Y or a lower alkyl group being optionally substituted with one or more of the following groups: hydroxy, alkoxy, halo, N-oxy, amino, alkylamino, dialkylamino, imidazolyl, alkylpiperazinyl, morpholino, thio and thioether;
or R
1
may represent the replacement of one —CH═ group in the aromatic ring by an —N═ (aza) group;
the aziridine may be at any available aromatic ring position;
R
2
represents the optional presence at either or both aziridine ring positions independently one or more substituents independently selected from methyl or ethyl;
provided that when X is CO, R
1
is an NO
2
group, the two NO
2
groups being in the 2 and 4 positions on the ring, if the aziridine is in the 5 position and there are no substituents on the aziridine ring, then Y is not H, or an unsubstituted lower alkyl having 1 to 6 carbon atoms;
and provided that when X is CO, R
1
is an NO
2
group, the two NO
2
groups being at the 3 and 5 positions, if the aziridine is in the 2 position and there are no substituents on the aziridine ring, then Y is not H;
and provided that when X is CO, R
1
is an NO
2
group, the two NO
2
groups being at the 3 and 5 positions, if the aziridine is in the 4 position and there are no substituents on the aziridine ring, then Y is not H;
and provided that when X is SO
2
, R
1
is H, the NO
2
group is in the 3 position, if the aziridine is in the 4 position, and there are no substituents on the aziridine ring, then Y is not H;
and provided that when X is CO and Y is H, R
1
is an NO
2
group, the two NO
2
groups being in the 2 and 4 positions, if the aziridine is in the 5 position, then R
2
is not a methyl, two methyls or an ethyl group at a single position of the aziridine ring.
In this application, ‘lower alkyl’ represents a straight or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, cyclopentyl, and more preferably methyl or ethyl. ‘Halo’ represents a radical of any of the halogens, e.g. F, Cl, I, Br. The ‘alkyl’ in alkylamino, dialkylamino and alkyl piperazinyl represents an alkyl group of 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably methyl or ethyl. ‘Thioether’ represents a sulphur atom attached to an alkyl group, wherein the alkyl group has 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. ‘Alkoxy’ represents an oxygen atom attached to an alkyl group, wherein the alkyl group has 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. ‘Substituted with one or more’ means substitution with, for example one, two, three, four, but more preferably only one or two, groups.
The invention also comprises salts forms of the basic or acidic compounds of formula (I) as defined in the second aspect that form pharmaceutically acceptable salts with both organic and inorganic acids and/or organic and inorganic bases. Examples of suitable acids for salt formation are hydrochloric, s
Atwell Graham John
Denny William Alexander
Palmer Brian Desmond
Wilson William Robert
Auckland Uniservices Limited
Bozicevic Field & Francis LLP
Ceperley Mary E.
Sherwood Pamela J.
LandOfFree
Nitrophenylaziridine compounds and their use as prodrugs does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Nitrophenylaziridine compounds and their use as prodrugs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nitrophenylaziridine compounds and their use as prodrugs will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3180189