Chemical compounds

Details Chemical compounds Chemical compounds

1999-05-19

2001-08-21

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C514S490000, C514S381000, C514S558000

Reexamination Certificate

active

06277880

ABSTRACT:

The invention relates to compounds for use in antibody directed enzyme prodrug therapy (ADEPT), processes for their preparation, pharmaceutical compositions containing them and methods for their use as well as to a two component system comprising 1) a conjugate of an enzyme and an antibody or antibody fragment and 2) a compound of the present invention. The compounds are particularly of interest as pro-drugs for use in conjunction with carboxypeptidase G enzymes, particularly carboxypeptidase G2 (CPG2).
Many cytotoxic compounds have been discovered which are of potential use in cancer chemotherapy. Nitrogen mustards form one important family of such cytotoxic compounds. The clinical use of cytotoxic compounds in general and nitrogen mustards in particular has been limited because of the poor selectivity in the cytotoxic effect between tumour cells and normal cells.
One approach to overcome this problem has involved the development of so-called pro-drugs which are derivatives of the cytotoxic drug, often a relatively simple derivative, whose cytotoxic properties are considerably reduced compared to those of the parent drug. Proposals have been made for the administration of such pro-drugs to patients under regimes whereby the pro-drug is only converted to the cytotoxic drug in the region of the intended site of action.
One approach involves linkage of a cytotoxic parent nitrogen mustard with an amino acid to form a pro-drug which can be converted to the parent nitrogen mustard at the site of intended action under the influence of an enzyme. This approach can be put into practise by the utilisation of an antibody/enzyme conjugate in association with a pro-drug. The antibody/enzyme conjugate is formed from an antibody selective for tumours and an enzyme that will convert the pro-drug to the cytotoxic drug. In clinical practice, the antibody/enzyme conjugate is first administered to the patient and is allowed to bind to the tumour. After a suitable period of time, to allow clearance of the antibody/enzyme conjugate from the rest of the body, the pro-drug is administered to the patient. Conversion of the pro-drug, under the influence of the localised enzyme, to the cytotoxic drug takes place mainly in the region of the tumour. Such a system is described in International Application PCT/GB88/00181 published as WO88/07378 and U.S. Pat. No. 4,975,278.
Known pro-drugs for ADEPT cleaved by CPG yield benzoic acid mustards as their active drugs. However there is a need for more active drugs to be produced by CPG cleavage to increase the therapeutic potency against tumour cells. A further need arises to increase the selectivity of ADEPT therapy with CPG, that is to say the ratio of toxicity to cancer cells compared with healthy cells.
The present invention is based on the discovery of novel pro-drugs for use in ADEPT therapy that are cleaved by CPG and which yield significantly more active cytotoxic drugs than known products of CPG catalysed reactions. CPG acts naturally as a folate degrading enzyme which specifically hydrolyses glutamic and aspartic acids from folate derivatives (Sherwood, R. F. et al., Eur. J. Biochem. (1985), 148, 447-453). Carboxypeptidase G enzymes do not recognise non-classical folate analogues (Kalghatgi, K. K. et al., Cancer Research (1979), 39, 3441-3445) and are therefore considered conservative in substrate specificity. Surprisingly the pro-drugs of the present invention are substrates for CPG enzymes such as CPG1, but particularly for CPG2 enzymes. CPG2 is an exopeptidase with specificity for L-glutamate. It is known to hydrolyse the glutamic acid moiety from folic acid and analogues thereof and glutamyl-p-aminobenzoic acid by cleavage at —CO—NH— of the partial structure -aromatic ring-CO—NH-Glu. In the present invention a partial structure for comparative purposes is -aromatic-ring-X—CO—NH-Glu wherein X is —NH—, —O— or —CH2—; thus altering the distance between the cleavage point and the aromatic ring as well as altering the electron distribution across the —CO—NH— bond, particularly when X is NH or O. CPG2 could not be predicted to accommodate these spatial and electronic differences.
According to one feature of the present invention there are provided compounds of Formula I, which are pro-drug substrates for CPG enzymes,
wherein R
1
and R
2
each independently represents chlorine, bromine, iodine, OSO
2
Me, or OSO
2
phenyl (wherein phenyl is optionally substituted with 1,2,3,4 or 5 substituents independently selected from C
1-4
alkyl, halogen, —CN or —NO
2
);
R
1a
and R
2a
each independently represents hydrogen, C
1-4
alkyl or C
1-4
haloalkyl;
R
3
and R
4
each independently represents hydrogen, C
1-4
alkyl or C
1-4
haloalkyl;
R5a, R5b, R5c and R5d each independently represents hydrogen, C
1-4
alkyl optionally containing one double bond or one triple bond, C
1-4
alkoxy, halogen, cyano, —NH
2
, —CONR
7
R
8
(wherein R
7
and R
8
are as defined below), —NH(C
1-4
-alkyl), —N(C
1-4
-alkyl)
2
and C
2-5
alkanoyl; or R5a and R5b together represent
a) C4 alkylene optionally having one double bond;
b) C3 alkylene; or
c) —CH═CH—CH═CH—, —CH═CH—CH2— or —CH2—CH═CH— each optionally substituted with 1, 2, 3 or 4 substituents said substituents each independently selected from the group consisting of C
1-4
alkyl, C
1-4
alkoxy, halogen, cyano, nitro, C
2-5
alkanoyl and —CONR7R8 (wherein R7 and R8 are as defined below);
X represents O, NH or —CH
2
—;
Y represents O;
Z represents —V—W where V is —CH2—T— in which T is —CH2—, —O—, —S—, —(SO)— or —(SO
2
)— (provided that when V has sulphur or oxygen as its second atom, W is other than —COOH) and said group V optionally further carrying one or two substituents Q1 and/or Q2 on carbon;
wherein Q
1
and Q
2
each independently represents C
1-4
alkyl or halogen; or, when Q1 and Q2 are bonded to adjacent carbon atoms, Q
1
and Q
2
together may additionally represent a C
3
-C
4
alkylene radical optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C
1-4
alkyl and halogen; and
W represents
(1) COOH,
(2) —(C═O)—O—R6 wherein R6 represents a C
1-6
alkyl, C
3-6
cycloalkyl or aryl (as defined in 3 below) group;
(3) —(C═O)—NR7R8 wherein R7 and R8 each independently represent hydrogen or a C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl linked to N via carbon or C7-9aralkyl group wherein aryl is phenyl;
heteroaryl is a 5 or 6 membered ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and sulphur; the aryl moiety per se, the heteroaryl moiety and the aryl moiety of the aralkyl group may be substituted on carbon with 1-4 substituents selected from the group consisting of —COOH, —OH, —NH
2
, —CH
2
—NH
2
, —(CH2)
1-4
-COOH, tetrazol-5-yl and —SO
3
H and the alkyl moiety may optionally carry a methyl group;
(4) —SO
2
NHR9 wherein R9 is as defined for R7 but may additionally represent —CF
3
, —CH
2
CF
3
or aryl as defined above;
(5) SO
3
R10 in which R10 represents H, C
1-6
alkyl or C
3-6
cycloalkyl,
(6) PO
3
R10R10 (wherein the R10 radicals, which may be the same or different, are as herein defined)
(7) a tetrazol-5-yl group;
(8) —CONH—SO
2
R11 in which R11 represents
(a) C
3-7
cycloalkyl;
(b) C
1-6
-alkyl optionally substituted with substituents selected from the group consisting of aryl as defined below, C
1-4
-alkyl, CF
3
or halogen; and
(c) perfluoro-C
1-6
alkyl; wherein aryl is phenyl or phenyl having 1-5 substituents wherein the substituents are selected from the group consisting of halogen, —NO
2
, —CF
3
, C
1-4
alkyl, C
1-4
alkoxy, —NH
2
, —NHCOCH
3
, —CONH
2
, —OCH
2
COOH, —NH(C
1-4
-alkyl), —N(C
1-4
-alkyl)
2
, —NHCOOC
1-4
alkyl, —OH, —COOH, —CN and —COOC
1-4
alkyl; and
(9)-H-Het wherein H represents S, SO or SO2 and Het represents a 5 or 6 membered heterocyclic aromatic ring linked to M via a carbon atom of the aromatic ring, said aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N and S said aromatic ring optionally being substituted on carbon atoms of the ring with 1, 2, 3

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