Therapeutic agents

Details Therapeutic agents Therapeutic agents

1999-11-09

2002-01-01

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S049000, C514S050000, C536S027400, C536S028500

Reexamination Certificate

active

06335322

ABSTRACT:

This invention relates to certain nucleoside derivatives which have been found to have valuable properties for the treatment of tumours.
The nucleoside derivatives are esters of 1-&bgr;-D-arabinofuranosylcytosine (Ara-C) of formula A:
Ara-C is also sometimes known as cytosar.
Ara-C has long been known as a chemotherapeutic agent in the treatment of acute myelogenous leukaemia but has limited efficiency against solid tumours (Fre et al., Cancer Res. 29 (1969), 1325-1332; Davis et al., Oncology, 29 (1974), 190-200; Cullinan et al., Cancer Treat. Rep. 61 (1977), 1725-1726). However, even in the treatment of leukaemia Ara-C has found only limited use due to its very short biological half-life and its high toxicity.
With a view to overcoming these difficulties, a number of workers have prepared and tested pro-drug derivatives of Ara-C. For example, Hamamura et al. investigated 3′-acyl and 3′,5′-diacyl derivatives of Ara-C (J. Med. Chem. 19 (1976) No. 5, 667-674). These workers prepared and tested numerous Ara-C derivatives with saturated or unsaturated ester groups containing from 2 to 22 carbon atoms, and they found that many of the compounds showed a higher activity against L1210 Leukaemia in mice than the parent nucleoside alone.
The work by Hamamura et al., and others, on pro-drug analogues of Ara-C was reviewed by Hadfield et al. in Advances in Pharmacology and Chemotherapy, 20, 1984, pages 21-67. In discussing 5′-esters of Ara-C, these authors conclude (page 27):
“ . . . though many of these agents appear to function as very efficient depot forms of ara-C in mice, the analogous action in man has not been demonstrated.”.
Although work has continued on pro-drugs based on Ara-C, including 3′- and 5′-acyl derivatives (see, for instance, Rubas et al. in Int. J. Cancer, 37, 1986, pages 149-154 who tested liposomal formulations of, inter alia, 5′-oleyl-Ara-C against L1210 Leukaemia and Melanoma B16) to date no such drugs have become available to the clinician.
The mode of action of Ara-C relies on its enzymatic recognition as a 2′-deoxy-riboside and subsequent phosphorylation to a nucleoside triphosphate which competes with the normal CTP for incorporation into DNA. The 2′-hydroxyl group causes steric hindrance to rotation of the pyrimidine base around the nucleosidic bond. The bases of polyarabinonucleotides cannot stack normally, as do the bases of polydeoxynucleotides. Ara-C inhibits DNA repair and DNA synthesis both by slowing down chain elongation and movement of newly replicated DNA through the matrix-bound replication apparatus. The mechanism of action of Ara-C results in an “unbalanced growth” in dividing cells. Ara-C acts in the S-phase of the cell cycle. For continuos inhibition of the DNA synthesis and finally cell death, it is crucial that Ara-C is a present at a sufficiently high concentration during at least one cell cycle.
A main reason why Ara-C is not used in the treatment of solid tumours is again the rapid clearance of the active drug from cancer cells and plasma. It is apparently not possible to achieve significant intracellular levels of drug in the neoplastic tissue, even though the tumour in question is sensitive to Ara-C in-vitro. The surprisingly prolonged half life and altered tissue distribution. of the products of this invention will be of great importance for the therapeutic effect of these products.
We have found, as shown in
FIGS. 7
,
8
and
9
, that 3′- and 5′-O-esters of Ara-C and certain saturated and unsaturated fatty acids unexpectedly exhibit good activity against different tumours in contrast to Ara-C itself and also other mono- and diesters.
It is felt by the present inventors that the test model which is commonly used (injection of leukaemia cells into the abdominal cavity of mice and treated i.p.) is more comparable to an in vitro model than to an actual clinical situation and may have served to hide the particularly valuable properties of the selected Arab esters used in the present invention, as will be described below.
More specifically, the 3′- and 5′-O-esters which are used according to the present invention are those which are derived from C
18
or C
20
saturated and monounsaturated fatty acids.
Thus, the esters used according to the present invention may be represented by the formula 1:
wherein R
1
and R
2
are independently selected from hydrogen, and C
18
- and C
20
- saturated and mono-unsaturated acyl groups, with the provisos that R
1
and R
2
cannot both be hydrogen.
The double bond of the mono-unsaturated acyl groups may be in either the cis or the trans configuration, although the therapeutic effect may differ depending on which configuration is used.
The position of the double bond in the mono-unsaturated acyl groups also seems to affect the activity. Currently, we prefer to use esters having their unsaturation in the &ohgr;-9 position. (In the &ohgr;-system of nomenclature, the position (&ohgr;) of the double bond of a monounsaturated fatty acid is counted from the terminal methyl group, so that, for example, eicosenoic acid (C
20
:1 &ohgr;-9) has 20 carbon atoms in the chain and the single double bond is formed between carbon atoms 9 and 10 counting from the methyl end of the chain). Thus, we prefer to use Ara-C esters derived from oleic acid (C
18
:1, &ohgr;-9, cis) elaidic acid (C
18
:1, &ohgr;-9, trans) and eicosenoic acid (C
20
:1, &ohgr;-9, cis) and (C
20
:1, &ohgr;-9, trans) and stearic acid (C
18
:0) and eicosanoic acid (C
20
:0).
Both 3′-O- and 5′-O-monoesters and 3′, 5′-O-diesters can be used in the treatment of different tumours in accordance with the present invention, but in general the 5′-O-monoesters are preferred. The 3′,5′-O-diesters are expected to be useful in those cases where lipophilic properties are of advantage, e.g. absorption or uptake in lipid tissues.
The compounds of formula (I) wherein R
1
and R
2
are independently selected from hydrogen, elaidoyl, oleoyl. stearoyl, eicosenoyl (cis or trans) and eicosanoyl, with the provisos that R
1
and R
2
cannot both be hydrogen, oleoyl or stearoyl, R
1
cannot be hydrogen when R
2
is oleoyl or stearoyl, and R
2
cannot be hydrogen when R
1
is elaidoyl, oleoyl or stearoyl, are new compounds not previously reported in the prior art.
More specifically these new compounds of formula (1) are defined in the below Table A wherein R
1
and R
2
are as given:
TABLE A
R
1
R
2
hydrogen
elaidoyl
hydrogen
eicosenoyl (cis)
hydrogen
eicosenoyl (trans)
eicosenoyl (cis)
hydrogen
eicosenoyl (trans)
hydrogen
eicosenoyl (cis)
eicosenoyl (cis)
eicosenoyl (trans)
eicosenoyl (trans)
eicosenoyl (cis)
eicosenoyl (trans)
eicosenoyl (trans)
eicosenoyl (cis)
eicosenoyl (cis)
elaidoyl
eicosenoyl (trans)
elaidoyl
elaidoyl
eicosenoyl (cis)
eiaidoyl
eicosenoyl (trans)
eicosenoyl (cis)
oleoyl
eicosenoyl (trans)
oleoyl
oleoyl
eicosenoyl (cis)
oleoyl
eicosenoyl (cis)
eicosanoyl
eicosanoyl
eicosanoyl
stearoyl
stearoyl
eicosanoyl
elaidoyl
stearoyl
eicosenoyl (cis)
stearoyl
eicosenoyl (trans)
stearoyl
elaidoyl
eicosanoyl
eicosenoyl (cis)
eicosanoyl
eicosenoyl (trans)
eicosanoyl
stearoyl
oleoyl
oleoyl
stearoyl
A limiting factor for the use of Ara-C is its degradation by cytidine deaminase and deoxycytidine-monophosphate (dCMP) deaminase to inactive metabolites. We have surprisingly found that the monoesters of this invention are poor substrates for these deactivating enzymes. This difference could imply that these ester-derivatives are more suited than Ara-C itself for systemic or local treatment of malignant tumours, especially malignant tumours in the RES and CNS.
This is clearly demonstrated in the leukaemia brain-metastasis model described in
FIGS. 10
,
11
and
12
and especially with the more aggressive B-cell lymphoma shown in
FIG. 11
were Ara-C itself is void of activity.
In the clinical treatment of myelogenous leukaemia, the rapid deactivation of Ara-C is compensated by continues infusion over 5-7 days to establish a reasonably stable therapeutic acti

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