Cytostatic agents

Details Cytostatic agents Cytostatic agents

2000-10-05

2002-12-17

Barts, Samuel (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S513000, C514S551000, C514S563000, C514S575000, C546S242000, C558S253000, C560S040000, C560S169000

Reexamination Certificate

active

06495597

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
This application is an 371 of PCT/9399/00053 filed Feb. 12, 1999 and claims priority from United Kingdom Patent Applications GB 9802968.9, filed on Feb. 13, 1998, and GB 9827804.7, filed on Dec. 16, 1998.
FIELD OF THE INVENTION
The present invention relates to N-formyl hydroxylamine derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine. In particular, the compounds are inhibitors of the proliferation of a range of rapidly dividing tumor cells, for example melanoma and/or lymphoma cells.
BACKGROUND TO THE INVENTION
Anti-Proliferative Agents
There is a need in cancer therapy for therapeutic compounds which are inhibitors of the proliferation of tumor cells. One compound which is known to have such activity is 5-fluorouracil (5-FU).
Patent publication WO 98/11063 describes and claims the use of certain hydroxamic acid derivatives as inhibitors of tumor cell proliferation, and also describes and claims certain novel hydroxamic acids useful for that purpose.
Anti-Metastatic and Anti-Invasive Agents
Compounds which have the property of inhibiting the action of the metalloproteinase enzymes involved in connective tissue breakdown and remodelling, such as fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1 (known as “matrix metalloproteinases”, and herein referred to as MMPs) have been proposed and are being tested in the clinic for the treatment of solid tumors. Cancer cells are particularly adept at utilising the MMPs to achieve rapid remodelling of the extracellular matrix, thereby providing space for tumor expansion and permitting metastasis. MMP inhibitors should minimise these processes and thus slow or prevent cancer progression.
MMP inhibitors having an N-formyl hydroxylamine group as the zinc binding group have been proposed in the following publications, although very few examples of such compounds have been specifically made and described therein:
EP-B-0236872 (Roche)
WO 92/09563 (Glycomed)
WO 92/04735 (Syntex)
WO 95/19965 (Glycomed)
WO 95/22966 (Sanofi Winthrop)
WO 95/33709 (Roche)
WO 96/23791 (Syntex)
WO 96116027 (Syntex/Agouron)
WO 97/03783 (British Biotech)
WO 97/18207 (DuPont Merck)
WO 98/38179 (GlaxoWellcome)
WO 98/47863 (Labs Jaques Logeais)
BRIEF DESCRIPTION OF THE INVENTION
This invention is based on the identification of a class of ester and thioester compounds containing an N-formyl hydroxylamine group, which inhibit proliferation of rapidly dividing cells. The ester and thioester compounds in question have certain structural similarities to known MMP inhibitors generically disclosed in the foregoing patent publications. However, most of those prior art publications are concerned with amides rather than esters or thioesters group. Despite the similarity of structure, it has been shown that compounds of the invention which have little or no MMP inhibitory activity are nonetheless potent inhibitors of such cell proliferation, implying a novel mechanism is at work. This antiproliferation property suggests a utility for the compounds of the present invention in the treatment of cancers.
The ester and thioester compounds useful according to the invention differ in structure from the hydroxamic acid derivatives disclosed as antiproliferative agents in WO 98/11063, mainly in that an N-formyl hydroxylamine group replaces the hydroxamic group.
Although the patent publications listed above predominantly disclose MMP inhibiting N-formyl hydroxylamine compounds having a terminal amide group, a few (WO 92/09563, WO 95/19965 and WO 95/22966) include within their generic disclosure compounds having a carboxylate ester group in place of the amide group. The carboxylate ester compounds with which this invention is concerned thus represent a selection of a notional subclass from the compounds proposed in the art as MMP inhibitors, for a specific and previously unrecognized pharmaceutical utility. The present inventors findings of inhibition of proliferation of rapidly dividing cells, including such tumor cells as lymphoma, leukemia, myeloma, adenocarcinoma, carcinoma, mesothelioma, teratocarcinoma, choriocarcinoma, small cell carcinoma, large cell carcinoma, melanoma, retinoblastoma, fibrosarcoma, leiomyosarcoma or endothelioma cells, by the esters and thioesters of the present invention, by a mechanism other than MMP inhibition, is not disclosed in or predictable from those earlier publications.
DETAILED DESCRIPTION OF THE INVENTION
In its broadest aspect, the present invention provides a method for inhibiting proliferation of tumor cells in mammals, comprising administering to the mammal suffering such proliferation an amount of a compound of general formula (I) or a pharmaceutically acceptable salt hydrate or solvate thereof sufficient to inhibit such proliferation:
wherein
R is hydrogen or (C
1
-C
6
)alkyl;
R
1
is hydrogen;
(C
1
-C
6
)alkyl or fluoro-substituted alkyl;
(C
2
-C
6
)alkenyl;
phenyl or substituted phenyl;
phenyl(C
1
-C
6
)alkyl or substituted phenyl(C
1
-C
6
)alkyl;
phenyl(C
2
-C
6
)alkenyl or substituted phenyl(C
2
-C
6
)alkenyl
heterocyclyl or substituted heterocyclyl;
heterocyclyl(C
1
-C
6
)alkyl or substituted heterocyclyl(C
1
-C
6
)alkyl;
a group BSO
n
A— wherein n is 0, 1 or 2 and B is hydrogen or a (C
1
-C
6
) alkyl, phenyl, substituted phenyl, heterocyclyl substituted heterocyclyl, (C
1
-C
6
)acyl, phenacyl or substituted phenacyl group, and A represents (C
1
-C
6
)alkylene;
amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, di(C
1
-C
6
)alkyamino(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, mercapto(C
1
-C
6
)alkyl or carboxy(C
1
-C
6
)alkyl
wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated;
lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino;
a cycloalkyl, cycloalkenyl, cycloalkyl(C
1
-C
6
alkyl)—, cycloalkenyl(C
1
-C
6
alkyl)— or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C
1
-C
6
alkyl, C
2
-C
6
alkenyl, halo, cyano(—CN), —CO
2
H, —CO
2
R, —CONH
2
, —CONHR, —CON(R)
2
, —OH, —OR, oxo—, —SH, —SR, —NHCOR, and —NHCO
2
R wherein R is C
1
-C
6
alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;
R
2
is a C
1
-C
12
alkyl,
C
2
-C
12
alkenyl,
C
2
-C
12
alkynyl,
phenyl(C
1
-C
6
alkyl)—,
heteroaryl(C
1
-C
6
alkyl)—,
phenyl(C
2
-C
6
alkenyl)—,
heteroaryl(C
2
-C
6
alkenyl)—,
phenyl(C
2
-C
6
alkynyl)—,
heteroaryl(C
2
-C
6
alkynyl)—,
cycloalkyl(C
1
-C
6
alkyl)—,
cycloalkyl(C
2
-C
6
alkenyl)—,
cycloalkyl(C
2
-C
6
alkynyl)—,
cycloalkenyl(C
1
-C
6
alkyl)—,
cycloalkenyl(C
2
-C
6
alkenyl)—,
cycloalkenyl(C
2
-C
6
alkynyl)—,
phenyl(C
1
-C
6
alkyl)O(C
1
-C
6
alkyl)—, or
heteroaryl(C
1
-C
6
alkyl)O(C
1
-C
6
alkyl)— group,
any one of which may be optionally substituted by
C
1
-C
6
alkyl,
C
1
-C
6
alkoxy,
halo,
cyano(—CN),
phenyl or heteroaryl, or
phenyl or heteroaryl substituted by
C
1
-C
6
alkyl,
C
1
-C
6
alkoxy,
halo, or
cyano(—CN);
R
3
is the characterising group of a natural or non-natural a amino acid in which any functional groups may be protected; and
R
4
is an ester or thioester group,
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
In another broad aspect of the invention, there is provided the use of a compound of formula (I) as defined in the immediately preceding paragraph, in the preparation of a pharmaceutical composition for inhibiting proliferation of tumor cells in mammals.
The present invention also provides novel compounds of general formula (I) above wherein R, R
1
, R
2
, R
3
and R
4
are as defined above with reference to formula (I), and pharmaceutically acceptable salts, hydrates or solvates thereof, PROVIDED THAT (i) R
3
is not a bicyclicarylmethyl group or (ii) R
2
is not a phenyl(C
1
-C
6
alkyl)O(C
1
-C
6
alkyl)—, or het

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