Cytostatic agents

Details Cytostatic agents Cytostatic agents

1997-09-08

2001-01-02

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S575000, C562S445000, C562S553000

Utility Patent

active

06169075

ABSTRACT:

The present invention relates to therapeutically active esters and thioesters, 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 tumour 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 tumour cells. One compound which is known to have such activity is 5-fluorouracil (5-FU).
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 metalloproteinase”, and herein referred to as MMPs) have been proposed and are being tested in the clinic for the treatment of solid tumours. Cancer cells are particularly adept at utilising the MMPs to achieve rapid remodelling of the extracellular matrix, thereby providing space for tumour expansion and permitting metastasis. MMP inhibitors should minimise these processes and thus slow or prevent cancer progression.
A known class of MMP inhibitors having a hydroxamic acid group as the zinc binding group may be represented by the structural formula (IA)
in which the groups R
1
to R
5
are variable in accordance with the specific prior art disclosures of such compounds. Examples of patent publications disclosing MMP inhibitors of formula (IA) are:
US 4599361
(Searle)
WO 93/24475
(Celltech)
EP-A-2321081
(ICI)
EP-A-0574758
(Roche)
EP-A-0236872
(Roche)
EP-A-0575844
(Roche)
EP-A-0274453
(Bellon)
WO 94/02446
(British Biotech)
WO 90/05716
(British Biotech)
WO 94/02447
(British Biotech)
WO 90/05719
(British Biotech)
WO 94/21612
(Otsuka)
WO 91/02716
(British Biotech)
WO 94/21625
(British Biotech)
WO 92/09563
(Glycomed)
WO 94/24140
(British Biotech)
US 5183900
(Glycomed)
WO 94/25434
(Celltech)
US 5270326
(Glycomed)
WO 94/25435
(Celltech
WO 92/17460
(SB)
WO 95/04033
(Celltech)
EP-A-0489577
(Celltech)
WO 95/04735
(Syntex)
EP-A-0489579
(Celltech)
WO 95/04715
(Kanebo)
EP-A-0497192
(Roche)
WO 95/06031
(Immunex)
US 5256657
(Sterling)
WO 95/09841
(British Biotech)
WO 92/13831
(British Biotech)
WO 95/12603
(Syntex)
WO 92/22523
(Research Corp)
WO 95/19956
(British Biotech)
WO 93/09090
(Yamanouchi)
WO 95/19957
(British Biotech)
WO 93/09097
(Sankyo)
WO 95/19961
(British Biotech)
WO 93/20047
(British Biotech)
WO 95/19965
(Glycomed)
WO 93/24449
(Celltech)
WO 95/22966
(Sanofi Winthrop)
WO 95/23790
(SB)
BRIEF DESCRIPTION OF THE INVENTION
This invention is based on the identification of a class of ester and thioester compounds which inhibit proliferation of rapidly dividing cells. The ester and thioester compounds in question have certain structural similarities to known MMP inhibitors of general formula (IA) above disclosed in the foregoing patent publications. How ever, instead of the amide group —CONR
4
R
5
of formula (IA), they have an ester or thioester 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.
Although the patent publications listed above predominantly disclose MMP inhibiting compounds of formula (IA), ie having an amide group —CONR
4
R
5
, a few (WO 92/09563, U.S. Pat. No. 5,183,900, U.S. Pat. No. 5,270,326, EP-A-0489577, EP-A-0489579, WO 93/09097, WO 93/24449, WO 94/25434, WO 94/25435, WO 95/04033, 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 unrecognised pharmaceutical utility.
WO 95/04033 discloses N
4
-hydroxy-N
1
-(1-(S)-methoxycarbonyl-2,2-dimethylpropyl)-2-(R)-(4-chlorophenylpropyl)succinamide as an intermediate for the preparation of the corresponding methylamide MMP inhibitor. In addition,
Int. J. Pept. Protein Res
. (1996), 48(2), 148-155 discloses the compound
Ph—CH
2
CH(CO-Ile-OtBu)CH
2
CONHOH
as an intermediate in the preparation of compounds which are inhibitors of neurotensin-degrading enzymes. However, those two appear to be the only specific known carboxylate ester compounds of the kind with which this invention is concerned.
The present inventors' findings of inhibition of proliferation of rapidly dividing cells, including such tumour 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 tumour 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;
(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;
hydroxy or (C
1
-C
6
)alkoxy;
amino, protected amino, acylamino, (C
1
-C
6
)alkylamino or di-(C
1
-C
6
)alkylamino;
mercapto or (C
1
-C
6
)alkylthio;
amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, di(C
1
-C
6
)alkylamino(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; or
a cycloalkyl, cycloalkenyl 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
phenyl substituted by
C
1
-C
6
alkyl,
C
1
-C
6
alkoxy,
halo, or
cyano (—CN

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