Cytostatic agents

Details Cytostatic agents Cytostatic agents

1998-06-19

2002-10-08

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

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C560S312000, C562S445000, C514S506000

Reexamination Certificate

active

06462023

ABSTRACT:

The invention relates to therapeutically active esters and thioesters, processes for preparing them, pharmaceutical compositions containing the same, as well as their uses, i.e., treating proliferative cell growth disorders and inhibiting cells characterized by with hyper-proliferative cell growth. A particular use contemplated by the compounds of the invention lies is the in vitro and in vivo inhibition of growth and proliferation of hyper-proliferative tumourgenic cells such as melanoma and/or lymphoma cells.
BACKGROUND OF 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 remodeling, 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 tumours.
Cancer cells are particularly adept at utilizing MMPs to achieve rapid remodeling of the extracellular matrix, thereby providing space for tumour expansion and permitting metastasis. Accordingly, MMP inhibitors should minimize 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 presented 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:
U.S. Pat. No.
(Searle)
WO 93/24475
(Celltech)
4599361
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)
U.S. Pat. No.
(Glycomed)
WO 94/25434
(Celltech)
5183900
U.S. Pat. No.
(Glycomed)
WO 94/25435
(Celltech
5270326
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)
U.S. Pat. No.
(Sterling)
WO 95/09841
(British Biotech)
5256657
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
(CeIItech)
WO 95/22966
(Sanofi Winthrop)
WO 95/23790
(SB)
It is noteworthy that all of the compounds embraced by formula (1A) generally act extracellulary and are not shown to enter the target cells i.e., tumourgenic cells, in order to perform their respective functions.
International patent application No. PCT/GB97/02398 describes, inter alia, a method for inhibiting growth and proliferation of tumour cells in mammals. The method comprises administering to a mammal in need thereof an inhibiting amount of a compound of general formula (1) or a pharmaceutically acceptable salt hydrate or solvate thereof sufficient to inhibit proliferation the tumour cells:
wherein
R is hydrogen or (C
1
-C
6
)alkyl;
R
1
is hydrogen;
(C
2
-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
1
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
1
-C
12
alkenyl,
C
1
-C
12
alkynyl,
phenyl(C
1
-C
6
alkyl)- ,
heteroaryl(C
1
-C
6
alkyl)- ,
phenyl(C
1
-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);
R
3
is the characterizing 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.
Objects and Summery of the Invention
An object of the invention resides in providing anti-proliferative ester and thioester's which inhibit proliferation of rapidly dividing cells that generally attend proliferative cell growth disorders. Exemplary of such disorders are lymphoma, leukemia, myeloma, adenocarcinoma, carcinoma, mesothelioma, teratocarcinoma, choriocarcinoma, small cell carcinoma, large cell carcinoma, melanoma, retinoblastoma, fibrosarcoma, leiomyosarcoma or endothelioma 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. However, 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 anti-proliferation property suggests a utility for the compounds of the present invention in the treatment of cancers. That the compounds of the invention i.e., esters and thioesters maybe used to inhibit growth and proliferation of cells with hyper-proliferative cell growth is neither disclosed nor taught by the prior art.
Although the patent publications listed above predominantly disclose MMP inhibiting compounds of formula (IA), i.e., 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 f

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