Cycloheptene compounds

Details Cycloheptene compounds Cycloheptene compounds

2002-01-16

2003-10-28

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S357000, C546S330000, C546S334000, C546S329000, C548S336100, C548S335500, C548S339500, C548S340100

Reexamination Certificate

active

06638962

ABSTRACT:

SUMMARY OF THE INVENTION
The present invention relates to new cycloheptene compounds, to a process for their preparation and to pharmaceutical compositions containing them.
The compounds of the invention are useful as farnesyl transferase inhibitors.
DESCRIPTION OF THE PRIOR ART
A large number of proteins are subject to post-translational changes which alter their localisation and their function. In particular, lipid-type modifications allow certain proteins that are inactive in their free form to be anchored in the plasma membrane, which is a crucial step for ensuring their function. This applies to prenylation (
Curr. Opin. Cell. Biol.,
4, 1992, 1008-1016), which is catalysed by several enzymes: farnesyl transferase (FTase) and the two geranylgeranyl transferases (GGTase-I and GGTase-II) which couple a prenyl group to 15 (trans,trans-farnesyl) or 20 (all-trans-geranylgeranyl) carbons on the carboxy terminal moiety of substrate proteins (
J. Biol. Chem.,
271, 1996, 5289-5292;
Curr. Opin. Struct. Biol.,
7, 1997, 873-880). FTase catalyses that transfer, starting from farnesyl pyrophosphate, to form a thio ether bond on the cysteine of the terminal tetrapeptide consensus sequence CA
1
A
2
X found on substrate proteins, C denoting cysteine, A
1
and A
2
denoting an aliphatic amino acid and X denoting a serine, an alanine or a methionine. GGTase-I uses geranylgeranyl pyrophosphate as donor substrate for effecting a similar transfer, but this time the consensus sequence CAAX is terminated by a leucine or a phenylalanine. Those two heterodimeric enzymes share an alpha subunit of 48 kDa, and possess two distinct beta chains, although they have 30% homology of amino acid sequences. GGTase-II acts on terminal sequences of the XXCC and XCXC types and has alpha and beta subunits different from those of the afore-mentioned enzymes.
The interest in inhibiting one of those enzymes, FTase, is based on the implication in tumour progression of the prenylated oncogene Ras (
Annu. Rev. Biochem.,
56, 1987, 779-827). Ras proteins exist in four major forms, Harvey or H-Ras, N-Ras, and Kirsten or K-Ras A and B. Those proteins are expressed in a mutated form in at least a quarter of cancers with an even greater incidence for some histological types of tumour and according to the form of Ras. For example, mutations of K-Ras B are found in 80 to 90% of pancreatic carcinomas and 30 to 60% of colon cancers (
Int. J. Oncol.,
7, 1995, 413-421). Numerous preclinical data have demonstrated the role of that oncogene in tumour progression, more especially in cell growth phenomena. It is an essential link in the transmission of extracellular signals—such as those activated by growth factors—to diverse cytosolic kinases and then to the nucleus, for integration in terms of proliferation, cell death and cell survival (
Cancer Met. Rev.,
13, 1994, 67-89
; Curr. Opin. Genetics
&
Develop.,
8, 1998, 49-54
; J. Biol. Chem.
273, 1998, 19925-19928), or of regulation with the tumour environment—angiogenesis in particular (
Cancer Res.,
55, 1995, 4575-4580).
BACKGROUND OF THE INVENTION
The search for FTase inhibitors is thus of considerable interest in oncology (
Curr. Opin. Chem. Biol.,
2, 1998, 40-48). As 0.5% of animal proteins are probably prenylated and in the majority geranylgeranylated, specific inhibitors of FTase relative to the GGTases, and more especially GGTase-I, which is similar in structure to FTase, are of considerable interest. The first work with such inhibitors, peptidomimetic analogues of the farnesylation consensus sequence, and the following work with molecules obtained by chemical library screening, confirmed the anti-tumour strategy in in vitro and animal experiments (
Annu. Rev. Pharmacol. Toxicol.,
37, 1997, 143-166;
Biochim. Biophys. Acta,
1423, 1999, C19-C30;
Cancer Res.,
58, 1998, 4947-4956). Fibroblasts specially transfected with the mutated H-Ras protein gene and implanted in an animal develop a tumour mass the growth of which is reduced as a function of the dose of FTase inhibitor received by the animal. In the case of transgenic animals that express a mutated form of H-Ras under the control of an appropriate promoter causing the random appearance of spontaneous mammary or salivary tumours, those same inhibitors bring about the regression of established tumours and block the appearance of new ones for the duration of the treatment. Finally, such products are also active in reducing the growth of human xenotransplants in the mouse, with a possible effect of increasing survival, depending on the model. The mutated Ras protein is not the only indirect target of those inhibitors in tumour pathology. The study of multiple tumour models has enabled confirmation of inhibition of tumour growth independently of the presence of mutated Ras proteins. That effect could be partly associated with a direct antiangiogenic activity and thus could be independent of the oncogenic profile of the tumour (
Eur. J. Cancer,
35, 1999, 1394-1401). This observation reinforces and increases the potential for anti-tumour use of that class of inhibitors, and the absence of debilitating side effects on normal cell functions is also favourable for the inhibition of FTase in any pathology associated with mechanisms changed or amplified by a farnesylated protein or by farnesylated proteins. Aside from cancer, this applies especially, for example, to restenosis following angioplasty or vascular surgery, and to type I neurofibromatosis (
Mol. Cell. Biol.,
17, 1997, 862-872).
The compounds of the invention have a novel structure and are capable of selective inhibition of FTase relative to the GGTases. They will accordingly be useful in the treatment of all pathologies associated with intracellular signalling through Ras proteins or other farnesylated proteins, and in pathologies associated with angiogenesis amplification. They will thus be of use in the treatment of cancer, but also in the treatment of restenosis following angioplasty or vascular surgery, and in the treatment of type I neurofibromatosis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula (I):
wherein:
X represents a bond or a group selected from alkylene, CO, S(O)
n
, *—S(O)
n
—A
1
—, *—CO—A
1
—, —A
1
—S(O)
n
—A′
1
— and —A
1
—CO—A′
1
— (wherein A
1
and A′
1
, identical or different, represent an alkylene group and n is 0, 1 or 2), the symbol “*” indicating the point of attachment of those groups to the cycloheptene,
Y represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of those groups being unsubstituted or substituted by one or more, identical or different, R
8
groups,
R
1
, R
2
, R
3
and R
4
each independently of the others represent a hydrogen atom or an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of those groups being unsubstituted or substituted by one or more, identical or different, R
8
groups,
or R
1
, R
2
, R
3
and R
4
, taken in pairs, together form a bond,
or R
1
and R
2
, or R
2
and R
3
, or R
3
and R
4
, taken in pairs with the carbon atoms to which they are bonded, form a fused benzene ring or a fused aromatic or partially unsaturated heterocycle, having 5 or 6 ring members and containing 1 or 2 hetero atoms selected from nitrogen, oxygen and sulphur, on the understanding that only one ring can be fused on the 7-membered structure,
T represents a —CH(R
5
)—, —N(R
5
)— or *—N(R
5
)CO— group (wherein R
5
represents a hydrogen atom or an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group, each of those groups being unsubstituted or substituted by one or more, identical or different, R
7
groups), the symbol “*” indicating the point of attachment of the group to the cycloheptene,
V represents a hydrogen atom or an aryl or heteroaryl group, each of those groups being unsubstituted or substituted by one or more, identical or different, R
7
groups,
A
2
represents a [C(R
6
)(R′
6
)]
p
group wherein p is 0, 1, 2, 3 or 4 when T represents a —CH(R
5
)— or *—N(R
5
)CO— group, or p is 1, 2, 3 or 4 when

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