Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-02
2001-04-17
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...
C514S323000, C514S410000, C514S423000, C546S200000, C546S276700, C548S425000
Reexamination Certificate
active
06218406
ABSTRACT:
The present invention relates to novel benzoperhydroisoindole derivatives, to their preparation, to the pharmaceutical compositions which contain them and to their use in the preparation of medicaments.
The protein farnesyl transferase is an enzyme which catalyses the transfer of the farnesyl group from farnesyl pyrophosphate (FPP) to the terminal cysteine residue of the tetrapeptide sequence CAAX of a certain number of proteins and in particular of the p21Ras protein, which expresses the ras oncogene. The ras (H-, N- or K-ras) oncogene is known to play a key role in cell signalling pathways and cell division processes. The mutation of the ras oncogene or its over expression is often associated with human cancer: the mutated p21Ras protein is found in many human cancers and in particular in more than 50% of cancers of the colon and 90% of cancers of the pancreas (Kohl et al., Science, 260, 1834-1837, 1993).
The inhibition of farnesyl transferase and consequently of the farnesylation of the p21Ras protein blocks the ability of the mutated p21Ras protein to induce cell proliferation and to transform normal cells into cancerous cells.
Moreover, it has been demonstrated that farnesyl transferase inhibitors are also active with respect to tumoral cell lines which do not express mutated or overexpressed ras, but which exhibit the mutation of an oncogene or the over expression of an oncoprotein, the signalling pathway of which uses the farnesylation of a protein, such as a normal ras (Nagasu et al., Cancer Research 55, 5310-5314, 1995; Sepp-Lorenzino et al., Cancer Research 55, 5302-5309, 1995).
The inhibitors of the protein farnesyl transferase are inhibitors of cell proliferation and consequently are antitumour and antileukaemic agents.
It has now been discovered, and this is also a subject of this invention, that the novel compounds of formula (I) presented hereinbelow possess, entirely surprisingly and unexpectedly, an inhibitory activity for the protein farnesyl transferase and prove to be notable antitumour and antileukaemic agents.
In particular, it has been discovered, according to the invention, that the biological activity of the compounds according to the invention is very markedly improved, contrary to all expectations, by the presence of specific groups (represented by Ar hereinbelow) substituted at the 9 position of the benzoperhydroisoindole skeleton.
In particular, the corresponding compounds exhibit activities which are much higher than those obtained to date with compounds having similar structures but not having these Ar substituents.
The present invention relates to the novel compounds of formula (I):
in which:
Ar represents
a phenyl radical substituted by one or more atoms or radicals, which are identical or different and are selected from halogen atoms and the radicals: alkyl, alkenyl containing 2 to 4 carbon atoms, hydroxyl, mercapto, alkylthio, alkylsulphonyl, alkylsulphinyl, amino, alkylamino, dialkylamino, formyl, alkylcarbonyl, carboxyl, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, and alkyloxy, the alkyl portions and radicals being optionally perhalogenated, or
a phenyl radical condensed with a 4- to 7-membered nonaromatic heterocycle containing one or more heteroatoms selected from oxygen, nitrogen and sulphur atoms, or
a polycyclic aromatic radical, wherein the polycylic aromatic radical can contain at least one cycle that is saturated or only partially unsaturated but at least one cycle thereof must be aromatic, or
a monocyclic 5- to 12-membered heterocyclic aromatic radical incorporating one or more heteroatoms selected from oxygen, nitrogen and sulphur atoms, the heterocyclic aromatic radical being bonded to the condensed ring via a carbon—carbon bond and optionally being substituted by one or more atoms or radicals, which are identical or different and are selected from halogen atoms and the radicals: alkyl, alkenyl containing 2 to 4 carbon atoms, hydroxyl, alkyloxy, mercapto, alkylthio, alkylsulphonyl, alkylsulphinyl, amino, alkylamino, dialkylamino, formyl, alkylcarbonyl, carboxyl, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, and trifluoromethyl,
wherein each of the alkyl portions and radicals in the definition of Ar contains 1 to 4 carbon atoms;
R represents
a radical of formula:
—(CH
2
)
m
—X
1
—(CH
2
)
n
—Z
in which
X
1
represents a single bond or an oxygen or sulphur atom,
m represents an integer equal to 0 or 1, and
n represents an integer equal to 0, 1 or 2;
wherein one or more methylene radicals in said R radical can be substituted by a carboxyl, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amino, alkylamino or dialkylamino radical, wherein each of the alkyl portions and radicals in the definition of R contains 1 to 4 carbon atoms;
Z represents
a carboxyl radical, or
a COOR
6
radical, in which R
6
represents a straight or branched alkyl radical containing 1 to 3 carbon atoms, or
a radical of formula CON(R
7
)(R
8
) in which
R
7
represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms, and
R
8
represents
a hydrogen atom, or
a hydroxyl radical, or
an arylsulphonyl radical, optionally substituted by one or more atoms or radicals, which are identical or different and are selected from halogen atoms and alkyl and alkyloxy radicals, or
a 5- to 7-membered heterocycle incorporating one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, it being possible for said heterocycle to be bonded to the N in said CON(R
7
)(R
8
) radical via a heteroatom, or
an amino radical optionally substituted by one or two radicals, which are identical or different and are selected from the radicals:
alkyl,
carbocyclic aryl, optionally substituted by one or more radicals, which are identical or different and are selected from alkyl and alkyloxy radicals,
5- to 7-membered heterocyclyl containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms,
arylcarbonyl, optionally substituted by one or more radicals, which are identical or different and are selected from alkyl and alkyloxy radicals,
or R
8
represents an alkyloxy radical containing 1 to 6 straight- or branched-chain carbon atoms optionally substituted by a phenyl radical, or
a straight or branched alkyl radical containing 1 to 6 carbon atoms, optionally substituted by at least one radical selected from amino, alkylamino, dialkylamino, hydroxyl, alkyloxy, mercapto, alkylthio, alkyloxycarbonyl, carboxyl, cyano, and optionally substituted mono- and polycyclic aromatic having from 5 to 12 ring members which may or may not incorporate one or more heteroatoms selected from oxygen, nitrogen and sulphur atoms, it being possible for the mono- and polycyclic aromatic radicals incorporating one or more nitrogen heteroatoms to be in the form of the N-oxide,
or Z represents
a PO(OR
9
)
2
radical in which R
9
represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms, or
an —NH—CO—T radical in which T represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms, optionally substituted by an amino, carboxyl, alkyloxycarbonyl, hydroxyl, alkyloxy, mercapto, or alkylthio radical, or
a
radical having an anion as a counterion,
wherein each of the alkyl portions and radicals provided in the definition of Z, including, for example, R
8
, which is part of Z, and that is not of a specifically defined carbon length contains 1 to 4 carbon atoms;
R
1
and R
2
, which are identical or different, are selected from a hydrogen atom, a halogen atom, an alkyl radical, and an alkyloxy radical, wherein each of said radicals may optionally be substituted by a dialkylamino radical, wherein the two alkyl portions of said dialkylamino radical may form, together with the nitrogen atom to which they are attached, a saturated heterocycle containing 5 or 6 ring members, and from an alkylthio radical and an alkyloxycarbonyl radical; or alternatively, situated at the ortho position with
Bourzat Jean-Dominique
Capet Marc
Cheve Michel
Commercon Alain
Dereu Norbert
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Stockton Laura L.
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