Process for preparing benzoperhydroisoindole compounds

Details Process for preparing benzoperhydroisoindole compounds Process for preparing benzoperhydroisoindole compounds

1999-07-26

2001-09-18

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S426000

Reexamination Certificate

active

06291679

ABSTRACT:

The present invention relates to a novel process for the preparation of compounds of benzoperhydroisoindole type of general formula (I):
The compounds of general formula and their activity as farnesyl transferase inhibitors are disclosed in Applications WO 98/29390 and FR 2,772,764.
The protein farnesyl transferase is an enzyme which catalyzes 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 signaling pathways and cell division processes. The mutation of the ras oncogene or its overexpression 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 overexpression of an oncoprotein, the signaling 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) or such as rhoB (Wei et al., Molecular and Cellular Biology, 19, 1831-1840, 1999). The inhibitors of Farnesyl transferase are inhibitors of cell proliferation and consequently antitumor and antileukemic agents.
The process for the preparation of the compounds of general formula (I) is also disclosed in Applications WO 98/29390 and FR 2,772,764: According to this process, the final compounds are obtained in the form of a racemic mixture, which requires a subsequent separation of the enantiomers constituting this mixture. The result of this is therefore a problematic additional stage, the consequence of which is to decrease the overall yield with respect to the starting material and to each of the reactants.
According to the present invention, a process has been discovered which makes it possible to obtain the products of general formula (I) directly in the form of optical isomers, without employing a separation. This process comprises an enzymatic stage which makes possible the enantiomeric resolution of the compounds of general formula (I).
The present invention therefore relates to a process for the preparation of the optical isomers of the compounds disclosed in Applications WO 98/29390 and FR 2,772,764, which are incorporated here by reference.
The compounds capable of being prepared by the process according to the present invention are the compounds of general formula (I):
in which:
A represents:
either a phenyl radical fused with the isoindole nucleus, and in this case:
R
3
and R
4
, which are identical or different, represent a hydrogen or halogen atom or an alkyl, hydroxyl, alkyloxy, alkylcarbonyloxy, mercapto, alkylthio, alkylsulfonyl or alkylsulfinyl, amino, alkylamino or dialkylamino, alkyloxycarbonylamino, carboxyl, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, formyl, alkylcarbonyl, cyano or trifluoromethyl radical,
preferably, either R
3
and R
4
each represent a hydrogen atom or alternatively one of the R
3
or R
4
symbols represents a hydrogen atom and the other of the R
3
or R
4
symbols represents a methoxy radical, more advantageously at the 5 position of the benzoperhydroisoindole nucleus;
very advantageously, R
3
and R
4
each represent a hydrogen atom;
with, for all of the radicals possessing an alkyl group provided in the definition of R
3
and R
4
, alkyl comprising 1 to 4 carbon atoms,
or A represents a monocyclic or condensed bi- or tricyclic system in which each saturated or unsaturated ring comprises from 4 to 7 members and in which at least one of the rings comprises from 1 to 4 identical or different heteroatoms chosen independently from nitrogen, oxygen and sulfur atoms; this optionally substituted heterocyclic system can be condensed with the isoindole nucleus by any 2 of its adjacent atoms; A preferably represents a 5- to 9-membered aromatic mono- or bicyclic system comprising a nitrogen or sulfur atom; it also being possible for A to be chosen, without implied limitation, from the following radicals: thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, chromenyl, indolyl or quinolyl, as well as their iso isomers;
preferably, A represents a thienyl or indolyl radical; advantageously, according to the invention, A represents thienyl;
and in this case R
3
and R
4
represent a hydrogen atom,
Ar represents
a phenyl radical optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: alkyl comprising 1 to 4 carbon atoms, such as methyl, alkenyl comprising 2 to 4 carbon atoms, hydroxyl, mercapto, alkylthio, alkylsulfonyl or alkylsulfinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, or alkoxy comprising 1 to 4 carbon atoms, such as methoxy, the alkyl portion of which is optionally perhalogenated, such as trifluoromethoxy, or
a phenyl radical condensed with a 4- to 7-membered heterocycle comprising one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, it being possible for the bicyclic system thus formed to be in particular chosen from 2,3-dihydro-1,4-benzodioxin-6-yl or 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzopyran-6-yl or benzothienyl radicals or
a polycyclic aromatic or nonaromatic radical, such as 1- or 2-naphthyl or 5-indanyl or 1,2,3,4-tetrahydronaphth-6-yl
a 5- to 12-membered heterocyclic aromatic or nonaromatic radical incorporating one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, bonded to the condensed ring via a carbon-carbon bond, said radical being substituted, if appropriate, by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: alkyl, alkenyl comprising 2 to 4 carbon atoms, hydroxyl, alkoxy comprising 1 to 4 carbon atoms, mercapto, alkylthio, alkylsulfonyl or alkylsulfinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, preferably Ar represents a 2,3-dihydro-1,4-benzodioxin-6-yl or 2,3-dihydrobenzofuran-5-yl or benzothienyl radical or a phenyl radical optionally substituted at the 2 and/or 4 position, preferably by a halogen atom or a methyl, trifluoromethyl or methoxy radical; in particular, the 2,3-dihydro-1,4-benzodioxin-6-yl or benzothienyl radical; very advantageously, Ar represents a phenyl radical optionally substituted at the 4 position by a methyl radical or at the 2,4 position by a halogen atom, with, for all of these radicals, alkyl comprising 1 to 4 carbon atoms,
R represents
a radical of general formula
—(CH
2
)
m
—X
1
—(CH
2
)
n
—Z
in which
X
1
represents a single bond or an oxygen or sulfur atom,
m represents an integer equal to 0 or 1,
n represents an integer equal to 0, 1 or 2,
one or more methylene radicals can be substituted by a carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amino, alkylamino or dialkylamino radical with, for all of these radicals, alkyl comprising 1 to 4 carbon atoms,
Z represents
a carboxyl radical,
a COOR
6
radical, in which R
6
represents a straight or branched alkyl radical comprising 1 to 3 carbon atoms, such as the methyl, or
a radical of formula CON(R
7
) (R
8
) in which
R
7
represents a hydrogen a

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