Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-09-03
1999-12-28
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5462804, 546219, 546220, C07D21322, C07D40900, C07D41100, C07D21140
Patent
active
060083603
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE
This application is a 317 of PCT/FR97/00388 filed Mar. 5, 1997.
The present invention relates to novel glutarimides 3,3-disubstituted with an aryl group and a carboxy (C.sub.1 -C.sub.2)alkyl group, a method for their preparation via novel intermediates and use of said glutarimides for the preparation of the corresponding piperidines, which are 3,3-disubstituted with the same aryl group and a hydroxy (C.sub.2 -C.sub.3)alkyl group.
The EP 512 901 document describes antagonists of neurokinines which are prepared from piperidines which are 3,3-disubstituted with an aryl group and a hydroxyalkyl group. These 3,3-disubstituted piperidines are prepared from nitriles by reduction to the amines and cyclisation.
The publications of X. Edmonds-Alt et al., European Journ. Pharmacol., 1993, 250, 403-413 and Life Sciences 1995, 56 (1), 27-32 respectively describe an NK.sub.1 -antagonist, the chloride of (S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl ]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane or SR 140333 and an NK.sub.3 -antagonist, (S)-N-[1-[3-{1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl}propyl]-4-phen ylpiperidin-4-yl]-N-methylacetamide or SR 142801.
The preparation of these two products is described in EP 591 040 and EP 673 928, respectively. These documents describe 3,3-disubstituted piperidines as intermediates which can be represented by the following formula (A): ##STR2## in which X is methylene or ethylene and Ar represents a phenyl non substituted or substituted one or more times with one of the substitutents selected from a halogen atom, a hydroxyl, a (C.sub.1 -C.sub.4)alkoxy, a trifluoromethyl, a (C.sub.1 -C.sub.4)alkyl, said substituents being identical or different; a pyridyl group; a thienyl group.
According to EP 512 901, EP 591 040 and EP 673 928, the preparation of the final products in optically pure form comprises the separation of the optical isomers of the compounds of formula (A) above.
In EP 673 928, the preparation of a 3,3-disubstituted piperidine of formula (A) in which X is ethylene and Ar is 3,4-dichlorophenyl is carried out from 3,4-dichlorophenylacetonitrile (i) by the action of methyl acrylate, cyclising methyl 4-cyano-4-(3,4-dichlorophenyl)-heptanedioate (ii) to give 3-(3,4-dichlorophenyl)-3-(2-methoxycarbonyl)ethyl-2-oxopiperidine (iii), saponifying this product in order to obtain the corresponding free acid (iv) and reducing the latter, according to the SCHEME A below. ##STR3##
It has now been found that in saponifying the compound (ii) above, the corresponding dicarboxylic acid is obtained which cyclises very easily with a very high yield giving a 3,3-disubstituted glutarimide.
It has also been found that this novel glutarimide can easily be resolved and converted into an optically pure compound of formula (A) by simple reduction.
It has also been found that, in the method of preparation of certain said glutarimides, it is possible to separate the optical isomers earlier when the intermediates possess an asymmetric carbon.
More generally, all a series of 3-carboxylalkyl-3-aryl-disubstituted glutarimides has been found which constitute useful intermediates for the preparation of 3,3-disubstituted piperidines of formula (A) above. Compared to the piperidine diones described in the WO94/21609 application, these 3,3-disubstituted glutarimides are interesting in that they may be resolved and used in the optically active form.
Thus, according to one of its aspects, the invention relates to a method of preparation of the glutarimides of formula (I): ##STR4## in which Ar represents a phenyl non substituted or substituted one or more times with one of the substituents selected from a halogen atom, a hydroxyl, a (C.sub.1 -C.sub.4)alkoxy, a trifluoromethyl, a (C.sub.1 -C.sub.4)alkyl, said substituents being identical or different; a pyridyl group; a thienyl group; and X is methylene or ethylene; and their salts and enantiomers, said method being, according to a first alternative, characterised in that: ##STR5## in which Ar and X ire such as defin
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Camus Philippe
Descamps Marcel
Radisson Joel
Alexander Michael D.
Desai Rita
Rotman Alan L.
Sanofi-Synthelabo
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