Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-12
2002-01-29
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S208000, C546S220000, C546S229000, C544S130000, C562S512000
Reexamination Certificate
active
06342607
ABSTRACT:
The subject of the present invention is 3-(3-phenyl-2,6-dioxopiperidin-3-yl)propionamide derivatives, their method of preparation and their use.
3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid is described in patent application WO 97/32852.
There has now been found a novel compound of formula:
in which:
X represents a halogen, preferably a chlorine atom or fluorine atom;
R
1
and R
2
each independently represent hydrogen, a C
1
-C
6
alkyl which is unsubstituted or substituted with a hydroxyl, a benzyl which is unsubstituted or substituted with a C
1
-C
6
alkyl, a hydroxyl or R
1
and R
2
together constitute with the nitrogen atom to which they are attached a heterocyclic radical chosen from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl and morpholin-4-yl,
it being possible for said heterocyclic radicals to be mono- or disubstituted.
As substituents of said heterocyclic radicals, there may be mentioned groups, which are similar or different, chosen from a C
1
-C
4
alkyl, a phenyl, a benzyl, an amino, a (C
1
-C
4
)alkylamino and a di(C
1
-C
4
)alkylamino.
Compound (I) exists in racemic form or in 2 enantiomerically pure forms. There is preferred the compound having the configuration described by the formula:
There are preferred the compounds of formula (I) or of formula (II) in which NR
1
R
2
represents a dialkylamino group such as dimethylamino, butylamino, ethanolamino, (N-methyl)ethanolamino, benzylamino, morpholino or piperidino. There are also preferred the compounds of formula (I) or of formula (II) in which NR
1
R
2
represents a 4-methylamino-4-phenylpiperdin-1-yl group.
The compounds of formula (I) or of formula (II) are intermediates which are useful for the preparation of the compounds of formula:
in which X is as defined above for (I).
It appears in patent application WO 97/03852 that the compounds of formula (III) or (IV) are useful for the preparation of neurokinin antagonist compounds such as that described in the the publication by X. Emonds-Alt et al., Life Sci., 1995, 56 (1), 27-32, namely (S)-N-[1-[3-{1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl}propyl]-4-phenylpiperidin-4-yl]-N-methylacetamide or SR 142801 whose international nonproprietary name is osanetant. This compound is an NK
3
antagonist.
In particular, the subject of the present invention is a compound of formula:
in which X is as defined above for (I).
The subject of the present invention is also a method of preparing a compound of formula (I). Said method is characterized in that a compound of formula:
in which X is as defined above for (I), is cyclized by elimination of water.
The compound of formula (VI) may be obtained by the action of an amine of formula HNR
1
R
2
in which R
1
and R
2
are as defined above for (I) on a compound of formula:
The preparation of the compound of formula (VI) is carried out in water, in an alcoholic solvent, in an ethereal solvent, in a chlorinated solvent or in an aromatic solvent, at a temperature between room temperature and the reflux temperature of the solvent. Preferably, water or methanol is used.
The cyclization of the compound of formula (VI) by elimination of a molecule of water is carried out after activation of the carboxyl group of the compound of formula (VI) by formation of a mixed anhydride. For that, an anhydride is used in excess, for example acetic anhydride or methanesulfonic anhydride, at a temperature between room temperature and 100° C.
The compounds of formula (VI) are novel and form part of the present invention.
The compounds of formula (III) are described in patent application WO 97/32852.
According to the present invention, it has been observed that starting with a compound of formula (III) in racemic form, a racemic compound of formula (VI) is obtained in which the 2 enantiomers are in the same proportion as for the starting compound. A racemic compound of formula (I) is then obtained by cyclization in which the 2 enantiomers are in the same proportion as for the starting compound.
According to the present invention, it has been found, using as starting material a pure enantiomer of the compound of formula (III), that the formation of the hexanoic acid derivative of formula (VI) occurs with retention of configuration, and that the cyclization then occurs with inversion of configuration.
The method according to the invention thus applies to the preparation of compounds in optically pure form. Thus, advantageously, the present invention relates to a method for the preparation of a compound of formula (II) characterized in that a compound of formula:
in which X is as defined above for (I), is cyclized by elimination of water, to give a compound of formula:
The compound of formula (VII) may be obtained by the action of an amine of formula HNR
1
R
2
in which R
1
and R
2
are as defined above for (I) on a compound of formula:
According to the present invention, the compound of formula (I) may be prepared using another method characterized in that an amine of formula HNR
1
R
2
in which R
1
and R
2
are as defined above for (I) is reacted with a compound of formula:
in which X is as defined above for (I).
The compounds of formula (VIII) may be obtained from an acid of formula:
The compounds of formula (VIII) are novel and constitute a subsequent aspect of the present invention.
The action of an amine on an acid chloride of formula (VIII) is preferred for the preparation of a compound of formula (V) and most particularly for the preparation of an enantiomer of the compound of formula (V) of formula:
This method is characterized in that 4-methylamino-4-phenylpiperidine is reacted with a compound of formula:
The compound of formula (X) may be prepared from the acid of formula:
The acid chloride is prepared in a known manner, for example by the action of thionyl chloride in the absence of solvent or in an anhydrous solvent such as toluene, dimethylformamide or dichloromethane or alternatively in a mixture of these solvents.
The action of 4-methylamino-4-phenylpiperidine is carried out in an anhydrous solvent, in a basic medium, for example in the presence of triethylamine.
The 4-methylamino-4-phenylpiperidine is prepared according to Biorg. Med. Chem. Letters, 1996, 4 (19), 2307-2310.
According to the present invention, the compound of formula (I) makes it possible to obtain, by acidolysis, the acid of formula (III). Likewise, according to the present invention, the compound of formula (II) makes it possible to obtain, by acidolysis, the acid of formula:
The acidolysis is carried out in a manner known to persons skilled in the art, for example with a C
1
-C
4
carboxylic acid.
Thus, the present invention relates to a method of preparing a compound of formula (III) by hydrolysis of a compound of formula (I). It also relates to a method of preparing a compound of formula (IV) by hydrolysis of a compound of formula (II).
According to a subsequent aspect of the present invention, the compound of formula (I) makes it possible to obtain, by reduction, a compound of formula:
in which X, R
1
and R
2
are as defined for (I).
The reduction is carried out by means known to persons skilled in the art. The reducing agents used are borane complexes such as for example borane-tetrahydrofuran or borane-dimethyl sulfide or alternatively a mixed alkali metal hydride such as lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride in solution in toluene (Red-Al®, the borane-tetrahydrofuran complex being preferred.
The reduction with borane is carried out in a solvent, preferably an aprotic solvent such as tetrahydrofuran at the reflux temperature of the solvent. In general, after 1 to 6 hours of heating, the reduction is complete and the 3,3-disubstituted piperidine is isolated, according to conventional methods, by first destroying the excess borane with methanol. The free base may be isolated by evaporation of the solvent, and then the residue is taken up in water, the medium is acidified with hydrochloric acid, treated with a base, preferably sodium hydroxide, and extracted with
Castro Bertrand
Mattras Hélène
Previero Aldo
Alexander Michael D.
Aulakh Charanjit S.
Sanofi-Synthelabo
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