Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-07
2001-02-06
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S112000, C546S183000
Reexamination Certificate
active
06184229
ABSTRACT:
This application is a 371 of PCT/FR98/01446 filed Jul. 07, 1998, now WO 99/02517 published Jan. 21, 1999.
The present invention relates to the compounds of general formula (I)
in which
R
1
represents a hydrogen atom, a (C
1
-C
4
)alkyl group or a phenyl(C
1
-C
4
)alkyl group,
R
2
represents a hydrogen atom or a (C
1
-C
4
) alkyl group, and
R
3
, R
4
and R
5
each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy group.
When R
2
represents a hydrogen atom, the molecules of general formula (I) contain two asymmetric carbon atoms, i.e. the carbon atom in position 6 and the carbon atom of the pyrrolidine ring to which it is attached; for the same combination of substituents R
1
, R
3
, R
4
and R
5
, the compounds of the invention can thus exist in the form of 4 different isomers.
When R
2
is other than a hydrogen atom, the carbon atom in position 7 is also asymmetric; for the same combination of substituents R
1
, R
2
, R
3
, R
4
and R
5
, the compounds of the invention can thus exist in the form of 8 different optical isomers.
The compounds of the invention can also exist in the form of bases or addition salts with acids.
In accordance with the invention, the compounds of general formula (I) can be prepared according to a process illustrated by the scheme which follows.
A derivative of general formula (II), in which X represents a halogen atom and R
2
, R
3
, R
4
and R
5
are as defined above, is reacted with diethyl propanedioate in basic medium in order to obtain, via a bis-alkylation, a cyclized diester of general formula (III), which is saponified under acidic conditions, or optionally under basic conditions, into an acid of general formula (IV) in which Y represents a hydroxyl group; this acid can be converted into an ester of general formula (IV) in which Y represents an alkoxy group, or alternatively into a Weinreb amide of general formula (IV) in which Y represents an (N-alkoxy)alkylamino group.
The derivative of general formula (IV) is then treated either according to the method described in
Tetrahedron Lett.,
(1984) 25(46) 5271, or according to the method described in
J. Med. Chem.
(1997) 39 3235. According to the first method, the derivative of general formula (IV) is reacted with the organomagnesium reagent derived from 3-bromopropanamine, in which the amine function is protected with a silyl function, after which this function is hydrolysed in acidic medium; according to the second method, the derivative of general formula (IV) is reacted with N-vinylpyrrolid-2-one under basic conditions in order to form an intermediate which is hydrolysed in acidic medium.
An imine of general formula (V) is obtained, which is reduced to a derivative of general formula (VI) by an agent such as sodium borohydride or sodium cyanoborohydride in a suitable solvent.
The cis and trans stereoisomers formed during this step can be separated by chromatography into more polar isomers and less polar isomers.
If so desired, it is also possible at this stage to separate the enantiomers, for example by treating a cis or trans stereoisomer of general formula (VI) with a chiral substrate, for example an S-proline derivative, under peptide coupling conditions, for example in the presence of dicyclohexylcarbodiimide, in order to obtain a derivative of general formula (I) in which R
1
represents a prolinyl group, in the form of a mixture of diastereoisomers which can be separated by chromatography. The enantiomers are then obtained by treating each of the diastereoisomers in acidic medium. Finally, and if it is desired to introduce a group R
1
other than a hydrogen atom, an alkylation of the nitrogen in the pyrrolidine ring is carried out by any known method, for example a reductive methylation according to the Eschweiler-Clarck method (formaldehyde and formic acid), or by reductive amination in the presence of an aldehyde and sodium cyanoborohydride, or alternatively by acylation, in order to form an amide, which is reduced to an amine, using an agent such as lithium aluminium hydride.
For certain compounds, all the substituents R
2
, R
3
, R
4
and R
5
cannot be present in the starting compound of general formula (II); depending on their nature, these substituents can be introduced onto one and/or the other of the compounds of general formulae (III), (IV), (V), (VI) and (I), in which R
2
, R
3
, R
4
and/or R
5
represent hydrogen atoms, according to any known methods, for example the method described in
J. Het. Chem.
(1996) 33 1051-1056, optionally after activation of the nitrogen in the pyridine ring by formation of the corresponding N-oxide.
The examples which follow illustrate the preparation of a number of compounds of the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained.
The numbers indicated in parentheses in the example titles correspond to those in the 1st column of Table 1 given later.
In the compound names, the hyphen “-” forms part of the name, and the underscore mark “_” serves merely to indicate the line break; it should be removed if a line break does not occur at that point, and should not be replaced either with a normal hyphen or with a space.
REFERENCES:
patent: 5227391 (1993-07-01), Caldwell et al.
patent: 5232933 (1993-08-01), Lippiello et al.
N.D. Cosford et al., “(S)-(-)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine Maleate (SIB-1508Y): A Novel Anti-Parkinsonian Agent with Selectivity for Neuronal Nicotinic Acetylcholine Receptors”, Journal of Medicinal Chemistry, vol. 39, No. 17, pp. 3235-3237, (1996).
Galli Frederic
Jegham Samir
Lochead Alistair
Aulakh C. S.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Sanofi-Synthelabo
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