Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-09-15
2000-11-07
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546115, 546116, A61K 31435, C07D491048
Patent
active
061437611
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR98/00531 filed Mar. 17, 1998.
The subject of the present patent application is 2,3-dihydrofuro[3,2-b]pyridine derivatives, their preparation and their application in therapeutics.
The compounds of the invention correspond to the general formula (I) ##STR2## in which R.sub.1 represents a hydrogen atom, a (C.sub.1 -C.sub.6)alkyl group or a phenyl(C.sub.1 -C.sub.4)alkyl group which is optionally substituted, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy group.
The two carbon atoms by which the pyrrolidine ring and the furo[3,2-b]pyridine ring are bonded are asymmetric; a compound according to the invention can thus exist in the form of a pure (R,R), (R,S), (S,R) or (S,S) optical isomer or of a mixture of such isomers.
A compound according to the invention can also exist in the form of the free base or of an addition salt with an acid.
Compounds having structures and properties similar to those of the compounds of the invention are disclosed in international application WO-9705139.
Advantageous compounds are those in which R.sub.1 and R.sub.2 each represent a hydrogen atom or an alkyl group, preferably a methyl group, and R.sub.3, R.sub.4 and R.sub.5 each represent a hydrogen or halogen atom, preferably chlorine, or a (C.sub.1 -C.sub.4)alkyl, preferably methyl, or (C.sub.1 -C.sub.4)alkoxy, preferably methoxy, group. ##STR3##
In accordance with the invention, the compounds of general formula (I) can be prepared by a process illustrated by the above scheme.
A 2-halopyridin-3-ol of general formula (II), in which R.sub.3, R.sub.4 and R.sub.5 are as defined above and X represents a halogen atom, is first reacted with 1,1-dimethylethyl 2-ethynylpyrrolidine-1-carboxylate of formula (III), under the conditions of a Castro-Stephens reaction, as described in J. Org. Chem. (1966), 31, 4071, or else in the presence of copper(I), as described in Synthesis (1986), 749-751, in order to obtain the cyclized derivative of general formula (IV). For some compounds, not all the R.sub.3, R.sub.4 and R.sub.5 substituents may be present from the beginning of the synthesis; in these cases, their introduction can be carried out starting from the compound of general formula (IV), in which R.sub.3, R.sub.4 and R.sub.5 each represent a hydrogen atom, according to any known method, for example that described in J. Het. Chem. (1996), 33, 1051-1056, optionally after activation of the nitrogen of the pyridine ring by formation of the corresponding N-oxide. The nitrogen of the pyrrolidine ring is subsequently deprotected in order to obtain the compound of general formula (V). The latter is subjected to catalytic hydrogenation in order to obtain the compound of general formula (VI) and finally, and if desired, the nitrogen of the pyrrolidine ring is alkylated by any known method, for example a methylation according to the Eschweiler-Clarke method (formaldehyde and formic acid) or by a reductive amination in the presence of an aldehyde and of sodium cyanoborohydride, or alternatively is acylated in order to form an amide, followed by a reduction in the presence of a reducing agent, such as lithium aluminium hydride.
The 2-halopyridin-3-ols are commercially available or can be prepared according to any method known to a person skilled in the art.
1,1-Dimethylethyl (S)-2-ethynylpyrrolidine-1-carboxylate and 1,1-dimethylethyl (R)-2-ethynylpyrrolidine-1-carboxylate can be prepared from (S)- or (R)-proline by the Corey-Fuchs method described in Tetrahedron Letters (1990), 31, (28), 3957-3960.
The examples which will follow illustrate the preparation of some compounds of the invention. The elemental microanalyses and the I.R. and N.M.R. spectra confirm the structures of the compounds obtained. The numbers shown between brackets in the titles of the examples correspond to those in the 1st column in Table 1 given later.
In the names of the compounds, the "--" forms part of the word and the ".sub.-- " is used only for the break at the line end; it i
Gallet Thierry
Galli Frederic
Jegham Samir
Lochead Alistair
Dentz Bernard
Sanofi-Synthelabo
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