Use of benzoylalkyl-1,2,3,6-tetrahydropyridines

Details Use of benzoylalkyl-1,2,3,6-tetrahydropyridines Use of benzoylalkyl-1,2,3,6-tetrahydropyridines

1999-08-05

2002-03-19

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S340000, C546S344000

Reexamination Certificate

active

06358965

ABSTRACT:

CROSS-REFERENCE
This application is a 371 of PCT/FR97/02424 filed Dec. 24, 1997.
The present invention relates to the use of certain benzoyl-1,2,3,6-tetrahydropyridines as neurotrophic and neuroprotective agents as well as of novel derivatives, a process for their preparation and pharmaceutical compositions containing them.
EP-0 458 696 describes the use of a 1-(2-naphthylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine for the preparation of medicines designed for the treatment of cerebral and neuronal disorders.
WO 91/08200 describes derivatives of tetrahydropyridine with protective activity towards damage caused by hypoxic/ischemic states.
WO 93/11107 describes certain ketones used as intermediates in the preparation of the corresponding alcohols.
It has now been found that certain benzoyl-1,2,3,6-tetrahydropyridines exert a neutrotrophic action on the nervous system similar to that of the nerve growth factor (NGF) and may restore the function of the damaged cells or cells exhibiting anomalies in their physiological functions.
Hence, according to one of its features, the present invention relates to the use of compounds of formula (I)
in which
R
1
is halogen, a CF
3
, (C
1
-C
4
) alkyl or (C
1
-C
4
) alkoxy group; n is 0 or 1
R
2
is hydrogen or a (C
1
-C
4
) alkyl group;
R
3
is hydrogen, (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy; halogen; a CF
3
group, hydroxy, a group selected from (C
3
-C
7
) cycloalkyl, phenyl, phenoxy, phcnylmethyl or phenylethyl, said group being optionally mono- or polysubstituted on the phenyl group by halogen, CF
3
, (C
1
-C
4
) alkyl or (C
1
-C
4
) alkoxy;
R
4
and R
5
is each independently hydrogen, (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, halogen, a CF
3
group or hydroxy;
as well as to their salts and solvates and their quaternary ammonium salts, for the preparation of medicines designed for the treatment and/or the prophylaxis of the diseases which involve neuronal degeneration.
In the present description the term “(C
1
-C
4
) alkyl” designates the groups methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
The term “(C
1
-C
6
) alkyl” designates a hydrocarbon radical containing from 1 to 6 carbon atoms such as, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, t-pentyl, n-hexyl, i-hexyl.
When R
3
is a phenyl group, the nomenclature given to the biphenyl radical is that in conformity with the IUPAC rules, namely the numbering of the positions of the two rings is the following:
and the radicals having this structure are named:
Among the compounds of formula (I), a preferred group is constituted by the compounds of formula (I) where n is zero.
Another preferred group is constituted by the compounds of formula (I) where R
2
is hydrogen.
Another preferred group is constituted by the compounds of formula (I) where one of R
3
, R
4
and R
5
is hydrogen.
Particularly advantageous compounds according to the present invention are the compounds of formula (I) where the group R
1
is a CF
3
group in position 3 of the phenyl group.
Among the compounds of formula (I) those of formula (I′)
in which
R′
1
is halogen, a CF
3
, (C
1
-C
4
) alkyl or (C
1
-C
4
) alkoxy group;
R′
2
is (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy; halogen, a CF
3
group, hydroxy, a group selected from (C
3
-C
7
) cycloalkyl, phenyl, phenoxy, phenylmethyl or phenylethyl, said group being optionally mono- or polysubstituted on the phenyl group by halogen, CF
3
, (C
1
-C
4
) alkyl or (C
1
-C
4
) alkoxy;
R′
3
is hydrogen, (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, halogen, a CF
3
or hydroxy group; as well as their salts and solvates and their quaternary ammonium salts, are novel compounds and constitute a further feature of the present invention.
The preferred quaternary ammonium salts are those of formula (I″)
where X
−
is a pharmaceutically acceptable anion, preferably Cl
−
, Br
−
, I
−
, CH
3
SO
3
−
, C
6
H
5
SO
3
−
and Alk being (C
1
-C
4
) alkyl, preferably methyl.
Among the compounds of formula (I′), particularly advantageous compounds are the following:
1-{2-(3′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(2′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(4′-chlorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(4-isobutylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(4-benzylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(4-cyclohexylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(4′-fluorobiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(4-n-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(biphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(4-t-butylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(3,4-diethylphenyl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(3′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
1-{2-(4′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine;
as well as their salts and solvates.
The compounds of formula (I) are prepared as described in WO 91/08200 and WO 93/11107.
According to another of its features, the present invention relates to a process for the preparation of the compounds of formula (I′), their salts or solvates and their quaternary ammonium salts, characterized in that
(a) an aryl-1,2,3,6-tetrahydropyridine of formula (II)
in which R′
1
is as defined above, is reacted with a compound of formula (III)
in which R′
2
and R′
3
are as previously defined and L is a leaving group such as, for example, a chlorine, bromine or iodine atom or a methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethylsulfonyloxy group, bromine being preferred; and
(b) the compound of formula (I′) thus obtained is isolated and optionally converted into one of its salts or solvates or one of its quaternary ammonium salts.
The reaction is carried out in an organic solvent at a temperature included between room temperature and the reflux temperature of the solvent used.
An aliphatic alcohol having from 1 to 6 carbon atoms such as methanol, ethanol, isopropanol, n-butanol, n-pentanol is used as preferred organic solvent, but other solvents such as hexane, dimethylformamide, dimethylsulfoxide, sulfolane, acetonitrile, pyridine and the like may also be used.
The reaction is advantageously carried out in the presence of a basic agent such as an alkali hydroxide or carbonate or triethylamine, particularly in the case where L is a halogen atom.
The reaction temperature may vary between room temperature (about 20° C.) and that of reflux and the reaction times vary accordingly. In general, the reaction is terminated after 0.5 to 12 hours of heating at reflux and the final product thus obtained can be isolated according to conventional procedures in the form of the free base or one of its salts or solvates and the free base is optionally converted into one of its salts by simple salification in an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether like 1,2-dimethoxyethane, ethyl acetate, acetone or a hydrocarbon like hexane.
The compound of formula (I′) obtained and isolated according to the usual procedures is optionally converted into one of its quaternary ammonium salts by reaction with an alkyl halide of formula (IV)
Alk-Hal&em

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