Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-15
2004-02-10
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S337000, C546S256000, C546S281100, C546S284100
Reexamination Certificate
active
06689797
ABSTRACT:
The present invention relates to novel tetrahydropyridines, to a method for the preparation thereof and to the pharmaceutical compositions containing them.
WO92/07831 describes tetrahydropyridines substituted with a benzofuran-6-yl alkyl group carrying a triple bond in the alkyl chain, having dopaminergic activity.
It has now been found that certain tetrahydropyridines, substituted with a benzofuryl alkyl radical or benzothienyl alkyl radical, have powerful activity with respect to the modulation of TNF-alpha (from Tumour Necrosis Factor).
TNF-alpha is a cytokine which has recently provoked interest as a mediator of immunity, of inflammation, of cell proliferation, of fibrosis, etc. There is a very high concentration of this mediator in inflamed synovial tissue and it exercises an important role in the pathogenesis of autoimmunity (Annu. Rep. Med. Chem., 1997, 32:241-250).
Thus, according to one of its aspects, the present invention relates to tetrahydropyridines of formula (I):
in which
R
1
represents a hydrogen or halogen atom, or a group CF
3
;
R
2
and R
3
represent, independently, a hydrogen atom or a methyl group;
n and n′ each represent, independently, 0 or 1;
* represents the positions of attachment;
A represents N or CH;
X represents a sulfur or oxygen atom;
R
4
and R
5
represent, independently, a hydrogen atom or a (C
1
-C
6
) alkyl group;
and their salts or solvates.
In the present description, the term “(C
1
-C
6
) alkyl” denotes a monovalent radical comprising a straight- or branched-chain saturated C
1
-C
6
hydrocarbon.
In the present description, the term “halogen” denotes an atom chosen from chlorine, bromine, iodine and fluorine.
Preferred compounds are those in which n is zero.
Other preferred compounds are those in which R
1
is in position 3 of the benzene.
Other preferred compounds are those in which R
1
is a group CF
3
.
Other preferred compounds are those in which R
2
and R
3
are each a hydrogen atom.
Other preferred compounds are those in which R
4
and R
5
are each a methyl group.
The salts of the compounds of formula (I) according to the present invention comprise both the addition salts with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic, sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate, etc., and the addition salts which allow suitable separation or crystallization of the compounds of formula (I), such as picrate, oxalate or the addition salts with these optically active acids, for example camphosulfonic acids and mandelic or substituted mandelic acids.
The stereoisomers which are optically pure, and also the mixtures of isomers of the compounds of formula (I), due to the asymmetric carbon, when one of R
2
and R
3
is a methyl and the other a hydrogen, in any proportion, are part of the present invention.
The compounds of formula (I) can be synthesized using a method which envisions
(a) reacting the compound of formula (II):
in which A and R
1
are defined as above, with a functional derivative of the acid of formula (III):
in which R
2
, R
3
, R
4
, R
5
, n and X are as defined above,
(b) reducing the carbonyl group of the compound of formula (IV):
(c) dehydrating the intermediate piperidinol of formula (V):
(d) isolating the compound of formula (I) thus obtained and, optionally, transforming it into one of its salts or solvates, or its N-oxide (n′=1 in formula I).
As a suitable functional derivative of the acid of formula (III), use may be made of the free acid, optionally activated (for example with BOP=benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), an anhydride, a mixed anhydride, an active ester or an acid halide, preferably bromide. Among the active esters, the p-nitrophenyl ester is particularly preferred, but the methoxyphenyl, trityl and benzhydryl esters and similar esters are also suitable.
The reaction of step (a) can be suitably carried out in an organic solvent at a temperature of between −10° C. and the reflux temperature of the reaction mixture.
It may be preferable to carry out the reaction under cold conditions when it is exothermic, as when chloride is used as the functional derivative of the acid of formula (III).
As the reaction solvent, use is preferably made of a halogen-based solvent, such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform and the like, but also of other organic solvents compatible with the reagents used, for example dioxane, tetrahydrofuran or a hydrocarbon such as hexane, may also be used.
The reaction may be suitably carried out in the presence of a proton acceptor, for example of an alkali metal carbonate or of a tertiary amine such as triethylamine.
The reduction of step (b) can be suitably carried out with suitable reducing agents, such as borane complexes, for example borane dimethyl sulfide ([CH
3
]
2
S—BH
3
), aluminum hydrides or a complex hydride of lithium and aluminum, in an inert organic solvent at a temperature of between 0° C. and the reflux temperature of the reaction mixture according to usual techniques.
The term “inert organic solvent” is intended to mean a solvent which does not interfere with the reaction. Such solvents are, for example, ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane or 1,2-dimethoxyethane.
According to a preferential embodiment, the procedure is carried out with borane dimethyl sulfide used in excess relative to the starting compound (II), at the reflux temperature, optionally under inert atmosphere. The reduction is normally terminated after a few hours.
The dehydration of step (c) is easily carried out, for example, using an acetic acid/sulfuric acid mixture, at a temperature of between ambient temperature and the reflux temperature of the solvent used, or using para-toluenesulfonic acid in an organic solvent, such as, for example, benzene, toluene or chlorobenzene.
The compounds of formula (I) may also be prepared by condensation of a tetrahydropyridine of formula (VI):
in which A and R
1
are as defined above, with a compound of formula (VII):
in which R
2
, R
3
, R
4
, R
5
, n and X are as defined above and Q is a leaving group, isolation of the compound of formula (I) thus obtained and optional transformation into one of its salts or solvates, or its N-oxide.
As leaving group Q, use may be made, for example, of a halogen atom or any group which can be condensed with an amine. The condensation reaction is carried out conventionally by mixing the starting compounds (VI) and (VII) in an organic solvent such as an alcohol, for example methanol or butanol, in the presence of a base such as an alkali metal carbonate, at a temperature of between ambient temperature and the reflux temperature of the solvent chosen.
The desired compound is isolated according to conventional techniques in the form of a free base or of one of its salts. The free base may be transformed into one of its salts by simple salification in an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether such as 1,2-dimethoxyethane, ethyl acetate or acetone, or a hydrocarbon such as hexane. It may be transformed into N-oxide by oxidation according to conventional methods, for example with 3-chloroperbenzoic acid.
The starting compounds of formulae (II), (III), (VI) and (VII) are known or else they may be prepared in a similar way to the known compounds.
The compounds of the invention have properties which are advantageous with respect to the inhibition of TNF-&agr;.
These properties were demonstrated using a test aimed at measuring the effect of molecules on TNF-&agr; synthesis induced in Balb/c mice by lipopolysaccharide (LPS) of
Escherichia Coli
(055:B5, Sigma, St Louis, Mo.).
The products to be tested are administered orally to groups of 5 female 7- to 8-week-old Balb/c mice (Charles River, France). One hour later, the LPS is administered intravenously (10 &mgr;g/mouse). A blood sample is taken from each animal 1.
Baroni Marco
Bourrie Bernard
Cardamone Rosanna
Casellas Pierre
Alexander Michael D.
Dentz Bernard
Sanofi-Synthelabo
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