Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-19
2003-01-21
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C546S148000, C546S149000, C546S152000, C546S174000
Reexamination Certificate
active
06509351
ABSTRACT:
The present invention relates to novel phenyl- and pyridyl-tetrahydropyridines, to pharmaceutical compositions containing them, to a process for preparing them and to synthetic intermediates in this process.
U.S. Pat. Nos. 5,118,691 and 5,620,988 disclose tetrahydropyridines substituted with a 3-quinolylalkyl radical, which show dopaminergic activity.
It has now been found that certain tetrahydropyridines substituted with a quinolinylalkyl or isoquinolylalkyl radical have powerful activity with respect to modulating TNF-alpha (tumour necrosis factor).
TNF-alpha is a cytokine which has recently aroused interest as a mediator of immunity, of inflammation, of cell proliferation, of fibrosis, etc. This mediator is present in abundance in inflamed synovial tissue and exerts 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
X represents N or CH;
R
1
represents a hydrogen or halogen atom or a CF
3
group;
R
2
and R
3
independently represent a hydrogen atom or a methyl group;
n is 0 or 1;
A represents a group of formula (a) or (b)
in which
R
4
represents a hydrogen or halogen atom, a (C
1
-C
4
) alkyl group, a CF
3
group, an amino group, a mono(C
1
-C
4
) alkylamino group or a di (C
1
-C
4
) alkylamino group;
R
5
represents a hydrogen or halogen atom, a (C
1
-C
4
) alkoxy group, a (C
1
-C
4
) alkyl group or a CF
3
group;
R
6
represents a hydrogen atom, a (C
1
-C
4
)alkyl group or a (C
1
-C
4
)alkoxy group;
as well as the salts or solvates thereof.
In the present description, the term “(C
1
-C
4
)alkyl” denotes a monovalent radical of a saturated straight-chain or branched-chain C
1
-C
4
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
2
and R
3
are hydrogen.
Other preferred compounds are those in which R
1
is a CF
3
group.
Other preferred compounds are those in which R
1
is a fluorine atom.
Other preferred compounds are those in which X is CH and R
1
is in position 2 or 3 of the benzene.
Other preferred compounds are those in which X is CH and R
1
is a CF
3
group.
Other preferred compounds are those in which X is a nitrogen atom and the pyridine is substituted in positions 2 and 6.
According to the present invention, the compounds of formula (I) can exist as N-oxide derivatives. As indicated in the above formula, the compounds of formula (I) can in particular bear the N-oxide group on the tetrahydropyridine or on the quinoline or the isoquinoline of the group A, or alternatively two N-oxide groups may be simultaneously present.
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 the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulphonate 2-naphthalenesulphonate, etc., and the addition salts which allow a suitable separation or crystallization of the compounds of formula (I), such as the picrate or oxalate, or the addition salts with optically active acids, for example camphorsulphonic acids and mandelic acids or substituted mandelic acids.
The optically pure stereoisomers, and the mixtures of isomers of the compounds of formula (I), due to the asymmetric carbon, when either R
2
or R
3
is a methyl and the other is a hydrogen, in any proportion, form part of the present invention.
The compounds of formula (I) can be synthesized by a process which involves
(a) reacting the compound of formula (II):
in which X and R
1
are defined as above, with a functional derivative of the acid of formula (III):
in which R
2
, R
3
, n and A are as defined above,
(b) reducing the carbonyl group of the compound of formula (IV) thus obtained:
(c) dehydrating the intermediate piperidinol of formula (V) thus obtained:
(d) isolating the compound of formula (I) thus obtained and optionally converting it into a salt or solvate thereof or into the N-oxide derivatives thereof.
The reaction in 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 perform the reaction without heating when it is exothermic, such as in the case in which the chloride is used as functional derivative of the acid of formula (III).
Suitable functional derivatives of the acid of formula (III) which can be used are the free acid, optionally activated (for example with BOP=tris(dimethylamino)benzotriazol-1-yloxyphosphonium hexafluorophosphate), an anhydride, a mixed anhydride, an active ester or an acid halide, preferably the bromide. Among the active esters, the one which is particularly preferred is the p-nitrophenyl ester, but the methoxyphenyl, trityl and benzhydryl esters and the like are also suitable.
The reaction solvent preferably used is a halogenated solvent such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform and the like, but other organic solvents that are compatible with the reagents used, for example dioxane, tetrahydrofuran or a hydrocarbon such as hexane, can also be used.
The reaction may be carried out conveniently in the presence of a proton acceptor, for example an alkaline carbonate or a tertiary amine such as triethylamine.
The reduction in step (b) can be carried out conveniently using suitable reducing agents such as borane complexes, for example dimethyl sulphide/borane ([CH
3
]
2
S—BH
3
), aluminium hydrides or a lithium aluminium hydride complex in an inert organic solvent at a temperature of between 0° C. and the reflux temperature of the reaction mixture, according to the usual techniques.
The expression “inert organic solvent” means 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 one preferred procedure, the process is performed with the dimethyl sulphide/borane used in excess relative to the starting compound (II), at the reflux temperature, optionally under inert atmosphere. The reduction is normally complete after a few hours.
The dehydration in step (c) is readily carried out, for example, using an acetic acid/sulphuric acid mixture, at a temperature of between room temperature and the reflux temperature of the solvent used.
According to a preferred method, the reaction in step (c) is carried out in an acetic acid/sulphuric acid mixture in a ratio of 3/1 by volume, by heating to a temperature of about 100° C. for 1-3 hours.
The desired compound is isolated according to the conventional techniques in the form of free base or a salt thereof. The free base can be converted 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, acetone or a hydrocarbon such as hexane.
The compound of formula (I) obtained is isolated according to the usual techniques and optionally converted into a salt or solvate thereof or into the N-oxide derivatives thereof.
The compounds of formula (I) can also be prepared by a coupling/reduction reaction starting with a compound of formula (VI):
in which X and R
1
are as defined above, with an aldehyde of formula (VII):
in which R
2
, R
3
, n and A are as defined above, isolation of the compound of formula (I) and optional conversion into a salt or solvate thereof or into the N-oxide derivatives thereof.
The coupling/reduction reaction is carried out by mixing the starting compounds (VI) and (VII) in an organic solvent such as an alcohol such as for example, methanol, in acidic medium, in the presence of a reducing agent such as sodium cyanoborohydride, according to the conventional methods.
Baroni Marco
Bourrie Bernard
Cardamone Rosanna
Casellas Pierre
Guzzi Umberto
Alexander Michael D.
Dupont Paul E.
Sanofi-Syntelabo
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