Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-19
2001-03-13
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S304000, C514S305000, C546S125000, C546S135000, C546S274400, C546S210000, C546S199000
Reexamination Certificate
active
06200991
ABSTRACT:
The subject of the present invention is imidazole derivatives of general formula (I)
in which:
A represents a saturated or unsaturated heterocycle comprising a nitrogen atom of formula (B), (D), (E) or (F):
R
1
and R
2
represent, independently of each other, a hydrogen, a C
1-6
alkyl group, or together form a polymethylene group —(CH
2
)
n
—, it being possible for n to take the values from 3 to 6,
R
5
represents a phenyl or a 2-, 3- or 4-pyridine, the phenyl or the pyridine being substituted with R
3
and R′
3
,
where R
3
and R′
3
represent, independently of each other, a hydrogen atom, a halogen atom, a hydroxyl, a C
1-4
alkyl or C
1-6
alkoxy group,
R
6
represents a phenyl or a 2-, 3- or 4-pyridine, the phenyl or the pyridine being substituted with R
4
and R′
4
,
where R
4
and R′
4
represent, independently of each other, a hydrogen atom, a halogen atom, a hydroxyl, an amino, a cyano, a sulphonamide, an aminocarbonyl, a trifluoromethyl, a C
1-6
-alkoxy, (di)hydroxy-C
1-6
alkoxy or C
1-4
alkyl group, and
R
7
represents a hydrogen atom or a C
1-2
alkyl group.
Among these, the preferred compounds according to the invention are the compounds for which: A represents a piperidine (B), more especially A represents a piperidine (B) and R
5
represents a phenyl.
Among the latter, the compounds for which R
6
also represents a phenyl and R
7
represents a hydrogen are even more particularly preferred.
Within the framework of the present invention, there is understood by:
C
1-z
, where z may take the values between 2 and 6, a carbon chain which may have from 1 to z carbon atoms,
alkyl, a linear or branched saturated aliphatic group; for example, a C
1-6
alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, or preferably of 1 to 6, and more particularly consists of a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like;
alkoxy, an alkyloxy group with a linear or branched saturated aliphatic chain, and
halogen atom, a fluorine, a chlorine, a bromine or an iodine.
The compounds of general formula (I) may exist in the form of a free base, N-oxide or of addition salts with pharmaceutically acceptable acids, which also form part of the invention.
The compounds of general formula (I) comprise one or more asymmetric carbon atoms. They may therefore is exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as mixtures thereof, including the racemic mixtures, form part of the invention.
The compounds of the invention can be prepared by processes illustrated in the schemes which follow, for which the operating conditions are routine for persons skilled in the art.
An epoxide of formula (II) is reacted successively with triflic acid in dimethyl sulphoxide and then with diisopropylethylamine to give the hydroxyketone (III) according to the method described by B. M. Trost in Tetrahedron letters 29, (18) 2163-66 (1988).
The hydroxyketone (III) is reacted with an arylurea (R
5
NHCONH
2
) at 180° C. in hexanol, optionally in the presence of a molecular sieve, to give the imidazolone (IV).
This imidazolone (IV) can also be obtained from the alpha-haloketone (V), by successive reactions of potassium phthalimide (PhthalK) and then of concentrated hydrobromic acid and of acetic acid, to give, first of all, the hydrobromide of the aminoketone (VI) which, by treatment with a phenylisocyanate (R
5
NCO) in pyridine or dimethylformamide, gives the compound (IV).
Alternatively, the imidazolone (IV) may be prepared as indicated in Scheme 2 according to the method described in U.S. Pat. No. 3,432,520.
A propargylamine of formula (XV), in which R
1
is as defined above and R′
2
represents R
2
minus a carbon atom (R
2
═R′
2
—(C≡)—), is reacted with a phenylisocyanate (R
5
—NCO) in toluene to give the urea (XVI) which, by treatment with an alkali metal alcoholate, such as sodium methoxide or ethoxide or potassium tert-butoxide, in the corresponding alcohol, causes an allenic rearrangement followed by cyclization to give the imidazolone (IV).
The imidazolone (IV) is then heated at the reflux temperature of phosphorus oxichloride, optionally in the presence of phosphorus pentachloride or of gaseous hydrochloric acid, to give the chloroimidazole (VII).
The condensation of the chloroimidazole (VII) with an alcohol of formula (XIV), in which A, R
6
and R
7
are as defined above, is carried out by the prior action of a non-nucleophilic base such as sodium hydride on this alcohol, followed by the reaction with the chloroimidazole in dimethylformamide at temperatures of between 20 and 120° C. (oil bath or microwave oven) to give the compounds of formula (I).
Alternatively, the compounds of formula (I) may be obtained from an alpha-haloketone of formula (V) which is thermally condensed with formamide to give the imidazole (VIII).
This imidazole (VIII) is then subjected to the action of a triarylbismuth ((R
5
)
3
Bi) in the presence of copper acetate and of triethylamine in dichloromethane to give the imidazole (IX).
The proton at the 2-position of this imidazole (IX) is then removed by means of butyllithium in tetrahydrofuran at temperatures of between −78 and −10° C. The anion thus formed is trapped by means of dimethyl disulphide to give the sulphide (X).
Alternatively, the sulphides of formula (X) and more particularly those for which R
2
is a hydrogen atom may be obtained according to the Scheme 3.
The isothiocyanate of formula (XVIII) is brought into contact, in an organic solvent such as toluene or dichloromethane, with a dialkyl acetal of formula (XIX) to give, in an intermediate phase, a thiourea which is cyclized into an imidazolinethione of formula (XX) by heating in an aqueous solution (0.01 to 12 N) of hydrochloric acid. The imidazolinethione of formula (XX) may be S-methylated by the successive action of sodium hydride and of methyl iodide in dimethylformamide at temperatures of between −20° C. and 60° C., to give the compound of formula (X), or alternatively by the action of methanol in hydrochloric acid at temperatures of between 20° C. and the reflux temperature.
The sulphide (X) is oxidized into a sulphone (XI) by the action of Oxone® (potassium peroxymonosulphate) in the presence of moist alumina. However, other oxidizing agents may be used, such as hydrogen peroxide or potassium permanganate in acetic acid.
The condensation of the sulphone (XI) with an alcoholate, formed by the action of a non-nucleophilic base such as sodium hydride on the alcohol of formula (XIV), is carried out in dimethylformamide at temperatures of between 20 and 120° C., to give the compounds of formula (I).
Alternatively, the compounds of formula (I), in which R
6
is a phenyl, R
4
═H and R′
4
═H, can be modified in order to give other derivatives of formula (I) as indicated in Scheme 4.
The compounds of formula (I), in which R
6
represents a phenyl, R
4
and R′
4
═H are debenzylated by the action of ammonium formate at the reflux temperature of methanol in the presence of a catalytic quantity of palladium on carbon, to give the derivative (XII).
The compounds of formula (XII) may then be reacted with an aryl halide of formula (XVII, R
6
=phenyl or pyridyl in which R
4
and R′
4
may be different from a halogen) in the presence of a proton-accepting amine or of an inorganic base such as potassium carbonate, or by reductive amination by means of an aldehyde of formula (XXI, R
6
being as defined above) in the presence of hydrochloric acid or of sodium cyanoborohydride in methanol, to give the compounds of formula (I), in which R
4
and/or R′
4
do not represent a hydrogen.
In the case where (R
4
and/or R′
4
) and/or (R
3
and/or R′
3
) is a derivatizable functional group, it may be optionally oxidized, reduced, alkylated or dealkylated by conventional methods known to persons skilled in the art.
The compounds of formula (XIV) are commercially available or may be synthesized according to methods
Bovy Philippe
Courtemanche Gilles
Crespin Olivier
DeFosse Gerard
Alexander Michael D.
D'Souza Andrea M.
McKane Joseph K.
Sanofi-Synthelabo
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