Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-26
2003-11-18
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S194000
Reexamination Certificate
active
06649627
ABSTRACT:
This invention concerns new phenoxypropanolamines, the pharmaceutical compositions that contain them, a process for their preparation and intermediate products in this process.
BE 902897 describes aryloxypropanolamines with a 4-piperidininyl-1group substituted on the amine, these compounds having beta-blocking and alpha-blocking activity.
J. Org. Chem., 1988, 63:889:894 describes other aryloxypropanolamines having a 4-piperidininyl-1 group substituted on the amine.
It has now been found that phenoxypropanolamines having a 1-(pyrid-2-yl)-piperidine-4-yl radical on the amine have an agonistic activity with regard to adrenergic &bgr;
3
receptors.
Accordingly the present invention concerns, in one of its aspects, phenoxypropanolamines of formula (Ia)
R
1a
represents hydrogen, an —S(O)
z
—(C
1
-C
4
)Alk group, a —CO(C
1
-C
4
)Alk group, an —NHSO
2
—(C
1
-C
4
)Alk group, an NHCO(C
1
-C
4
)Alk group, a 2-furyl group or a halogen;
R
2
represents hydrogen, or a (C
1
-C
4
)Alk group, a (C
1
-C
4
)alkoxyl group, a halogen, —COOH, —COO(—(C
1
-C
4
)Alk, —CN—CONR
3
R
4
—NO
2
, —SO
2
NH
2
, —NHSO
2
(C
1
-C
4
)Alk;
m and n are independently 0, 1 or 2;
R
3
and R
4
independently represent hydrogen or a (C
1
-C
4
)Alk group;
Z is 1 or 2;
and their salts or solvates.
According to another of its aspects, the invention concerns compounds of formula (I):
wherein
R
1
represents hydrogen, an —S(O),—(C
1
-C
4
)Alk group, a —CO(C
1
-C
4
)Alk group or an —NHSO
2
—(C
1
-C
4
)Alk group;
R
2
represents hydrogen or a (C
1
-C
4
)Alk group, a (C
1
-C
4
)alkoxyl group, a halogen, —COOH, —COO(C
1
-C
4
)Alk;
m and n are independently 0, 1 or 2;
R
3
and R
4
independently represent hydrogen or a (C-C
4
)Alk group;
Z is 1 or 2 and their salts or solvates.
In the present description the term “(C
1
-C
4
)Alk” designates a monovalent radical of a saturated hydrocarbon in C
1
-C
4
with a straight or branched chain.
The salts of compounds of formula (I) according to the present invention comprise equally the addition salts with inorganic or organic acids that are pharmaceutically acceptable such as hydrochloride, hydrobromate, sulphate, hydrogen-sulphate, dihydrogenphosphate, citrate, maleate, tartrate, fumarate, gluconate, methane sulphonate, 2-naphthalene sulphonate, and so on, and the addition salts that permit separation or suitable crystallisation of compounds of formula (I), such as the picrate, oxalate or the addition salts with optically active acids, for example the camphor sulphonic acids and the mandelic or substituted mandelic acids.
Moreover, when the compounds of formula (I) and (Ia) possess a free carboxyl group the salts also comprise the salts with inorganic bases, preferably those with alkaline metals such as sodium or potassium, or with organic bases.
The optically pure stereo-isomers, together with the mixtures of isomers of compounds of formula (I) and (Ia), due to asymmetrical carbons or to the sulfinyl group, in the meaning of R
1a
or R
1
, in any proportions, form part of the present invention.
Preferred compounds of the present invention comprise the compounds of formula (I) and (Ia) in which the R
2
group is at position 5 of the pyridine.
Other preferred compounds comprise the compounds of formula (I) or (la) wherein the R
2
group is in position 6 of the pyridine.
Other preferred compounds are those in which the (C
1
-C
4
) Alk group is a methyl or ethyl group.
Other preferred compounds are those in which R
2
is one of the following: —COOH, —COO(C
1
-C
4
)Alk, —CN, —NO
2
, —CONR
2
R
3
, or —NHSO
2
(C
1
-C
4
)Alk.
Other preferred compounds are those in which R
2
is a halogen, notably chlorine.
Other preferred compounds are those in which n and m are zero.
The compounds of formula (I) and (Ia) can be prepared by treating a compound of formula (II)
in which R
1
b is R
1a
or R
1
as indicated above, P′ is a protective group and X is a group of formula (a) or (b)
where Gp is an initial group such as tosylate, mesylate or a halogen, with an amine of formula (III).
wherein n, m and R
2
are as defined above, with the P′ group split off by the usual methods and as appropriate converting the compound of formula (I) or (Ia) obtained into one of these salts.
More particularly, the reaction between the compounds of formulas (I) and (III) is carried out in an organic solvent, for example a lower alcohol such as methanol, ethanol or isopropanol; dimethylsulphoxide; a linear or cyclic ether; an amide such as dimethylformamide or dimethylacetamide; using at least equimolecular quantities of the reagents, with a slight excess of amine as appropriate.
The reaction temperature is between room temperature and the reflux temperature of the chosen solvent.
The protective groups P′ can be the usual protective groups for the hydroxyl groups such as for example methoxyethoxymethyl (MEM) or benzyl.
These protective groups are split off using the normal methods for the protective group selected; for example in the case of the benzyl group by hydrogenation in the presence of a catalyst such as Pd/C in a suitable solvent; however in the case of methoxyethoxymethyl (MEM) it is possible to use an acid such as trifluoroacetic acid.
Most of the epoxides in formula (II) are compounds known in the literature or alternatively can be prepared by processes similar to those described in the literature. For example certain epoxides of formula (II) are described in WO 96/04233 and in U.S. Pat. No. 4,396,629.
The pure isomers of the compounds of formula (II) in which X is a group (a) and R
ab
represents the SOCH
3
group, resolved to the asymmetrical carbon, are new, having been obtained for the first time as pure stereo-isomers free of other stereo-isomers or impurities.
Certain epoxides of formula (II) are new and constitute another object of the present invention.
More particularly, these are compounds of formula (II′):
wherein P′ is as defined in formula (II), X is a group (a) as defined above and Y represents an atom of bromine or a 2-furyl group, their optically active isomers and their salts. They are prepared as described in examples 44 and 47.
The amines of formula (III) can be prepared by reacting appropriate pyridines of formula (IV)
where Hal represents a halogen and R
2
and m are as defined above, with a piperidine of formula (V) below
where n is as defined above and P represents a protective group, in an organic solvent in the presence of a base, followed by splitting off the P group from the compounds of formula (VI) obtained.
As a reaction solvent for example, it is possible to use dimethylformamide, pyridine, dimethylsulphoxide, a linear or cyclic ether or a chlorinated solvent such as dichloromethane.
As a base for example one can use an alkaline hydroxide, an alkaline carbonate such as potassium carbonate or a tertiary amine such as triethylamine.
The above condensation reaction takes a few hours, normally between 2 and 12 hours.
The reaction temperature is between room temperature and the reflux temperature for the chosen solvent.
As protective groups P it is possible to use the usual protective groups for amines, for example ter-butoxycarbonyl, acetyl, or carbobenzyloxy.
These protective groups are split off using the normal methods described for the selected protective group; for example in the case of ter-butoxycarbonyl, splitting off is normally done by acid hydrolysis.
Certain intermediate amines of a formula (III) and (VI), grouped together in formula (VII) below
where
P° is hydrogen or a protective group;
n° and m° are 0, 1 or 2;
R°
2
is a (C
1
-C
4
)Alk; (C
1
-C
4
)alkoxyl, —COOH, —COO(C
1
-C
4
)Alk, —CN, —NO
2
, —CONR
3
°R
4
°, —SO
2
NH
2
, or
—NHSO
2
(C
1
-C
4
)Alk;
R°
3
and R°
4
are hydrogen or a (C
1
-C
4
)Alk group; on condition that:
when n° and m° are zero, R°
2
is other than methoxyl at position 6 and other than halogen in position 3 or 6 on the pyridine; when n° is 1, m° is 0, R°
2
is other than chlorine in position 6 of the pyridine and when n° is 0, m° is 0 or 1, R°
2
is other than methyl; and their salts, are new compounds and are
Cecchi Roberto
Croci Tiziano
Guzzi Umberto
Marsault Eric
Alexander Michael D.
Covington Raymond
Rotman Alan L.
Sanofi-Synthelabo
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