Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-09
2001-12-18
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...
C546S176000
Reexamination Certificate
active
06331549
ABSTRACT:
The present invention relates to 1-amino-ethylquinoline derivatives, to their preparation and to their therapeutic application.
The publication Chemical Abstracts, Vol.83, No.9 (Jan. 9, 1975) discloses 8-(1-aminoethyl)quinoline, but describes only the process for preparing it.
According to one of the aspects of the invention, it relates to compounds corresponding to the general formula (I)
in which:
A represents a hydrogen atom, an azido, a halogen, a hydroxyl, a thiol, an amino, a phenyl, a C
1-6
alkyl, C
1-6
alkylamino, di(C
1-6
alkyl)amino, hydroxylamine, C
1-6
alkylhydroxylamine, N,O—C
1-6
dialkylhydroxylamine, C
1-6
alkoxy or C
1-6
alkylsulphanyl group,
B and D represent, independently of each other, a hydrogen atom, a phenyl, a C
1-6
alkyl, C
2-6
alkenyl, C
1-6
fluoroalkyl or C
1-2
perfluoroalkyl group, or together form an oxo,
R
1
represents a hydrogen atom, a halogen, a carbonyl, a hydroxycarbonyl, a cyano, a carboxamide, a C
1-6
alkyl, C
2-6
alkenyl, C
3-6
cycloalkyl, C
1-6
alkoxycarbonyl, C
1-6
hydroxyalkyl, C
1-6
alkoxy, (C
1-6
)alkoxy(C
1-3
)alkyl, C
1-6
fluoroalkyl, C
1-2
perfluoroalkyl or CF
3
(OH)CH group, or R
1
and R
2
together form a C
3-5
alkylene or C
3-5
alkenylene chain or form, with the carbon atoms to which they are attached, a phenyl,
R
2
, R
3
and R4 represent, independently of each other, a hydrogen atom, a halogen or a C
1-6
alkyl group, or R
2
and R
3
together form a C
3-5
alkylene or C
3-5
alkenylene chain or R
1
and R
2
, together, are as defined above, and
R
5
and R
6
represent, independently of each other, a hydrogen atom, a C
1-6
alkyl, C
2-6
alkenyl, C
3-6
cycloalkyl, C
3-6
cycloalkenyl, C
1-6
fluoroalkyl or C
1-2
perfluoroalkyl group or R
5
and R
6
together form a C
2-6
alkylene or C
3-6
alkenylene chain, to give, with the nitrogen to which they are attached, a heterocycle such as, for example, a piperidyl, azetidinyl or pyrrolidyl, this heterocycle optionally being substituted with a C
1-4
alkyl group, and salts thereof.
The compounds that are preferred according to the invention are chosen from the following subgroups, in which:
A represents a halogen, a hydroxyl, a thiol, a phenyl or a C
1-6
alkyl, hydroxylamine, C
1-6
alkylhydroxylamine, N,O—C
1-6
dialkylhydroxylamine, C
1-6
alkoxy or C
1-6
alkylsulphanyl group, and more particularly a hydroxyl, a phenyl or a C
1-6
alkyl, N,O—C
1-6
dialkylhydroxylamine or C
1-6
alkoxy group; or
B and D represent, independently of each other, a hydrogen atom, a phenyl or a C
1-6
alkyl group or together form an oxo; or
R
1
represents a C
1-6
alkyl, C
2-6
alkenyl, C
1-6
fluoroalkyl or C
1-2
perfluoroalkyl, more particularly C
1-6
alkyl or C
1-2
perfluoroalkyl or CF
3
(OH)CH group, or R
1
and R
2
together form a C
3-5
alkylene or C
3-5
alkenylene chain, more particularly a C
3-5
alkylene chain, or R
1
and R
2
form, with the carbons to which they are attached, a phenyl; or
R
5
and R
6
represent, independently of each other, a C
1-6
alkyl or C
2-6
alkenyl group, or R
5
and R
6
together form a C
2-6
alkylene or C
3-6
alkenylene chain, to give, with the nitrogen to which they are attached, a heterocycle, this heterocycle optionally being substituted with a C
1-4
alkyl and more particularly C
1-2
alkyl group.
One subgroup of compounds of formula (I) which is particularly preferred is the one in which A, B, D, R
1
, R
5
and R
6
are as defined above in the subgroups of preferred compounds, and R
2
, R
3
and R4 are as defined above.
In particular, the subgroup of compounds below is particularly preferred:
A represents a hydroxyl, a phenyl or a C
1-3
alkyl, N,O—C
1-3
dialkylhydroxylamine or C
1-3
alkoxy group;
B and D represent, independently of each other, a hydrogen atom, a phenyl or a C
1-3
alkyl group or together form an oxo;
R
1
represents a C
1-3
alkyl or C
1-2
perfluoroalkyl group or R
1
and R
2
together form a C
3-5
alkylene chain, or R
1
and R
2
form, with the carbons to which they are attached, a phenyl;
R
2
, R
3
and R
4
represent, independently of each other, a hydrogen atom, a halogen or a C
1-3
alkyl group, or R
2
and R
3
together form a C
3
-C
5
alkylene chain, or R
1
and R
2
, together, are as defined above,
R
5
and R
6
represent, independently of each other, a C
1-6
alkyl group, or R
5
and R
6
together form a piperidyl, this piperidyl optionally being substituted with a C
1-2
alkyl group.
In the present patent application:
C
1-z
(or C
2-z
or C
3-z
), in which z may take values between 2 and 6, represents a carbon-based chain which may contain from 1 (or 2 or 3) to z carbon atoms,
the terms alkyl, alkenyl and alkoxy represent, respectively, an alkyl, alkenyl or alkoxy containing a linear or branched carbon-based chain,
the terms alkylene and alkenylene represent, respectively, a divalent alkyl or alkenyl containing a linear or branched carbon-based chain,
Pg represents a protecting group; examples of protecting groups and methods of protection and deprotection are given in Protective groups in
Organic Synthesis Greene
et al., 2nd Ed. (John Wiley & Sons, Inc., New York), and
halogen represents an iodine, bromine, chlorine or fluorine atom.
The compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
When a compound according to the invention shows stereoisomerism, for example of axia-equatorial or Z-E type, the invention comprises all the stereoisomers of these compounds.
The compounds of general formula (I) may be in the form of the free base or in the form of addition salts with acids, which also form part of the invention. According to the present invention, these salts comprise those with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphorsulphonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, maleate, fumarate, 2-naphthalenesulphonate, pamoate or para-toluene-sulphonate.
Although the pharmaceutically acceptable salts are preferred, the other salts form part of the present invention. These salts may be prepared according to methods known to those skilled in the art, for example by reacting the base with the acid in a suitable solvent, such as an alcoholic solution or an organic solvent, followed by separation from the medium containing it by evaporating off the solvent or by filtration.
The compounds of the invention may be prepared according to processes illustrated by the schemes which follow. The preparation processes form part of the present invention.
1. The compounds of formula (I), in particular those for which A represents a hydroxyl group, may be prepared according to the process described in Scheme 1.
According to this process, an ethenyl derivative of formula IV is reacted with an oxidizing agent, such as sodium periodate, osmium tetroxide or meta-chloroperbenzoic acid, in basic or acidic medium so as to form a diol of formula III. The hydroxyl group geminal to the group B (or D) is selectively protected with a protecting group Pg, in a manner which is known to those skilled in the art, for example by forming a silyl ether, so as to obtain the compound of formula II. The hydroxyl group borne by the carbon alpha to the heterocycle in the compound thus obtained is activated, in a manner which is known to those skilled in the art, so as to give a nucleofugal group such as a mesyl or tosyl group or a bromine atom. The compound of formula (I) according to the invention is then prepared from this compound by reacting the latter with an excess of amine NHR
5
R
6
, in an organic solvent such as chloroform, acetonitrile or tetrahydrofuran. The reaction is preferably p
Bovy Philippe
Braun Alain
DeFosse Gerard
Mougenot Patrick
Philippo Christophe
Alexander Michael D.
Davis Zinna Northington
Sanofi-Synthelabo
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