2-arylquinoline derivatives, preparation and therapeutic use...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C546S173000, C546S176000, C514S311000, C514S314000

Reexamination Certificate

active

06617336

ABSTRACT:

The subject matter of the invention is 2-arylquinoline derivatives, their preparation and their application in therapeutics.
The compounds correspond to the general formula (I)
in which:
A represents a hydrogen atom, a hydroxyl, a C
1-3
alkoxy group, a hydroxy(C
1-6
alkyl) group, a (C
1-3
alkoxy)(C
1-3
alkyl) group, a thiol, (C
1-6
alkyl)sulfanyl or a halogen;
B and D represent, independently of one another, a hydrogen atom, a C
1-6
alkyl group, a fluoro(C
1-6
alkyl) group or a perfluoro(C
1-2
alkyl) group or B and D together from an oxo;
R
1
represents a phenyl, a naphthyl or a heteroaryl comprising 4 or 5 carbon atoms and, as heteroatom, an oxygen, a sulfur or a nitrogen; it being possible for the phenyl, the naphthyl or the heteroaryl to be substituted by one, two or three substituents chosen from the group consisting of a halogen, a hydroxyl, a nitro, an amino, an azido, a C
1-6
alkyl group, a hydroxy(C
1-6
alkyl) group, a (C
1-6
alkyl)carbonyl group, a (C
1-6
alkyl)amino group, a di(C
1-6
alkyl)amino group, a fluoro(C
1-6
alkyl) group, a perfluoro(C
1-2
alkyl) group, a C
1-6
alkoxy group, a phenyl and a benzyl, and a benzyloxy;
R
2
and R
3
represent, independently of one another, a hydrogen atom, a halogen or a C
1-6
alkyl group,
R
4
represents a hydrogen atom, a hydroxyl or a halogen, and
R
5
and R
6
represent, independently of one another, a hydrogen atom, a C
1-6
alkyl group, a C
2-6
alkenyl group, a C
3-6
cycloalkyl group, a C
3-6
cycloalkenyl group, a fluoro(C
1-6
alkyl) group or a perfluoro(C
1-2
alkyl) group or R
5
and R
6
together form a C
2-6
alkylene chain or a 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 by a C
1-4
alkyl group; and their salts.
The preferred compounds according to the invention are chosen from the following subgroups, in which:
A represents a hydrogen, hydroxyl, a thiol or a halogen and more particularly a hydroxyl; and/or
B and D represent a hydrogen atom; and/or
R
1
represents a phenyl, a naphthyl or a heteroaryl comprising 4 or 5 carbon atoms and, as heteroatom, a sulfur or a nitrogen, it being possible for the phenyl, the naphthyl or the heteroaryl to be substituted by one, two or three substituents chosen from the group consisting of a halogen, a hydroxyl, a nitro, an amino, an azido, a C
1-3
alkyl group, a hydroxy(C
1-3
alkyl) group, a (C
1-3
alkyl)carbonyl group, a (C
1-3
alkyl)amino group, a di(C
1-3
alkyl)amino group, a fluoro(C
1-6
alkyl) group, a perfluoro(C
1-2
alkyl) group, a C
1-3
alkoxy group, a phenyl, a benzyl and a benzyloxy; and/or
R
2
and R
3
represent, independently of one another, a hydrogen atom or a C
1-6
alkyl group, more particularly a C
1-3
alkyl group; and/or
R
5
and R
6
represent, independently of one another, a hydrogen atom or a C
1-6
alkyl group, more particularly a C
1-3
alkyl group, or R
5
and R
6
together form a C
2-6
alkylene chain, to give, with the nitrogen to which they are attached, a heterocycle, such as, for example, a piperidyl, azetidinyl or pyrrolidyl, more particularly piperidyl, this heterocycle optionally being substituted by a C
1-4
alkyl group, more particularly a C
1-2
alkyl group.
A particularly preferred subgroup of compounds of formula (I) is that in which A, B, D, R
1
, R
2
, R
3
, R
5
and R
6
are as defined above in the subgroups of preferred compounds and R
4
is as defined above.
In particular, the following subgroup of compounds is particularly preferred:
A represents a hydroxyl,
B and D and R
4
represent a hydrogen atom,
R
1
represents a naphthyl, a thiophene, a pyridine or a phenyl, it being possible for the phenyl to be substituted by one, two or three substituents chosen from the group consisting of a a halogen, a hydroxyl, a nitro, an amino, an azido, a C
1-3
alkyl group, a hydroxy(C
1-3
alkyl) group, a (C
1-3
alkyl)carbonyl group, a (C
1-3
dialkyl)amino group, a perfluoro(C
1-2
alkyl) group, a C
1-3
alkoxy group, a phenyl and a benzyloxy,
R
2
and R
3
represent, independently of one another, a hydrogen atom or a C
1-3
alkyl group, and
R
5
and R
6
represent, independently of one another, a C
1-3
alkyl group or R
5
and R
6
, together with the nitrogen to which they are attached, a piperidyl, this piperidyl optionally being substituted a C
1-2
alkyl group.
The preferred compounds are shown in the table below; mention may more particularly be made of the following compounds:
2-Phenyl-3-methyl-8-(1-diethylamino-2-hydroxyethyl)quinoline,
2-Phenyl-3-methyl-8-(1-(R)-[2′-(R)methylpiperidino]-2-hydroxyethyl)quinoline,
2-Phenyl-8-(1-diethylamino-2-hydroxyethyl)quinoline,
2-Thiophen-2-yl-8-(1-diethylamino-2-hydroxyethyl)quinoline, and
2-(2-Fluorophenyl)-3-methyl-8-(1-diethylamino-2-hydroxyethyl)quinoline.
In the present application:
C
1−z
(or C
2−z
or C
3−z
), where z can take the values between 2 and 6, represents a carbonaceous chain which can have from 1 (or 2 or 3) to z carbon atoms,
the term alkyl, alkenyl or alkoxy respectively represents an alkyl, alkenyl or alkoxy with a linear or branched carbonaceous chain,
the term alkylene or alkenylene respectively represents a divalent alkyl or alkenyl with a linear or branched carbonaceous chain,
the term heteroaryl represents an aromatic ring comprising 4 or 5 carbon atoms and a heteroatom; such a ring is, for example, a thiophene, a furan or a pyridine,
Pg represents a protective group; examples of protective groups and protection and deprotection methods 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) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and their mixtures, including racemic mixtures, form part of the invention.
When a compound according to the invention exhibits stereoisomerism, for example of axial-equatorial or Z-E type, the invention comprises all the stereoisomers of these compounds.
The compounds of general formula (I) can be provided in the form of the free base or in the form of addition salts with acids, which also form part of the invention. These salts, according to the present invention, comprise those with inorganic or organic acids which make possible 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 camphorsulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, maleate, pamoate, fumarate, 2-naphthalenesulfonate or para-toluenesulfonate. Even if the pharmaceutically acceptable salts are preferred, the other salts form part of the present invention. These salts can be prepared according to methods known to a person skilled in the art, for example by reaction of the base with the acid in an appropriate solvent, such as an alcoholic solution or an organic solvent, and then separation from the medium in which they are present by evaporation of the solvent or by filtration.
The compounds of the invention can be prepared by processes illustrated by the schemes which follow.
The compounds of formula (I), in particular those for which A represents hydroxyl, can be prepared according to the process described in scheme 1.
According to this process, a quinoline derivative of formula V, in which Y represents a nucleofuge group, such as a halogen or an activated hydroxyl group, for example activated in the triflate form, is reacted by palladium-catalyzed Stille coupling with a compound of formula VI, under the conditions defined by McKean, D. R.; Parinello, G.; Renaldo, A. F.; Stille, J. K., J. Org. Chem., 52, 1987, 492, to

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

2-arylquinoline derivatives, preparation and therapeutic use... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 2-arylquinoline derivatives, preparation and therapeutic use..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2-arylquinoline derivatives, preparation and therapeutic use... will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-3032934

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.