Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-01
2002-07-02
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S290000, C514S297000, C546S079000, C546S093000, C546S104000, C546S176000
Reexamination Certificate
active
06413984
ABSTRACT:
The present invention relates to &agr;-azacyclomethylquinoline derivatives, to their preparation and to their therapeutic application.
The compounds correspond to the general formula (I):
in which:
A represents either a hydrogen atom or a hydroxyl group,
B represents a 2-pyrrolidinyl (D) or 2-piperidyl (E),
R
1
represents a hydrogen atom, a C
1-6
alkyl, C
2-6
alkenyl, C
1-2
perfluoroalkyl or C
1-6
fluoroalkyl group,
R
2
, R
3
or R
4
represent, independently of each other, a hydrogen atom, a C
1-6
alkyl group or a C
2-6
alkenyl group, or
R
1
and R
2
together may also form a C
1-6
alkylene chain or a C
3-6
alkenylene chain,
R
5
represents a C
1-6
alkyl group,
R
6
represents 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 or a benzyl, and
“n” represents 0, 1 or 2.
More particularly, the compounds for which A represents a hydroxyl group are preferred.
Moreover, the compounds for which R
1
represents a C
1-6
alkyl group, preferably C
1-3
alkyl and more particularly an ethyl, are found to be advantageous.
Other preferred compounds are the compounds for which R
2
and R
3
represent, independently of each other, a hydrogen atom or a C
1-3
alkyl group, more particularly a methyl.
The compounds for which A, R
1
, R
2
and R
3
are as defined in the groups of preferred compounds are most particularly preferred.
In the context of the present invention, the term “C
1-6
alkyl” means a saturated, linear or branched aliphatic group comprising from 1 to 6 carbon atoms, such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. group. The term “C
1-6
alkylene” denotes a divalent C
1-6
alkyl group.
The term “C
2-6
alkenyl” denotes a monounsaturated or polyunsaturated, linear or branched aliphatic group comprising from 2 to 6 carbon atoms. According to the invention, an alkenyl group preferably comprises 1 or 2 ethylenic unsaturations. The term “C
2-6
alkenylene” denotes a divalent C
2-6
alkenyl group.
The term “C
3-6
cycloalkyl” denotes a saturated cyclic aliphatic system comprising from 3 to 6 carbon atoms.
The term “C
3-6
cycloalkenyl” denotes a unsaturated cyclic aliphatic system comprising from 3 to 6 carbon atoms. According to the invention, a C
3-6
cycloalkenyl group preferably comprises 1 or 2 unsaturations.
The term “protecting group Pg” means a group which firstly protect a reactive function such as a hydroxyl or an amine during a synthesis, and secondly allows the reactive function to be regenerated intact at the end of the synthesis. Examples of protecting groups and protection and deprotection methods are given in
Protective group in Organic Synthesis Greene
et al., 2nd Ed. (John Wiley & Sons, Inc., New York).
Moreover, in the schemes, &Circlesolid; represents a solid support.
A solid support consists of an insoluble material bearing functionalization intended to capture a chemical compound.
Examples of such materials are polymers, plastics, resins, polysaccharides and silica derivatives. Preferably, resins are used, and more preferably polystyrene resins or resins of mixed polystyrene/ethylene glycol (PS-PEG) type.
Functionalization depends on the molecule to be captured. For example, this functionalization may consist of a halo, hydroxyl, aldehyde, carboxyl, amino, trityl or thiol group.
Such solid supports comprising suitable functionalization or which require a preactivation by methods known to those skilled in the art are commercially available in particular from Novabiochem, Rapp Polymer, Sigma, Aldrich, Polymer Laboratories or Argonaut Technologies.
Preferably, the solid support is a carboxy resin activated as acid chloride or a trityl chloride resin or an Elleman dihydropyran resin.
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 the mixtures thereof including racemic mixtures, form part of the invention.
The compounds of general formula (I) may be in the form of free base or 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 camphorsulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, maleate, fumarate, citrate, pamoate, 2-naphthalenesulfonate or paratoluenesulfonate. 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 compound of formula (I) in base form with the acid in a suitable solvent, such as an alcoholic solution or an organic solvent, followed by separation from the medium containing them by evaporation of the solvent or by filtration.
The compounds derived from &agr;-azacyclomethylquinoline of formula (I) according to the invention may be prepared according to different processes. 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, the compounds of formula (I) for which R
6
represents a hydrogen atom are obtained by cleaving from the solid support the compounds of formula (II) derived from the deprotection of the protecting group Pg on the nitrogen of the compound of formula (III), according to methods known to those skilled in the art. Such a protecting group may be, for example, a C
1-6
alkoxycarbonyl group such as tert-butyloxycarbonyl (tBoc). The meanings of R
1
, R
2
, R
3
, R
4
, R
5
and n in the compounds of formulae (II) and (III), are those given in formula (I).
The secondary amine in the compounds of formula (II) thus obtained may then be functionalized, according to processes known to those skilled in the art, for example by reductive amination (under the conditions described by Balasubranian et al., Tetrahedron Letters, vol. 37, No. 27, pp. 4819-4822) to give, after cleavage from the solid support, a compound of formula (I) in which R
6
is not a hydrogen.
The compounds of formula (III) may be obtained by uptake using an activated solid support of the reaction mixture derived from the reaction of an aldehyde of formula (VIII), in which Pg represents a protecting group known to those skilled in the art, with a derivative (IV) obtained by metallation of the halo derivative of formula (V). The meanings of R
1
, R
2
, R
3
, R
4
, R
5
, B and n in the compounds of formulae (V) (IV) and (VIII) are those given in formula (I). The metallation reaction may be carried out in an organic solvent such as tetrahydrofuran, by forming the Grignard reagent of the halo derivative of formula (V), in which Y represents a halogen, or more advantageously by reacting the halo derivative of formula (V) in the presence of n-butyllithium preferably at temperatures of about −78° C. The term “metal” in formula (IV) represents, for example, lithium Li.
The aldehydes of formula (VIII) may be obtained by reduction, for example according to the method described by Jurczack J. et al., Chem. Rev (1989), 89, 149, starting with the corresponding N-protected &agr;-amino acid derivatives of formula (IX) which are themselves derived from the &agr;-amino acids of formula (X). R
5
, B and n have the meanings given in formula (I). Pg is defined as above and Z represents a group, which is known to those skilled in the art, allowing controlled reduction which stops at the formation of an aldehyde, inter alia, N-methyl-O-methylhydroxylamine (Nahm and Weinreb (1981), Tet., Lett., 22, 3815).
The compounds of formula (V) may themselves be prepared either by a Skraup or Doebner
Bovy Philippe R.
Braun Alain
Philippo Christophe
Alexander Michael D.
Dupont Paul E.
Sanofi-Synthelabo
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