Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-18
2002-06-11
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S174000, C546S177000, C546S178000
Reexamination Certificate
active
06403610
ABSTRACT:
The present invention relates to quinolylpropylpiperidine derivatives of formula:
which are active as antimicrobials. The invention also relates to their preparation, to their use, and to compositions comprising them.
in which the R
1
radical can be (C1-C6)alkoxy, R
2
is hydrogen, R
3
is in the 2- or 3-position and represents (C1-C6)alkyl which can optionally be substituted by 1 to 3 substituents chosen from thiol, halogen, alkylthio, trifluoromethyl, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxyl optionally substituted by alkyl, and the like, R
4
is a —CH
2
—R
5
group in which R
5
is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, and the like, n is 0 to 2, m is 1 or 2, and A and B are in particular oxygen, sulfur, sulfinyl, sulfonyl, or CR
6
R
7
in which R
6
and R
7
represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, amino, and the like.
European Patent Application EP30044 discloses quinoline derivatives, for use as cardiovasculars, corresponding to the formula:
in which R
1
can be alkyloxy, A-B is —CH
2
—CH
2
—, —CHOH—CH
2
—, —CH
2
—CHOH—, —CH
2
CO—, or —CO—CH
2
—, R
1
is H, OH or alkyloxy, R
2
is ethyl or vinyl, R
3
can be alkyl, hydroxyalkyl, cycloalkyl, hydroxyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, optionally substituted diphenylalkyl, optionally substituted phenylalkenyl, optionally substituted benzoyl or benzoylalkyl, or optionally substituted heteroaryl or heteroarylalkyl, and Z is H or alkyl or forms, with R
3
, a cycloalkyl radical.
It has now been found, and it is this which forms the subject of the present invention, that the products of formula (I) in which:
R
1
is a hydrogen atom, a halogen atom, or a hydroxyl radical;
R′
1
is a hydrogen atom or can represent halogen when R
1
is a halogen atom; and
R° is a hydrogen atom; or
R
1
and R° together form a bond; and
R′
1
is a hydrogen atom;
R
2
represents a carboxyl, carboxymethyl, or 2-carboxyethyl radical; and
R
3
represents an alkyl radical having 1 to 6 carbon atoms substituted by 1 to 3 substituents chosen from hydroxyl, halogen, oxo, carboxyl, alkyloxycarbonyl, alkyloxy, and alkylthio;
or from phenyl, phenylthio, or phenylalkylthio radicals, which radicals are unsubstituted or substituted by 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, acetamido having 1 to 4 carbon atoms, and amino;
or from cycloalkyl or cycloalkylthio radicals, the cyclic part of which comprises 3 to 7 members;
or from 5- to 6-membered aromatic heterocyclyl or heterocyclylthio radicals comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur and being unsubstituted or substituted by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino;
or R
3
represents a propargyl radical substituted by a phenyl radical which is unsubstituted or substituted by 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, and amino;
or the propargyl radical is substituted by a cycloalkyl radical comprising 3 to 7 members;
or the propargyl radicals is substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur and being unsubstituted or substituted by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino;
or R
3
represents cinnamyl or 4-phenylbuten-3-yl;
or R
2
represents a hydroxymethyl, alkyloxycarbonyl, alkyloxycarbonylmethyl, or 2-(alkyloxycarbonyl)ethyl radical, wherein the alkyl parts of the radicals comprise 1 to 6 carbon atoms; and
R
3
represents an alkyl radical having 1 to 6 carbon atoms substituted by a phenylthio radical which is unsubstituted or substituted by 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, and amino;
or the alkyl radical is substituted by a cycloalkylthio radical, the cyclic part of which comprises 3 to 7 members;
or the alkyl radical is substituted by a 5- to 6-membered aromatic heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur and being unsubstituted or substituted by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino;
or R
3
represents a propargyl radical substituted by a phenyl radical which is unsubstituted or substituted by 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, and amino;
or the propargyl radical is substituted by a cycloalkyl radical comprising 3 to 7 members;
or the propargyl radical is substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur and being unsubstituted or substituted by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino;
and R
4
represents an alkyl radical comprising 1 to 6 carbon atoms, or an alkenyl-CH
2
— or an alkynyl-CH
2
— radical, the alkenyl or alkynyl parts of which comprise 2 to 6 carbon atoms;
it being understood that the alkyl radicals and alkyl portions of radicals are straight- or branched-chain radicals and portions of radicals and comprise, except when specifically mentioned, 1 to 4 carbon atoms;
the diastereoisomers thereof, the mixtures of diastereoisomers thereof, and the salts thereof;
are powerful antibacterial agents.
It is understood that the alkyl radicals and portions of radicals are straight- or branched-chain radicals and portions and comprise, except when specifically mentioned, 1 to 4 carbon atoms and that, in the alternative where R
1
or R′
1
represent a halogen atom or when R
3
carries a halogen substituent, the latter can be chosen from fluorine, chlorine, bromine, or iodine, and is typically fluorine.
In the above formula (I), when R
3
carries an aromatic heterocyclyl substituent, the latter can be chosen, without implied limitation, from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, or pyrimidinyl. It is also understood that, in the definition of R
3
, the substituted alkyl radical only simultaneously carries a single cyclic radical.
According to the invention, the products of formula (I) can be obtained by condensation of an R
3
chain onto a quinolylpropylpiperidine derivative of formula:
in which R
4
is defined as above, R″
1
and R′″
1
represent hydrogen atoms or together form an oxo radical, and R′
2
represents a protected carboxyl, carboxymethyl, or 2-carboxyethyl radical, or an alkyloxycarbonyl, alkyloxycarbonylmethyl, or 2-(alkyloxycarbonyl)ethyl radical, in order to obtain a quinolylpropylpiperidine derivative of formula:
in which R″
1
, R′″
1
, R′
2
, and R
4
are defined as above and R
3
is also defined as above,
followed, if appropriate, by the removal of the acid-protecting radical,
then, if appropriate, followed by the reduction of the oxo radical represented by R″
1
and R′″
1
to an alcohol in which R
1
represents hydroxyl, then, optionally, by halogenation, if it is desired to obtain a quinolylpropylpiperidine derivative in which R
1
is a halogen atom, and, optionally, by dehydrohalogenation of the corresponding halogenated derivative, in order to obtain a quinolylpropylpiperidine derivative in which R
1
and R° together form a bond, or else by dihalogenation of the product of formula (III) in which R″
1
and R′″
1
together form an oxo radical, in order to ob
Ahmad Youssef El
Carry Jean-Christophe
Cheve Michel
Evers Michel
Malleron Jean-Luc
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner LLP
Seaman D. Margaret
LandOfFree
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