Quinolylpropylpiperidine derivatives, their preparation, and...

Details Quinolylpropylpiperidine derivatives, their preparation, and... Quinolylpropylpiperidine derivatives, their preparation, and...

2003-03-14

2004-11-09

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S177000, C546S178000, C546S179000, C546S180000

Reexamination Certificate

active

06815547

ABSTRACT:

One embodiment of the present invention relates to quinolyl-propylpiperidine derivatives of general formula (I):
which are active as antimicrobials. Other embodiments of the invention relate to their preparation and to compositions containing them.
Patent Application Publications WO 99/37635 and WO 00/43383 describe antimicrobial quinolylpropylpiperidine derivatives of general formulas:
In which the radical R
1
may be (C
1-6
)alkoxy; R
2
is hydrogen; R
3
is at the 2- or 3-position and represents (C
1-6
)alkyl, which may be optionally substituted with 1 to 3 substituents chosen from thiol, halogen, alkylthio, trifluoromethyl, carboxyl, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxyl optionally substituted with alkyl, and the like; R
4
is a group —CH
2
—R
5
, wherein R
5
is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, which is optionally substituted, phenylalkenyl, which is optionally substituted, heteroarylalkyl, which is optionally substituted, heteroaryl, which is optionally substituted, and the like; n is 0 to 2; m is 1 or 2; A and B may be oxygen, sulfur, sulfinyl, sulfonyl, NR
11
, CR
6
R
7
, wherein R
6
and R
7
represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, or amino; and Z
1
to Z
5
are N or CR
1a
, and the like.
European Patent Application EP30044, describes quinoline derivatives that are useful as cardiovascular agents and that correspond to the general formula:
in which R
1
may 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
may be alkyl, hydroxyalkyl, cycloalkyl, hydroxyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, diphenylalkyl, which is optionally substituted, phenylalkenyl, which is optionally substituted, benzoyl, or benzoylalkyl, which is optionally substituted, heteroaryl or heteroaryl-alkyl, which is optionally substituted; and Z is H or alkyl or forms with R
3
a cycloalkyl radical.
The inventors have now found that the compounds of formula (I) are potent antibacterial agents. In the compounds of formula (I),
R
1
represents a, hydrogen atom, a halogen atom, or a hydroxyl, amino, alkylamino, dialkylamino, hydroxyamino, alkyloxyamino, or alkylalkyloxyamino radical;
R
2
represents a carboxyl, carboxymethyl, or hydroxymethyl radical;
R
3
represents an alkyl radical containing 1 to 6 carbon atoms, substituted with a phenylthio radical, which may itself carry 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro-methoxy, carboxyl, alkyloxycarbonyl, cyano, and amino, or substituted with a cycloalkylthio radical in which the cyclic portion contains 3 to 7 members, or substituted with a 5- to 6-membered aromatic heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur, and itself optionally substituted with halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro-methoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino; or
R
3
represents a propargyl radical substituted with a phenyl radical, which may itself be substituted with 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, and amino, or substituted with a 3- to 7-membered cycloalkyl radical or substituted with a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur, and itself optionally substituted with halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino; and
R
4
represents an alkyl radical (containing 1 to 6 carbon atoms), alkenyl-CH
2
—, alkynyl-CH
2
— (in which the alkenyl or alkynyl portions contain 2 to 6 carbon atoms), cycloalkyl or cycloalkylalkyl radical (in which the cycloalkyl portion contains 3 to 8 carbon atoms).
The compounds of the invention include the diastereoisomeric forms of the compounds of formula (I), their mixtures, and their cis or trans forms, as well as their salts.
It is understood that the alkyl radicals and alkyl portions of the compounds of the invention may be in the form of a straight or branched chain and contain, unless otherwise stated, 1 to 4 carbon atoms, and that in the alternative case where R
1
represents a halogen atom or when R
3
carries a halogen substituent, the latter may be chosen from fluorine, chlorine, bromine, and iodine.
Other than in the working examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
In formula (I), when R
3
carries an aromatic heterocyclyl substituent, the latter may be chosen, without limitation, from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, and pyrimidinyl.
According to the invention, the compounds of formula (I) may be obtained by condensing an R
3
radical with a quinolylpropylpiperidine derivative of formula (II):
in which R
4
is as defined above for compounds of formula (I), R′
1
represents a hydrogen atom or a hydroxyl radical, and R′
2
represents a protected carboxyl or carboxymethyl radical, to obtain a quinolylpropylpiperidine derivative of formula (III):
for which R′
1
, R′
2
, R
3
, and R
4
are as defined above.
Where appropriate, this reaction may be followed by either a) the halogenation of a derivative for which R′
1
is a hydroxyl radical, if it is desired to obtain a quinolylpropylpiperidine derivative for which R
1
is a halogen atom, or b) the conversion of a hydroxyl radical to an oxo radical, and then to a hydroxyimino or alkyloxyimino radical according to known methods which do not adversely affect the rest of the molecule, to obtain a quinolylpropylpiperidine derivative of formula (IV):
for which R′
2
, R
3
, and R
4
are as defined above, and R
5
is a hydrogen atom or an alkyl radical. Where appropriate or desired, this reaction may be followed by: a) the reduction of a derivative of formula (IV) for which R
5
is a hydrogen atom to an amine, and optionally by the conversion to a monoalkylated or dialkylated amine; b) the reduction of the derivative of formula (IV) for which R
5
is a hydrogen atom to a hydroxylamine; c) the reduction of a derivative of formula (IV) for which R
5
is an alkyl radical to an alkyloxyamine, and then, where appropriate to obtain a derivative for which R
1
is alkylalkyloxy-amino, the derivative obtained for which R
1
is alkyl-oxyamino can be converted by alkylation, and/or d) the reduction of a protected carboxyl radical R′
2
to a hydroxymethyl radical according to known methods that do not adversely affect the rest of the molecule. The final step can be optionally followed by the separation of the diastereoisomers, by the separation of the cis and trans forms, by removal, where appropriate, of the acid-protecting radical, and/or by the conversion of the fina

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