Heterocyclylalkylpiperidine derivatives, their preparation...

Details Heterocyclylalkylpiperidine derivatives, their preparation... Heterocyclylalkylpiperidine derivatives, their preparation...

2001-11-14

2003-08-05

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S122000, C546S123000, C514S300000, C514S314000

Reexamination Certificate

active

06603005

ABSTRACT:

The present invention relates to heterocyclylalkyl-piperidine derivatives of general formula:
which are active as antimicrobial agents. The invention also relates to their preparation and to compositions containing them.
Patent applications WO 99/37635 and WO 00/43383 disclose antimicrobial quinolylpropylpiperidine derivatives of general formula:
in which the radical R
1
is especially (C1-6) alkoxy, R
2
is hydrogen, R
3
is in position −2 or −3 and represents (C1-6) alkyl which may optionally be substituted with from 1 to 3 substituents chosen from thiol, halogen, alkylthio, trifluoromethyl, carboxyl, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxyl optionally substituted with alkyl, etc., R
4
is a group —CH
2
—R
5
for which R
5
is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, etc., n is 0 to 2, m is 1 or 2 and A and B are especially oxygen, sulfur, sulfinyl, sulfonyl, NR
11
, CR
6
R
7
for which R
6
and R
7
represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, amino, and Z
1
to Z
5
are N or CR
1a
, etc.
These products show antimicrobial activity. However, no derivative disubstituted in position −4 of the piperidine had been synthesized hitherto and consequently no biological activity had been discovered for such products either.
Since slight modifications to the structures already known can result in large variations in activity, it was not obvious that derivatives disubstituted in position −4 of the piperidine would also have antibacterial activity.
European patent application EP 30044 discloses quinoline derivatives which are useful as cardiovascular agents, corresponding to the general formula:
in which R
1
is especially 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
is especially alkyl, hydroxyalkyl, cycloalkyl, hydroxyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, optionally substituted diphenylalkyl, optionally substituted phenylalkenyl, optionally substituted benzoyl or benzoylalkyl, 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 this forms the subject of the present invention, that the products of general formula (I) for which:
X
1
, X
2
, X
3
, X
4
and X
5
represent, respectively, >C—R′
1
to >C—R′
5
, or alternatively not more than one of them represents a nitrogen atom,
R
1
, R′
1
, R′
2
, R′
3
, R′
4
and R′
5
are identical or different and represent a hydrogen or halogen atom or an alkyl, cycloalkyl, phenyl, phenylthio, mono- or bicyclic aromatic heterocyclyl or heterocyclylthio, hydroxyl, alkyloxy, trifluoromethoxy, alkylthio, trifluoromethylthio, cycloalkyloxy, cycloalkylthio, cyano, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, —NRaRb or —CONRaRb radical (for which Ra and Rb can represent hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain another heteroatom chosen from O, S, and N and, where appropriate, bearing an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent on the nitrogen atom or, where appropriate, the sulfur atom of which is oxidized in the form of sulfinyl or sulfonyl), or represent a methylene radical substituted with fluoro, hydroxyl, alkyloxy, alkylthio, cycloalkyloxy, cycloalkylthio, phenyl, mono- or bicyclic aromatic heterocyclyl, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, —NRaRb or —CONRaRb for which Ra and Rb are defined as above, or represent phenoxy, heterocyclyloxy, benzyloxy, heterocyclylmethyloxy, or alternatively R
1
can also represent difluoromethoxy, or a radical of structure —C
m
F
2m+1
, —SC
m
F
2m+1
or —OC
m
F
2m+1
for which m is an integer from 1 to 6, or alternatively R′
5
can also represent trifluoroacetyl,
R
2
represents carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, cyano, —CONRaRb (for which Ra and Rb represent, respectively, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, or Ra or Rb represents hydroxyl, alkyloxy, cycloalkyloxy, or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain another heteroatom chosen from O, S and N and, where appropriate, bearing an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent on the nitrogen atom or, where appropriate, the sulfur atom of which is oxidized in the form of sulfinyl or sulfonyl), or R
2
represents hydroxymethyl, alkyl containing 1 or 2 carbon atoms substituted with carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, cyano or —CONRaRb for which Ra and Rb are defined as above, or R
2
represents a radical of structure —CF
2
—Rc, —C(CH
3
)
2
—Rc, —CO—Rc, —CHOH—Rc, —C(cycloalkyl)-Rc, or —CH═CH—Rc for which Rc is carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, or —CONRaRb for which Ra and Rb are defined as above,
R
3
represents a phenyl, mono- or bicyclic aromatic heterocyclyl or alk-R°
3
radical for which alk is an alkyl radical and R°
3
represents hydrogen, halogen, hydroxyl, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl-N-alkylamino, —N-(cycloalkyl)
2
, acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylamino, N-alkyl-N-phenylamino, N-cycloalkyl-N-phenylamino, —N-(phenyl)
2
, phenylalkyloxy, phenylalkylthio, phenylalkylsulfinyl, phenylalkylsulfonyl, phenylalkylamino, N-alkyl-N-phenylaminoalkyl, N-cycloalkyl-N-phenylalkylamino, benzoyl, mono- or bicyclic aromatic heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, heterocyclylamino, N-alkyl-N-heterocyclylamino, N-cycloalkyl-N-heterocyclylamino, heterocyclylcarbonyl, heterocyclylalkyloxy, heterocyclylalkylthio, heterocyclylalkylsulfinyl, heterocyclylalkylsulfonyl, heterocyclylalkylamino, N-alkyl-N-heterocyclylaminoalkyl, N-cycloalkyl-N-heterocyclylaminoalkyl, (the heterocyclyl portions mentioned above being mono- or bicyclic aromatic), carboxyl, alkyloxycarbonyl, —NRaRb or —CO—NRaRb for which Ra and Rb are defined as above in the definition of R
2
, or alternatively R°
3
represents —CR′b=CR′c-R′a for which R′a represents phenyl, phenylalkyl, heterocyclyl or heterocyclylalkyl in which the heterocyclyl portion is mono- or bicyclic aromatic, phenoxyalkyl, phenylthioalkyl, phenylsulfinylalkyl, phenylsulfonylalkyl, phenylaminoalkyl, N-alkyl-N-phenylaminoalkyl, heterocyclyloxyalkyl, heterocyclylthioalkyl, heterocyclylsulfinylalkyl, heterocyclylsulfonylalkyl, heterocyclylaminoalkyl, N-alkyl-N-heterocyclylaminoalkyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, (the heterocyclyl portions mentioned above being mono- or bicyclic aromatic), phenylthio, phenylsulfinyl, phenylsulfonyl, and for which R′b and R′c represent hydrogen, alkyl or cycloalkyl, or alternatively R°
3
represents a radical —C≡C—Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, mono- or bicyclic aromatic heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, heterocyclylthioalkyl, heterocyclylaminoalkyl, N-alkyl-N-heterocyclylaminoalkyl, (the heterocyclyl portions mentioned above being mono- or bicyclic aromatic), or alternatively R°
3
represents a —CF
2
-phenyl or mono- or bicyclic aromatic —CF
2
-heterocyclyl radical,
Y represents a radical >CH—Re for which Re is hydrogen, fluoro, hydroxyl, alkyloxy, cycloalkyloxy, carboxyl, alkyloxycarbonyl, cycloalky

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