Quinoline derivatives and their use as antibacterial agents

Details Quinoline derivatives and their use as antibacterial agents Quinoline derivatives and their use as antibacterial agents

2001-05-24

2003-08-05

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S306000, C514S313000, C514S248000, C514S258100, C546S122000, C546S138000, C546S159000, C546S163000, C544S235000, C544S293000

Reexamination Certificate

active

06602882

ABSTRACT:

This application is a 371 of PCT/EP99/07766, filed on Oct. 11, 1999.
This invention relates to novel medicaments, being novel antibacterial compounds and compositions.
JP04095071 discloses piperidyl carbamic acid derivatives for treating dementia by ameliorating memory disturbance.
This invention provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof:
wherein:
one of Z
1
, Z
2
, Z
3
, Z
4
and Z
5
is N or CR
1a
and the remainder are CH;
R
1
is selected from hydroxy; (C
1-6
)alkoxy optionally substituted by (C
1-6
)alkoxy, amino, piperidyl, guanidino or amidino optionally N-substituted by one or two (C
1-6
)alkyl, acyl or (C
1-6
)alkylsulphonyl groups, NH
2
CO, hydroxy, thiol, (C
1-6
)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C
1-6
)alkylsulphonyloxy; (C
1-6
)alkoxy-substituted (C
1-6
)alkyl; halogen; (C
1-6
)alkyl; (C
1-6
)alkylthio; nitro; trifluoromethyl; azido; acyl; acyloxy; acylthio; (C
1-6
)alkylsulphonyl; (C
1-6
)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (C
1-6
)alkyl, acyl or (C
1-6
)alkylsulphonyl groups, or when one of Z
1
, Z
2
, Z
3
, Z
4
and Z
5
is N, R
1
may instead be hydrogen;
R
1a
is selected from hydrogen and the groups listed above for R
1
;
either R
2
is hydrogen; and
R
3
is in the 2- or 3-position and is hydrogen or (C
1-6
)alkyl or (C
2-6
)alkenyl optionally substituted with 1 to 3 groups selected from:
thiol; halogen; (C
1-6
)alkylthio; trifluoromethyl; azido; (C
1-6
)alkoxycarbonyl; (C
1-6
)alkylcarbonyl; (C
2-6
)alkenyloxycarbonyl; (C
2-6
)alkenylcarbonyl; hydroxy optionally substituted by (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkoxycarbonyl, (C
1-6
)alkylcarbonyl, (C
2-6
)alkenyloxycarbonyl, (C
2-6
)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkylcarbonyl or (C
2-6
)alkenylcarbonyl; amino optionally mono- or disubstituted by (C
1-6
)alkoxycarbonyl, (C
1-6
)alkylcarbonyl, (C
2-6
)alkenyloxycarbonyl, (C
2-6
)alkenylcarbonyl, (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkylsulphonyl, (C
2-6
)alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (C
1-6
)alkyl or (C
2-6
)alkenyl; aminocarbonyl wherein the amino group is optionally mono- or disubstituted by (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkoxycarbonyl, (C
1-6
)alkylcarbonyl, (C
2-6
)alkenyloxycarbonyl or (C
2-6
)alkenylcarbonyl; oxo; (C
1-6
)alkylsulphonyl; (C
2-6
)alkenylsulphonyl; or (C
1-6
)aminosulphonyl wherein the amino group is optionally substituted by (C
1-6
)alkyl or (C
2-6
)alkenyl;
or when R
3
is in the 2-position it may with R
4
form a C
3-5
alkylene group optionally substituted by a group R
5
selected from:
(C
3-12
)alkyl; hydroxy(C
3-12
)alkyl; (C
1-12
)alkoxy(C
3-12
)alkyl; (C
1-12
)alkanoyloxy(C
3-12
)alkyl; (C
3-6
)cycloalkyl(C
3-12
)alkyl; hydroxy-, (C
1-12
)alkoxy- or (C
1-12
)alkanoyloxy-(C
3-6
)cycloalkyl(C
3-12
)alkyl; cyano(C
3-12
)alkyl; (C
2-12
)alkenyl; (C
2-12
)alkynyl; tetrahydrofuryl; mono- or di-(C
1-12
)alkylamino(C
3-12
)alkyl; acylamino(C
3-12
)alkyl; (C
1-12
)alkyl- or acyl-aminocarbonyl(C
3-12
)alkyl; mono- or di-(C
1-12
)alkylamino(hydroxy)(C
3-12
)alkyl; optionally substituted phenyl(C
1-2
)alkyl, phenoxy(C
1-12
)alkyl or phenyl(hydroxy)(C
1-2
)alkyl; optionally substituted diphenyl(C
1-2
)alkyl; optionally substituted phenyl(C
2-3
)alkenyl; optionally substituted benzoyl or benzoylmethyl; optionally substituted heteroaryl(C
1-2
)alkyl; and optionally substituted heteroaroyl or heteroaroylmethyl;
or R
3
is in the 3-position and R
2
and R
3
together are a divalent residue ═CR
5
1
R
6
1
where R
5
1
and R
6
1
are independently selected from H, (C
1-6
)alkyl, (C
2-6
)alkenyl, aryl(C
1-6
)alkyl and aryl(C
2-6
)alkenyl, any alkyl or alkenyl moiety being optionally substituted by 1 to 3 groups selected from those listed above for substituents on R
3
;
R
4
forms a group with R
3
as above defined or is a group —CH
2
—R
5
in which R
5
is as defined above:
n is 0, 1 or 2; and
A is NHC(O)NH or NHC(O)O.
In one aspect the invention provides compounds of formula (I) where R1 and R1a are selected from the groups listed above other than trifluoromethyl.
The invention also provides a method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment of an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for use in the treatment of bacterial infections in mammals.
The invention also provides a pharmaceutical composition for use in the treatment of bacterial infections in mammals comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
Preferably Z
1
-Z
5
are each CH or Z
1
is N and Z
2
-Z
5
are each CH.
When R
1
or R
1a
is substituted alkoxy it is preferably (C
1-6
)alkoxy substituted by optionally N-substituted amino, piperidyl, guanidino or amidino, more preferably by amino or guanidino. Suitable examples of R
1
alkoxy include methoxy, n-propyloxy, i-butyloxy, aminoethyloxy, aminopropyloxy, aminopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy, phthalimido pentyloxy or 2-aminocarbonylprop-2-oxy. Preferably R
1
is methoxy, amino(C
3-5
)alkyloxy, guanidino(C
3-5
)alkyloxy, nitro or fluoro, most preferably methoxy.
Preferably R
1a
is hydrogen.
Preferably n is 0.
Preferably A is NHCONH.
R
3
is preferably hydrogen, (C
1-6
)alkyl, (C
1-6
)alkenyl, optionally substituted 1-hydroxy-(C
1-6
)alkyl, more preferably hydroxymethyl or 1,2-dihydroxy(C
2-6
)alkyl wherein the 2-hydroxy group is optionally substituted. Preferred examples of R
3
include hydroxymethyl, 1-hydroxyethyl or 1,2-dihydroxyethyl wherein the 2-hydroxy group is optionally substituted with alkylcarbonyl or aminocarbonyl where the amino group is optionally substituted. Other suitable examples of R
3
include 2-hydroxyethyl, 2- or 3-hydroxypropyl, ethyl or vinyl.
R3 is preferably in the 3-position.
When R
2
and R
3
together form a group, this is preferably ═CHCH
3
.
When R3 and R4 together form a group, this is preferably —(CH
2
)
4
— optionally substituted by R
5
. Preferably R
5
on this cyclic group is (C
4-9
)alkyl, unsubstituted phenyl(C
1-2
)alkyl or unsubstituted phenyl(C
2-3
)alkenyl, more preferably n-pentyl or n-hexyl. most preferably n-pentyl.
Suitable groups R
4
include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, methoxybutyl, phenylethyl, phenylpropyl or 3-phenyl-prop-2-en-yl optionally substituted on the phenyl ring, 3-benzoylpropyl, 4-benzoylbutyl, 3-pyridylmethyl, 3-(4-fluorobenzoyl)propyl, cyclohexylmethyl, cyclobutylmethyl, t-butoxycarbonylaminomethyl and phenoxyethyl.
Preferably R
4
is (C
5-10
)alkyl, unsubstituted phenyl(C
2-3
)alkyl or unsubstituted phenyl(C
3-4
)alkenyl, more preferably hexyl, heptyl, 5-methylhexyl, 6-methyl heptyl, 3-phenyl-prop-2-en-yl or 3-phenylpropyl, most preferably n-heptyl.
Most preferably R
5
is unbranched at the &agr; and, where appropriate, &bgr; positions.
Halo or halogen includes fluoro, chloro, bromo and iodo.
The term ‘heterocyclic’ as used herein includes aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups selected from optionally substituted amino. halogen, (C
1-6
)alkyl, (C
1-6
)alkoxy, halo(C
1-6
)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C
1-6
)alkoxycarbonyl, (C
1-6
)alkoxycarbonyl(C
1-6
)alkyl, aryl, and oxo groups. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include car

Affiliated with

Also associated with

Rating

Quinoline derivatives and their use as antibacterial agents does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Quinoline derivatives and their use as antibacterial agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Quinoline derivatives and their use as antibacterial agents will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3100078