U.S. patent application number 11/292011 was filed with the patent office on 2006-04-13 for aminopiperidine derivatives as antibacterials.
This patent application is currently assigned to SmithKline Beecham p.l.c.. Invention is credited to David Thomas Davies, Andrew Lightfoot, Roger Edward Markwell, Neil David Pearson.
Application Number | 20060079546 11/292011 |
Document ID | / |
Family ID | 10857877 |
Filed Date | 2006-04-13 |
United States Patent
Application |
20060079546 |
Kind Code |
A1 |
Davies; David Thomas ; et
al. |
April 13, 2006 |
Aminopiperidine derivatives as antibacterials
Abstract
Aminopiperidine derivatives of Formula (I) and pharmaceutically
acceptable derivatives thereof useful in methods of treatment of
bacterial infections in mammals, particularly in man: ##STR1##
Inventors: |
Davies; David Thomas; (Ware,
GB) ; Lightfoot; Andrew; (Ware, GB) ;
Markwell; Roger Edward; (Great Dunmow, GB) ; Pearson;
Neil David; (Knebworth, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property
UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham p.l.c.
|
Family ID: |
10857877 |
Appl. No.: |
11/292011 |
Filed: |
December 1, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10031844 |
Jul 17, 2002 |
7001913 |
|
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PCT/EP00/06938 |
Jul 17, 2000 |
|
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11292011 |
Dec 1, 2005 |
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Current U.S.
Class: |
514/300 ;
514/314; 546/122; 546/159; 546/169 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 31/04 20180101; C07D 401/06 20130101 |
Class at
Publication: |
514/300 ;
514/314; 546/122; 546/159; 546/169 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; A61K 31/4709 20060101 A61K031/4709; C07D 401/02
20060101 C07D401/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 23, 1999 |
GB |
9917408.8 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable
derivative thereof: ##STR12## wherein: Z.sup.1, Z.sup.2, Z.sup.3,
Z.sup.4 and Z.sup.5 are each CH; R.sup.1 is hydroxy;
(C.sub.1-6)alkoxy optionally substituted by (C.sub.1-6)alkoxy,
amino, piperidyl, guanidino or amidino optionally N-substituted by
one or two (C.sub.1-6)alkyl, acyl or (C.sub.1-6)alkylsulphonyl
groups, CONH.sub.2, hydroxy, thiol, (C.sub.1-6)alkylthio,
heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio,
acyloxy or (C.sub.1-6)alkylsulphonyloxy;
(C.sub.1-6)alkoxy-substituted (C.sub.1-6)alkyl; halogen;
(C.sub.1-6)alkyl; (C.sub.1-6)alkylthio; nitro; azido; acyl;
acyloxy; (C.sub.1-6)alkylsulphonyl; (C.sub.1-6)alkylsulphoxide;
arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or
amidino group optionally N-substituted by one or two
(C.sub.1-6)alkyl, acyl or (C.sub.1-6)alkylsulphonyl groups; R.sup.2
is hydrogen, or (C.sub.1-4)alkyl or (C.sub.1-4)alkenyl optionally
substituted with 1 to 3 groups selected from: amino optionally
substituted by one or two (C.sub.1-4)alkyl groups; carboxy;
(C.sub.1-4)alkoxycarbonyl; (C.sub.1-4)alkylcarbonyl;
(C.sub.2-4)alkenyloxycarbonyl; (C.sub.2-4)alkenylcarbonyl;
aminocarbonyl wherein the amino group is optionally substituted by
hydroxy, (C.sub.1-4)alkyl, hydroxy(C.sub.1-4)alkyl,
aminocarbonyl(C.sub.1-4)alkyl, (C.sub.2-4)alkenyl,
(C.sub.1-4)alkylsulphonyl, trifluoromethylsulphonyl,
(C.sub.1-4)alkenylsulphonyl, (C.sub.1-4)alkoxycarbonyl,
(C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl or
(C.sub.2-4)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl
optionally substituted by R.sup.10;
3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;
tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally
substituted by R.sup.10; 5-oxo-1,2,4-oxadiazol-3-yl; thiol;
halogen; (C.sub.1-4)alkylthio; trifluoromethyl; azido; hydroxy
optionally substituted by (C.sub.1-4)alkyl, (C.sub.2-4)alkenyl,
(C.sub.1-4)alkoxycarbonyl, (C.sub.1-4)alkylcarbonyl,
(C.sub.2-4)alkenyloxycarbonyl, (C.sub.2-4)alkenylcarbonyl; oxo;
(C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or
(C.sub.1-4)aminosulphonyl wherein the amino group is optionally
substituted by (C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; R.sup.3 is
hydrogen; or R.sup.3 is in the 2-, 3- or 4-position and is:
carboxy; (C.sub.1-6)alkoxycarbonyl; aminocarbonyl wherein the amino
group is optionally substituted by hydroxy, (C.sub.1-6)alkyl,
hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, (C.sub.1-6)alkylsulphonyl,
trifluoromethylsulphonyl, (C.sub.1-6)alkenylsulphonyl,
(C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl,
(C.sub.2-6)alkenyloxycarbonyl or (C.sub.2-6)alkenylcarbonyl and
optionally further substituted by (C.sub.1-6)alkyl,
hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl or
(C.sub.2-6)alkenyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl
optionally substituted by R.sup.10;
3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;
tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally
substituted by R.sup.10; or 5-oxo-1,2,4-oxadiazol-3-yl; or
(C.sub.1-4)alkyl or ethenyl substituted with any of the
substituents listed above for R.sup.3 and up to 3 groups R.sup.12
independently selected from: thiol; halogen; (C.sub.1-6)alkylthio;
trifluoromethyl; azido; (C.sub.1-6)alkoxycarbonyl;
(C.sub.1-6)alkylcarbonyl; (C.sub.2-6)alkenyloxycarbonyl;
(C.sub.2-6)alkenylcarbonyl; hydroxy optionally substituted by
(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl,
(C.sub.2-6)alkenylcarbonyl or aminocarbonyl wherein the amino group
is optionally substituted by (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.2-6)alkenylcarbonyl; amino
optionally mono- or disubstituted by (C.sub.1-16)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl,
(C.sub.2-6)alkenylcarbonyl, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.1-6)alkylsulphonyl, (C.sub.2-6)alkenylsulphonyl or
aminocarbonyl wherein the amino group is optionally substituted by
(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; aminocarbonyl wherein the
amino group is optionally substituted by (C.sub.1-6)alkyl,
hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl or
(C.sub.2-6)alkenylcarbonyl and optionally further substituted by
(C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl,
aminocarbonyl(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; oxo;
(C.sub.1-6)alkylsulphonyl; (C.sub.2-6)alkenylsulphonyl; or
(C.sub.1-6)aminosulphonyl wherein the amino group is optionally
substituted by (C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; in addition
when R.sup.3 is disubstituted with a hydroxy or amino containing
substituent and carboxy containing substituent these may together
form a cyclic ester or amide linkage, respectively; or when R.sup.3
is in the 3- or 4-position it may with R.sup.2 or R.sup.4 form a
C.sub.3-5 alkylene group optionally substituted by a group R.sup.5
selected from: (C.sub.1-12)alkyl; hydroxy(C.sub.1-12)alkyl;
(C.sub.1-12)alkoxy(C.sub.1-12)alkyl;
(C.sub.1-12)alkanoyloxy(C.sub.1-12)alkyl; (C.sub.3-6)cycloalkyl;
hydroxy(C.sub.3-6)cycloalkyl;
(C.sub.1-12)alkoxy(C.sub.3-6)cycloalkyl;
(C.sub.1-12)alkanoyloxy(C.sub.3-6)cycloalkyl;
(C.sub.3-6)cycloalkyl(C.sub.1-12)alkyl; hydroxy-,
(C.sub.1-12)alkoxy- or
(C.sub.1-12)alkanoyloxy-(C.sub.3-6)cycloalkyl(C.sub.1-12)alkyl;
cyano; cyano(C.sub.1-12)alkyl; (C.sub.2-12)alkenyl;
(C.sub.2-12)aynyl; tetrahydrofuryl; mono- or
di-(C.sub.1-12)alkylamino(C.sub.1-12)alkyl;
acylamino(C.sub.1-12)alkyl; (C.sub.1-12)alkyl- or
acyl-aminocarbonyl(C.sub.1-12)alkyl; mono- or di-
(C.sub.1-12)alkylamino(hydroxy) (C.sub.1-12)alkyl; optionally
substituted phenyl(C.sub.1-12)alkyl, phenoxy(C.sub.1-12)alkyl or
phenyl(hydroxy)(C.sub.1-12)alkyl; optionally substituted
diphenyl(C.sub.1-12)alkyl; optionally substituted
phenyl(C.sub.2-12)alkenyl; optionally substituted benzoyl or
benzoyl(C.sub.1-12)alkyl; optionally substituted heteroaryl or
heteroaryl(C.sub.1-12)alkyl; and optionally substituted heteroaroyl
or heteroaroyl(C.sub.1-12)alkyl; R.sup.4 forms a group with R.sup.3
as above defined, or is a group --CH.sub.2--R.sup.5 where R.sup.5
is as defined above: n is 0, 1 or 2; A is NR.sup.11 or
CR.sup.6R.sup.7 and B is NR.sup.11, O, SO.sub.2 or CR.sup.8R.sup.9
and wherein: each of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is
independently selected from: hydrogen; (C.sub.1-6)alkylthio; halo;
trifluoromethyl; azido; (C.sub.1-6)alkyl; (C.sub.2-6)alkenyl;
(C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl;
(C.sub.2-6)alkenyloxycarbonyl; (C.sub.2-6)alkenylcarbonyl; hydroxy,
amino or aminocarbonyl optionally substituted as for corresponding
substituents in R.sup.3; (C.sub.1-6)alkylsulphonyl;
(C.sub.2-6)alkenylsulphonyl; or (C.sub.1-6)aminosulphonyl wherein
the amino group is optionally substituted by (C.sub.1-6)alkyl or
(C.sub.1-6)alkenyl; or R.sup.6 and R.sup.8 together represent a
bond and R.sup.7 and R.sup.9 are as above defined; or R.sup.6 and
R.sup.7 or R.sup.8 and R.sup.9 together represent oxo; provided
that: when A is NR.sup.11, B is not NR.sup.11, O or SO.sub.2; when
A is CO, B is not CO, O or SO.sub.2; when n is 0 and A is
NR.sup.11, CR.sup.8R.sup.9 can only be CO; when A is
CR.sup.6R.sup.7 and B is SO.sub.2, n is 0; when n is 0, B is not
NR.sup.11 or O; and when A-B is CR.sup.7.dbd.CR.sup.9, n is 1 or 2;
R.sup.10 is selected from (C.sub.1-4)alkyl; (C.sub.2-4)alkenyl and
aryl any of which may be optionally substituted by a group R.sup.12
as defined above; carboxy; aminocarbonyl wherein the amino group is
optionally substituted by hydroxy, (C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, (C.sub.1-6)alkylsulphonyl,
trifluoromethylsulphonyl, (C.sub.1-6)alkenylsulphonyl,
(C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl,
(C.sub.2-6)alkenyloxycarbonyl or (C.sub.2-6)alkenylcarbonyl and
optionally further substituted by (C.sub.1-6)alkyl or
(C.sub.2-6)alkenyl; (C.sub.1-6)alkylsulphonyl;
trifluoromethylsulphonyl; (C.sub.1-6)alkenylsulphonyl;
(C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl;
(C.sub.2-6)alkenyloxycarbonyl; and (C.sub.2-6)alkenylcarbonyl;
R.sup.11 is hydrogen; trifluoromethyl, (C.sub.1-6)alkyl;
(C.sub.1-6)alkenyl; (C.sub.1-6)alkoxycarbonyl;
(C.sub.1-6)alkylcarbonyl; aminocarbonyl wherein the amino group is
optionally substituted by (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.1-6)alkenyloxycarbonyl,
(C.sub.2-6)alkenylcarbonyl, (C.sub.1-6)alkyl or (C.sub.1-6)alkenyl
and optionally further substituted by (C.sub.1-6)alkyl or
(C.sub.1-6)alkenyl.
2. A compound according to claim 1 wherein R.sup.1 is methoxy,
amino(C.sub.3-5)alkyloxy, guanidino(C.sub.3-5)alkyloxy,
piperidyl(C.sub.3-5)alkyloxy, nitro or fluoro.
3. A compound according to claim 1 wherein R.sup.3 is hydrogen;
optionally substituted aminocarbonyl; optionally substituted
(C.sub.1-6)alkyl; carboxy(C.sub.1-4)alkyl; optionally substituted
aminocarbonyl(C.sub.1-4)alkyl; cyano(C.sub.1-4)alkyl; optionally
substituted 2-oxo-oxazolidinyl or optionally substituted
2-oxo-oxazolidinyl(C.sub.1-4alkyl).
4. A compound according to claim 1 wherein R.sup.3 is in the
3-position and the substitutents at the 3- and 4-position of the
piperidine ring are cis.
5. A compound according to claim 1 wherein A is NH and B is CO, or
A is CHOH and B is CH.sub.2.
6. A compound according to claim 1 wherein R.sup.11 is
hydrogen.
7. A compound according to claim 1 wherein R.sup.4 is
(C.sub.5-12)alkyl, optionally substituted phenyl(C.sub.2-3)alkyl or
optionally substituted phenyl(C.sub.3-4)alkenyl.
8. A pharmaceutical composition comprising a compound of formula
(I) according to claim 1, or a pharmaceutically acceptable
derivative thereof, and a pharmaceutically acceptable carrier.
9. A method of treatment of bacterial infections in mammals which
method comprises the administration to a mammal in need of such
treatment an effective amount of a compound of formula (I)
according to claim 1, or a pharmaceutically acceptable derivative
thereof.
Description
[0001] This is a divisional of U.S. application Ser. No.
10/031,844, filed Jul. 17, 2002, which is a 371 of International
Application PCT/EP00/06938, filed Jul. 17, 2000, which claims
benefit from GB priority application 9917408.8, filed Jul. 23,
1999.
FIELD OF THE INVENTION
[0002] This invention relates to novel aminopiperidine compounds,
compositions containing them and their use as antibacterials.
BACKGROUND OF THE INVENTION
[0003] DE2315148A, EP0030044, NL7908030, EP0053964, EP0031753,
EP0042781 and BE706646 disclose quinoline compounds having
cardiovascular, hypnotic, anticonvulsant, and antimalarial
effects.
[0004] EP0579263, EP0742207, JP2169569, EP0296560, WO9103243,
EP0449186 disclose piperidine compounds as acetylcholinesterase
inhibitors and sigma receptor antagonists.
[0005] WO9802438 and WO9703069 disclose certain bicyclic
heteroaromatic compounds having protein tyrosine kinase and cell
proliferation inhibitor activity.
[0006] WO9217475, WO9802438, WO9703069 and WO9639145 disclose
certain bicyclic heteroaromatic compounds having cholinesterase
inhibitor, protein tyrosine kinase inhibitor, cell proliferation
inhibitor and human epidermal growth factor receptor type 2
inhibitor activity.
SUMMARY OF THE INVENTION
[0007] We have now found a novel group of aminopiperidines which
have antibacterial activity.
[0008] This invention provides a compound of formula (I) or a
pharmaceutically acceptable derivative thereof: ##STR2## wherein:
[0009] one of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 is N,
and the remainder are CR.sup.1a; [0010] R.sup.1 and R.sup.1a are
independently hydrogen; hydroxy; (C.sub.1-6)alkoxy optionally
substituted by (C.sub.1-6)alkoxy, amino, piperidyl, guanidino or
amidino optionally N-substituted by one or two (C.sub.1-6)alkyl,
acyl or (C.sub.1-6)alkylsulphonyl groups, CONH.sub.2, hydroxy,
thiol, (C.sub.1-6)alkylthio, heterocyclylthio, heterocyclyloxy,
arylthio, aryloxy, acylthio, acyloxy or
(C.sub.1-6)alkylsulphonyloxy; (C.sub.1-6)alkoxy-substituted
(C.sub.1-6)alkyl; halogen; (C.sub.1-6)alkyl; (C.sub.1-6)alkylthio;
nitro; azido; acyl; acyloxy; (C.sub.1-6)alkylsulphonyl;
(C.sub.1-6)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an
amino, piperidyl, guanidino or amidino group optionally
N-substituted by one or two (C.sub.1-6)alkyl, acyl or
(C.sub.1-6)alkylsulphonyl groups; and [0011] additionally when
Z.sup.5 is CR.sup.1a, R.sup.1a may be (C.sub.1-4)alkyl-CO.sub.2H or
(C.sub.1-4)alkyl-CONH.sub.2 in which the C.sub.1-4 alkyl is
substituted by R.sup.12; (C.sub.1-4)alkyl substituted by cyano,
amino or guanidino; aminocarbonyl optionally substituted by
hydroxy, (C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl,
aminocarbonyl(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.1-6)alkylsulphonyl, trifluoromethylsulphonyl,
(C.sub.1-6)alkenylsulphonyl, (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl,
(C.sub.2-6)alkenylcarbonyl, or CH(R.sup.13)CO.sub.2H or
CH(R.sup.13)CO.sub.2NH.sub.2 optionally further substituted by
(C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl,
aminocarbonyl(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl;
hydroxy(C.sub.1-6)alkyl; carboxy; cyano or
(C.sub.1-6)alkoxycarbonyl; [0012] wherein R.sup.13 is a natural
.alpha.-amino acid side chain or its enantiomer; [0013] provided
that when Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 are
CR.sup.1a, then R.sup.1 is not hydrogen; [0014] R.sup.2 is
hydrogen, or (C.sub.1-4)alkyl or (C.sub.1-4)alkenyl optionally
substituted with 1 to 3 groups selected from: [0015] amino
optionally substituted by one or two (C.sub.1-4)alkyl groups;
carboxy; (C.sub.1-4)alkoxycarbonyl; (C.sub.1-4)alkylcarbonyl;
(C.sub.2-4)alkenyloxycarbonyl; (C.sub.2-4)alkenylcarbonyl;
aminocarbonyl wherein the amino group is optionally substituted by
hydroxy, (C.sub.1-4)alkyl, hydroxy(C.sub.1-4)alkyl,
aminocarbonyl(C.sub.1-4)alkyl, (C.sub.2-4)alkenyl,
(C.sub.1-4)alkylsulphonyl, trifluoromethylsulphonyl,
(C.sub.1-4)alkenylsulphonyl, (C.sub.1-4)alkoxycarbonyl,
(C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl or
(C.sub.2-4)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl
optionally substituted by R.sup.10;
3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;
tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally
substituted by R.sup.10; 5-oxo-1,2,4-oxadiazol-3-yl; thiol;
halogen; (C.sub.1-4)alkylthio; trifluoromethyl; azido; hydroxy
optionally substituted by (C.sub.1-4)alkyl, (C.sub.2-4)alkenyl,
(C.sub.1-4)alkoxycarbonyl, (C.sub.1-4)alkylcarbonyl,
(C.sub.2-4)alkenyloxycarbonyl, (C.sub.2-4)alkenylcarbonyl; oxo;
(C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or
(C.sub.1-4)arinosulphonyl wherein the amino group is optionally
substituted by (C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; [0016]
R.sup.3 is hydrogen; or [0017] R.sup.3 is in the 2-, 3- or
4-position and is: [0018] carboxy; (C.sub.1-6)alkoxycarbonyl;
aminocarbonyl wherein the amino group is optionally substituted by
hydroxy, (C.sub.1-16)alkyl, hydroxy(C.sub.1-6)alkyl,
aminocarbonyl(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.1-6)alkylsulphonyl, trifluoromethylsulphonyl,
(C.sub.1-6)alkenylsulphonyl, (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl or
(C.sub.2-6)alkenylcarbonyl and optionally further substituted by
(C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl,
aminocarbonyl(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; cyano;
tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R.sup.10;
3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;
tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally
substituted by R.sup.10; or 5-oxo-1,2,4-oxadiazol-3-yl; or [0019]
(C.sub.1-4)alkyl or ethenyl substituted with any of the
substituents listed above for R.sup.3 and up to 3 groups R.sup.12
independently selected from:
[0020] thiol; halogen; (C.sub.1-6)alkylthio; trifluoromethyl;
azido; (C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl;
(C.sub.2-6)alkenyloxycarbonyl; (C.sub.2-6)alkenylcarbonyl; hydroxy
optionally substituted by (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl,
(C.sub.2-6)alkenyloxycarbonyl, (C.sub.2-6)alkenylcarbonyl or
aminocarbonyl wherein the amino group is optionally substituted by
(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkylcarbonyl or
(C.sub.2-6)alkenylcarbonyl; amino optionally mono- or disubstituted
by (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl,
(C.sub.2-6)alkenyloxycarbonyl, (C.sub.2-6)alkenylcarbonyl,
(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkylsulphonyl,
(C.sub.2-6)alkenylsulphonyl or aminocarbonyl wherein the amino
group is optionally substituted by (C.sub.1-6)alkyl or
(C.sub.2-6)alkenyl; aminocarbonyl wherein the amino group is
optionally substituted by (C.sub.1-6)alkyl,
hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl or
(C.sub.2-6)alkenylcarbonyl and optionally further substituted by
(C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl,
aminocarbonyl(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; oxo;
(C.sub.1-6)alkylsulphonyl; (C.sub.2-6)alkenylsulphonyl; or
(C.sub.1-6)aminosulphonyl wherein the amino group is optionally
substituted by (C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; [0021] in
addition when R.sup.3 is disubstituted with a hydroxy or amino
containing substituent and carboxy containing substituent these may
together form a cyclic ester or amide linkage, respectively; or
[0022] when R.sup.3 is in the 3- or 4-position it may with R.sup.2
or R.sup.4 form a C.sub.3-5 alkylene group optionally substituted
by a group R.sup.5 selected from: [0023] (C.sub.1-12)alkyl;
hydroxy(C.sub.1-12)alkyl; (C.sub.1-12)alkoxy(C.sub.1-12)alkyl;
(C.sub.1-12)alkanoyloxy(C.sub.1-12)alkyl; (C.sub.3-6)cycloalkyl;
hydroxy(C.sub.3-6)cycloalkyl;
(C.sub.1-12)alkoxy(C.sub.3-6)cycloalkyl;
(C.sub.1-12)alkanoyloxy(C.sub.3-6)cycloalkyl;
(C.sub.3-6)cycloalkyl(C.sub.1-12)alkyl; hydroxy-,
(C.sub.1-12)alkoxy- or
(C.sub.1-12)alkanoyloxy-(C.sub.3-6)cycloalkyl(C.sub.1-12)alkyl;
cyano; cyano(C.sub.1-12)alkyl; (C.sub.2-12)alkenyl;
(C.sub.2-12)alkynyl; tetrahydrofuryl; mono- or
di-(C.sub.1-12)alkylamino(C.sub.1-12)alkyl;
acylamino(C.sub.1-12)alkyl; (C.sub.1-12)alkyl- or
acyl-aminocarbonyl(C.sub.1-12)alkyl; mono- or di-
(C.sub.1-2)alkylamino(hydroxy) (C.sub.1-2)alkyl; optionally
substituted phenyl(C.sub.1-12)alkyl, phenoxy(C.sub.1-12)alkyl or
phenyl(hydroxy)(C.sub.1-12)alkyl; optionally substituted
diphenyl(C.sub.1-12)alkyl; optionally substituted
phenyl(C.sub.2-12)alkenyl; optionally substituted benzoyl or
benzoyl(C.sub.1-12)alkyl; optionally substituted heteroaryl or
heteroaryl(C.sub.1-2)alkyl; and optionally substituted heteroaroyl
or heteroaroyl(C.sub.1-12)alkyl; [0024] R.sup.4 forms a group with
R.sup.3 as above defined, or is a group --CH.sub.2--R.sup.5 where
R.sup.5 is as defined above: [0025] n is 0, 1 or 2; [0026] A is
NR.sup.11 or CR.sup.6R.sup.7 and B is NR.sup.11, O, SO.sub.2 or
CR.sup.8R.sup.9 and wherein: [0027] each of R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 is independently selected from: hydrogen;
(C.sub.1-6)alkylthio; halo; trifluoromethyl; azido;
(C.sub.1-6)alkyl; (C.sub.2-6)alkenyl; (C.sub.1-6)alkoxycarbonyl;
(C.sub.1-6)alkylcarbonyl; (C.sub.2-6)alkenyloxycarbonyl;
(C.sub.2-6)alkenylcarbonyl; hydroxy, amino or aminocarbonyl
optionally substituted as for corresponding substituents in
R.sup.3; (C.sub.1-6)alkylsulphonyl; (C.sub.2-6)alkenylsulphonyl; or
(C.sub.1-6)aminosulphonyl wherein the amino group is optionally
substituted by (C.sub.1-6)alkyl or (C.sub.1-6)alkenyl; [0028] or
R.sup.6 and R.sup.8 together represent a bond and R.sup.7 and
R.sup.9 are as above defined; [0029] or R.sup.6 and R.sup.7 or
R.sup.8 and R.sup.9 together represent oxo; [0030] provided that:
[0031] when A is NR.sup.11, B is not NR.sup.11, O or SO.sub.2;
[0032] when A is CO, B is not CO, O or SO.sub.2; [0033] when n is 0
and A is NR.sup.11, CR.sup.8R.sup.9 can only be CO; [0034] when A
is CR.sup.6R.sup.7 and B is SO.sub.2, n is 0; [0035] when n is 0, B
is not NR.sup.11 or O; and [0036] when A-B is
CR.sup.7.dbd.CR.sup.9, n is 1 or 2; [0037] R.sup.10 is selected
from (C.sub.1-4)alkyl; (C.sub.2-4)alkenyl and aryl any of which may
be optionally substituted by a group R.sup.12 as defined above;
carboxy; aminocarbonyl wherein the amino group is optionally
substituted by hydroxy, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.1-6)alkylsulphonyl, trifluoromethylsulphonyl,
(C.sub.1-6)alkenylsulphonyl, (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl or
(C.sub.2-6)alkenylcarbonyl and optionally further substituted by
(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; (C.sub.1-6)alkylsulphonyl;
trifluoromethylsulphonyl; (C.sub.1-6)alkenylsulphonyl;
(C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl;
(C.sub.2-6)alkenyloxycarbonyl; and (C.sub.2-6)alkenylcarbonyl;
[0038] R.sup.11 is hydrogen; trifluoromethyl, (C.sub.1-6)alkyl;
(C.sub.1-6)alkenyl; (C.sub.1-6)alkoxycarbonyl;
(C.sub.1-6)alkylcarbonyl; aminocarbonyl wherein the amino group is
optionally substituted by (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkylcarbonyl, (C.sub.1-6)alkenyloxycarbonyl,
(C.sub.2-6)alkenylcarbonyl, (C.sub.1-6)alkyl or (C.sub.1-6)alkenyl
and optionally further substituted by (C.sub.1-6)alkyl or
(C.sub.1-6)alkenyl;
[0039] This 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
an effective amount of a compound of formula (I), or a
pharmaceutically acceptable derivative thereof.
[0040] 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.
[0041] The invention also provides a pharmaceutical composition
comprising a compound of formula (I), or a pharmaceutically
acceptable derivative thereof, and a pharmaceutically acceptable
carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0042] Preferred groups of compounds include those where: [0043]
(a) Z.sup.1 is N, and Z.sup.2-Z.sup.5 are CH, [0044] (b)
Z.sup.1-Z.sup.5 are each CH, and [0045] (c) Z.sup.5 is N, and
Z.sup.1-Z.sup.4 are CH.
[0046] When R.sup.1 or R.sup.1a is substituted alkoxy it is
preferably (C.sub.2-6)alkoxy substitituted by optionally
N-substituted amino, guanidino or amidino, or (C.sub.1-6)alkoxy
optionally substituted by piperidyl. Suitable examples of R.sup.1
and R.sup.1a alkoxy include methoxy, n-propyloxy, iso-butyloxy,
aminoethyloxy, aminopropyloxy, aminobutyloxy, amiinopentyloxy,
guanidinopropyloxy, piperidin-4-ylmethyloxy and phthalimido
pentyloxy.
[0047] Preferably R.sup.1 and R.sup.1a are independently methoxy,
amino(C.sub.3-5)alkyloxy, guanidino(C.sub.3-5)alkyloxy,
piperidyl(C.sub.3-5)alkyloxy, nitro or fluoro; more preferably
methoxy, amino(C.sub.3-5)alkyloxy or
guanidino(C.sub.3-5)alkyloxy.
[0048] Z.sup.2 and Z.sup.4 are preferably CH.
[0049] When Z.sup.5 is CR.sup.1a, R.sup.1a is preferably hydrogen,
cyano, hydroxymethyl or carboxy.
[0050] Preferably n is 0.
[0051] R.sup.2 is preferably hydrogen; (C.sub.1-4)alkyl substituted
with carboxy, optionally substituted hydroxy, optionally
substituted aminocarbonyl, optionally substituted amino or
(C.sub.1-4)alkoxycarbonyl; or (C.sub.1-4)alkenyl substituted with
(C.sub.1-4)alkoxycarbonyl or carboxy. More preferred groups for
R.sup.2 are hydrogen, carboxymethyl, hydroxyethyl,
aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl and
carboxyallyl.
[0052] Preferred examples of R.sup.3 include hydrogen; optionally
substituted aminocarbonyl; optionally substituted (C.sub.1-6)alkyl;
carboxy(C.sub.1-4)alkyl; optionally substituted
aminocarbonyl(C.sub.1-4)alkyl; cyano(C.sub.1-4)alkyl; optionally
substituted 2-oxo-oxazolidinyl and optionally substituted
2-oxo-oxazolidinyl(C.sub.1-4alkyl). More preferred R.sup.3 groups
are hydrogen; CONH.sub.2; 1-hydroxyalkyl e.g. CH.sub.2OH,
CH(OH)CH.sub.2CN; CH.sub.2CO.sub.2H; CH.sub.2CONH.sub.2;
1,2-dihydroxyalkyl e.g. CH(OH)CH.sub.2OH; CH.sub.2CN;
2-oxo-oxazolidin-5-yl and
2-oxo-oxazolidin-5-yl(C.sub.1-4alkyl).
[0053] R.sup.3 is preferably in the 3- or 4-position.
[0054] In a preferred aspect, when R.sup.3 is in the 3-position the
substitutents at the 3- and 4-position of the piperidine ring are
cis.
[0055] Preferably A is CHOH or NR.sup.11.
[0056] Preferably B is CH.sub.2, SO.sub.2 or CO.
[0057] Particularly preferred are those compounds where A is NH and
B is CO, or A is CHOH and B is CH.sub.2, when more preferably A is
the R-isomer of CHOH.
[0058] Preferably R.sup.11 is hydrogen or (C.sub.1-4)alkyl e.g.
methyl, more preferably hydrogen.
[0059] Preferably R.sup.4 is (C.sub.5-12)alkyl, unsubstituted
phenyl(C.sub.2-3)alkyl or unsubstituted phenyl(C.sub.3-4)alkenyl.
Suitable groups R.sup.4 include n-pentyl, n-hexyl, n-heptyl,
n-octyl, n-nonyl, n-decyl, n-dodecyl, phenylethyl, phenylpropyl or
3-phenyl-prop-2-en-yl optionally substituted on the phenyl ring;
more preferably R.sup.4 is hexyl, heptyl, 5-methylhexyl, 6-methyl
heptyl or 3-phenyl-prop-2-en-yl, especially heptyl or hexyl.
[0060] When used herein, the term "alkyl" includes groups having
straight and branched chains, for instance, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl,
pentyl and hexyl. The term `alkenyl` should be interpreted
accordingly.
[0061] Preferred R.sup.5 groups are unbranched at the .alpha. and,
where appropriate, .beta. positions.
[0062] Halo or halogen includes fluoro, chloro, bromo and iodo.
[0063] The term "heterocyclic" as used herein includes optionally
substituted 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.sub.1-6)alkyl,
(C.sub.1-6)alkoxy, halo(C.sub.1-6)alkyl, hydroxy, carboxy, carboxy
salts, carboxy esters such as (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkoxycarbonyl(C.sub.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
carbocyclic rings and need include only one heterocyclic ring.
Compounds within the invention containing a heterocyclyl group may
occur in two or more tautometric forms depending on the nature of
the heterocyclyl group; all such tautomeric forms are included
within the scope of the invention.
[0064] Where an amino group forms part of a single or fused
non-aromatic heterocyclic ring as defined above suitable optional
substituents in such substituted amino groups include
(C.sub.1-6)alkyl optionally substituted by hydroxy,
(C.sub.1-6)alkoxy, thiol, (C.sub.1-6)alkylthio, halo or
trifluoromethyl, and amino-protecting groups such as acyl or
(C.sub.1-6)alkylsulphonyl groups.
[0065] The term "heteroaryl" includes the aromatic heterocyclic
groups referred to above. Examples of heteroaryl groups include
pyridyl, triazolyl, tetrazolyl, indolyl, thienyl, isoimidazolyl,
thiazolyl, furanyl, quinolinyl, imidazolidinyl and
benzothienyl.
[0066] When used herein the term "aryl", includes phenyl and
naphthyl.
[0067] Aryl groups, e.g. phenyl and benzoyl; heteroaryl and
heteroaroyl groups may be optionally substituted with up to five,
preferably up to three, groups selected from halogen, mercapto,
(C.sub.1-6)alkyl, phenyl, (C.sub.1-6)alkoxy,
hydroxy(C.sub.1-6)alkyl, mercapto (C.sub.1-6)alkyl,
halo(C.sub.1-6)alkyl, hydroxy, optionally substituted amino, nitro,
carboxy, (C.sub.1-6)alkylcarbonyloxy, (C.sub.1-6)alkoxycarbonyl,
formyl, and (C.sub.1-6)alkylcarbonyl groups.
[0068] The term "acyl" includes formyl and (C.sub.1-6)alkylcarbonyl
group.
[0069] The term "acyloxy" includes (C.sub.1-6)alkoxycarbonyl.
[0070] Some of the compounds of this invention may be crystallised
or recrystallised from solvents such as aqueous and organic
solvents. In such cases solvates may be formed. This invention
includes within its scope stoichiometric solvates including
hydrates as well as compounds containing variable amounts of water
that may be produced by processes such as lyophilisation.
[0071] Since the compounds of formula (I) are intended for use in
pharmaceutical compositions it will readily be understood that they
are each preferably provided in substantially pure form, for
example at least 60% pure, more suitably at least 75% pure and
preferably at least 85%, especially at least 98% pure (% are on a
weight for weight basis). Impure preparations of the compounds may
be used for preparing the more pure forms used in the
pharmaceutical compositions; these less pure preparations of the
compounds should contain at least 1%, more suitably at least 5% and
preferably from 10 to 59% of a compound of the formula (I) or
pharmaceutically acceptable derivative thereof.
[0072] Particular compounds according to the invention include
those mentioned in the examples and their pharmaceutically
acceptable derivatives.
[0073] Pharmaceutically acceptable derivatives include salts and
esters.
[0074] Suitable pharmaceutically acceptable esters will be apparent
to those skilled in the art and include for example benzyl,
p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl,
2,2,2-trichloroethyl, 2,2,2-tribromoethyl, tert-butyl, tert-amyl,
allyl, diphenylmethyl, triphenylmethyl, adamantyl,
2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl,
tetrahydropyran-2-yl, pentachlorophenyl, acetonyl,
p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or
phosphorus-containing group, an oxime radical of formula
--N.dbd.CHR.sup.y where R.sup.y is aryl or heterocyclyl, or an in
vivo hydrolysable ester radical such as defined below.
[0075] Examples of suitable in vivo hydrolysable ester groups
include, for example, acyloxy(C.sub.1-6)alkyl groups such as
acetoxymethyl, pivaloyloxymethyl, .alpha.-acetoxyethyl,
.alpha.-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and
(1-aminoethyl)carbonyloxymethyl;
(C.sub.1-6)alkoxycarbonyloxy(C.sub.1-6)alkyl groups, such as
ethoxycarbonyloxymethyl, .alpha.-ethoxycarbonyloxyethyl and
propoxycarbonyloxyethyl; di(C.sub.1-6)alkylamino(C.sub.1-6)alkyl
especially di(C.sub.1-4)alkylamino(C.sub.1-4)alkyl groups such as
dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or
diethylaminoethyl;
2-((C.sub.1-6)alkoxycarbonyl)-2-(C.sub.2-6)alkenyl groups such as
2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl;
lactone groups such as phthalidyl and dimethoxyphthalidyl.
[0076] Suitable pharmaceutically acceptable salts will be apparent
to those skilled in the art and include for example acid addition
salts formed with inorganic acids e.g. hydrochloric, hydrobromic,
sulphuric, nitric or phosphoric acid; and organic acids e.g.
succinic, maleic, acetic, fumaric, citric, tartaric, benzoic,
p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid.
Other salts e.g. oxalates, may be used, for example in the
isolation of compounds of formula (I) and are included within the
scope of this invention.
[0077] Compounds of formula (I) may also be prepared as the
corresponding N-oxides.
[0078] Certain of the compounds of formula (I) may exist in the
form of optical isomers, e.g. diastereoisomers and mixtures of
isomers in all ratios, e.g. racemic mixtures. The invention
includes all such forms, in particular the pure isomeric forms. For
example the invention includes compound in which an A-B group
CH(OH)--CH.sub.2 is in either isomeric configuration, the R-isomer
is preferred. The different isomeric forms may be separated or
resolved one from the other by conventional methods, or any given
isomer may be obtained by conventional synthetic methods or by
stereospecific or asymmetric syntheses.
[0079] In a further aspect of the invention there is provided a
process for preparing compounds of formula (I), and
pharmaceutically acceptable derivatives thereof, which process
comprises: [0080] reacting a compound of formula (IV) with a
compound of formula (V): ##STR3## wherein Z.sup.1, Z.sup.2,
Z.sup.3, Z.sup.4, Z.sup.5 and n are as defined in formula (I);
R.sup.1, R.sup.2', R.sup.3' and R.sup.4' are R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 as defined in formula (I) or groups convertible
thereto; and X and Y may be the following combinations: [0081] (i)
X is A'-COW, Y is H and n is 0; [0082] (ii) X is
CR.sup.6.dbd.CR.sup.8R.sup.9, Y is H and n is 0; [0083] (iii) X is
oxirane, Y is H and n is 0; [0084] (iv) X is N.dbd.C.dbd.O and Y is
H; [0085] (v) X is NH.sub.2 and Y is CO.sub.2W; [0086] (vi) one of
X and Y is CO.sub.2R.sup.y and the other is
CH.sub.2CO.sub.2R.sup.x; [0087] (vii) X is CHR.sup.6R.sup.7 and Y
is CR.sup.80; [0088] (viii) X is CR.sup.6.dbd.PR.sup.z.sub.3 and Y
is CR.sup.8O; [0089] (ix) X is CR.sup.6O and Y is
CR.sup.8.dbd.PR.sup.z.sub.3; [0090] (x) one of X and Y is COW and
the other is NHR.sup.11' or NCO; [0091] (xi) X is CR.sup.6O and Y
is NHR.sup.11 or X is NHR.sup.11' and Y is C R.sup.8O; [0092] (xii)
X is NHR.sup.11' and Y is CR.sup.8R.sup.9W; [0093] (xiii) X is
CR.sup.6R.sup.7W and Y is NR.sup.11' or O; or [0094] (xiv) X is
CR.sup.6R.sup.7SO.sub.2W and Y is H and n=0; [0095] (xv) X is
NR.sup.11' and Y is SO.sub.2W; [0096] in which W is a leaving
group, e.g. halogen; R.sup.x and R.sup.y are (C.sub.1-6)alkyl;
R.sup.z is aryl or (C.sub.1-6)alkyl; A' and NR.sup.11' are A and
NR.sup.11 as defined in formula (I), or groups convertible thereto;
and oxirane is: ##STR4## wherein R.sup.6, R.sup.8 and R.sup.9 are
as defined in formula (I); [0097] and thereafter optionally or as
necessary converting A', R.sup.1', R.sup.2', R.sup.3', R.sup.4' and
NR.sup.11'; to A, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
NR.sup.11'; converting A-B to other A-B, interconverting R.sup.1,
R.sup.2, R.sup.3 and/or R.sup.4, and/or forming a pharmaceutically
acceptable derivative thereof.
[0098] Process variant (i) initially produces compounds of formula
(I) wherein A-B is A'-CO.
[0099] Process variant (ii) initially produces compounds of formula
(I) wherein A-B is CHR.sup.6--CR.sup.8R.sup.9.
[0100] Process variant (iii) initially produces compounds of
formula (I) wherein A-B is CR.sup.6(OH)--CR.sup.8R.sup.9.
[0101] Process variants (iv) and (v) initially produce compounds of
formula (I) where A-B is NH--CO.
[0102] Process variant (vi) initially produces compounds of formula
(I) wherein A-B is CO--CH.sub.2 or CH.sub.2--CO.
[0103] Process variant (vii) initially produces compounds of
formula (I) wherein A-B is CR.sup.6R.sup.7--CR.sup.8OH.
[0104] Process variant (viii) and (ix) initially produce compounds
of formula (I) wherein A-B is CR.sup.6.dbd.CR.sup.8.
[0105] Process variant (x) initially produces compounds of formula
(I) where A-B is CO--NR.sup.11' or NR.sup.11'--CO.
[0106] Process variant (xi) initially produces compounds of formula
(I) wherein A-B is CHR.sup.6--NR.sup.11' or
NR.sup.11'--CHR.sup.6.
[0107] Process variant (xii) initially produces compounds of
formula (I) wherein A-B is NR.sup.11'--CR.sup.8R.sup.9.
[0108] Process variant (xiii) initially produces compounds of
formula (I) wherein A-B is CR.sup.6R.sup.7--NR.sup.11' or
CR.sup.6R.sup.7--O.
[0109] Process variant (xiv) initially produces compounds of
formula (I) where A-B is CR.sup.6R.sup.7--SO.sub.2.
[0110] Process variant (xv) initially produces compounds of formula
(I) where A-B is NR.sup.11'--SO.sub.2.
[0111] In process variants (i), (v) and (x) the reaction is a
standard amide formation reaction involving e.g.: [0112] 1.
Activation of a carboxylic acid (e.g. to an acid chloride, mixed
anhydride, active ester, O-acyl-isourea or other species), and
treatment with an amine (Ogliaruso, M. A.; Wolfe, J. F. in The
Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The
Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979),
pp 442-8; Beckwith, A. L. J. in The Chemistry of Functional Groups
(Ed. Patai, S.) Suppl. B: The Chemistry of Amides (Ed. Zabricky,
J.) (John Wiley and Sons, 1970), p 73 ff. The acid and amide are
preferably reacted in the presence of an activating agent such as
1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or
1-hydroxybenzotriazole (HOBT); or [0113] 2. The specific methods
of: [0114] a. in situ conversion of an acid into the amine
component by a modified Curtius reaction procedure (Shioiri, T.,
Murata, M., Hamada, Y., Chem. Pharm. Bull. 1987, 35, 2698) [0115]
b. in situ conversion of the acid component into the acid chloride
under neutral conditions (Villeneuve, G. B.; Chan, T. H.,
Tetrahedron. Lett. 1997, 38, 6489).
[0116] The process variant (ii) is a standard addition reaction
using methods well known to those skilled in the art. The process
is preferably carried out in a polar organic solvent e.g.
acetonitrile in the presence of an organic base e.g.
triethylamine.
[0117] In process variant (iii) the coupling may be effected in
acetonitrile at room temperature in the presence of one equivalent
of lithium perchlorate as catalyst (general method of J. E.
Chateauneuf et al, J. Org. Chem., 56, 5939-5942, 1991). In some
cases an elevated temperature such as 40-70.degree. C. may be
beneficial. Alternatively, the piperazine may be treated with a
base, such as one equivalent of butyl lithium, and the resulting
salt reacted with the oxirane in an inert solvent such as
tetrahydrofuran, preferably at an elevated temperature such as
80.degree. C. Use of a chiral epoxide will afford single
diastereomers. Alternatively, mixtures of diastereomers may be
separated by preparative HPLC or by conventional resolution through
crystallisation of salts formed from chiral acids.
[0118] The process variant (iv) is a standard urea formation
reaction from the reaction of an isocyanate with an amine and is
conducted by methods well known to those skilled in the art (for
example see March, J; Advanced Organic Chemistry, Edition 3 (John
Wiley and Sons, 1985), p802-3). The process is preferably carried
out in a polar solvent such as N,N-dimethylformamide
[0119] In process variant (vi) the process is two step: firstly a
condensation using a base, preferably sodium hydride or alkoxide,
sodamide, alkyl lithium or lithium dialkylamide, preferably in an
aprotic solvent e.g. ether, THF or benzene; secondly, hydrolysis
using an inorganic acid, preferably HCl in aqueous organic solvent
at 0-100.degree. C. Analogous routes are described in DE330945,
EP31753, EP53964 and H. Sargent, J. Am. Chem. Soc. 68, 2688-2692
(1946). Similar Claisen methodology is described in Soszko et. al.,
Pr. Kom. Mat. Przyr. Poznan. Tow. Przyj. Nauk., (1962), 10, 15.
[0120] In process variant (vii) the reaction is carried out in the
presence of a base, preferably organometallic or metal hydride e.g.
NaH, lithium diisopropylamide or NaOEt, preferably in an aprotic
solvent, preferably THF, ether or benzene at -78 to 25.degree. C.
(analogous process in Gutswiller et al. (1978) JACS 100, 576).
[0121] In process variants (viii) and (ix) if a base is used it is
preferably NaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide
e.g. NaOEt, sodamide or lithium dialkylamide e.g.
di-isopropylamide. An analogous method is described in U.S. Pat.
No. 3,989,691 and M. Gates et. al. (1970) J. Amer. Chem. Soc., 92,
205, as well as Taylor et al. (1972) JACS 94, 6218.
[0122] In process variant (xi) where X or Y is CHO the reaction is
a standard reductive alkylation using, e.g., sodium
triacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents
for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons,
1995), p 4649).
[0123] The process variants (xii) and (xiii). are standard
alkylation reactions well known to those skilled in the art, for
example where an alcohol or amine is treated with an alkyl halide
in the presence of a base (for example see March, J; Advanced
Organic Chemistry, Edition 3 (John Wiley and Sons, 1985), p364-366
and p342-343). The process is preferably carried out in a polar
solvent such as N,N-dimethylformamide
[0124] In process variant (xiv) and (xv) the reaction is a standard
sulphonamide formation reaction well known to those skilled in the
art. This may be e.g. the reaction of a sulphonyl halide with an
amine.
[0125] Reduction of a carbonyl group B to CHOH can be readily
accomplished using reducing agents well known to those skilled in
the art, e.g. sodium borohydride in aqueous ethanol or lithium
aluminiun hydride in ethereal solution. This is analogous to
methods described in EP53964, US384556 and J. Gutzwiller et al, J.
Amer. Chem. Soc., 1978, 100, 576.
[0126] The carbonyl group B may be reduced to CH.sub.2 by treatment
with a reducing agent such as hydrazine in ethylene glycol, at e.g.
130-160.degree. C., in the presence of potassium hydroxide.
[0127] Reaction of a carbonyl group B with an organometallic
reagent yields a group where R.sup.8 is OH and R.sup.9 is
alkyl.
[0128] A hydroxy group on A or B may be oxidised to a carbonyl
group by oxidants well known to those skilled in the art, for
example, manganese dioxide, pyridinium chlorochromate or pyridinium
dichromate.
[0129] A hydroxyalkyl A-B group CHR.sup.6CR.sup.8OH or
CR.sup.6(OH)CHR.sup.8 may be dehydrated to give the group
CR.sup.6.dbd.CR.sup.8 by treatment with an acid anhydride such as
acetic anhydride.
[0130] Methods for conversion of CR.sup.6.dbd.CR.sup.8 by reduction
to CHR.sup.6CHR.sup.8 are well known to those skilled in the art,
for example using hydrogenation over palladium on carbon as
catalyst. Methods for conversion of CR.sup.6.dbd.CR.sup.8 to give
the A-B group CR.sup.6(OH)CHR.sup.8 or CHR.sup.6CR.sup.8OH are well
known to those skilled in the art for example by epoxidation and
subsequent reduction by metal hydrides, hydration, hydroboration or
oxymercuration.
[0131] An amide carbonyl group may be reduced to the corresponding
amine using a reducing agent such as lithium aluminium hydride.
[0132] A hydroxy group in A or B may be converted to azido by
activation and displacement e.g. under Mitsunobu conditions using
hydrazoic acid or by treatment with diphenylphosphorylazide and
base, and the azido group in turn may be reduced to amino by
hydrogenation.
[0133] R.sup.1', R.sup.2', R.sup.3 and R.sup.4' are preferably
R.sup.1, R.sup.2, R.sup.3 and R.sup.4. R.sup.1 is preferably
methoxy. R.sup.2' is preferably hydrogen. R.sup.3' is preferably
hydrogen, CONH.sub.2, CH.sub.2OH, CH.sub.2CO.sub.2H,
CH.sub.2CONH.sub.2, CH(OH)CH.sub.2OH, CH(OH)CH.sub.2CN, CH.sub.2CN,
2-oxo-oxazolidin-5-yl and 2-oxo-oxazolidin-5-yl(C.sub.1-4alkyl).
R.sup.4' is preferably heptyl.
[0134] Conversions of R.sup.1', R.sup.2', R.sup.3 and R.sup.4' and
interconversions of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
conventional. In compounds which contain an optionally protected
hydroxy group, suitable conventional hydroxy protecting groups
which may be removed without disrupting the remainder of the
molecule include acyl and alkylsilyl groups.
[0135] For example R.sup.1' methoxy is convertible to R.sup.1'
hydroxy by treatment with lithium and diphenylphosphine (general
method described in Ireland et al, J. Amer. Chem. Soc., 1973, 7829)
or HBr. Alkylation of the hydroxy group with a suitable alkyl
derivative bearing a leaving group such as halide and a protected
amino, piperidyl, amidino or guanidino group or group convertible
thereto, yields, after conversion/deprotection, R.sup.1 alkoxy
substituted by optionally N-substituted amino, piperidyl, guanidino
or amidino.
[0136] R.sup.3 alkenyl is convertible to hydroxyalkyl by
hydroboration using a suitable reagent such as
9-borabicyclo[3.3.1]nonane, epoxidation and reduction or
oxymercuration.
[0137] R.sup.3 1,2-dihydroxyalkyl can be prepared from R.sup.3'
alkenyl using osmium tetroxide or other reagents well known to
those skilled in the art (see Advanced Organic Chemistry, Ed.
March, J., John Wiley and Sons, 1985, p 732-737 and refs. cited
therein) or epoxidation followed by hydrolysis (see Advanced
Organic Chemistry, Ed. March, J. John Wiley and Sons, 1985, p 332,
333 and refs. cited therein).
[0138] R.sup.3 vinyl can be chain extended by standard
homologation, e.g. by conversion to hydroxyethyl followed by
oxidation to the aldehyde, which is then subjected to a Wittig
reaction.
[0139] Opening an epoxide-containing R.sup.3' group with cyanide
anion yields a CH(OH)--CH.sub.2CN group.
[0140] Opening an epoxide-containing R.sup.3' group with azide
anion yields an azide derivative which can be reduced to the amine.
Conversion of the amine to a carbamate is followed by ring closure
with base to give the 2-oxo-oxazolidinyl containing R.sup.3
group.
[0141] Substituted 2-oxo-oxazolidinyl containing R.sup.3 groups may
be prepared from the corresponding aldehyde by conventional
reaction with a glycine anion equivalent, followed by cyclisation
of the resulting amino alcohol (M Grauert et al, Ann. Chem., 1985,
1817; Rozenberg et al, Angew. Chem. Int. Ed. Engl., 1994, 33(1),
91). The resulting 2-oxo-oxazolidinyl group contains a carboxy
group which can be converted to other R.sup.10 groups by standard
procedures.
[0142] Carboxy groups within R.sup.3 may be prepared by Jones'
oxidation of the corresponding alcohols CH.sub.2OH using chromium
acid and sulphuric acid in water/methanol (E. R. H. Jones et al, J.
Chem. Soc., 1946, 39). Other oxidising agents may be used for this
transformation such as sodium periodate catalysed by ruthenium
trichloride (G. F. Tutwiler et al, J. Med. Chem., 1987, 30(6),
1094), chromium trioxide-pyridine (G. Just et al, Synth. Commun.,
1979, 9(7), 613), potassium permanganate (D. E. Reedich et al, J.
Org. Chem., 1985, 50(19), 3535), and pyridinium chlorochromate (D.
Askin et al, Tetrahedron Lett., 1988, 29(3), 277).
[0143] Other routes to the synthesis of carboxy groups within
R.sup.3 are well known to those skilled in the art.
[0144] R.sup.3 groups containing a cyano group may be prepared by
conversion of an alcohol to a suitable leaving group such as the
corresponding tosylate by reaction with para-toluenesulphonyl
chloride (M. R. Bell, J. Med. Chem., 1970, 13, 389), or the iodide
using triphenylphosphine, iodine, and imidazole (G. Lange, Synth.
Commun., 1990, 20, 1473). The second stage is the displacement of
the leaving group with cyanide anion (L. A. Paquette et al, J. Org.
Chem., 1979, 44(25), 4603; P. A. Grieco et al, J. Org. Chem., 1988,
53(16), 3658.
[0145] Other functional groups in R.sup.3 may be obtained by
conventional conversions of carboxy or cyano groups.
[0146] Tetrazoles are conveniently prepared by reaction of sodium
azide with the cyano group (e.g. F. Thomas et al, Bioorg. Med.
Chem. Lett., 1996, 6(6), 631; K. Kubo et al, J. Med. Chem., 1993,
36, 2182) or by reaction of azidotri-n-butyl stannane with the
cyano group followed by acidic hydrolysis (P. L. Ornstein, J. Org.
Chem., 1994, 59, 7682 and J. Med. Chem, 1996, 39 (11), 2219).
[0147] The 3-hydroxy-3-cyclobutene-1,2-dion-4-yl group (e.g. R. M.
Soil, Bioorg. Med. Chem. Lett., 1993, 3(4), 757 and W. A. Kinney,
J. Med. Chem., 1992, 35(25), 4720) can be prepared by the following
sequence:--(1) a compound where R.sup.3 is (CH.sub.2).sub.nCHO
(n=0, 1, 2) is treated with triethylamine,
carbontetrabromide-triphenylphosphine to give initially
(CH.sub.2).sub.nCH.dbd.CHBr; (2) dehydrobromination of this
intermediate to give the corresponding bromoethyne derivative
(CH.sub.2).sub.nC.ident.CBr (for this 2 stage sequence see D.
Grandjean et al, Tetrahedron Lett., 1994, 35(21), 3529); (3)
palladium-catalysed coupling of the bromoethyne with
4-(1-methylethoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-1,2-dione
(Liebeskind et al, J. Org. Chem., 1990, 55, 5359); (4) reduction of
the ethyne moiety to --CH.sub.2CH.sub.2-- under standard conditions
of hydrogen and palladium on charcoal catalysis (see Howard et al,
Tetrahedron, 1980, 36, 171); and finally (4) acidic hydrolysis of
the methylethoxyester to generate the corresponding
3-hydroxy-3-cyclobutene-1,2-dione group (R. M. Soll, Bioorg. Med.
Chem. Lett., 1993, 3(4), 757).
[0148] The tetrazol-5-ylaminocarbonyl group may be prepared from
the corresponding carboxylic acid and 2-aminotetrazole by
dehydration with standard peptide coupling agents such as
1,1'-carbonyldiimidazole (P. L. Ornstein et al, J. Med Chem, 1996,
39(11), 2232).
[0149] The alkyl- and alkenyl-sulphonylcarboxamides are similarly
prepared from the corresponding carboxylic acid and the alkyl- or
alkenyl-sulphonamide by dehydration with standard peptide coupling
agents such as 1,1'-carbonyldiimidazole (P. L. Omstein et al, J.
Med. Chem., 1996, 39(11), 2232).
[0150] The hydroxamic acid groups are prepared from the
corresponding acids by standard amide coupling reactions e.g. N. R.
Patel et al, Tetrahedron, 1987, 43(22), 5375.
[0151] 2,4-Thiazolidinedione groups may prepared from the aldehydes
by condensation with 2,4-thiazolidinedione and subsequent removal
of the olefinic double bond by hydrogenation.
[0152] The preparation of 5-oxo-1,2,4-oxadiazoles from nitrites is
decribed by Y. Kohara et al, Bioorg. Med. Chem. Lett., 1995, 5(17),
1903.
[0153] 1,2,4-Triazol-5-yl groups may be prepared from the
corresponding nitrile by reaction with an alcohol under acid
conditions followed by reaction with hydrazine and then an
R.sup.10-substituted activated carboxylic acid (see J. B. Polya in
"Comprehensive Heterocyclic Chemistry" Edition 1, p762, Ed A. R.
Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984 and J. J.
Ares et al, J. Heterocyclic Chem., 1991, 28(5), 1197).
[0154] Other substituents on R.sup.3 alkyl or alkenyl may be
interconverted by conventional methods, for example hydroxy may be
derivatised by esterification, acylation or etherification. Hydroxy
groups may be converted to halogen, thiol, alkylthio, azido,
alkylcarbonyl, amino, aminocarbonyl, oxo, alkylsulphonyl,
alkenylsulphonyl or aminosulphonyl by conversion to a leaving group
and substitution by the required group or oxidation as appropriate
or reaction with an activated acid, isocyanate or alkoxyisocyanate.
Primary and secondary hydroxy groups can be oxidised to an aldehyde
or ketone respectively and alkylated with a suitable agent such as
an organometallic reagent to give a secondary or tertiary alcohol
as appropriate.
[0155] Compounds of formula (I) where R.sup.2 and R.sup.3 are a
divalent residue .dbd.CR.sup.5, R.sup.61 can be prepared by
treatment of a compound of formula (I) where R.sup.3 is alken-1-yl
with a strong base in an aprotic solvent. Suitable bases include
Ph.sub.2PLi/PhLi (as described in Ireland et al, J. Amer. Chem.
Soc., 1973, 7829), t-BuLi, and suitable solvents include THF and
ether.
[0156] NH is converted to NR.sup.4 by conventional means such as
alkylation with an alkyl halide in the presence of base,
acylation/reduction or reductive alkylation with an aldehyde.
[0157] It will be appreciated that under certain circumstances
interconvertions may interfere, for example, A or B hydroxy groups
in A or B and the piperidine NH will require protection e.g. as a
carboxy- or silyl-ester group for hydroxy and as an acyl derivative
for piperidine nitrogen, during conversion of R.sup.1', R.sup.2',
R.sup.3' or R.sup.4'.
[0158] Compounds of formula (IV) where X is
CR.sup.6R.sup.7SO.sub.2W may be prepared by a route analogous to
that of Ahmed El Hadri et al, J. Heterocyclic Chem., 1993, 30(3),
631. Thus compounds of formula (IV) where X is CH.sub.2SO.sub.2OH
may be prepared by reacting the corresponding 4-methyl compound
with N-bromosuccinimide, followed by treatment with sodium sulfite.
The leaving group W may be converted to another leaving group W,
e.g. a halogen group, by conventional methods.
[0159] The isocyanate of formula (IV) may be prepared
conventionally from a 4-amino derivative such as 4-amino-quinoline,
and phosgene, or phosgene equivalent (eg triphosgene) or it may be
prepared more conveniently from a 4-carboxylic acid by a `one-pot`
Curtius Reaction with diphenyl phosphoryl azide (DPPA) [see T.
Shiori et al. Chem. Pharm. Bull. 35, 2698-2704 (1987)].
[0160] The 4-amino derivatives are commercially available or may be
prepared by conventional procedures from a corresponding 4-chloro
derivative by treatment with ammonia (O. G. Backeberg et. al., J.
Chem Soc., 381, 1942.) or propylamine hydrochloride (R. Radinov et.
al., Synthesis, 886, 1986).
[0161] 4-Alkenyl compounds of formula (IV) may be prepared by
conventional procedures from a corresponding 4-halogeno-derivative
by e.g. a Heck synthesis as described in e.g. Organic Reactions,
1982, 27, 345.
[0162] 4-Halogeno derivatives of compounds of formula (IV) are
commercially available, or may be prepared by methods known to
those skilled in the art. A 4-chloroquinoline is prepared from the
corresponding quinolin-4-one by reaction with phosphorus
oxychloride (POCl.sub.3) or phosphorus pentachloride, PCl.sub.5. A
4-chloroquinazoline is prepared from the corresponding
quinazolin-4-one by reaction with phosphorus oxychloride
(POCl.sub.3) or phosphorus pentachloride, PCl.sub.5. A
quinazolinone and quinazolines may be prepared by standard routes
as described by T. A. Williamson in Heterocyclic Compounds, 6, 324
(1957) Ed. R. C. Elderfield.
[0163] 4-Carboxy derivatives of compounds of formula (IV) are
commercially available or may be prepared by conventional
procedures for preparation of carboxy heteroaromatics well known to
those skilled in the art. For example, quinazolines may be prepared
by standard routes as described by T. A. Williamson in Heterocyclic
Compounds, 6, 324 (1957) Ed. R. C. Elderfield. Pyridazines and
napthyridines may be prepared by routes analogous to those
described in Comprehensive Heterocyclic Chemistry, Volumes 2 &
3, Ed A. J. Boulton and A. McKillop. These 4-carboxy derivatives
may be activated by conventional means, e.g. by conversion to an
acyl halide or anhydride.
[0164] A 4-oxirane derivative of compounds of formula (IV) is
conveniently prepared from the 4-carboxylic acid by first
conversion to the acid chloride with oxalyl chloride and then
reaction with trimethylsilyldiazomethane to give the diazoketone
derivative. Subsequent reaction with 5M hydrochloric acid gives the
chloromethylketone. Reduction with sodium borohydride in aqueous
methanol gives the chlorohydrin which undergoes ring closure to
afford the epoxide on treatment with base, e.g. potassium hydroxide
in ethanol-tetrahydrofuran.
[0165] If a chiral reducing agent such as (+) or
(-)-B-chlorodiisopinocamphenylborane [`DIP-chloride` ] is
substituted for sodium borohydride, the prochiral
chloromethylketone is converted into the chiral chlorohydrin with
ee values generally 85-95% [see C. Bolm et al, Chem. Ber. 125,
1169-1190, (1992)]. Recrystallisation of the chiral epoxide gives
material in the mother liquor with enhanced optical purity
(typically ee 95%).
[0166] The (R)-epoxide, when reacted with a piperazine derivative
gives ethanolamine compounds as single diastereomers with
(R)-stereochemistry at the benzylic position.
[0167] Alternatively, the epoxide may be prepared from the
4-carboxaldehyde by a Wittig approach using trimethylsulfonium
iodide [see G. A. Epling and K-Y Lin, J. Het. Chem., 1987, 24,
853-857], or by epoxidation of a 4-vinyl derivative.
[0168] 4-Hydroxy-1,5-naphthyridines can be prepared from
3-aminopyridine derivatives by reaction with ethoxymethylenemalonic
ester to produce the 4-hydroxy-3-carboxylic acid ester derivative
with subsequent hydrolysis to the acid, followed by thermal
decarboxylation in quinoline (as for example described for
4-Hydroxy-[1,5]naphthyridine-3-carboxylic acid, Joe T. Adams et
al., J. Amer. Chem. Soc., 1946, 68, 1317. A
4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro
derivative by heating in phosphorus oxychloride. A 4-amino
1,5-naphthyridine can be obtained from the 4-chloro derivative by
reaction with n-propylamine in pyridine. Similarly,
6-methoxy-1,5-naphthyridine derivatives can be prepared from
3-amino-6-methoxypyridine.
[0169] 1,5-Naphthyridines may be prepared by other methods well
known to those skilled in the art (for examples see P. A. Lowe in
"Comprehensive Heterocyclic Chemistry" Volume 2, p581-627, Ed A. R.
Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984).
[0170] For compounds of formula (V), suitable amines may be
prepared from the corresponding 4-substituted piperidine acid or
alcohol. In a first instance, an N-protected piperidine containing
an acid bearing substituent, can undergo a Curtius rearrangement
and the intermediate isocyanate can be converted to a carbamate by
reaction with an alcohol. Conversion to the amine may be achieved
by standard methods well known to those skilled in the art used for
amine protecting group removal. For example, an acid substituted
N-protected piperidine can undergo a Curtius rearrangement e.g. on
treatment with diphenylphosphoryl azide and heating, and the
intermediate isocyanate reacts in the presence of
2-trimethylsilylethanol to give the trimethylsilylethylcarbamate
(T. L. Capson & C. D. Poulter, Tetrahedron Lett., 1984, 25,
3515). This undergoes cleavage on treatment with tetrabutylammonium
fluoride to give the 4-amine substituted N-protected
piperidine.
[0171] In a second instance, an N-protected piperidine containing
an alcohol bearing substituent undergoes a Mitsunobu reaction (for
example as reviewed in Mitsunobu, Synthesis, (1981), 1), for
example with succinimide in the presence of diethyl
azodicarboxylate and triphenylphosphine to give the
phthalimidoethylpiperidine. Removal of the phthaloyl group, for
example by treatment with methylhydrazine, gives the amine of
formula (V).
[0172] Conversions of R.sup.1', R.sup.2', R.sup.3' and R.sup.4' may
be carried out on the intermediates of formulae (IV), and (V) prior
to their reaction to produce compounds of formula (I) in the same
way as described above for conversions after their reaction.
[0173] Further details for the preparation of compounds of formula
(I) are found in the examples.
[0174] The compounds of formula (I) may be prepared singly or as
compound libraries comprising at least 2, for example 5 to 1,000
compounds, and more preferably 10 to 100 compounds of formula (I).
Libraries of compounds of formula (I) may be prepared by a
combinatorial `split and mix` approach or by multiple parallel
synthesis using either solution phase or solid phase chemistry, by
procedures known to those skilled in the art.
[0175] Thus according to a further aspect of the invention there is
provided a compound library comprising at least 2 compounds of
formula (I) or pharmaceutically acceptable derivatives thereof.
[0176] Novel intermediates of formulae (IV) and (V) are also part
of this invention.
[0177] The antibacterial compounds according to the invention may
be formulated for administration in any convenient way for use in
human or veterinary medicine, by analogy with other
antibacterials.
[0178] The pharmaceutical compositions of the invention include
those in a form adapted for oral, topical or parenteral use and may
be used for the treatment of bacterial infection in mammals
including humans.
[0179] The composition may be formulated for administration by any
route. The compositions may be in the form of tablets, capsules,
powders, granules, lozenges, creams or liquid preparations, such as
oral or sterile parenteral solutions or suspensions.
[0180] The topical formulations of the present invention may be
presented as, for instance, ointments, creams or lotions, eye
ointments and eye or ear drops, impregnated dressings and aerosols,
and may contain appropriate conventional additives such as
preservatives, solvents to assist drug penetration and emollients
in ointments and creams.
[0181] The formulations may also contain compatible conventional
carriers, such as cream or ointment bases and ethanol or oleyl
alcohol for lotions. Such carriers may be present as from about 1%
up to about 98% of the formulation. More usually they will form up
to about 80% of the formulation.
[0182] Tablets and capsules for oral administration may be in unit
dose presentation form, and may contain conventional excipients
such as binding agents, for example syrup, acacia, gelatin,
sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example
lactose, sugar, maize-starch, calcium phosphate, sorbitol or
glycine; tabletting lubricants, for example magnesium stearate,
talc, polyethylene glycol or silica; disintegrants, for example
potato starch; or acceptable wetting agents such as sodium lauryl
sulphate. The tablets may be coated according to methods well known
in normal pharmaceutical practice. Oral liquid preparations may be
in the form of, for example, aqueous or oily suspensions,
solutions, emulsions, syrups or elixirs, or may be presented as a
dry product for reconstitution with water or other suitable vehicle
before use. Such liquid preparations may contain conventional
additives, such as suspending agents, for example sorbitol, methyl
cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,
carboxymethyl cellulose, aluminium stearate gel or hydrogenated
edible fats, emulsifying agents, for example lecithin, sorbitan
monooleate, or acacia; non-aqueous vehicles (which may include
edible oils), for example almond oil, oily esters such as
glycerine, propylene glycol, or ethyl alcohol; preservatives, for
example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if
desired, conventional flavouring or colouring agents.
[0183] Suppositories will contain conventional suppository bases,
e.g. cocoa-butter or other glyceride.
[0184] For parenteral administration, fluid unit dosage forms are
prepared utilizing the compound and a sterile vehicle, water being
preferred. The compound, depending on the vehicle and concentration
used, can be either suspended or dissolved in the vehicle. In
preparing solutions the compound can be dissolved in water for
injection and filter sterilised before filling into a suitable vial
or ampoule and sealing.
[0185] Advantageously, agents such as a local anaesthetic,
preservative and buffering agents can be dissolved in the vehicle.
To enhance the stability, the composition can be frozen after
filling into the vial and the water removed under vacuum. The dry
lyophilized powder is then sealed in the vial and an accompanying
vial of water for injection may be supplied to reconstitute the
liquid prior to use. Parenteral suspensions are prepared in
substantially the same manner except that the compound is suspended
in the vehicle instead of being dissolved and sterilization cannot
be accomplished by filtration. The compound can be sterilised by
exposure to ethylene oxide before suspending in the sterile
vehicle. Advantageously, a surfactant or wetting agent is included
in the composition to facilitate uniform distribution of the
compound.
[0186] The compositions may contain from 0.1% by weight, preferably
from 10-60% by weight, of the active material, depending on the
method of administration. Where the compositions comprise dosage
units, each unit will preferably contain from 50-500 mg of the
active ingredient. The dosage as employed for adult human treatment
will preferably range from 100 to 3000 mg per day, for instance
1500 mg per day depending on the route and frequency of
administration. Such a dosage corresponds to 1.5 to 50 mg/kg per
day. Suitably the dosage is from 5 to 20 mg/kg per day.
[0187] No toxicological effects are indicated when a compound of
formula (I) or a pharmaceutically acceptable derivative thereof is
administered in the above-mentioned dosage range.
[0188] The compound of formula (I) may be the sole therapeutic
agent in the compositions of the invention or a combination with
other antibacterials. If the other antibacterial is a .beta.-lactam
then a .beta.-lactamase inhibitor may also be employed.
[0189] Compounds of formula (I) are active against a wide range of
organisms including both Gram-negative and Gram-positive
organisms.
[0190] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0191] The following examples illustrate the preparation of certain
compounds of formula (I) and the activity of certain compounds of
formula (I) against various bacterial organisms.
EXAMPLES
Example 1
cis-3-(R/S)-Ethoxycarbonyl-4-(S/R)-heptylamino-1-[2-(R)-hydroxy-2-(6-metho-
xyquinolin-4-yl)]ethylpiperidine dioxalate Example 1.
cis-3-(R/S)-Ethoxycarbonyl-4-(S/R)-heptylamino-1-[2-(R)-hydroxy-2-(6-meth-
oxyquinolin-4-yl)]ethylpiperidine dioxalate
(a) [R]-2-(6-Methoxyquinolin-4-yl)oxirane
[0192] A solution of 6-methoxyquinoline-4-carboxylic acid (10 g) in
dichloromethane was heated under reflux with oxalyl chloride (5 ml)
and dimethylformamide (2 drops) for 1 hour and evaporated to
dryness. The residue, in dichloromethane (100 ml) was treated with
a 2M solution of trimethylsilyldiazomethane in hexane (50 ml) and
stirred at room temperature for 18 hours. 5M Hydrochloric acid (150
ml) was added and the solution was stirred at room temperature for
3 hours. It was basified with sodium carbonate solution, extracted
with ethyl acetate and chromatographed on silica gel eluting with
ethyl acetate-hexane to give the chloromethyl ketone (4.2 g). A
batch of the chloromethyl ketone (20 g) was reduced with
(+)-B-chlorodiisopinocamphenylborane (40 g) in dichloromethane (400
ml) at room temperature for 18 hours followed by treatment with
diethanolamine (30 g) for 3 hours. The product was chromatographed
on silica gel eluting with ethyl acetate-hexane to give the
chloroalcohol (16.8 g), which was dissolved in tetrahydrofuran (100
ml) and reacted with sodium hydroxide (2.6 g) in water (13 ml) for
1.5 hours. The reaction mixture was evaporated to dryness and
chromatographed on silica gel eluting with ethyl acetate-hexane to
give the title compound as a solid (10.4 g) (84% ee by chiral
HPLC). Recrystallisation from ether-pentane gave mother-liquor (7.0
g) (90% ee).
[0193] MS (+ve ion electrospray) m/z 202 (MH+)
[0194] The absolute stereochemistry was defined to be (R) by an NMR
study on the Mosher's esters derived from the product obtained by
reaction with 1-t-butylpiperazine.
(b)
1-tert-Butoxycarbonyl-3-ethoxycarbonyl-4-heptylamino-1,2,5,6-tetrahydr-
opyridine
[0195] A solution of
1-tert-butoxycarbonyl-3-ethoxycarbonyl-piperidin-4-one (prepared
from 3-ethoxycarbonyl-piperidin-4-one and di-tert-butyl-dicarbonate
in dichloromethane and triethylamine) (8.5 g) and heptylamine (3.61
g) in toluene (100 ml) was heated under reflux in a Dean and Stark
apparatus for 18 hours and then evaporated to dryness to give an
oil.
(c)
cis-1-tert-Butoxycarbonyl-3-(R/S)-ethoxycarbonyl-4-(S/R)-heptylamino-p-
iperidine
[0196] The enamine (1b) in ethanol (100 ml) was hydrogenated at 50
psi (Parr reaction vessel) over 10% palladium-carbon (2 g) for 48
hours, filtered and evaporated to dryness to give an oil. The
product was chromatographed on silica gel (ethyl acetate-hexane) to
afford the title compound (4.5 g), as an oil.
[0197] MS (+ve ion electrospray) m/z 371 (MH+).
(d) cis-3-(R/S)-Ethoxycarbonyl-4-(S/R)-heptylamino-piperidine
[0198] The amine (1c) (1.2 g) was treated with dichloromethane (30
ml) and trifluoroacetic acid (30 ml) at room temperature for 3.5
hours and evaporated to dryness. It was basified with sodium
carbonate solution, extracted with dichloromethane, dried over
sodium sulfate and evaporated to afford an oil (0.9 g).
(e) Title compound
[0199] A solution of [R]-2-(6-methoxyquinolin-4-yl)oxirane (1a)
(0.626 g) and the piperidine (1d) (0.85 g) in acetonitrile (5 ml)
containing lithium perchlorate (0.332 g) was stirred at room
temperature for 15 hours and evaporated to dryness. The product was
dissolved in dichloromethane, washed with sodium carbonate, dried
over sodium sulfate, and chromatographed on silica gel (ethyl
acetate-hexane) to afford the title compound (0.69 g) as the oily
free base.
[0200] MS (+ve ion electrospray) m/z 472 (MH+).
[0201] The free base was treated with 2 molar equivalents of oxalic
acid in ether and the resulting solid was collected, triturated
with ether, to afford the dioxalate salt as a white solid.
Example 2
cis-4-(S/R)-Heptylamino-3-(R/S)-hydroxymethyl-1-[2-(R)-hydroxy-2-(6-methox-
yquinolin-4-yl)]ethylpiperidine dioxalate
[0202] ##STR5##
[0203] The ester Example (1) (0.105 g) in dry tetrahydrofuran (5
ml) at -10.degree. C. was treated with lithium aluminium hydride
(0.27 ml of a 1M solution in ether) for 3 hours and then quenched
by the addition of 2M sodium hydroxide. Dichloromethane and sodium
sulfate were added and the solution was filtered and evaporated to
dryness. The product was chromatographed on silica gel
(methanol-dichloromethane) to afford the title compound (0.057 g),
as the oily free base.
[0204] MS (+ve ion electrospray) m/z 430 (MH+).
[0205] .sup.1H NMR (CDCl.sub.3) .delta.: 0.88 (3H, t), 1.30 (9H,
bs), 1.47 (2H, bs), 1.75 (1H, bt), 1.95-2.80 (.about.8H, m), 2.98
(2H, m), 3.85 (1H, m), 3.95 (3H, s), 4.25 (1H, bt), 5.41 (1H, m)
7.17 (1H, bs), 7.39 (1H, dd), 7.65 (1H, d), 8.05 (1H, d), 8.78 (1H,
d).
[0206] The free base in dichloromethane-ether was converted to the
dioxalate salt in the normal manner, affording a white solid.
Example 3
cis-3-(R/S)-Carboxy-4-(S/R)-heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquino-
lin-4-yl)]ethylpiperidine trihydrochloride
[0207] The ester Example (1) (0.07 g) was heated in 2M hydrochloric
acid (7 ml) under reflux for 5 hours and then evaporated to dryness
to give the title compound as a foam. MS (+ve ion electrospray) m/z
444 (MH+).
Example 4
cis-3-(R/S)-Aminocarbonyl-4-(S/R)-heptylamino-1-[2-(R)-hydroxy-2-(6-methox-
yquinolin-4-yl)]ethylpiperidine dioxalate
[0208] ##STR6##
[0209] The ester Example (1) (0.18 g) in methanol (3 ml) was heated
with ammonia (3 ml) and sodium cyanide (5 mg) at 50.degree. C.
(sealed bomb) for 4 days and evaporated to dryness. Chromatography
on silica gel (ethyl-acetate then methanol-dichloromethane) gave
the title compound (0.046 g), as the free base.
[0210] MS (+ve ion electrospray) m/z 443 (MH+). [0211] The free
base in dichloromethane-ether was converted to the dioxalate salt
in the normal manner, affording a white solid.
Example 5
4-Hexylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine
oxalate
[0212] ##STR7##
(a)
4-(1,3-Dioxolan-2-yl)-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethy-
lpiperidine
[0213] [R]-2-(6-Methoxyquinolin-4-yl)oxirane (1a) (470 mg) and
1,4-dioxa-8-azaspiro-[4,5]-decane (0.33 ml) were dissolved in dry
dichloromethane (5 ml) and ytterbium triflate (30 mol %) was added.
The mixture was stirred for 6 hours, filtered through celite,
evaporated and chromatographed on silica gel (dichloromethane then
methanol-dichloromethane) to afford the title compound (690
mg).
[0214] MS (+ve ion electrospray) m/z 345 (MH+).
(b)
4-Oxo-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine
[0215] The acetal (5a) was cleaved by treatment with 5M HCl (10 ml)
in acetone (20 ml) at 60.degree. C. overnight. The mixture was
basified with sodium bicarbonate solution and concentrated.
Extraction into dichloromethane, evaporation and chromatography on
silica gel (dichloromethane then methanol-dichloromethane) gave a
yellow gum (482 mg).
(c) Title Compound
[0216] The ketone (5b) (159 mg) was treated with hexylamine (0.12
ml) in methanol for 1 hour and sodium triacetoxyborohydride (170
mg) was added. The mixture was stirred for 4 hours, evaporated, and
the residue partitioned between dichloromethane/water. The
dichloromethane extract was evaporated and chromatographed on
silica gel (dichloromethane then methanol-dichloromethane) to give
a colourless oil as the free base (150 mg) which was converted to
the dioxalate salt in the normal manner, affording a white
solid.
[0217] MS (+ve ion electrospray) m/z 386 (MH+).
Example 6
4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine
dioxalate
[0218] ##STR8##
[0219] The title compound was prepared from the ketone (5b) as
described in Example (5c), using heptylamine.
[0220] MS (+ve ion electrospray) m/z 400 (MH+).
Example 7
4-Heptylamino-1-[2-(S)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine
dioxalate
(a) [S]-2-(6-Methoxyquinolin-4-yl)oxirane
[0221] This was prepared by the method of Example (1a) except that
the chloromethylketone was reduced with
(-)-B-chlorodiisopinocamphenylborane. The product had 90% ee.
[0222] MS (+ve ion electrospray) m/z 202 (MH+).
(b) Title Compound
[0223] The title compound was prepared from
[S]-2-(6-methoxyquinolin-4-yl)oxirane (7a) as described in Example
(5) using heptylamine.
[0224] MS (+ve ion electrospray) m/z 400 (MH+).
Example 8
4-Heptylamino-1-(6-methoxy-[1,5]-naphthyridin-4-yl)aminocarbonylpiperidine
[0225] ##STR9##
(a) 4-Hydroxy-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl
ester
[0226] 3-Amino-6-methoxypyridine (12.41 g) and diethyl
ethoxymethylene malonate (20.2 ml) in Dowtherm A (400 ml) were
heated at reflux, under argon for 1 hour. The cooled reaction
mixture was poured into pentane (1 litre). The precipitated solid
was collected by filtration, washed with pentane and dried to
afforded a solid (24.78 g, crude). MS (+ve ion electrospray) m/z
249 (MH+).
(b) 4-Hydroxy-6-methoxy-[1,5]naphthyridine-3-carboxylic acid
[0227] The ester (8a) (0.642 g) in 10% aqueous sodium hydroxide
(115 ml) was heated at reflux for 1.5 hours. The reaction mixture
was cooled then acidified with glacial acetic acid. The
precipitated solid was collected by filtration, washed with water
and dried in vacuo to afford a beige solid (0.542 g).
[0228] MS (+ve ion electrospray) m/z 221 (MH+).
(c) 4-Chloro-6-methoxy-[1,5]naphthyridine
[0229] The acid (8b) (6.82 g) was heated in quinoline (20 ml) at
reflux for 2 hours, the mixture was cooled and poured into ether
(200 ml) and the orange solid was filtered and washed with ether
(5.times.200 ml). A sample (3.87 g) of the dried solid was treated
with phosphorus oxychloride (30 ml) at room temp for 3 hours, the
solvent was removed in vacuo and the residue quenched with crushed
ice (200 g). The mixture was basified with ammonia solution and
filtered. The solid was washed with dichloromethane (10.times.100
ml), which was evaporated and chromatographed on silica gel
(dichloromethane as eluent) to give a yellow solid (3.0 g).
[0230] MS (+ve ion electrospray) m/z 195, 197 (MH.sup.+).
(d) 4-Amino-6-methoxy-[1,5]naphthyridine
[0231] A solution of the chloro compound (8c) (2.0 g) in pyridine
(30 ml) was treated with n-propylamine hydrochloride (6.0 g) and
the mixture heated at reflux for 16 hours. The reaction mixture was
cooled and partitioned between water and ethyl acetate. The aqueous
phase was washed with ethyl acetate, the combined organics dried
(Na.sub.2SO.sub.4) and the solvent removed under reduced pressure.
Purification by chromatography on silica gel (5-10% methanol in
dichloromethane) afforded a yellow solid (1.0 g).
[0232] .sup.1H NMR (CDCl.sub.3) .delta.: 4.05 (3H, s), 5.36 (2H,
bs), 6.71 (1H, d, J=5 Hz), 7.08 (1H, d, J=9 Hz), 8.10 (1H, d, J=9
Hz), 8.40 (1H, d, J=5 Hz).
[0233] MS (+ve ion electrospray) m/z: 176 (MH.sup.+).
(e)
4-Oxo-1-(6-methoxy-[1,5]-naphthyridin-4-yl)aminocarbonylpiperidine,
ethylene ketal
[0234] A solution of the amine (8d) (0.32 g, 2 mmol) in chloroform
(6 ml) was treated with N,N-dimethylaminopyridine (0.24 g, 2 mmol)
then 1,1'-carbonyldiimidazole (0.42 g, 2.6 mmol). After 2 hours the
chloroform was removed by evaporation and the residue treated with
a solution of 4-oxopiperidine, ethylene ketal (0.31 g, 0.22 mmol)
in N,N-dimethylformamide (5 ml). The mixture was heated at
100.degree. C. for 1 hour, then partitioned between ethyl acetate
and dilute brine. The organic extract was washed with water
(3.times.), brine, dried and evaporated to give a yellow solid (0.8
g). Chromatography on silica gave the product as a white solid
(0.47 g, 71%).
[0235] MS (+ve ion electrospray) m/z 345 (MH+).
(f)
4-Oxo-1-(6-methoxy-1,5-naphthyridin-4-yl)aminocarbonylpiperidine
[0236] A solution of Example (8e) (0.46 g, 1.4 mmol) in acetone (25
ml) and water (5 ml) was treated with concentrated hydrochloric
acid (0.2 ml) and the mixture heated to reflux for 4 hours. The
cooled mixture was partitioned between ethyl acetate and saturated
aqueous sodium bicarbonate solution. The organic extract was dried
and evaporated to give a white solid (0.4 g). Chromatography gave
the title compound (0.2 g, 46%).
[0237] MS (+ve ion electrospray) m/z 301 (MH+).
(g) Title Compound
[0238] A solution of Example (8f) (0.17 g, 0.6 mmol) in methanol (5
ml) was treated with heptylamine (0.13 ml, 0.1 g, 0.85 mmol) and
sodium triacetoxyborohydride (0.18 g, 0.85 mmol). After 3 hours the
mixture was partitioned between ethyl acetate and saturated aqueous
sodium bicarbonate solution. The organic extract was dried and
evaporated to give a white solid (0.3 g). Chromatography gave the
title compound (0.13 g, 60%).
[0239] MS (+ve ion electrospray) m/z 400 (MH+).
Example 9
4-(N-Ethoxycarbonylmethyl-N-heptylamino)-1-[2-(R)-hydroxy-2-(6-methoxyquin-
olin-4-yl)]ethylpiperidine oxalate
[0240]
4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpip-
eridine (Example 6) (100 mg) was alkylated with ethyl bromoacetate
(0.026 ml) in the presence of potassium carbonate (105 mg) in
dimethylformamide (3 ml). After removal of solvent, the crude
product was dissolved in dichloromethane and washed with water.
Chromatography on silica gel (10% methanol/dichloromethane) gave
the title compound (85 mg, 70%). This was converted to the oxalate
salt in the normal manner.
[0241] MS (+ve ion electrospray) m/z 486 (MH+).
Example 10
4-(N-Carboxymethyl-N-heptylamino)-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4--
yl)]ethylpiperidine oxalate
[0242] The ester Example (9) (60 mg) was hydrolysed in 2M
hydrochloric acid at 1000C. After evaporation to dryness, the
product was triturated with ether. The salt obtained was converted
to the free base, and then to the oxalate salt in the normal
manner.
[0243] MS (+ve ion electrospray) m/z 458 (MH+).
Example 11
4-(N-heptyl-N-2-hydroxyethylamino)-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-
-yl)]ethylpiperidine dioxalate
[0244] The ester Example (9) (60 mg) was dissolved in dry
tetrahydrofuran (2 ml) and treated with lithium aluminium hydride
(1M in ether, 0.14 ml) at 0.degree. C. for 3 hours. The mixture was
treated with sodium hydroxide, and magnesium sulfate, filtered and
evaporated to give the free base (38 mg, 68%). This was converted
to the dioxalate salt in the normal manner.
[0245] MS (+ve ion electrospray) m/z 444 (MH+).
Example 12
4-(N-Aminocarbonylmethyl-N-heptylamino)-1-[2-(R)-hydroxy-2-(6-methoxyquino-
lin-4-yl)]ethylpiperidine oxalate
[0246]
4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpip-
eridine (Example 6) (100 mg) was alkylated with 2-bromoacetamide
(38 mg) in the presence of potassium carbonate (105 mg) in
dimethylformamide (5 ml). After removal of solvent, the crude
product was dissolved in dichloromethane and washed with water.
Chromatography on silica gel (dichloromethane) gave the title
compound (43 mg, 38%). This was converted to the dioxalate salt in
the normal manner. MS (+ve ion electrospray) m/z 457 (MH+).
Example 13
4-(N-2-Aminoethyl-N-heptylamino)-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-y-
l)]ethylpiperidine tetrahydrochloride
[0247]
4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpip-
eridine (Example 6) (190 mg) was acylated with a mixture of
N-tert-butoxycarbonylglycine (87 mg),
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (230 mg) and
N-methyl morpholine (0.11 ml) in dry dichloromethane (10 ml). The
mixture was poured into water and extracted with dichloromethane.
The extract was washed with water and brine, dried and evaporated.
The crude product was chromatographed on silica gel (2-10%
methanov/dichloromethane) to give a mixture of N-acylated and
N,O-diacylated products (86 mg).
[0248] The above acylated mixture (43 mg) was reduced with lithium
aluminium hydride as in Example (11). Chromatography on silica gel
(dichloromethane) gave an N-(2-tert-butoxycarbonylaminoethyl)
product (15 mg) which was heated in 5M hydrochloric acid at
100.degree. C. Evaporation to dryness gave the title compound (12
mg).
[0249] MS (+ve ion electrospray) m/z 443 (MH+).
Example 14
4-(N-3-Ethoxycarbonylallyl-N-heptylamino)-1-[2-(R)-hydroxy-2-(6-methoxyqui-
nolin-4-yl)]ethylpiperidine
[0250]
4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpip-
eridine (Example 6) (200 mg) was alkylated with ethyl
4-bromocrotonate (96 mg) in the presence of potassium carbonate
(210 mg) in dimethylformamide (10 ml). After removal of solvent,
the crude product was dissolved in dichloromethane and washed with
water. Chromatography on silica gel (dichloromethane) gave the
title compound (43 mg, 17%). MS (+ve ion electrospray) m/z 512
(MH.sup.+).
Example 15
4-(N-3-Carboxyallyl-N-heptylamino)-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-
-yl)]ethylpiperidine trihydrochloride
[0251] The ester Example (14) (35 mg) was hydrolysed in 5M
hydrochloric acid at 100.degree. C. Evaporation to dryness gave the
title compound (60 mg).
[0252] MS (+ve ion electrospray) mnz 484 (MH+).
Example 16
4-Heptylamino-4-methoxycarbonyl-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl-
)]ethylpiperidine dioxalate
(a) Methyl
4-amino-1-tert-butoxycarbonylpiperidine-4-carboxylate
[0253] 4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylate (5 g)
in acetonitrile (22 ml) and methanol (2 ml) was treated with
di-isopropylethylamine (3.65 ml) and trimethylsilyldiazomethane (2M
in hexane, 13.9 ml). After overnight stirring and evaporation of
solvent, the crude product was chromatographed on silica gel (0-50%
ethyl acetate/petrol) to give a yellow oil (4 g, 76%).
[0254] MS (+ve ion electrospray) m/z 259 (MH+).
(b) Methyl
1-tert-butoxycarbonyl-4-heptylaminopiperidine-4-carboxylate
[0255] A solution of the aminoester (16a) (3.77 g) in methanol (40
ml) was treated with heptaldehyde (2.03 ml) and stirred for 2
hours. Sodium triacetoxyborohydride (3.43 g) was added and the
mixture was stirred for 16 hours. Solvent was evaporated and the
residue was dissolved in dichloromethane, washed with water, dried
and evaporated, to give a yellow oil (4.34 g, 83%).
[0256] MS (+ve ion electrospray) m/z 357 (MH+).
(c) Methyl 4-heptylaminopiperidine-4-carboxylate
[0257] To a solution of the tert-butoxycarbonylpiperidine (16b)
(0.2 g) in dichloromethane (1 ml) was added trifluoroacetic acid (1
ml). When hydrolysis was complete the mixture was extracted with
water. The aqueous extract was washed with ether, basified with
sodium hydrogen carbonate and saturated with sodium chloride, then
extracted with 5% methanol/dichloromethane. The extract was dried
and evaporated to give a yellow oil (90 mg, 63%).
[0258] MS (+ve ion electrospray) m/z 257 (MH+).
(d) Title Compound
[0259] A mixture of the piperidine (16c) (0.5 g), oxirane Example
1(a) (0.43 g) and lithium perchlorate (0.28 g) in acetonitrile (2
ml) was stirred for 3 days at room temperature, then heated at
50.degree. C. for 16 hours. Solvent was evaporated and the residue
was dissolved in dichloromethane, washed with water, dried and
evaporated. The crude product was chromatographed on silica gel
(ethyl acetate) to give the free base (0.35 g, 39%), which was
converted to the dioxalate salt in the normal manner.
[0260] MS (+ve ion electrospray) m/z 458 (MH+).
Example 17
4-Carboxy-4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylp-
iperidine trihydrochloride
[0261] The ester Example (16) (50 mg) was heated under reflux in 2M
hydrochloric acid for 18 hours. Evaporation to dryness and
trituration with ethyl acetate and ether gave the title compound
(51 mg).
[0262] MS (+ve ion electrospray) m/z 444 (MH+).
Example 18
4-Heptylamino-4-hydroxymethyl-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]-
ethylpiperidine dioxalate
[0263] ##STR10##
[0264] The ester Example (16) (60 mg) was reduced with lithium
aluminium hydride as in Example (11). Chromatography on silica gel
(0-20% methanol/dichloromethane) gave the title compound (31
mg).
[0265] MS (+ve ion electrospray) m/z 430 (MH+).
[0266] .sup.1H NMR (CDCl.sub.3): .delta.0.88 (3H, t, J=7), 1.28
(8H, m), 1.46 (2H, m), 1.68 (4H, m), 2.41-2.58 (5H, m), 2.73 (1H,
quintet, J=5), 2.85 (2H, dd, J=12,3), 3.38 (2H, s), 3.93 (3H, s),
5.43 (1H, dd, J=13,3), 7.18 (1H.d, J=3), 7.37 (1H, dd, J=9,3), 7.63
(1H, d, J=4.5), 8.03 (1H, d, J=9), 8.77 (1H, d,J=4.5)
The free base was converted to the dioxalate salt in the normal
manner, giving a white solid.
Example 19
4-Heptylamino-4-methoxycarbonyl-1-(6-methoxy-[1,5]-naphthyridine-4-yl)amin-
ocarbonylpiperidine
[0267] A solution of amine (8d) (0.26 g) in chloroform (7 ml) was
treated with 4-dimethylaminopyridine (0.2 g) and
1,1'-carbonyldiimidazole (0.44 g) and stirred for 18 hours. The
solvent was evaporated and replaced with dimethyl formamide (5 ml).
The piperidine ester Example (16c) (0.46 g) was added and the
mixture was stirred for 2 hours at 100.degree. C. The mixture was
diluted with water and extracted with ethyl acetate. The extract
was washed with brine, dried and evaporated The crude product was
chromatographed on silica gel (1:1 hexane/ethyl acetate) to give
the free base (0.25 g, 34%).
[0268] MS (+ve ion electrospray) m/z 458 (MH+).
Example 20
4-Heptylamino-4-hydroxymethyl-1-(6-methoxy-[1,5]-naphthyridine-4-yl)aminoc-
arbonylpiperidine
[0269] ##STR11##
[0270] The ester Example (19) (0.1 g)) was reduced with lithium
aluminium hydride as in Example 11. The reaction mixture was
diluted with water and extracted with ethyl acetate. The extract
was washed with water and brine, dried and evaporated. The crude
product was chromatographed on silica gel (0-1%
methanol/dichloromethane) to give the title compound (50 mg, 53%)
as a white solid.
[0271] MS (+ve ion electrospray) m/z 430 (MH+).
[0272] .sup.1H-NMR (CDCl.sub.3): .delta. 0.88(3H,t,J=7 Hz),
1.28(8H,m), 1.47(2H,m), 1.70(4H,m), 2.51(2H,t,J=7 Hz), 3.452H,s),
3.59(2H,dm,J=13 Hz), 3.73(2H,dm,J=13 Hz), 4.05(3H,s), 7.13(1H,d,J=9
Hz), 8.20(1H,d,J=9 Hz), 8.31(1H,d,J=5 Hz), 8.64(1H,d,J=5 Hz),
9.08(1H,s).
Biological Activity
[0273] The MIC (.mu.g/ml) of test compounds against various
organisms was determined: S. aureus Oxford, S. aureus WCUH29, S.
pneumoniae 1629, S. pneumoniae N1387, S. pneumoniae ERY 2.
[0274] Example 4 has an MIC of less than or equal to 1 .mu.g/ml
against one or more of the above range of gram positive and gram
negative bacteria.
* * * * *