U.S. patent application number 11/604045 was filed with the patent office on 2007-06-14 for nitrogen-containing bicycle heterocycles for use as antibacterials.
This patent application is currently assigned to SmithKline Beecham p.l.c.. Invention is credited to Gerald Brooks, David Thomas Davies, Graham Elgin Jones, Roger Edward Markwell, Neil David Pearson.
Application Number | 20070135422 11/604045 |
Document ID | / |
Family ID | 9915342 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135422 |
Kind Code |
A1 |
Brooks; Gerald ; et
al. |
June 14, 2007 |
Nitrogen-containing bicycle heterocycles for use as
antibacterials
Abstract
Cyclohexane and cyclohexene derivatives and pharmaceutically
acceptable derivatives thereof useful in methods of treatment of
bacterial infections in mammals, particularly man.
Inventors: |
Brooks; Gerald; (Harlow,
GB) ; Davies; David Thomas; (Harlow, GB) ;
Jones; Graham Elgin; (Harlow, GB) ; Markwell; Roger
Edward; (Harlow, GB) ; Pearson; Neil David;
(Harlow, 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: |
9915342 |
Appl. No.: |
11/604045 |
Filed: |
November 22, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10478154 |
Apr 6, 2004 |
7141564 |
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PCT/EP02/05708 |
May 24, 2002 |
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11604045 |
Nov 22, 2006 |
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Current U.S.
Class: |
514/224.8 ;
514/230.5; 514/300; 514/303; 544/105; 544/51; 546/118; 546/123;
556/122 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 31/00 20180101; C07D 405/12 20130101; C07D 491/04 20130101;
A61P 31/04 20180101; C07D 417/12 20130101; C07D 401/12 20130101;
C07D 513/04 20130101 |
Class at
Publication: |
514/224.8 ;
514/300; 514/303; 546/118; 556/122; 546/123; 544/051; 514/230.5;
544/105 |
International
Class: |
A61K 31/5415 20060101
A61K031/5415; A61K 31/538 20060101 A61K031/538; A61K 31/4745
20060101 A61K031/4745; C07D 471/02 20060101 C07D471/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 25, 2001 |
GB |
0112834.7 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt,
solvate or N-oxide thereof: ##STR138## wherein: one of Z.sup.1,
Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 is CR.sup.1a and the
remainder are CH; R.sup.v and R.sup.w are hydrogen; R.sup.v is
R.sup.3; or R.sup.v and R.sup.w together are a bond; R.sup.1 and
R.sup.1a are independently selected from hydrogen; hydroxy;
(C.sub.1-6) alkoxy optionally substituted by (C.sub.1-6)alkoxy,
amino, piperidyl, guanidino or amidino any of which amino,
piperidyl, guanidino or amidino is optionally N-substituted by one
or two (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy-carbonyl, formyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.1-6)alkylsulphonyl groups,
CONH.sub.2, hydroxy, (C.sub.1-6)alkylthio, heterocyclylthio,
heterocyclyloxy, arylthio, aryloxy, (C.sub.1-6)alkoxycarbonylthio,
formylthio, (C.sub.1-6)alkylcarbonylthio,
(C.sub.1-6)alkoxy-carbonyloxy, formyloxy,
(C.sub.1-6)alkylcarbonyloxy 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; trifluoromethyl; nitro;
azido; (C.sub.1-6)alkoxycarbonyl; formyl; (C.sub.1-6)alkylcarbonyl;
(C.sub.1-6)alkoxycarbonylthio; formylthio;
(C.sub.1-6)alkylcarbonylthio; (C.sub.1-6)alkoxycarbonyloxy;
formyloxy; (C.sub.1-6)alkyl carbonyloxy; (C.sub.1-6)alkylsulphonyl;
(C.sub.1-6)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an
amino, piperdinyl, guanidine or amidino group optionally
N-substituted by one or two (C.sub.1-6)alkyl,
(C.sub.1-6)alkoxycarbonyl, formyl, (C.sub.1-6)-alkylcarbonyl or
(C.sub.1-6)alkylsulphonyl groups, or when Z.sup.1 is CR.sup.1a
R.sup.1 and R.sup.1a may together represent (C.sub.1-2)
alkylenedioxy, provided that R.sup.1 is not hydrogen; or when
Z.sup.5 is CR.sup.1a, R.sup.1a may instead be cyano, hydroxymethyl
or carboxy; R.sup.2 is hydrogen, or (C.sub.1-4)alkyl or
(C.sub.2-4)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.2-4)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; halogen;
(C.sub.1-4)alkylthio; trifluoromethyl; 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; when R.sup.v
and R.sup.w are a bond, R.sup.3 is in the 2-, 3- or 4-position and
when R.sup.v and R.sup.w are not a bond, R.sup.3 is in the 1-, 2-,
3- or 4-position and R.sup.3 is: hydrogen; 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.2-6)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.2-4)alkyl or ethenyl optionally substituted with any of the
groups listed above for R.sup.3 and/or 0 to 2 groups R.sup.12
independently selected from: halogen; (C.sub.1-6)alkylthio;
trifluoromethyl; (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; or hydroxy
optionally substituted by (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.1-6)alkoxycarbonyl, (C.sub.1-.sub.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; or amino optionally mono- or
disubstituted by (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkyl-carbonyl, (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; provided that when R.sup.3
is in the 4-position it is not optionally substituted hydroxyl or
amino; in addition when R.sup.3 is disubstituted with a hydroxy or
amino containing substituent and a carboxy containing substituent
these may optionally together form a cyclic ester or amide linkage,
respectively; R.sup.10 is selected from (C.sub.1-4)alkyl and
(C.sub.2-4)alkenyl either 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.2-6)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.2-6)alkenylsulphonyl;
(C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl;
(C.sub.2-6)alkenyloxycarbonyl; and (C.sub.2-6)alkenylcarbonyl;
R.sup.4 is a group --CH.sub.2--R.sup.5.sub.1 in which R.sup.5.sub.1
is selected from: (C.sub.4-8)alkyl; hydroxy(C.sub.4-8)alkyl;
(C.sub.2-4)alkoxy(C.sub.4-8)alkyl;
(C.sub.2-4)alkanoyloxy(C.sub.4-8)alkyl;
(C.sub.3-8)cycloalkyl(C.sub.4-8)alkyl; hydroxy-, (C.sub.1-6)alkoxy-
or (C.sub.1-6)alkanoyloxy-(C.sub.3-8)cycloalkyl(C.sub.4-8)alkyl;
cyano(C.sub.4-8)alkyl; (C.sub.4-8)alkenyl; (C.sub.4-8)alkynyl;
tetrahydrofuryl; mono- or di-(C.sub.1-6)alkylamino(C.sub.4-8)alkyl;
acylamino(C.sub.4-8)alkyl; (C.sub.1-6)alkyl- or
acyl-aminocarbonyl(C.sub.4-8)alkyl; mono- or
di-(C.sub.1-6)alkylamino(hydroxy) (C.sub.4-8)alkyl; or R.sup.4 is a
group --U--R.sup.5.sub.2 where R.sup.5.sub.2 is an optionally
substituted bicyclic carbocyclic or heterocyclic ring system (A):
##STR139## containing up to four heteroatoms in each ring in which
at least one of rings (a) and (b) is aromatic; X.sup.1 is C or N
when part of an aromatic ring or CR.sup.14 when part of a non
aromatic ring; X.sup.2 is N, NR.sup.13, O, S(O).sub.x, CO or
CR.sup.14 when part of an aromatic or non-aromatic ring or may in
addition be CR.sup.14R.sup.15 when part of a non aromatic ring;
X.sup.3 and X.sup.5 are independently N or C; y.sup.1 is a 0 to 4
atom linker group each atom of which is independently selected from
N, NR.sup.13, O, S(O).sub.x, CO and CR.sup.14 when part of an
aromatic or non-aromatic ring or may additionally be
CR.sup.14R.sup.15 when part of a non aromatic ring, y.sup.2 is a 2
to 6 atom linker group, each atom of y.sup.2 being independently
selected from N, NR.sup.13, O, S(O).sub.x, CO and CR.sup.14 when
part of an aromatic or non-aromatic ring or may additionally be
CR.sup.14R.sup.15 when part of a non aromatic ring; each of
R.sup.14 and R.sup.15 is independently selected from: H;
(C.sub.1-4)alkylthio; halo; carboxy(C.sub.1-4)alkyl;
halo(C.sub.1-4)alkoxy; halo(C.sub.1-4)alkyl; (C.sub.1-4)alkyl;
(C.sub.2-4)alkenyl; (C.sub.1-4)alkoxycarbonyl; formyl;
(C.sub.1-4)alkylcarbonyl; (C.sub.2-4)alkenyloxycarbonyl;
(C.sub.2-4)alkenylcarbonyl; (C.sub.1-4)alkylcarbonyloxy;
(C.sub.1-4)alkoxycarbonyl(C.sub.1-4)alkyl; hydroxy;
hydroxy(C.sub.1-4)alkyl; mercapto(C.sub.2-4)alkyl;
(C.sub.2-4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl
optionally substituted as for corresponding substituent in R.sup.3;
(C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or
aminosulphonyl wherein the amino group is optionally substituted by
(C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; aryl; aryl(C.sub.1-4)alkyl;
aryl(C.sub.1-4)alkoxy; each R.sup.13 is independently H;
trifluoromethyl; (C.sub.1-4)alkyl optionally substituted by
hydroxy, carboxy, (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkoxy,
(C.sub.1-6)alkylthio, halo or trifluoromethyl; (C.sub.2-4)alkenyl;
aryl; aryl (C.sub.1-4)alkyl; arylcarbonyl; heteroarylcarbonyl;
(C.sub.1-4)alkoxycarbonyl; (C.sub.2-4)alkylcarbonyl; formyl;
(C.sub.1-6)alkylsulphonyl; or aminocarbonyl wherein the amino group
is optionally substituted by (C.sub.1-4)alkoxycarbonyl,
(C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl,
(C.sub.2-4)alkenylcarbonyl, (C.sub.1-4)alkyl or (C.sub.2-4)alkenyl
and optionally further substituted by (C.sub.1-.sub.4)alkyl or
(C.sub.2-4)alkenyl; each x is independently 0, 1 or 2; U is CO,
SO.sub.2 or CH.sub.2; or R.sup.4 is a group
--X.sup.1a--X.sub.2a--X.sup.3a--X.sup.4a in which: X.sup.1a is
CH.sub.2, CO or SO.sub.2; X.sup.2a is CR.sup.14aR.sup.15a; X.sup.3a
is NR.sup.13a, O, S, SO.sub.2 or CR.sup.14aR.sup.15a; wherein: each
of R.sup.14a and R.sup.15a is independently selected from the
groups listed above for R.sup.14 and R.sup.15, provided that
R.sup.14a and R.sup.15a on the same carbon atom are not both
selected from optionally substituted hydroxy and optionally
substituted amino; or R.sup.14a and R.sup.15a together represent
oxo; R.sup.13a is hydrogen; trifluoromethyl; (C.sub.1-6)alkyl;
(C.sub.2-6)alkenyl; (C.sub.1-6)alkoxycarbonyl;
(C.sub.1-6)alkylcarbonyl; or aminocarbonyl wherein the amino group
is optionally substituted 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 or (C.sub.2-6)alkenyl
and optionally further substituted by (C.sub.1-6)alkyl or
(C.sub.2-6)alkenyl; or two R.sup.14a groups or an R.sup.13a and an
R.sup.14a group on adjacent atoms together represent a bond and the
remaining R.sup.13a, R.sup.14a and R.sup.15a groups are as above
defined; or two R.sup.14a groups and two R.sup.15a groups on
adjacent atoms together represent bonds such that X.sup.2a and
X.sup.3a is triple bonded; X.sup.4a is phenyl or C or N linked
monocyclic aromatic 5- or 6-membered heterocycle containing up to
four heteroatoms selected from O, S and N and: optionally
C-substituted by up to three groups selected from
(C.sub.1-4)alkylthio; halo; carboxy(C.sub.1-4)alkyl;
halo(C.sub.1-4)alkoxy; halo(C.sub.1-4)alkyl; (C.sub.1-4)alkyl;
(C.sub.2-4)alkenyl; (C.sub.1-4)alkoxycarbonyl; formyl;
(C.sub.1-4)alkylcarbonyl; (C.sub.2-4)alkenyloxycarbonyl;
(C.sub.2-4)alkenylcarbonyl; (C.sub.1-4)alkylcarbonyloxy;
(C.sub.1-4)alkoxycarbonyl(C.sub.1-4)alkyl; hydroxy;
hydroxy(C.sub.1-4)alkyl; mercapto(C.sub.1-4)alkyl;
(C.sub.1-4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl
optionally substituted as for corresponding substituent in R.sup.3;
(C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or
aminosulphonyl wherein the amino group is optionally substituted by
(C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; aryl, aryl(C.sub.1-4)alkyl
or aryl(C.sub.1-4)alkoxy; and optionally N substituted by
trifluoromethyl; (C.sub.1-4)alkyl optionally substituted by
hydroxy, (C.sub.1-6)alkoxy, (C.sub.1-6)alkylthio, halo or
trifluoromethyl; (C.sub.2-4)alkenyl; aryl; aryl(C.sub.1-4)alkyl;
(C.sub.1-4)alkoxycarbonyl; (C.sub.1-4)alkylcarbonyl; formyl;
(C.sub.1-6)alkylsulphonyl; or aminocarbonyl wherein the amino group
is optionally substituted by (C.sub.1-4)alkoxycarbonyl,
(C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl,
(C.sub.2-4)alkenylcarbonyl, (C.sub.1-4)alkyl or (C.sub.2-4)alkenyl
and optionally further substituted by (C.sub.1-4)alkyl or
(C.sub.2-4)alkenyl; n is 0 or 1 and AB is NR.sup.11CO, CONR.sup.11,
CO--CR.sup.8R.sup.9, CR.sup.6R.sup.7--CO, O--CR.sup.8R.sup.9,
CR.sup.6R.sup.7--O, NR.sup.11--CR.sup.8R.sup.9,
CR.sup.6R.sup.7--NR.sup.11, NR.sup.11SO.sub.2,
CR.sup.6R.sup.7--SO.sub.2 or CR.sup.6R.sup.7--CR.sup.8R.sup.9,
provided that when R.sup.v and R.sup.w are a bond and n=0, B is not
NR.sup.11 , O or SO.sub.2, or n is 0 and AB is NH--CO--NH or
NH--CO--O and R.sup.v/R.sup.w are not a bond; or n is 0 and AB is
CR.sup.6R.sup.7SO.sub.2NR.sup.2, CR.sup.6R.sup.7CONR.sup.2 or
CR.sup.6R.sup.7CH.sub.2NR.sup.2 and R.sup.v/R.sup.w are not a bond;
provided that R.sup.6 and R.sup.7, and R.sup.8 and R.sup.9 are not
both optionally substituted hydroxy or amino; and wherein: each of
R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is independently selected
from: H; (C.sub.1-6)alkoxy; (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
substituent 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.2-6)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; and each R.sup.11 is independently H; trifluoromethyl;
(C.sub.1-6)alkyl; (C.sub.2-6)alkenyl; (C.sub.1-6)alkoxycarbonyl;
(C.sub.1-6)alkylcarbonyl; or aminocarbonyl wherein the amino group
is optionally substituted 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 or (C.sub.2-6)alkenyl
and optionally further substituted by (C.sub.1-6)alkyl or
(C.sub.2-6)alkenyl.
2. A compound according to claim 1 wherein Z.sup.5 is CH, Z.sup.3
is CH or CF and Z.sup.1, Z.sup.2 and Z.sup.4 are each CH.
3. A compound according to claim 1 wherein R.sup.1 is methoxy or
fluoro and R.sup.1a is H or when Z.sup.3 is CR.sup.1a it may be
C--F.
4. A compound according to claim 1 wherein R.sup.2 is hydrogen.
5. A compound according to claim 1 wherein R.sup.3 is hydrogen or
hydroxy substituted in the 1- or 3-position.
6. A compound according to claim 1 wherein n is 0 and either A is
CHOH or CH.sub.2 and B is CH.sub.2 or A is NH and B is CO, and
AB(CH.sub.2)n and NR.sup.2R.sup.4 are trans.
7. A compound according to claim 1 wherein R.sup.4 is
--U--R.sup.5.sub.2, the group --U-- is --CH.sub.2--, and
R.sup.5.sub.2 is an aromatic heterocyclic ring (A) having 8-11 ring
atoms including 2-4 heteroatoms of which at least one is N or
NR.sup.13 in which y.sup.2 contains 2-3 heteroatoms, one of which
is S and 1-2 are N, with one N bonded to X.sup.3, or the
heterocyclic ring (A) has ring (a) aromatic selected from
optionally substituted benzo and pyrido and ring (b) non-aromatic
and y.sup.2 has 3-5 atoms including a heteroatom bonded to X.sup.5
selected from NR.sup.13, O or S bonded to X.sup.5, where R.sup.13
is other than hydrogen, and NHCO bonded via N to X.sup.3, or O
bonded to X.sup.3.
8. A compound according to claim 1 wherein R.sup.5.sub.2 is
selected from: benzo[1,2,5]thiadiazol-5-yl;
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl
(4H-benzo[1,4]thiazin-3-one-6-yl)
2,3-dihydro-benzo[1,4]dioxin-6-yl; benzo[1,2,3]thiadiazol-5-yl;
3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl;
7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl;
2-oxo-2,3-dihydro-1H-pyrido[2,3-b]thiazin-7-yl;
2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl;
3-oxo-3,4-dihydro-2H-pyrido[2,3-b]oxazin-6-yl; and
[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl.
9. A compound selected from:
Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarb-
oxylic acid (8-fluoro-6-methoxy-quinolin-4-yl)-amide;
Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarb-
oxylic acid (6-methoxy-quinolin-4-yl)-amide;
Trans-4-[(Benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-cyclohexanecarboxylic
acid (6-methoxy-quinolin-4-yl)-amide;
Trans-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amin-
o]-cyclohexanecarboxylic acid (6-methoxy-quinolin-4-yl)-amide;
Trans-6-({4-[2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-cyclohexylamino-
}-methyl)-4-H-benzo[1,4]thiazin-3-one;
Trans-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}--
1-(6-methoxy-quinolin-4-yl)-ethanol;
Trans-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}--
1-(6-methoxy-quinolin-4-yl)-ethanone; Trans
4-[(3-Oxo-3,4-dihydro-2-H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohexan-
ecarboxylic acid (6-methoxy-quinolin-4-yl)-amide;
Trans-4-[(3-Oxo-3,4-dihydro-2-H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cycl-
ohexanecarboxylic acid (8-fluoro-6-methoxy-quinolin-4-yl)-amide;
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl-
)-amino]-r-cyclohexanecarboxylic acid
(2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-amide;
(1S,3S,4S)-3-Hydroxy-4-[-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiaz-
in-6-ylmethyl)-amino]-cyclohexanecarboxylic acid
(6,8-difluoro-quinolin-4-yl)-amide and
(1R,3R,4R)-3-Hydroxy-4-[-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][]1,4]thia-
zin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid
(6,8-difluoroquinolin-4-yl)-amide;
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl-
)-amino-r-cyclohexanecarboxylic acid
(8-fluoro-6-methoxy-quinolin-4-yl)-amide;
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl-
)-amino-r-cyclohexanecarboxylic acid
(6-methoxy-quinolin-4-yl)-amide;
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl-
)-amino-r-cyclohexanecarboxylic acid
(6,8-difluoro-quinolin-4-yl)-amide; and compounds of Table A, B and
C: TABLE-US-00007 TABLE A ##STR140## LINKER R NHCONH
(CH.sub.2).sub.4Me NHCONH (CH.sub.2).sub.4Me trans stereochem.
NHCONH quinoxalin-2-yl CONH quinoxalin-2-yl NHCO (CH.sub.2).sub.5Me
CH(OH)CH.sub.2NH (CH.sub.2).sub.4Me NHCOO
3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1,4]thiazin-6-yl ##STR141##
TABLE-US-00008 TABLE B ##STR142## Stereochemistry X R
1S,3S,4S/1R,3R,4R CH 3-Oxo-3,4-dihydro-2H-pyrido
[3,2-b][1,4]thiazin-6-yl ##STR143##
TABLE-US-00009 TABLE C ##STR144## X R F
2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl ##STR145## F
2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl ##STR146## H
7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl
##STR147## H 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl ##STR148##
H 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl ##STR149## OMe
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl ##STR150## F
7-Chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl
##STR151##
or a pharmaceutically acceptable salt, solvate or N-oxide of any of
the foregoing compounds.
10. 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 according to claim
1.
11. (canceled)
12. A pharmaceutical composition comprising a compound according to
claim 1, and a pharmaceutically acceptable carrier.
13. (canceled)
14. A compound of formula (VI): ##STR152## wherein the variables
R.sup.1, Z.sup.1-Z.sup.5, A, B, n, R.sup.v, R.sup.w and R.sup.3 are
as described for formula (I) in claim 1.
15. A compound of formula (VII): ##STR153## wherein the variables
R.sup.1, Z.sup.1-Z.sup.5, A, B, n, R.sup.v, R.sup.w and R.sup.3 are
as described for formula (I) in claim 1.
16. The method of claim 10 wherein the mammal is human.
Description
[0001] This invention relates to novel compounds, compositions
containing them and their use as antibacterials.
[0002] WO099/37635, WO00/21948, WO00/21952, WO00/43383, WO00/78748,
WO01/07433, WO01/07432, WO02/08224, WO02/24684 and WO01/25227
disclose quinoline and naphthyridine derivatives having
antibacterial activity.
[0003] This invention provides a compound of formula (I) or a
pharmaceutically acceptable derivative thereof: ##STR1## wherein:
[0004] one of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 is N,
one is CR.sup.1a and the remainder are CH or one of Z.sup.1,
Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 is CR.sup.1a and the
remainder are CH; [0005] R.sup.v and R.sup.w are hydrogen or
R.sup.v and R.sup.w together are a bond; [0006] R.sup.1 and
R.sup.1a are independently selected from hydrogen; hydroxy,
(C.sub.1-6) alkoxy optionally substituted by (C.sub.1-6)alkoxy,
amino, piperidyl, guanidino or amidino any of which is optionally
N-substituted by one or two (C.sub.1-6)alkyl, acyl or
(C.sub.1-6)alkylsulphonyl groups, CONH2, hydroxy,
(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; trifluromethyl; nitro;
azido; acyl; acyloxy, acylthio; (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, orwhen Z.sup.1 is CR.sup.1a,
R.sup.1 and R.sup.1a may together represent
(C.sub.1-2)alkylenedioxy, [0007] provided that when Z.sup.1,
Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 are CR.sup.1a or CH, then
R.sup.1 is not hydrogen; [0008] R.sup.2 is hydrogen or
(C.sub.1-4)alkyl or (C.sub.2-4)alkenyl optionally substituted with
1 to 3 groups selected from: [0009] 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.2-4)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; halogen;
(C.sub.1-4)alkylthio; trifluoromethyl; 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; [0010]
R.sup.3 is hydrogen; or [0011] when R.sup.v and R.sup.w are a bond,
R.sup.3 is in the 2-, 3- or 4-position and when R.sup.v and R.sup.w
are not a bond, R.sup.3 is in the 1-, 2-, 3- or 4-position and
R.sup.3 is: [0012] 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.2-6)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 [0013]
(C.sub.1-4)alkyl or ethenyl optionally substituted with any of the
groups listed above for R.sup.3 and/or 0 to 2 groups R.sup.12
independently selected from: [0014] halogen; (C.sub.1-6)alkylthio;
trifluoromethyl; (C.sub.1-6)alkoxycarbonyl;
(C.sub.1-6)alklycarbonyl; (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)alkencarbonyl; amino
optionally mono- or disubstituted 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, (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; or [0015]
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; or [0016]
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; [0017] provided that when R.sup.3 is in the 4
position it is not optionally substituted hydroxyl or amino; [0018]
in addition when R.sup.3 is disubstituted with a hydroxy or amino
containing substituent and a carboxy containing substituent these
may optionally together form a cyclic ester or amide linkage,
respectively; [0019] R.sup.10 is selected from (C.sub.1-4)alkyl and
(C.sub.2-4)alkenyl either 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.2-6)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.2-6)alkenylsulphonyl;
(C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl;
(C.sub.2-6)alkenyloxycarbonyl; and (C.sub.2-6)alkenylcarbonyl;
[0020] R.sup.4 is a group --CH.sub.2--R.sup.5.sub.1 in which
R.sup.5.sub.1 is selected from: [0021] (C.sub.4-8)alkyl;
hydroxy(C.sub.4-8)alkyl; (C.sub.1-4)alkoxy(C.sub.4-8)alkyl;
(C.sub.1-4)alkanoyloxy(C.sub.4-8)alkyl;
(C.sub.3-8)cycloalkyl(C.sub.4-8)alkyl; hydroxy-, (C.sub.1-6)alkoxy-
or (C.sub.1-6)alkanoyloxy-C.sub.3-8)cycloalkyl(C.sub.4-8)alkyl;
cyano(C.sub.4-8)alkyl; (C.sub.4-8)alkenyl; (C.sub.4-8)alkynyl;
tetrahydrofuryl; mono- or di-
(C.sub.1-6)alkylamino(C.sub.4-8)alkyl; acylamino(C.sub.1-8)alkyl;
(C.sub.1-6)alkyl- or acyl-aminocarbonyl(C.sub.4-8)alkyl; mono- or
di- (C.sub.1-6)alkylamino(hydroxy) (C.sub.4-8)alkyl; or [0022]
R.sup.4 is a group --U-R.sup.5.sub.2 where R.sup.5.sub.2 is an
optionally substituted bicyclic carbocyclic or heterocyclic ring
system (A): ##STR2## [0023] containing up to four heteroatoms in
each ring in which [0024] at least one of rings (a) and (b) is
aromatic; [0025] X.sup.1 is C or N when part of an aromatic ring or
CR.sup.14 when part of a non aromatic ring; [0026] X.sup.2 is N,
NR.sup.13, O, S(O).sub.x, CO or CR.sup.14 when part of an aromatic
or non-aromatic ring or may in addition be CR.sup.14R.sup.15 when
part of a non aromatic ring; [0027] X.sup.3 and X.sup.5 are
independently N or C; [0028] Y.sup.1 is a 0 to 4 atom linker group
each atom of which is independently selected from N, NR.sup.13, O,
S(O).sub.x, CO and CR.sup.14 when part of an aromatic or
non-aromatic ring or may additionally be CR.sup.14R.sup.15 when
part of a non aromatic ring, [0029] Y.sup.2 is a 2 to 6 atom linker
group, each atom of Y.sup.2 being independently selected from N,
NR.sup.13, O, S(O).sub.x, CO and CR.sup.14 when part of an aromatic
or non-aromatic ring or may additionally be CR.sup.14R.sup.15 when
part of a non aromatic ring; each of R.sup.14 and R.sup.15 is
independently selected from: H; (C.sub.1-4)alkylthio; halo;
carboxy(C.sub.1-4)alkyl; halo(C.sub.1-4)alkoxy;
halo(C.sub.1-4)alkyl; (C.sub.1-4)alkyl; (C.sub.2-4)alkenyl;
(C.sub.1-4)alkoxycarbonyl; formyl; (C.sub.1-4)alkylcarbonyl;
(C.sub.2-4)alkenyloxycarbonyl; (C.sub.2-4)alkenylcarbonyl;
(C.sub.1-4)alkylcarbonyl oxy,
(C.sub.1-4)alkoxycarbonyl(C.sub.1-4)alkyl; hydroxy,
hydroxy(C.sub.1-4)alkyl; mercapto(C.sub.1-4)alkyl;
(C.sub.1-4)alkoxy, nitro; cyano; carboxy, amino or aminocarbonyl
optionally substituted as for corresponding substituents in
R.sup.3; (C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or
aminosulphonyl wherein the amino group is optionally substituted by
(C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; aryl; aryl(C.sub.1-4)alkyl;
aryl(C.sub.1-4)alkoxy; [0030] each R.sup.13 is independently H;
trifluoromethyl; (C.sub.1-4)alkyl optionally substituted by
hydroxy, carboxy, (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkoxy,
(C.sub.1-6)alkylthio, halo or trifluoromethyl; (C.sub.2-4)alkenyl;
aryl; aryl (C.sub.1-4)alkyl; arylcarbonyl; heteroarylcarbonyl;
(C.sub.1-4)alkoxycarbonyl; (C.sub.1-4)alkylcarbonyl; formyl;
(C.sub.1-6)alkylsulphonyl; or aminocarbonyl wherein the amino group
is optionally substituted by (C.sub.1-4)alkoxycarbonyl,
(C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl,
(C.sub.2-4)alkenylcarbonyl, (C.sub.1-4)alkyl or (C.sub.2-4)alkenyl
and optionally further substituted by (C.sub.1-4)alkyl or
(C.sub.2-4)alkenyl; [0031] each x is independently 0, 1 or 2;
[0032] U is CO, SO.sub.2 or CH.sub.2; or [0033] R.sup.4 is a group
-X.sup.1a-X.sup.2a-X.sup.3a-X.sup.4a in which: [0034] X.sup.1a is
CH.sub.2, CO or SO.sub.2; [0035] X.sup.2a is CR.sup.14aR.sup.15a;
[0036] X.sup.3a is NR.sup.13a, O, S, SO.sub.2 or
CR.sup.14aR.sup.15a; wherein: [0037] each of R.sup.14a and
R.sup.15a is independently selected from the groups listed above
for R.sup.14 and R.sup.15, provided that R.sup.14a and R.sup.15a on
the same carbon atom are not both selected from optionally
substituted hydroxy and optionally substituted amino; or [0038]
R.sup.14a and R.sup.15a together represent oxo; [0039] R.sup.13a is
hydrogen; trifluoromethyl; (C.sub.1-6)alkyl; (C.sub.2-6)alkenyl;
(C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl; or
aminocarbonyl wherein the amino group is optionally substituted 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 or (C.sub.2-6)alkenyl and optionally furter
substituted by (C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; or [0040]
two R.sup.14a groups or an R.sup.13a and an R.sup.14a group on
adjacent atoms together represent a bond and the remaining
R.sup.13a, R.sup.14a and R.sup.15a groups are as above defined; or
[0041] two R.sup.14a groups and two R.sup.15a groups on adjacent
atoms together represent bonds such that X.sup.2a and X.sup.3a is
triple bonded; [0042] X.sup.4a is phenyl or C or N linked
monocyclic aromatic 5- or 6-membered heterocycle containing up to
four heteroatoms selected from O, S and N and: optionally
C-substituted by up to three groups selected from
(C.sub.1-4)alkylthio; halo; carboxy(C.sub.1-4)alkyl;
halo(C.sub.1-4)alkoxy, halo(C.sub.1-4)alkyl; (C.sub.1-4)alkyl;
(C.sub.2-4)alkenyl; (C.sub.1-4)alkoxycarbonyl; formyl;
(C.sub.1-4)alkylcarbonyl; (C.sub.2-4)alkenyloxycarbonyl;
(C.sub.2-4)alkenylcarbonyl; (C.sub.1-4)alkylcarbonyl oxy;
(C.sub.1-4)alkoxycarbonyl(C.sub.1-4)alkyl; hydroxy,
hydroxy(C.sub.1-4)alkyl; mercapto(C.sub.1-4)alkyl;
(C.sub.1-4)alkoxy, nitro; cyano; carboxy, amino or aminocarbonyl
optionally substituted as for corresponding substituents in
R.sup.3; (C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or
aminosulphonyl wherein the amino group is optionally substituted by
(C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; aryl, aryl(C.sub.1-4)alkyl
or aryl(C.sub.1-4)alkoxy, and [0043] optionally N substituted by
trifluoromethyl; (C.sub.1-4)alkyl optionally substituted by
hydroxy, (C.sub.1-6)alkoxy, (C.sub.1-6)alkylthio, halo or
trifluoromethyl; (C.sub.2-4)alkenyl; aryl; aryl(C.sub.1-4)alkyl;
(C.sub.1-4)alkoxycarbonyl; (C.sub.1-4)alkylcarbonyl; formyl;
(C.sub.1-6)alkylsulphonyl; or aminocarbonyl wherein the amino group
is optionally substituted by (C.sub.1-4)alkoxycarbonyl,
(C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl,
(C.sub.2-4)alkenylcarbonyl, (C.sub.1-4)alkyl or (C.sub.2-4)alkenyl
and optionally further substituted by (C.sub.1-4)alkyl or
(C.sub.2-4)alkenyl; [0044] n is 0 or 1 and AB is NR.sup.11CO,
CONR.sup.11, CO--CR.sup.8R.sup.9, CR.sup.6R.sup.7--CO,
O--CR.sup.8R.sup.9, CR.sup.6R.sup.7--O,
NHR.sup.11--CR.sup.8R.sup.9, CR.sup.6R.sup.7--NHR.sup.11,
NR.sup.11SO.sub.2, CR.sup.6R.sup.7--SO.sub.2 or
CR.sup.6R.sup.7--CR.sup.8R.sup.9, provided that when R.sup.v and
R.sup.w are a bond and n=0, B is not NR.sup.11, O or SO.sub.2, or n
is 0 and AB is NH--CO--NH or NH--CO--O and R.sup.v/R.sup.w are not
a bond; or n is 0 and AB is CR.sup.6R.sup.7SO.sub.2NR.sup.2,
CR.sup.6R.sup.7CONR.sup.2 or CR.sup.6R.sup.7CH.sub.2NR.sup.2 and
R.sup.v/R.sup.w are not a bond; [0045] provided that R.sup.6 and
R.sup.7, and R.sup.8 and R.sup.9 are not both optionally
substituted hydroxy or amino; [0046] and wherein: [0047] each of
R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is independently selected
from: H; (C.sub.1-6)alkoxy; (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.2-6)alkenyl; [0048] or R.sup.6 and R.sup.8 together
represent a bond and R
.sup.7 and R.sup.9 are as above defined; [0049] and each R.sup.11
is independently H; trifluoromethyl; (C.sub.1-6)alkyl;
(C.sub.2-6)alkenyl; (C.sub.1-6)alkoxycarbonyl;
(C.sub.1-6)alkylcarbonyl; or aminocarbonyl wherein the amino group
is optionally substituted 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 or (C.sub.2-6)alkenyl
and optionally further substituted by (C.sub.1-6)alkyl or
(C.sub.2-6)alkenyl; [0050] or where one of R.sup.3 and R.sup.6,
R.sup.7, R.sup.8 or R.sup.9 contains a carboxy group and the other
contains a hydroxy or amino group they may together form a cyclic
ester or amide linkage or where R.sup.3 contains a carboxy group
and A or B is NH they may be condensed to form a cyclic amide.
[0051] 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.
[0052] The invention also provides a pharmaceutical composition, in
particular 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.
[0053] The invention further 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 a compound of formula (I), or a
pharmaceutically acceptable derivative thereof.
[0054] In one aspect R.sup.1 and R.sup.1a do not together represent
(C.sub.1-2)alkylenedioxy, and R13 does not represent carboxy or
(C.sub.1-6)alkoxycarbonyl.
[0055] Preferably Z.sup.5 is CH or N, Z.sup.3 is CH or CF and
Z.sup.1, Z.sup.2 and Z.sup.4 are each CH, or Z.sup.1 is N, Z.sup.3
is CH or CF and Z.sup.2, Z.sup.4 and Z.sup.5 are each CH.
[0056] When R.sup.1 or R.sup.1a is substituted alkoxy it is
preferably (C.sub.2-6)alkoxy substituted by optionally
N-substituted amino, guanidino or amidino, or (C.sub.1-6)alkoxy
substituted by piperidyl. Suitable examples of R.sup.1 alkoxy
include methoxy, trifluoromethoxy, n-propyloxy, i-butyloxy,
aminoethyloxy, aminopropyloxy, aminobutyloxy, aminopentyloxy,
guanidinopropyloxy, piperidin4-ylmethyloxy, phthalimido pentyloxy
or 2-aminocarbonylprop-2-oxy. Preferably 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.
[0057] 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, fluoro, amino(C.sub.3-5)alkyloxy or
guanidino(C.sub.3-5)alkyloxy. Preferably R.sup.1a is H or F. Most
preferably R.sup.1 is methoxy or fluoro and R.sup.1a is H or when
Z.sup.3 is CR.sup.1a it may be C--F.
[0058] When Z.sup.5 is CR.sup.1a, R.sup.1a is preferably hydrogen,
cyano, hydroxymethyl or carboxy, most preferably hydrogen.
[0059] 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.2-4)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, most preferably hydrogen.
[0060] Preferred examples of R.sup.3 include hydrogen; hydroxy,
(C.sub.1-4) alkyl; ethenyl; optionally substituted
1-hydroxy-(C.sub.1-4) alkyl; optionally substituted aminocarbonyl;
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; hydroxy, 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;
--CONHCH.sub.2CONH.sub.2; 1,2-dihydroxyalkyl e.g. CH(OH)CH.sub.2OH;
CH.sub.2CN; 2-oxo-oxazolidin-5-yl;
2-oxo-oxazolidin-5-yl(C.sub.1-4alkyl); optionally substituted
hydroxy. Most preferably R.sup.3 is hydrogen or hydroxy, and if
hydroxy, most preferably substituted in the 1-or 3-position.
R.sup.3 in the 3-position preferably has R stereochemistry.
[0061] When R.sup.3 and R.sup.6, R.sup.7, R.sup.8 or R.sup.9
together form a cyclic ester or amide linkage, it is preferred that
the resulting ring is 5-7 membered. It is further preferred that
the group A or B which does not form the ester or amide linkage is
CH.sub.2.
[0062] When A is CH(OH) the R-stereochemistry is preferred.
[0063] Preferably A is NH, NCH.sub.3, CH.sub.2, CHOH, CH(NH.sub.2),
CMe) (OH) or CH(Me).
[0064] Preferably B is CH.sub.2 or CO.
[0065] Preferably n=0.
[0066] Preferably, when R.sup.v and R.sup.w are not a bond and n=1
or AB(CH.sub.2)n is NHCONH or NHCOO, AB(CH.sub.2).sub.n and
NR.sup.2R.sup.4 are cis.
[0067] Preferably, when R.sup.v and R.sup.w are not a bond and n=0
and AB is not NHCONH or NHCOO, AB(CH.sub.2).sub.n and
NR.sup.2R.sup.4 are trans.
[0068] Most preferably: n is 0 and either A is CHOH, CH.sub.2 and B
is CH.sub.2 or A is NH and B is CO.
[0069] Preferably R.sup.11 is hydrogen or (C.sub.1-4)alkyl e.g.
methyl, more preferably hydrogen.
[0070] When R.sup.4 is CH.sub.2R.sup.5.sub.1, preferably
R.sup.5.sub.1 is (C.sub.6-8)alkyl.
[0071] When R.sup.4 is a group
-X.sup.1a-X.sup.2a-X.sup.3a-X.sup.4a:
[0072] X.sup.1a is preferably CH.sub.2.
[0073] X.sup.2a is preferably CH.sub.2 or together with X.sup.3a
forms a CH.dbd.CH or C.ident.C group.
[0074] X.sup.3a is preferably CH.sub.2, O, S or NH, or together
with X.sup.2a forms a CH.dbd.CH or C.ident.C group.
[0075] Preferred linker groups -X.sup.1a-X.sup.2a-X.sup.3a- include
--(CH.sub.2).sub.2--O--, --CH.sub.2--CH.dbd.CH--,
--(CH.sub.2).sub.3--, --CH.sub.2).sub.2--NH-- or
--C.sub.2CONH--.
[0076] Monocyclic aromatic heterocyclic groups for X.sup.4a include
pyridyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, thienyl,
isoimidazolyl, thiazolyl, furanyl and imidazolyl, 2H-pyridazone,
1H-pyrid-2-one. Preferred aromatic heterocyclic groups include
pyrid-2-yl, pyrid-3-yl, thiazole-2-yl, pyrimidin-2-yl,
pyrimidin-5-yl and fur-2-yl.
[0077] Preferred substituents on heterocyclic X.sup.4a include halo
especially fluoro, trifluoromethyl and nitro.
[0078] Preferred substituents on phenyl X.sup.4a include halo,
especially fluoro, nitro, cyano, trifluoromethyl, methyl,
methoxycarbonyl and methylcarbonylamino.
[0079] Preferably X.sup.4a is 2-pyridyl, 3-fluorophenyl,
3,5-difluorophenyl or thiazol-2-yl.
[0080] Preferably R.sup.4 is --U--R.sup.5.sub.2.
[0081] The group --U-- is preferably --CH.sub.2--.
[0082] Preferably R.sup.5.sub.2 is an aromatic heterocyclic ring
(A) having 8-11 ring atoms including 2-4 heteroatoms of which at
least one is N or NR.sup.13 in which preferably Y.sup.2 contains
2-3 heteroatoms, one of which is S and 1-2 are N, with one N bonded
to X.sup.3.
[0083] Alternatively and preferably the heterocyclic ring (A) has
ring (a) aromatic selected from optionally substituted benzo and
pyrido and ring (b) non-aromatic and Y.sup.2 has 3-5 atoms
including a heteroatom bonded to X.sup.5 selected from O, S or
NR.sup.13, where R.sup.13 is other than hydrogen, and NHCO bonded
via N to X.sup.3, or O bonded to X.sup.3. Examples of rings (A)
include optionally substituted:
(a) and (b) Aromatic.
[0084] 1H-pyrrolo[2,3-b]-pyridin-2-yl,
1H-pyrrolo[3,2-b]-pyridin-2-yl, 3H-imidazo[4,5-b]-pyrid-2-yl,
3H-quinazolin-4-one-2-yl, benzimidazol-2-yl,
benzo[1,2,3]-thiadiazol-5-yl, benzo[1,2,5]-oxadiazol-5-yl,
benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl,
benzoxazol-2-yl chromen-4-one-3-yl, imidazo[1,2-a]pyridin-2-yl,
imidazo-[1,2-a]-pyrimidin-2-yl, indol-2-yl, indol-6-yl,
isoquinolin-3-yl, [1,8]-naphthyridine-3-yl,
oxazolo[4,5-b]-pyridin-2-yl, quinolin-2-yl, quinolin-3-yl,
quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl,
1,3-dioxo-isoindol-2yl, benzimidazol-2-yl, benzothiophen-2-yl,
1H-benzotriazol-5-yl, 1H-indol-5-yl, 3H-benzooxazol-2-one-6-yl,
3H-benzooxazol-2-thione-6-yl, 3H-benzothiazol-2-one-5-yl,
3H-quinazolin-4-one-2-yl, 3H-quinazolin-4-one-6-yl,
4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl, benzo[1,2,3]thiadiazol-6-yl,
benzo[1,2,5]thiadiazol-5-yl, benzo[1,4]oxazin-2-one-3-yl,
benzothiazol-5-yl benzothiazol-6-yl, cinnolin-3-yl
imidazo[1,2-a]pyridazin-2-yl, imidazo[1,2-b]pyridazin-2-yl,
pyrazole[1,5-a]pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl,
pyrazolo[1,5-a]pyrimidin-6-yl, pyrazolo[5,1-c][1,2,4]triazin-3-yl,
pyrido[1,2-a]pyrimdin-4-one-2-yl,
pyrido[1,2-a]pyrimidin-4-one-3-yl, quinazolin-2-yl, quinoxalin-6yl,
thiazolo[3,2-a]pyrimidin-5-one-7-yl, thiazolo[5,4-b]pyridin-2-yl,
thieno[3,2-b]pyridin-6-yl, thiazolo[5,4b]pyridin-6-yl,
4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl,
1-oxo-1,2-dihydro-isoquinolin-3-yl, thiazolo[4,5-b]pyridin-5-yl,
[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-1-one-3-yl
(a) is Non Aromatic. [0085] (2S)-2,3-dihydro-1H-indol-2-yl,
(2S,-2,3-dihydro-benzo[1,4]dioxine-2-yl,
3-(R,S)-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl,
3-(R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,
3-(S)-2,3dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,
2,3-dihydro-benzo[1,4]dioxan-2-yl,
3-substituted-3H-quinazolin-4-one-2-yl, (b) is Non Aromatic. [0086]
1,1,3-trioxo-1,2,3,4-tetrahydro-1 l.sup.6-benzo[1,4]thiazin-6-yl,
benzo[1,3]dioxol-5-yl, 4H-benzo[1,4]oxazin-3-one-6-yl,
2,3-dihydro-benzo[1,4]dioxin-6-yl,
2-oxo-2,3-dihydro-benzooxazol-6-yl, 4H-benzo[1,4]oxazin-3-one-6-yl
(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl),
4H-benzo[1,4]thiazin-3-one-6-yl(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-yl-
), 4H-benzo[1,4]oxazin-3-one-7-yl,
4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-yl,
5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl,
benzo[1,3]dioxol-5-yl,
2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,
2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl,
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,
2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,
2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,
2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,
6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl, 3-oxo-3,4
dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl,
2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-yl,
2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,
6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-yl,
3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,
3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,
3-substituted-3H-benzooxazol-2-one-6yl,
3-substituted-3H-benzooxazole-2-thione-6-yl,
3-substituted-3H-benzothiazol-2-one-6-yl,
2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,
3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,
3,4-dihydro-1H-quinolin-2-one-7-yl,
3,4-dihydro-1H-quinoxalin-2-one-7-yl,
6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one-2-yl,
5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl,
2-oxo-3,4-dihydro-1H-[1,8]naphthyridin-6-yl.
[0087] R.sup.13 is preferably H if in ring (a) or in addition
(C.sub.1-4)alkyl such as methyl or isopropyl when in ring (b). More
preferably, in ring (b) R.sup.13 is H when NR.sup.13 is bonded to
X.sup.3 and (C.sub.1-4)alkyl when NR.sup.13 is bonded to
X.sup.5.
[0088] R.sup.14 and R.sup.15 are preferably independently selected
from hydrogen, halo, hydroxy, (C.sub.1-4) alkyl, (C.sub.1-4)alkoxy,
trifluoromethoxy, nitro, cyano, aryl(C.sub.1-4)alkoxy and
(C.sub.1-4)alkylsulphonyl.
[0089] More preferably R.sup.15 is hydrogen.
[0090] More preferably each R.sup.14 is selected from hydrogen,
chloro, fluoro, hydroxy, methyl, methoxy, trifluoromethoxy,
benzyloxy, nitro, cyano and methylsulphonyl. Most preferably
R.sup.14 is selected from hydrogen, hydroxy, fluorine or nitro.
Preferably 0-3 groups R.sup.14 are substituents other than
hydrogen.
[0091] Most preferably R.sup.14 and R.sup.15 are each H.
[0092] Most preferred groups R.sup.5.sub.2 include: [0093]
[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl [0094]
1H-Pyrrolo[2,3-b)pyridin-2-yl [0095]
2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl [0096]
2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl [0097]
2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl [0098]
2,3-dihydro-benzo[1,4]dioxin-6-yl [0099]
2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl [0100]
2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl [0101]
3,4-dihydro-2H-benzo[1,4]oxazin-6-yl [0102]
3-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl [0103]
3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl [0104]
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl [0105]
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl(4H-benzo[1,4]thiazin-3-one6-y-
l) [0106] 4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl [0107]
6-nitro-benzo[1,3]dioxol-5-yl [0108]
7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl [0109]
8-Hydroxy-1-oxo-1,2-dihydro-isoquinolin-3-yl [0110]
8-hydroxyquinolin-2-yl [0111] benzo[1,2,3]thiadiazol-5-yl [0112]
benzo[1,2,5]thiadiazol-5-yl [0113] benzothiazol-5-yl [0114]
thiazolo-[5,4-b]pyridin-6-yl [0115]
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl [0116]
7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl [0117]
7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl [0118]
2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl [0119]
especially [0120] benzo[1,2,5]thiadiazol-5-yl [0121]
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl(4H-benzo[1,4]thiazin-3-one-6--
yl) [0122] 2,3-dihydro-benzo[1,4]dioxin-6-yl [0123]
benzo[1,2,3]thiadiazol-5-yl [0124]
3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl [0125]
7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl [0126]
2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4)thiazin-7-yl [0127]
2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl [0128]
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl [0129]
[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl [0130]
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl [0131]
7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl [0132]
7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl [0133]
2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl [0134] most
especially [0135]
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl [0136]
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl [0137]
7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b](1,4]thiazin-6-yl [0138]
7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl [0139]
2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4)thiazin-7-yl.
[0140] 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.
[0141] Halo or halogen includes fluoro, chloro, bromo and iodo.
[0142] Haloalkyl moieties include 1-3 halogen atoms.
[0143] Unless otherwise defined, 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 C-substituted by, for example, up to three groups selected from
(C.sub.1-4)alkylthio; halo; carboxy(C.sub.1-4)alkyl;
halo(C.sub.1-4)alkoxy, halo(C.sub.1-4)alkyl; (C.sub.1-4)alkyl;
(C.sub.2-4)alkenyl; (C.sub.1-4)alkoxycarbonyl; formyl;
(C.sub.1-4)alkylcarbonyl; (C.sub.2-4)alkenyloxycarbonyl;
(C.sub.2-4)alkenylcarbonyl; (C.sub.1-4)alkylcarbonyloxy;
(C.sub.1-4)alkoxycarbonyl(C.sub.1-4)alkyl; hydroxy,
hydroxy(C.sub.1-4)alkyl; mercapto(C.sub.1-4)alkyl;
(C.sub.1-4)alkoxy; nitro; cyano; carboxy, amino or aminocarbonyl
optionally substituted as for corresponding substituents in
R.sup.3; (C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or
aminosulphonyl wherein the amino group is optionally substituted by
(C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; optionally substituted aryl
aryl(C.sub.1-4)alkyl or aryl(C.sub.1-4)alkoxy 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.
[0144] 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 H;
trifuoromethyl; (C.sub.1-4)alkyl optionally substituted by hydroxy,
(C.sub.1-6)alkoxy, (C.sub.1-6)alkylthio, halo or triluoromethyl;
(C.sub.2-4)alkenyl; aryl; aryl (C.sub.1-4)alkyl;
(C.sub.1-4)alkoxycarbonyl; (C.sub.1-4)alkylcarbonyl; formyl;
(C.sub.1-6)alkylsulphonyl; or aminocarbonyl wherein the amino group
is optionally substituted by (C.sub.1-4)alkoxycarbonyl,
(C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl,
(C.sub.2-4)alkenylcarbonyl, (C.sub.1-4)alkyl or (C.sub.2-4)alkenyl
and optionally further substituted by (C.sub.1-4)alkyl or
(C.sub.2-4)alkenyl.
[0145] When used herein the term `aryl`, includes phenyl and
naphthyl each optionally substituted with up to five, preferably up
to three, groups selected from(C.sub.1-4)alkylthio; halo;
carboxy(C.sub.1-4)alkyl; halo(C.sub.1-4)alkoxy,
halo(C.sub.1-4)alkyl; (C.sub.1-4)alkyl; (C.sub.2-4)alkenyl;
(C.sub.1-4)alkoxycarbonyl; formyl; (C.sub.1-4)alkylcarbonyl;
(C.sub.2-4)alkenyloxycarbonyl; (C.sub.2-4)alkenylcarbonyl;
(C.sub.1-4)alkylcarbonyloxy,
(C.sub.1-4)alkoxycarbonyl(C.sub.1-4)alkyl; hydroxy,
hydroxy(C.sub.1-4)alkyl; mercapto(C.sub.1-4)alkyl;
(C.sub.1-4)alkoxy, nitro; cyano, carboxy, amino or aminocarbonyl
optionally substituted as for corresponding substituents in
R.sup.3; (C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or
aminosulphonyl wherein the amino group is optionally substituted by
(C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; phenyl,
phenyl(C.sub.1-4)alkyl or phenyl(C.sub.1-4)alkoxy.
[0146] The term `acyl` includes (C.sub.1-6)alkoxycarbonyl, formyl
or (C.sub.1-6) alkylcarbonyl groups.
[0147] Some of the compounds of this invention may be crystallised
or recrystallised from solvents such as aqueous and organic
solvents. In such cases solvates maybe 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.
[0148] Since the compounds of formula (I) are intended for use in
pharmaceutical compositions it will readily be understood that they
are each 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.
[0149] Pharmaceutically acceptable derivatives of the
above-mentioned compounds of formula (I) include the free base form
or their acid addition or quaternary ammonium salts, for example
their salts with mineral acids e.g. hydrochloric, hydrobromic,
sulphuric nitric or phosphoric acids, or organic acids, e.g.
acetic, fumaric, succinic, maleic, citric, benzoic,
p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or
tartaric acids. Compounds of formula (I) may also be prepared as
the N-oxide. Compounds of formula (I) having a free carboxy group
may also be peared as an in vivo hydrolysable ester. The invention
extends to all such derivatives.
[0150] Examples of suitable pharmaceutically acceptable in vivo
hydrolysable ester-forming groups include those forming esters
which break down readily in the human body to leave the parent acid
or its salt Suitable groups of this type include those of part
formulae (i), (ii), (iii), (iv) and (v): ##STR3##
[0151] wherein R.sup.a is hydrogen, (C.sub.1-6) alkyl, (C.sub.3-7)
cycloalkyl, methyl, or phenyl, R.sup.b is (C.sub.1-6) alkyl,
(C.sub.1-6) alkoxy, phenyl, benzyl, (C.sub.3-7) cycloalkyl,
(C.sub.3-7) cycloalyloxy, (C.sub.1-6) alkyl (C.sub.3-7) cycloalkyl,
1-amino (C.sub.1-6) alkyl, or 1-(C.sub.1-6 alkyl)amino (C.sub.1-6)
alkyl; or R.sup.a and R.sup.b together form a 1,2-phenylene group
optionally substituted by one or two methoxy groups; R.sup.c
represents (C.sub.1-6) alkylene optionally substituted with a
methyl or ethyl group and R.sup.d and R.sup.e independently
represent (C.sub.1-6) alkyl; R.sup.f represents (C.sub.1-6) alkyl;
R.sup.g represents hydrogen or phenyl optionally substituted by up
to three groups selected from halogen, (C.sub.1-6) alkyl, or
(C.sub.1-6) alkoxy, Q is oxygen or NH; R.sup.h is hydrogen or
(C.sub.1-6) alkyl; R.sup.i is hydrogen, (C.sub.1-6) alkyl
optionally substituted by halogen, (C.sub.2-6) alkenyl, (C.sub.1-6)
alkoxycarbonyl, aryl or heteroaryl; or R.sup.h and R.sup.i together
form (C.sub.1-6) alkylene; R.sup.j represents hydrogen, (C.sub.1-6)
alkyl or (C.sub.1-6) alkoxycarbonyl; and R.sup.k represents
(C.sub.1-8) alkyl, (C.sub.1-8) alkoxy, (C.sub.1-6)
alkoxy(C.sub.1-6)alkoxy or aryl.
[0152] 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-(cyclohexylcabonyloxy)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.
[0153] A further suitable pharmaceutically acceptable in vivo
hydrolysable ester-forming group is that of the formula:
##STR4##
[0154] wherein R.sup.k is hydrogen, C.sub.1-6 alkyl or phenyl.
[0155] R is preferably hydrogen.
[0156] Certain of the above-mentioned 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 examples 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.
[0157] In a further aspect of the invention there is provided a
process for preparing compounds of formula (I), or a
pharmaceutically acceptable derivative thereof, which process
comprises reacting a compound of formula (M) with a compound of
formula (V): ##STR5## [0158] wherein n is as defined in formula
(I); Z.sup.1', Z.sup.2', Z.sup.3', Z.sup.4', Z.sup.5', R.sup.1' and
R.sup.3' are Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, Z.sup.5, R.sup.1
and R.sup.3 as defined in formula (I) or groups convertible
thereto; R.sup.v and R.sup.w are as defined in formula (I); [0159]
Q.sup.1 is NR.sup.2'R.sup.4' or a group convertible thereto wherein
R.sup.2' and R.sup.4' are R.sup.2 and R.sup.4 as defined in formula
(I) or groups convertible thereto and Q.sup.2 is H or R.sup.3' or
Q.sup.1 and Q.sup.2 together form an optionally protected oxo
group; [0160] and X and Y may be the following combinations: [0161]
(i) one of X and Y is CO.sub.2R.sup.y and the other is
CH.sub.2CO.sub.2R.sup.x; [0162] (ii) X is CHR.sup.6R.sup.7 and Y is
C(.dbd.O)R.sup.9; [0163] (iii) X is CR.sup.7.dbd.PR.sup.z.sub.3 and
Y is C(.dbd.O)R.sup.9; [0164] (iv) X is C(.dbd.O)R.sup.7 and Y is
CR.sup.9.dbd.PR.sup.z.sub.3; [0165] (v) one of Y and X is COW and
the other is NHR.sup.11', NCO or NR11'COW; [0166] (vi) X is
NHR.sup.11' and Y is C(.dbd.O)R.sup.8 or X is C(.dbd.O)R.sup.6 and
Y is NHR.sup.11'; [0167] (vii) X is NHR.sup.11' and Y is
CR.sup.8R.sup.9W; [0168] (viii) X is W or OH and Y is CH.sub.2OH;
[0169] (ix) X is NHR.sup.11' and Y is SO.sub.2W; [0170] (x) one of
X and Y is (CH.sub.2).sub.p--W and the other is
(CH.sub.2).sub.qNHR.sup.11', (CH.sub.2).sub.qOH, (CH.sub.2).sub.qSH
or (CH.sub.2).sub.qSCOR.sup.x where p+q=1; [0171] (xi) one of X and
Y is OH and the other is --CH=N.sub.2; [0172] (xii) X is NCO and Y
is OH or NH.sub.2; [0173] (xiii) X is CR.sup.6R.sup.7SO.sub.2W,
A'COW, CR.sup.6.dbd.CH.sub.2 or oxirane and Y is NHR.sup.2'; [0174]
(xiv) X is W and Y is CONHR.sup.11 or OCONH.sub.2 [0175] (xv) X is
W and Y is --C.ident.CH followed by hydrogenation of the
intermediate --C.ident.C-- group; [0176] in which W is a leaving
group, e.g. halo, methanesulphonyloxy, [0177]
trifluoromethanesulphonyloxy or imidazolyl; 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: ##STR6## [0178] wherein
R.sup.6, R.sup.8 and R.sup.9 are as defined in formula (I); [0179]
and thereafter optionally or as necessary converting Q.sup.1 and
Q.sup.2 to NR.sup.2'R.sup.4'; converting A', Z.sup.1', Z.sup.2',
Z.sup.3', Z.sup.4', Z.sup.5', R.sup.1', R.sup.2', R.sup.3',
R.sup.4' and NR.sup.11' to A, Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4,
Z.sup.5, 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.v, R.sup.w,
R.sup.1, R.sup.2, R.sup.3 and/or R.sup.4, and/or forming a
pharmaceutically acceptable derivative thereof.
[0180] Process variant (i) initially produces compounds of formula
(I) wherein A-B is CO--CH.sub.2 or CH.sub.2--CO.
[0181] Process variant (ii) initially produces compounds of formula
(I) wherein A-B is CR.sup.6R.sup.7--CR.sup.9OH.
[0182] Process variant (ii) and (iv) initially produce compounds of
formula (I) wherein A-B is CR.sup.7.dbd.CR.sup.9.
[0183] Process variant (v) initially produces compounds of formula
(I) where A-B is CO--NR.sup.11 or NR.sup.11--CO.
[0184] Process variant (vi) initially produces compounds of formula
(I) wherein A-B is NR.sup.11--CHR.sup.8. or
CHR.sup.6--NHR.sup.11.
[0185] Process variant (vii) initially produces compounds of
formula (I) wherein A-B is NR.sup.11'--CR.sup.8R.sup.9.
[0186] Process variant (viii) initially produces compounds of
formula (I) wherein A-B is O--CH.sub.2.
[0187] Process variant (ix) initially produces compounds where AB
is NR.sup.11SO.sub.2.
[0188] Process variant (x) initially produces compounds of formula
(I) wherein one of A and B is CH.sub.2 and the other is NHR.sup.11,
O or S.
[0189] Process variant (xi) initially produces compounds of formula
(I) wherein A-B is OCH.sub.2 or CH.sub.2O.
[0190] Process variant (xii) initially produces compounds where AB
is NH--CO--NH or NH--CO--O.
[0191] Process variant (xiii) initially produces compounds where n
is 0 and AB is CR.sup.6R.sup.7SO.sub.2NR.sup.2, A'-CONR.sup.2 or
CR.sup.6R.sup.7CH.sub.2NR.sup.2.
[0192] Process variant (xiv) produces compounds where AB is
NR.sup.11CO or NH--CO--O.
[0193] Process variant (xv) produces compounds where AB is
--CH.sub.2CH.sub.2-- or --CH.dbd.CH--.
[0194] In process variants (v) and (xiii) (second variant) the
reaction is a standard amide or urea formation reaction involving
e.g.: [0195] 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
amine are preferably reacted in the presence of an activating agent
such as 1-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC) or 1-hydroxybenzotriazole (HOBT) or
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU); or 2. The specific methods of: [0196]
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) [0197] 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).
[0198] A' may be, for example. protected hydroxymethylene.
[0199] The process variant (xiii) (third variant) 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.
[0200] In process variant (xiii) (fourth variant) 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) or
more preferably with ytterbium trifiate in dichloromethane. In some
cases an elevated temperature such as 40-70.degree. C. may be
beneficial. Alternatively, the compound of formula (V) 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 tetrahydrofiuran, 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.
[0201] The process variant (xii) is a standard urea or carbamate
formation reaction from the reaction of an isocyanate with an amine
or alcohol 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), p 802-3). The process is
preferably carried out in a polar solvent such as
N,N-dimethylformamide.
[0202] In process variant (i) 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 HCI 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.
[0203] In process variant (ii) 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) J. Am. Chem. Soc.
100, 576).
[0204] In process variants (iii) and (iv) 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.
[0205] In process variant (vi) the reaction is a standard reductive
alkylation using, e.g., sodium borohydride or sodium
triacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents
for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons,
1995), p 4649).
[0206] The process variant (vii) is a standard alkylation reaction
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), p 364-366 and p 342-343).
The process is preferably carried out in a polar solvent such as
N,N-dmethylformamide
[0207] In process variant (xiii) (first variant) 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.
[0208] In process variant (viii) where X is W such as halogen,
methanesulphonyloxy or trifluoromethanesulphonyloxy, the hydroxy
group in Y is preferably converted to an OM group where M is an
alkali metal by treatment of an alcohol with a base. The base is
preferably inorganic such as NaH, lithium diisopropylamide or
sodium. Where X is OH, the hydroxy group in Y is activated under
Mitsunobu conditions (Fletcher et. al. J Chem Soc. (1995), 623).
Alternatively the X=O and Y=CH.sub.2OH groups can be reacted
directly by activation with 1,3-dicyclohexylcarbodiimide (DCC)
(Chem. Berichte 1962, 95, 2997 or Angewante Chemie 1963 75,
377).
[0209] In process variant (ix) the reaction is conducted in the
presence of an organic base such as triethylanine or pyridine such
as described by Fuhrman et. al., J. Amer. Chem. Soc.; 67, 1245,
1945. The X=NR.sup.11'SO.sub.2W or Y=SO.sub.2W intermediates can be
formed from the requisite amine e.g. by reaction with
SO.sub.2Cl.sub.2 analogously to the procedure described by the same
authors Fubrman et. al., J. Amer. Chem. Soc.; 67, 1245, 1945.
[0210] In process variant (x) where one of X and Y contains
NHR.sup.11 the leaving group W is halogen and the reaction is a
standard amine formation reaction such as direct alkylation
described in (Malpass, J. R., in Comprehensive Organic Chemistry,
Vol. 2 (Ed. Sutherland, I. O. ), p 4 ff.) or aromatic nucleophilic
displacement reactions (see references cited in Comprehensive
Organic Chemistry, Vol. 6, p 946-947 (reaction index); Smith, D. M.
in Comprehensive Organic Chemistry, Vol. 4 (Ed. Sammes, P. G.) p 20
ff.). This is analogous to the methods described in GB 1177849.
[0211] In process variant (x) where one of X and Y contains OH or
SH, this is preferably converted to an OM or SM group where M is an
alkali metal by treatment of an alcohol, thiol or thioacetate with
a base. The base is preferably inorganic such as NaH, lithium
diisopropylamide or sodium, or, for SH, metal alkoxide such as
sodium methoxide. The X/Y group containing the thioacetate
SCOR.sup.x is prepared by treatment of an alcohol or alkyl halide
with thioacetic acid or a salt thereof under Mitsunobu conditions.
The leaving group V is a halogen. The reaction may be carried out
as described in Chapman et. al., J. Chem Soc., (1956), 1563,
Gilligan et. al., J. Med. Chem., (1992), 35, 4344, Aloup et al., J.
Med. Chem. (1987), 30, 24, Gilman et al., J. A. C. S. (1949), 71,
3667 and Clinton et al., J. A. C. S. (1948), 70, 491, Barluenga et
al., J. Org. Chem. (1987) 52, 5190. Alternatively where X is OH and
Y is CH.sub.2V, V is a hydroxy group activated under Mitsunobu
conditions (Fletcher et. al. J Chem Soc. (1995), 623).
[0212] In process variant (xi) the reaction is as described in den
Hertzog et. al., recl. Trav. Chim. Pays-Bas, (1950), 69, 700.
[0213] In process variant (xiv) the leaving group W is preferably
chloro, bromo or trifluoromethylsulphonyl and the reaction is the
palladium catalysed process known as the "Buchwald" reaction (J.
Yin and S. L. Buchwald, Org. Lett., 2000, 2, 1101).
[0214] In process variant (xv) coupling of the acetylene compound
(V) with the compound (IV) is accomplished using standard
Pd-mediated chemistry, for example using
Pd(Ph.sub.3P).sub.2Cl.sub.2 as the catalyst along with the addition
of Cul in a mixture of triethylamine and dimethylformamide.
Hydrogenation of the intermediate --C.ident.C-- group is carried
out conventionally over a suitable catalyst eg Pd/C, either
partially to --CH.dbd.CH-- or fully to --CH.sub.2--CH.sub.2--.
[0215] Reduction of a carbonyl group A or 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
aluminium hydride in ethereal solution. This is analogous to
methods described in EP53964, U.S. Pat. No. 384,556 and J.
Gutzwiller et al, J Amer. Chem. Soc., 1978, 100, 576.
[0216] The carbonyl group A or 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.
[0217] Reaction of a carbonyl group A or B with an organometallic
reagent yields a group where R.sup.6 or R.sup.8 is OH and R.sup.7
or R.sup.9 is alkyl.
[0218] 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.
[0219] A hydroxyalkyl A-B group CHR.sup.7CR.sup.9OH or
CR.sup.7(OH)CHR.sup.9 may be dehydrated to give the group
CR.sup.7.dbd.CR.sup.9 by treatment with an acid anhydride such as
acetic anhydride.
[0220] Methods for conversion of CR.sup.7.dbd.CR.sup.9 by reduction
to CHR.sup.7CHR.sup.9 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.7.dbd.CR.sup.9 to give
the A-B group CR.sup.7(OH)CHR.sup.9 or CHR.sup.7CR.sup.9OH are well
known to those skilled in the art for example by epoxidation and
subsequent reduction by metal hydrides, hydration, hydroboration or
oxymercuration. Where R.sup.v and R.sup.w together represent a bond
it will be appreciated that such conversions may be
inappropriate.
[0221] An amide carbonyl group may be reduced to the corresponding
amine using a reducing agent such as lithium aluminium hydride.
[0222] 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.
[0223] An example of a group Q.sup.1 convertible to NR.sup.2
R.sup.4 is NR.sup.2'R.sup.4' or halogen. Halogen may be displaced
by an amine HNR2'R.sup.4' by a conventional alkylation.
[0224] When Q.sup.1 Q.sup.2 together form a protected oxo group
this may be an acetal such as ethylenedioxy which can subsequently
be removed by acid treatment to give a compound of formula (VI):
##STR7## wherein the variables are as described for formula (I)
[0225] Intermediates of formula (VI) are novel and as such form
part of the invention.
[0226] The ketone of formula (VI) is reacted with an amine
HNR.sup.2'R.sup.4' by conventional reductive alkylation as
described above for process variant (x).
[0227] Other novel intermediates of the invention are compounds of
formula (V): ##STR8## wherein the variables are as described for
formula (I). Examples of groups Z.sup.1', Z.sup.2', Z.sup.3',
Z.sup.4', Z.sup.5', are CR.sup.1a' where R.sup.1a' is a group
convertible to R.sup.1a, Z.sup.1', Z.sup.2', Z.sup.3', Z.sup.4' and
Z.sup.5' are preferably Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and
Z.sup.5.
[0228] R.sup.1a', R.sup.1' and R.sup.2' are preferably R.sup.1a,
R.sup.1 and R.sup.2. R.sup.1' is preferably methoxy. R.sup.2' is
preferably hydrogen. R.sup.3' is R.sup.3 or more preferably
hydrogen, vinyl, alkoxycarbonyl or carboxy. R.sup.4' is R.sup.4 or
more preferably H or an N-protecting group such as
t-butoxycarbonyl, benzyloxycarbonyl or
9-fluorenylmethyloxycarbonyl.
[0229] Conversions of R.sup.1a', R.sup.1', R.sup.2', R.sup.3' and
R.sup.4' and interconversions of R.sup.1a, R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are conventional. In compounds which contain an
optionally substituted hydroxy group, suitable conventional hydroxy
protecting groups which may be removed without disrupting the
remainder of the molecule include acyl and alkylsilyl groups. N
protecting groups are removed by conventional methods.
[0230] 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. (1973) J. Amer. Chem. Soc.,
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.
[0231] 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.
[0232] R.sup.3 1,2-dihydroxy 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).
[0233] 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.
[0234] Opening an epoxide R.sup.3' group with cyanide anion yields
a CH(OR)--CH.sub.2CN group.
[0235] 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.
[0236] 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 tto a leaving
group and substitution by the required group, hydrolysis 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
alkyated with a suitable agent such as an organometallic reagent to
give a secondary or tertiary alcohol as appropriate. A carboxylate
group may be converted to an hydroxymethyl group by reduction of an
ester of this acid with a suitable reducing agent such as lithium
aluminium hydride.
[0237] 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.
[0238] Carboxy groups within R.sup.3 may be prepared by Jones'
oxidation of the corresponding alcohols CH.sub.2OH using chromic
acid and sulphuric acid in waterlmethanol (E. R. S. Jones et al,
J.C.S. 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-pyxidine (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 Letters, 1988, 29(3), 277.
[0239] The carboxy group may alternatively be formed in a two stage
process, with an initial oxidation of the alcohol to the
corresponding aldehyde using for instance dimethyl sulphoxide
activated with oxalyl chloride (N. Cohen et al, J. Am. Chem. Soc.,
1983, 105, 3661) or dicyclohexylcarbodiimide (R. M. Wengler, Angew.
Chim. Int. Ed. Eng., 1985, 24(2), 77), or oxidation with
tetrapropylammonium perruthenate (Ley et al, J. Chem. Soc. Chem
Commun., 1987, 1625). The aldehyde may then be separately oxidised
to the corresponding acid using oxidising agents such as silver
(II) oxide (R. Grigg et al, J. Chem. Soc. Perkin1, 1983, 1929),
potassium permanganate (A. Zurcher, Helv. Chim. Acta, 1987, 70 (7),
1937), sodium peniodate catalysed by ruthenium trichloride (T.
Sakata et al, Bull. Chem. Soc. Jpn., 1988, 61(6), 2025), pyridinium
chlorochromate (R. S. Reddy et al, Synth. Commun., 1988, 18(51),
545) or chromium trioxide (R. M. Coates et al, J. Am. Chem. Soc.,
1982, 104, 2198).
[0240] An R.sup.3 CO.sub.2H group may also be prepared from
oxidative cleavage of the corresponding diol, CH(OH)CH.sub.2OH,
using sodium periodate catalysed by ruthenium trichloride with an
acetonitrile-carbontetrachloride-water solvent system (V. S. Martin
et al, Tetrahedron Letters, 1988, 29(22), 2701).
[0241] R.sup.3 groups containing a cyano or carboxy group may also
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). Finally acidic
hydrolysis of the nitrile group gives the desired acids (H.
Rosemeyer et al, Heterocycles, 1985, 23 (10), 2669). The hydrolysis
may also be carried out with base e.g. potassium hydroxide (H.
Rapoport, J. Org. Chem., 1958, 23, 248) or enzymatically (T. Beard
et al, Tetrahedron Asymmetry, 1993, 4 (6), 1085).
[0242] Other functional groups in R.sup.3 may be obtained by
conventional conversions of carboxy or cyano groups.
[0243] 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).
[0244] The 3-hydroxy-3-cyclobutene-1,2-dion-4-yl group (e.g. R. M.
Soll, 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 R3 is (CH.sub.2).sub.nCHO
(n=0,1,2) is treated with triethylamine, carbon
tetrabromide/triphenylphosphine to give initially
(CH.sub.2).sub.nCH.dbd.CBr.sub.2; (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 Letters, 1994, 35 (21), 3529); (3)
palladium-catalysed coupling of the bromoethyne with
4-(1-methylethoxy)-3-(tri-n-butylstamnyl)cyclobut-3-ene-1,2-dione
(Liebeslind et al, J. Org. Chem., 1990, 55, 5359); (4) reduction of
the ethyne moity to --CH2CH2-- 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).
[0245] The tetazol-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).
[0246] 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).
[0247] The hydroxamic acid groups are prepared from the
corresponding acids by standard amide coupling reactions eg N. R.
Patel et al, Tetrahedron, 1987, 43 (22), 5375
[0248] 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.
[0249] The preparation of 5-oxo-1,2,4-oxadiazoles from nitriles is
decribed by Y. Kohara et al, Bioorg. Med. Chem. Lett., 1995, 5(17),
1903.
[0250] 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 p 762, 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).
[0251] The cyclohexylamine or cyclohexenylamine NH.sub.2 is
converted to NR.sup.2R.sup.4 by conventional means such as amide or
sulphonamide formation with an acyl derivative for compounds where
U or X.sup.1a is CO or SO.sub.2 or, where R.sup.4 is
--CH.sub.2R.sup.5.sub.1 or U or X.sup.1a is CH.sub.2, by alkylation
with an alkyl halide or other alkyl derivative R.sub.4--W in the
presence of base, acylation/reduction or reductive alkylation with
an aldehyde.
[0252] Where one of R.sup.3 and R.sup.6, R.sup.7, R.sup.8 or
R.sup.9 contains a carboxy group and the other contains a hydroxy
or amino group they may together form a cyclic ester or amide
linkage. This linkage may form spontaneously during coupling of the
compounds of formulae (IV) and (V) or in the presence of standard
peptide coupling agents.
[0253] It will be appreciated that under certain circumstances
interconvertions may interfere, for example, hydroxy groups in A or
B and the cyclohexyl- or cyclohexenylamine will require protection
e.g. as a carboxy- or silyl-ester group for hydroxy and as an acyl
derivative for nitrogen, during conversion of R.sup.1a', R.sup.1',
R.sup.2', R.sup.3' or R.sup.4', or during the coupling of the
compounds of formulae (IV) and (V).
[0254] Compounds of formulae (IV) and (V) are known compounds, (see
for example Smith et al, J. Amer. Chem. Soc., 1946, 68, 1301) or
prepared analogously, see for example the references cited
above.
[0255] 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.
[0256] 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)].
[0257] 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).
[0258] 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.
[0259] 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-bromo-substituent may be prepared from the quinolin- or
naphthyridin-4-one by reaction with phosphorus tribromide (PBr3) in
DMF. 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.
[0260] Activated carboxy derivatives X.dbd.A'COW of formula (IV)
may be prepared from X.dbd.A'CO.sub.2H derivatives in turn prepared
from CO.sub.2H derivatives by conventional methods such as
homologation.
[0261] 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 maybe prepared
by standard routes as described by T. A. Williamson in Heterocyclic
Compounds, 6, 324 (1957) Ed. R. C. Elderfield. These 4-carboxy
derivatives may be activated by conventional means, e.g. by
conversion to an acyl halide or anhydride.
[0262] 4-Carboxy derivatives such as esters may be reduced to
hydroxymethyl derivatives with for example lithium aluminium
hydride. Reaction with mesyl chloride and triethylamine would give
the mesylate derivative. A diazo compound (X is --CH.dbd.N.sub.2)
may be prepared from the 4-carboxaldehyde via the tosyl hydrazone.
The 4-carboxaldehyde may be obtained from from the acid by standard
procedures well known to those skilled in the art.
[0263] 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.
[0264] Alternatively and preferably, 4-oxirane derivatives can be
prepared from bromomethyl ketones which can be obtained from
4-hydroxy compounds by other routes well known to those skilled in
the art. For example, hydroxy compounds can be converted to the
corresponding 4-trifluoromethanesulphonates by reaction with
trifluoromethanesulphonic anhydride under standard conditions (see
K. Ritter, Synthesis, 1993, 735). Conversion into the corresponding
butyloxyvinyl ethers can be achieved by a Heck reaction with butyl
vinyl ether under palladium catalysis according to the procedure of
W. Cabri et al, J. Org. Chem, 1992, 57 (5), 1481. (Alternatively,
the equivalent intermediates can be attained by Stille coupling of
the trifluoromethanesulphonates or the analaogous chloro
derivatives with (1-ethoxyvinyl)tributyl tin, (T. R. Kelly, J. Org.
Chem., 1996, 61, 4623.) The alkyloxyvinyl ethers are then converted
into the corresponding bromomethylketones by treatment with
N-bromosuccinimide in aqueous tetrahydrofuran in a similar manner
to the procedures of J. F. W. Keana, 3. Org. Chem., 1983, 48, 3621
and T. R. Kelly, J. Org. Chem., 1996, 61, 4623.
[0265] The 4-hydroxyderivatives can be prepared from an
aminoaromatic by reaction with methylpropiolate and subsequent
cyclisation, analogous to the method described in N. E. Heindel et
al, J. Het. Chem., 1969, 6, 77. For example, 5-amino-2-methoxy
pyridine can be converted to 4-hydroxy-6-methoxy-[1,5]naphthyrdine
using this method.
[0266] 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%).
[0267] The (R)-epoxide, when reacted with an amine derivative gives
ethanolamine compounds as single diastereomers with
(R)-stereochemistry at the benzylic position.
[0268] Alternatively, the epoxide may be prepared from the
4carboxaldehyde 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.
[0269] Pyidazines may be prepared by routes analogous to those
described in Comprehensive Heterocyclic Chemistry, Volume 3, Ed A.
J. Boulton and A. McKillop and napthyridines may be prepared by
routes analogous to those described in Comprehensive Heterocyclic
Chemistry, Volume 2, Ed A. J. Boulton and A. McKillop.
[0270] 4-Hydroxy-1,5-naphthyridines can be prepared from
3-aminopyridine derivatives by reaction with diethyl
ethoxymethylene malonate 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, J. 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, or to the
4-methanesulphonyloxy or 4-trifluoromethanesulphonyloxy derivative
by reaction with methanesulphonyl chloride or
trifiuoromethanesulphonic anhydride, respectively, in the presence
of an organic base. A 4-amino 1,5-naphthyridine can be obtained
from the 4-chloro, 4-methanesulphonyloxy or
4-trifluoromethanesulphonyloxy derivative by reaction with
n-propylamine in pyridine.
[0271] Similarly, 6-methoxy-1,5-naphthyridine derivatives can be
prepared from 3-amino-6-methoxypyridine.
[0272] 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, p 581-627, Ed A.
R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984).
[0273] The 4-hydroxy and 4-amino-cinnolines may be prepared
following methods well known to those skilled in the art [see A. R.
Osborn and K. Schofield, J. Chem. Soc. 2100 (1955)]. For example, a
2-aminoacetophenone is diazotised with sodium nitrite and acid to
produce the 4-hydroxycinnoline with conversion to chloro and amino
derivatives as described for 1,5-naphthyridines.
[0274] The compounds of formula (V) are either commercially
available or may be prepared by conventional methods.
[0275] For compounds of formula (V), where Y is NHR.sup.11'
suitable amines may be prepared from the corresponding
4-substituted cyclohexyl- or cyclohexenyl acid or alcohol. In a
first instance, an N-protected cyclohexyl- or cyclohexenyl amine
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 cyclohexyl- or cyclohexenyl amine can
undergo a Curtius rearrangement e.g. on treatment with
diphenylphosphoryl azide and heating, and the intermediate
isocyanate reacts in the presence of 2-trirethylsilyledianol 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 compound of formula (V).
Alternatively, an acid group (CH.sub.2).sub.n-1CO.sub.2H may be
converted to (CH.sub.2).sub.nNHR.sup.11 by reaction with an
activating agent such as isobutyl chloroformate followed by an
amine R.sup.11' NH.sub.2 and the resulting amide reduced with a
reducing agent such as LiAlH.sub.4.
[0276] In a second instance, an N-protected cyclohexyl- or
cyclohexenyl amine 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 phthnlimidoethylcyclohexyl- or cyclohexenyl amine. Removal
of the phthaloyl group, for example by treatment with
methylhydrazine, gives the amine of formula (V).
[0277] Compounds of formula (V) where n=1 may be prepared from the
compound where n=0 by homologation eg starting from a compound of
formula (V) where Y.dbd.CO.sub.2H.
[0278] Compounds of formula (V) with a --C.ident.CH group may be
prepared from the ketone treated with trimethylsilylacetylene and
n-butyl lithium in dimethylformamide at low temperature followed by
removal of the trimethylsilyl group with potassium carbonate in
methanol or a fluoride source such as KF or tetrabutylammonium
fluoride.
[0279] Compounds of formula (V) with a --CONHR.sup.11 group may be
prepared from the corresponding nitrile by partial hydrolysis with
with concentrated mineral acid at ambient temperature, such as
concentrated hydrochloric acid (M. Brown et al, J. Med. Chem.,
1999, 42, (9), 1537) or with concentrated sulphuric acid (F. Macias
et al Tetrahedron, 2000, 56, (21), 3409).
[0280] Compounds of formula (V) with a --OCONH.sub.2 group may be
prepared from the corresponding alcohol by reaction with phosgene
followed by ammonia.
[0281] Compounds of formula (V) substituted by R.sup.3 at the 1- or
4-position maybe prepared from a 1-keto derivative via a
cyanohydrin reaction with sodium cynnide/hydrochloric acid in an
ether/water two phase system (J. Marco et al Tetrahedron, 1999, 55,
(24), 7625), or using trimethylsilylcyanide and zinc iodide
catalysis in dichloromethane (A. Abad et al, J. Chem. Soc., Perlin
1, 1996, 17, 2193), followed by hydrolysis by heating in
concentrated hydrochloric acid to give the .alpha.-hydroxy acid
(Compound(V), Y.dbd.CO.sub.2H, n=0, R.sup.3' .dbd.OH and Q.sup.1 is
NR.sup.2'R.sup.4') or partial hydrolysis to the carboxamide
--CONH.sub.2 as described above. In examples where there is
trimethylsilyl protection of the alcohol, this is removed under the
acidic conditions of cyanide hydrolysis. it will be appreciated
that the amine protecting group eg N-carboxylic acid tert-butyl
ester is concommitantly removed during the acid hydrolysis step,
necessitating a standard reprotection with di-tert-butyl
dicarbonate, giving key intermediates (V) such as
(4-carbamoy-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester.
It is noteworthy that during the cyanohydrin formation there is
little or no stereoselectivity with regard to relative
stereochemistry, and the
(4-carbamoyl-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester
produced in this process is a mixture of cis and trans
stereoisomers. These isomers can be separated by careful
chromatography.
[0282] The same 1-keto-derivative could undergo a Wittig reaction
with Ph.sub.3PCH.dbd.CO.sub.2Me to give the
.alpha.,.beta.-unsatrrsted carboxylic ester
MeO.sub.2C--CH.dbd.C<Ring, which could be epoxidised (eg
meta-chloroperbenzoic acid) to give the .alpha.,.beta.-epoxy-ester.
Alternatively this could be formed directly from the
keto-derivative via a glycidic ester condensation with an
.alpha.-halogeno-ester. Base hydrolysis would afford the
.alpha.,.beta.-epoxy arboxylic acid, which on reduction (eg lithium
triethylborohydride--see J. Miklefield et al J. Amer. Chem. Soc.
117, 1153-1154 (1995) or hydrogenation over platinum oxide (see
Artamonow Zh. Obshch. Kim. 28 1355-1359 (1958)) would afford the
.beta.-hydroxy acid (Compound (V) Y.dbd.CO.sub.2H, n=1, R.sup.3'
.dbd.OH). Alternatively a Reformatsky reaction with the
keto-derivative and an .alpha.-bromocarboxylic acid ester and zinc,
followed by acid hydrolysis would afford the
.beta.-hydroxycarboxylic acid directly. The 1-keto-derivative could
also undergo a Strecker type synthesis via a Bucherer-Bergs
procedure (potassium cyanide/ammonium carbonate) [see T. Scott
Yokum et al. Tetrahedron Letters, 38, 4013-4016 (1997)] to give the
.alpha.-amino-carboxylic acid (Compound (V) Y.dbd.CO.sub.2H, n=0,
R.sup.3' .dbd.NH.sub.2).
[0283] An alternative route to I-substituted compounds (V) involves
a Diels Alder reaction between butyl acrylate and acetoxy butadiene
to give (1). Elimination of acetic acid and hetero Diels Alder
reaction with an in-situ generated acyl nitroso compound gives the
bicyclic hydroxylamnine product (3). The ester is transformed to an
amide in two steps, and catalytic hydrogenation is used to reduce
the double bond, remove the nitrogen protection and cleave the NO
bond. After reprotection of the amino group, the cyclohexane amide
with the required stereochemistry is obtained. ##STR9## Two steps
can be avoided by starting with acrylamide: ##STR10##
[0284] Compounds of formula (V) substituted by R.sup.3 at the 2- or
3-position may be prepared from the corresponding substituted
phenyl derivative 1-Y(CH.sub.2).sub.nPh(-R3)-4-NR.sub.2 (eg where
Y=carboxylic acid) by hydrogenation at elevated temperature and
pressure using a Pt or Ru catalyst.
[0285] Compounds of formula (V) with a 3-hydroxyl group may be
prepared from a 3,4 oxirane-cyclohexane carboxylic acid by reaction
with an amine NHR.sup.2R.sup.4 or azide (followed by conversion of
the azide to amino). [See for example K. Krajewski et al.
Tetrahedron Asymmetry 10, 4591-4598 (1999)]. The ester group maybe
epimerised by heating in strong base, hydrolysed to the carboxylic
acid and cyclised to the lactone using a conventional coupling
reagent (EDC). Other conventional reagents eg DCC, Im.sub.2CO, HATU
etc. may also be used. The lactone is readily purified by
chromatography. The lactone is readily opened with aqueous ammonia
in tetrahydrofuran to give the required (racemic) amide.
##STR11##
[0286] An improved procedure starting from 3-cyclohexene carboxylic
acid may be used to prepare single enantiomers. 3-Cyclohexene
carboxylic acid (2) is resolved via .alpha.-Me benzylamine salt
(Schwartz et al, J. Am. Chem. Soc., 100, 5199, (1978)). A higher
yield of lactone (3) can be achieved using a larger excess of
reagents. Lacetone opening with ammonia gives (4), which is treated
with azide to give (5) which has the required trans relative
stereochemistry between the amide and N-substituent. Finally, azide
reduction and Boc protection gives (1) a compound of formula (V).
##STR12##
[0287] R.sup.4-halides and R.sup.4-W derivatives, acyl derivatives
or aldehydes are commercially available or are prepared
conventionally. The aldehydes may be prepared by partial reduction
of the corresponding ester with lithium almentum hydride or
di-isobutylaluminium hydride or more preferably by reduction to the
alcohol, with lithium aluminium hydride or sodium borohydride (see
Reductions by the Alumino-and Borohydrides in Organic Synthesis 2nd
ed., Wiley, N.Y., 1997; JOC, 3197, 1984; Org. Synth. Coll., 102,
1990; 136, 1998; JOC, 4260, 1990; TL, 995, 1988; JOC, 1721, 1999;
Liebigs Ann./Recl., 2385, 1997; JOC, 5486, 1987), followed by
oxidation to the aldehyde with manganese (II) dioxide, or by a
`Swern` procedure (oxalyl chloride/DMSO), or by using potassium
dichromate (PDC). The aldehydes may also be prepared from
carboxylic acids in two stages by conversion to a mixed anhydride
for example by reaction with isobutyl chloroformate followed by
reduction with sodium borohydride (R. J. Alabaster et al.,
Synthesis, 598, 1989) to give the hydroxymethyl substituted
heteroaromatic or aromatic and then oxidation with a standard
oxidising agent such as pyridinium dichromate or manganese (II)
dioxide. Acyl derivatives may be prepared by activation of the
corresponding ester. R.sup.4-halides such as bromides may be
prepared from the alcohol R.sup.4OH by reaction with phosphorus
tribromide in dichloromethane/triethylamine. Where X.sup.2a is CO
and X.sup.3a is NR.sup.13a the R.sup.4-halide may be prepared by
coupling an X.sup.4a--NH.sub.2 amine and bromoacetyl bromide.
R.sup.4--W derivatives such as methanesulphonyl derivatives may be
prepared from the alcohol R.sup.4OH by reaction with methane
sulphonyl chloride. The leaving group W may be converted to another
leaving group W, e.g. a halogen group, by conventional methods.
Alternatively the aldehyde R.sup.5.sub.2CHO and sulphonic acid
derivative R.sup.5.sub.2SO.sub.2W may be generated by treatment of
the R.sup.5.sub.2H heterocycle with suitable reagents. For example
benzoxazinones, or more preferably their N-methylated derivatives
can be formylated with hexamine in either trifluoroacetic acid or
methanesulfonic acid, in a modified Duff procedure [O. I. Petrov et
al. Collect. Czech. Chem. Commun. 62, 494-497 (1997)].
4-Methyl-4H-benzo[1,4]oxazin-3-one may also be formylated using
dichloromethyl methyl ether and aluminium chloride giving
exclusively the 6-formyl derivative.
[0288] Reaction of a R.sup.5.sub.2H heterocycle with
chlorosulphonic acid gives the sulphonic acid derivative (by
methods analogous to Techer et. al., C. R. Hebd. Seances Acad. Sci.
Ser. C; 270, 1601, 1970).
[0289] The aldehyde R.sup.5.sub.2CHO may be generated by conversion
of an R.sup.5.sub.2halogen or R.sup.5.sub.2trifluoromethane
sulphonyloxy derivative into an olefin with subsequent oxidative
cleavage by standard methods. For example, reaction of a bromo
derivative under palladium catalysis with trans-2-phenylboronic
acid under palladium catalysis affords a styrene derivative which
upon ozonolysis affords the required R.sup.5.sub.2CHO (Stephenson,
G. R., Adv. Asymmetric Synth. (1996), 275-298. Publisher: Chapman
& Hall, London).
[0290] Where R.sup.5.sub.2 is an optionally substituted
benzoimidazol-2-yl group, the compound of formula (V) where
R.sup.4' is R.sup.4 may be obtained by converting a R.sup.4'
cyanomethyl group with partial hydrolysis to give the
2-ethoxycarbonimidoylethyl group which can then be condensed with
an appropriately substituted 1,2-diaminobenzene to give the
required benzoimidazol-2-yl group.
[0291] R.sup.5.sub.2H heterocycles are commercially available or
may be prepared by conventional methods. For example where a
benzoxazinone is required, a nitrophenol may be alkylated with for
example ethyl bromoacetate and the resulting nitro ester reduced
with Fe in acetic acid (alternatively Zn/AcOH/HCl or H.sub.2/Pd/C
or H.sub.2/Raney Ni). The resulting amine may undergo spontaneous
cyclisation to the required benzoxazinone, or cyclisation may be
induced by heating in acetic acid. Alternatively a nitrophenol may
be reduced to the aminophenol, which is reacted with chloroacetyl
chloride [method of X. Huang and C. Chan, Synthesis 851 (1994)] or
ethyl bromoacetate in DMSO [method of Z. Moussavi et al. Eur. J.
Med. Chim. Ther. 24, 55-60 (1989)]. The same general routes can be
applied to prepare benzothiazinones [See for example F. Eiden and
F. Meinel, Arch. Pharm. 312, 302-312 (1979), H. Fenner and R
Grauert Liebigs. Ann. Chem. 193-313 (1978)]]. A variety of routes
are available to prepare aza analogues of benzothiazinones via the
key corresponding aldehydes. For instance,
2-oxo-2,3-dihydrom-1H-pyrido[3,4-b][1,4]thiazine-7-carbaldehyde may
be accessed from 5-fluoro-2-picoline (E. J. Blanz, F. A. French, J.
R. DoAmaral and D. A. French, J. Med. Chem. 1970, 13, 1124-1130) by
constructing the thiazinone ring onto the pyridyl ring then
functionalising the methyl substituent, as described in the
Examples. The dioxin analogue of this aza substitution patern,
2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde is
accessible from Kojic acid by aminolysis from pyrone to pyridone
then annelating the dioxin ring, again as described in the
subsequent experimental data. Other aza substitution patterns with
pyridothiazin-3-one, pyridooxazin-3-one, and pyridodioxin ring
systems are also accessible, again as descibed in the Examples.
Ortho-aminothiophenols may be conveniently prepared and reacted as
their zinc complexes [see for example V. Taneja et al Chem. Ind.
187 (1984)]. Benzoxazolones may be prepared from the corresponding
aminophenol by reaction with carbonyl diinidazole, phosgene or
triphosgene. Reaction of benzoxazolones with diphosporus
pentasulfide affords the corresponding 2-thione. Thiazines and
oxazines can be prepared by reduction of the corresponding
thiazinone or oxazinone with a reducing agent such as lithium
aluminium hydride.
[0292] The amines R.sup.2'R.sup.4'NH are available commercially or
prepared conventionally. For example amines may be prepared from a
bromo derivative by reaction with sodium azide in dimethylformamide
(DMF), followed by hydrogenation of the azidomethyl derivative over
palladium-carbon. An alternative method is to use potassium
phthalimde/DMF to give the phthalimidomethyl derivative, followed
by reaction with hydrazine in DCM to liberate the primary
amine.
[0293] Amines where X.sup.2a is CO and X.sup.3a is NR.sup.13a may
be prepared by reacting an N-protected glycine derivative
HO.sub.2C--X.sup.1a--NH.sub.2 with X.sup.4a--NH.sub.2 by
conventional coupling using eg EDC.
[0294] Conversions of R.sup.1a', R.sup.1', R.sup.2', R.sup.3' and
R.sup.4' may be carried out on the intermediates of formulae V and
(V) prior to their reaction to produce compounds of formula (I) in
the same way as described above for conversions after their
reaction.
[0295] 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.
[0296] The antibiotic 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
antibiotics.
[0297] The composition may be formulated for administration by any
route, such as oral, topical or parenteral. 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.
[0298] 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.
[0299] 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.
[0300] 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, tragacantl, or polyvinylpyrollidone; 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.
[0301] Suppositories will contain conventional suppository bases,
e.g. cocoa-butter or other glyceride.
[0302] 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.
[0303] 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.
[0304] 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.
[0305] No toxicological effects are indicated when a compound of
formula (I) or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof is administered in the above-mentioned
dosage range.
[0306] The compound of formula (I) may be the sole therapeutic
agent in the compositions of the invention or a combination with
other antibiotics or with a .beta.-lactamase inhibitor may be
employed.
[0307] Compounds of formula (I) are active against a wide range of
organisms including both Gram-negative and Gram-positive
organisms.
[0308] 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
Trans-4-[(8-Hydroxy-quinolin-2-ylmethyl)-amino]-cyclohexanecarboxylic
acid (6-methoxy-[1,5]naphthyridin-4-ylamide oxalate salt
[0309] ##STR13## (a) 4-Hydroxy6-methoxy-[1,5]-naphthyridine.
[0310] 5-Amino-2-methoxypyridine (55 g, 0.44 mol) in methanol (1000
mL) with methyl propiolate (40 mL, 0.44 mol) was stirred for 48
hours, then evaporated and the product purified by chromatography
on silica gel (dichloromethane) followed by recrystallisation from
dichloromethane-hexane (44.6 g, 48%).
[0311] The unsaturated ester (10.5 g, 0.05 mol) in warm Dowtherm A
(50 mL) was added over 3 minutes to refluxing Dowtherm A, and after
a further 20 minutes at reflux the mixture was cooled and poured
into diethyl ether. The precipitate was filtered to give a solid
(6.26 g, 70%).
(b) 1,1,1-Trifluoro-methanesulfonic acid
6-methoxy-[1,5]naphthyridin-4-yl ester.
[0312] Pyridone (1a) (10 g, 0.057 mol) in dichloromethane (200 mL)
containing 2,6-lutidine (9.94 mL, 0.086 mol) and
4-dimethylaminopyridine (0.07 g, 0.0057 mol) was cooled in ice and
treated with trifluoromethanesulfonic anhydride (10.5 ml, 0.063
mol). After stirring for 2.5 hours the mixture was washed with
saturated ammonium chloride solution, dried, evaporated and
purified on silica gel (dichloromethane) to give a solid (13.2
g).
(c) 6-Methoxy-[1,5]naphthyridin-4-ylamine.
[0313] A solution of triflate (1b) (8.0 g) and propylamine
hydrochloride (15.8 g) in pyridine (120 mL) was heated at reflux
for 4 hours. The solvent was evaporated and the mixture dissolved
in 0.05M hydrochloric acid (600 mL) and washed with
dichloromethane. The mixture was basified with 40% sodium hydroxide
and extracted with dichloromethane. The extracts were dried,
evaporated and chromatographed on silica gel (2-5% methanol in
dichloromethane) to give an orange solid (3.6 g, 63%). .delta.H
(CDCl.sub.3, 250 Mz), 8.39 (1H, d,), 8.09 (1H, d,), 7.08 (1H, d,),
6.71 (1H, d,), 5.25 (2H, brs), 4.05 (3H,s). MS (+ve ion
electrospray) m/z: 176 (MH.sup.+).
(d)
[4-(6-Methoxy-[1,5]naphthyridin-4-ylcarbamoyl)-cyclohexyl]-carbamic
acid tert-butyl ester.
[0314] Amine (1c) (2.44 g, 13.94 mmol)
4-trans-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (3.39
g, 13.94 mmol) and
O(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramnethyluronium
hexafluorophosphate (5.30 g, 13.94 mmol) were combined as a slurry
in N,N'-dimethylformamiide (70 mL). To this mixture was added
triethylamine (3.88 mL, 27.88 mmol) and the reaction vessel was
heated to 60.degree. C. for 10 hours. After this period the solvent
was removed under vacuum and the residue partitioned between ethyl
acetate (2.times.200 mL) and brine (50 mL). The organic phases were
combined and dried over magnesium sulfate after which they were
concentrated in vacuo. The resulting oil was purified by column
chromatography on silica gel using a dichloromethane and methanol
solvent gradient. This provided the desired compound as a white
solid (3.33 g, 60%).
[0315] MS (APCI+) m/z 401 (MH+).
(e) 4-Amino-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide
[0316] Amide (1d) (3.33 g, 8.325 mmol) was dissolved in
dichloromethane (200 mL). To this solution was added
trifluoroacetic acid (50 mL) and the resulting mixture stirred at
room temperature for 2 hours. The volatiles were removed under
reduced pressure and the residue was treated with 4M hydrochloric
acid in 1,4-dioxan (100 mL). The resulting solid was filtered and
then stirred over potassium carbonate (4.59 g, 33.3 mmol) in a
mixture of chloroform and 15% methanol (2.times.150 mL). The slurry
was filtered and the filtrate concentrated under vacuum to provide
the desired compound as an off white solid (1.82 g, 73%). MS
(APCI+) m/z 301 (MH+).
(f) Title Compound
[0317] Amide (1d) (796 mg, 1.99 mmol) was dissolved in
dichloromethane (5 mL) and cooled to 0.degree. C. Trifluoroacetic
acid (5 mL) was added and the resulting solution stirred at room
temperature for 20 hours. The reaction was concentrated under
vacuum and the residue re-dissolved in anhydrous dichloromehane (5
mL) and methanol (1 mL). To this solution was added activated 3
.ANG. molecular sieves (1 g), 8-hydroxy-quiolino-2-carbaldehyde
(263 mg, 1.52 mmol) and triethylamine (0.21 mL, 1.52 mmol). The
resulting solution was stirred at room temperature for 20 hours and
then sodium borohydride (116 mg, 3.05 mmol) was added. The
resulting slurry was stirred at room temperature for a further 10
hours. The reaction mixture was quenched by the addition of water
(2 mL) and the volatiles removed in vacuo. The residue was
partitioned between ethyl acetate (2.times.100 mL) and brine (20
mL). The organic phases were combined and dried over magnesium
sulfate. The volatiles were again removed under reduced pressure
and the resulting oil was subjected to purification on silica gel
using a methanol and dichloromethane gradient. This afforded the
free base of the desired compound as a colourless oil (33 mg,
4%).
[0318] .delta.H (CD.sub.3OD, 250 MHz), 8.46 (1H, d), 8.34 (1H, d),
8.07 (1H d), 8.04 (1H, d), 7.35-7.19 (3H, m), 7.11 (1H, d), 6.97
(1H, dd), 4.09 (2H, s), 4.01 (3H, s), 2.61-2.49 (2H, m), 2.14-2.01
(4H, m), 1.45-1.22 (2H, m), 1.37-1.22 (2H, m). MS (APCI+) m/z 458
(MH+).
[0319] A solution of the oil (33 mg) in dichloromethne (1 mL) was
added to oxalic acid (6.5 mg) in diethyl ether (10 mL) to generate
the oxalate salt. The title compound was isolated by
centrifugation, washing with diethyl ether and subsequent drying in
vacua.
Example 2
Trans-4-[(Benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-cyclohexanecarboxylic
acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide fumarate salt
[0320] ##STR14## (a) Benzo[1,2,5]thiadiazol-5-yl-methanol.
[0321] Benzo[1,2,5]thiadiazole-5-carboxylic acid (2.00 g, 11.11
mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to
0.degree. C. To this was added triethylamine (1.80 mL, 12.87 mmol)
followed by isobutylchloroformate (1.62 mL, 12.40 mmol) in a
dropwise manner. The resulting slurry was stirred for a further 30
minutes at 0.degree. C. and then filtered into a mixture of sodium
borohydride (0.83 g, 21.84 mol) in ice water (20 mL). The resulting
mixture was stirred at 0.degree. C. for 30 minutes, evaporated to
one quarter of its volume and then extracted with dichloromethane
(3.times.50 mL). The organic phases were combined and then dried
over sodium sulfate. This was followed by concentration under
reduced pressure to provide the desired product as a white solid
which was used without further purification (1.50 g, 81%).
(b) Methanesulfonic acid benzo[1,2,5]thiadiazol-5-ylmethyl
ester.
[0322] Alcohol (2a) (200 mg, 1.20 mmol), was dissolved in
dichloromethane (6 mL). This solution was cooled to 0.degree. C.
and triethylamine (0.22 mL, 1.57 mmol) was added. This was followed
by the dropwise addition of methane sulfonylchloride (0.11 mL, 1.45
mmol). The resulting mixture was stirred at room temperature for 2
hours and then partitioned between a 10% aqueous solution of sodium
hydrogen carbonate (25 mL) and dichloromethane (2.times.50 mL). The
organic phases were combined and dried over magnesium sulfate. They
were then dried under reduced pressure to afford the desired
product which was used without further purification (241 mg, 70%
w/w).
(c) Title Compound.
[0323] Amine (1e) (160 mg, 0.533 mmol) was dissolved in
N,N'-dimethylformamide (5 mL). To this solution was added potassium
carbonate (74 mg, 0.533 mmol) and mesylate (2b) (130 mg, 0.533
mmol). The resulting suspension was stirred at room temperature for
10 hours. The reaction was concentrated under vacuum and the
residue partitioned between ethyl acetate (2.times.100 mL) and
brine (20 mL). The organic phases were combined and dried over
magnesium sulfate. The volatiles were again removed under reduced
pressure and the resulting oil was subjected to purification on
silica gel using a methanol and dichloromethane gradient. This
afforded the free base of the desired compound as a colourless oil
(71 mg, 30%). .delta.H (CDCl.sub.3, 250 MHz), 9.50 (1H, bs), 8.70
(1H, d), 8.54 (1H, d), 8.22 (1H, d), 7.97 (2H, m), 7.63 (1H, dd),
7.13 (1H, m), 4.10 (3H, s), 4.00 (2H, s), 2.65-2.62 (1H, m),
2.46-2.40 (1H, m), 2.21-2.17 (4H, m), 1.71-1.66 (2H, m), 1.38-1.20
(2H, m). MS (APCI+) m/z 449 (MH+).
[0324] A solution of the oil (71 mg) in dichloromethane (1 mL) was
added to fiumaric acid (18 mg) in dichloromethane and methanol
(1:1, 10 mL) to generate the fulmarate salt. The title compound was
isolated by removal of volatiles in vacuo.
Example 3
Trans-4-[(1H-Pyrrolo[2,3-b]pyridin-2-ylmethyl)-amino]-cyclohexanecarboxyli-
c acid (6-methoxy-[1,5]naphthyridinyl)amide fumarate salt
[0325] ##STR15## (a) 7-Azaindole-2-carboxylic acid.
[0326] A solution of 7-azaindole (2.0 g) in tetrahydrofuran (30 ml)
was cooled to -70.degree. C. and n-butyrithium (1.6M in hexanes,
11.1 ml) was added dropwise. After 0.5 h at -70.degree. C., carbon
dioxide was bubbled through for 10 min, followed by 10 min stirring
The mixture was allowed to warm to 0.degree. C. and the mixture was
evaporated under vacuum to approximately half-volume. Fresh
tetrahydrofuran (15 ml) was added, the mixture was cooled to
-70.degree. C. and tert-butyl lithium (1.7M inpentane, 10.5 ml) was
added dropwise. After siring for 1 h at -70.degree. C., carbon
dioxide was bubbled through for 10 min followed by stirring for 30
min. Water (1.2 ml) was added and the mixture was allowed to warm
to room temperature before pouring into saturated ammonium
chloride. The aqueous solution was washed with diethyl ether,
filtered and acidified to pH3.5. The white precipitate was
collected and dried to give the acid (2.38 g).
[0327] MS (+ve ion electrospray) m/z 163 (MH+).
(b) Methyl 7-azaindole-2-carboxylate.
[0328] Acid (3a) (1.0 g) was partially dissolved in
N,N'-dimethylformamide (20 ml) and methanol (2 ml) and treated
dropwise with trimethylsilyldiazomethane (2M in hexanes, 3.1 ml).
The mixture was stirred overnight then evaporated. Chromatography
on silica using an ethyl acetate and hexane solvent gradient gave
the ester (0.35 g).
[0329] MS (+ve ion electrospray) m/z 177 (MH+).
(c) 7-Azaindole-2-carboxaldehyde.
[0330] Ester (3b) (0.3 g) in tetrahydrofuran (5 ml) was treated
dropwise with lithium aluminium hydride (1M in tetrahydrofuran, 1.9
ml) at 0C.degree. C. After 2 h the mixture was treated with 8%
sodium hydroxide, dichloromethane and sodium sulfate, filtered and
evaporated. The resulting crude alcohol was dissolved in
tetrahydroffrin (4 ml) and stirred with manganese (II) oxide (0.74
g) for 4 h Filtration and evaporation of solvent gave the aldehyde
(100 mg).
[0331] MS (+ve ion electrospray) m/z 147 (MH+).
(d) Title Compound.
[0332] Amine (1e) (245 mg, 0.822 mmol) and aldehyde (3c) (120 mg,
0.822 mmol) was dissolved in chloroform (6 mL) and methanol (2 mL).
The solution was heated to 70.degree. C. for 5 hours with 3 .ANG.
molecular sieves (1 g). After this period the mixture was cooled to
0.degree. C. and sodium triacetoxyborohydride (522 mg, 2.466 mmol)
was added. The mixture was stirred at room temperature for 10 hours
and then quenched by the addition of water (2 mL). The volatiles
were removed in vacuo and the residue partitioned between ethyl
acetate (2.times.100 mL) and brine (25 mL). The organic phases were
combined and dried over magnesium sulfate then evaporated. The
resulting oil was purified by silica gel chromatography using a
dichloromethane and methanol solvent gradient This provided the
free base of the desired compound as a colourless oil (74 mg, 22%).
.delta.H (CDCl.sub.3, 250 MHz), 9.51 (1H, bs), 8.68 (1H, d), 8.50
(1H, d), 8.28 (1H, d), 8.22 (1H, d), 7.84 (1H, dd), 7.15 (1H, d),
7.05 (1H, dd), 6.31 (1H, s), 4.11 (2H, s), 4.09 (3H, s), 2.64-2.60
(1H, m), 2.42-2.37 (1H, m), 2.19-2.17 (4H, m), 1.73-1.63 (2H, m),
1.31-1.22 (2H, m). MS (APCI+) m/z 431 (MH+).
[0333] The fumarate salt was prepared by the method of Example
2.
Example 4
Trans-4-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cycloh-
exane carboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
fumarate salt
[0334] ##STR16## (a)
3-Oxo3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid.
[0335] 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid
methyl ester (6.74 g) was suspended in tetrahydrofuran (100 mL) and
2M sodium hydroxide (30 mL) was added followed by water (20 mL).
The solution was stirred for 2.5 hours, evaporated to half volume
and acidified with 2M hydrochloric acid. The product was collected,
washed with water and dried in vacuo, to give a white solid (6.2
g).
[0336] MS (-ve ion electrospray) m/z 208 (M-H).sup.-
(b) 6-Hydroxymethyl-4H-benzo[1,4]thiazin-3-one.
[0337] Acid (4a) in tetrahydrofuran (50 mL) and triethylamine (4.7
mL) was cooled to 0.degree. C. and isobutylchloroformate (4.02 mL)
was added dropwise and the solution was stirred at 0.degree. C. for
2 hours, when it was filtered into a stirred solution of sodium
borohydride (3.14 g) in icewater (50 mL). The mixture was stirred
at 0.degree. C. for 1 hour and allowed to warmn to room
temperature. It was acidified with 2M hydrochloric acid, evaporated
to half volume, and the resulting product was collected, washed
with water and dried in vacuo, to give a white solid (4.5 g).
[0338] MS (-ve ion electrospray) mz 194 (M-H).sup.-
(c) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde.
[0339] A stirred solution of alcohol (4b) (3.5 g) in chloroform
(150 mL) and tetraydrofliran (300 mL) was treated with manganese
dioxide (7.8 g) for 18 hours and was filtered and evaporated to
give a white solid (2.5 g). MS (-ve ion electrospray) m/z 194
(M-H).sup.-
(d) Title Compound.
[0340] Amine (1e) (260 mg, 0.866 mmol) and aldehyde (4c) (167 mg,
0.866 mmol) was dissolved in chloroform (5 mL) and methanol (3 mL).
The solution was heated to 70.degree. C. for 7 hours with 3 .ANG.
molecular sieves (1 g). After this period the mixture was cooled to
0.degree. C. and sodium triacetoxyborohydride (550 mg, 2.598 mmol)
was added. The mixture was stirred at room temperature for 10 hours
and then quenched by the addition of water (2 mL). The volatiles
were removed in vacuo and the residue was purified by silica gel
chromatography using a dichloromethane and methanol solvent
gradient This provided the free base of the desired compound as a
colourless oil (145 mg, 35%).
[0341] .delta.H (d.sub.6-DMSO, 250 Mz), 10.52 (1H, bs), 9.80 (1H,
bs), 8.66 (1Hz d), 8.39 (1H, d), 8.26 (1H, d), 7.31 (1H, d), 7.26
(1H, d), 6.99-6.96 (2H, m), 4.14 (3H1, s), 3.73 (2H s), 3.44 (2H,
s), 2.68 (1H, m), 2.51-2.48 (1H, m), 2.04-1.90 (4H, m), 1.52-1.47
(2H, m), 1.24-1.17 (2H, m). MS (+ve ion electrospray) m/z
478(MH+).
[0342] The fumarate salt was prepared by the method of Example
2.
Example 5
Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarbo-
xylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide fumarate
salt
[0343] ##STR17## (a)
(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-methanol.
[0344] 2,3-Dihydro-benzo[1,4]dioxine&carbaldehyde [RN
29668-44-8] (3.04 g, 18.54 mmol) was dissolved in ethanol (100 mL)
and cooled to 0.degree. C. To the resulting solution was added
sodium borohydride (1.41 g, 37.07 mmol). The resulting slurry was
stirred at room temperature for 1 hour and then quenched with water
(10 mL) before being concentrated to dryness under reduced
pressure. The residue was partitioned between a 5% aqueous solution
of sodium hydrogen carbonate (20 mL) and dichloromethane
(2.times.50 mL). The organic phases were combined and dried over
magnesium sulfate then evaporated under reduced pressure to provide
and oil which was purified on silica gel using a dichloromethane
and methanol solvent gradient. This provided the desired product as
a colourless oil (3.00 g, 97%).
(b) Methanesulfonic acid 2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl
ester.
[0345] Alcohol (5a) (640 mg, 3.855 mmol), was dissolved in
dichloromethane (20 mL). This solution was cooled to 0.degree. C.
and triethylamine (0.70 mL, 5.012 mmol) was added. This was
followed by the dropwise addition of methane sulfonylchloride (0.36
mL, 4.627 mmol). The resulting mixture was stirred at room
temperature for 2 hours and then partitioned between a 10% aqueous
solution of sodium hydrogen carbonate (25 mL) and dichloromethane
(2.times.100 mL). The organic phases were combined and dried over
magnesium sulfate. They were then dried under reduced pressure to
afford the desired product which was used without further
purification (1.00 g, 60% w/w).
(c) Title Compound.
[0346] Amine (1e) (150 mg, 0.50 mmol) was dissolved in
N,N'-dimethylformamide (10 mL). To this solution was added
potassium carbonate (76 mg, 0.55 mmol) and mesylate (5b) (122 mg,
0.50 mmol). The resulting suspension was stred at 50.degree. C. for
3 hours. The reaction was concentrated under vacuum and the residue
partitioned between dichloromethane (2.times.100 mL) and an aqueous
solution of saturated sodium hydrogen carbonate (20 mL). The
organic phases were combined and dried over magnesium sulfate. The
volatiles were again removed under reduced pressure and the
resulting oil was subjected to purification on silica gel using a
methanol and ethyl acetate gradient. This afforded the free base of
the desired compound as a colourless oil (70 mg, 31%). .delta.H
(CDCl.sub.3, 250 MHz), 9.48 (1H, bs), 8.68 (1H, d), 8.52 (1H, d),
8.21 (1H, d), 7.15 (1H, d), 6.86-6.79 (3H, m), 4.24 (4H, m), 4.14
(3H, s), 3.79 (2H, m), 2.88-2.61 (1H, m), 2.49-2.40 (1H, m),
2.20-2.15 (4H, m), 1.68-1.63 (2H, m), 1,58-1.34 (2H, m). MS (APCI+)
m/z 449 (+).
[0347] The fumarate salt was prepared by the method of Example
2.
Example 6
Trans-4-[(Benzo[1,2,3]thiadiazol-5-ylmethyl)-amino]-cyclohexanecarboxylic
acid (6methoxy-[1,5]naphthyridin-4-ylamide fumarate salt
[0348] ##STR18## (a) Benzo[1,2,3]thiadiazol-5-yl-methanol.
[0349] Benzo[1,2,3]thiadiazole-5-carboxylic acid (2.70 g, 15.0
mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to
0.degree. C. To this was added triethylamine (2.50 mL, 18.0 mmol)
followed by isobutylchloroformate (2.15 mL, 16.5 mmol) in a
dropwise manner. The resulting slurry was stirred for a further 30
minutes at 0.degree. C. and then filtered into a mixture of sodium
borohydride (1.14 g, 30 mmol) in ice water (20 mL). The resulting
mixture was stirred at 0.degree. C. for 15 minutes, evaporated to
one quarter of its volume and then partitioned between a saturated
aqueous solution of sodium hydrogen carbonate (20 mL) and ethyl
acetate (3.times.50 mL). The organic phases were combined and then
dried over sodium sulfate. This was followed by concentration under
reduced pressure to provide an oil which was purified by column
chromatography on silica gel using an ethyl acetate and hexane
solvent system. This provided the desired product as a yellow solid
(1.40 g, 56%).
(b) Methanesulfonic acid benzo[1,2,3]thiadiazol-5-ylmethyl
ester.
[0350] Alcohol (6a) (150 mg, 0.904 mmol) was dissolved in
dichloromethane (2 mL). This solution was cooled to 0.degree. C.
and triethylamine (0.14 mL, 0.994 mmol) was added. This was
followed by the dropwise addition of methane sulfonylchloride (0.07
mL, 0.904 mmol). The resulting mixture was stirred at room
temperature for 1 hour and then partitioned between water (25 mL)
and dichloromethane (2.times.50 mL). The organic phases were
combined and dried over magnesium sulfate. They were then dried
under reduced pressure to afford the desired product which was used
without further purification.
(c) Title Compound.
[0351] Amine (1e) (50 mg, 0.166 mmol) was dissolved in
N,N'-dimethylfomanide (3 mL). To this solution was added potassium
carbonate (46 mg, 0.332 mmol) and mesylate (6b) (218 mg, 0.893
mmol). The resulting suspension was stirred at room temperature for
10 hours. The reaction was concentrated under vacuum and the
residue partitioned between ethyl acetate (2.times.100 mL) and
brine (20 mL). The organic phases were combined and dried over
magnesium sulfate. The volatiles were again removed under reduced
pressure and the resulting oil was subjected to purification on
silica gel using a methanol and dichloromethane gradient. This
afforded the free base of the desired compound as a colourless oil
(22 mg, 29%). .delta.H (CDCl.sub.3, 250 MHz), 9.51 (1H, bs), 8.69
(1H, d), 8.61 (1H, m), 8.51 (1H, d), 8.21 (1H, d), 8.03 (1H, d),
7.72 (1H, dd), 7.16 (1H, d), 4.11 (3H, s), 4.00 (2H, s), 2.70-2.64
(1H, m), 2.47-2.41 (1H, m), 2.23-2.18 (4H, m), 1.76-1.63 (2H, m),
1.40-1.25 (2H, m). MS (APCI+) m/z 449 (MH+).
[0352] The fumarate salt was prepared by the method of Example
2.
Example 7
Trans-4-[(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-amino]-cycloh-
exanecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
oxalate salt
[0353] ##STR19## (a)
3-Methyl-2-oxo-2,3-dihydro-benzooxazole-6-carbaldehyde.
[0354] 3-Methyl-3H-benzooxazol-2-one (2.00 g, 13.42 mmol) and
hexamethylenetetramine (3.76 g, 26.84 mmol) were dissolved in
trifluoroacetic acid (20 mL) and heated at reflux for 20 hours. The
volatiles were removed in vacuo and the residue was treated with
ice water (60 mL). The resultant mixture was stirred for 30 minutes
and then made basic with sodium carbonate. The solid was isolated
by filtration and washed with water then dried under vacuum. The
solid was purified by column chromatography on silica gel eluting
with an ethyl acetate and hexane solvent gradient. This provided
the desired product as a white solid (1.07 g, 45%).
[0355] .delta.H (CDCl.sub.3, 250 MHz), 9.95 (1H, s), 7.80-7.76 (1H,
dd), 7.33 (1H, d), 7.10 (1H, d), 3.48 (3H, s).
(b) Title Compound.
[0356] Amide (1d) (311 mg, 0.778 mmol) was dissolved in
dichloromethane (2 mL) and cooled to 0.degree. C. Trifluoroacetic
acid (2 mL) was added and the resulting solution stirred at room
temperature for 1 hour. The reaction was concentrated under vacuum
and the residue re-dissolved in anhydrous dichloromethane (5 mL)
and methanol (1 mL). To this solution was added activated 4 .ANG.
molecular sieves (1 g), aldehyde (7a) (138 mg, 0.778 mmol) and
diisopropyl ethylamine (0.40 mL, 2.333 mmol). The resulting
solution was stirred at room temperature for 5 hours and then
sodium borohydride (89 mg, 2.333 mmol) was added. The resulting
slurry was stirred at room temperature for a further 48 hours. The
reaction mixture was quenched by the addition of water (2 mL) and
the volatiles removed in vacuo. The residue was partitioned between
ethyl acetate (2.times.100 mL) and brine (20 mL). The organic
phases were combined and dried over magnesium sulfate. The
volatiles were again removed under reduced pressure and the
resulting oil was subjected to purification on silica gel using a
methanol and dichloromethane gradient. This afforded the free base
of the desired compound as a colourless oil (50 mg, 14%).
[0357] .delta.H (CD.sub.3OD, 250 MHz), 8.66 (1H, d), 8.54 (1H, d),
8.25 (1H, d), 7.40 (1H, m), 7.34-7.24 (2H, m), 7.21 (1H, d), 4.22
(3H, s), 4.03 (2H, s), 3.46 (3H, s), 2.80-2.65 (2H, m), 2.24 (4H,
m), 1.58-1.53 (2H, m), 1.41-1.33 (2H, m). MS (APCI+) m/z 462
(MH+).
[0358] The oxalate salt was prepared by the method of Example
1.
Example 8
Trans-4-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohe-
xanecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
fumarate salt
[0359] ##STR20## (a) (4-Formyl-2-nitro-phenoxy)-acetic acid ethyl
ester.
[0360] A solution of 4-hydroxy-3-nitro-benzaldehyde (6.9 g) and
ethyl bromoacetate (5.0 mL) in dimethylformamide (250 mL) was
treated with anhydrous potassium carbonate (10 g) and the mixture
was heated at 60.degree. C. for 18 hours and evaporated to dryness.
The residue was partitioned between water and diethyl ether, and
the diethyl ether layer was washed with 0.5M sodium hydroxide. It
was then dried over anhydrous sodium sulfate and evaporated to give
an oil that was chromatographed on silica gel (ethyl
acetateldichloromethane) to afford an oil (1.9 g).
[0361] MS (+ve ion electrospray) m/z 253 (MH+).
(b) 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde.
[0362] Ester (8a) (1.9 g) in acetic acid (40 mL) was treated with
iron powder (4.2 g) and the mixture was stirred at 60.degree. C.
for 0.75 hours, filtered and evaporated to dryness. It was
partitioned between aqueous sodium bicarbonate and ethyl acetate.
The organic fraction was chromatographed on silica gel (ethyl
acetate) to give a white solid (0.88 g).
[0363] MS (-ve ion electrospray) m/z 176 (M-H).sup.-
(c) Title Compound.
[0364] Amine (1e) (200 mg, 0.66 mmol) and aldehyde (8b) (130 mg,
0.73 mmol) was dissolved in chloroform (5 mL) and methanol (3 mL).
The solution was heated to reflux for 5 hours with 3 .ANG.
molecular sieves (1 g). The solvents were then removed by
evaporation and replaced with N,N'-dimethylformamide (2 mL) and
toluene (2 mL) The mixture was stirred at reflux for a further 1
hour. These solvents were removed in vacuo and replaced with
chloroform (2 mL) and methanol (2 mL). The mixture was cooled to
0.degree. C. and sodium borohydride (230 mg, 6.05 mmol) was added.
The mixture was then stirred at room temperature for 1 hour and
quenched by the addition of water (2 mL). The volatiles were
removed in vacuo and the residue was partitioned between chloroform
(2.times.100 mL) and a saturated aqueous solution of sodium
hydrogen carbonate (20 mL). The organic phases were combined, dried
over magnesium sulfate and then concentrated under vacuum. The
resulting oil was purified by silica gel chrormatography using an
ethyl acetate and methanol solvent gradient. This provided the
desired compound as a colourless solid. Recrystallisation from
ethyl acetate and methanol afforded the free base of the desired
compound (60 mg, 19%).
[0365] .delta.H (CD.sub.3OD, 250 MHz), 8.62 (1H, d), 8.51 (1H, d),
8.20 (1H, d), 7.27 (1H, d), 7.03-6.93 (3H, m), 4.56 (2H, s), 4.10
(3H, s), 3.86 (2H, s), 2.75-2.60 (2H, m), 2.20-2.16 (4H, m),
1.67-1.63 (2H, m), 1.42-1.28 (2H, m).
[0366] The fumarate salt was prepared by the method of Example
2.
Example 9
Trans-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino-
]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dioxalate salt
[0367] ##STR21## (a) 5-Amino-2-fluoro-4-hydroxy-benzonitrile.
[0368] This was prepared from 2-fluoro-4-hydroxy-benzonitrile by
nitration (concentrated nitric acid in acetic acid at 40.degree.
C.) followed by hydrogenation in ethanol over 10%
palladium/carbon.
(b)
7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile.
[0369] This was prepared by the general method of Xian Huang and
Cheng-Chu Chan, Synthesis, 851 (1984). A mixture of nitrile (9a) (1
g), benzyltriethylammonium chloride (1.5 g) and sodium bicarbonate
(2.22 g) in chloroform (20 ml) at 0.degree. C. was treated with
chloroacetyl chloride (0.632 mL) in chloroform (5 mL) and then
stirred at 5.degree. C. for 1 hour and then heated at 55.degree. C.
for 5 hours. The mixture was evaporated to dryness, treated with
water, and filtered to give a solid that was recrystallised from
ethanol to give a white solid (0.35 g). A further (0.24 g) was
obtained after chromatography of the mother liquors on silica gel
(chloroform then methanol/dichloromethane).
[0370] MS (-ve ion electrospray) m/z 191 (M-H).sup.-
(c) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic
acid.
[0371] Nitrite (9b) (0.2 g) was heated under reflux in
tetrahydrofuran (20 mL) and water (20 mL) containing sodium
hydroxide (0.167 g) for 72 hours. It was acidified with 2M
hydrochloric acid and the product was collected and dried in vacuo
to give a white solid (0.18 g).
[0372] MS (-ve ion electrospray) m/z 210 (M-H).sup.-
(d) 7-Fluoro-6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one.
[0373] This was prepared from acid (9c) (1.7 g) via reduction of
the mixed anhydride in a manner analogous to Example 4 to give a
solid (0.7 g).
[0374] MS (-ve ion electrospray) m/z 196 (M-H).sup.-
(e)
7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde
[0375] This was prepared from alcohol (9d) (0.7 g) by oxidation
with manganese dioxide according to the procedure in Example 4 to
give a solid (0.51 g).
[0376] MS (-ve ion electrospray) m/z 194 (M-H).sup.-
(f) Title Compound
[0377] Amine (1e) (300 mg, 1.00 mmol) and aldehyde (9e) (214 mg,
1.10 mmol) were dissolved in chloroform (5 mL) and methanol (3 mL).
The solution was heated to reflux for 4 hours with 3 .ANG.
molecular sieves (1 g). After this period the mixture was cooled to
0.degree. C. and sodium borohydride (230 mg, 6.05 mmol) was added.
The mixture was stirred at room temperature for 10 hours and then
quenched by the addition of water (2 mL). The volatiles were
removed in vacuo and the residue was partitioned between chloroform
(2.times.100 mL) and a saturated aqueous solution of sodium
hydrogen carbonate (20 mL). The organic phases were combined, dried
over magnesium sulfate and then concentrated under vacuum. The
resulting oil was purified by silica gel chromatography using an
ethyl acetate and methanol solvent gradient. This provided the free
base of the desired compound as a colourless oil (43 mg, 9%).
[0378] .delta.H (CDCl.sub.3, 250 MHz), 9.51 (1H, bs), 8.68 (1H, d),
8.51 (1H, d), 8.22 (1H, d), 7.16 (1H, d), 6.87 (1H, d), 6.70 (1H,
d), 4.56 (2H, s), 4.10 (3H, s), 3.78 (2H, s), 2.60-2.40 (2H, m),
2.16-2.05 (4H, m), 1.76-1.66 (2H, m), 1.39-1.25 (2H, m). MS (APCI+)
m/z 480 (MH+).
[0379] The oxalate salt was prepared by the method of Example
1.
Example 10
Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarbo-
xylic acid (8-fluoro-6-methoxy-quinolin-4-yl)-amide fumarate
salt
[0380] ##STR22## (a) 8-Fluoro-6-methoxy-quinolin-4-ol.
[0381] 2-Fluoro-4-methoxy-phenylamine (3.80 g, 26.7 mmol) and
methyl propiolate (2.37 ml, 0.267 mol) in methanol (100 ml) was
stirred for 72 hours at room temperature, then heated at 50.degree.
C. for 24 hours. It was evaporated and the product purified by
chromatography on silica gel (dichloromethane) to give a solid
(1.66 g), a portion of which was recrystallised from
dichloromethane-hexane.
[0382] The unsaturated ester (0.96 g) in warm Dowtherm A (5 ml) was
added over 3 minutes to refluxing Dowtherm A (15 ml), and after a
further 20 minutes at reflux the mixture was cooled and poured into
diethyl ether. The precipate was filtered to give the title
compound (0.50 g, 61%)
(b) 1,1,1-Trifluoro-methanesulfonic acid
8-fluoro-6-methoxy-quinolin-4-yl ester.
[0383] Pyridone (10a) (0.48 g) and dimethylaminopyridine (0.03 g)
in dichloromethane (20 ml) and 2,6-lutidine (0.48 ml) was treated
dropwise with triflic anhydride (0.48 ml) and the mixture was
stirred at room temperature for 4 hours. It was washed with
saturated ammonium chloride, dried, evaporated, and chromatographed
on silica gel (dichloromethane) to afford a yellow solid (0.69
g).
[0384] MS (+ve ion electrospray) m/z 326 (MH+).
(c) 8-Fluoro-6-methoxy-quinolin-4-ylamine.
[0385] A solution of triflate (10b) (0.69 g) in pyridine (10 ml)
was treated with n-propylamine hydrochloride (1.2 g) and the
mixture heated at reflux for 16 hours. The reaction mixture was
evaporated, dissolved in 0.05M HCl, washed with dichloromethane,
basified with sodium hydroxide solution and re-extracted with
dichloromethane. The combined organic phases were dried over sodium
sulfate, evaporated, and chromatographed on silica gel (2-5%
methanol in dichloromethane) to afford an orange solid (1.0 g). MS
(+ve ion electrospray) m/z 193 (MH.sup.+).
(d)
[4-(8-Fluoro-6-methoxy-quinolin-4-ylcarbamoyl)-cyclohexyl]-carbamic
acid tert-butyl ester.
[0386] Amine (10c) (1.333 g, 6.943 mmol),
4-trans-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.68
g, 6.943 mmol) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (2.64 g, 6.943 mmol) were combined as a slurry
in N,N'-dimethylformamide (70 mL). To this mixture was added
triethylamine (1.93 mL, 13.87 mmol) and the reaction vessel was
heated to 60.degree. C. for 10 hours. After this period the solvent
was removed under vacuum and the residue partitioned between ethyl
acetate (2.times.200 mL) and brine (50 mL). The organic phases were
combined and dried over magnesium sulfate after which they were
concentrated in vacuo. The resulting oil was purified by column
chromatography on silica gel using a dichloromethane and methanol
solvent gradient. This provided the desired compound as an off
white solid (1.67 g, 58%). MS (APCI+) m/z 418 (MH+).
(e) 4-Amino-cyclohexanecarboxylic acid
(8-fluoro-6-methoxy-quinolinyl)-amide
[0387] Amide (10d) (1.47 g, 3.525 mmol) was dissolved in
dichloromethane (20 mL). To this solution was added trifluoroacetic
acid (10 mL) and the resulting mixture stirred at room temperature
for 3 hours. The volatiles were removed under reduced pressure and
the residue was treated with 4M hydrochloric acid in 1,4-dioxan (50
mL). The resulting solid was filtered and then stirred over
potassium carbonate (1.95 g, 14.1 mmol) in a mixture of chloroform
and 15% methanol (2.times.100 mL). The slurry was filtered and the
filtrate concentrated under vacuum to provide the desired compound
as an off white solid (0.615 g, 55%).
[0388] MS (APCI+) m/z 318 (MH+).
(f) Title Compound
[0389] 4-Amino-cyclohexanecarboxylic acid
(8-fluoro-6-methoxy-quinolin-4-yl)-amide (10e) (186 mg, 0.587 mmol)
was dissolved in N,N'-dimethylformamide (5 mL). To this solution
was added potassium carbonate (130 mg, 0.939 mmol) methanesulfonic
acid 2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl ester (5b) (215 mg,
0.881 mmol). The resulting suspension was stirred at room
temperature for 10 hours. The reaction was concentrated under
vacuum and the residue partitioned between ethyl acetate
(2.times.100 mL) and brine (20 mL). The organic phases were
combined and dried over magnesium sulfate. The volatiles were again
removed under reduced pressure and the resulting oil was subjected
to purification on silica gel using a methanol and dichloromethane
gradient. This afforded the free base of the desired compound as a
colourless oil (130 mg, 48%).
[0390] .delta.H (CDCl.sub.3, 250 MHz), 8.81 (1H, bs), 8.67 (1H, d),
8.16 (1H, d), 7.12 (1H, m), 7.08 (1H, dd), 7.01 (1H, m), 6.88 (1H,
m), 6.80 (1H, m), 4.21 (4H, m), 3.96 (3H, s), 3.77 (2H, m), 2.68
(1H, m), 2.46 (1H, m), 2.12-1.95 (4H, m), 1.58-1.53 (2H, m),
1.32-1.25 (2H, m). MS (APCI+) m/z 466 (MH+).
[0391] The fumarate salt was prepared by the method of Example
2.
Example 11
Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarbo-
xylic acid (6-methoxy-quinolin-4-yl)-amide fumarate salt
[0392] ##STR23## (a) 4-Amino-6-methoxyquinoline.
[0393] Curtius rearrangement of 6-methoxyquinoline-4-carboxylic
acid Example 51a of WO99/37635) (4 g, 20 mmol) with
diphenylphosphoryl azide (4.3 mL, 20 mmol) and triethylamine (3.5
mL) in tert-butanol (25 ml) at 85.degree. C. gave, after
chromatography (silica gel, ethyl acetate-dichloromethane) the
N-tert-butoxycarbamate (2.47 g). Treatment with aqueous
hydrochloric acid at reflux, followed by basification and
extraction with ethyl acetate gave the 4-aminoquinoline (0.74
g).
[0394] This compound may also be prepared from
4-hydroxy-6-methoxyquinoline by chlorination with phosphorus
oxychloride, to give the 4-chloroquinoline, followed by treatment
with n-propylamine hydrochloride.
(b) [4-(6-Methoxy-quinolin-4-ylcarbamoyl)-cyclohexyl]-carbamic acid
tert-butyl ester.
[0395] Amine (11a) (4.31 g, 24.77 mmol),
4-trans-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (6.02
g, 24.77 mmol) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (9.41 g, 24.77 mmol) were combined as a slurry
in N,N'-dimethylformamide (100 mL). To this mixture was added
triethylamine (6.89 mL, 49.54 mmol) and the reaction vessel was
heated to 60.degree. C. for 10 hours. After this period the solvent
was removed under vacuun and the residue partitioned between ethyl
acetate (2.times.200 mL) and brine (50 mL). The organic phases were
combined and dried over magnesium sulfate after which they were
concentrated in vacuo. The resulting oil was purified by column
chromatography on silica gel using a dichloromethane and methanol
solvent gradient. This provided the desired compound as a white
solid (9.50 g, 96%).
[0396] MS (APCI+) m/z 400 (MH+).
(c) 4-Amino-cyclohexanecarboxylic acid
(6-methoxy-quinolin-4-yl)-amide.
[0397] Amide (11b) (13.0 g, 32.58 mmol) was dissolved in
dichloromethane (200 mL). To this solution was added
trifluoroacetic acid (50 mL) and the resulting mixture stirred at
room temperature for 3 hours. The volatiles were removed under
reduced pressure and the residue was treated with 4M hydrochloric
acid in 1,4-dioxan (100 mL). The resulting solid was isolated by
filtration and stirred over potassium carbonate (12.66 g, 91.75
mmol) in a mixture of chloroform and 15% methanol (2.times.150 mL).
The slurry was filtered and the filtrate concentrated under vacuum
to provide the desired compound as an off white solid (6.00 g,
62%).
[0398] MS (APCI+)m/z 300 (MH+).
(d) Title Compound.
[0399] Amine (11c) (200 mg, 0.667 mmol) was dissolved in
N,N'-dimethylformamide (10 mL). To this solution was added
potassium carbonate (276 mg, 2.00 mmol) methanesulfonic acid
2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl ester (5b) (488 mg, 2.00
mmol). The resulting suspension was stirred at room temperature for
10 hours and then at 60.degree. C. for 2 hours. The reaction was
concentrated under vacuum and the residue partitioned between ethyl
acetate (2.times.100 mL) and an aqueous solution of saturated
sodium hydrogen carbonate (20 mL). The organic phases were combined
and dried over magnesium sulfate. The volatiles were again removed
under reduced pressure and the resulting oil was subjected to
purification on silica gel using a methanol and dichloromethane
gradient This afforded the free base of the desired compound as a
colourless oil (87 mg, 48%).
[0400] .delta.H (CDCl.sub.3, 250 MHz), 8.68 (1H, d), 8.32 (1H, d),
8.30 (1H, bs), 8.00 (1H, d), 7.39 (1H, dd), 7.12 (1H, d), 6.84-6.76
(3H, m), 4.25 (4H, s), 3.93 (3H, s), 3.71 (2H, s), 2.58 (1H, m),
2.44 (1H, m), 2.20-2.01 (4H, m), 1.75-1.55 (2H, m), 1.25-1.10 (2H,
m). MS (APCI+) m/z 448 (MH+).
[0401] The fumarate salt was prepared by the method of Example
2.
Example 12
Trans-4-(Benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-cyclohexanecarboxylic
acid (6-methoxy-quinolin-4yl)-amide fumarate salt
[0402] ##STR24##
[0403] Amine (11c) (138 mg, 0.45 mmol) was dissolved in
N,N'-dimethylformamide (3 mL). To this solution was added potassium
carbonate (169 mg, 0.69 mmol). methanesulfonic acid
benzo[1,2,5]thiadiazol-5-ylmethyl ester (2b) (169 mg, 0.69 mmol).
The resulting suspension was stirred at room temperature for 10
hours. The reaction was concentrated under vacuum and the residue
partitioned between ethyl acetate (2.times.100 mL) and brine (20
mL). The organic phases were combined and dried over magnesium
sulfate. The volatiles were again removed under reduced pressure
and the resulting oil was subjected to purification on silica gel
using a methanol and dichloromethane gradient. This afforded the
free base of the desired compound as a colourless oil (67 mg,
33%).
[0404] .delta.H (CDCl.sub.3, 250 Mz), 8.71 (1H, d), 8.16 (1H, d),
8.04 (1H, d), 7.95 (2H, m), 7.67-7.60 (2H, m), 7.22 (1H, dd), 7.00
(1H, d), 4.05 (2H, s), 3.98 (3H, s), 2.65 (1H, m), 2.44 (1H, m),
2.17 (4H, m), 1.75-1.71 (2H, m), 1.33-1.25 (2H, m). MS (+ve ion
electrospray) m/z 448 (MH+).
[0405] The fumarate salt was prepared by the method of Example
2.
Example 13
Trans-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino-
]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt
[0406] ##STR25## (a)
6-Methoxycarbonylmethylsulfanyl-5-nitro-nicotinic acid methyl
ester.
[0407] A solution of 6-chloro-5-nitro-nicotinic acid methyl ester
(1.0 g) [prepared as descrided by A. H. Berrie et al. J. Chem. Soc.
2590-2594 (1951)] in dichloromethane (10 mL) containing
triethylamine (0.76 mL) was treated with mercapto-acetic acid
methyl ester (0.44 mL) and the solution was stirred at room
temperature for 1 hour and evaporated to dryness. Sodium
bicarbonate solution was added and the mixture was extracted with
dichloromethane, dried (anhydrous sodium sulfate) and evaporated to
afford a solid (1.0 g).
[0408] MS (+ve ion electrospray) m/z 287 (MH+).
(b) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylic
acid methyl ester.
[0409] The ester (13a) (1.0 g) in acetic acid (50 mL) was treated
with iron powder (10 g) and the mixture was stirred and heated at
60.degree. C. for 1 hour, cooled and filtered. The filtrate was
evaporated, treated with sodium bicarbonate solution and extracted
with warm chloroform. It was dried (anhydrous sodium sulfate) and
evaporated to give a white solid (0.85 g).
[0410] MS (+ve ion electrospray) m/z 225 (MH+).
(c) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylic
acid.
[0411] The ester (13b) (2.8 g) was hydrolysed with aqueous sodium
hydroxide in tetrahydrofuran by the method of Example (4a) to
afford a solid (2.5 g).
[0412] MS (-ve ion electrospray) m/z 209 (M-H.sup.-).
(d) 7-Hydroxymethyl-1H-pyrido[2,3-b][1,4]thiazin-2-one.
[0413] The carboxylic acid (13c) (2.48 g) was reacted with
isobutylchloroformate and sodium borohydride by the method of
Example (4b) to afford a solid (1.3 g), after recrystallisation
from chloroform-methanol (9:1).
[0414] MS (+ve ion electrospray) m/z 197 (MH+).
(e)
2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde
[0415] The alcohol (13d) (1.22 g) was oxidised with manganese
dioxide by the method of Example (4c) to afford a solid (0.7
g).
[0416] MS (-ve ion electrospray) m/z 193 (M-H.sup.-).
(f) Title Compound
[0417] This was prepared from amine (1e) (200 mg) and
carboxaldehyde (13e) (129 mg) by the method of Example (4d) to
provide the free base of the desired compound as a colourless solid
(138 mg).
[0418] .delta.H (CDCl.sub.3/CD.sub.3OD 250 MHz), 8.65 (1H, d), 8.52
(1H, d), 8.22 (1H, d), 8.10 (1H, d), 7.28 (1H, d), 7.21 (1H, d),
4.15 (3H, s), 3.90 (2H, s), 3.60 (2H, s), 2.74 (1H, m), 2.52 (1H,
m), 2.20 (4H, m), 1.70 (2H, m) 1.40 (2H, m). MS (+ve ion
electrospray) m/z 479 (MH+).
[0419] The oxalate salt was prepared by the method of Example 1
Example 14
Trans-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino-
]-cyclohexanecarboxylic acid (6-methoxy-quinolin-4-ylamide oxalate
salt
[0420] ##STR26##
[0421] This was prepared from amine (11c) (200 mg) and
carboxaldehyde (13e) (129 mg) by the method of Example (4d) to
provide the free base of the desired compound as a colourless solid
(43 mg).
[0422] .delta.H (CDCl.sub.3/CD.sub.3OD 250 MHz), 8.55 (1H,d), 8.07
(1H, d), 8.02 (1H, d), 7.90 (1H, d), 7.43 (1H, d), 7.38 (1H, dd),
7.30 (1H, d), 3.97 (3H, s), 3.90 (2H, s), 3.55 (2H, s), 2.60 (2H,
m), 2.10 (4H, m), 1.70 (2H, m) 1.30 (2H, m). MS (+ve ion
electrospray) m/z 478(MH+).
[0423] The oxalate salt was prepared by the method of Example 1
Example 15
Trans-4-[(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexaneca-
rboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate
salt
[0424] ##STR27## (a)
(3,4-Dihydro-2H-benzo[1,4]oxazin-6-yl)-methanol.
[0425] A solution of carboxaldehyde (8b) (1.45 g) in dry
tetrahydrofuran (100 mL) was treated with a 1M solution of lithium
aluminium hydride in diethyl ether (24 mL) and the mixture was
heated under reflux for 18 hours. It was cooled and a solution of
saturated sodium carbonate was added cautiously. Chloroform was
added and anhydrous sodium sulfate and the mixture was stirred for
1 hour and filtered. The fitrate was evaporated to afford a white
solid (0.70 g).
[0426] MS (-ve ion electrospray) m/z 164(M-H.sup.-).
(b) 3,4-Dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde and
4H-benzo[1,4]oxazine-6-carboxaldehyde.
[0427] A solution of the alcohol (15a) (0.22 g) in dichloromehane
(10 mL) was stirred with manganese dioxide (0.6 g) for 6 hours. It
was then filtered, evaporated and chromatographed on silica gel,
eluting with chloroform, to give a mixture of two aldehydes as an
oil (90 mg).
[0428] MS (+ve ion electrospray) m/z 162 and 164 (MH.sup.+)
(c) Title Compound.
[0429] This was prepared from amine (1e) (165 mg) and the mixture
of carboxaldehydes (15b) (90 mg) by the method of Example (4d). The
product in tetrahydrofuran (15 mL) and methanol (15 mL) was treated
with sodium cyanoborohydride (25 mg) for 18 hours. The mixture was
evaporated, treated with water and extracted with
chloroform-methanol (99:1), dried (sodium sulfate), evaporated and
chromatographed on silica gel (chloroform then
methanol-dichloromethane) to provide the title compound (free base)
as a colourless solid (55 mg).
[0430] .delta.H (CDCl.sub.3/CD.sub.3OD 250 MHz), 8.65 (1H,d), 8.50
(1H, d), 8.18 (1H, d), 7.22 (1H, d), 6.75 (2H, m), 6.60 (1H, dd),
4.25 (1H, m), 4.15 (3H, s), 3.92 (2H, s), 3.40 (4H, m), 3.00 (1H,
m), 2.65 (1H, m), 2.25 (4H, m), 1.70 (4H, m).
[0431] MS (+ve ion electrospray) m/z 448(W+).
[0432] The oxalate salt was prepared by the method of Example 1
Example 16
Trans-4-[Thiazolo[5,4-b]-pyridin-6-ylmethyl)-amino]-cyclohexanecarboxylic
acid (6-methoxy-[1,5]naphthyridinylamide oxalate salt
[0433] ##STR28## (a)
5-Amino-thioxo-1,6-dihydro-pyridine-3-carboxylic acid methyl
ester.
[0434] A mixture of sodium sulfide nonahydrate (2.17 g) and sulfur
(0.29 g) was heated in boiling water (20 mL) until the solution was
homogeneous and added to a solution of 6-chloro-5-nitronicotinic
acid methyl ester (see Example 13a) (3.10 g) in methanol (50 mL).
The mixture was boiled for 15 minutes and cooled. The resulting
disulfide was collected and washed with water to give a yellow
solid (2.46 g). The solid (5 g) in acetic acid (100 mL) and 4M HCl
in dioxan (50 mL) was treated with zinc dust (12 g) and the mixture
was stirred at room temperature for 30 minutes, filtered and
evaporated to dryness. Sodium acetate and sodium sulfate were added
and the mixture was extracted with warm chloroform and
chromatographed on silica gel, eluting with chloroform then
methanol-chloroform to afford a yellow solid (2.3 g).
[0435] MS (+ve ion electrospray) m/z 185(MH+)
(b) Thiazolo[5,4-b]pyridine-6-carboxylic acid methyl ester.
[0436] The amine (16a) (0.7 g) was heated in formic acid (30 mL)
under reflux for 30 minutes and was evaporated and chromatographed
on silica gel (chloroform) to give a solid (0.65 g).
[0437] MS (+ve ion electrospray) m/z 195(MH+)
(c) Thiazolo[5,4-b]pyridin-6-yl-methanol.
[0438] A solution of ester (16b) (200 mg) in dry tetrahydrofuran
(15 mL) and dry diethyl ether (15 mL), cooled to -45.degree. C.,
was treated with a 1M solution of lithium aluminium hydride in
diethyl ether (1.55 mL) and the mixture was heated under reflux for
18 hours. It was cooled and an aqueous solution of saturated sodium
carbonate was added cautiously. Dichloromethane and anhydrous
sodium sulfate were added and the mixture was stirred for 15
minutes and filtered. The fitrate was evaporated to afford a white
solid (95 mg).
[0439] MS (+ve ion electrospray) m/z 167(MH+)
(d) Thiazolo[5,4-b]pyridine-6-carboxaldehyde.
[0440] The alcohol (16c) (65 mg) in chloroform (10 mL) was stirred
with manganese dioxide (200 mg) for 5 hours, filtered and
evaporated and chromatographed on silica gel, eluting with
dichloromethane then chloroform, to give a solid (65 mg).
[0441] MS (+ve ion electrospray) m/z 165(MH+)
(e) Title Compound
[0442] This was prepared from amine (1e) (181 mg) and
carboxaldehyde (16d) (90 mg) by the method of Example (4d) to
provide the free base of the desired compound as a colourless solid
(89 mg).
[0443] .delta.H (CDCl.sub.3 250 MHz), 9.50 (1H, br.s) 9.15 (1H, s),
8.70 (2H, m), 8.55 (1H, d), 8.38 (1H, d), 8.25 (1H, d), 7.16 (1H,
d), 4.12 (3H, s), 4.10 (2H, s), 2.70 (1H, m), 2.48 (1H, m), 2.20
(4H, m), 1.70 (2H, m) 1.40 (2H, m). MS (+ve ion electrospray) m/z
449(MH+).
[0444] The oxalate salt was prepared by the method of Example 1
Example 17
Trans-4-[(8-Hydroxy-1-oxo-1,2-dihydro-isoquinolin-3-ylmethyl)-amino]-cyclo-
hexanecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
dihydrochloride salt
[0445] ##STR29## (a) Ethyl 2-methoxymethoxy-6-methylbenzoic
acid.
[0446] A solution of ethyl 2-hydroxy-6-methylbenzoic acid (4.56 g,
25.3 mmol) and diisopropylethylamine (13.2 mL, 76 mmol) in dry
dichloromethane (30 mL) was cooled in an ice-bath. Chloromethyl
methyl ether (3.83 mL, 50.6 mmol) was added slowly and the mixture
was allowed to stand at 0.degree. C., warming slowly to room
temperature. After 36 hours a further portion of chloromethyl
methyl ether (1.9 mL) was added and the mixture was left at room
temperature overnight. The mixture was then washed with 10% citric
acid, water and brine, dried and evaporated to give the title
compound (6.34 g, 100%).
[0447] MS (+ve ion electrospray) m/z 225 (MH+).
(b) 8-Methoxymethoxy-1-oxo-1H-isochromene-3-carboxylic acid ethyl
ester.
[0448] n-Butyllithium (1.6M in hexanes, 16.0 mL, 25.5 mmol) was
added to a solution of diisopropylamine (3.64 mL, 25.5 mmol) and
N,N,N',N'-tetraethylethylenediamine (4.01 mL, 25.5 mmol) in dry
tetrahydrofuran (36 mL) at -78.degree. C. After 10 min a solution
of the ester (17a, 5.10 g, 22.8 mmol) in dry tetrahydrofuran (18
mL) was added dropwise, keeping the internal temperature
<-60.degree. C. The deep red solution was stirred at -78.degree.
C. for 40 min, then diethyl oxalate (3.10 mL, 22.8 mmol) in
tetrahydrofuran (18 mL) was added over 5 min. The mixture was
stirred at -78.degree. C. for 6.5 hours, then treated with 10%
citric acid. After warming to room temperature the phases were
separated and the aqueous phase was extracted with ethyl acetate.
The combined organic phases were washed with brine, dried and
evaporated. Chromatography on silica gel (20-40% ethyl
acetate/hexane) gave the title compound (2.05 g, 32%).
[0449] MS (+ve ion electrospray) m/z 235 (loss of methoxymethyl
from MH+).
(c) 8-Methoxymethoxy-1,2-dihydro-1-oxo-isoquinoline-3-carboxylic
acid ethyl ester.
[0450] The isochromene (17b, 2.04 g, 7.34 mmol) was heated under
reflux with ammonium acetate (4.99 g) in ethanol (200 mL) for 24
hours. Solvent was evaporated and the residue was dissolved in
ethyl acetate and water. The aqueous phase was extracted with ethyl
acetate and combined organics were washed with water, dried and
evaporated. Chromatography on silica gel (50-100% ethyl
acetate/hexane) gave impure product and recovered isochromene. The
latter was treated again with ammonium acetate (1.3 g) in refluxing
ethanol (50 mL) for 48 hours, then worked up as before. The crude
material was combined with the initial impure product for
chromatography on silica gel (0-2% methanol/dichloromethane).
Eluted material was re-chromatographed (50-100% ethyl
acetate/hexane) to give the title compound (0.87 g, 42%).
[0451] MS (+ve ion electrospray) m/z 278 (MM+).
(d) 8-Hydroxy-3-hydroxymethyl-2H-isoquinolin-1-one.
[0452] The ester (17c, 0.66 g, 2.38 mmol) and sodium borohydride
(0.14 g, 3.6 mmol) were heated in refluxing tert-butanol (3 mL)
while methanol (0.6 mL) was added over 1 hour. Heating was
continued for 2 hours, then the cooled mixture was partitioned
between ethyl acetate and water. The aqueous phase was re-extracted
with ethyl acetate and the combined organics were washed with
brine, dried and evaporated to give the title compound (0.51 g,
91%).
[0453] MS (+ve ion electrospray) m/z 236 (MH+).
(e)
8-Methoxymethoxy-1,2-dihydro-1-oxo-isoquinoline-3-carboxaldehyde
[0454] The alcohol (17d, 0.51 g, 2.17 mol) was stirred with
manganese (IV) oxide (3.12 g) in 1:1
dichloromethane/tetrahydrofuran (40 mL) at room temperature for 5
hours. The mixture was filtered and evaporated to give the aldehyde
(0.32 g, 63%).
[0455] MS (-ve ion electrospray) m/z 232 (M-H.sup.-).
(f)
4-[(8-Methoxymethoxy-1-oxo-1,2-dihydro-isoquinolin-3-ylmethyl)-amino-
]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide
[0456] The aldehyde (17e, 0.23 g, 0.99 mol) and amine (1e, 0.30 g,
1 mmol) were heated with 3 .ANG. molecular sieves under reflux in
dry chloroform (8 mL) and methanol (1 mL) for 7 hours. After
cooling, sodium triacetoxyborohydride (1.06 g, 5 mmol) was added
and the mixture was stirred at room temperature for 3 days. Water
and dichloromethane were added, the aqueous phase was basified with
sodium carbonate and extracted with dichloromethane. Combined
organics were washed with water, dried and evaporated.
Chromatography on silica gel (2-10% methanol/dichloromethane) gave
the title compound (0.157 g, 30%).
[0457] MS (+ve ion electrospray) m/z 518 (MH+).
(g) Title Compound.
[0458] The methoxymethyl compound (17f, 0.157 g, 0.3 mmol) was
partially dissolved in 5M hydrochloric acid (10 mL) and 1,4-dioxane
(10 mL) and stirred at room temperature for 3.5 hours. Evaporation
to dryness gave the title compound (0.16 g, 98%).
[0459] .delta.H (CDCl.sub.3, 250 MHz), 12.88 (1H, br s), 11.92 (1H,
s), 10.30 (1H, s), 9.69 (1H, br s), 8.91 1H, d), 8.68 (1H, d), 8.50
(1H, d), 7.59 (2H, m), 7.09 (1H, d), 6.92 (1H, s), 6.86 (1H, d),
4.24 (3H,s), 4.16 (2H, m), 3.19 (1H, m), 2.29 (1H, m), 2.26 (2H,
m), 2.15 (2H, m), 1.59 (4H, m). MS (+ve ion electrospray) m/z 474
(MH.sup.+)
Example 18
Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-ylmethyl)-amino]-cycloh-
exanecarboxylic acid (6methoxy-[1,5]naphthyridin-4-yl)amide oxalate
salt
[0460] ##STR30## (a)
2-(2-Iodo-6-methyl-pyridin-3-yloxy)-ethanol.
[0461] 2-Iodo-6-methyl-pyridin-3-ol (6.49 g, 27.6 mmol) was
dissolved in an aqueous solution of sodium hydroxide (1M, 30 mL).
2-bromoethanol (3.91 mL, 55.2 mmol) was added dropwise and then the
solution was heated to 100.degree. C. for 3 hours. The resulting
mixture was extracted with chloroform (2.times.200 mL) and the
combined organic phases then back extracted with aqueous sodium
hydroxide solution (1M, 50 mL). The organic phase was dried over
magnesium sulfate and the volatiles removed in vacuo to afford the
desired product (5.26 g) which was used without further
purification.
[0462] MS (APCI+) m/z 210 (MH+).
(b) 6-Methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine.
[0463] Alcohol (18a) (6.52 g, 23.37 mmol) was dissolved in
N,N'-dimethylformamide (30 mL) and cooled to 0.degree. C. To this
was added sodium hydride (60% w/w, 1.12 g, 28.04 mmol), powdered
copper (0.62 g, 9.82 mmol) and copper(II)sulfate (1.87 g, 11.69
mmol). The resulting slurry was heated to 100.degree. C. for 18
hours and then the solvent removed under reduced pressure. The
residue was partitioned between ethyl acetate (2.times.100 mL) and
water (25 mL). The organic phases were combined and dried over
magnesium sulfate then the volatiles removed in vacuo. The residue
was subjected to purification on silica gel using a dichloromethane
and methanol gradient. This afforded the desired product as a brown
crystalline solid (480 mg, 14%).
[0464] MS (APCI+) m/z 152 MH+).
(c) 6-Methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-N-oxide.
[0465] Pyridyldioxin (18b) (190 mg, 1.26 mmol) was dissolved in
dichloromethane (10 mL) and cooled to 0.degree. C. To this solution
was added meta-chloroperbenzoic acid (388 mg, 1.26 mmol) and string
was continued for 5 hours at room temperature. The volatiles were
removed under reduced pressure and the residue purified on silica
gel using a dichloromethane and methanol gradient. This provided
the desired compound as a white solid (146 mg, 69%).
[0466] MS (APCI+) m/z 168 (MH+).
(d) Acetic acid 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-ylmethyl
ester.
[0467] N-oxide (18c) (146 mg, 0.874 mmol) was dissolved in acetic
anhydride (5 mL). The solution was heated to reflux for 10 hours
after which time the volatiles were removed This afforded the
desired product which was used without further purification.
(e) (2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-methanol
[0468] Ester (18d) (182 mg, 0.87 mmol) was dissolved in a mixture
of tetrahydrofuran and water (1:1, 4 mL) and treated with sodium
hydroxide (70 mg, 1.74 mmol). The resulting solution was stirred at
room temperature for 12 hours after which time the solvent was
removed under reduced pressure. The product obtained in this
fashion was used without further purification.
(f) 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-6-carbaldehyde
[0469] Alcohol (18e) (145 mg, 0.87 mmol) was dissolved in
dichloromethane (5 mL) and treated with manganese dioxide (151 mg,
1.74 mmol). The resulting slurry was stirred at room temperature
and after 5 hours a further batch of manganese dioxide (151 mg,
1.74 mmol) was added. The slurry was stirred for a further 10 hours
and then filtered through Celite and the volatiles removed in
vacuo. The residue was purified on silica gel to afford the desired
product (95 mg, 66%).
[0470] MS (APCI+) m/z 166 (MH+).
(g) Title Compound.
[0471] This was prepared from amine (1e) (260 mg, 0.864 mmol) and
carboxaldehyde (18f) (95 mg, 0.576 mmol) by the method of Example
(4d) to provide the free base of the desired compound as a
colourless solid (220 mg, 85%).
[0472] .delta.H (CDCl.sub.3, 250 MHz), 9.48 (1H, s), 8.67 (1H, d),
8.50 (1H, d), 8.24 (1H, d), 7.18 (1H, d), 7.14 (1H, d), 6.91 (1H,
d), 4.45 (2H, m), 4.27 (2H, m), 4.13 (3H, s), 3.99 (2H, s), 2.76
(1H, m), 2.45 (1H, m), 2.20-2.15 (4H, m), 1.74-1.51 (4H, m). MS
(+ve ion electrospray) m/z 450 (NM+).
[0473] The oxalate salt was prepared by the method of Example
1.
Example 19
Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-cycloh-
exanecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
oxalate salt
[0474] ##STR31## (a) 4,5-Dihydroxy-pyridine-2-carboxylic acid ethyl
ester.
[0475] 4,5-Dihydroxy-pyridine-2-carboxylic acid (844 mg, 5.45 mmol)
was dissolved in ethanol (20 mL). Gaseous hydrochloric acid was
bubbled through the mixture for 5 minutes whilst it was cooled in
an ice bath The solution was then heated to reflux for 2 hours.
This procedure was repeated a further two times and then the
mixture heated for 24 hours. The volatiles were removed in vacuo
and water added (5 mL). This was also removed under reduced
pressure. The hydrochloride salt of the desired product was
produced in this way and used without further purification.
[0476] MS (APCI+) m/z 184 (MH+).
(b) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxylic acid ethyl
ester.
[0477] Ester (19a) (540 mg, 2.95 mmol) was dissolved in
N,N'-dimethylformamide and potassium carbonate (1.22 g, 8.85 mmol)
was added. The mixture was slurried by stirring rapidly and
1,2-dibromoethane (0.51 mL, 5.90 mmol) was added. The reaction was
heated to 70.degree. C. for 10 hours after which time the solvent
was removed under reduced pressure. The residue was subjected to
column chromatography on silica gel using a dichloromethane and
methanol gradient. This provided the desired compound as a brown
solid (284 mg, 46%).
[0478] MS (APCI+) m/z 210 (MH+).
(c) (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol.
[0479] Pyridyldioxin (19b) (284 mg, 1.36 mmol) was dissolved in
tetrahydrofuran (10 mL) and cooled to -30.degree. C. A solution of
lithium aluminium hydride (1M, 2.72 mL, 2.72 mmol) was added
dropwise. The solution was allowed to warm to room temperature over
2 hours after which time the reaction was quenched by the addition
of water (2 mL). The volatiles were removed in vacuo and the
residue partitioned between ethyl acetate/chloroform (2.times.200
mL) and a saturated solution of sodium hydrogen carbonate (20 mL).
The organic phases were combined and dried over magnesium sulfate.
The solvent was removed under reduced pressure and the residue
purified on silica gel using a methanol and dichloromethane solvent
gradient. This provided the desired compound as a colourless oil
(98 mg, 43%).
[0480] MS (APCI+) m/z 168 (MH+).
(d) 2,3-Dihydro-[1,4]dioxino[2,3-c)pyridine-7-carbaldehyde.
[0481] Alcohol (19c) (98 mg, 0.587 mmol) was dissolved in
dichloromethane (10 mL) and manganese dioxide (152 mg, 1.76 mmol)
was added. The slurry was stirred at room temperature for 3 hours
and then another batch of manganese dioxide (152 mg, 1.76 mmol)
added. After 10 hours further stirring at room temperature the
oxidant was removed by filtration through Celite and the solvent
removed under reduced pressure to provide the desired product which
was used without further purification
[0482] MS (APCI+) m/z 166 (MH+).
(e) Title Compound
[0483] This was prepared from amine (1e) (1.76 mg, 0.587 mmol) and
aldehyde (19f). (65 mg, 0.392 mmol) by the method of Example (4d)
to provide the free base of the desired compound as a colourless
solid (120 mg, 68%).
[0484] .delta.H (CDCl.sub.3, 250 MHz), 9.47 (1H, s), 8.69 (1H, d),
8.53 (1H, d), 8.25 (1H, d), 8.08 (1H, s), 7.16 (1H, d), 6.87 (1H,
s), 4.40-4.30 (4H, m), 4.13 (3H, s), 4.04 (2H, s), 2.77 (1H, m),
2.48 (1H, m), 2.30-2.06 (4H, m), 1.69-1.57 (4H, m). MS (+ve ion
electrospray) m/z 450 (MH+).
[0485] The oxalate salt was prepared by the method of Example
1.
Example 20
Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)-amino]-cycloh-
exanecarboxylic acid (6methoxy-[1,5]naphthyridin-4-yl)amide oxalate
salt
[0486] ##STR32## (a) 5-Bromo-pyridine-2,3-diol.
[0487] This compound was made according to the procedure of
Dallacker, F; Fechter, P; Mues, V Journal Z. Naturforsch, 1979,
34b, 1729-1736 from 2-furaldehyde.
[0488] MS (APCI+) m/z 190/192 (MH+).
(b) 7-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine.
[0489] Diol (20a) (13.50 g, 71.43 mmol) was treated in a similar
manner to Example (19b) to obtain the desired compound as a brown
oily solid (1.14 g, 7%).
[0490] MS (APCI+) m/z 216/218 (MH+).
(c) 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylic acid butyl
ester.
[0491] Bromide (20b) was slurried in butanol at room temperature
and degassed with a stream of carbon monoxide gas for 10 minutes.
1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL, 3.38 mmol), palladium
dichloride (30 mg, 0.169 mmol) and
1,3-bis(diphenylphosphino)propane (139 mg, 0.338 mmol) was added.
The mixture was heated to 100.degree. C. under an atmosphere of
carbon monoxide for 12 hours. The volatiles were then removed under
reduced pressure and the residue partitioned between ethyl acetate
(2.times.100 mL) and water (20 mL). The organic phases were
combined and dried over magnesium sulfate. The solvent was once
again removed in vacuo and the residue subjected to purification on
silica gel employing an ethyl acetate and hexane solvent gradient.
This provided the desired product as a colourless oil (0.436 g,
54%).
[0492] MS (APCI+) m/z 238 (MH+).
(d) (2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-methanol.
[0493] Ester (20c) was dissolved in tetrahydrofuran (10 mL) The
solution was cooled to 0.degree. C. and a solution of lithium
aluminium hydride in tetrahydrofuran (1M, 3.68 mL, 3.68 mmol) was
added dropwise. The reaction was stirred at 0.degree. C. for 1 hour
and then quenched by the addition of water (2 mL). The volatiles
were removed in vacuo and the residue partitioned between ethyl
acetate (3.times.100 mL) and water (20 mL). The organic phases were
combined and concentrated to provide the desired compound which was
used without further purification (320 mg).
[0494] MS (APCI+) m/z 168 (MH+).
(e) 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbaldehyde
[0495] The alcohol (20d) was transformed into an aldehyde according
to the procedure used in Example (19d). This provided the desired
compound as a colourless oil (282 mg, 89%).
[0496] MS (APCI+) m/z 166 (MH+).
(f) Title Compound
[0497] This was prepared from amine (1e) (252 mg, 0.836 mmol) and
aldehyde (20e) (138 mg, 0.836 mmol) by the method of Example (4d)
to provide the free base of the desired compound as a colourless
solid (195 mg, 52%).
[0498] .delta.H (CDCl.sub.3, 250 Mz), 9.50 (1H, s), 8.67 (1H, d),
8.51 (1H, d), 8.25 (1H, d), 7.79 (1H, d), 7.30 (1H, d), 7.15 (1H,
d), 4.50 (2H, m), 4.27 (2H, m), 4.13 (3H, s), 3.84 (2H, s), 2.73
(1H, m), 2.48 (1H, m), 2.20-2.10 (4H, m), 1.72-1.60 (2H, m),
1.55-1.40 (2H, m). MS (+ve ion electrospray) m/z 450 (NH+).
[0499] The oxalate salt was prepared by the method of Example
1.
Example 21
Trans-6-({4-[2-Hydroxy-2-(6-methoxy-quinolin-4-yl)ethyl]-cyclohexylamino}--
methyl)-4-H-benzo[1,4]thiazin-3-one oxalate salt
[0500] ##STR33## (a)
2-(4-tert-Butoxycarbonylamino-cyclohexyl)-3-(6-methoxy-quinolin-4-yl)-3-o-
xo-propionic acid methyl ester.
[0501] (4-Tert-Butoxycarbonylamino-cyclohexyl)-acetic acid methyl
ester (1.00 g, 3.69 mmol) was dissolved in tetrahydrofuran (20 mL)
and cooled to -78.degree. C. To the solution lithium
hexamethyldisilazide in tetrahydrofuran (1M, 11.0 mL, 11.0 mmol)
was added dropwise. The reaction mixture was stirred for 20 minutes
at -78.degree. C. and then 6-methoxy-quinolin-4-carboxylic acid
methyl ester (1.60 g, 7.38 mmol) was added as a solution in
tetrahydrofuran (10 mL). The mixture was allowed to warm to room
temperature and stirred for 12 hours. The reaction was quenched by
the addition of water (2 mL), the solvent removed in vacuo and the
residue partitioned between ethyl acetate (2.times.100 mL) and
water (20 mL). The pH of the aqueous phase was adjusted to 10 to
obtain the maximum degree of extracted material into the organic
phases. The organic phases were combined, dried over magnesium
sulfate and the volatiles removed under suction. The resulting
residue was purified by column chromatography on silica gel using
an ethyl acetate and hexane solvent gradient to provide the desired
compound as a colourless oil (190 mg, 12%).
[0502] MS (APCI+) m/z 457 (MH+).
(b) 2-(4-Amino-cyclohexyl)1-(6-methoxy-quinolin-4-yl)-ethanone
hydrochloride.
[0503] Ketone (21a) (190 mg, 0.42 mmol) was dissolved in an aqueous
solution of hydrochloric acid (5M, 10 mL). The solution was
refluxed under argon for 5 hours and then the volatiles were
removed in vacuo. This provided the desired product as a
hydrochloride salt (154 mg).
[0504] MS (APCI+) m/z 299 (MH+).
(c)
{4-[2-(6-Methoxy-quinolin-4-yl)-2-oxo-ethyl]-cyclohexyl}-carbamic
acid tert-butyl ester.
[0505] Amine hydrochloride (21b) (2.77 g, 8.28 mmol) was dissolved
in dichloromethane (20 mL), triethylamine (3.46 mL, 24.84 mmol) was
then added. Di-tert butyl dicarbonate (1.80 g, 8.28 mmol) was added
to the solution and the reaction mixture stirred at room
temperature for 6 hours. The organic phase was extracted with a
saturated solution of sodium hydrogen carbonate (20 mL). The
organic phase was dried over magnesium sulfate and the volatiles
removed in vacuo. The residue was purified on silica gel using a
dichloromethane and methanol solvent gradient. This provided the
desired product as a colourless oil.
[0506] MS (APCI+) m/z 399 (MH+).
(d)
{4-[2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-cyclohexyl}-carbami-
c acid tert-butyl ester.
[0507] Ketone (21c) (862 mg, 2.17 mmol) was dissolved in
iso-propanol (10 mL) and the solution cooled to 0.degree. C. To
this, sodium borohydride (125 mg, 3.25 mmol) was added and the
resulting slurry stirred at 0.degree. C. for 3 hours. The volatiles
were removed under reduced pressure and the residue partitioned
between ethyl acetate (2.times.100 mL) and water (20 mL). The
organic phases were combined and dried over magnesium sulfate and
then the solvent removed in vacuo. This provided the desired
compound which was used without further purification.
[0508] MS (APCI+) m/z 401 (MH+).
(e) Title Compound
[0509] Alcohol (21d) was dissolved in dichloromethane, cooled to
0.degree. C. and treated with trifluoroacetic acid. The solution
was stirred at room temperature for 3 hours and then concentrated
under vacuum. The residue was treated with an aqueous solution of
sodium hydroxide (1M, 10 mL) and then concentrated in vacuo. The
residue was dissolved in chloroform (10 ml) and methanol (5 mL),
aldehyde (4c) (170 mg; 0.825 mmol) added, and the mixture was
heated at reflux with 3 .ANG. molecular sieves (2 g) for 12 hours.
The slurry was then cooled and sodium triacetoxyborohydride (525
mg, 2.48 mmol) adde. This was stirred at room temperature for 48
hours. The slurry was filtered through Celite and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel employing a dichloromethane and methanol solvent gradient. This
provided the desired product as a white solid (226 mg, 57%).
[0510] .delta.H (CD.sub.3OD, 250 MHz), 8.66 (1H, d), 7.95 (1H, d),
7.66 (1H, d), 7.44-7.33 (3H, m), 7.13 (1H, dd), 7.07 (1H, d), 5.50
(1H, m), 4.18 (2H, s), 3.95 (3H, s), 3.44 (2H, s), 3.14-3.09 (1H,
m), 2.36-2.19 (3H, m), 1.91-1.65 (4H, m), 1.55-1.40 (2H, m),
1.25-1.05 (2H, m). MS (APCI+) m/z 478(MH+).
[0511] The oxalate salt was prepared by the method of Example
1.
Example 22
Trans-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-1-
-(6-methoxy-quinolin-4-yl)-ethanol oxalate salt
[0512] ##STR34## (a)
2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-1-(6-m-
ethoxy-quinolin-4-yl)-ethanone.
[0513] Amine hydrochloride (21b) (233 mg, 0.697 mmol) was dissolved
in N,N'-dimethylformamide (5 mL). To the solution potassium
carbonate (289 mg, 2.09 mmol) was added followed by mesylate (5b)
(256 mg, 1.045 mmol). The mixture was stirred at room temperature
for 10 hours and then the volatiles were removed in vacuo. The
residue was purified by column chromatography on silica gel using a
methanol and dichloromethane solvent gradient. This provided the
desired product as a colourless oil (42 mg, 14%).
[0514] MS (APCI+) m/z 447(MH+).
(b) Title Compound.
[0515] Ketone (22a) was dissolved in iso-propanol (1 mL) and cooled
to 0.degree. C. The solution was treated with sodium borohydride (7
mg, 0.168 mmol). Stirring was continued at room temperature for 10
hours and then the volatiles removed under reduced pressure. The
residue was purified on silica gel using a dichloromethane and
methanol solvent gradient. This provided the free base of the
desired compound as a colourless oil (25 mg, 50%).
[0516] .delta.H (CDCl.sub.3, 250 MHz), 8.71 (1H, d), 8.01 (1H, d),
7.55 (1H, d), 7.36 (1H, dd), 7.15 (1H, d), 6.76 (3H, m), 5.42 (1H,
dd), 4.22 (4H, s), 3.92 (3H, s), 3.69 (2H, s), 2.59-2.50 (2H, m),
2.21-2.08 (1H, m), 2.08-1.95 (2H, m), 1.85-1.60 (4H, m), 1.35-1.20
(2H, m), 1.17-1.00 (2H, m). MS (APCI+) m/z 449 (+).
[0517] The oxalate salt was prepared according to the method in
Example 1.
Example 23
Trans-4-[(6-Nitro-benzo[1,3]dioxol-5-ylmethyl)-amino]-cyclohexanecarboxyli-
c acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt
[0518] ##STR35##
[0519] A solution of amine (1e) (0.3 g, 1 mmol) and
6-nitro-benzo[1,3]dioxole-5-carbaldehyde (0.21 g, 1.1 mmol) in
chloroform/methanol (2 ml/1 ml) was stirred for 1 h. The resulting
precipitate (imine) was dissolved by the addition of more methanol
(3 ml) and treated with sodium borohydride (80 mg, 2.2 mmol). After
1 h the mixture was partitioned between chloroform and water. The
organic extract was dried and evaporated to give an oil (0.4 g).
Chromatography on silica eluting with a methanol-ethyl acetate
gradient afforded the free base of the title compound (0.16 g,
33%).
[0520] .delta.H (CDCl.sub.3, 250 MHz), 9.50 (1H, bs), 8.70 (1H, d),
8.55 (1H, d), 8.20 (1H, d), 7.50 (1H, d), 7.15 (1H, d), 7.10 (1H,
s), 6.10 (2H, s), 4.15 (3H, s), 4.00 (2H, s), 2.65-2.60 (1H, m),
2.40-2.35 (1H, m), 2.20-2.10 (4H, m), 1.80-1.60 (2H, m), 1.30-1.20
(2H, m). MS (+ve ion electrospray) m/z 480 (MH+).
[0521] This was converted to the oxalate salt according to the
procedure of Example 1.
Example 24
Trans-4-[(6-Amino-benzo[1,3]dioxol-5-ylmethyl)-amino]-cyclohexanecarboxyli-
c acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dioxalate salt
[0522] ##STR36##
[0523] This was prepared from nitro compound (23a) (100 mg, 0.223
mmol) by hydrogenation in the presence of 10% palladium metal on a
carbon support (20 mg). After 5 hours the catalyst was removed by
filtration through Celite and the solvent removed under reduced
pressure. The residue was purified by column chromatography on
silica gel using a methanol and dichloromethane solvent gradient.
This provided the free base of the desired compound as a colourless
oil (56 mg, 60%).
[0524] .delta.H (CDCl.sub.3, 250 MHz), 9.50 (1H, s), 8.70 (1H, d),
8.51 (1H, d), 8.22 (1H, d), 7.16 (1H, d), 6.59 (1H, s), 6.29 (1H,
d), 5.86 (2H, s), 4.12 (3H, m), 3.78 (2H, s), 2.60 (1H, m), 2.43
(1H, m), 2.21-2.15 (4H, m), 1.75-1.61 (2H, m), 1.32-1.26 (2H, m).
MS (APCI+) m/z 450 (MH+).
[0525] The dioxalate salt was prepared by a method analogous to
that of Example 1.
Example 25
Trans-4-[(Benzothiazol-5-ylmethyl)-amino]cyclohexanecarboxylic
acid(6methoxy-[1,5]naphthyridine-4-yl)amide oxalate salt
[0526] ##STR37## (a) Benzothiazol-5-ylcarboxylic acid.
[0527] 4-Chloro-3-nitrobenzoic acid (22 g, 0.11 mol) was suspended
in water, sodium hydroxide (4.33 g, 0.11 mol) and sodium sulfide
hydrate (32 g) were added, and the mixture heated at reflux for 24
hours. After acidification with 5M hydrochloric acid the mixture
was extracted with ethyl acetate. The extracts were dried over
magnesium sulfate and evaporated under reduced pressure. The
product from this reaction (1 g, 5.9 mmol) was dissolved in formic
acid and heated at reflux in the presence of zinc (0.1 g) for 6
hours. The mixture was allowed to cool and was concentrated under
reduced pressure. The residue was diluted with water and
neutralised with saturated aqueous sodium hydrogen carbonate.
Extraction with tetrahydrofuran and ethyl acetate (1:1) gave a pale
yellow solid (0.48 g) that was purified on silica gel using a
methanol dichloromethane gradient.
(b) Benzothiazol-5-ylcarbaldehyde.
[0528] This was prepared from carboxylic acid 23(b) by the method
of 4(b) and (c).
[0529] .delta.H (CDCl.sub.3, 250 MHz), 10.17 (1H, d), 9.14 (1H, s),
8.60 (1H, d), 8.12 (1H, d), 8.00 (1H, dd),
(c) Title Compound.
[0530] Amine (1e) (0.20 g, 0.66 mmol) and
benzothiazol-5-ylcarbaldehyde (0.11 g, 0.67 mmol) were heated at
reflux in methanol (1 mL) and chloroform (4 mL) in the presence of
3 .ANG. sieves for 8 hours. The mixture was then cooled to room
temperature and sodium triacetoxyborohydride (0.4 g) added. After
24 hours further sodium triacetoxyborohydride (0.3 g) was added and
a further addition (0.2 g) was made after another 8 hours. After
stirring for 14 hours the mixture was diluted with methanol and
solid sodium hydrogen carbonate added. After stirring for 0.25
hours the mixture was filtered and evaporated. Purification on
silica gel eluting with methanol dichloromethane mixtures gave the
free base of the title compound (0.143 g, 48%).
[0531] .delta.H (CDCl.sub.3, 250 MHz), 9.45 (1H, s), 9.02 (1H, s),
8.68 (1H, d), 8.58-8.39 (2H, m), 8.26 (1H, d), 8.17 (1H, d), 7.97
(1H, d), 7.54 (1H, dd), 7.17 (1H, d), 4.20-4.07 (2H, m), 4.13 (3H,
s), 2.95-2.80 (1H, m), 2.53-2.37 (1H, m), 2.33-2.00 (4H, m),
1.72-1.49 (4H, m). MS (APCI+) m/z 448 (MH+).
[0532] The oxalate salt was prepared by the method of Example
1.
Example 26
Trans-4-[(4-Oxo-4H
pyrido[1,2-a]pyrimidin-2-ylmethyl)-amino]-cyclohexanecarboxylic
acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt
[0533] ##STR38##
[0534] A mixture of amine (1e) (0.5 g, 1.7 mmol) and
2-chloromethyl-pyrido[1,2-a]pyrimidin-4-one (0.32 g, 1.7 mmol)
(prepared by the method of W. Boehme and K. Heinrich, Arch Pharm,
1977, 310, 26) and potassium carbonate (0.25 g, 1.8 mmol) in
N,N-dimethylformamide (15 ml) was heated at 40.degree. C. for 16 h.
The mixture was partitioned between ethyl acetate and water. The
organic extract was dried and evaporated. Chromatography on silica
gel eluting with a methanol-ethyl acetate gradient afforded the
free base of the title compound as an oil (0.17 g, 22%).
[0535] .delta.H (CDCl.sub.3, 250 MHz), 9.50 (1H, bs), 9.00 (1H, d),
8.70 (1H, d), 8.55 (1H, d), 8.20 (1H, d), 7.70 (1H, m), 7.60 (1H,
d), 7.20-7.10 (2H, m), 6.55 (1H, s), 4.10 (3H, s), 3.90 (2H, s),
2.65-2.60 (1H, m), 2.40-2.35 (1H, m), 2.20-2.10 (4H, m), 1.80-1.60
(2H, m), 1.30-1.20 (2H, m). MS (+ve ion electrospray) m/z 459
(MH+).
[0536] This was converted to the oxalate salt according to the
procedure of Example 1.
Example 27
Trans-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-1-
-(6-methoxy-quinolin-4-yl)-ethanone oxalate salt
[0537] ##STR39##
[0538] Amine hydrochloride (21b) (233 mg, 0.697 mmol) was dissolved
in N,N-dimethylformamide (5 mL). To this was added potassium
carbonate (289 mg, 2.09 mmol) and mesylate (5b) (256 mg, 1.045
mmol). The resulting slurry was stirred at room temperature for 48
hours and then the solvent was removed under reduced pressure. The
residue was purified by column chromatography on silica gel using a
dichloromethane and methanol solvent gradient. This provided the
desired compound as a colourless oil (42 mg, 14%).
[0539] .delta.H (CDCl.sub.3, 250 MHz), 8.85 (1H, d), 8.03 (1H, d),
7.79 (1H, d), 7.55 (1H, d), 7.41 (1H, dd), 6.87-6.82 (3H, m), 4.23
(4H, s), 3.92 (3H, s), 3.69 (2H, s), 2.91 (2H, d), 2.57-2.48 (1H,
m), 2.04-2.01 (2H, m), 1.91-1.86 (2H, m), 1.37-1.25 (2H, m),
1.15-1.01 (2H, m). MS (+ve ion electrospray) m/z 447 (MH+).
[0540] This was converted to the oxalate salt according to the
procedure of Example 1.
Example 28
Trans
4-[(3-Oxo-3,4-dihydro-2-H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclo-
hexanecarboxylic acid (6-methoxy-quinolin-4-yl)-amide
[0541] ##STR40##
[0542] Amine (11c) (389 mg, 1.295 mmol) and aldehyde (4c) (250 mg,
1.295 mmol) were heated at reflux in methanol (1 mL) and chloroform
(4 mL) in the presence of 3 .ANG. sieves for 8 hours. The mixture
was then cooled to room temperature and sodium
triacetoxyborohydride (0.83 g) added. After 24 hours further sodium
triacetoxyborohydride (0.55 g). After stirring for 48 hours the
mixture was evaporated under reduced pressure. Purification on
silica gel eluting with methanol dichloromethane mixtures gave the
free base of the title compound as a white solid (311 mg, 56%).
[0543] .delta.H (d.sup.6-DMSO, 250 MHz), 9.98 (1H, s), 8.62 (1H,
d), 7.98 (1H, d), 7.90 (1H, d), 7.60 (1H, d), 7.43 (1H, dd), 7.27
(1H, d), 7.00 (2H, m), 3.95 (3H, s), 3.79 (2H, m), 3.45 (2H, s),
2.69 (1H, m), 2.50 (1H, m), 2.09-1.90 (4H, m), 1.56-1.49 (2H, m),
1.37-1.23 (2H, m). MS (APCI+) m/z 477 (MH+).
Example 29
Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarbo-
xylic acid [6-(3-amino-propoxy)-[1,5]naphthyridin-4-yl]-amide
dioxalate
[0544] ##STR41## (a) 8-Amino1-H-[1,5]naphthyridin-2-one
hydrobromide.
[0545] A suspension of amine (1c) (4.20 g, 24 mmol) in concentrated
hydrobromic acid (35 mL) was heated at 120.degree. C. for 2 h. The
mixture was set aside in the fridge for 2 h, then filtered, washing
with small amounts of cold water then diethyl ether. Drying in
vacuo afforded the product as a white solid (6.1 g, 100%).
[0546] MS (+ve ion electrospray) m/z 162 (MH+).
(b) [3-(8-Amino-[1,5]naphthyridin-2-yloxy)-propyl]-carbamic acid
benzyl ester.
[0547] A suspension of hydrobromide salt (29a) (1.2 g, 5 mmol) in
N,N-dimethylformamide (10 mL) at 40.degree. C. was treated with
potassium carbonate (2.1 g, 15 mmol) then after 0.25 h with a
solution of (3-bromo-propyl)-carbamic acid benzyl ester (2 g, 7.4
mmol) in N,N-diethylformamide (5 mL). The mixture was heated for 4
h at 40.degree. C., then evaporated to dryness. The residue was
partitioned between ethyl acetate and dilute aqueous sodium
chloride solution. The organic extract was dried and evaporated to
give a brown oil (2.2 g) This was chromatographed on silica eluting
with a methano/ethyl acetate gradient affording the product as a
clear oil (1.0 g, 57%).
[0548] MS (+ve ion electrospray) m/z 353 (MH+).
(c)
{4-[6-(3-Benzyloxycarbonylamino-propoxy)-[1,5]naphthyridin-4-ylcarba-
moyl]-cyclohexyl}-carbamic acid tert-butyl ester.
[0549] A solution of
trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (0.7 g,
2.8 mmol) and triethylamine (0.43 mL, 0.3 g, 3.1 mmol) in
N,N'-dimethylformamide (3 mL) was treated with
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramnethyluronium
hexafluorophosphate (1.1 g, 2.84 mmol). After 0.5 h the amine (29b)
(1.0 g, 2.84 mmol) in N,N'-diethylformamide (7 mL) was added and
the mixture was heated at 60.degree. C. for 22 h The mixture was
evaporated and the residue was partitioned between ethyl acetate
and dilute aqueous sodium chloride solution. The organic extract
was dried and evaporated to give a brown oil (2.1 g) This was
chromatographed on silica eluting with a methanol/ethyl acetate
gradient affording the product as a clear oil (0.9, 55%).
[0550] MS (+ve ion electrospray) m/z 578 (MH+).
(d) [3-(8-{
(1-(4-Amino-cyclohexyl)-methanoyl]-amino}-[1,5]naphthyridin-2-yloxy)-prop-
yl]-carbamic acid benzyl ester.
[0551] A solution of (29c) (29 g, 0.52 mmol)in trifluoroacetic
acid/dichloromethane (5 mL/5 mL) was maintained at room temperature
for 0.25 h then evaporated to dryness. The residue was partitioned
between ethyl acetate and saturated aqueous sodium bicarbonate
solution. The organic extract was dried and evaporated.
Chromatography on silica eluting with a methanol/ethyl acetate
gradient afforded an oil (0.15 g, 60%).
[0552] MS (+ve ion electrospray) m/z 478 (MH+).
(e)
(3-{8-[(1-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]cycloh-
exyl}-methanoyl)-amino]-[1,5]naphthyridin-2-yloxy}-propyl)carbamic
acid benzyl ester
[0553] A solution of (29d) (0.15 g, 0.3 mmol) and
2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehyde (82 mg, 0.5 mmol) in
methanol/dichloromethane (0.3 mL/2.7 mL) was treated with
freshly-activated 3 .ANG. molecular sieves and heated to reflux
under argon for 2 h Sodium triacetoxyborohydride (0.21 g, 1 mol)
was added and the mixture was stirred at 40.degree. C. for 1 h. The
mixture was partitioned between ethyl acetate and saturated aqueous
sodium bicarbonate solution. The organic extract was dried and
evaporated to give a brown oil. Chromatography on silica eluting
with a methanol/ethyl acetate gradient afforded an oil (105 mg,
54%).
[0554] MS (+ve ion electrospray) m/z 626 (H+).
(f) Title Compound
[0555] A solution of (29e) (100 mg, 0.17 mmol) in ethanol (10 mL)
was treated with 10% palladium on charcoal (50% dispersion with
water, 60 mg) and hydrogenated for 2 h. More 10% palladium on
charcoal (100 mg) was added and the mixture hydrogenated for a
further 2 h. Filtration and evaporation gave the free base of the
product as a white solid (75 mg, 90%)
[0556] .delta.H (CD.sub.3OD, 250 MHz), 8.65(1H, d), 8.55 (1H, d),
8.20 (1H, d), 8.03 (1H, d), 7.30 (1H, d), 7.00-6.80 (3H, m), 4.75
(2H, t), 4.25 (4H, s), 3.90 (2H, s), 3.20 (2H, t), 2.90-2.70 (2H,
m), 2.40-2.10 (7H, m), 1.80-1.40 (3H, m). MS (APCI+) m/z 492
(MH+).
[0557] The oxalate salt (90 mg) was prepared by the method of
Example 1.
Example 30
Trans-4-[(3-Oxo-3,4-dihydro-2-H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclo-
hexanecarboxylic acid (8-fluoro-6-methoxy-quinolin-4-yl)-amide
oxalate
[0558] ##STR42##
[0559] Amine (10e) (225 mg, 0.710 mmol) was reacted with aldehyde
(4c) (137 mg, 0.710 mmol) according to the procedure in Example 4d.
This provided the free base of the desired compound as a white
solid (74 mg, 21%).
[0560] .delta.H (d.sup.6-DMSO, 250 MHz), 8.64 (1H, d), 8.08 (1H,
d), 7.47 (1H, m), 7.38 (1H, dd), 7.25 (1H, d), 6.98-6.95 (2H, m),
3.96 (3H, s), 3.69 (2H, m), 3.43 (2H, s), 2.68 (1H, m), 2.49 (1H,
m), 1.98-1.90 (4H, m), 1.50-1.46 (2H, m), 1.15-1.00 (2H, m). MS
(APCI+) m/z 495 (MH+).
[0561] The oxalate salt was prepared by the method of Example
1.
Example 31
Trans-4-[(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-
-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate
[0562] ##STR43## (a)
6-Methyl-4H-pyrido[3,2-b][1,4]oxazin-3-one.
[0563] A solution of 2-amino-6-methyl-pyridin-3-ol (5.7 g, 46 mmol)
(prepared by reduction of 6-methyl-2-nitro-pyridin-3-ol according
to the procedure of J. Kaminski et al, [J. Med. Chem, 30 (11), 2031
(1987)] in dimethylsulphoxide (60 ml) was treated with sodium
hydride (44 mmol) under argon. After 0.25 hours methyl
chloroacetate (4 mL, 5 g, 46 mmol) was added and the mixture heated
at 100.degree. C. for 3.5 hours. The reaction mixture was quenched
with saturated aqueous ammonium chloride solution (10 mL), then
partitioned between dichloromethane and water. The organic extracts
were dried and evaporated and the residue was chromatographed
eluting with 0-20% ethyl acetate in dichloromethane affording the
product as a white crystalline solid (4.7 g, 62%).
[0564] MS (+ve ion electrospray) m/z 165 (MH+).
(b) 6-Methyl-4H-pyrido[3,2-b][1,4]oxazin-3-one N-oxide.
[0565] A solution of (31a) (4.58 g, 28 mmol) in dichloromethane
(100 mL) at 0.degree. C. was treated with a solution of
meta-chloroperbenzoic acid (8.75 g, .about.55% pure, .about.28
mmol) in dichloromethane (100 mL). After 1 hour more
meta-chloroperbenzoic acid (1.7 g) was added. After a further 2
hours the mixture was loaded directly onto a silica gel column.
Chromatography, eluting with a solvent mixture of aqueous ammonia:
methanol: ethyl acetate (3:27:70), afforded the product as a white
crystalline solid (3.5 g, 70%).
[0566] MS (+ve ion electrospray) m/z 181 (MH+).
(c) Acetic acid
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl ester.
[0567] A solution of (31b) (3.0 g) in acetic anhydride (20 mL) was
treated with acetyl chloride (0.14 mL) and heated to reflux
overnight. The mixture was evaporated to dryness and the residue
partitioned between ethyl acetate and half saturated aqueous sodium
bicarbonate solution. The ethyl acetate extract was filtered
through celite and the filtrate evaporated. The residue was
chromatographed eluting with a gradient of 0-10% ethyl acetate in
dichloromethane affording an oil (1.0 g). Analysis of this material
showed it to be a 2:1 mixture of the product and starting material
(31b), equivalent to 19% yield of the desired product (31c).
[0568] MS (+ve ion electrospray) m/z 223 (MH+).
(d) 6-Hydroxymethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one.
[0569] A solution of impure (31c) (1.0 g, equivalent to 3.5 mmol)
and sodium hydroxide (3.5 mmol) in water/dioxan (17 mL/30 mL) was
stirred at room temperature for 3 days. Silica gel was added and
the solvent was removed. Chromatography eluting with 0-100% ethyl
acetate in dichloromethane afforded the product as a white foam
(0.2 g, 32%).
[0570] MS (+ve ion electrospray) m/z 181 (MH+).
(e)
3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde
[0571] A solution of (31d) (0.20 g, 1.1 mmol) in
chloroform/dioxan/tetrahydrofuran (10 mL/10 mL/5 mL) was heated at
40.degree. C. with manganese dioxide (1.5 g) for 2 hours.
Filtration and evaporation afforded the product as a white solid
(0.14 g, 70%).
[0572] MS (+ve ion electrospray) m/z 179 (MH+).
(f) Title Compound
[0573] A mixture of amine (1e) (210 mg, 0.7 mmol), aldehyde (31e)
(0.14 g, 0.78 mmol) and 3 A molecular sieves in chloroform/methanol
(3 mL/0.5 ml) was heated to reflux for 5 hours, then stabilised at
40.degree. C. Sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was
added, and the mixture stirred at 40.degree. C. for 0.5 hours.
Water (2 mL) was added and the resulting white solid was isolated
by filtration. This solid was partitioned between ethyl acetate and
half saturated aqueous sodium bicarbonate solution. The ethyl
acetate extract was dried and evaporated giving the free base of
the title compound as a white solid (140 mg, 43%).
[0574] .delta.H (d6-DMSO, 250 MHz): 8.65(1H, d), 8.35 (1H, d), 8.20
(1H, d), 7.25 (2H, m), 7.00 (1H, m), 4.65 (2H, s), 4.08 (3H, s),
3.65 (2H, s), 2.60 (1H, m), 2.37 (1H, m), 1.90 (4H, m), 1.40 (2H,
m), 1.20 (2H, m). MS (+ve ion electrospray) m/z 463 (MH+).
[0575] The free base was converted to the oxalate salt (170 mg) by
the method of Example 1
Example 32
Trans-4-[([1,2,3]Thiadiazolo[5,4-b]pyridin-6-ylmethyl)-amino]-cyclohexanec-
arboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)amide oxalate
[0576] ##STR44## (a) [1,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxylic
acid methyl ester.
[0577] The amine (16a) (1.3 g) was suspended in 0.5 M hydrochloric
acid (200 mL) and cooled to -3.degree. C. A solution of sodium
nitrite (487 mg) in water (3 mL) was added dropwise over 10 minutes
and the mixture was stirred for 2 hours when the solid product was
collected and chromatographed on silica gel (chloroform) to afford
a solid (0.90 g)
[0578] MS (+ve ion electrospray) m/z 196 (MH+)
(b) [1,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxylic acid.
[0579] The ester (32a) (0.94 g) was hydrolysed with aqueous sodium
hydroxide in tetrahydrofuran by the method of Example (4a) to
afford a solid (0.84 g).
[0580] MS (-ve ion electrospray) m/z 180 (M-H.sup.-).
(c) [1,2,3]Thiadiazolo[5,4-b]pyridin-6-yl-methanol.
[0581] The carboxylic acid (32b) (0.82 g) was reacted with
isobutylchloroformate and sodium borohydride by the method of
Example (4b) to afford a semi-solid (0.12 g), after chromatography
on silica gel (chloroform).
(d) [1,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxaldehyde.
[0582] The alcohol (32c) (0.10 g) was oxidised with manganese
dioxide by the method of Example (4c) to afford a solid (51
mg).
[0583] MS (+ve ion electrospray in methanol) m/z 198 (MH+ for
methanol adduct)
(e) Title Compound
[0584] This was prepared from amine (1e) (102 mg) and
carboxaldehyde (32d) (51 mg) by the method of Example (4d) (slow
reduction with sodium triacetoxyborohydride so mixture of imine and
product was retreated with extra sodium acetoxyborohydride for 72
hours) to provide the free base of the desired compound as a
colourless solid (44 mg).
[0585] .delta.H (CDCl.sub.3 250 MHz), 9.50 (1H, br.s) 8.95 (1H, d),
8.89 (1H, d), 8.70 (1H, d), 8.52 (1H, d), 8.25 (1H, d), 7.15 (1H,
d), 4.16 (2H, s), 4.11 (3H, s), 2.68 (1H, m), 2.45-2.15 (5H, m),
1.70 (2H, m), 1.35 (2H, m). MS (+ve ion electrospray) m/z 450
(MH+).
[0586] The oxalate salt was prepared by the method of Example 1
Example 33
Trans-4-3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonylamino)-cyclohexa-
necarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
[0587] ##STR45## (a)
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride.
[0588] Powdered 4H-benzo[1,4]thiazin-3-one (7.0 g) was added
cautiously, portionwise (over 20 minutes), to chlorosulfonic acid
(15 mL), cooled in ice. After 1 hour the blue solution was allowed
to warm to room temperature and it was heated at 45.degree. C. for
2 hours, cooled and poured into ice. The solid was collected,
washed with water, and hexane, and dried in vacuo, to give a white
solid (7.0 g).
(b) Title Compound.
[0589] A solution of amine (1e) (0.20 g, 0.66 mmol) in
dichloromethane (20 mL) was treated with triethylamine (0.23 mL,
1.7 mmol) then the sulfonyl chloride (33a) (0.28 g, 1 mmol) was
added in one portion. After 1 day the mixture was filtered, washing
with dichloromethane. The resulting solid was recrystallised from
boiling methanol to afford the title compound as a white solid (7
mg, 2%).
[0590] .delta.H (d6-DMSO, 250 MHz): 10.85 (1H, bs), 9.70 (1H, bs),
8.62(1H, d), 8.38 (1H, d), 8.25 (1H, d), 7.75 (1H, d), 7.50 (1H,
d), 7.45-7.30 (2H, m), 7.25 (1H, d), 4.10 (3H, s), 3.57 (2H, s),
2.95 (1H, m), 2.60 (1H, m), 1.95 (2H, m), 1.75 (2H, m) 1.50 -1.20
(4H, m) MS (+ve ion electrospray) m/z 528 (MH+).
Example 34
Trans-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amin-
o]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt
[0591] ##STR46## (a) 2,4-Difluoro-5-nitro-benzoic acid ethyl
ester.
[0592] 2,4-Difluorobenzoic acid ethyl ester (5.33 g) was cooled to
0.degree. C. and treated with concentrated sulfuric acid (3.5 mL)
and then fuming nitric acid (3.5 mL). The mixture was stirred for 2
hours at 0.degree. C. and then partitioned between dichloromethane
(2.times.50 mL) and water (25 mL). The organic phase was back
extracted with water (25 mL) and then dried over magnesium sulfate
and concentrated in vacuo. This provided the desired compound as a
white solid (5.00 g) which was used without further
purification.
(b) 2-Fluoro-4-methoxycarbonylmethylsulfanyl-5-nitro-benzoic acid
ethyl ester.
[0593] Ester (34a) (2.82 g, 12.21 mmol) was dissolved in
dichloromethane (50 mL) and triethylamine was added (2.04 mL, 14.65
mmol). The mixture was cooled to 0.degree. C. and methyl
thioglycolate (0.98 mL, 10.98 mmol) was added dropwise. Stirring
was continued at 0.degree. C. for 3 hours after which time the
volatiles were removed in vacuo. The residue was purified by column
chromatography on silica gel using an ethylacetate and hexanes
solvent gradient. This provided the desired compound as a yellow
solid (2.05 g).
(c) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic
acid ethyl ester.
[0594] This was prepared by an iron mediated reductive cyclisation
of nitro compound (34b) using a method similar to Example (13b)
This provided the desired compound as a white solid (1.02 g).
(d) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic
acid.
[0595] This was prepared by hydrolysis of ethyl ester (34c) using
the method of Example (4a) to give a white solid (1.00 g).
(e) 7-Fluoro-6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one
[0596] This was prepared by reduction of the mixed anhydride of
acid (34d) according to the method of Example (4b) to give the
alcohol (0.93 g). m/z (APCI+) 214 (MH+).
(f)
7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde
[0597] Oxidation of alcohol (34e) with manganese dioxide was
performed according to the procedure of Example (4c), to give the
aldehyde (1.00 g).
(g) Title Compound.
[0598] Amine (1e) was reductively alkylated with aldehyde (34f) in
the same manner as Example (4d). This provided the free base (30
mg) of the desired compound after purification on silica gel.
[0599] The oxalate salt was generated in the same fashion as
Example 1
[0600] MS (APCI+) m/z 496 (MH+) .delta.H (d6-DMSO, 250 MHz) 10.60
(1H, bs), 9.76 (1H, bs), 8.67 (1H, d), 8.39 (1H, d), 8.26 (1H, d),
7.32 (1H, d), 7.22 (1H, bm), 7.11 (1H, d), 4.14 (3H, s), 3.40 (2H,
s), 3.30 (2H, s), 2.70 (1H, m), 2.54 (1H, m), 2.05 (4H, m), 1.51
(2H, m), 1.10 (2H, m). m/z (APCI+) 496 (MH+).
Example 35
Trans-4-[(8-Nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-
-cyclohexanecarboxylic acid
(6-methoxy)-[1,5]naphthyridin-4-yl)-amide oxalate
[0601] ##STR47## (a)
8-Nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde.
[0602] The carboxaldehyde (8b) (0.18 g, 1.0 mmol) was stirred and
cooled in ice, while fuming nitric acid (0.1 mL) was added. The
mixture was stirred at room temperature for 3 hours then diluted
with water and extracted with ethyl acetate the extracts were
washed with brine, dried and evaporated. Chromatography on silica
gel (0-1% methanol in dichloromethane) gave a solid (0.16 g,
71%).
(b) Title Compound.
[0603] A solution of the amine (1e) (0.30 g 1.0 mmol) and aldehyde
(35a) in methanol (2 mL) and chloroform (8 mL) was stirred at
56.degree. C. over 3A molecular sieves for 7 hours. Sodium
triacetoxyborohydride (1.04 g) was added and the mixture stirred at
room temperature for 7 days then at 56.degree. C. for 7 days. The
mixture was diluted with methanol and solid sodium bicarbonate
added. After being stirred for 15 minutes the mixture was
evaporated and chromatographed on silica gel (2-10% methanol in
dichloromethane). The mixture of imine and amine (0.103 g) thus
obtained was dissolved in methanol (2 mL) and chloroform (5 mL),
sodium triacetoxyborohydride (0.13 g) was added and the mixture
stirred at room temperature for 24 hours, further sodium
triactoxyborohydride (0.13 g) was added and stirring continued for
24 hours. The mixture was worked up as before and chromatographed
on silica gel (2-7.5% methanol in DCM) to give the title compound
as the free base(0.036 g, 7%).
[0604] MS (+ve ion electrospray) m/z 507 (MH+) .delta.H
(CDCl.sub.3, 250 MHz), 8.68 (1H, d), 8.52 (1H, d), 8.25 (1H, d),
7.77 (1H, s), 7.28 (1H, s), 7.19 (1H, d), 4.62 (2H, s), 4.36 (2H,
s), 4.15 (3H, s), 2.63-2.20 (4H, m), 2.18-2.00 (2H, m), 1.78 (4H,
m).
[0605] The oxalate salt was prepared by the method of Example 1
[0606] A mixture of the title compound and
4-[(8-nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-imino]-cycl-
ohexanecarboxylic acid (6-methoxy)-[1,5]naphthyridin4-yl)-amide
(0.059 g) was also obtained during chromatography.
Example 36
Trans-4-[(8-Amino-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-
-cyclohexanecarboxylic acid
(6-methoxy)-[1,5]naphthyridin-4-yl)-amide oxalate
[0607] ##STR48##
[0608] The mixture of compound Example (35) and
4-[(8-nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-imino]-cycl-
ohexanecarboxylic acid (6-methoxy)-[1,5]naphthyridin-4-yl)-amide
obtained from Example (35b) (0.059 g) was dissolved in ethanol and
hydrogenated over 10% palladium on charcoal for 18 hours. The
mixture was filtered through kieselguhr and evaporated.
Chromatography on silica gel (5-10% methanol/DCM then 5-10%
methanol/dichloromethane containing 0.5-1% NH.sub.4OH) gave the
title compound as the free base (0.13 g).
[0609] MS (+ve ion electrospray) m/z 477 (MH+) .delta.H
(CDCl.sub.3+MeOD, 250 MHz), 8.68 (1H, d), 8.51 (1H, d), 8.22 (1H,
d), 7.17 (1H, d), 6.57 (1H, s), 6.33 (1H, s), 4.52 (2H, s), 4.12
(3H, s), 3.79 (2H, s), 2.61 (1H, m), 2.44 (1H, m), 2.19 (4H, m),
1.72 (2H, m), 1.26 (2H, m).
[0610] The oxalate salt was prepared by the method of Example 1
[0611] The following Examples were prepared by analogous methods.
TABLE-US-00001 ##STR49## salt Method G oxalate of A Hydrochloride
Example synthesis R.sub.1 LINKER AY Dioxalate R 100 A
6-O(CH.sub.2).sub.3NH2 NHCO G benzo[1,2,3]thiadiazol-5-yl 101 B
6-OMe NHCO G 2-oxo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl
102 B 6-OMe NHCO G 5-nitro-3-oxo-3,4-dihydro-2H-
benzo[1,4]oxazin-6-yl 103 a 6-OMe NHCO G
5-amino-3-oxo-3,4-dihydro-2H- benzo[1,4]oxazin-6-yl 104 B 6-OMe
NHCO G 2,3-dihydro-1H-pyrido[2,3-b] [1,4]oxazin-7-yl 105 A
6-(OCH.sub.2).sub.3NH.sub.2 NHCO AY 4H-benzo[1,4]thiazin-3-one-6-yl
106 b 6-OMe NHCO A 6-[3-oxo-2,3-dihydro-
benzo[1,4]thiazin-4-yl)-acetic acid] 107 c 6-OMe NHCO G
6-[3-oxo-2,3-dihydro- benzo[1,4]thiazin-4-yl)-acetic acid
tert-butyl ester] 108 d 6-OMe NHCO G
1,1,3-Trioxo-1,2,3,4-tetrahydro-1 l.sup.6-benzo[1,4]thiazin-6-yl
109 e 6-OMe NHCONH AY quinoxalin-2-yl cis stereochem 110 f 6-OMe
NHCOO free base 3-oxo-3,4-dihydro-2H- trans
pyrido[3,2-b][1,4]thiazin-6-yl stereochem 111 g 6-OMe NHCOO free
base 3-oxo-3,4-dihydro-2H- cis benzo[1,4]thiazin-6-yl stereochem A:
by method of Example 29 B: by method of Example 4 a Prepared from
Example 102 by hydrogenation over palladium/carbon following the
Method of Example 36 b Prepared from Example 107 by reaction with
trifluoroacetic acid in dichloromethane c Prepared by alkylation of
Example (4c) with tert-butyl bromoacetate followed by reaction with
amine (1c) and sodium triacetoxyborohydride by Method of Example 4
d Prepared from alcohol (4b) by oxidation with m-chloroperbenzoic
acid followed by manganese dioxide and reaction of the
carboxaldehyde with amine (1c) and sodium triacetoxyborohydride by
Method of Example 4 e Prepared via
cis-1-tert-butoxycarbonylamino-4-aminocyclohexane and
6-methoxy[1,5]naphthyridine-4-isocyanate f Prepared from trans
4-aminocyclohexanol by tert-butyloxycarbonyl protection of the
amino group, followed by conversion of the hydroxy group to
aminocarbonyloxy by reaction with phosgene followed by ammonia. The
resulting trans-(4-carbamoyloxy-cyclohexyl)-carbamic acid tert
butyl ester was then coupled with triflate (1b) according to the
palladium-catalysed procedure of (300d). Removal of the
tert-butoxycarbonyl protecting group #and reductive alkylation with
aldehyde (301d) using sodium cyanoborohydride according to Example
(311e) afforded the final compound. g Prepared from
cis-4-aminocyclohexanol by the same methodology as (f) above,
except that aldehyde (4c) was used in place of aldehyde (301d)
Example 150
(R/S)-4-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cycloh-
ex-1-ene carboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
oxalate
[0612] ##STR50## (a)
(R/S)-4-tert-Butoxycarbonylamino-cyclohex-1-enecarboxylic acid.
[0613] A solution of potassium hydroxide (25 g, 446 mmol) in water
(30 mL) was added dropwise to a vigorously stirred solution of
4-tert-butoxycarbonylaminocyclohexanone (13.53 g, 63.8 mmol) and
benzyltriethylammonium chloride (0.15 g, 0.64 mmol) in bromoform
(25 mL) at 0.degree. C. An exothermic reaction occurred, the
internal temperature reaching 80-90.degree. C. before falling.
Stirring, with external cooling, was continued for 1 hour. Water
and dichloromethane were added and the phases were separated. The
aqueous phase was washed with dichloromethane, then cooled in ice,
acidified to pH 4 (dilute hydrochloric acid) and extracted with
dichloromethane. The extracts were dried and evaporated to give the
acid (7.78 g, 47%).
(b) (R/S)-4-tert-Butoxycarbonylamino-cyclohex-1-enecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide.
[0614] Method A. To a solution of the acid (150a) (2.58 g, 10 mmol)
in dry dichloromethane (20 mL) was added 1,1'-carbonyldiimidazole
(2.26 g, 14 mmol). The mixture was stirred for 7 hours at room
temperature, then evaporated. The residue was dissolved in dry DMF
(20 mL), 6-methoxy-[1,5]naphthyridin-4-ylamine (Example 1c) [RN
249889-69-8] (2.49 g, 14 mmol) and N,N-dimethylaminopyridine (0.15
g) were added and the mixture was heated at 100.degree. C. for 48
hours. After evaporation of solvent, the residue was partitioned
between ethyl acetate and water. The aqueous phase was re-extracted
and the combined organics were washed with water, dried and
evaporated. Chromatography on silica gel (0-10%
methanol/dichloromethane) gave an impure product which was
chromatographed again (silica, 1-2% methanol/dichloromethane) to
give the amide (1.15 g. 29%).
[0615] Method B. To a solution of the acid (150a) (5.0 g, 20.8
mmol) in dry DMF (40 mL) were added
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (7.98 g, 21 mmol) and triethylamine (5.88 mL,
42 mmol). After 0.5 hours stirring at room temperature
6-methoxy-[1,5]naphthyridin-4-ylamine (Example 1c) (3.64 g, 20.8
mmol) was added and the mixture was stirred at 50.degree. C. for 48
hours. Work-up as for Method A and chromatography on silica gel
(1-3% methanol/dichloromethane) gave the amide (5.73 g, 69%).
[0616] MS (+ve ion electrospray) m/z 399 (MH+).
(c) (R/S)-4-Amino-cyclohex-1-enecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide.
[0617] The amide (150b) (0.83 g, 2.1 mmol) was dissolved in
dichloromethane (5 mL) and trifluoroacetic acid (5 mL), and the
solution was allowed to stand at room temperature for 2 hours, then
evaporated. The residue was dissolved in a small volume of aqueous
sodium bicarbonate, basified to pH10-11 with 40% sodium hydroxide
and extracted thoroughly with 10% methanol/dichloromethane (total
125 mL). The extracts were dried and evaporated to give the amine
(0.69 g, 100%).
[0618] MS (+ve ion electrospray) m/z 299 (MH+).
(d) Title Compound.
[0619] A solution of the amine (150c) (0.10 g, 0.33 mmol) and
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (Example
4c) (0.064 g, 0.33 mmol) in dry chloroform (2 mL) and methanol (0.2
mL) was heated with 3A molecular sieves for 15 hours. After
cooling, sodium triacetoxyborohydride (0.35 g, 1.65 mmol) was added
and the mixture was stirred at room temperature overnight. The
mixture was basified with aqueous sodium bicarbonate and the phases
were separated. The aqueous phase was extracted with
dichloromethane and the combined organics were washed with water,
dried and evaporated. Chromatography on silica gel (5-7%
methanol/dichloromethane) gave the title compound as free base
(0.08 g, 51%).
[0620] .delta.H (d.sub.6-DMSO, 400 MHz), 10.49 (1H, s), 9.88 (1H,
s), 8.69 (1H, d), 8.43 (1H, d), 8.28 (1H, d), 7.33 (1H, d), 7.24
(1H, d), 7.00-6.97 (2H, m), 6.91 (1H, br s), 4.10 (3H, s), 3.72
(2H, s), 3.42 (2H, s), 2.74 (1H, m), 2.67-2.37 (3H, m), 2.08 (1H,
m), 1.98 (1H, m), 1.51 (1H, m). MS (+ve ion electrospray) m/z
476(MH+).
[0621] The oxalate salt was prepared by the method of Example
1.
Example 151
(R/S)-4-[(Benzo[1,2,5]thiadiazol-5-ylmethyl-amino]-cyclohexene
carboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
oxalate
[0622] ##STR51## (a) Benzo[1,2,5]thiadiazole-5-carboxaldehyde.
[0623] This was prepared by oxidation of
benzo[1,2,5]thiadiazol-5-yl-methanol (2a) with manganese dioxide in
dichloromethane by the method of Example (4c).
(b) Title Compound.
[0624] A solution of the amine (150c) (0.10 g, 0.3 mmol) and the
carboxaldehyde (51a) (0.055 g, 0.33 mmol) in dry chloroform (2 mL)
and methanol (0.2 mL) was heated with 3A molecular sieves for 15
hours. After cooling, sodium triacetoxyborohydride (0.35 g, 1.65
mmol) was added and the mixture was stirred at room temperature for
48 hours. The mixture was basified with aqueous sodium bicarbonate
and extracted with dichloromethane. The extracts were dried and
evaporated. Chromatography on silica gel (2-5%
methanol/dichloromethane)gave the title compound as the free base
(0.079 g, 53%).
[0625] .delta.H (CDCl.sub.3, 250 MHz), 9.37 (1H, s), 8.70 (1H, d),
8.55 (1H, d), 8.21 (1H, d), 7.92-8.03 (2H, m), 7.64 (1H, dd), 7.16
(1H, d), 6.94 (1H, br s), 4.10 (3H, s), 4.08 (2H, s), 3.06-2.91
(1H, m), 2.80-2.39 (2H, m), 2.32-2.07 (2H, m), 1.79-1.45 (3H, m).
MS (+ve ion electrospray) m/z 447 (M.sup.+).
[0626] The oxalate salt was prepared by the method of Example
1.
Example 152
(R/S)-4-[(Benzo[1,2,3]thiadiazol-5-ylmethyl)-amino]-cyclohex-1-ene
carboxylic acid (6-methoxy-[1,5]naphthyridin-4yl)amide oxalate
[0627] ##STR52## (a) Benzo[1,2,3]thiadiazole-5-carboxaldehyde.
[0628] This was prepared by oxidation of
benzo[1,2,3]thiadiazol-5-yl-methanol (6a) with manganese dioxide in
dichloromethane by the method of Example (4c).
(b) Title Compound.
[0629] This was prepared from the carboxaldehyde (152a) by the
method of Example 151 (0.75 g, 47%).
[0630] .delta.H (CDCl.sub.3, 250MHz), 9.85 (1H, s), 8.69 (1H, d),
8.61 (1H, d), 8.54 (1H,d), 8.20 (1H, d), 8.05 (1H, d), 7.73 (1H,
dd), 7.15 (1H, d), 6.94 (1H, br s), 4.14 (2H,s), 4.09 (3H,s),
3.08-2.94 (1H, m), 2.80-2.43 (2H, m), 2.33-2.08 (2H, m), 1.82-1.53
(3H, m). MS (+ve ion electrospray) m/z 447 (MH+).
[0631] The oxalate salt was prepared by the method of Example
1.
Example 153
(R/S)-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino-
]-cyclohex-1-ene carboxylic acid
(6methoxy-[1,5]naphthyridin-4-yl-amide oxalate
[0632] ##STR53##
[0633] A solution of the amine (150c) (0.10 g, 0.33 mmol) and
2-oxo-2,3 dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde
(Example 13e) (0.064 g, 0.33 mmol) in dry chloroform (2 mL) and
methanol (0.2 mL) was heated with 3A molecular sieves for 15 hours.
After cooling, sodium triacetoxyborohydride (0.35 g, 1.65 mmol) was
added and the mixture was stirred at room temperature overnight. A
further portion of sodium triacetoxyborohydride (0.16 g) was added
and stirring continued overnight. The mixture was basified with
aqueous sodium bicarbonate and the phases were separated. The
aqueous phase was extracted with dichloromethane/methanol and the
combined organics were washed with brine, dried and evaporated.
Chromatography on silica gel (2-5% methanol/dichloromethane) gave
the title compound as the free base (0.055 g, 35%).
[0634] .delta.H (CDCl.sub.3/CD.sub.3OD, 250 MHz), 9.93 (1H, s),
8.66 (1H, d), 8.55 (1H, d), 8.21 (1H, d), 8.10 (1H, br s),
7.23-7.19 (2H, m), 6.94 (1H, br s), 4.12 (3H, s), 3.84(2H, s), 3.55
(2H, s), 2.93 (1H, m), 2.80-2.45 (3H, m), 2.16 (2H, m), 1.67 (1H,
m). MS (+ve ion electrospray) m/z 477(MH+).
[0635] The oxalate salt was prepared by the method of Example
1.
Example 154
(R/S)-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino-
]-cyclohex-1-ene carboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate
[0636] ##STR54##
[0637] This was prepared from the amine (150c) (0.10 g, 0.33 mmol)
and
7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde
(Example 9e) (0.065 g, 0.33 mmol) by the method of Example 153.
Chromatography on silica gel (2-5% methanol/dichloromethane) gave
the title compound as the free base (0.071 g, 39%).
[0638] .delta.H (CDCl.sub.3, 250 MHz), 9.86 (1H, s), 8.70 (1H, d),
8.55 (1H, d), 8.22 (1H, d), 7.16 (1H, d), 6.93 (1H, br s), 6.84
(1H, d), 6.72 (1H, d), 4.60 (2H, s), 4.10 (3H, s), 3.84(2H, s),
2.90 (1H, m), 2.78-2.43 (3H, m), 2.24-2.00 (2H, m), 1.63 (m). MS
(+ve ion electrospray) m/z 478(MH+).
[0639] The oxalate salt was prepared by the method of Example
1.
Example 155
(R/S)-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylmethyl)-amino]-
-cyclohex-1-enecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate
[0640] ##STR55## (a) 6-Ethoxycarbonylmethoxy-5-nitro-nicotinic acid
methyl ester.
[0641] A solution of ethyl glyoxalate (2.80 g) in dry dioxan (100
mL), cooled in ice, was treated with sodium hydride (60% dispersion
in oil; 1.30 g) and the mixture was heated at 50.degree. C. for 30
minutes and cooled in ice. A solution of 6-chloro-5-nitro-nicotinic
acid methyl ester (5.25 g) [prepared as described by A. H. Berrie
et al. J. Chem. Soc. 2590-2594 (1951)] in dioxan (40 mL) was added
and the solution was stirred at 0.degree. C. for 30 minutes and
then at room temperature overnight. The reaction mixture was
evaporated to dryness, sodium bicarbonate solution was added to pH
7, and the mixture extracted with chloroform, dried (anhydrous
sodium sulfate) and evaporated to afford a semi-solid that was
chromatographed on silica gel [dichloromethane-hexane (1:1) then
dichloromethane] to afford the product (4.70 g).
[0642] MS (+ve ion electrospray) m/z 285 (MH+).
(b) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic
acid methyl ester.
[0643] The ester (155a) (1.0 g) in acetic acid (80 mL) was treated
with iron powder (10 g) and the mixture was stirred and heated at
60.degree. C. for 2.5 hours, cooled and filtered. The filtrate was
evaporated, treated with anhydrous sodium carbonate and extracted
with warm chloroform-methanol (98:2). It was dried (anhydrous
sodium sulfate) and evaporated to give a white solid (5.2 g).
[0644] MS (+ve ion electrospray) m/z 209 (MH+).
(c) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic
acid.
[0645] The ester (155b) (4.5 g) was hydrolysed with aqueous sodium
hydroxide in tetrahydrofuran by the method of Example (4a) to
afford a solid (3.0 g).
[0646] MS (-ve ion electrospray) m/z 193 (M-H.sup.-).
(d) 7-Hydroxymethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one.
[0647] The relatively insoluble carboxylic acid (155c) (1.20 g) was
reacted with isobutylchloroformate and sodium borohydride by the
method of Example (4b), except the initial solvent was
tetrahydrofuran (350 mL), chloroform (50 mL) and dimethylformamide
(10 mL). The reaction mixture was evaporated to one quarter volume,
extracted with dichloromethane, and the aqueous fraction evaporated
to dryness, dissolved in methanol-chloroform (1:3) and
chromatographed on silica gel [methanol-dichloromethane (1:9)] to
afford a solid (0.43 g).
[0648] MS (-ve ion electrospray) m/z 179 (M-H.sup.-).
(e)
2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxaldehyde
[0649] The alcohol (155d) (0.42 g) in tetrahydrofuran (200 mL) and
chloroform (100 mL) was oxidised with excess manganese dioxide by
the method of Example (4c) to afford the required product (0.30 g),
containing 17% of alcohol (55d) by NMR
[0650] MS (-ve ion electrospray) m/z 177 (M-H.sup.-).
(f) Title Compound
[0651] This was prepared from the amine (150c) (0.132 g) and crude
carboxaldehyde (155e) (0.090 g) by the method of Example 153.
Chromatography on silica gel (2-10% methanol/dichloromethane) gave
the free base of the title compound as a solid (0.090 g).
[0652] .delta.H (CD.sub.3OD, 250 MHz), 8.55 (1H, d), 8.50 (1H, d),
8.20 (1H, d), 7.86 (1H, d), 7.38 (1H, d), 7.28 (1H, d), 4.84 (2H,
s), 4.17 (3H, s), 4.02 (2H, s), 2.93 (1H, m), 2.70 (1H, m) 2.25
(4H, m), 1.75 (2H, m) 1.45 (2H, m). MS (+ve ion electrospray) m/z
463(MH+).
[0653] The oxalate salt was prepared by the method of Example 1
Example 156
(R/S)-4-[Carboxymethyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-
-amino]-cyclohex-1-enecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide bis(trifluoroacetate)
salt
[0654] ##STR56## (a)
(R/S)-4-(tert-Butoxycarbonylmethylamino)-cyclohex-1-enecarboxylic
acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide.
[0655] A solution of the amine (150c) (0.20 g, 0.66 mmol) in dry
DMP (5 mL) was treated with tert-butyl bromoacetate (0.107 mL, 0.66
mmol) and potassium carbonate and the mixture was stirred overnight
at room temperature. After evaporation of solvent, the residue was
chromatographed on silica gel (0-2% methanol/dichloromethane) to
give the ester (0.093 g, 34%).
[0656] MS (+ve ion electrospray) m/z 413(MH+).
(b)
(R/S)-4-[tert-Butoxycarbonylmethyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]t-
hiazin-6-ylmethyl)-amino]-cyclohex-1-enecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide.
[0657] A solution of the ester (156a) (0.09 g, 0.2 mmol) and
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (Example
4c) (0.064 g, 0.33 mmol) in dry 1,2-dichloroethane (3 mL) was
heated under reflux with 4A molecular sieves for 7.5 hours. After
cooling to room temperature, sodium triacetoxyborohydride (0.175 g)
was added and the mixture was stirred overnight. More sodium
triacetoxyborohydride (0.92 g) and aldehyde (0.14 g) were added at
intervals during which time the mixture was heated under reflux
overnight. Aqueous sodium bicarbonate and dichloromethane were
added and the phases separated. The aqueous phase was re-extracted
with dichloromethane and the combined organics were washed with
water, dried and evaporated. Chromatography on silica gel (2-5%
methanol/dichloromethane) gave the alkylated product (0.012 g),
plus a 2:1 mixture of product and starting material (0.046 g).
[0658] MS (+ve ion electrospray) m/z 590(MH+).
(c) Title Compound.
[0659] The pure ester (156b) (0.012 g) was dissolved in
dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and the
solution was allowed to stand at room temperature for 2 hours.
Evaporation to dryness gave the title compound (0.018 g).
[0660] .delta.H (CD.sub.3OD, 250 MHz) 8.88 (1H, d), 8.83 (1H, d),
8.38 (1H, d), 7.57 (1H, d), 7.43 (1H, d), 7.24 (1H, dd), 7.17 (1H,
d), 7.04 (1H, br s), 4.49 (2H, s), 4.23 (3H, s), 4.06 (2H, s), 3.78
(1H, m), 3.46 (2H, s), 3.00-2.85 (2H, m), 2.85-2.55 (2H, m),2.44
(1H, m), 1.95 (1H, m). MS (+ve ion electrospray) m/z 534(MH+).
[0661] The following Examples were prepared by analogous methods.
TABLE-US-00002 ##STR57## salt Method of G oxalate Example synthesis
LINKER AY Dioxalate R 200 a NHCONH G (CH.sub.2).sub.4Me 201 b
NHCONH G (CH.sub.2).sub.4Me trans stereochem. 202 a NHCONH AY
quinoxalin-2-yl 203 d CONH AY quinoxalin-2-yl 204 c NHCO
(CH.sub.2).sub.5Me 205 e CH(OH)CH.sub.2NH G (CH.sub.2).sub.4Me 206
f NHCOO free base 3-oxo-3,4-dihydro- 2H-pyrido[3,2-b]
[1,4]thiazin-6-yl ##STR58## a Prepared via
cis-1-tert-butoxycarbonylamino-4-aminocyclohexane and
6-methoxyquinoline-4-isocyanate b Prepared from
trans-1-tert-butoxycarbonylamino-4-aminocyclohexane and
6-methoxyquinoline-4-isocyanate c Prepared from
4-cis-tert-butoxycarbonylamino-cyclohexanecarboxylic acid and
6-methoxyquinoline-4-ylamine by the Method of Example 1d d Prepared
from from cis-1-tert-butoxycarbonylamino-4-aminocyclohexane and
6-methoxyquinoline-4-carboxylic acid by the method of Example 1d e
Prepared from cis-1-tert-butoxycarbonylamino-4-aminocyclohexane by
reaction with [R]-2-(6-methoxyquinolin-4-yl)oxirane f Prepared by
analogous procedures to those of Example 110
[0662] Unless otherwise stated, the following compounds were
prepared by analogous methods by reaction of an appropriate
carboxaldehyde and amine with sodium triacetoxyborohydride (Method
of Example 153). TABLE-US-00003 ##STR59## salt Method of B
Dihydrochloride synthesis A Hydrochloride Example (aldehyde)
Stereochemistry R Trihydrochloride R 210 (Example 301d) trans- B
3-Oxo-3,4-dihydro-2H- cyclohexane pyrido[3,2-b][1,4]thiazin-6-yl
##STR60## 211 a cyclohexene single B 3-Oxo-3,4-dihydro-2H-
enantiomer (slow) benzo[1,4]thiazin-6-yl ##STR61## 212 a
cyclohexene single B 3-Oxo-3,4-dihydro-2H- enantiomer (fast)
benzo[1,4]thiazin-6-yl ##STR62## 213 b trans- B
7-Fluoro-2,3-dihydro- cyclohexane benzo[1,4]dioxin-6-yl ##STR63##
214 c trans- B 3,4-Dihydro-2H- cyclohexane benzo[1,4]thiazin-6-yl
##STR64## 215 d trans- B 1-Oxo-1,2-dihydro- cyclohexane
isoquinolin-3-yl ##STR65## 216 e cis-cyclohexane B
3-Oxo-3,4-dihydro-2H- benzo[1,4]thiazin-6-yl ##STR66## a Prepared
from Example 150b by preparative HPLC to give the single
enantiomers, which were converted to Examples 211 (from
slow-running enantiomer) & Example 212 (from fast-running
enantiomer) by method of Example 150c/d b
7-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehyde prepared
from 6-fluoro-2,3-dihydro-benzo[1,4]dioxine [V. Daukas et al
Chemija, 1999, 10 (1), 59] by reaction of dichloromethyl methyl
ether and titanium tetrachloride. c
3,4-Dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde prepared from
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl
ester by reaction with lithium aluminium hydride followed by
oxidation with manganese dioxide. d Prepared from
1-oxo-1,2-dihydro-isoquinoline-3-carboxaldehyde [AR. Modi et al
Indian J. Chem. 17b 624-6 (1979)] e Prepared from
cis-4-amino-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridine-4-yl)-amide (itself derived from
cis-cyclohexane-1,4-dicarboxylic acid mono-tert-butyl ester using
the palladium-catalysed chemistry of Example 300d) by analogous
methods to the trans-series (Example 1f)
Example 300
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]--
r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0663] ##STR67## (a)
trans/cis-(4-Cyano-4-hydroxy-cyclohexyl)-carbamic acid tert butyl
ester.
[0664] (4-Oxo-cyclohexyl)-carbamic acid tert-butyl ester (50 g, 230
mmol) was added to a vigorously stirred mixture of ethyl acetate (1
litre) and water (750 ml) containing sodium hydrogen carbonate (40
g) and potassium cyanide (23 g, 352 mmol). After 20 hours, the
phases were separated and the organic extract washed with water
then brine. The ethyl acetate phase was dried (MgSO4) then
evaporated to give a pale yellow foam (55.2 g, 100%) which was used
without further purification.
[0665] MS (+ve ion electrospray) m/z 241 (MH+).
(b) trans/cis-4-Amino-1-hydroxy-cyclohexanecarboxylic acid amide
hydrochloride.
[0666] The cyanohydrins (300a) (27.6 g, 115 mmol) were dissolved in
concentrated hydrochloric acid (300 ml) (caution--mildly exothermic
on this scale, and evolution of CO2). After 2 hours the mixture was
evaporated to dryness, azeotroping with toluene then chloroform (ca
3 times each). The material was used crude.
[0667] MS (+ve ion electrospray) m/z 159 (MH+).
(c) (4-Carbamoyl-r-4-hydroxy-c-cyclohexyl)-carbamic acid tert butyl
ester (Method A).
[0668] The amine (300b) (approximately 115 mmol) was dissolved in
2M aqueous sodium hydroxide (200 ml) then treated with a solution
of di-tert-butyl dicarbonate (26.7 g, 123 mmol) in dioxan (125 ml).
The mixture was stirred for 2 hours then filtered.
[0669] The filtrate was partitioned between ethyl acetate (ca 1.5
litres) and brine (ca 1 litres The organic extract was washed with
brine, dried, and evaporated to give a white solid (ca 6.5 g) which
was approximately a 1:1 mixture of trans/cis. Chromatography on
silica gel, eluting with a 0-10% methanol in dichloromethane
gradient, afforded the single carbamate as a white solid (2.5 g)
(slower running isomer).
[0670] MS (+ve ion electrospray) m/z 259 (MH+).
(d)
[r-4-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylcarbamoyl)-c-cyclohe-
xyl]-carbamic acid tert-butyl ester.
[0671] A mixture of the amide (300c) (0.51 g), cesium carbonate
(0.818 g), tris(dibenzylideneacetone)dipalladium(0) (38 mg), and
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (77.4 mg) in dry
dioxan (20 ml) under argon, was sonicated for 10 minutes.
1,1,1-trifluoro-methanesulfonic acid
6-methoxy-[1,5]naphthyridin-4-yl ester (1b) (0.64 g) was added, and
the mixture was stirred and heated at 85.degree. C. for 18 hours,
under argon. The mixture was cooled, filtered, and the filtrate
evaporated and chromatographed on silica gel, eluting with
chloroform, then (1-2%) methanol-dichloromethane, to afford a solid
(0.85 g).
[0672] MS (+ve ion electrospray) m/z 417 (MH+).
(e) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid
(6-hydroxy-[1,5]naphthyridin-4-yl)-amide
[0673] The carbamate (300d) (0.85 g) in dichloromethane (30 ml) was
treated with trifluoroacetic acid (30 ml) for 2 hours and
evaporated. Water and sodium carbonate solution were added and the
resulting solid was collected, washed with water and dried in
vacuo, to afford a white solid (0.64 g).
[0674] MS (+ve ion electrospray) m/z 317 (MH+).
(f) Title Compound
[0675] A mixture of carboxaldehyde (4c) (69 mg) and amine (300e)
(95 mg) in chloroform (4 ml) and methanol (4 ml) with 3A molecular
sieves was heated under reflux for 3 hours, cooled, and treated
with sodium triacetoxyborohydride (191 mg). After stirring at room
temperature for 4 days, the mixture was diluted with chloroform (20
ml) and washed with aqueous sodium carbonate. The aqueous was
re-extracted with chloroform and the combined organic fractions
dried (Na.sub.2SO.sub.4) and evaporated and chromatographed on
silica gel, eluting with 2-10% methanol-dichloromethane to give
free base of the title compound (80 mg).
[0676] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.5-1.7 (2H, m),
1.8-2.0 (4H, m), 2.0-2.2 (2H, m), 2.72 (1H, m), 3.45 (2H, s), 3.85
(2H, s), 4.17 (3H, s), 6.92 (1H, d), 7.02 (1H, dd), 7.24 (1H, d),
7.32 (1H, d), 8.20 (1H, d), 8.57 (1H, d), 8.65 (1H, d) MS (+ve ion
electrospray) m/z 494 (MH.sup.+) The free base in
chloroform/methanol (1:1) was treated with 4M HCl in dioxan (0.5
ml) and evaporated to dryness. The solid was triturated with ether,
filtered and dried in vacuo, to provide title compound (85 mg).
Alternative preparation of Example (300c)
(4-Carbamoyl-r-4-hydroxy-c-cyclohexyl)-carbamic acid tert-butyl
ester (Method B)
(g) 2-Acetoxycyclohex-3-enecarboxylic acid butyl ester.
[0677] 1-Acetoxy-1,3-butadiene (30.1 g, 0.268 mol) was dissolved in
toluene (20 mL). To this was added butyl acrylate (37.9 mL, 0.265
mol) and hydroquinone (0.14 g). The colourless solution was heated
at 120.degree. C. for 26 h under argon. More
1-acetoxy-1,3-butadiene (10.6 g, 0.095 mol) in toluene (2 mL) was
then added, and heating continued for a further 68 h. The solution
was cooled then evaporated in vacuo to give a viscous yellow oil
(69 g), which was used without further purification.
[0678] .delta.H (CDCl.sub.3) 0.91-0.95 (3H, m), 1.3-2.2 (11H, m),
2.6-2.72 (1H, m), 4.01-4.16 (2H, m), and 5.48-6.07 (3H, m).
(h) Cyclohexa-1,3dienecarboxylic acid butyl ester
[0679] Crude butyl ester (300 g) (55.25 g, max 0.207 mol) was
dissolved in dry tetrahydrofuran (320 mL) and cooled in an ice/salt
bath. To this was added slowly, over 1 h, potassium t-butoxide in
tetrahydrofuran (1 M, 220 mL, 0.22 mol). After 0.5 h water and
petroleum ether were added and the mixture filtered quickly through
kieselguhr. The phases were separated and the aqueous extracted
with more petroleum ether (.times.2). The combined organic extracts
were washed with brine, dried and evaporated to give a mobile
orange oil (31.85 g, 86%), which was used immediately without
further purification.
[0680] .delta.H (CDCl.sub.3) 0.93-0.99 (3H, m), 1.3-1.7 (4H, m),
2.2-2.5 (4H, m), 4.1-4.2 (2H, m), 6.0-6.2 (2H, m), and 6.95-7.02
(1H, m).
(i) 2-Oxa-3-aza-bicyclo[2.2.2]oct-5-ene-1,3-dicarboxylic acid
3-benzyl ester 1-butyl ester
[0681] Crude butyl ester(300h) (31.84 g, max 0.176 mol) was
dissolved in dichloromethane (300 mL). To this was added N-hydroxy
carbamic acid benzyl ester (30.9 g, 0.185 mol). This solution was
cooled in an ice/salt bath then a solution of tetrabutylammonium
periodate (80.1 g, 0.185 mol) in dichloromethane (100 mL) was added
dropwise over 1 h. After stirring for a further 1 h, with cooling,
the mixture was reduced to a small volume in vacuo then stirred
vigorously while adding diethyl ether (1 L). The mixture was
filtered washing well with diethyl ether. The filtrate was then
washed with aqueous sodium bisulphite (.times.2), and brine, dried
and evaporated to give a brown oil. This residue was purified by
chromatography on silica gel, eluting with 25-28% diethyl ether in
petroleum ether, to give a viscous pale orange oil (42.41 g,
.about.69%) (contaminated with a little benzyl alcohol).
[0682] .delta.H (CDCl3) 0.94 (3H, t), 1.35-1.75 (6H, m), 2.15-2.4
(2H, m), 4.2-4.35 (2H, m), 4.84-4.89 (1H, m), 5.12-5.20 (2H, m),
6.59-6.71 (2H, m), and 7.28-7.39 (5H, m).
(j) 2-Oxa-3-aza-bicyclo[2.2.2]oct-5-ene-1,3-dicarboxylic acid
3-benzyl ester
[0683] To a solution of di-ester (300i) (42.13 g, 0.122 mol) in
1,4-dioxane (250 mL) was added aqueous sodium hydroxide solution
(0.5 M, 250 mL, 0.125 mol). The mixture was stirred for 50 min then
washed with diethyl ether (.times.3). The aqueous phase was
adjusted to pH2 with 5 M hydrochloric acid, and extracted with
ethyl acetate (.times.3). The combined organic extracts were washed
with brine, dried and evaporated to give a cream solid (29.53 g,
84%).
[0684] .delta.H (CDCl.sub.3/CD.sub.3OD) 1.53-1.79 (2H, m),
2.13-2.39 (2H, m), 4.82-4.89 (1H, m), 5.11-5.23 (2H, m), 6.57-6.69
(2H, m), and 7.3-7.4 (5H, m).
(k) 1-Carbamoyl-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic
acid benzyl ester
[0685] The benzyl ester (300j) (12.0 g, 41.5 mmol) and
1-hydroxy-7-azabenzotriazole (6.26 g, 46 mmol) were dissolved in
DMF (100 mL) then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (8.79 g, 46 mmol) added. After stirring for 5 min
ammonium hydrogen carbonate (8.22 g, 104 mmol) was added. Four
further small portions of ammonium hydrogen carbonate were added
over the next 7 h. The mixture was then stirred overnight, diluted
with water and extracted with ethyl acetate (.times.4). The
combined organic extracts were washed with 5% aqueous citric acid
then brine, dried and evaporated to give an off-white solid (9.9 g,
83%).
[0686] MS (+ve ion electrospray) m/z 289 (MH+).
(c) (4-Carbamoyl-r-4-hydroxy-c-cyclohexyl)-carbamic acid tert butyl
ester.
[0687] The benzyl ester (300k) (9.75 g, 33.8 mmol) was dissolved in
1,4-dioxane (150 mL) and water (60 mL) and hydrogenated over 10%
palladium on carbon (50% aqueous paste, 3.3 g) at 40.degree. C. and
55 psi for 68 h. More catalyst (2 g) was added after 4 h. The
mixture was then filtered through kieselguhr, washing well with
1,4-dioxane and water. To this solution was added 2 N sodium
hydroxide (25 mL, 50 mmol) followed by a solution of di-tert-butyl
dicarbonate (11.12 g, 51 mmol) in 1,4-dioxane (10 mL). The reaction
mixture was stirred for 5 h then reduced in volume in vacuo, before
extracting with ethyl acetate (.times.5). The combined organic
extracts were dried and evaporated to give a white solid (5.96 g),
which was chromatographed on silica (400 g). Blution with 0-6.5%
methanol in dichloromethane gave a white powder (5.52 g, 63%),
identical to the material produced earlier.
[0688] .delta.H (d.sub.6-DMSO) 1.3-1.76 (17H, m), 3.17 (1H, br s),
4.95 (1H, s), 6.71 (1H, d), 7.0 (1H, s), and 7.14 (1H, s).
Alternative preparation of
1-carbamoyl-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic acid
benzyl ester (300k)
Acetic acid 6-carbamoyl-cyclohex-2-enyl ester
[0689] 1-Acetoxy-1,3-butadiene (20.79 g, 0.185 mol) was dissolved
in toluene (21 mL). To this was added acrylamide (11.98 g, 0.168
mol) and hydroquinone (0.111 g). The colourless solution was heated
at 110.degree. C. for 116 h under argon. More
1-acetoxy-1,3-butadiene (5.67 g, 0.051 mol) was then added, and
heating continued for a further 24 h. The solution was cooled then
dichloromethane added. This solution was purified by Biotage 75
chromatography twice on silica (2.times.400 g) to give the title
compound as a viscous oil (21.76 g, 71%), which solidified on
standing;
[0690] .delta.H (CDCl.sub.3) 1.85-2.7 (8H, m), and 5.5-6.08 (5H,
m).
(m) Cyclohexa-1,3-dienecarboxylic acid amide
[0691] The ester (300l) (16.28 g, 89 mmol) was dissolved in dry
tetrahydrofuran (200 mL) and cooled in an ice bath. To this was
added slowly, over 0.5 h, potassium t-butoxide in tetrahydrofuran
(1 M, 100 mL, 100 mmol). After stirring for 0.5 h with cooling and
2.5 h at room temperature, ethyl acetate was added and the solution
washed with a little water. The organic phase was dried and
evaporated to give a brown oil (>100%). This was used
immediately without further purification.
(k) 1-Carbamoyl-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic
acid benzyl ester
[0692] Crude amide (300m) (max 89 mmol) was dissolved in
dichloromethane (150 mL). To this was added N-hydroxy carbamic acid
benzyl ester (15.61 g, 93.5 mmol). This solution was cooled in an
ice bath then a solution of tetrabutylammonium periodate (40.49 g,
93.5 mmol) in dichloromethane (50 mL) was added dropwise over 0.5
h. After stirring for a further 14 h the mixture was reduced to a
small volume in vacuo then diluted with ethyl acetate(500 mL). The
mixture was then washed with water, aqueous sodium bisulphite
(.times.3), and brine, dried and evaporated to give a yellow solid.
This residue was purified by Biotage 75 chromatography on silica
(800 g), eluting with 22-60% ethyl acetate in petroleum ether, to
give a white solid (9.47 g, 37%);
[0693] .delta.H (CDCl.sub.3) 1.52-1.62 (1H, m), 1.75-1.86 (1H, m),
2.12-2.24 (2H, m), 4.81-4.88 (1H, m), 5.11-5.23 (2H, m), 5.6 (1H,
br s), 6.51-6.64 (3H, m), and 7.3-7.4 (5H, m).
Example 301
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[32,-b][1,4]thiazin-6-ylmethyl)-
-amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0694] ##STR68## (a) Methyl
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate.
[0695] A solution of ethyl 2-mercaptoacetate (1.473 ml) in DMF (48
ml) was ice-cooled and treated with sodium hydride (540 mg of a 60%
dispersion in oil). After 1 hour methyl
6-amino-5-bromopyridine-2-carboxylate (3 g) (T. R. Kelly and F.
Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture
stirred for 16 hours at room temperature. The solution was diluted
with EtOAc (1 litre), washed with water (3.times.300 ml), dried and
evaporated to about 10 ml. The white solid was filtered off and
washed with a little EtOAc to the ester (0.95 g).
[0696] MS (APCI.sup.-) m/z 223 ([M-H].sup.-, 100%)
(b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic
acid.
[0697] A solution of ester (301a) (788 mg) in dioxan (120 ml)/water
(30 ml) was treated dropwise over 2 hours with 0.5M NaOH solution
(8 ml) and stirred overnight. After evaporation to approx. 3 ml,
water (5 ml) was added and 2N HCl to pH4. The precipitated solid
was filtered off, washed with a small volume of water and dried
under vacuum to give a solid (636 mg).
[0698] MS (APCI.sup.-) m/z 209 ([M-H].sup.-, 5%),
165([M-COOH].sup.-, 100%)
(c)
6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine.
[0699] A solution of the carboxylic acid (301b) (500 mg) in TBF (24
ml) with triethylamine (0.396 ml) was cooled to -10.degree. C. and
isobutyl chloroformate (0.339 ml) added. After 20 minutes the
suspension was filtered through kieselguhr into an ice-cooled
solution of sodium borohydride (272 mg) in water (8 ml), the
mixture stirred 30 minutes and the pH reduced to 7 with dilute HCl.
The solvent was evaporated and the residue triturated under water.
The product was filtered and dried under vacuum to give a white
solid (346 mg).
[0700] MS (APCI.sup.-) m/z 195 ([M-H].sup.-, 50%), 165(100%)
(d)
3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde.
[0701] A solution of the alcohol (301c) (330 mg) in dichloromethane
(30 ml)/THF (30 ml) was treated with manganese dioxide (730 mg) and
stirred at room temperature. Further manganese dioxide was added
after 1 hour (730 mg) and 16 hours (300 mg). After a total of 20
hours the mixture was filtered through kieselguhr and the filtrate
evaporated. The product was triturated with EtOAc/hexane (1:1) and
collected to give a solid (180 mg).
[0702] MS (APCI.sup.-) m/z 195 ([M-H].sup.-, 95%), 165 (100%)
(e) Title Compound
[0703] A mixture of the carboxaldehyde (301d) (62 mg) and amine
(300e) (100 mg) in chloroform (1.5 ml)/methanol (1.5 ml) with 3A
molecular sieves was refluxed 8 hours, cooled and treated with
sodium triacetoxyborohydride (237 mg). After stirring overnight,
the mixture was diluted with chloroform (20 ml) and washed with
aqueous NaHCO.sub.3. The aqueous was re-extracted with chloroform
and the combined organic fractions dried over MgSO.sub.4 and
evaporated. Chromatography of the residue
(CHCl.sub.3/MeOH/NH.sub.4OH 95:5:0.5) gave free base of the title
compound (100 mg).
[0704] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.5-1.7 (2H, m),
1.8-2.0 (4H, m), 2.0-2.2 (2H, m), 2.6-2.7 (1H, m), 3.50 (2H, s),
3.87 (2H, s), 4.17 (3H, s), 6.98 (1H, d), 7.24 (1H, d), 7.67 (1H,
d), 8.18 (1H, d), 8.53 (1H, d), 8.63 (1H, d)
[0705] This material as a solution in chloroform/methanol 1:1 was
treated with 1M HCl in ether (0.5 ml) and evaporated to dryness.
The solid was triturated under ether, filtered and dried under
vacuum to provide the title compound (112 mg).
[0706] MS (+ve ion electrospray) m/z 495 (MH.sup.+, 100%)
Example 302
1-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-
-amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0707] ##STR69## (a) 5-Fluoro-2-picoline N-oxide. The preparation
was based on E. J. Blanz, F. A. French, J. R. DoAmaral and D. A.
French, J. Med. Chem. 13, 1970, 1124-1130. 5-Amino-2-picoline (12.5
g) in ethanol (105 ml) and 50% fluoroboric acid (44.5 ml) was
stirred at -5.degree. C. and treated dropwise over 45 minutes with
n-butyl nitrite (31.25 ml). The solution was maintained at this
temp for 3 hours, treated with ether (100 ml, precooled to
-20.degree. C.) and the solid filtered off, quickly transferred to
a flask and covered with hexane (precooled to -20.degree. C.).
After allowing to warm to approx. 20.degree. C. and standing for 3
days the hexane was decanted and 2M NaOH solution added until basic
(pH 10). The mixture was filtered and the filtrate extracted with
dichloromethane (10.times.200 ml). The organic solution was dried,
evaporated to 200 ml and treated with m-chloroperbenzoic acid (26.5
g). After stirring 16 hours the solution was washed with excess
aqueous sodium bicarbonate and the aqueous re-extracted with
dichloromethane (10.times.200 ml). The organic fraction was dried
and evaporated and the residue chromatographed (15% EtOH/EtOAc) to
give the pyridine N-oxide (5.5 g).
[0708] MS (APCI.sup.+) m/z 128 (MH.sup.+, 100%)
(b) 5-Fluoro-4-nitro-2-picoline N-oxide.
[0709] The pyridine N-oxide (302a) (2.12 g) was treated with an
ice-cooled mixture of fuming nitric acid (7.1 ml) and conc.
sulfuric acid (7.1 ml), heated at 35-40.degree. C. for 1 hour and
65-70.degree. C. for 5.5 hours, cooled and ice (45 g) added. 10M
NaOH was added to pH 10 and the mixture extracted with EtOAc
(3.times.30 ml). The organic fraction was dried and evaporated to
give a yellow solid (2.16 g).
[0710] MS (APCI.sup.+) m/z 173 (MH.sup.+, 30%), 127 (100%)
(c) 5-Ethoxycarbonylmethylthio-4-nitro-2-picoline N-oxide.
[0711] Ethyl 2-mercaptoacetate (1.51 g) in dioxan (15.6 ml) under
argon was treated with sodium hydride (550 mg of a 60% dispersion
in oil) and stirred for 4 hours. The pyridine N-oxide (302b) (2.16
g) was added and stirring was continued for 3 days. Water (50 ml)
was added and the mixture extracted with chloroform (3.times.50
ml). The organic fraction was dried and evaporated to give a yellow
solid (3.31 g).
[0712] MS (APCI.sup.+) m/z 273 (MH.sup.+, 80%), 125 (100%)
(d) 2-Acetoxymethyl-5-ethoxycarbonylmethylthio-4-nitropyridine.
[0713] A solution of the ester (302c) (3.31 g) in acetic anhydride
(43 ml) was heated to 80.degree. C. for 6 hours, evaporated, xylene
(100 ml) added and evaporated. Chromatography of the residue
(eluent EtOAc/hexane 1:1) gave the pyridine (1.03 g).
(e)
7-Acetoxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine
[0714] A solution of the pyridine (302d) (1.03 g) in glacial acetic
acid (27.5 ml) was treated with iron powder (1.75 g), stirred at
60.degree. C. for 3 hours, filtered through kieselguhr and
evaporated to dryness. Saturated aqueous sodium bicarbonate (300
ml) was added and the mixture extracted with EtOAc (3.times.200
ml). The organic fraction was dried and evaporated. The residue was
redissolved in acetic acid (30 ml), heated to 100.degree. C. for 24
hours, evaporated and chromatographed (eluent EtOAc/hexane 1:1) to
give a solid (340 mg).
[0715] MS (APCI.sup.-) m/z 237 ([M-H].sup.-, 90%), 195 (100%)
(f)
7-Hydroxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine
[0716] A solution of the pyridothiazinone (302e) (340 mg) in dioxan
(9 ml) was treated dropwise over 2 hours with 0.5M NaOH (3.7 ml),
stirred for 18 hours and evaporated. Water (10 ml) was added and
the product filtered off, washed with water and dried under vacuum
to give a white solid (231 mg).
[0717] MS (APCI.sup.-) m/z 195 ([M-H].sup.-, 100%)
(g)
2-Oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7-carboxaldehyde.
[0718] A mixture of the pyridothiazinone (226 mg), manganese
dioxide (600 mg), THF (22.5 ml) and 1,2-dichloroethane (22.5 ml)
was heated at 65.degree. C. for 18 hours under argon. Filtration
through kieselguhr and evaporation of solvent gave the product as
an off-white solid (173 mg).
[0719] MS (APCI.sup.-) m/z 193 ([M-H].sup.-, 100%)
(h) Title Compound
[0720] A mixture of the carboxaldehyde (302 g) (62 mg) and amine
(300e) (100 mg) in chloroform (1.5 ml)/methanol (1.5 ml) with 3A
molecular sieves was refluxed for 24 hours, cooled and treated with
sodium triacetoxyborohydride (237 mg). After stirring overnight,
the mixture was diluted with chloroform (20 ml) and washed with
aqueous NaHCO.sub.3. The aqueous fraction was re-extracted 3 times
with 20% ethanol in chloroform and the combined organic fraction
dried over MgSO.sub.4 and evaporated. Chromatography of the residue
(CHCl.sub.3/MeOH/NH.sub.4OH 95:5:0.5) gave free base of the title
compound (88 mg).
[0721] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.5-1.7 (2H, m),
1.8-2.2 (6H, m), 2.5-2.7 (1H, m), 3.48 (2H, s), 3.87 (2H, s), 4.17
(3H, s), 6.91 (1H,s), 7.22 (1H, d), 8.17.(1H, d), 8.37 (1H, s),
8.54 (1H, d), 8.62 (1H, d)
[0722] This material as a solution in chloroform/methanol 1:1 was
treated with 1M HCl in ether (0.5 ml) and evaporated to dryness.
The solid was dried under vacuum to provide the title compound (78
mg).
[0723] MS (+ve ion electrospray) m/z 495 (MH.sup.+, 100%)
Example 303
1-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-
-amino]-r-cylohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0724] ##STR70## (a) Title Compound.
[0725] A mixture of the carboxaldehyde (13e) (37 mg) and amine
(300e) (55 mg) in chloroform (4 ml)/methanol (4 ml) with 3A
molecular sieves was refluxed for 3 hours, cooled and treated with
sodium triacetoxyborohydride (300 mg), portionwise. After stirring
at room temperature for 7 days, the mixture was diluted with
chloroform and washed with aqueous Na.sub.2CO.sub.3 solution, dried
over Na.sub.2SO.sub.4 and evaporated The residue was
chromatographed on silica gel, eluting with 2-10%
methanol-dichloromethane to give the free base of the title
compound (30 mg).
[0726] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.5-1.7 (2H, m),
1.8-2.2 (6H, m), 2.65 (1H, m), 3.60 (2H, s), 3.81 (2H, s), 4.17
(3H, s), 6.91 (1H,s), 7.21 (1H, d), 7.25 (1H, d), 8.10 (1H, d),
8.18 (1H, d), 8.55 (1H, d), 8.62 (1H, d)
[0727] This material as a solution in chloroform/methanol 1:1 was
treated with 4M HCl in dioxan (0.2 ml) and evaporated to dryness.
The solid was dried in vacuo to provide the title compound (35
mg).
[0728] MS (+ve ion electrospray) m/z 495 (MH.sup.+, 100%)
Example 304
1-Hydroxy-t-4-[(7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-y-
lmethyl)-amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0729] ##STR71## (a) Methyl
6-amino-3,5-dibromopyridine-2-carboxylate.
[0730] A solution of methyl 6-amino-3-bromopyridine-2-carboxylate
(20.62 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996,
4623-4633) in chloroform (570 ml) was treated dropwise over 2 hours
with bromine (4.62 ml) in chloroform (115 ml) and stirred 16 hours.
The solution was washed with excess aqueous sodium bicarbonate,
dried and evaporated. Crystallisation from EtOAc/hexane gave the
bromopyridine (13.5 g).
[0731] MS (APCI.sup.+) m/z 309, 311, 313 (MH.sup.+, 70%), 295, 297,
299 (100%).
(b) Methyl
7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate.
[0732] This was prepared from methyl
6-amino-3,5-dibromopyridine-2-carboxylate (12.75 g) by the method
of Example (301a) to give 5.85 g.
[0733] MS (APCI.sup.+) m/z 303, 305 (MH.sup.+, 30%), 271, 273
(100%)
(c)
7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic
acid.
[0734] This compound was prepared (73%) from the ester (304b) by
the method of Example (301b)
[0735] MS (APCI.sup.-) m/z 287, 289 ([M-H].sup.-, 3%), 243, 245
([M-COOH].sup.-, 100%)
(d)
7-Bromo-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiaz-
ine.
[0736] This compound was prepared (80%) from carboxylic acid (304c)
by the method of Example (301c).
[0737] MS (APCI.sup.+) m/z 275, 277 (MH.sup.+, 20%), 257, 259
(100%)
(e)
7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxalde-
hyde
[0738] A mixture of the 7-bromo-pyridothiazinone (304d) (518 mg),
manganese dioxide (870 mg), THF (45 ml) and 1,2-dichloroethane (45
ml) was heated at 60.degree. C. under argon. Further manganese
dioxide was added after 4 hours (870 mg) and 20 hours (600 mg).
After a total of 30 hours filtration through kieselguhr and
evaporation of solvent gave a solid (320 mg).
[0739] MS (APCI.sup.-) m/z 271, 273 ([M-H].sup.-, 40%), 152
(100%)
(f) Title Compound
[0740] A mixture of the carboxaldehyde (304e) (87 mg) and the amine
(300e) (100 mg) in chloroform (2 ml)/methanol (2 ml) with 3A
molecular sieves was refluxed 18 hours, cooled and treated with
sodium triacetoxyborohydride (237 mg). After stirring overnight,
the mixture was diluted with chloroform (20 ml) and washed with
aqueous NaHCO.sub.3. The aqueous fraction was re-extracted with 20%
ethanol in chloroform and the combined organic fractions dried
(MgSO.sub.4) and evaporated. Chromatography of the residue
(CHCl.sub.3/MeOH/NH.sub.4OH 95:5:0.5) gave free base of the title
compound (80 mg).
[0741] .sup.1HNMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.5-1.7 (2H, m),
1.8-2.2 (6H, m), 2.6-2.8 (1H, m), 3.51 (2H, s), 3.99 (2H, s), 4.17
(3H, s), 7.22 (1H, d), 7.85 (1H, s), 8.18 (1H, d), 8.54 (1H, d),
8.63 (1H, d)
[0742] This material as a solution in chloroform/methanol 1:1 was
treated with 1M HCl in ether (0.35 ml) and evaporated to dryness.
The solid was triturated under ether, filtered and dried under
vacuum to provide the title compound (90 mg).
[0743] MS (+ve ion electrospray) m/z 573 and 575 (MH.sup.+,
100%)
Example 305
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)--
amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0744] ##STR72## (a) 2-Bromo-5-hydroxy-6-nitropyridine.
[0745] 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved
in methanol (400 ml) and a solution of 25% sodium methoxide in
methanol (33 ml, 0.13 mole) was added at room temperature. The
mixture was stirred for 30 min, then was cooled to 0.degree. C.,
and bromine (7.2 ml, 0.14 mole) was added slowly. The reaction was
then stirred at 0.degree. C. for 30 mm, then was quenched with
glacial AcOH (2.5 ml). The solvent was removed in vacuo to afford
material (30 g, 96%), which was used without further
purification.
[0746] MS(ES) m/z 219.0 (M+H).sup.+.
(b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate.
[0747] The hydroxypyridine (305a) (30 g, 0.14 mole) was suspended
in acetone (200 ml), and potassium carbonate (39 g, 0.28 mole) was
added, followed by ethyl bromoacetate (15.7 ml, 0.14 mmole). The
reaction was heated at reflux for 10 hr, then was cooled to room
temperature and diluted with Et.sub.2O. The precipitate was removed
by suction filtration, and the filtrate was concentrated in vacuo
to afford material (38 g, 89%), which was used without further
purification.
[0748] MS (ES) m/z 305.0 (M+H).sup.+.
(c) 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one.
[0749] The nitropyridine (305b) (38 g, 0.125 mole) was dissolved in
glacial AcOH (150 ml), and iron powder (20 g, 0.36 mole) was added.
The mixture was mechanically stirred and heated at 90.degree. C.
for 5 hr, then was cooled to room temperature and diluted with
EtOAc (300 ml). The mixture was filtered through a pad of silica
gel and the filtrate was concentrated in vacuo and the residue
recrystallized from MeOH (15 g, 52%).
[0750] MS (ES) m/z 229.0 (M+H).sup.+.
(d) 6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one.
[0751] The bromopyridine (305c) (6.0 g, 26.3 mmole) and
trans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved
in 1,4-dioxane (150 ml) and the solution was degassed with argon.
(Ph.sub.3P).sub.4Pd (230 mg, 0.2 mmole) was added, followed by a
solution of potassium carbonate (6.9 g, 50 mmole) in H.sub.2O (20
ml). The reaction was heated at reflux under argon overnight, then
was cooled to room temperature and diluted with EtOAc (200 ml). The
solution was washed sequentially with H.sub.2O and brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The solid residue
was purified by flash chromatography on silica gel (5-10%
EtOAc/CHCl.sub.3) to afford a solid (2.5 g, 38%).
[0752] MS (ES) m/z 253.0 (M+H).sup.+.
(e)
3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde
[0753] The pyridine (305d) (1.2 g, 4.8 mmole) was dissolved in
CH.sub.2Cl.sub.2 (200 ml) and the solution was cooled to
-78.degree. C. Ozone was bubbled through the solution with stirring
until a pale blue color appeared, then the excess ozone was removed
by bubbling oxygen through the solution for 15 min. Dimethylsulfide
(1.76 ml 24 mmole) was added to the solution, and the reaction was
stirred at -78.degree. C. for 3 hr, then at room temperature
overnight The solvent was removed in vacuo, and the residue was
triturated with Et.sub.2O (50 ml). The collected solid was washed
with additional Et.sub.2O and dried to afford a solid (700 mg,
82%).
[0754] MS (ES) m/z 179.0 (M+H).sup.+.
(e) Title Compound
[0755] A mixture of the carboxaldehyde (305e) (0.5 g; 2.8 mmol) and
amine (300e) (0.93 g; 2.94 mmol) in methanol (35
ml)/dimethylformamide (35 ml)/acetic acid (3.5 ml) was heated at
80.degree. C. with 3A molecular sieves for 3 hours, cooled and
treated with sodium cyanoborohydride (0.6 g; 9.5 mmol). After
stirring overnight at room temperature, the mixture was diluted
with methanol-chloroform (1:1), filtered and the filtrate
evaporated to dryness. It was treated with aqueous sodium carbonate
and extracted (4.times.) with methanol-chloroform (1:9), dried
(sodium sulfate), and evaporated to dryness. Chromatography of the
residue (2-10% methanol-dichloromethane) gave free base of the
title compound (1.03 g; 74%).
[0756] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.5-1.7 (2H, m),
1.8-2.0 (4H, m), 2.0-2.12 (2H, m), 2.6-2.7 (1H, m), 3.38 (2H, s),
3.83 (2H, s), 4.17 (3H, s), 6.96 (1H, d), 7.25 (2H, m), 8.18 (1H,
d), 8.53 (1H, d), 8.62 (1H, d).
[0757] This material as a solution in chloroform/methanol 1:1 was
treated with excess 4M HCl in dioxan and evaporated to dryness. The
solid was triturated with ether, filtered and dried in vacuo to
give the title compound, as a white solid.
[0758] MS (+ve ion electrospray) m/z 479 (MH.sup.+)
Example 306
1-Hydroxy-t-4-[(7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6--
ylmethyl)-amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0759] ##STR73## (a) Methyl
6-amino-5-bromo-3-chloropyridine-2-carboxylate.
[0760] To a solution methyl 6-amino-5-bromopyridine-2-carboxylate
(20.04 g) in acetic acid (900 ml) was added N-chlorosuccinimide
(13.96 g) and the resultant solution was heated to 120.degree. C.
for 1 hour. The solution was then evaporated and treated with
excess aqueous sodium bicarbonate and extracted with
dichloromethane. The organic fraction was dried and evaporated to
give the product (21.98 g).
[0761] MS (+ve ion electrospray) m/z 265 and 267 (MH.sup.+,
100%)
(b) Methyl
7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate.
[0762] This was prepared (51%) from the ester (306a) (23.8 g) by
the method of Example (301a) to give a solid (11.8 g).
[0763] MS (+ve ion electrospray) m/z 257 (MH.sup.+, 100%)
(c)
7-Chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxyli-
c acid.
[0764] This compound was prepared (96%) from the ester (306b)
(11.84 g) by the method of Example (301b) to give a solid (9.6
g).
[0765] MS (APCI-) m/z 243 ([M-H]--, 2%), 199 ([M-COOH]--, 100%)
(d)
7-Chloro-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thia-
zine.
[0766] This compound was prepared (70%) from the carboxylic acid
(306c) by the method of Example (301c).
[0767] MS (+ve ion electrospray) m/z 231 (MH.sup.+, 100%)
(e)
7-Chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxald-
ehyde
[0768] This compound was prepared (49%) from the alcohol (306d) by
the method of Example (304e) to give a solid (2.01 g).
[0769] MS (+ve ion electrospray) m/z 229 (MH+, 100%)
(f) Title Compound
[0770] A mixture of the carboxaldehyde (306e) (134 mg) and the
amine (300e) (187 mg) in chloroform (3 ml)/methanol (3 ml) with 3A
molecular sieves was refluxed 18 hours, cooled and treated with
sodium triacetoxyborohydride (376 mg). After stirring overnight,
the mixture was diluted with dichloromethane (50 ml) and washed
with aqueous NaHCO.sub.3. The aqueous fraction was re-extracted
with 10% methanol in dichloromethane and the combined organic
fractions dried (MgSO.sub.4) and evaporated. Chromatography of the
residue (CH.sub.2Cl.sub.2:MeOH 90:10) gave free base of the title
compound (84 mg). 1H NMR .delta.(DMSO) 1.4-1.5 (2H, m), 1.7-1.9
(6H, m), 2.49-2.54 (1H, m), 3.59 (2H, s), 3.89 (2H, s), 4.10 (3H,
s), 6.09 (1H,s), 7.33 (1H, d), 7.95 (1H, s), 8.28 (1H, d), 8.44
(1H, d), 8.69 (1H, d), 11.09 (2H, br s)
[0771] This material as a solution in dichloromethane:methanol 1:1
was treated with 4M HCl in dioxane (0.10 ml) and evaporated to
dryness. The solid was triturated under ether, filtered and dried
under vacuum to provide the title compound (75 mg).
[0772] MS (+ve ion electrospray) m/z 529 (MH+, 100%).
Example 307
1-Hydroxy-t-4[(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-2-ylmethyl)amin-
o]-r-cyclohexanecarboxylic acid
(6methoxy-[1,5]naphthyridine-4-yl)-amide dihydrochloride
[0773] ##STR74## (a)
6-Amino-5-((E)-ethoxycarbonyl-vinyl)-pyridine-2-carboxylic acid
methyl ester.
[0774] To a degassed solution of methyl
6-amino-5-bromopyridine-2-carboxylate (1.06 g), ethyl acrylate
(2.49 ml), tri-o-tolylphosphine (280 mg), triethylamine (3.18 ml)
in dimethylformamide (50 ml) was added
tris(dibenzylideneacetone)palladium (0) (211 mg) and the resultant
solution was heated at 50.degree. C. for 72 h. After stirrng
overnight, the mixture was evaporated and the residue treated with
dichloromethane (50 ml) and washed with H.sub.2O. The aqueous
fraction was re-extracted with 10% methanol in dichloromethane and
the combined organic fractions dried (MgSO.sub.4) and evaporated.
Chromatography of the residue (60-80 petroleum ether-ethyl acetate
4:1) gave the product (360 mg, 31%).
[0775] MS (+ve ion electrospray) m/z 251 (MH+, 100%).
(b) 6-Amino-5-(2-ethoxycarbonyl-ethyl)-pyridine-2-carboxylic acid
methyl ester.
[0776] A solution of the ester (307a) (350 mg) in MeOH (50 ml) was
hydrogenated over palladium on carbon (10%) (35 mg) for 24 h. The
suspension was filtered and evaported to give the product (345 mg,
97%).
[0777] MS (+ve ion electrospray) m/z 253 (MH+, 100%)
(c) 7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthryridine-2-carboxylic acid
methyl ester.
[0778] A solution of amine (307b) (345 mg) in acetic acid (20 ml)
was heated at 100.degree. C. for 1 h. The acetic acid was then
evaporated to give a solid (276 mg, 98%).
[0779] MS (+ve ion electrospray) m/z 206 (MH+, 100%)
(d) 7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthryridine-2-carboxylic
acid.
[0780] This compound was prepared (96%) from the ester (307c) (272
mg) by the method of Example (301b) to give a solid (263 mg).
[0781] MS (APCI-) m/z 191 ([M-H]-, 1%), 147 ([M-COOH]-, 100%)
(e) 7-Hydroxymethyl-3,4-dihydro-1-H-[1,8]naphthyridin-2-one
[0782] This compound was prepared (80%) from the carboxylic acid
(307d) by the method of Example (301c).
[0783] MS (+ve ion electrospray) m/z 179 (MH.sup.+, 100%)
(f) 7-Oxo-5,6,7,8-tetrahydro-[1,8]napthyridine-2-carboxaldehyde
[0784] This compound was prepared (28%) from alcohol (307e) by the
method of Example (304e) to give a solid (72 mg).
[0785] MS (+ve ion electrospray) m/z 229 (MH+, 100%)
(g) Title Compound.
[0786] A mixture of the carboxaldehyde (307f) (72 mg) and amine
(300e) (130 mg) in methanol (5 ml)/dimethylformamide (5 ml)/acetic
acid (0.5 ml) was heated at 80.degree. C. with 3A molecular sieves
for 3 hours, cooled and treated with sodium cyanoborohydride (0.6
g; 9.5 mmol). After stirring overnight at room temperature, the
mixture was diluted with methanol-chloroform (1:1), filtered and
the filtrate evaporated to dryness. It was treated with aqueous
sodium carbonate and extracted (4.times.) with methanol-chloroform
(1:9), dried (sodium sulfate), and evaporated to dryness.
Chromatography of the residue (0-10% methanol-dichloromethane) gave
free base of the title compound (102 mg; 52%).
[0787] 1H NMR .delta.(DMSO) 1.4-1.5 (2H, m), 1.7-1.9 (6H, m),
2.47-2.51 (1H, m), 2.83-2.87 (2H, t), 3.17-3.31 (4H, m), 3.75 (2H,
s), 4.10 (3H, s), 6.08 (1H, s), 7.04 (1H, d), 7.33 (1H, d), 7.54
(2H, m), 8.27 (1H, d), 8.44 (1H, d), 8.68 (1H, d), 10.32,
11.08.
[0788] This material as a solution in chloroform/methanol 1:1 was
treated with excess 4M HCl in dioxan and evaporated to dryness. The
solid was triturated with ether, filtered and dried in vacuo to
give the title compound, as a white solid.
[0789] MS (+ve ion electrospray) m/z 477 (MH+)
Example 308
1-Hydroxy-t-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6y-
lmethyl)-amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0790] ##STR75## (a) Methyl
6-amino-5-bromo-3-fluoropyridine-2-carboxylate.
[0791] A mixture of methyl 6-amino-5-bromopyridine-2-carboxylate
(19.8 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996,
4623-4633) and
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (34.3 g) in acetonitrile (340 ml) under
argon was heated to 40.degree. C. for 1 hour, 60.degree. C. for 1
hour and then 80.degree. C. overnight. After partitioning between
EtOAc and water (500 ml each) the aqueous fraction was re-extracted
with EtOAc (300 ml) and the combined organic solution dried with
MgSO.sub.4 and evaporated. Chromatography (20% then 30% EtOAc in
hexane) separated various byproducts from the required ester (2.09
g).
[0792] MS (+ve ion electrospray) m/z 249 and 251 (MH.sup.+,
100%)
(b) Methyl
6-amino-5-ethoxycarbonylmethylthio-3-fluoropyridine-2-carboxylate.
[0793] A solution of ethyl mercaptoacetate (1.15 ml) in DMF (40 ml)
was ice-cooled under argon, treated with sodium hydride (420 mg of
a 60% dispersion in oil) and stirred until all was in solution
(about 1 hour). The ester (308a) (2.48 g) was added, the mixture
allowed to warm to room temp. and stirred overnight. EtOAc (150 ml)
was added, the solution washed with water (3.times.150 ml), dried
and evaporated. Chromatography of the residue (30 then 40% EtOAc in
hexane) gave the product as an oil (1.7 g).
[0794] MS (+ve ion electrospray) m/z 289 (MH.sup.+, 100%)
(c) Methyl
7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate.
[0795] A solution of the fluoropyridine (308b) (1.7 g) in acetic
acid (100 ml) was heated at 110.degree. C. overnight, evaporated
and dried under vacuum to give the product as a white solid (1.55
g, containing 0.33 equivalent of acetic acid).
[0796] MS (+ve ion electrospray) m/z 243 (MH.sup.+, 85%), 211
(100%)
(d)
7-Fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxyli-
c acid.
[0797] This compound was prepared from the ester (308c) by the
method of Example (301b) (86%).
(e)
7-Fluoro-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thia-
zine
[0798] This compound was prepared from carboxylic acid (308d) by
the method of Example (301c) (73%).
[0799] MS (-ve ion electrospray) m/z 213 ([M-H].sup.-, 100%)
(f)
7-Fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxald-
ehyde
[0800] A mixture of the 7-fluoro-pyridothiazinone (308e) (971 mg),
manganese dioxide (3.72 g), THF (70 ml) and 1,2-dichloroethane (70
ml) was heated at 60.degree. C. under argon for 20 hours.
Filtration through kieselguhr and evaporation of solvent gave a
solid which was triturated under EtOAc/hexane 1:3 and collected
(608 mg).
[0801] MS (+ve ion electrospray) m/z 213 (MH.sup.+, 100%)
(g) Title Compound.
[0802] A mixture of the carboxaldehyde (308f) (94 mg) and the amine
(300e) (120 mg) in chloroform (2.5 ml)/methanol (2.5 ml) with 3A
molecular sieves was refluxed 18 hours, cooled and treated with
sodium triacetoxyborohydride (285 mg). After stirring for 6 hours,
the mixture was filtered, diluted with chloroform (20 ml) and
washed with aqueous NaHCO.sub.3. The aqueous fraction was
re-extracted with 10% ethanol in chloroform and the combined
organic fractions dried MgSO.sub.4) and evaporated. Chromatography
of the residue (CHCl.sub.3/MeOH/NH.sub.4OH 95:5:0.5) gave the free
base of the title compound (117 mg).
[0803] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.5-1.7 (2H, m),
1.8-2.0 (4H, m),2.0-2.2 (2H, m), 2.6-2.7 (1H, m), 3.50 (2H, s),
3.93 (2H, s), 4.16 (3H, s), 7.21 (1H, d), 7.47 (1H, d), 8.16 (1,
d), 8.55 (1H, d), 8.63 (1H, d)
[0804] This material as a solution in chloroform/ethanol 1:1 was
treated with 1M HCl in ether (0.5 ml) and evaporated to dryness.
The solid was triturated under ether, filtered and dried under
vacuum to provide the title compound (135 mg).
[0805] MS (+ve ion electrospray) m/z 513 (MH.sup.+, 100%)
Example 309
1-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-ylmethyl)--
amino]-r-cyclohexanecarboxylic acid
(6-methyl-[1,5]naphthyridin-4-yl)-amide
[0806] ##STR76## (a) 5-Hydroxy-2-methylpyridine N-oxide.
[0807] 5-Hydroxy-2-methylpyridine (25 g) was suspended in
chloroform (500 ml) and treated with m-chloroperbenzoic acid (57 g
of material described as 57-86% pure). After stirring for 1 hour
the solution was dried with MgSO.sub.4 and poured onto a silica
column. Elution with EtOAc to remove byproducts and then with
20-50% EtOH in EtOAc gave the product (27.7 g).
[0808] MS (APCI.sup.+) m/z 126 (MH.sup.+, 60%) 109 (100%)
(b) 5-Methoxycarbonylmethoxy-2-methylpyridine N-oxide.
[0809] A solution of the pyridine N-oxide (309a) (21.12 g) in DMF
(450 ml) was treated with potassium carbonate (26.2 g) and, after
30 mins., with methyl bromoacetate (16 ml), and stirred overnight.
Solvent was evaporated, saturated brine (500 ml) added and the
mixture extracted with chloroform (6.times.200 ml). The combined
organic solution was dried and evaporated and the residue
chromatographed (20% EtOH in EtOAc) to give product (18.5 g).
[0810] MS (APCI.sup.+) m/z 198 (MH.sup.+, 100%)
(c) 5-Carboxymethoxy-2-methyl-4-nitropyridine N-oxide.
[0811] The pyridine N-oxide (309b) (18.5 g) was dissolved in a cold
mixture of fuming nitric acid (90 ml) and conc. suiluic acid (90
ml) and heated to 40.degree. C. for 1 hour, then 65.degree. C.
overnight The mixture was cooled, poured onto ice and EtOAc (250
ml) added. When the ice had melted, the mixture was shaken and
solid filtered off. The EtOAc was dried and evaporated, the residue
triturated under ether and solid filtered. The solids filtered off
were combined, giving the product (8.4 g).
[0812] MS (+ve ion electrospray) m/z 229 (MH.sup.+, 70%),
154(100%)
(d) 5-Methoxycarbonylmethoxy-2-methyl-4-nitropyridine N-oxide.
[0813] The carboxylic acid (309c (8.4 g) in DMF (100 ml) was
treated with potassium carbonate (7.6 g) and iodomethane (2.8 ml)
and stirred for 3 days. After evaporation of solvent, water (200
ml) was added, the mixture stirred 10 mins. and solid filtered off
and dried under vacuum to give the product (5.32 g).
[0814] MS (+ve ion electrospray) m/z 243 (MH.sup.+, 100%)
(e)
5-Methoxycarbonylmethoxy-4-nitro-2-trifluoroacetoxymethylpyridine
[0815] The pyridine N-oxide (309d) (3.8 g) in trifluoroacetic
anhydride (120 ml) was refluxed under argon for 24 hours, the
solvent evaporated and the residue partitioned between chloroform
and aqueous NaHCO.sub.3 (50 ml each). The aqueous fraction was
re-extracted with chloroform (3.times.50 ml) and the combined
organic solution dried and evaporated to give the product (1.8
g).
[0816] MS (+ve ion electrospray) m/z 339 (MH.sup.+, 100%)
(f) Mixture of
5-methoxycarbonylmethoxy-4-nitro-2-trifluoroacetoxymethylpyridine
and 2-hydroxymethyl-5-methoxycarbonylmethoxy-4-nitropyridine
[0817] When material (309e) was chromatographed on silica gel,
partial loss of trifluoroacetyl group occurred to give the product
mixture.
(g)
7-Acetoxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine.
[0818] The mixture of nitropyridines (309f) (7.37 mmole) in acetic
acid (55 ml) was treated with iron powder (4.2 g) and stirred at
60.degree. C. for 1 hour, cooled and filtered through kieselguhr.
The filtrate was heated to 110.degree. C. overnight, evaporated to
dryness and partitioned between chloroform and aqueous
NaHCO.sub.3(100 ml each). After filtration to remove iron salts and
separation of the layers, the aqueous fraction was re-extracted
with chloroform (10.times.50 ml) and the combined organic solution
dried and evaporated to give product (1.17 g).
[0819] MS (-ve ion electrospray) m/z 221 ([M-H].sup.-, 100%)
(h)
7-Hydroxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine
[0820] A solution of acetate (309 g) (1.17 g) in dioxan (75
ml)/water (15 ml) was treated dropwise with 2M NaOH solution (3 ml)
and left overnight. The pH was reduced to 6 with dilute HCl and the
solvent evaporated. Water (5 ml) was added, the pH readjusted to 6
and the solid filtered off and dried under vacuum to give product
(877 mg).
[0821] MS (-ve ion electrospray) m/z 179 ([M-H].sup.-, 100%)
(i)
2-Oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-7-carboxaldehyde
[0822] A mixture of the hydroxymethyloxazinone (309 h) (584 mg),
manganese dioxide (2.3 g), THF (50 ml) and 1,2-dichloroethane (50
ml) was heated at 60.degree. C. under argon for 20 hours.
Filtration through kieselguhr and evaporation of solvent gave a
solid which was triturated under EtOAc/hexane 1:3, filtered off and
dried (383 mg).
[0823] MS (-ve ion electrospray) m/z 177 ([M-H].sup.-, 100%)
(j) Title Compound
[0824] A mixture of the carboxaldehyde (309i) (68 mg) and the amine
(300e) (120 mg) in chloroform (2.5 ml)/methanol (2.5 ml) with 3A
molecular sieves was refluxed 18 hours, cooled and treated with
sodium triacetoxyborohydride (285 mg). After stirring for 3 hours
at room temp. and 1 hour at 60.degree. C., the mixture was
filtered, diluted with chloroform (20 ml) and washed with aqueous
NaHCO.sub.3. The aqueous fraction was re-extracted with 10% ethanol
in chloroform (6.times.10 ml) and the combined organic fractions
dried (MgSO.sub.4) and evaporated. Chromatography of the residue on
silica gel (CHCl.sub.3/MeOH/NH.sub.4OH 95:5:0.5) gave the free base
of the title compound (92 mg).
[0825] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.5-1.7 (2H, m),
1.8-2.0 (4H, m), 2.0-2.2 (2H, m), 2.6-2.7 (1H, m), 3.85 (2H, s),
4.17 (3H, s), 4.68 (2H, s), 6.89 (1H, s), 7.20 (1H, d), 8.13 (1H,
s), 8.18 (1H, d), 8.54 (1H, d), 8.61 (1H, d)
[0826] This material as a solution in chloroform/ethanol 1:1 was
treated with 1M HCl in ether (0.4 ml) and evaporated to dryness.
The solid was triturated under ether, filtered and dried under
vacuum to provide the title compound (98 mg).
[0827] MS (+ve ion electrospray) m/z 479 (MH.sup.+, 100%)
Example 310
1-Hydroxy-t-4-[(7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6--
ylmethyl)-amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0828] ##STR77## (a) Methyl
7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate.
[0829] Methyl
7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate
(Example 304b) (1.50 g, 4.95 mmol), tetramethyltin (1.71 mL, 12
mmol) and bis(triphenylphosphine)palladium(II) chloride (0.84 g,
1.2 mmol) in dimethylformamide (30 mL) were heated at 120.degree.
C. for 24 h. The mixture was filtered through Kieselguhr, washed
through with ethyl acetate and evaporated. Chromatography on silica
gel (10-50% ethyl acetate/petroleum ether) gave the title compound
(1.0 g, 85%).
[0830] MS (+ve ion electrospray) m/z 239 (MH.sup.+)
(b)
7-Methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxyli-
c acid.
[0831] Aqueous sodium hydroxide (2M, 2.5 mL, 5 mmol) was added
slowly to a stirred suspension of ester (310a) (0.99 g, 4.16 mmol)
in tetrahydrofuran (25 mL). The mixture, which gradually formed a
clear solution, was stirred at room temperature for 24 h, then
extracted with ethyl acetate. The aqueous phase, containing a heavy
precipitate, was acidified to pH2 and extracted several times with
ethyl acetate/methanol. The extracts were dried and evaporated to
give the product (0.87 g, 93%).
[0832] MS (+ve ion electrospray) m/z 225 (MH.sup.+)
(c)
6-Hydroxymethyl-7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4-thia-
zine.
[0833] This compound was prepared from acid (310b) (0.87 g, 3.9
mmol) by the method of Example (301c). After neutralisation, the
mixture was extracted several times with ethyl acetate. The
extracts were dried and evaporated and the residue was
chromatographed on silica (1:1 ethyl acetate/hexane, then ethyl
acetate) to give a solid (0.48 g, 59%).
[0834] MS (+ve ion electrospray) m/z 211 (MH.sup.+)
(d)
7-Methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxald-
ehyde.
[0835] A solution of alcohol (310c) (0.47 g, 2.2 mmol) in
dichloromethane (50 mL) was stirred with manganese dioxide (2.8 g)
at room temperature for 16 h. The mixture was filtered through
Kieselguhr, washed through with dichloromethane/methanol and
evaporated to give the title compound (0.34 g), containing some of
the corresponding methyl hemiacetal.
[0836] MS (+ve ion electrospray) m/z 209 (MH.sup.+)
(e) Title Compound
[0837] The aldehyde (310d) (0.13 g, 0.63 mmol) and amine (Example
300e) (0.20 g, 0.63 mmol) in anhydrous
chloroform/dimethylformamide/methanol (10:5:1, 16 mL) was heated
over 3A molecular sieves at 100.degree. C. for 16 h. After cooling,
sodium (triacetoxy)borohydride (0.60 g) was added and the mixture
was stirred at room temperature for 3 days. The mixture was
basified with sodium bicarbonate and diluted with dichloromethane
and water. The aqueous phase was extracted several times with 10%
methanol/dichloromethane and the combined organics were washed with
water, dried and evaporated. Chromatography on silica gel (5-8%
methanol/dichloromethane) gave the free base of the title compound
(0.143 g, 45%).
[0838] .sup.1H NMR .delta.(CDCl.sub.3) 1.9-2.2 (8H, m), 2.13 (3H,
s), 2.96 (1H, m), 3.38 (2H, s), 3.99 (3H, s), 4.02 (2H, s),
7.06(1H, d), 7.31(1H, s), 8.15(1H, d), 8.46 (1H, d), 8.62 (1H, d),
11.04(1H, s)
[0839] MS (+ve ion electrospray) m/z 509 (MH.sup.+)
[0840] The free base in chloroform was treated with 2 equivalents
of 0.4 M hydrochloric acid in dioxan. Evaporation of solvent and
trituration with ether gave the dihydrochloride salt.
Example 311
1-Hydroxy-t-4-[(7-ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-y-
lmethyl)-amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0841] ##STR78## (a) Methyl
7-ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate.
[0842] Methyl
7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate
(Example 304b) (2.00 g, 6.6 mmol), tetramethyltin (3.17 mL, 16
mmol) and bis(triphenylphosphine)palladium(II) chloride (1.12 g,
1.6 mmol) in dimethylformamide (40 mL) were heated at 120.degree.
C. for 24 h. The mixture was filtered through Kieselguhr, washed
through with ethyl acetate and evaporated. Chromatography on silica
gel (20-50% ethyl acetate/petroleum ether) gave a mixture of the
7-ethyl and 7-vinyl compounds (0.29 g). This mixture was
hydrogenated in methanol/ethyl acetate (2:1, 60 mL) over 10%
palladium on carbon (60 mg) (1 atmosphere, room temperature) for 24
h. Filtration and evaporation of solvent gave the product (0.28
g).
[0843] MS (+ve ion electrospray) m/z 253 (MH.sup.+)
(b)
7-Ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic
acid.
[0844] Aqueous sodium hydroxide (2M, 0.67 mL, 1.33 mmol) was added
slowly to a stirred suspension of ester (311a) (0.28 g, 1.11 mmol)
in tetrahydrofuran (10 mL). The mixture was stirred at room
temperature for 16 h, then additional sodium hydroxide (2M, 0.4 mL,
0.8 mmol) was added. After stirring for another 8 h, the mixture
was evaporated. The residue was dissolved in water acidified to pH3
and the precipitate was filtered off, washed with water and dried
to give a solid (0.25 g, 95%).
[0845] MS (+ve ion electrospray) m/z 239 (MH.sup.+)
(c)
7-Ethyl-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiaz-
ine.
[0846] This compound was prepared from acid (311b) (0.25 g, 1.05
mmol) by the method of Example (310c). Chromatography on silica gel
(ethyl acetate) gave the alcohol (0.11 g, 47%).
[0847] MS (+ve ion electrospray) m/z 225 (MH.sup.+)
(d)
7-Ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxalde-
hyde.
[0848] A solution of alcohol (311c) (0.11 g, 0.49 mmol) in
dichloromethane (10 mL) was stirred with manganese dioxide (0.7 g)
at room temperature for 16 h. The mixture was filtered through
Kieselguhr, washed through with dichloromethane/methanol and
evaporated to give the title compound (0.078 g), containing some of
the corresponding methyl hemiacetal.
[0849] MS (+ve ion electrospray) m/z 223 (MH.sup.+)
(e) Title Compound
[0850] The aldehyde (311d) (0.078 g, 0.35 mmol) and amine (Example
300e) (0.11 g, 0.35 mmol) in dimethylformamide/methanol/acetic acid
(10:10:1, 11.5 mL) was heated over 3A molecular sieves at
80.degree. C. for 4 h. After cooling, sodium cyanoborohydride
(0.066 g, 1.05 mmol) was added and the mixture was stirred at room
temperature for 16 h. The mixture was evaporated and the residue
was basified with sodium bicarbonate, diluted with water and
extracted several times with 10% methanol/dichloromethane. The
combined organics were dried and evaporated. Chromatography on
silica (2-10% methanol/dichloromethane) gave the free base of the
title compound (0.082 g, 45%). 1H NMR
.delta.(CDCl.sub.3/CD.sub.3OD) 1.25 (3H, t), 1.68(2H, q), 1.88(2H,
d), 1.97(2H, d), 2.08(2H, m), 2.65(2H, q), 2.70 (1H, m), 3.49 (2H,
s), 3.90(2H, s), 4.17 (3H, s), 7.24(1H, d), 7.68(1H, s), 8.18(1H,
d), 8.54 (1H, d), 8.62 (1H, d)
[0851] MS (+ve ion electrospray) m/z 523 (MH.sup.+)
[0852] The free base in chloroform/methanol was treated with 2
equivalents of 0.4M hydrochloric acid in dioxan. Evaporation of
solvent and trituration with ether gave the dihydrochloride
salt.
Example 312
1-Hydroxy-t-4-[(6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazin-3-ylmet-
hyl)-amino]-r-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4yl)-amide dihydrochloride
[0853] ##STR79## (a) 4-Amino-3,6-dichloropyridazine.
[0854] A suspension of 3,4,6-trichloropyridazine (prepared by the
method of B. Kasnar et al, Nucleosides and Nucleotides, 1994, 13,
459) (10.0 g) in conc. aqueous ammonia (1 L) was heated at
75.degree. C. for 16 h. The mixture was concentrated to a small
volume and extracted several times with ethyl acetate. The extracts
were washed with brine, dried and evaporated. The crude product was
recrystallised from ethyl acetate to give the product (5.03 g).
(b)
3-Chloro-6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine.
[0855] To a well-stirred suspension of sodium hydride (60% in
mineral oil, 0.35 g, 8.5 mmol) in anhydrous dimethylformamide (10
mL) at 0.degree. C. was added methyl mercaptoacetate (0.70 mL, 7.9
mmol). After stirring at this temperature for 20 min. a solution of
amine (312a) (1.29 g, 7.87 mmol) in dimethylformamide (10 mL) was
added. The mixture was stirred at room temperature for 16 h, then
most of the solvent was removed in vacuo. The residue was ted with
water, the precipite was filtered off, washed with water and dried.
Chromatography on silica gel (0-2% methanol/dichloromethane) gave
the product (0.21 g, 13%).
[0856] MS (+ve ion electrospray) m/z 202/204 (MH.sup.+)
(c)
6-Oxo-3-vinyl-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine.
[0857] To a mixture of the pyridazinothiazinone (312b) (0.15 g,
0.75 mmol), bis(triphenylphosphine)palladium(II) chloride (84 mg,
0.12 mmol) and lithium chloride (63 mg, 1.2 mmol) in
dimethylformamide (3 mL) was added tributyl(vinyl)tin (0.36 mL, 1.2
mmol). The mixture was heated at 110-120.degree. C. for 16 h, then
evaporated. The residue was partitioned between water and ethyl
acetate, the aqueous phase was extracted further with ethyl acetate
and the combined organics were dried and evaporated. Chromatography
on silica gel (0-3% methanol/dichloromethane) gave the product (45
mg, 31%).
[0858] MS (+ve ion electrospray) m/z 194 (MH.sup.+)
(d)
6-Oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine-3-carboxaldehyde-
.
[0859] To a suspension of vinyl compound (312c) (0.6 g, 3.35 mmol)
in 1,4-dioxan (60 mL) was added osmium tetroxide (4% in water, 2
mL, 0.335 mmol), sodium periodaie (1.43 g, 6.7 mmol) and water (20
mL). The mixture was stirred at room temperature for 7 h, then
diluted with water and dichloromethane and phases separated. The
aqueous phase was extracted twice with 10% methanol/dichloromethane
and the combined organics were dried and evaporated. Chromatography
on silica gel (0-2% methanol/dichloromethane) gave the aldehyde
(0.206 g), containing some of the corresponding methyl
hemiacetal.
(e) Title Compound
[0860] The aldehyde (312d) (84 mg, 0.4 mmol) and amine (300e) (0.13
g, 0.4 mmol) in 1:1 methanol/chloroform (10 mL) were stirred over
3A molecular sieves at 65.degree. C. for 16 h. The cooled mixture
was diluted with 1:1 methanol/chloroform (20 mL) and sodium
(triacetoxy)borohydride (excess) was added The mixture was stirred
over 5 days with periodic further additions of sodium
(triacetoxy)borohydride. The mixture was then diluted with
chloroform, filtered and evaporated to a small volume. The residue
was basified with aqueous sodium carbonate and extracted four times
with 10% methanol/chloroform. The extracts were dried and
evaporated, and the residue was chromatographed on silica gel
(2-10% methanol/dichloromethane) to give the free base of the title
compound (31 mg, 16%).
[0861] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.61(2H, m),
1.80-2.15(6H, m), 2.65 (1H, m), 3.70 (2H, s), 4.06(2H, s), 4.17(3H,
s), 7.04(1H, s), 7.22(1H, d), 8.18(1H, d), 8.54 (1H, d), 8.62 (1H,
d)
[0862] MS (+ve ion electrospray) m/z 496 (MH.sup.+)
[0863] The free base in chloroform/methanol was treated, with 2
equivalents of 4M hydrochloric acid in dioxan. Evaporation of
solvent and trituration with ether gave the dihydrochloride
salt.
Example 313
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-
-amino]-r-cyclohexanecarboxylic acid
[6-(2-methoxy-ethoxy)-[1,5]naphthyridin-4-yl]-amide
dihydrochloride
[0864] ##STR80## (a)
6-(2-Methoxy-ethoxy)-[1,5]naphthyridin-4-ylamine.
[0865] This was prepared in 42% yield (1.9 g) from Example (29a)
according to the procedure for (29b) with 2-bromoethylmethyl ether
as the alkylating agent.
[0866] MS (+ve ion electrospray) m/z 220 (MH+).
(b) 8-Bromo-2-(2-methoxy-ethoxy)-[1,5]naphthyridine.
[0867] A solution of (313a) (1.9 g, 8.7 mmol), copper(Il) sulphate
(4.2 g, 26.1 mmol) and sodium bromide (3.6 g, 34.8 mmol) in 9M
sulphuric acid/methanol (35 ml/18 ml) was treated at 0.degree. C.
with a solution of sodium nitrite (0.9 g, 13.1 mol) in water (18
ml). The mixture was allowed to come to room temperature over 0.5
hour, then heated at 40.degree. C. for 0.5 hour. The mixture was
partitioned between dilute aqueous sodium hydroxide solution and
ethyl acetate. The organic extract was dried, filtered and
evaporated. The residue was chromatographed on silica eluting with
0-50% ethyl acetate in dichloromethane affording an oil (1.1 g,
45%).
[0868] MS (+ve ion electrospray) m/z 284 (MH+).
(c)
{r-4-Hydroxy-4-[6-(2-methoxy-ethoxy)-[1,5]naphthyridin-4-ylcarbamoyl-
]-c-cyclohexyl}-carbamic acid tert-butyl ester.
[0869] This was prepared in approximately quantitative yield (1.8
g) from (313b) according to the procedure of Example (300d).
[0870] MS (+ve ion electrospray) m/z 461 (MH+).
(d) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid
[6-(2-methoxy-ethoxy)-[1,5]naphthyridin-4-yl]-amide.
[0871] This was prepared from (313c) in 40% yield (280 mg) by
treatment with trifluoroacetic acid followed by a basic workup
according to the procedure of Example (300e).
[0872] MS (+ve ion electrospray) m/z 361 (MH+).
(e) Title Compound
[0873] This was prepared from amine (313d) and aldehyde (301d) by
reductive alkylation with sodium cyanoborohydride according to the
procedure of Example (357), affording the free base of the title
compound as a white solid (62 mg, 29%)
[0874] .delta.H (CDCl.sub.3, 250 MHz): 8.62 (1H, d), 8.45 (1H, d),
8.15 (1H, d), 7.55 (1H, d), 7.15 (1H, d), 6.90 (1H, d), 4.65 (2H,
m), 4.00 (2H, s), 3.85 (2H, s), 3.80 (2H, m), 3.45 (2H, s), 3.30
(3H, s), 2.65 (1H, m), 2.20-1.50 (8H, m)
[0875] MS (+ve ion electrospray) m/z 539 (MH+).
[0876] This was converted to the title compound (70 mg) by the same
procedure as for Example 300.
Example 314
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-
-amino]-r-cyclohexanecarboxylic acid
(2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-amide
dihydrochloride
[0877] ##STR81## (a)
7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamine.
[0878] A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (32 g,
212 mmol) in dichloromethane (1 liter) was treated with a solution
of bromine (10.8 ml, 212 mmol) in dichloromethane (100 ml) at
0.degree. C. After the addition the mixture was stirred at room
temperature for 1 hour then washed with saturated aqueous sodium
bicarbonate solution containing a small amount of sodium sulphite.
The organic organic extract was dried and evaporated affording an
oil that was chromatographed on silica gel eluting with
dichloromethane to afford an oil (14.8 g, 30%).
[0879] MS (+ve ion electrospray) m/z 231 (MH+).
(b)
5-[(7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-methylene]-2,2
dimethyl-[1,3]dioxane-4,6-dione.
[0880] A mixture of aniline (314a) (14.8 g, 64.3 mmol), triethyl
orthoformate (12.7 ml, 77.2 mmol) and
2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum's acid) (11.1 g, 77.2
mmol) in ethanol (70 ml) was heated to reflux. After 1 hour the
mixture was allowed to cool to room temperature then filtered,
washing with ethanol then ether, to afford a white solid (22.9 g,
93%).
[0881] MS (+ve ion electrospray) m/z 385 (MH+).
(c) 6-Bromo-2,3-dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one.
[0882] Enamine (314b) (22.9 g) was added portionwise to refluxing
Dowtherm A (45 ml) over 3 minutes. After a further 3 minutes at
reflux the mixture was cooled to room temperature. Ethyl
acetatelhexue (10 ml/20 ml) was added and a black solid isolated by
filtration. This residue was dissolved in hot methanol (400 ml) and
filtered through Keiselguhr. Water (800 ml) was added and the
mixture stored at 5.degree. C. overnight. Filtration and drying
afforded a pale yellow solid (10.3 g, 61%).
[0883] MS (APCI.sup.-) m/z 281 [M-H].sup.-
(d) 2,3-Dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one.
[0884] A suspension of (314c) (3.4 g, 12 mmol) in water/dioxan (150
ml/80 ml) was treated with 1M aqueous sodium hydroxide solution
then hydrogenated over 10% palladium on charcoal (1.5 g) for 20
hours. The mixture was filtered then acidified with 5M aqueous
hydrochloric acid. On concentrating to ca 100 ml, a solid began to
crystallise out. The mixture was stored at 5.degree. C. overnight.
Filtration and drying afforded a pale yellow solid (2.8 g,
100%).
[0885] MS (APCI.sup.-) m/z 202 [M-H].sup.-
(e) 10-Bromo-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline
[0886] A mixture of (314d) (2.5 g) and phosporus oxybromide (7.8 g)
was heated at 120.degree. C. for 0.75 hour. After cooling to room
temperature the mixture was treated with water, basified with
potassium carbonate and extracted with ethyl acetate. The organic
extract was dried and evaporated to afford an oil (475 mg,
14%).
[0887] MS (+ve ion electrospray) m/z 268 (MH+).
(f)
[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-10-ylcarbamoyl)-r-4-hydr-
oxy-c-cyclohexyl]-carbamic acid tert-butyl ester
[0888] This was prepared in 25% yield (0.2 g) from (314e) according
to the procedure of Example (300d).
[0889] MS (+ve ion electrospray) m/z 444 (MH+).
(g) t-4-Amino-1-hydroxy-c-cyclohexanecarboxylic acid
(2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-amide.
[0890] This was prepared from carbamate (314f) in 52% yield (80 mg)
by treatment with trifluoroacetic acid followed by a basic workup,
according to the procedure of Example (300e).
[0891] MS (+ve ion electrospray) m/z 344 (MH+).
(h) Title Compound
[0892] This was prepared from amine (314 g) and aldehyde (301d) by
reductive alkylation with sodium cyanoborohydride according to the
procedure of Example (357) to afford the free base of the title
compound as a white solid (21 mg,17%).
[0893] .delta.H (CD.sub.3OD, 250 Mz): 8.60 (1H, d), 8.50 (1H, d),
7.65 (1H, d), 7.50 (1H, d), 7.35 (1H, d), 7.05 (1H, d), 4.55 (2H,
m), 4.42 (2H, m), 4.15 (2H, s), 3.50 (2H, s), 2.62 (1H, m),
2.20-1.50 (8H, m)
[0894] MS (+ve ion electrospray) m/z 522 (MH+).
[0895] This was converted to the title compound (18 mg) by the same
procedure as for Example (300).
[0896] Unless otherwise stated, the following Examples were
prepared from amine (300e) and the appropriate carboxaldehyde by
analogous methods to that of Example (300f) TABLE-US-00004
##STR82## salt Method of B Dihydrochloride Exam- synthesis A
Hydrochloride ple (aldehyde) R Trihydrochloride R 320 a B
4-Fluoro-1H- benzoimidazol-2-yl ##STR83## 321 B
2,3-Dihydro-benzo[1,4] dioxin-6-yl ##STR84## 322 (Example 9e) B
7-Fluoro-3-oxo-3,4- dihydro-2H-benzo[1,4] thiazin-6-yl ##STR85##
323 (Example 32d) B [1,2,3]thiadiazolo [5,4-b]pyridin-6-yl
##STR86## 324 b B 7-Fluoro-2,3-dihydro- benzo[1,4]dioxin-6-yl
##STR87## 325 (Example 19d) B 2,3-Dihydro-[1,4]dioxino
[2,3-c]pyridin-7-yl ##STR88## 326 c B 2,3-Dihydro-1H-pyrido
[2,3-b][1,4]thiazin-7-yl ##STR89## 327 (mesylate 6b) B
Benzo[1,2,3]thiadiazol- 5-yl ##STR90## 328 d B 3,4-Dihydro-2H-benzo
[1,4]thiazin-6-yl ##STR91## 329 (Example 20e) B
2,3-Dihydro-[1,4]dioxino [2,3-b]pyridin-7-yl ##STR92## 330 e B
3,4-Dihydro-2H-pyrido [3,2-b][1,4]thiazin-6-yl ##STR93## 331 f R
3,4-Dihydro-2H-pyrido [3,2-b][1,4]oxazin-6-y ##STR94## 332 g A
5,6,7,8-Tetrahydro-[1,8] naphthyridin-2-yl ##STR95## 333 h B
3-Thia-1,2,5-triaza- inden-6-yl ##STR96## 334 cis-isomer B
3-Oxo-3,4-dihydro-2H- i benzo[1,4]thiazin-6-yl ##STR97## 335
(Example 25b) B Benzothiazol-5-yl ##STR98## 336 j B
2-Methyl-thiazolo[5,4-b] pyridin-6-yl ##STR99## 337 (Example 16d) B
Thiazolo[5,4-b]pyridin- 6-yl ##STR100## 338 k B
2-Methyl-benzothiazol- 5-yl ##STR101## 339 1 B
4-Oxo-4H-pyrido[1,2-a] pyrimidin-2-yl ##STR102## 340 m B
5-Amino-2,3-dihydro- [1,4]dioxino[2,3-c] pyridin-7-yl ##STR103##
341 n B Thiazolo[4,5-b]pyridin- 5-yl ##STR104## 342 o B
8-Chloro-2,3-dihydro- [1,4]dioxino[2,3-c] pyridin-7-yl ##STR105##
343 p 6,7-Dihydro-[1,4]dioxino [2,3-d]pyrimidin-2-yl ##STR106## a
Prepared from 4-fluoro-1H-benzoimidazole-2-carboxaldehyde, itself
prepared from 3-fluoro-benzene-1,2-diamine by reaction with
glycolic acid followed by oxidation with manganese dioxide b
7-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehyde prepared
from 6-fluoro-2,3-dihydro-benzo[1,4]dioxine [V. Daukas et al
Chemija, 1999, 10 (1), 59] by reaction of dichloromethyl methyl
ether and titanium tetrachloride - see Example 213. c Prepared by
reacting ester (13b) with lithium aluminium hydride followed by
oxidation with manganese dioxide to give the carboxaldehyde d
Prepared by reacting
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl
ester with lithium aluminium hydride followed by oxidation with
manganese dioxide to give the carboxaldehyde e Prepared by reacting
ester (301a) with lithium aluminium hydride followed by oxidation
with manganese dioxide to give the carboxaldehyde f Prepared by
reacting (305e) with lithium aluminium hydride followed by
oxidation with manganese dioxide to give the carboxaldehyde g
5,6,7,8-Tetrahydro-[1,8]naphthyridine-2-carboxaldehyde prepared
according to the procedure of WO 98/08840 h Prepared from
[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxaldehyde, itself prepared
from (302b) by reaction with sodium benzylmercaptan in dioxan,
heating in acetic anhydride to form the acetoxymethyl-pyridine,
reducing the nitro group with iron in acetic acid at 60.degree. C.,
reaction with sodium nitrite in cold dilute hydrochloric acid to
form the thiadiazole ring, and oxidising the resulting alcohol with
manganese dioxide. i Prepared from
(4-carbamoyl-r-4-hydroxy-t-cyclohexyl)-carbamic acid tert-butyl
ester (see Example 300c-faster running isomer) by the method of
Example (300d-f) j The carboxaldehyde was prepared by heating amine
(16a) with acetic anhydride/acetic acid/sodium acetate to afford
the 2-methylthiazole, followed by reduction of the ester with
lithium aluminium hydride at -30.degree. C., followed by oxidation
with manganese dioxide k The carboxaldehyde was prepared from the
zinc salt of 4-mercapto-3-nitro-benzoic acid ethyl ester by heating
in acetic anhydride followed by reduction of the ester with lithium
aluminium hydride at -30.degree. C., followed by oxidation with
manganese dioxide. l Prepared by reaction of amine (300e) with
2-chloromethyl-pyrimido[1,2-a]pyrimidin-4-one in DMF containing
anhydrous potassium carbonate (by the method of Example 26). m
Prepared from Example (19c) by nitration, manganese (II) oxidation
to give 8-nitro-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde,
reductive alkylation with amine (300e) according to the method of
Example (300f), and finally hydrogenation of the nitro group to
amino giving the free base of the title compound. n Prepared from
Example (304a) by reaction with the sodium salt of
3-mercapto-propionic acid ethyl ester to unexpectedly give
6-amino-5-mercapto-pyridine-2-carboxylic acid methyl ester,
followed by cyclisation with formic acid at 100.degree. C. to give
the thiazolopyridine, which was debrominated by hydrogenation (Pd/C
in ethanol). Treatment of the ester with LiAlH4 in THF gave the
thiazolo[45-b]pyridine-5-carboxaldehyde, which was converted to
Example (341). o Prepared from
5-benzyloxy-2-hydroxymethyl-1H-pyridin-4-one (T. Teitei, Aust. J.
Chem., 1983, 36, (11), 2307) by chlorination with
N-chlorosuccinimide in acetic acid to give
5-benzyloxy-3-chloro-2-hydroxymethyl-1H-pyridin-4-one, followed by
hydrogenation to remove the benzyl group and reaction with
1,2-dibromoethane and potassium carbonate to give
(8-chloro-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol,
followed by oxidation with manganese (II)oxide to give
8-chloro-2,3-
#dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde, followed by
reductive alkylation with amine (300e) according to the method of
Example (300f) giving the free base of the title compound. p
Prepared from 5-benzyloxy-2-hydroxymethyl-3H-pyrimidin-4-one (A.
Harris, Aust. J. Chem., 1976, 29, 1335) by hydrogenolysis of the
benzyl protecting group and cyclisation with dibromoethane to give
(6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl)-methanol followed
by oxidation with manganese(II)oxide to give
6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine-2-carbaldehyde and
reductive alkylation with amine (300e) according to the method of
Example (300f)
Example 350
(1S,3S,4S)-3-Hydroxy-4[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-y-
lmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and
(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-
-ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0897] ##STR107## (a) (1R,3S,4S)- and
(1S,3R,4R)-4-tert-Butoxycarbonylamino-3-hydroxy-cyclohexanecarboxylic
acid methyl ester.
[0898] This was prepared essentially as described by K. Krajewski
et al Tetrahedron: Asymmetry 10 (1999) 4591-4598, and contained
about 20% of the 3-tert-butoxycarbonylamino-4-hydroxy-regioisomer.
A portion was purified by silica gel chromatography (exane-ethyl
acetate 2:1) and recrystallised from ether-pentane to afford
crystals that gave an X-ray structure confirming the configuration
above.
(b) (1S,3S,4S)- and
(1R,3R,4R)-4-tert-Butoxycarbonylamino-3-hydroxy-cyclohexanecarboxylic
acid methyl ester.
[0899] The crude ester (350a) (21.19 g) in dry methanol (200 ml)
was treated with 25% sodium methoxide in methanol (33.5 ml) and
heated at 70.degree. C. for 3 days. It was cooled in ice,
neutralised with 2N hydrochloric acid, and evaporated to dryness.
Water was added and the resulting solid collected, washed with
water and dried to give the product (8.0 g). Extraction of the
aqueous fraction with dichloromethane, followed by silica gel
chromatography (2% methanol-dichloromethane) gave a further 4.3 g
of less pure material.
(c) (1S,3S,4S)- and
(1R,3R,4R)-4-tert-Butoxycarbonylamino-3-hydroxy-cyclohexanecarboxylic
acid.
[0900] The ester (350b) (2.4 g) in dioxan (100 ml) and water (5 ml)
was treated with 2N sodium hydroxide (6.6 ml) and stirred overnight
at room temperature. The mixture was acidified with 2N hydrochloric
acid, evaporated to one quarter volume, extracted (5.times.) with
ethyl acetate, washed with a little water, dried (sodium sulfate),
and evaporated to give the product as a foam (2.4 g).
[0901] MS (-ve ion electrospray) m/z 258 (M-H.sup.-)
(d) ((1S,4S,5S)- and
-(1R,4R,5R)-7-Oxo-6-oxa-bicyclo[3.2.1]oct-4-yl)-carbamic acid
tert-butyl ester.
[0902] The carboxylic acid (350c) (2.6 g) in dry dichloromethane
(50 ml) was treated with triethylamine (1.01 g) and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.11
g) and stirred at room temperature overnight. The product was
evaporated to dryness, water and sodium bicarbonate were added and
the solution was extracted with dichloromethane and dried (sodium
sulfate). It was chromatographed on silica gel (0.5-2%
methanol-dichloromethane) to afford a white solid (0.90 g). umax
1,780 cm.sup.-1
(e) (1S,2S,4S) and
-(1R,2R,4R)-4-Carbamoyl-2-hydroxy-cyclohexyl)-carbamic acid
tert-butyl ester
[0903] The lactone (350d) (3.14 g) in tetrahydrofuran (150 ml) was
treated with 32% ammonia in water (100 ml) and the mixture was well
stirred overnight and evaporated to dryness to afford a solid (3.25
g).
[0904] MS (-ve ion electrospray) m/z 257 (M-H.sup.-)
(f) [(1S,2S,4S)- and
(1R,2R,4R)-2-Hydroxy-4(6-methoxy-[1,5]naphthyridin-4-ylcarbamoyl)-cyclohe-
xyl]-carbamic acid
[0905] A mixture of the amide (350e) (0.215 g), cesium carbonate
(0.344 g), tris(dibenzylideneacetone)dipalladium(0) (16.3 mg), and
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (32.6 mg) in dry
dioxan (9 ml) under argon, was sonicated for 10 minutes,
1,1-trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl
ester (1b) (0.27 g) was added, and the mixture was stirred and
heated at 80-85.degree. C. for 24 hours, under argon. The mixture
was cooled, filtered, and the filtrate evaporated and
chromatographed on silica gel, eluting with chloroform, then (1-2%)
methanol-dichloromethane, to afford a solid (0.21 g).
[0906] MS (+ve ion electrospray) m/z 417 (MH+).
(g) (1S,3S,4S)- and
(1R,3R,4R)-4-Amino-3-hydroxy-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide.
[0907] The carbamate (350f) (0.21 g) in dichloromethane (10 ml) was
treated with trifluoroacetic acid (10 ml) for 2 hours and
evaporated. Sodium carbonate solution was added and the solution
was extracted (5.times.) with 10% methanol-chloroform, dried
(sodium sulfate) and evaporated to give a white solid (0.148
g).
[0908] MS (+ve ion electrospray) m/z 317 (MH+).
(h) Title Compound
[0909] A mixture of carboxaldehyde (301d) (45 mg) and amine (350 g)
(70 mg) in chloroform (5 ml) and methanol (5 ml) with 3A molecular
sieves was heated under reflux for 4 hours, cooled, treated with
sodium triacetoxyborohydride (300 mg). and heated at 40.degree. C.
overnight. The mixture was cooled, diluted with chloroform and
methanol, filtered and evaporated. The residue was treated with
aqueous sodium carbonate and extracted (3.times.) with 10%
methanol-chloroform arnd the combined organc fractions dried
(NaSO.sub.4), evaporated and chromatographed on silica gel, eluting
with 2-10% methanol-dichloromethane to give free base of the title
compound (80 mg).
[0910] .sup.1H NMR .delta.(250 MHz, CDCl.sub.3/CD.sub.3OD) 1.2-1.8
(3H, m), 2.15 (2H, m), 2.35 (1H, m), 2.5 (1H, m), 2.72 (1H, m),
3.49 (2H, s), 3.55 (1H, m), 3.80 (1H, d), 3.95 (1H, d), 4.17 (3H,
s), 6.96 (1H, d), 7.23 (1H, d), 7.62 (1H, d), 8.20 (1H, d), 8.50
(1H, d), 8.65 (1H, d)
[0911] MS (+ve ion electrospray) m/z 495 (MH.sup.+)
[0912] The free base in chloroform/methanol (1:1) was treated with
4M HCl in dioxan (0.5 ml) and evaporated to dryness. The solid was
triturated with ether, filtered and dried in vacuo, to provide
title compound (87 mg).
[0913] The racemic free base was subjected to preparative HPLC
[Chiralpak AD 250 mm.times.20 mm i.d.; 10 micron particle size;
eluent:n-hexane-ethanol (both with 0.1% DEA), 70:30 v/v; flow-rate
:15.0 ml min-.sup.-1] to afford a faster eluting single enantiomer
[retention time 13.4 mins] and a slower eluting single enantiomer
[retention time 16.9 mins], both with 100% ee.
Example 351
(1R,3R,4R)-3-Hydroxy-4[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-y-
lmethyl)-amino]-cyclohexanecarboIylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0914] ##STR108## (a)
(1R,4S,5R)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one.
[0915] (R)-Cyclohex-3-enecarboxylic acid (2.30 g, 18.2 mmol)
([.alpha.].sub.D=+83.8.degree. (c=1, CHCl.sub.3)=88.2% e.e.,
resolved by the method of Schwartz et al, J. Am. Chem. Soc., 100,
5199, (1978)) was reacted with trimethylsilyl bromide and DMSO (by
the method of Iwata et al, Heterocycles., 31, 987 (1990)) to give a
white solid, (2.13 g, 10.4 mmol, 57%);
[0916] .sup.1H NMR .delta. (400 MHz, CDCl.sub.3) 1.68 (1H, dddd),
1.86 (1H, d), 1.98-2.02 (1H m), 2.20 (1H, dddd), 2.42 (1H, ddd),
2.50-2.56 (1H, m), 2.73 (1H, br s), 4.15 (1H, dd), 4.91 (1H,
d).
(b) (1R,3R,4S)-4-bromo-3-hydroxycyclohexanecarboxylic amide.
[0917] (1R,4S,5R)-4bromo-6-oxabicyclo[3.2.1]octan-7-one (351a)
(2.13 g, 10.4 mmol) was taken up in TBF (20 mL) and treated with
0.880 ammonia (5.3 mL) at 20.degree. C. for 24 h with stitring. The
solvent was then removed in vacuo to give a white solid in
quantitative yield; [.alpha.].sub.D=+40.6.degree. (c=1, MeOH).
[0918] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.63 (1H, dd),
1.73-1.80 (1H, m), 1.85-2.03 (3H, m), 2.16-2.21 (1H, m), 2.36 (1H,
tt), 3.54 (1H, dt), 4.55 (1H, bs).
(c) (1R,3R,4R)-4-azido-3-hydroxy-cyclohexanecarboxylic acid
amide.
[0919] (1R,3R,4S)-4-Bromo-3-hydroxycyclohexanecarboxylic amide
(351b) (2.31 g, 10.4 mmol) was treated with sodium azide (1.35 g,
20.8 mmol) in DMF (100 mL) at 60.degree. C. for 15.5 h. The solvent
was removed in vacuo and the residue purified by flash column
chromatography (Silica gel, DCM:MeOH 0-10%) to give a white solid
(1.09 g, 5.93 mmol, 57%); [.alpha.].sub.D=-15.5.degree. (c=1,
MeOH).
[0920] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.30 (1H, dq),
1.42-1.56 (2H, m), 1.83 (1H, dt), 1.99-2.08 (2H, m), 2.30 (1H, tt),
3.16(1H, ddd), 3.41 (1H, ddd).
(d) (1R,3R,4R)-4-amino-3-hydroxy-cyclohexanecarboxylic acid amide,
acetate salt.
[0921] To (1R,3R,4R)-4-azido-3-hydroxy-cyclohexanecarboxylic acid
amide (351c) (765 mg, 4.15 mmol) in MeOH/AcOH (9:1, 30 mL) was
added Pd/C (10%, 300 mg), and the mixture hydrogenated under
atmospheric pressure for 22 h. On completion of reaction the
mixture was filtered through Celite.RTM., the filter pad washed
with MeOH, and the combined organic solutions concentrated in vacuo
to give a white solid in quantitative yield.
[0922] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.42-1.59 (3H, m),
1.87-1.92 (1H, m), 1.92 (3H, s), 2.07-2.14 (2H, m), 2.37 (1H, tt),
2.84 (1H, dt), 3.50 (1H, dt).
(e) ((1R,2R,4R)-4-Carbamoyl-2-hydroxy-cyclohexyl)-carbamic acid
tert-butyl ester
[0923] The amide, acetate salt (351d) (905 mg, 4.15 mmol) was
treated with N,N-diisopropylethylamine (868 uL, 4.98 mmol) and
di-tert-butyl-dicarbonate (1.08 g, 4.98 mmol) in dioxane (30 mL),
and MeOH (50 mL) for 16 h. The solvent was then removed in vacuo
and the residue purified by flash column chromatography (Silica
gel, DCM:MeOH 0-10%) to give a white solid (804 mg, 3.11 mmol,
75%); [.alpha.].sub.D=-17.0.degree. (c=1, MeOH).
[0924] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.18-1.32 (1H, m),
1.44 (9H, s), 1.43-1.55 (2H, m), 1.81 (1H, bd), 1.98 (1H, bd), 2.09
(1H, bd), 2.29 (1H, tt), 3.22 (1H, dt), 3.33 (1H, dt).
(f)
[(1R,2R,4R)-2-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylcarbamoyl)--
cyclohexyl]-carbamic acid tert-butyl ester
[0925] The amide (351e) (671 mg, 2.60 mmol) was reacted with the
triflate ester (1b) (801 mg, 2.60 mmol) by the procedure of Example
(350f), but carried out at 60.degree. C., to give a white solid
(889 mg, 2.13 mmol, 82%);
[0926] .sup.1H NMR .delta. (400 Mz; CD.sub.3OD) 1.34-1.50 (1H, m),
1.46 (9H, s), 1.62-1.71 (2H, m), 2.04-2.12 (2H, m), 2.32-2.38 (1H,
m), 2.70-2.78 (1H, m), 3.27-3.34 (1H, m), 3.45-3.51 (1H, m), 4.15
(3H, s), 7.24 (1H, d), 8.17 (1H, d), 8.47 (1H, d), 8.60 (1H,
d);
[0927] MS (+ve ion electrospray) m/z 417 (MH.sup.+, 100%).
(g) (1R,3R,4R)-Amino-3-hydroxy-cyclohexanecarboxilic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-cyclohexyl]-amide.
[0928] The carbamate (351f) (860 mg, 2.06 mmol) in DCM (30 mL) was
treated with trifluoroacetic acid (10 mL). After 35 min the solvent
was removed in vacuo and the residue purified by flash column
chromatography (silica gel, DCM:MeOH/NH.sub.3 (2M) 0-15%) to give a
white solid (624 mg, 1.97 mmol, 95%); [.alpha.].sub.D=-0.8.degree.
(c=1, MeOH).
[0929] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.30-1.41 (1H, m),
1.57-1.70 (2H, m), 1.99-2.10 (2H, m), 2.25-2.31 (1H, m), 2.53-2.59
(1H, m), 2.76-2.84 (1H, m), 3.30-3.36 (1H, m), 4.17 (3H, s), 7.26
(1H, d), 8.19 (1H, d), 8.49 (1H, d), 8.61 (1H, d); MS (+ve ion
electrospray) m/z 317 (MH.sup.+, 100%).
(h) Title Compound
[0930] The amine (351g) (0.664 mmol) under argon in MEOH (21 mL)
and DMF (21 mL) was treated with carboxaldehyde (301d) (0.664
.mu.mol), and 3A molecular sieves (1 g), followed by AcOH (2.1 mL).
Sodium cyanoborohydride (83 mg, 1.33 mmol) was added after 20 min.
Once the reaction had gone to completion the mixture was adsorbed
onto an SCX cartridge, washed with MeOH, eluted with MeOH/NH.sub.3
(2M), and the solvent removed in vacuo from the appropriate
fractions. The residue was purified by flash column chromatography
(Silica gel, DCM:MeOH/NH.sub.3 (2M) 0-12%) to give the free base of
the title compound (72% yield);
[0931] .sup.1H NMR .delta. (400 MHz; CDCl.sub.3/CD.sub.3OD)
1.23-1.33 (1H, m), 1.58-1.74 (2H, m), 2.10-2.22 (2H, m), 2.32-2.38
(1H, m), 2.43-2.50 (1H, m), 2.62 (1H, tt), 3.46-3.53 (1H, m), 3.48
(2H, s), 3.78, 3.95 (2H, ABq), 4.14 (3H, s), 6.93 (1H, d), 7.20
(1H, d), 7.60 (1H, d), 8.20 (1H, d), 8.50 (1H, d), 8.64 (1H, d); MS
(+ve ion electrospray) m/z 495 (MH.sup.+, 100%).
[0932] Analytical HPLC [Chiralpak AD 250 mm.times.4.6 mm i.d.; 10
micron particle size; eluent: n-hexane-ethanol (both with 0.1%
DEA), 25:75 v/v; flow-rate:1.2 ml min.sup.-1] indicated that this
material had an ee of 69.8% with the faster eluting single
enantiomer [retention time 34.2 mins] being the minor component
relative to the slower eluting single enantiomer [retention time
50.9 mins].
[0933] This material as a solution in DCM/MeOH 1:1 was treated with
4M HCl in dioxane (0.5 mL), evaporated to dryness, then dried under
vacuum to provide the title compound.
Example 352
(1S,3S,4S)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6--
ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0934] ##STR109## (a)
(1S,4R,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one.
[0935] (S)-Cyclohex-3-enecarboxylic acid (1.98 g, 15.7 mmol)
([.alpha.].sub.D=-92.7.degree. (c=1, CHCl.sub.3)=97.5% e.e.,
resolved by the method of Schwartz et al, J. Am. Chem. Soc., 100,
5199, (1978)) was reacted with trimethylsilyl bromide (4.10 mL,
31.3 mmol), DMSO (2.23 mL, 31.3 mmol), and
N,N-diisopropylethylamine (4.45 mL, 31.3 mmol) (by a modification
of the method of Iwata et al, Heterocycles., 31, 987 (1990)) to
give a white solid, (2.91 g, 14.2 mmol, 90%);
[.alpha.].sub.D=-68.3.degree. (c=1, CHCl.sub.3).
[0936] .sup.1H NMR .delta. (400 MHz; CDCl.sub.3) 1.68 (1H, dddd),
1.86 (1H, d), 1.97-2.06 (1H, m), 2.20 (1H, dddd), 2.42 (1H, ddd),
2.50-2.57 (1H, m), 2.73 (1H, br s), 4.16 (1H, dd), 4.92 (1H, d
(b) (1S,3S,4R)-4-Bromo-3-hydroxycyclohexanecarboxylic amide.
[0937] (1S,4R,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (352a)
(2.88 g, 14.0 mmol) was taken up in THF (27 mL) and treated with
0.880 ammonia (7.1 mL) at 20.degree. C. for 24 h with stirring. The
solvent was then removed in vacuo to give a white solid in
quantitative yield; [.alpha.].sub.D=-55.4.degree. (c=1, MeOH).
[0938] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.64 (1H, dd),
1.74-1.82 (1H, m), 1.85-2.05 (3H, m), 2.13-2.22 (1H, m), 2.37 (1H,
tt), 3.53 (1H, dt), 4.55 (1H, bs).
(c) (1S,3S,4S)-4-Azido-3-hydroxy-cyclohexanecarboxylic acid
amide.
[0939] (1S,3S,4R)-4-Bromo-3-hydroxycyclohexanecarboxylic amide
(352b) (3.11 g, 14.0 mmol) was treated with sodium azide (1.82 g,
28.0 mmol) in DMF (140 mL) at 60.degree. C. for 16 h. The solvent
was removed in vacuo and the residue purified by flash column
chromatography (silica gel, DCM:MeOH/NH.sub.3 (2N) 0-5%) to give
the a white solid (1.30 g, 7.0 mmol, 50%);
[.alpha.].sub.D=+17.7.degree. (c=1, MeOH).
[0940] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.30 (1H, dq),
1.44-1.57 (2H, m), 1.82 (1H, dt), 2.00-2.10 (2H, m), 2.30 (1H, tt),
3.16 (1H, ddd), 3.41 (1H, ddd).
(d) (1S,3S,4S)-4-amino-3-hydroxy-cyclohexanecarboxylic acid
amide.
[0941] To (1S,3S,4S)-4-azido-3-hydroxy-cyclohexanecarboxylic acid
amide (352c) (760 mg, 4.13 mmol) in MeOH (30 mL) was added Pd/C
(10%, 500 mg), and the mixture hydrogenated under atmospheric
pressure for 18 h. On completion of reaction the mixture was
filtered through Celite.RTM., the filter pad washed with MeOH, and
the combined organic solutions concentrated in vacuo to give a
white solid in quantitative yield;
[0942] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.22 (1H, dq,)
1.4-1.54 (2H, m), 1.76-1.83 (1H, m), 1.89-1.96 (1H, m), 1.99-2.07
(1H, m), 2.32 (1H, tt), 2.47 (1H, dt), 3.19 (1H, dt).
(e) ((1S,2S,4S)-4-Carbamoyl-2-hydroxy-cyclohexyl)-carbamic acid
tert-butyl ester
[0943] The amide (352d) (653 mg, 4.13 mmol) was treated with
di-tert-butyl-dicarbonate (1.08 g, 4.95 mmol) in dioxane (30 mL),
and MeOH (50 mL) for 16 h. The solvent was then removed in vacuo
and the residue purified by flash column chromatography (silica
gel, DCM:MeOH 5-10%) to give a white solid (890 mg, 3.45 mmol,
84%); [.alpha.].sub.D=+17.0.degree. (c=1, MeOH).
[0944] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.21-1.31 (1H, m),
1.44 (9H, s), 1.43-1.56 (2H, m), 1.81 (1H, bd), 1.98 (1H, bd), 2.09
(1H, bd), 2.29 (1H, tt), 3.21 (1H, dt), 3.34 (1H, dt
(f)
[(1S,2S,4S)-2-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylcarbamoyl)--
cyclohexyl]-carbamic acid tert-butyl ester
[0945] The carbamate (352e) (400 mg, 1.55 mmol) was reacted with
the triflate ester (1b) (477 mg, 1.55 mmol) by the procedure of
Example (350f) to give a white solid (400 mg, 0.960 mmol, 62%);
[0946] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.34-1.50 (1H, m),
1.46 (9H, s), 1.60-1.71 (2H, m), 2.04-2.12 (2H, m), 2.32-2.38 (1H,
m), 2.75 (1H, bt), 3.27-3.34 (1H, m), 3.42-3.51 (1H, m), 4.16 (3H,
s), 7.26 (1H, d), 8.18 (1H, d), 8.49 (1H, d), 8.61 (1H, d); MS (+ve
ion electrospray) m/z 417 (MH.sup.+, 100%).
(g) (1S,3S,4S)-4-Amino-3-hydroxy-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide.
[0947] The amide (352f) (691 mg, 1.66 mmol) in DCM (30 mL) was
treated with trifluoroacetic acid (20 mL). After 45 min the solvent
was removed in vacuo and the residue purified by flash column
chromatography (silica gel, DCM:MeOH/NH.sub.3 (2M) 5%) to give a
white solid (376 mg, 1.19 mmol, 72%); [.alpha.].sub.D=+0.5.degree.
(c=1, MeOH).
[0948] .sup.1H NMR .delta. (400 MHz; CD.sub.3OD) 1.33-1.46 (1H, m),
1.59-1.71 (2H, m), 2.00-2.12 (2H, m), 2.27-2.32 (1H, m), 2.57-2.65
(1H, m), 2.76-2.84 (1H, m), 3.32-3.40 (1H, m), 4.17 (3H, s), 7.27
(1H, d), 8.19 (1H, d), 8.50 (1H, d), 8.61 (1H, d); MS (+ve ion
electrospray) m/z 317 (MH.sup.+, 100%).
(h) Title Compound
[0949] This was prepared following the method of Example (351h) on
a 0.657 mmol scale from amide (352g), and aldehyde (301d), to give
the free base of the title compound in 53% yield;
[0950] .sup.1H NMR .delta. (400 MHz; CDCl.sub.3) 1.29-1.41 (1H, m),
1.6-1.8 (2H, m), 2.15 (1H, bd), 2.24 (1H, bd), 2.41 (1H, bd),
2.49-2.63 (2H, m), 3.40, 3.44 (2H, ABq), 3.58 (1H, m), 3.85 (1H,
d), 4.05 (1H, d), 4.10 (3H, s), 4.5 (1H, b) 6.91 (1H, d), 7.13 (1H,
d), 7.54 (1H, d), 8.20 (1H, d), 8.48 (1H, d), 8.67 (1H, d), 9.49
(1H, s); MS (+ve ioon electrospray) m/z 495 (MH.sup.+, 100%).
[0951] Analytical HPLC [Chiralpak AD 250 mm.times.4.6 mm i.d.; 10
micron particle size; eluent; n-hexane-ethanol (both with 0.1%
DEA), 25:75 v/v; flow-rate:1.2 ml min.sup.-1] indicated that this
material had an ee of 89.6% with the faster eluting single
enantiomer [retention time 33.5 mins] being the major component
relative to the slower eluting single enantiomer [retention time
50.9 mins].
[0952] This material as a solution in DCM/MeOH 1:1 was treated with
4M HCl in dioxane (0.5 mL), evaporated to dryness, then dried under
vacuum to provide the title compound.
Example 353
(1S,3S,4S)-4-[(7-Chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-y-
lmethyl)-amino]-3-hydroxy-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide and
(1R,3R,4R)-4-[(7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6--
ylmethyl)-amino]-3-hydroxy-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0953] ##STR110## (a) Title Compound.
[0954] A mixture of the carboxaldehyde (306e) (54 mg) and racemic
amine (350g) (74 mg) in chloroform (3 ml)/methanol (3 ml) with 3A
molecular sieves was refluxed 18 hours, cooled and treated with
sodium triacetoxyborohydride (149 mg). After stirring overnight,
the mixture was diluted with dichloromethane (50 ml) and washed
with aqueous NaHCO.sub.3. The aqueous fraction was re-extracted
with 10% methanol in dichloromethane and the combined organic
fractions dried (MgSO.sub.4) and evaporated. Chromatography of the
residue (CH.sub.2Cl.sub.2:MeOH 90:10) gave the free base of the
title compound (23 mg).
[0955] .sup.1H NMR .delta. (DMSO) 1.11-1.56 (3H, m), 1.91-2.32 (4H,
m), 2.7-2.9 (1H, m), 3.55 (2H, s), 3.7-4.1 (3H, m), 4.12 (3H, s),
4.75 (1H, s), 7.3 (1H, d), 7.9 (1H, s), 8.2 (1H, d), 8.4 (1H, d),
8.7 (1H, d), 9.7 (1H, s), 11.10 (1H, s).
[0956] This martial as a solution in dichloromethane:methanol 1:1
was treated with 4M, HCl in dioxane (0.10 ml) and evaporated to
dryness. The solid was triturated under ether, filtered and dried
under vacuum to provide the title compound (25 mg).
[0957] MS (+ve ion electrospray) m/z 529 (MH+, 100%).
Example 354
(1S,3S,4S)-3-Hydroxy-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]t-
hiazin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and
(1R,3R,4R)-3-Hydroxy-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]-
thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0958] ##STR111##
[0959] A mixture of the carboxaldehyde (308f) (41 mg) and the amine
(350g) (60 mg) in chloroform (1.5 ml)/methanol (1.5 ml) with 3A
molecular sieves was refluxed 18 hours, cooled and treated with
sodium triacetoxyborohydride (143 mg). After stirring for 5 hours
at room temp., the mixture was filtered, diluted with chloroform
(20 ml) and washed with aqueous NaHCO.sub.3. The aqueous fraction
was re-extracted with 10% ethanol in chloroform (2.times.10 ml) and
the combined organic fractions dried (MgSO.sub.4) and evaporated.
Chromatography of the residue on silica gel
(CHCl.sub.3/MeOH/NH.sub.4OH 95:5:0.5) gave the free base of the
title compound (80 mg).
[0960] .sup.1H NMR .delta. (CDCl.sub.3) 1.3-1.5 (1H, m), 1.6-1.8
(2H, m), 2.13 (1H, broad d), 2.26 (1H, broad d), 2.41 (1H, broad
d), 2.45-2.6 (2H, m), 3.44 (2H, s), 3.55-3.65 (1H, m), 3.93 (1H,
d), 4.05-4.15 (4H, m including 3H, s at .delta. 4.09), 7.14 (1H,
d), 7.32 (1H, d), 8.21 (1H, d), 8.48 (1H, d), 8.68 (1H, d), 9.48
(1H, s)
[0961] This material as a solution in chloroform/ethanol 1:1 was
treated with 1M HCl in ether (0.4 ml) and evaporated to dryness to
provide the title compound (89 mg).
[0962] MS (+ve ion electrospray) m/z 513 (MH.sup.+, 100%)
Example 355
(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-y-
lmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and
(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7--
ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0963] ##STR112##
[0964] A mixture of the carboxaldehyde (309i) (34 mg) and the amine
(350g) (60 mg) in chloroform (1.5 ml)/methanol (1.5 ml) with 3A
molecular sieves was refluxed 18 hours, cooled and treated with
sodium triacetoxyborohydride (143 mg). After string for 5 hours at
room temp. and 2 hours at 45.degree. C., the mixture was filtered,
diluted with chloroform (20 ml) and washed with aqueous
NaHCO.sub.3. The aqueous fraction was re-extracted with 10% ethanol
in chloroform (3.times.10 ml) and the combined organic fractions
dried (MgSO.sub.4) and evaporated. Chromatography of the residue on
silica gel (CHCl.sub.3/MeOH/NH.sub.4OH 95:5:0.5) gave the free base
of the title compound (45 mg).
[0965] .sup.1H NMR .delta. (CDCl.sub.3/CD.sub.3OD) 1.2-1.4 (1H, m),
1.5-1.8 (2H, m), 2.1-2.3 (2H, m), 2.3-2.6 (2H, m), 2.6-2.8 (1H, m),
3.4-3.6 (1H, m), 3.80 (1H, d), 3.94 (1H, d), 4.16 (3H, s), 4.67
(2H, s), 6.91 (1H, s), 7.22 (1H, d), 8.13 (1H, s), 8.20 (1H, d),
8.50 (1H, d), 8.62 (1H, d)
[0966] This material as a solution in chloroform/ethanol 1:1 was
treated with 1M HCl in ether (0.2 ml) and evaporated to dryness to
provide the title compound (50 mg).
[0967] MS (+ve ion electrospray) m/z 479 (MH.sup.+, 100%)
Example 356
(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7--
ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and
(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4thiazin-7--
ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0968] ##STR113##
[0969] A mixture of the carboxaldehyde (302g) (20 mg) and the amine
(350g) (33 mg) in DMF (1.5 ml)/methanol (1.5 ml)/acetic acid (0.15
ml) was refluxed 3 hours, cooled and treated with sodium
cyanoborohydride (13 mg). After string for 18 hours at room temp.,
the mixture was diluted with 10% methanol in chloroform (20 ml),
filtered and evaporated to dryness. The residue was treated with
aqueous NaHCO.sub.3 (10 ml), extracted with 10% methanol in
chloroform (4.times.10 ml) and the combined organic fractions dried
(MgSO.sub.4) and evaporated. Chromatography of the residue on
silica gel (CHCl.sub.3/MeOH/NH.sub.4OH 93:7:0.7) gave the free base
of the title compound (25 mg).
[0970] This material as a solution in chloroform was treated with
1M HCl in ether (0.12 ml) and evaporated to dryness to provide the
title compound (24 mg).
Example 357
(1S,3S,4S)-3-Hydroxy-4-[(6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthal-
en-3-ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and
(1R,3R,4R)-3-hydroxy-4-[6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthal-
en-3-ylmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0971] ##STR114##
[0972] A mixture of the carboxaldehyde (312d) (55 mg) and the amine
(350g) (40 mg) in DMF (1.5 ml)/methanol (1.5 ml)/acetic acid (0.15
ml) was refluxed 8 hours with 3A molecular sieves, cooled and
treated with sodium cyanoborohydride (24 mg). After stirring for 18
hours at room temp., the mixture was diluted with 10% methanol in
chloroform, filtered and evaporated to dryness. The residue was
treated with aqueous Na.sub.2CO.sub.3, extracted with 10% methanol
in chloroform (4.times.) and the combined organic fractions dried
(Na.sub.2SO.sub.4) and evaporated. Chromatography of the residue on
silica gel (CHCl.sub.3 then 2-10% methanol-dichloromethane) gave
the free base of the title compound (32 mg).
[0973] .sup.1H NMR .delta. (CDCl.sub.3/CD.sub.3OD) 1.2-1.4 (1H, m),
1.5-1.8 (2H, m), 2.1-2.6 (4H, m), 2.6-2.8 (1H, m), 3.5 (1H, m), 3.7
(2H, s), 4.1 (2H, q), 4.16 (3H, s ), 7.05 (1H, s), 7.22 (1H, d),
8.20 (1H, d), 8.50 (1H, d), 8.62 (1H, d). MS (+ve ion electrospray)
m/z 496 (MH.sup.+)
[0974] This material as a solution in chloroform/methanol was
treated with 4M HCl in dioxan, evaporated to dryness and triturated
with ether, to provide the title compound (38 mg).
Example 358
(1S,3S,4S)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6--
ylmethyl)-amino]-cyclohexanecarboxylic acid
(6,8-difluoro-quinolin-4-yl)-amide dihydrochloride and
(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-
-ylmethyl)-amino]-cyclohexanecarboxylic acid
(6,8-difluoroquinolin-4-yl)-amide dihydrochloride
[0975] ##STR115## (a) 4-Bromo-6,8-difluoro-quinoline
[0976] This was prepared from 4-hydroxy-6,8-difluoro-quinoline by
heating with phosphorus tribromide in dimethylformamide.
(b) (1R,3S,4S)- and
)1S,3R,4R)-4-(6,8-Difluoro-quinolin-4-ylcarbamoyl)-2-hydroxy-cyclohexyl]--
carbamic acid tert butyl ester
[0977] A mixture of the amide (350e) (0.34 g), cesium carbonate
(0.52 g), tris(dibenzylideneacetone)dipalladium(0) (24.5 mg), and
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (49 mg) in dry
dioxan (15 ml) under argon, was sonicated for 10 minutes, the
bromo-quinoline (358a) (0.32 g) was added, and the mixture was
stirred and heated at 95.degree. C. for 12 hours, under argon. The
mixture was cooled, filtered, and the filtrate evaporated and
chromatographed on silica gel, eluting with chloroform, then (2-5%)
methanol-dichloromethane, to afford a solid (0.34 g). MS (+ve ion
electrospray) m/z 422 (MH+). [0978] (c) (1S,3S,4S)- and
(1R,3R,4R-4-Amino-3-hydroxy-cyclohexanecarboxylic acid
(6,8-difluoro-quinolin-4-yl)-amide
[0979] The carbamate (358b) (0.34 g) in dichloromethane (20 ml) was
treated with trifluoroacetic acid (20 ml) for 2 hours and
evaporated. Sodium carbonate solution was added and the solution
was extracted (5x) with 10% methanol-chloroform, dried (sodium
sulfate) and evaporated to give a white solid (0.245 g). MS (+ve
ion electrospray) m/z 322 (MH+).
(d) Title compound
[0980] A mixture of carboxaldehyde (301d)(43 mg) and amine
(358c)(72 mg) in anhydrous dimethylformamide (2 ml), methanol (2
ml) and acetic acid (0.2 ml) was heated over 3A molecular sieves at
80.degree. C. for 2 h. After cooling, sodium cyanoborohydride (42
mg) was added and the mixture was stirred at room temperature
overnight. The mixture was filtered, and evaporated and the residue
basified with sodium carbonate and extracted several times with 10%
methanol/chloroform and the combined organic fractions were dried
and evaporated. Chromatography on silica gel (2-10%
methanol/dichloromethane) gave the free base of the title compound
(50 mg).
[0981] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.2-1.8 (3H, m),
2.03 (1H, m), 2.25 (2H, m), 2.5 (1H, m), 2.78 (1H, m), 3.49 (3H,
m), 3.78 (1H, d), 3.95 (1H, d), 6.96 (1H, d), 735 (1H, m), 7.65
(1H, d), 7.8 (1H, m), 8.28 (1H, d), 8.75 (1H, d) MS (+ve ion
electrospray) m/z 500 (MH.sup.+)
[0982] The free base in chloroform/methanol (1:1) was treated with
4M HCl in dioxan (0.2 ml) and evaporated to dryness. The solid was
triturated with ether, filtered and dried in vacuo, to provide
title compound (59 mg).
Example 359
(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-y-
lmethyl)-amino]-cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4yl)-amide dihydrochloride
[0983] ##STR116##
[0984] The amine (351 g) (0.47 mmol) under argon in MeOH (15 mL)
and DMF (15 mL) was treated with the carboxaldehyde (305e) (0.47
mmol), and 3A molecular sieves (1 g), followed by AcOH (1.5 mL).
(Polystyrylmethyl)trimethylammonium cyanoborohydride 0.940 mmol)
was added after 20 min. Once the reaction had gone to completion
the resin was removed by filtration, and the solvent removed in
vacuo. The residue was purified by flash column chromatography
(silica gel, DCM:MeOH/NH.sub.3 (2M) 0-12%) to give the free base of
the title compound in 79% yield.
[0985] .sup.1H NMR .delta.(CD.sub.3OD/CDCl.sub.3) 1.24-1.35 (1H,
m), 1.58-1.74 (2H, m), 2.10-2.16 (1H, m), 2.17-2.23 (1H, m),
2.32-3.38 (1H, m), 2.43-2.50 (1H, m), 2.62 (1H, tt), 3.48-3.52 (1H,
m), 3.75, 3.94 (2H, ABq), 4.14 (3H, s), 4.64 (2H, s), 6.88 (1H, d),
7.20 (1H, d), 7.21 (1H, d), 8.21 (1H, d), 8.50 (1H, d), 8.65 (1H,
d); MS (+ve ion electrospray) m/z 479 (MH.sup.+, 100%).
[0986] This material as a solution in DCM/MeOH 1:1 was treated with
4M HCl in dioxane (0.5 mL), evaporated to dryness, then dried under
vacuum to provide the title compound.
Example 360
(1R,3R,4R)-3-Hydroxy-4-[(7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-
-6-ylmethyl)-amino]cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0987] ##STR117##
[0988] This was prepared by the method of Example (359) on a 0.449
mmol scale from amine (351 g) and aldehyde (310d), to give the free
base of the title compound in 74% yield;
[0989] .sup.1H NMR .delta.(CD.sub.3OD/CDCl.sub.3) 1.28-1.40 (1H,
m), 1.61-1.77 (2H, m), 2.12-2.18 (1H, m), 2.21-2.27 (1H, m), 2.25
(3H, s), 2.37-2.43 (1H, m), 2.48-+2.55 (1H, m), 2.62 (1H, tt), 3.45
(2H, s), 3.52-3.58 (1H, m), 3.77, 397 (2H, ABq), 4.14 (3H, s), 7.18
(1H, d), 7.40 (1H, s), 8.22 (1H, d), 8.50 (1H, d), 8.66 (1H, d); MS
(+ve ion electrospray) m/z 509 (MH.sup.+, 100%).
[0990] This material as a solution in DCM/MeOH 1:1 was treated with
4M HCl in dioxane (0.5 mL), evaporated to dryness, then dried under
vacuum to provide the title compound.
Example 361
(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3
-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]cyclohexanecarbox-
ylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide
dihydrochloride
[0991] ##STR118##
[0992] This was prepared by the method of Example (359) on a 0.470
mmol scale from amine (351 g) and aldehyde (302 g), to give the
free base of the title compound in 79% yield
[0993] .sup.1H NMR .delta.(400 MHz, CD.sub.3OD/CDCl.sub.3)
1.25-1.36 (1H, m), 1.59-1.72 (2H, m), 2.11-2.17 (1H, m), 2.18-2.24
(1H, m), 2.34-2.40 (1H, m), 2.43-2.50 (1H, m), 2.63 (1H, tt), 3.46
(2H, m), 3.46-3.52 (1H, m), 3.83, 3.97 (2H, ABq), 4.15 (3H, s),
6.91 (1H, s), 7.22 (1H, d), 8.20 (1H, d), 8.36 (1H, s), 8.50 (1H,
d), 8.63 (1H, d); MS (+ve ion electrospray) m/z 495 (MH.sup.+,
100%).
[0994] This material as a solution in DCM/MeOH 1:1 was treated with
4M HCl in dioxane (0.5 mL), evaporated to dryness, then dried under
vacuum to provide the title compound.
Example 362
(1S,3S,4S)-3-Hydroxy-4-[(7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-
-6-ylmethyl)-amino]cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0995] ##STR119##
[0996] This was prepared by the method of Example (359) on a 0.432
mmol scale from amine (352 g), and aldehyde (310d), to give the
free base of the title compound in 85% yield;
[0997] .sup.1H NMR .delta.(400 MHz; CD.sub.3OD/CDCl.sub.3)
1.28-1.37 (1H, m), 1.59-1.76 (2H, m), 2.13 (1H, bd), 2.20-2.24 (1H,
m), 2.25 (3H, s), 2.38 (1H, bd), 2.51 (1H, dt), 2.65 (1H, tt), 3.45
(2H, s), 3.52-3.58 (1H, m), 3.75, 395 (2H, ABq), 4.15 (3H, s), 7.21
(1H, d), 7.42 (1H, s), 8.20 (1H, d), 8.50 (1H, d), 8.64 (1H, d); MS
(+ve ion electrospray) m/z 509 (MH.sup.+, 100%).
[0998] This material as a solution in DCM/MeOH 1:1 was treated with
4M HCl in dioxane (0.5 mL), evaporated to dryness, then dried under
vacuum to provide the title compound.
Example 363
(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7--
ylmethyl)-amino]cyclohexanecarboxylic acid
(6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride
[0999] ##STR120##
[1000] This was prepared by the method of Example (359) on a 0.463
mmol scale from amine (352 ) and aldehyde (302 g), to give the free
base of the title compound in 52% yield; XXX
[1001] .sup.1H NMR .delta.(400 MHz; CD.sub.3OD/CDCl.sub.3)
1.25-1.36 (1H, m), 1.59-1.74 l (2H, m), 2.15 (1H, bd), 2.18-2.24
(1H, m), 2.38 (1H, bd), 2.47 (1H, dt), 2.65 (1H, tt), 3.45 (2H, m),
3.46-3.53 +(1H, m), 3.83, 3.97 (2H, ABq), 4.15 (3H, s), 6.92 (1H,
s), 7.22 (1H, d), 8.19 (1H, d), 8.36 (1H, s), 8.50 (1H, d), 8.63
(1H, d); MS (+ve ion electrospray) m/z 495 (MH.sup.+, 100%).
[1002] This material as a solution in DCM/MeOH 1:1 was treated with
4M HCl ini dioxane (0.5 mL), evaporated to dryness, then dried
under vacuum to provide the title compound.
[1003] the following compounds were made by the method of Example
350h). TABLE-US-00005 ##STR121## Method of salt synthesis B Example
(aldehyde) Stereochemistry Dihydrochloride X R 380 (4c)
1S,3S,4S/1R,3R,4R B N 3-Oxo-3,4-dihydro-2-benzo[1,4] thiazin-6-yl
##STR122## 381 (13e) 1S,3S,4S/1R,3R,4R B N
2-Oxo-2,3-dihydro-1H-pyrido [2,3-b][1,4]thiazin-7-yl ##STR123## 382
(20e) 1S,3S,4S/1R,3R,4R B N 2,3-Dihydro-[1,4]dioxino[2,3-b]
pyridin-7-yl ##STR124## 383 a 1S,3S,4S/1R,3R,4R B CH
3-Oxo-3,4-dihydro-2H-pyrido [3,2-b][1,4]thiazin-6-yl ##STR125## a
prepared from 4-bromo-6-methoxyquinoline (itself prepared from
6-methoxy-quinolin-4-ol by the method of Example 391a) by the
method of Example 350(f-h)
Example 390
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2b][1,4]thiazin-6-ylmethyl)--
amino-r-cyclohexanecarboxylic acid
(8-fluoro-6-methoxy-quinolin-4yl)-amide dihydrochloride
[1004] ##STR126## (a)
[4-(8-Fluoro-6-methoxy-quinolin-4-ylcarbamoyl)-r-4-hydroxy-c-cyclohexyl]-
carbamic acid tert-butyl ester
[1005] A mixture of amide (300c) (1.46 g, 5.66 mmol) and cesium
carbonate (2.66 g, 8.18 mmol in 1,4-dioxan was deoxygenated by
bubbling in a stream of argon for 5 mins.
Tris(dibenzylideneacetone)dipalladium(0) (0.125 g, 0.13 mmol) and
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.25 g, 0.40 mmol)
were added and deoxygenation continued for 2 mins. The mixture was
the sonicated for 15 mins. Triflate ester (10b) (2.2 g, 6.77 mmol)
was added and the mixture heated at 105.degree. C. overnight. The
reaction mixture was filtered and the filtered solids extracted
with hot chloroform/methanol. The combined organics were evaporated
and the crude product purified on silica gel eluting with 5%
methanol/dichloromethane to give a solid (1.29 g, 53%). MS (+ve ion
electrospray) m/z 434 MH+).
(b) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid
(8-fluoro-6-methoxy-quinolin-4-yl)-amide
[1006] The carbamate (390a) (1.28 g, 2.96 mmol) in dichloromethane
(20 ml) and trifluoroacetic acid (10 ml) was stirred for 2 hours at
room temperature and then evaporated. The residue was basified with
sodium carbonate and ice-water, the precipitate washed with water
and dried, to give a solid (0.97 g, 98%).
(c) Title compound
[1007] The amine (390b) (0.17 g, 0.51 mmol) and carboxaldehyde
(301d) (0.099 g, 0.51 mmol) in methanol (5 ml) and chloroform (5
ml) were stirred at 65.degree. C. with 3A sieves for 18 hours. The
mixture was allowed to cool and sodium triacetoxyborohydride (0.50
g, 2.36 mmol) was added. After the mixture had been stirred for 3
days it was filtered and evaporated. The residue was neutralised
with sodium carbonate solution and extracted with 10% methanol in
chloroform. The extracts were dried and evaporated and the crude
product purified on silica gel eluting with 0-10% methanol in
dichloromethane to give the free base of the title compound (0.224
g, 91%).
[1008] .sup.1H NMR .delta.(CDCl.sub.3/CD.sub.3OD) 1.6-1.8 (2H, m),
1.8-2.2 (7H, m) 2.72 (1H, m), 3.4 (2H, d), 3.5 (2H, s), 3.95 (2H,
s) 3.97 (3H, s), 6.92 (2H, m) 7.15 (1H, d) 7.65 (1H, d) 8.35 (1H,
d), 8.7 (1H, d).
[1009] Addition of 4M hydrochloric acid in dioxan and trituration
of the precipitate with ether effected conversion to the title
compound. MS (+ve ion electrospray) m/z 483 (MH+)
Example 391
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-
-amino-r-cyclohexanecarboxylic acid (6-methoxy-quinolin-4-yl)-amide
dihydrochloride
[1010] ##STR127## (a) 4-Bromo-6-methoxy-quinoline
[1011] This was prepared by heating 6-methoxy-quinolin-4-ol (1 g)
and phosphorus oxybromide (5 g) in chloroform (40 ml) under reflux
for 18 hours. The mixture was cooled, basified with sodium
bicarbonate, extracted with 5% methanol-chloroform, and dried
(sodium sulfate). The product was chromatographed on silica gel
(2-5% methanol-dichloromethane) to afford a solid (0.68 g). MS (+ve
ion electrospray) m/z 238/240 (MH+)
[1012] Alternatively, this material was prepared in approximately
90% yield by treatment with one equivalent of phosphorous
tribromide in N,Ndimethylformamide.
(b)
[4-(6-Methoxy-quinolin-4-ylcarbamoyl)-r-4hydroxy-c-cyclohexyl]-carba-
mic acid tert-butyl ester
[1013] A mixture of amide (300c) (0.84 g) and cesium carbonate
(120) in 1,4-dioxan (40 ml) was deoxygenated by bubbling in a
stream of argon for 5 mins.
Tris(dibenzylideneacetone)dipalladium(0) (60 mg) and
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (120 mg) were added
and deoxygenation continued for 2 mins. The mixture was the
sonicated for 10 mins. The bromide (391a) (0.8 g) was added and the
mixture heated at 103.degree. C. overnight. The reaction mixture
was filtered and the filtered solids extracted with hot
chloroform/methanol. The combined organics were evaporated and the
crude product purified on silica gel eluting with chloroform then
2% methanol/dichloromethane to give a solid (1.27 g). MS (+ve ion
electrospray) m/z 416 (MH+).
(c) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid
(6-methoxy-quinolin-4-yl)-amide
[1014] The carbamate (391b) (1.43 g) in dichloromethane (50 ml) and
trifluoroacetic acid (50 ml) was stirred for 2 hours at room
temperature and then evaporated. The residue was basified with
sodium carbonate and ice-water, the precipitate washed with water
and dried, to give a solid (0.8 g). MS (+ve ion electrospray) m/z
316 (MH+).
(d) Title compound
[1015] The amine (391c) (0.162 g) and carboxaldehyde (301d) (0.1 g)
in methanol (8 ml) and chloroform (8 ml) were stirred at 65.degree.
C. with 3A sieves for 18 hours. The mixture was allowed to cool and
sodium triacetoxyborohydride (0.50 g) was added. After the mixture
had been stirred for 2 days it was filtered and evaporated. The
residue was neutralised with sodium carbonate solution and
extracted with 5% methanol in chloroform. The extracts were dried
and evaporated and the crude product purified on silica gel eluting
with chloroform then 2-10% methanol in dichloromethane to give the
free base of the title compound (0.2 g).
[1016] .sup.1H NMR .delta. (CDCl.sub.3/CD.sub.3OD) 1.6-1.8 (2H, m),
1.8-2.2 (6H, m), 2.62 (1H, m), 3.4 (2H, d), 3.5 (2H, s), 3.87 (2H,
s), 4.0 (3H, s), 6.98 (2H, m), 7.2 (1H, d), 7.42 (1H, dd), 7.65
(1H, d), 7.95 (1H, d), 8.25 (1H, d), 8.62 (1H, d).
[1017] Addition of 4M hydrochloric acid in dioxan and trituration
of the precipitate with ether effected conversion to the title
compound.
[1018] MS (+ve ion electrospray) m/z 494 (MH+)
Example 392
1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-
-amino-r-cyclohexanecarboxylic acid
(6,8-difluoro-quinolin-4-yl)-amide dihydrochloride
[1019] ##STR128## (a) 1,1,1-Trifluoro-methanesulfonic acid
6,8-difluoro-quinolin-4-yl ester.
[1020] Sodium hydride 60% dispersion in oil (0.062 g, 1.55 mmol)
was washed with hexane and suspended in DMF. After cooling to
0.degree. C. 6,8-difluoro-quinolin-4-ol (0.20 g, 1.1 mmol) was
added and the mixture stirred at 0.degree. C. for 15 mins.
N-Phenyltrifluoromethane sulfonamide (0.47 g, 1.3 mmol) was added
and the mixture allowed to warm to room temperature and stirred
overnight. The solvent was evaporated and the residue partitioned
between ethyl acetate and water. The aqueous phase was extracted
with ethyl acetate and the combined organics dried evaporated and
chromatographed on silica gel eluting with dichloromethane to give
the triflate (0.318 g, 92%)
[1021] MS (+ve ion electrospray) m/z 314 (MH+).
(b)
[4-(6,8-Difluoro-quinolin-4-ylcarbamoyl)-r-4-hydroxy-c-cyclohexyl]-c-
arbamic acid tert-butyl ester.
[1022] The carboxamide (300c) (0.25 g, 0.97 mmol) and the triflate
ester (392a) (0.318 g, 1.0 mmol) were reacted by the method of
Example (391b) except that the mixture was heated at
100-105.degree. C. to give the carbamate (0.165 g, 40%).
[1023] MS (+ve ion electrospray) m/z 422 (MH+).
(c) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid
(6,8-difluoro-quinolin-4-yl)-amide.
[1024] The carbamate was deprotected with trifluoroacetic acid by
the method of Example (391c).
(d) Title Compound.
[1025] The amine (392c) (0.067 g, 0.21 mmol) was reacted with
carboxaldehyde (301d) (0.049 g, 0.25 mmol) in methanol (3 ml) and
chloroform (3 ml) in the presence of 3A sieves at 65.degree. C.
overnight. The mixture was allowed to cool and further chloroform
added (5 ml) to give a clear solution. Sodium triacetoxyborohydride
(0.4 g) was added and the mixture stirred at room temperature for
48 hours. After decanting from the sieves the mixture was
evaporated, treated with sodium carbonate solution and extracted
with 10% methanol in dichloromethane. The extracts were dried,
evaporated and chromatographed on silica gel eluting with 2-10%
methanol in dichloromethane to give the free base of the title
compound (0.076 g, 73%).
[1026] MS (+ve ion electrospray) m/z 500 (MH+). .sup.1H NMR .delta.
(CDCl.sub.3/CD.sub.3OD) 1.55-1.7 (2H, m), 1.85-2.2 (6H, m), 2.68
(1H, m), 3.5 (2H, s), 3.87 (2H, s), 6.92 (1H, d), 7.25-7.4 (2H, m),
7.65 (1H, d), 8.43 (1H, d), 8.81 (1H, d).
[1027] Addition of 4M hydrochloric acid in dioxan and trituration
of the precipitate with ether effected conversion to the title
compound.
[1028] The following compounds were prepared by analogous methods.
TABLE-US-00006 ##STR129## Method of salt Exam- synthesis B Dihydro-
ple (aldehyde) chloride X R 400 a B F 2,3-Dihydro-[1,4]dioxino
(19d) [2,3-c]pyridin-7-yl ##STR130## 421 a B F
2-oxo-2,3-dihydro-1H-pyrido (13e) [2,3-b][1,4]thiazin-7-yl
##STR131## 422 b B H 7-Bromo-3-oxo-3,4-dihydro- (304g)
2H-pyrido[3,2-b][1,4]thiazin- 6-yl ##STR132## 423 b B H
2,3-Dihydro-[1,4]dioxino (19d) [2,3-c]pyridin-7-yl ##STR133## 424 b
B H 3-oxo-3,4-dihydro-2H-pyrido (305e) [3,2-b][1,4]oxazin-6-yl
##STR134## 425 c B OMe 3-oxo-3,4-dihydro-2H-pyrido (301d)
[3,2-b][1,4]thiazin-6-yl ##STR135## 426 a B F
7-Chloro-3-oxo-3,4-dihydro- (306e) 2H-pyrido[3,2-b][1,4]thiazin-
6-yl ##STR136## a prepared by the method of Example (390) b
prepared by the method of Example (391) c prepared from
4-bromo-6,8-dimethoxy-quinoline by the method of Example (391)
Example 430
6-({4-hydroxy-4-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexylami-
no}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one
[1029] ##STR137## (a)
(4-Hydroxy-4-trimethylsilanyl-cyclohexyl)-carbamic acid tert-butyl
ester.
[1030] A solution of trimethylsilyl acetylene at -78.degree. C.
(4.14 g, 0.042 mol) in THF (60 mL) was treated with n-butyl lithium
(29 mL, 0.042 mol; 1.6 M solution in THF). The resulting mixture
was stirred at -78.degree. C. for 15 min. A solution of
N-4-Boc-aminocyclohexanone (3 g, 0.014 mol; Astatech, Inc) in THF
(120 mL) was added dropwise over a period of 30 min. The resulting
mixture was stirred at -78.degree. C. for 1 h and then allowed to
slowly warn up to room temperature over 1 h. The reaction was
quenched with a saturated solution of ammonium chloride and diluted
with EtOAc and washed with saturated aqueous NaHCO.sub.3 solution,
H.sub.2O, and saturated aqueous NaCl solution. The organic layer
was dried over MgSO.sub.4 and concentrated to yield an off-white
foam (4.38 g, 100%).
[1031] MS (+ve ion clectrospray) m/z 312 (M+H).sup.+.
(b) (4-Ethynyl-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl
ester.
[1032] A solution of the carbamate (430a) (4.38 g, 0.014 mol) in
MeOH (50 mL) was treated with K.sub.2CO.sub.3 (5.83 g, 0.42 mol)
and stirred at room temperature for 3 h. The solvent was removed in
vacuo and the residue was partitioned between EtOAc and aqueous
NaCl, and the organic layer was dried (MgSO.sub.4) and concentrated
to yield an oil (2.7 g, 89%).
[1033] MS (+ve ion electrospray) m/z 240 (M+H).sup.+.
(c)
[4-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylethynyl)-cyclohexyl]-c-
arbamic acid tert-butyl ester.
[1034] A solution of carbamate (430b) (2.7 g, 0.011 mol) and the
triflate ester (1b) (3.13 g, 0.01 mol) in a 1:1 mixture of
triethylamine and DMF (10 mL total volume) was treated with
(Ph.sub.3P).sub.2PdCl.sub.2 (0.3 g; 4% mol) and CuI (0.24 g, 8%
mol). The resulting mixture was heated at 70.degree. C. for 24 h.
The solvent was removed under reduced pressure and the residue was
partitioned between CH.sub.2Cl.sub.2 and aqueous NaCl, and the
organic layer was dried (MgSO.sub.4), and concentrated in vacuo.
The resulting oil was purified by flash column chromatography on
silica gel (gradient: 20-50% EtOAc/hexane) to afford an oil (2.24
g, 50%).
[1035] MS (+ve ion electrospray) m/z 398 (M+H).sup.+.
d)
{4-Hydroxy-4-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexyl}-c-
arbamic acid tert-butyl ester
[1036] A solution of carbamate (430c) (0.8 g, 2 mmol) in MeOH (10
mL) was treated with 10% palladium on carbon (catalytic) and
hydrogenated in a Parr bottle for 6 h at 40 psi. The solution was
filtered through a plug of celite.RTM., and the filter pad was
washed with MeOH. The filtrate was concentrated to yield a yellow
oil (0.7 g, 80%). The product was used without further
purification.
[1037] MS (+ve ion electrospray) m/z 402 (M+H).sup.+. NMR analysis
indicated that the compound was a 5:1 mixture of isomers. The
isomeric mixture was not further characterized and was carried on
through the remaining steps.
(e)
4-Amino-1-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexanol
[1038] A solution of carbamate (430d) (0.4 g, 1 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was treated with trifluoroacetic acid
(0.15 mL, 2 mmol). The solution was allowed to stir for 1 h at room
temperature and then concentrated under reduced pressure. MeOH was
added and the solution was again concentrated to remove any excess
TFA. The remaining solid was dissolved in MeOH (5 mL) and treated
with MP-Carbonate resin (1.00 g, 2.87 mmol; Argonaut Technologies,
Inc.). The solution was then filtered and concentrated to yield a
brown oil (0.3 g, 70%). The product was used without further
purification.
[1039] MS (+ve ion electrospray) m/z 302 (M+H).sup.+.
(f) Title Compound
[1040] The amine (430e) (0.169 g, 0.561 mmol) was added to a
solution of the carboxaldehyde (305e) (0.100 g, 0.561 mmol)
dissolved in DMF (3 mL), MEOH (2 mL) and acetic acid (0.2 mL). 3A
molecular sieves were then added to the reaction mixture and the
solution was allowed to stir at 80.degree. C. for 40 h. The
solution was cooled to 0.degree. C. and sodium borohydride (0.042
g, 1.12 mmol) was added. The reaction was stirred at ambient
temperature for 4 h. The reaction mixture was partitioned between
ethyl acetate and water. The organic layer was washed with water
(2.times.) and brine, dried (Na.sub.2SO.sub.4) and concentrated to
yield a yellow oil. The product was purified using flash column
chromatography on silica gel (90:10:1 CHCl.sub.3/MeOH/NH.sub.4OH)
to yield a yellow solid (0.025 g, 11%).
[1041] MS (+ve ion electrospray) m/z 464 (M+H)+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.72 (d, J=4.5 Hz, 1H), 8.18 (d, J=9.0 Hz,
1H), 7.40 (d, J=4.5 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.10 (d, J=9.0
Hz, 1H), 6.8 (d, J=9.0 Hz, 1H), 4.60 (s, 2H), 4.04 (s, 3H), 3.75
(s, 2H), 3.25 (m, 2H), 2.55 (m, 1H), 1.91 (br m, 6H); 1.69 (m, 2H);
1.45 (m, 2H).
Biological Activity
[1042] The MIC (.mu.g/ml) of test compounds against various
organisms was determined: [1043] S. aureus Oxford, S. aureus
WCUH29, S. pneumoniae 1629, S. pneumoniae N1387, S. pneumoniae ERY
2, E. faecalis I, E. faecalis 7, H. influenzae Q1, H. influenzae
NEMC1, M. catarrhalis 1502. [1044] Examples 2-6, 8, 9, 12, 13,
19-21, 23, 28, 30, 31, 32, 34, 35, 101, 150, 153, 154, 210-214,
300-305, 320-333, 380, 381, 390, 391, 400, 422, 423 had MIC values
.ltoreq.4 .mu.g/ml versus all these organisms. [1045] Examples 10,
11, 14-17, 22, 24, 26, 29, 102, 104, 155, 156, 215, 334-336, 382
had MIC values .ltoreq.16 .mu.g/ml versus all these organisms.
[1046] Examples 7, 18, 25, 27, 36, 100, 103, 105, 337 and 338 had
MIC values .ltoreq.64 .mu.g/ml versus all these organisms.
[1047] The MIC (mg/ml) of further test compounds against an
alternative selection of organisms was determined: [1048] S. aureus
WCUH29, S. pneumoniae 1629, H. influenzae ATCC 51907, M.
catarrhalis Ravisio. [1049] Examples 306-310, 312, 314, 350-363,
392, 421, 424-426, 430 had MIC values .ltoreq.4 .mu.g/ml versus all
these organisms. [1050] Examples 311, 313, 340, 342, 343, 383 had
MIC values .ltoreq.16 .mu.g/ml versus all these organisms. [1051]
Examples 110, 111, 206, 341 had MIC values .ltoreq.16 .mu.g/ml
versus somel of these organisms. Other examples except 106 and 203
had MIC values .ltoreq.64 F.mu.g/ml versus at least one of these
organisms.
* * * * *