U.S. patent application number 12/558407 was filed with the patent office on 2010-07-01 for peptoid compounds.
This patent application is currently assigned to UNIVERSITY OF WOLLONGONG. Invention is credited to Tim Boyle, John Bremner, Jonathan Coates, Dan Coghlan, Adel Garas, Paul Keller, Stephen Pyne, Helen Witchhard.
Application Number | 20100167995 12/558407 |
Document ID | / |
Family ID | 3830009 |
Filed Date | 2010-07-01 |
United States Patent
Application |
20100167995 |
Kind Code |
A1 |
Bremner; John ; et
al. |
July 1, 2010 |
PEPTOID COMPOUNDS
Abstract
The invention relates to new peptoid compounds of formula (I),
as well as their use in the treatment of bacterial infections, such
as those caused by vancomycin resistant microorganisms, and to
compositions thereof.
Inventors: |
Bremner; John; (Wollongong,
AU) ; Pyne; Stephen; (Wollongong, AU) ;
Keller; Paul; (Wollongong, AU) ; Coghlan; Dan;
(Wollongong, AU) ; Garas; Adel; (Wollongong,
AU) ; Witchhard; Helen; (Wollongong, AU) ;
Boyle; Tim; (Wollongong, AU) ; Coates; Jonathan;
(Richmond, AU) |
Correspondence
Address: |
SEED INTELLECTUAL PROPERTY LAW GROUP PLLC
701 FIFTH AVE, SUITE 5400
SEATTLE
WA
98104
US
|
Assignee: |
UNIVERSITY OF WOLLONGONG
Wollongong
AU
|
Family ID: |
3830009 |
Appl. No.: |
12/558407 |
Filed: |
September 11, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11592718 |
Nov 3, 2006 |
7612036 |
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12558407 |
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10481663 |
Oct 25, 2004 |
7160854 |
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PCT/AU02/00850 |
Jun 28, 2002 |
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11592718 |
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Current U.S.
Class: |
514/1.1 ;
514/2.7; 530/317; 530/331 |
Current CPC
Class: |
C07K 5/0812 20130101;
C07D 487/04 20130101; C07D 273/02 20130101; C07C 279/14 20130101;
C07D 255/04 20130101; C07C 229/36 20130101; C07K 5/1016 20130101;
C07D 209/86 20130101; A61K 38/00 20130101; C07C 251/24 20130101;
C07C 237/22 20130101; C07K 5/06086 20130101; A61P 31/04 20180101;
C07C 233/47 20130101; C07D 245/04 20130101; C07K 5/06095
20130101 |
Class at
Publication: |
514/11 ; 530/331;
514/18; 530/317 |
International
Class: |
A61K 38/12 20060101
A61K038/12; C07K 5/08 20060101 C07K005/08; A61K 38/06 20060101
A61K038/06; C07K 5/12 20060101 C07K005/12; A61P 31/04 20060101
A61P031/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 29, 2001 |
AU |
PR 6044 |
Claims
1. A compound of the formula (I): ##STR00082## wherein A is an
aromatic or heteroaromatic ring system or partially or fully
reduced derivatives thereof; Q is hydrogen, C.sub.1-C.sub.12
straight chain, branched or cyclic alkyl substituted with one or
more hydroxy groups, or a mono- or di-saccharide moiety; Z is
--CR.sup.10R.sup.11--, --NR.sup.12--, --C(O)O--, --C(O)NR.sup.12--
or --O--, where R.sup.10 and R.sup.11 are independently selected
from hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
aryl, C.sub.1-C.sub.6 alkoxy and --N(R.sup.13).sub.2 and where each
R.sup.13 is independently selected from hydrogen and
C.sub.1-C.sub.6 alkyl, and where R.sup.12 is selected from hydrogen
and C.sub.1-C.sub.6 alkyl; R.sup.1 is selected from hydrogen,
hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
--N(R.sup.13).sub.2 and --N(R.sup.12)--COR.sup.14; where R.sup.12
and R.sup.13 are as defined above, and where R.sup.14 is selected
from hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy and --NR.sup.12; R.sub.2 is selected from hydrogen, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, --N(R.sup.13).sub.2
and --N(R.sup.12)--COCHR.sup.2aR.sup.2b; where R.sup.2a and
R.sup.2b are selected from hydrogen, hydroxy, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, --N(R.sup.13).sub.2 and
--N(R.sup.12)--COR.sup.14; where R.sup.12, R.sup.13 and R.sup.14
are as defined above; R.sup.3, R.sup.4 and R.sup.5 are
independently selected from hydrogen, C.sub.1-C.sub.6 alkyl and
.alpha. side chains of .alpha.-amino acids or their enantiomers or
their derivatives; R.sup.6 is --CO.sub.2R.sup.15, --CONHR.sup.16,
--CONHOR.sup.16, --CONHNHR.sup.16, --SO.sub.2N(R.sup.16).sub.2,
--SO.sub.2R.sup.17 or --P(O)(OR.sup.18)(OR.sup.18) where each
R.sup.15, R.sup.16, R.sup.17 and R.sup.18 is independently selected
from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.6-C.sub.10 aryl and C.sub.7-C.sub.10 arylalkyl; B is an
.alpha.-amino acid residue, a .beta.-amino acid residue or an
a,a-disubstituted amino acid residue, such residue forming amide
linkages with the adjacent molecules; W is --O-- or
CR.sup.10R.sup.11 where R.sup.10 and R.sup.11 are as defined above;
Y is an optionally substituted amino group, a moiety containing an
optionally substituted amino group or a salt thereof; is a single
or double bond; R.sup.7 and R.sup.8a are hydrogen or are absent if
is a double bond; and R.sup.8b and R.sup.9 are hydrogen, and X is
selected from (CR.sup.10R.sup.11).sub.u,
--(CR.sup.10R.sup.11).sub.u--CH.dbd.CH--,
--NR.sup.12(CR.sup.10R.sup.11).sub.u--,
--(CR.sup.10R.sup.11).sub.uNR.sup.12--,
--O(CR.sup.10R.sup.11).sub.u--, --(CR.sup.10R.sup.11).sub.uO-- or
--O(CR.sup.10R.sup.11)CH.dbd.CH-- where R.sup.10, R.sup.11 and
R.sup.12 are as defined above; or R.sup.8b and R.sup.9 together
form a covalent bond between X and the carbon to which R.sup.8b is
attached, and X is selected from (CR.sup.10R.sup.11).sub.x,
--NR.sup.12(CR.sup.10R.sup.11).sub.x--,
--(CR.sup.10R.sup.11).sub.xNR.sup.12--,
--O(CR.sup.10R.sup.11).sub.x-- or --(CR.sup.10R.sup.11).sub.xO--,
where R.sup.10, R.sup.11 and R.sup.12 are as defined above; n, m, r
and t are independently selected from 0 or 1; s is an integer
selected from 0 to 3; p is an integer selected from 0 to 6,
provided that when W is --O--, p is at least 1; and u, x and q are
independently selected from 0 to 4; and salts and pharmaceutically
acceptable derivatives thereof.
2. A compound according to claim 1 having the formula (1A):
##STR00083## wherein A, Q, Z, R.sup.2a, R.sup.2b, R.sup.3, B, W, Y,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8a, R.sup.8b, R.sup.9, X,
r, s, n, m, p, q and t are as defined above. 5
3. A compound according to claim 1 wherein A is an optionally
substituted monoaryl group or an optionally substituted fused di-
or poly aryl or heteroaryl group wherein the optional substituents
are selected from one or more of C.sub.1-C.sub.6 alkyl, hydroxy,
C.sub.1-C.sub.6 alkoxy, amino, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 dialkylamino, halo, C.sub.1-C.sub.6 haloalkyl (for
example trifluoromethyl) nitro, nitrile, sulfonylsulfonamide,
alkylsulfonyl, arylsulfonyl, or carboxy groups.
4. A compound according to claim 3 wherein A is optionally
substituted phenyl, fluorene, phenanthrene, indole, indazole,
benzimidazole, carbazole, quinoline, isoquinoline, dibenzazepine
and dibenzazocine.
5. A compound according to claim 4 wherein A is optionally
substituted 1,4-linked phenyl, 1,3-linked fluorene or 3,6-linked 9H
carbazole.
6. A compound according to claim 1 wherein A is an optionally
substituted bridged or bonded di- or poly aryl or heteroaryl group
or their atropisomers wherein the optional substituents are
selected from one or more of C.sub.1-C.sub.6 alkyl, hydroxy,
C.sub.1-C.sub.6 alkoxy, amino, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 dialkylamino, halo, C.sub.1-C.sub.6 haloalkyl (for
example trifluoromethyl) nitro, nitrile, sulfonylsulfonamide,
alkylsulfonyl, arylsulfonyl, or carboxy groups.
7. A compound according to claim 6 wherein A is optionally
substituted bi-phenyl or bi-naphthyl or their atropisomers.
8. A compound according to claim 7 wherein A is a 3,3'-linked
2,2'-dimethoxy-1,1'-binaphthyl group or a 2,2'-linked
1,1'-binaphthyl group.
9. A compound according to claim 1 wherein Q is hydrogen.
10. A compound according to claim 1 wherein Z is --CH.sub.2-- or
--O--.
11. A compound according to claim 1 wherein s is 0, 1 or 2 and each
R.sup.1 is independently selected from hydrogen or hydroxy.
12. A compound according to claim 1 wherein R.sup.2 is hydrogen,
hydroxy or N(R.sup.12)COR.sup.2aR.sup.2b.
13. A compound according to claim 1 wherein R.sup.3 is
hydrogen.
14. A compound according to claim 1 wherein B is absent or a D- or
L-alanyl residue, a D-lysinyl residue, a D-arginyl residue or a
D-homoarginyl residue,
15. A compound according to claim 1 wherein Y is selected from a
group consisting of: --N(R.sup.13).sub.2,
--N(R.sup.12)--COR.sup.14,
--NR.sup.13C(.dbd.NR.sup.13)N(R.sup.13).sub.2,
--C(.dbd.NR.sup.13)N(R.sup.13).sub.2,
--NR.sup.13C(.dbd.O)N(R.sup.13).sub.2,
--N.dbd.NC(.dbd.NR.sup.13)N(R.sup.13).sub.2,
NR.sup.13NR.sup.13C(.dbd.O)NHN(R.sup.13).sub.2,
--NR.sup.13C(.dbd.)NHN(R.sup.13).sub.2, wherein R.sup.12 and each
R.sup.13 is independently selected from hydrogen and
C.sub.1-C.sub.6 alkyl and R.sup.14 is selected from hydrogen,
hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and
NR.sup.12; and a 3-8-membered N-containing cyclogroup.
16. A compound according to claim 15 wherein Y is an unsubstituted
amino group or a guanidino group, or their hydrochloride salts.
17. A compound according to claim 1 wherein R.sup.6 is
CO.sub.2R.sup.15 where R.sup.15 is C.sub.1-C.sub.6alkyl or
C.sub.7-C.sub.10arylalkyl.
18. A compound according to claim 17 wherein R.sup.15 is methyl or
benzyl.
19. A compound according to claim 1 wherein R.sup.8b and R.sup.9
are hydrogen and X is --(CR.sup.10R.sup.11).sub.u--,
--O(CH.sub.2).sub.u--, --CH.dbd.CH--,
--O(CR.sup.10R.sup.11)CH.dbd.CH-- or
--CR.sup.10R.sup.11--CH.dbd.CH-- where R.sup.10 and R.sup.11 are
hydrogen and u is an integer selected from 2 or 3.
20. A compound according to claim 1 wherein R.sup.8b and R.sup.9
together form a covalent bond between X and the carbon to which
R.sup.8b is attached and X is --(CR10R.sub.11).sub.x-- or
--O(CH.sub.2).sub.x-- wherein R.sup.10 and R.sup.11 are hydrogen
and x is an integer from 1 to 4.
21. A compound according to claim 1 selected from benzyl
(a/R/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3'-allyl-2,2'-dimethoxy-1,1'-bina-
phthyl]}-3,6-diaza-5-(4-{[tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononan-
oate
(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbon-
yl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12--
ene hydrochloride
(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1-
(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane
hydrochloride
(aR/S,7R,10S)-4-acetamido-6,9-diaza-10-benzyloxycarbonyl-7-(4-{[(tert-but-
oxy)carbonyl]amino}butyl)-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxo-
cyclotetradecaphane-12-ene methyl
(aR/S,2S,5R)-8-acetamido-2-allyl-9-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binap-
hthyl)]-3,6-diaza-5-(3-guanidinopropyl)-4,7-dioxononanoate
hydrochloride
(aR/S,7S,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbo-
nyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-
-ene hydrochloride
(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbo-
nyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-
-ene hydrochloride
(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbo-
nyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane
hydrochloride Methyl
(2S,5S,8R/S)-8-acetamido-2-allyl-9-[6-allyl-9-tert-butoxycarbonyl-9H-carb-
azol-3-yl]-3,6-diaza-5-{3-[(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-guani-
dino]propyl}-4,7-dioxononanoate
6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-diox-
o-[12](3,6)-1H-carbazolophane HCl (9S,12S)
6-Acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,-
10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S)
6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-diox-
o-[12](3,6)-1H-carbazolophane HCl (9R,12S)
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-ene-12-m-
ethoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S)
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12-
](3,6)-1H-carbazolophane HCl (9S,12S) Methyl
(2S,5S,8R/S)-8-Acetamido-5-(4-aminobutyl)-3,6-diaza-9-{9-[(4-methoxypheny-
l)methyl]-6-propyl-9H-carbazol-3-yl}-4,7-dioxo-2-propylnonanoate
hydrochloride
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12-
](3,6)-1H-carbazolophane HCl (9R,12S) methyl
(aR/S,2S,5R)-2-allyl-5-[2-({[(2'-allyloxy-1,1'-binaphthoxymethyl]carbonyl-
}amino)-3-aza-9-guanidino-4-oxononanoate hydrochloride
(aR,S,7R,10S)-6,9-diaza-3,15-dioxa-5,8-dioxo-7-(4-guanidinobutyl)-10-meth-
oxycarbonyl-1(1,2),2(1,2)-dinaphthalenacyclopentadecaphane-12-ene
hydrochloride methyl
(aS/R,2S,5R)-2-allyl-10-(2'-allyloxy-1,1'-binaphth-2-oxy)-5-(4-aminobutyl-
)-3,6-diaza-4,7-dioxodecanoate hydrochloride methyl
(aS/R,2S,5R)-2-allyl-10-(2'-allyloxy-1,1'-binaphth-2-oxy)-3,6-diaza-5-(4--
guanidinobutyl)-4,7-dioxodecanoate hydrochloride
(aR/S,9R,12S)-8,11-diaza-9-(4-guanidinobutyl)-12-methoxycarbonyl-1(1,2),2-
(1,2)-dinaphthalena-3,17-dioxa-7,10-dioxoheptadecaphane-15-ene
hydrochloride
22. A composition comprising a compound of formula (I), salts or
pharmaceutically acceptable derivatives thereof according to claim
1 together with one or more pharmaceutically acceptable carriers or
adjuvants.
23. A method of treating a bacterial infection in a mammal
comprising administering an effective amount of a compound of
formula (I), salts or pharmaceutically acceptable derivatives
thereof according to claim 1.
24. A method according to claim 24 where the mammal is a human.
25. A method according to claim 24 wherein the bacterial infection
is caused by Gram positive bacteria.
26. A method according to claim 26 wherein the bacterial infection
is caused, by vancomycin resistant Staphylococcus aureas.
27. The use of a compound of formula (I) according to claim 1 in
the manufacture of a medicament for treating bacterial infections.
Description
[0001] This invention relates to novel peptoid compounds, methods
for preparing them and their use as antibiotics.
[0002] The death rate from infectious diseases in the developed
world has increased over the last decade. This has been due to a
number of factors, including increasing mobility of people from
developed countries to less developed countries, increasing age of
the general population, increasing numbers of transplant, cancer
and AIDS patients who have lowered immunities to bacterial
infections and the increasing numbers of bacterial species that
have become multiply resistant to antibacterial drugs..sup.1-3
[0003] The vancomycin group of antibiotics represent one of the
last lines of defence against methicillin-resistant Staphylococcus
aureus and other Gram-positive microorganisms..sup.4-6 These
antibiotics interfere with cell-wall biosynthesis by binding to the
D-Ala-D-Ala terminus of the disaccharyl pentapeptide of the
peptidoglycan of the bacterial cell wall, resulting in cell
death..sup.4-6 Recently vancomycin resistant bacteria have
appeared. These bacteria have been identified as having a
D-Ala-D-lactate terminus rather than a D-Ala-D-Ala terminus of the
peptidoglycan. Vancomycin has a much lower affinity (ca. 1000 fold
decrease in affinity) for the D-Ala-D-lactate terminus in
vancomycin resistant bacteria and consequently it is much less
effective as an antibiotic..sup.4-6
[0004] The binding sites of vancomycin to the D-Ala-D-Ala terminus
of bacterial cells have been well characterised. The D-O-E ring
moiety of the vancomycin molecule is critical for binding to the
D-Ala-D-Ala terminus of bacterial cells and the binding includes a
number of hydrogen bonding interactions..sup.4-6 The more complex
left-hand side of the vancomycin molecule has recently been shown
to be critical for conformational control of the peptide moiety
binding side..sup.7
[0005] Biphenomycin A and B.sup.8,9 have also been found to be
potent antibiotics and are particularly active against
Gram-positive bacteria. Biphenomycin A has also been found to have
low toxicity in mice..sup.8 The biphenomycins are structurally much
simpler than vancomycin, The biphenomycins have a biphenyl group
instead of a diphenyl ether as found in vancomycin, and have only
one cyclic polypeptide ring and no sugar moieties. The
biphenomycins also inhibit cell wall synthesis but, unlike
vancomycin, not through binding to the D-Ala-D-Ala terminus of the
disaccharyl pentapeptide of the peptidoglycan of the bacterial cell
wall..sup.9
[0006] There is a need for new compounds which are useful in the
treatment of bacterial infections, especially those caused by
vancomycin resistant microorganisms.
[0007] According to one aspect of the invention there is provided a
compound of the formula (I):
##STR00001## [0008] wherein [0009] A is an aromatic or
heteroaromatie ring system or partially or fully reduced
derivatives thereof; [0010] Q is hydrogen, C.sub.1-C.sub.12
straight chain, branched or cyclic alkyl substituted with one or
more hydroxy groups, or a mono- or di-saccharide moiety; [0011] Z
is --CR.sup.10R.sup.11, --NR.sup.12--, --C(O)O--, --C(O)NR.sup.12--
or --O--, where R.sup.10 and R.sup.11 are independently selected
from hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
aryl, C.sub.1-C.sub.6 alkoxy and --N(R.sup.13).sub.2 and where each
R.sup.13 is independently selected from hydrogen and
C.sub.1-C.sub.6 alkyl, and where R.sup.12 is selected from hydrogen
and C.sub.1-C.sub.6 alkyl; [0012] R.sup.1 is selected from
hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
--N(R.sup.13).sub.2 and --N(R.sup.12)--COR.sup.14; where R.sup.12
and R.sup.13 are as defined above, and where R.sup.14 is selected
from hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy and --NR.sup.12; [0013] R.sup.2 is independently selected
from hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, --N(R.sup.13).sub.2 and
--N(R.sup.12)--COCHR.sup.2aR.sup.2b; where R.sup.2a and R.sup.2b
are independently selected from hydrogen, hydroxy, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, --N(R.sup.13).sub.2 and
--N(R.sup.12)--COR.sup.14 where R.sup.12, R.sup.13 and R.sup.14 are
as defined above; [0014] R.sup.3, R.sup.4 and R.sup.5 are
independently selected from hydrogen, C.sub.1-C.sub.6 alkyl and a
side chains of .alpha.-amino acids or their enantiomers or their
derivatives; [0015] R.sup.6 is --CO.sub.2R.sup.15, --CONHR.sup.16,
--CONHOR.sup.16, --CONHNHR.sup.16, --SO.sub.2N(R.sup.16).sub.2,
--SO.sub.2R.sup.17 or --P(O)(OR.sup.18)(OR.sup.18) where each
R.sup.15, R.sup.16, R.sup.17 and R.sup.18 is independently selected
from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.6-C.sub.10 aryl and C.sub.7-C.sub.10 arylalkyl; [0016] B is
an .alpha.-amino acid residue, a .beta.-amino acid residue or an
.alpha.,.alpha.-disubstituted amino acid residue, such residue
forming amide linkages with the adjacent molecules; [0017] W is
--O-- or CR.sup.10R.sup.11 where R.sup.10 and R.sup.11 are as
defined above; [0018] Y is an optionally substituted amino group, a
moiety containing an optionally substituted amino group or a salt
thereof; [0019] is a single or double bond; [0020] R.sup.7 and
R.sup.8a are hydrogen or are absent if is a double bond; and [0021]
R.sup.8b and R.sup.9 are hydrogen, and X is selected from
(CR.sup.10R.sup.11).sub.u,
--(CR.sup.10R.sup.11).sub.u--CH.dbd.CH--,
--NR.sup.12(CR.sup.10R.sup.11).sub.u--,
--(CR.sup.10R.sup.11).sub.uNR.sup.12--,
--O(CR.sup.10R.sup.11).sub.u-- or --(CR.sup.10R.sup.11).sub.uO--,
where R.sup.10, R.sup.11 and R.sup.12 are as defined above; or
[0022] R.sup.8b and R.sup.9 together form a covalent bond between X
and the carbon to which R.sup.8b is attached, and X is selected
from (CR.sup.10R.sup.11).sub.x,
--NR.sup.12(CR.sup.10R.sup.11).sub.x--,
--(CR.sup.10R.sup.11).sub.xNR.sup.12--,
--O(CR.sup.10R.sup.11).sub.x--, --O(CR.sup.10R.sup.11)CH.dbd.CH--
or --(CR.sup.10R.sup.11).sub.xO--, where R.sup.10, R.sup.11 and
R.sup.12 are as defined above; [0023] n, m, r and t are
independently selected from 0 or 1; [0024] s is an integer selected
from 0 to 3; [0025] p is an integer selected from 0 to 6, provided
that when W is --O--, p is at least 1; and [0026] u, x and q are
independently selected from 0 to 4; [0027] and salts and
pharmaceutically acceptable derivatives thereof.
[0028] The term "aromatic or heteroaromatic ring system" as used
herein refers to a monoaryl, monoheteroaryl, or bridged, bonded or
fused di- or poly-aryl or heteroaryl group and their atropisomers
and to which X and Z may be attached at any ring position. Examples
of fused di- or poly-aryl or heteroaryl groups include naphthene,
fluorene, phenanthrene, indole, indazole, benzimidazole, carbazole,
quinoline and isoquinoline, dibenzazepine and dibenzazocine.
[0029] Examples of bridged or bonded di- or poly-aryl or heteroaryl
group include groups consisting of two or more aromatic carbocyclic
or heterocyclic systems, such as benzene, naphthene, pyridine,
pyrimidine, quinoline, isoquinoline, indole, indazole, and
benzimidazole, or the like, joined by a covalent bond, and/or
bridging group or groups, of one or more atoms such as --O--,
--CH.sub.2--, --NH--, --SO.sub.2--. Examples of bonded di- or
poly-aryl or heteroaryl systems include biphenyl, binaphthyl,
biquinolyl, bi-isoquinolyl, bi-indole, bi-benzimidazole,
phenyl-isoquinolyl, phenyl-quinolyl, phenyl-naphthyl,
phenyl-indole, phenyl-benzimidazole, phenyl-indazole,
phenyl-pyridine, phenyl-pyrimidine, naphthyl-pyridine,
naphthyl-pyrimidine, naphthyl-isoquinolyl, naphthyl-quinolyl,
naphthyl-indole, naphthyl-benzimidazole, naphthyl-indazole,
quinolyl-isoquinolyl, quinolyl-indole, quinolyl-indazole,
quinolyl-benzimidazole, indole-indazole, indole-benzimidazole,
indazole-benzimidazole and the like, and their atropisomers. The
two aryl or heteroaryl groups may be linked at any position.
[0030] The aromatic or heteroaromatic groups or partially or fully
reduced derivatives thereof may optionally be substituted with one
or more C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 thioalkoxy, hydroxy,
C.sub.1-C.sub.6 alkoxy, amino, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 dialkylamino, halo, nitro, nitrile,
sulphonylsulphonamide or alkyl- or aryl-sulphonyl, C.sub.1-C.sub.6
haloalkyl (for example trifluoromethyl) or carboxy groups.
Preferably, the aromatic or heteroaromatic groups or partially or
fully reduced derivatives are unsubstituted or have from one to
four substituents selected from methyl, hydroxy, methoxy, amino,
halo, or trifluoromethyl. Any nitrogen atoms in the heteroaromatic
groups may be protected by protecting groups such as
t-butoxycarbonyl (BOC), 2,2,5,7,8-pentamethylchroman-6-sulfonyl
(Pmc), benzyl, acetyl, carbobenzyloxy and the like (see "Protective
Groups in Organic Synthesis" Theodora Greene and Peter Wuts, third
edition, Wiley Interscience, 1999).
[0031] Preferred aromatic and heteroaromatic ring systems include
1,1'-binaphthyl, especially where the binaphthyl is substituted at
the 2 and 2' positions with substituents selected from
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, or arylalkyl,
indole, phenyl, and N-protected or unprotected carbazole.
Particularly preferred aromatic ring systems are 3,3'-linked
1,1'-binaphthyl, where substitution of X and Z are at the 3 and
3'-positions respectively ("3,3'-linked binaphthyl compounds")
particularly those which are 2,2'-C.sub.1-C.sub.3 alkoxy
substituted, 2,2'-linked 1,1'-binaphthyl where substitution of X
and Z are at the 2 and 2' positions ("2,2'-linked binaphthyl
compounds"), 3,6-linked 9H-carbazole ("3,6-linked 9H-carbazole
compounds"), 1,3-linked indole ("1,3-linked indole compounds") and
1,4-linked phenyl ("1,4-linked phenyl compounds")systems.
[0032] As used herein the term "atropisomer" refers to an
enantiomer of a compound that exhibits conformational axial
chirality.
[0033] As used herein the term "monosaccharide moiety" refers to a
simple sugar substituent derived from a monosaccharide or a
derivative thereof. The monosaccharide may be a naturally occurring
monosaccharide moiety, or may be a substituted, protected or
otherwise derivatised analogue of a naturally occurring
monosaccharide. The monosaccharide may be mono, di- or
triphosphated, and may be in its fully oxygenated form, or a deoxy
form. Examples of monosaccharides from which the monosaccharide
moiety may be derived include, but are not limited to abequose,
iduronic acid, allose, lyxose, altrose, mannose, apiose, muramic
acid, arabinose, neuraminic acid, arabinitol, N-acetylneuraminic
acid, 2-deoxyribose, N-acetyl-2-deoxyneur-2-enaminic acid,
fructose, N-glycoloylneuraminic acid, fucose,
3-deoxy-D-manno-oct-2-ulosonic acid, fucitol, rhamnose, galactose,
3,4-di-O-methylrhamnose, galactosamine, psicose,
N-acetylgalactosamine, quinovose, .beta.-D-galactopyranose
4-sulfate, ribose, glucose, ribose 5-phosphate, glucosamine,
ribulose, 2,3-diamino-2,3-dideoxy-D-glucose, sorbose, glucitol,
tagatose, N-acetylglucosamine, talose, glucuronic acid, xylose,
ethyl glucopyranuronate, xylulose, gulose, 2-C-methylxylose, and
idose.
[0034] As used herein the term "disaccharide moiety" refers to a
sugar substituent composed of two glycosidically linked
monosaccharides, or derivatives thereof. Examples of suitable
disaccharide moieties include, but are not limited to, sucrose,
lactose and maltose.
[0035] As used herein the term "optionally substituted amino group"
refers to an unsubstituted amino group (NH.sub.2) or an amino group
substituted on the nitrogen atom with up to two substituents and
salts thereof. The term "moiety containing an optionally
substituted amino group" refers to groups that contain an amino
group (NH.sub.2) or an amino group substituted on the nitrogen atom
with up to two substituents. Examples of optional substituents
include C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.6-C.sub.10 aryl and suitable nitrogen protecting groups (see
"Protective Groups in Organic Synthesis" Theodora Greene and Peter
Wuts, third edition, Wiley Interscience, 1999). Preferably, the
amino group is capable of carrying a positive charge at biological
pH. In a preferred form of the invention, Y is selected from a
group consisting of: --N(R.sup.13).sub.2,
--N(R.sup.12)--COR.sup.14,
--NR.sup.13C(.dbd.NR.sup.13)N(R.sup.13).sub.2,
--C(.dbd.NR.sup.13)N(R.sup.13).sub.2,
--NR.sup.13C(.dbd.O)N(R.sup.13).sub.2,
--N.dbd.NC(.dbd.NR.sup.13)N(R.sup.13).sub.2,
NR.sup.13NR.sup.13C(.dbd.O)NHN(R.sup.13).sub.2,
--NR.sup.13C(.dbd.)NHN(R.sup.13).sub.2, wherein R.sup.12 and each
R.sup.13 is independently selected from hydrogen and
C.sub.1-C.sub.6 alkyl and R.sup.14 is selected from hydrogen,
hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and
NR.sup.12; and 3-8-membered N-containing cyclogroup such as
piperidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl or
piperazinyl, wherein the 3-8-membered N-containing cyclogroup can
be attached via a nitrogen or carbon atom. Preferred Y groups
include optionally substituted guanidino [--NHC(.dbd.NH)NH.sub.2],
amidino [--C(.dbd.NH)NH.sub.2], ureido [--NHC(.dbd.O)NH.sub.2],
carbazono [--N.dbd.NC(.dbd.)NHNH.sub.2], carbazido
[--NHNHC(.dbd.O)NHNH.sub.2] and semicarbazido
[--NHC(.dbd.O)NHNH.sub.2] and amino (NH.sub.2).
[0036] As used herein the term "C.sub.1-C.sub.6 alkyl" refers to
straight chain or branched alkyl groups having from 1 to 6 carbon
atoms. Examples of such groups include methyl, ethyl, n-propyl,
isopropyl and n-butyl.
[0037] As used herein the term "C.sub.3-C.sub.7 cycloalkyl" refers
to cyclic alkyl groups having from 3 to 7 carbon atoms. Examples of
such groups include cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl.
[0038] As used herein the term "C.sub.6-C.sub.10 aryl" refers to
carbocyclic aromatic systems having from 6 to 10 carbon atoms.
Examples of such groups include phenyl and naphthyl.
[0039] As used herein the term "C.sub.7-C.sub.10 arylalkyl" refers
to carbocyclic aromatic systems having 6 carbon atoms bonded to a
C.sub.1-C.sub.4 alkyl group. An example of an arylalkyl group is a
benzyl group.
[0040] As used herein the term "C.sub.1-C.sub.6 alkoxy" refers to
straight chain or branched alkoxy groups having from 1 to 6 carbon
atoms. Examples of such groups include methoxy, ethoxy, n-propoxy,
isopropoxy and different butoxy isomers.
[0041] The term .alpha. side chain of an .alpha.-amino acid
includes the .alpha.-R group of a naturally occurring .alpha.-amino
acid and may be selected from --CH.sub.3,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, --CH.sub.2CONH.sub.2,
--CH.sub.2CO.sub.2H, --CH.sub.2SH, --(CH.sub.2).sub.2CONH.sub.2,
--(CH.sub.2).sub.2CO.sub.2H, --CH.sub.2(4-imidazole),
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--(CH.sub.2).sub.3NH.sub.2, --(CH.sub.2).sub.4NH.sub.2,
--(CH.sub.2).sub.2SCH.sub.3, --CH.sub.2Ph, --CH.sub.2OH,
--CH(CH.sub.3)OH, --CH.sub.2(3-indolyl),
--CH.sub.2(4-hydroxyphenyl) and --CH(CH.sub.3).sub.2. This term
also includes the includes .alpha.-R groups of non-naturally
occurring .alpha.-amino acid such as those found in homoarginine,
homoserine, homocysteine, norvaline, norleucine or amidino
derivatives. For example such .alpha.-side chains include
--(CH.sub.2).sub.4NHC(.dbd.NH)NH.sub.2, --(CH.sub.2).sub.2OH,
--(CH.sub.2).sub.2SH, --CH.sub.2CH.sub.2CH.sub.3,
--(CH.sub.2).sub.3CH.sub.3, or (CH.sub.2).sub.vC(.dbd.NH)NH.sub.2
where v is an integer from 1 to 4. Other derivatives may include
.alpha.-side chains in which hydroxy, thiol or amino groups are
protected with suitable hydroxy, thiol or amino protecting groups
(see "Protective Groups in Organic Synthesis" Theodora Greene and
Peter Wuts, third edition, Wiley Interscience, 1999).
[0042] B is an .alpha.-amino acid residue, a .beta.-amino acid
residue or an .alpha.,.alpha.-disubstituted amino acid residue.
Suitable .alpha.-amino acids include those derived from naturally
occurring .alpha.-amino acids and non-naturally occurring
.alpha.-amino acids. Examples of suitable .alpha.-amino acids
include D- and L-.alpha.-amino acid residues derived from alanine,
arginine, homoarginine, asparagine, aspartic acid, cysteine,
homocysteine, glutamine, glutamic acid, glycine, histidine,
isoleucine, leucine, norleucine, lysine, methionine, phenylalanine,
serine, homoserine, threonine, tryptophan, tyrosine, proline,
valine and norvaline. Other suitable .alpha.-amino acid residues
may have a side chain containing an amidino group, for example,
(CH.sub.2).sub.vC(.dbd.NH)NH.sub.2 where v is an integer from 1 to
4. D-or L-alanyl, D-lysinyl, D-arginyl and D-homoarginyl residues
are particularly preferred. Suitable .beta.-amino acids include
H.sub.2NC(R.sup.1)R.sup.2C(R.sup.3)R.sup.4CO.sub.2H where R.sup.1,
R.sup.2, R.sup.3, R.sup.4 can be H and any of the substituents
described above for the .alpha.-amino acids, and all possible
stereoisomers. Suitable .alpha.,.alpha.-disubstituted amino acids
include any of the above .alpha.-amino acids having a further
substituent in the .alpha.-position. Suitable substituents include
C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6 alkoxy, amino,
C.sub.1-C.sub.6 alkyl amino, C.sub.1-C.sub.6 dialkylamino,
(CH.sub.2).sub.vNH.sub.2, (CH.sub.2).sub.vNHC.sub.1--C.sub.6 alkyl,
(CH.sub.2).sub.vN(C.sub.1-C.sub.6alkyl).sub.2,
(CH.sub.2).sub.vNHC(.dbd.NH)NH.sub.2, (CH.sub.2).sub.vOH,
(CH.sub.2).sub.vOC.sub.1--C.sub.6alkyl.
[0043] Preferred compounds of the present invention include:
[0044] benzyl
(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3'-allyl-2,2'-dimethoxy-1,1'-binap-
hthyl]}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononan-
oate
[0045]
(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarb-
onyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-1-
2-ene hydrochloride
[0046]
(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarb-
onyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane
hydrochloride
[0047]
(aR/S,7R,10S)-4-acetamido-6,9-diaza-10-benzyloxycarbonyl-7-(4-{[(te-
rt-butoxy)carbonyl]amino}butyl)-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-
-dioxocyclotetradecaphane-12-ene
[0048] methyl
(aR/S,2S,5R)-8-acetamido-2-allyl-9-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binap-
hthyl)]-3,6-diaza-5-(3-guanidinopropyl)-4,7-dioxononanoate
hydrochloride
[0049]
(aR/S,7S,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methox-
ycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaph-
ane-12-ene hydrochloride
[0050]
(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methox-
ycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaph-
ane-12-ene hydrochloride
[0051]
(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methox-
ycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaph-
ane hydrochloride
[0052] Methyl
(2S,5S,8R/S)-8-acetamido-2-allyl-9-[6-allyl-9-tert-butoxycarbonyl-9H-carb-
azol-3-yl]-3,6-diaza-5-{3-[(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-guani-
dino]propyl}-4,7-dioxononanoate
[0053]
6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,1-
0-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S)
[0054]
6-Acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbo-
nyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S)
[0055]
6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,1-
0-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S)
[0056]
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-en-
e-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl
(9S,12S)
[0057]
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dio-
xo-[12](3,6)-1H-carbazolophane HCl (9S,12S)
[0058] Methyl
(2S,5S,8R/S)-8-Acetamido-5-(4-aminobutyl)-3,6-diaza-9-{9-[(4-methoxypheny-
l)methyl]-6-propyl-9H-carbazol-3-yl}-4,7-dioxo-2-propylnonanoate
hydrochloride
[0059]
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dio-
xo-[12](3,6)-1H-carbazolophane HCl (9R,12S)
[0060] methyl
(aR/S,2S,5R)-2-allyl-5-[2-({[(2'-allyloxy-1,1'-binaphthoxymethyl]carbonyl-
}amino)-3-aza-9-guanidino-4-oxononanoate hydrochloride
[0061]
(aR,S,7R,10S)-6,9-diaza-3,15-dioxa-5,8-dioxo-7-(4-guanidinobutyl)-1-
0-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalenacyclopentadecaphane-12-ene
hydrochloride
[0062] methyl
(aS/R,2S,5R)-2-allyl-10-(2'-allyloxy-1,1'-binaphth-2-oxy)-5-(4-aminobutyl-
)-3,6-diaza-4,7-dioxodecanoate hydrochloride
[0063] methyl
(aS/R,2S,5R)-2-allyl-10-(2'-allyloxy-1,1'-binaphth-2-oxy)-3,6-diaza-5-(4--
guanidinobutyl)-4,7-dioxodecanoate hydrochloride
[0064]
(aR/S,9R,12S)-8,11-diaza-9-(4-guanidinobutyl)-12-methoxycarbonyl-1(-
1,2),2(1,2)-dinaphthalena-3,17-dioxa-7,10-dioxoheptadecaphane-15-ene
hydrochloride
[0065] It will be appreciated that the compounds of the present
invention have more than one asymmetric centre, and therefore are
capable of existing in more than one stereoisomeric form. Some of
the compounds may also exist as geometric isomers. Furthermore,
some compounds of the invention may also have conformational axial
chirality resulting in atropisomers. The invention extends to each
of these forms individually and to mixtures thereof, including
racemates. The isomers may be separated conventionally by
chromatographic methods or using a resolving agent. Alternatively
the individual isomers may be prepared by asymmetric synthesis
using chiral intermediates, reagents or catalysts.
[0066] The salts of the compound of formula (I) are preferably
pharmaceutically acceptable, but it will be appreciated that
non-pharmaceutically acceptable salts also fall within the scope of
the present invention, since these are useful as intermediates in
the preparation of pharmaceutically acceptable salts. The
pharmaceutically acceptable salts may include conventional
non-toxic salts or quaternary ammonium salts of these compounds,
which may be formed, e.g. from organic or inorganic acids or bases.
Examples of such acid addition salts include, but are not limited
to, those formed with pharmaceutically acceptable acids such as
acetic, propionic, citric, lactic, methanesulphonic,
toluenesulphonic, benzenesulphonic, salicyclic, ascorbic,
hydrochloric, orthophosphoric, sulphuric and hydrobromic acids.
Base salts includes, but is not limited to, those formed with
pharmaceutically acceptable cations, such as sodium, potassium,
lithium, calcium magnesium, ammonium and alkylammonium. Also, basic
nitrogen-containing groups may be quaternised with such agents as
lower alkyl halides, such as methyl, ethyl, propyl, and butyl
chlorides, bromides and iodides; dialkyl sulfates like dimethyl and
diethyl sulfate; and others.
[0067] Pharmaceutically acceptable derivatives may include any
pharmaceutically acceptable salt, hydrate, prodrug, or any other
compound which, upon administration to a subject, is capable of
providing (directly or indirectly) a compound of formula (I) or an
antibacterially active metabolite or residue thereof. For example,
compounds where a hydroxy group on the Q moiety has been replaced
with a phosphate ester are within the scope of pharmaceutically
acceptable derivatives.
[0068] The term "prodrug" is used in its broadest sense and
encompasses those derivatives that are converted in vivo to the
compounds of the invention. Such derivatives would readily occur to
those skilled in the art, and include N-.alpha.-acyloxy amides,
N-(acyloxyalkoxy carbonyl) amine derivatives and
.alpha.-acyloxyalkyl esters of phenols and alcohols. A pro drug may
include modifications to one or more of the functional groups of a
compound of the invention.
[0069] Throughout this specification the phrase "a group which is
capable of being converted in vivo" used in relation to another
functional group includes all those functional groups or
derivatives of such groups which upon administration into a mammal
may be converted into the stated functional group. Those skilled in
the art may readily determine whether a group may be capable of
being converted in vivo into the stated functional group using
routine enzymatic or animal studies.
[0070] Preferred compounds of the invention have the formula
(IA):
##STR00002##
[0071] wherein A, Q, Z, R.sup.2a, R.sup.2b, R.sup.3, B, W, Y,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8a, R.sup.8b, R.sup.9, X,
r, s, n, m, p q and t are as defined above.
[0072] Preferably one or more of the following definitions apply to
preferred compounds: [0073] Q is hydrogen; [0074] A is 2,2'-linked
1,1'-binaphthyl, 3,3'-linked 2,2'-dimethoxy-1,1.sup.1-binaphthyl,
phenyl preferably 1,4-linked, indolyl preferably 1,3-linked,
fluorenyl or 9H-carbazole preferably 3,6-linked; [0075] Z is --O--
or --CR.sup.10R.sup.11--, more preferably --O-- or --CH.sub.2--;
[0076] R.sup.1 is hydrogen or hydroxy; [0077] R.sub.2 is hydrogen,
hydroxy or NHC(.dbd.O)CHR.sup.2aR.sup.2b, preferably hydrogen or
NHC(.dbd.O)CH.sub.3; [0078] R.sub.3 is hydrogen; [0079] B is absent
or a D- or L-alanyl residue, a D- or L-lysinyl, a D- or L-arginyl
residue or a D- or L-homoarginyl residue; [0080] W is absent or is
CH.sub.2; [0081] Y is NH.sub.2, NHC(.dbd.NH)NH.sub.2 or salts
thereof; [0082] R.sub.4 is hydrogen; [0083] R.sub.5 is hydrogen;
[0084] R.sup.6 is --CO.sub.2R.sup.15, where R.sup.15 is
C.sub.1-C.sub.6 alkyl or C.sub.7-C.sub.10 arylalkyl, most
preferably R.sup.15 is methyl or benzyl; [0085] R.sup.8b and
R.sup.9 are hydrogen and X is --(CR.sup.10R.sup.11).sub.u--,
--CH.dbd.CH-- --O(CR.sup.10R.sup.11)CH.dbd.CH--, or
--CR.sup.10R.sup.11--CH.dbd.CH-- where R.sup.10 and R.sup.11 are
hydrogen and u is an integer selected from 2 or 3; [0086] R.sup.8b
and R.sup.9 together form a covalent bond between X and the carbon
to which R.sup.8b is attached and X is --CR.sup.10R.sup.11--, where
R.sup.10 and R.sup.11 are hydrogen.
[0087] Particularly preferred compounds in which A is a carbazole
moiety are:
[0088]
6-acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,1-
0-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S),
[0089] methyl
8-acetamido-3,6-diaza-5-[3-guanidinopropyl]-4,7-dioxo-2-propyl-9-[3-(6-pr-
opyl)-9H-carbazole]nonanoate HCl (2S,5R),
[0090]
6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbo-
nyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S),
[0091] methyl
8-acetamido-5-[4-aminobutyl]-3,6-diaza-4,7-dioxo-2-propyl-9-[3-(6-propyl)-
-9H-carbazole]nonanoate HCl (2S,5R),
[0092]
6-acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dio-
xo-[12](3,6)-1H-carbazolophane HCl (9S,12S),
[0093]
6-acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,1-
0-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S),
[0094]
6-acetamido-9-(4-aminobutyl)-8,11-diaza-14-ene-12-methoxycarbonyl-7-
,10-dioxo-[12](4,17)-1H-carbazolophane HCl (9R,12S),
[0095]
6-acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dio-
xo-[12](3,6)-1H-carbazolophane HCl (9R,12S),
[0096]
6-acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-en-
e-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl
(9S,12S),
[0097]
6-acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-12-me-
thoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl
(9S,12S),
[0098]
6-acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-1-(4-met-
hoxyphenylmethylene)-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl
(9S,12S),
[0099]
6-acetamido-9-(4-aminobutyl)-8,11-diaza-4-ene-12-methoxycarbonyl-1--
(4-methoxyphenylmethylene)-7,10-dioxo-[12](3,6)-1H-carbazolophane
HCl (9S,125),
[0100]
6-acetamido-9-(4-aminobutyl)-8,11-diaza-14-ene-12-methoxycarbonyl-7-
,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S),
[0101]
6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbo-
nyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S),
[0102] methyl
8-acetamido-5-[4-aminobutyl]-3,6-diaza-9-[3-(9-methoxyphenylmethylene)-6--
propyl-9H-carbazole]-4,7-dioxo-2-propylnonanoate HCl (2S,5S)
[0103] Particularly preferred compounds in which A is a
2,2'-disubstituted binaphthyl moiety are the compounds prepared in
Examples 15 and 21.
[0104] Compounds of formula (I) as described above, may be prepared
by reacting a compound of formula (II)
##STR00003##
[0105] wherein L is OH or an activating group; with a compound of
formula (III)
##STR00004##
[0106] wherein B is either H or an amino acid having a free amino
group; under appropriate conditions. Unless otherwise defined, A,
Q, X, Z, B, W, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8a, R.sup.8b, R.sup.9, n, m, p, q, r, s and
t in formulae (II) and (III) are as defined in formula (I).
[0107] The compound of formula (I) prepared by the coupling of
compounds of formulae (II) and (III) may be further transformed
using conventional approaches to provide other compounds of formula
(I).
[0108] Conveniently, the reaction between compounds of formulae
(II) and (III) is based on forming an amide bond and may be
conducted using approaches routinely used in peptide synthesis. For
example, the coupling reaction of an amine with a carboxylic acid
(L=OH) or an activated carbonyl carbon such as an acyl chloride,
acyl azide or an anhydride (L=Cl, N.sub.3, OC(O)R).
[0109] Compounds of formula (II) may be conveniently prepared from
an aromatic or heteroaromatic ring system carrying any of: [0110]
(a) desired substituents; or [0111] (b) functional groups which may
be converted into desired substituents using conventional
approaches known to those skilled in the art; or [0112] (c)
appropriately activated positions on the nucleus of the ring system
such that desired substituents may be placed on the ring system
using conventional approaches known to those skilled in the
art.
[0113] In addition the ring system includes a position that may be
converted into the group --(X).sub.tR.sup.9, and a position where
the side chain to be reacted with (III) may be formed. These
positions may be functional groups or may be appropriately
activated positions on the ring system such as to allow conversion
into functional groups using conventional approaches known to those
skilled in the art. For example, functional groups include halogen,
hydroxyl, amino, alkoxycarbonyl, and alkenyl. Examples of suitably
activated positions include those which may be halogenated,
hydroxylated, oxidised to a carbonyl group, alkylated or
acylated.
[0114] Suitable aromatic or heteroaromatic ring systems may be
commercially available or be readily prepared from commercially
available ring systems or ring system precursors.
[0115] The side chain to be reacted with a compound of formula
(III) may be formed using any suitable approach readily
ascertainable to those skilled in the art. Conveniently, a
haloalkyl group on the ring system may be alkylated to form the
side chain, in some cases after further modification. The side
chain includes appropriate functionality to allow for the reaction
between compounds of formulae (II) and (III). Preferably, this is
based on forming an amide bond and may be conducted using
approaches routinely used in peptide synthesis, for example, the
reaction of an amine with an appropriately activated carbonyl
carbon. Those skilled in the art can readily determine appropriate
methodology to build the desired side chain.
[0116] Where appropriate, protecting groups may be used to mask
certain positions on the compound of formula (II) so as to avoid or
limit unwanted side reactions.
[0117] Compounds of formula (III) may be prepared using approaches
familiar to those skilled in the art of peptide chemistry or simple
modifications of those approaches. Those skilled in the art can
readily determine appropriate methodology to build the desired
compound of formula (III).
[0118] Where appropriate protecting groups may be used to mask
certain positions on the compound of formula (III) so as to avoid
or limit unwanted side reactions.
[0119] Preferably, the compound of formula (III) includes a free
amino group and the compound of formula (II) includes a free
carboxylic acid or an activated carbonyl carbon that may be reacted
under appropriate conditions to form an amide bond.
[0120] Compounds of formula (I) where R.sup.8b and R.sup.9 together
form a covalent bond between X and the carbon to which R.sup.8b is
attached are conveniently formed by cyclisation of the
corresponding non-cyclised compound. Cyclisation may be achieved
using any ring closing reaction known to those skilled in the art.
For example, where the bond between CHR.sup.7 and
CHR.sup.8aR.sup.8b is a double bond, and --(X).sub.tR.sup.9
includes an alkenyl bond then ring closure may conveniently be
performed using a ring closing metathesis reaction. The resulting
cyclised alkene may be readily reduced to an alkyl bond using
conventional approaches.
[0121] Examples of these general approaches are described in more
detail in the experimental section.
[0122] The compounds of the present invention may be useful in the
treatment of bacterial infections in mammals, particularly humans.
They are particularly useful for treating infections caused by Gram
positive bacteria. In particular, the compounds of the invention
are useful for treating infections caused by Gram positive bacteria
such as Enterococcus faecium, Staphylococcus aureus, Staphylococcus
epidermis, Klebsiella pneumoniae, Streptococcus pneumoniae,
including multiresistant strains such as vancomycin resistant
Staphylococcus aureus and methicillin-resistant Staphylococcus
aureus.
[0123] Accordingly in a further aspect the invention provides a
method for the treatment of bacterial infection in a mammal
comprising the step of administering an effective amount of a
compound (I).
[0124] The invention also provides the use of a compound of formula
(I) in the manufacture of a medicament for the treatment or
prophylaxis of bacterial infections.
[0125] The compounds of the invention are administered to the
mammal in a treatment effective amount. As used herein, a treatment
effective amount is intended to include at least partially
attaining the desired effect, or delaying the onset of, or
inhibiting the progression of, or halting or reversing altogether
the onset or progression of the bacterial infection.
[0126] As used herein, the term "treatment effective amount"
relates to an amount of compound which, when administered according
to a desired dosing regimen, provides the desired therapeutic
activity. Dosing may occur at intervals of minutes, hours, days,
weeks, months or years, or continuously over any one of these
periods. Suitable dosages lie within the range of about 0.1 ng per
kg of body weight to 1 g per kg of body weight per dosage. The
dosage is preferably in the range of 1 ng to 1 g per kg of body
weight per dosage, such as is in the range of 1 mg to 1 g per kg of
body weight per dosage. Suitably, the dosage is in the range of 1
mg to 500 mg per kg of body weight per dosage, such as 1 mg to 200
mg per kg of body weight per dosage, or 1 mg to 100 mg per kg of
body weight per dosage. Other suitable dosages may be in the range
of 1 mg to 250 mg per kg of body weight, including 1 mg to 10, 20,
50 or 100 mg per kg of body weight per dosage or 10 mg to 100 mg
per kg of body weight per dosage. The compounds of the invention
may be administered in a single dose or a series of doses.
[0127] Suitable dosage amounts and dosing regimens can be
determined by the attending physician and may depend on the
particular condition being treated, the severity of the condition,
as well as the general health, age and weight of the subject being
treated.
[0128] While it is possible that, for use in therapy, a compound of
the invention may be administered as the neat chemical, it is
preferable to present the active ingredient as a pharmaceutical
formulation.
[0129] The invention thus further provides pharmaceutical
formulations comprising a compound of the invention or a
pharmaceutically acceptable salt or derivative thereof together
with one or more pharmaceutically acceptable carriers thereof and,
optionally, other therapeutic and/or prophylactic ingredients. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and not deleterious
to the recipient thereof.
[0130] Pharmaceutical formulations include those suitable for oral,
rectal, nasal, topical (including buccal and sub-lingual), vaginal
or parenteral (including intramuscular, sub-cutaneous and
intravenous) administration or in a form suitable for
administration by inhalation or insufflation. The compounds of the
invention, together with a conventional adjuvant, carrier, or
diluent, may thus be placed into the form of pharmaceutical
compositions and unit dosages thereof, and in such form may be
employed as solids, such as tablets or filled capsules, or liquids
such as solutions, suspensions, emulsions, elixirs, or capsules
filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile
injectable solutions for parenteral (including subcutaneous) use.
Such pharmaceutical compositions and unit dosage forms thereof may
comprise conventional ingredients in conventional proportions, with
or without additional active compounds or principles, and such unit
dosage forms may contain any suitable effective amount of the
active ingredient commensurate with the intended daily dosage range
to be employed. Formulations containing ten (10) milligrams of
active ingredient or, more broadly, 0.1 to two hundred (200)
milligrams, per tablet, are accordingly suitable representative
unit dosage forms. The compounds of the present invention can be
administered in a wide variety of oral and parenteral dosage forms.
It will be obvious to those skilled in the art that the following
dosage forms may comprise, as the active component, either a
compound of the invention or a pharmaceutically acceptable salt or
derivative of the compound of the invention.
[0131] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavouring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0132] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[0133] In tablets, the active component is mixed with the carrier
having the necessary binding capacity in suitable proportions and
compacted in the shape and size desired.
[0134] The powders and tablets preferably contain from five or ten
to about seventy percent of the active compound. Suitable carriers
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter, and
the like. The term preparation" is intended to include the
formulation of the active compound with encapsulating material as
carrier providing a capsule in which the active component, with or
without carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid forms suitable for oral administration.
[0135] For preparing suppositories, a low melting wax, such as
admixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0136] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[0137] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water-propylene glycol solutions.
For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol
solution.
[0138] The compounds according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for
example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added
preservative. The compositions may take such forms as suspensions,
solutions, or emulsions in oily or aqueous vehicles, and may
contain formulatory agents such as suspending, stabilising and/or
dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilisation from solution, for constitution with a suitable
vehicle, e.g. sterile, pyrogen-free water, before use.
[0139] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavours, stabilizing and thickening agents, as
desired.
[0140] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well known
suspending agents.
[0141] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavours, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0142] For topical administration to the epidermis the compounds
according to the invention may be formulated as ointments, creams
or lotions, or as a transdermal patch. Ointments and creams may,
for example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
contain one or more emulsifying agents, stabilising agents,
dispersing agents, suspending agents, thickening agents, or
colouring agents.
[0143] Formulations suitable for topical administration in the
mouth include lozenges comprising active agent in a flavoured base,
usually sucrose and acacia or tragacanth; pastilles comprising the
active ingredient in an inert base such as gelatin and glycerin or
sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier.
[0144] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The formulations may be provided in single or multidose
form. In the latter case of a dropper or pipette, this may be
achieved by the patient administering an appropriate, predetermined
volume of the solution or suspension. In the case of a spray, this
may be achieved for example by means of a metering atomising spray
pump. To improve nasal delivery and retention the compounds
according to the invention may be encapsulated with cyclodextrins,
or formulated with their agents expected to enhance delivery and
retention in the nasal mucosa.
[0145] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurised pack with a suitable propellant such
as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, carbon
dioxide, or other suitable gas. The aerosol may conveniently also
contain a surfactant such as lecithin. The dose of drug may be
controlled by provision of a metered valve.
[0146] Alternatively the active ingredients may be provided in the
form of a dry powder, for example a powder mix of the compound in a
suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP).
[0147] Conveniently the powder carrier will form a gel in the nasal
cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of, e.g., gelatin, or blister
packs from which the powder may be administered by means of an
inhaler.
[0148] In formulations intended for administration to the
respiratory tract, including intranasal formulations, the compound
will generally have a small particle size for example of the order
of 1 to 10 microns or less. Such a particle size may be obtained by
means known in the art, for example by micronization.
[0149] When desired, formulations adapted to give sustained release
of the active ingredient may be employed.
[0150] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0151] Liquids or powders for intranasal administration, tablets or
capsules for oral administration and liquids for intravenous
administration are preferred compositions.
[0152] The invention will now be described with reference to the
following examples which illustrate some preferred aspects of the
present invention. However, it is to be understood that the
particularity of the following description of the invention is not
to supersede the generality of the preceding description of the
invention.
[0153] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integers or steps.
EXAMPLES
[0154] General Experimental Information
[0155] Melting point (mp) determinations were carried out on a
Gallenkamp or Reichert melting point apparatus. Chemical ionisation
(CI) and electron impact (EI) mass spectra were obtained on a
Shimadzu QP-5000 mass spectrometer by a direct insertion technique
with an electron beam energy of 70 eV. Electrospray (ES) mass
spectra were obtained on a VG Quattro spectrometer. High-resolution
mass spectra (FIRMS) were determined on a VG Autospec spectrometer
or on a micromass QT.degree. F. spectrometer. The m/z values are
stated with their peak intensity as a percentage in parentheses.
Proton and carbon nuclear magnetic resonance (NMR) spectra were
determined with a Varian Unity 300 MHz spectrometer or with a
Varian Unity 400 MHz spectrometer where specified. Spectra were
recorded in (D)chloroform (CDCl.sub.3) using chloroform or TMS as
the internal standard, unless specified otherwise. Chemical shifts
(.delta.) in ppm were measured relative to the internal standard.
Where samples exhibited several isomers, the chemical shifts for
the major form are given since the major and minor isomers could
not be separated, and overlapping peaks made it difficult to
specify all the chemical shifts for the minor isomer(s). Analytical
thin layer chromatography (TLC) was carried out on Merck Kieselgel
60 F.sub.254 precoated aluminium plates with a thickness of 0.25
mm. All column chromatography was performed under flash conditions
on Merck Kieselgel 60 (230-400 mesh). Chromatography solvent
mixtures were measured by volume. Organic solvent extracts were
dried with anhydrous magnesium sulfate, and the solvent removed
under reduced pressure with a Buchi rotary evaporator. Solvents
were purified and dried by standard techniques. All compounds were
judged to be of greater than 90% purity based upon .sup.1H NMR and
TLC analysis. Starting materials and reagents were purchased from
Sigma-Aldrich Pty Ltd and were used as received. Petroleum spirit
refers to the 40-60.degree. C. by range material. The Grubbs'
ruthenium catalyst used was specifically
benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium.
Abbreviations
[0156] Ac acetyl
[0157] Boc tert-butyloxycarbonyl
[0158] DCM dichloromethane
[0159] DMF N,N-dimethylformamide
[0160] DMSO dimethyl sulfoxide
[0161] HCl hydrochloric acid
[0162] EtOAc ethyl acetate
[0163] MeOH methanol
[0164] Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl
[0165] PS petroleum spirit
[0166] TFA trifluoracetic acid
[0167] THF tetrahydrofuran
[0168] DMAP 4-dimethylaminopyridine
[0169] DCC 1,3-dicyclohexylcarbodiimide
[0170] HMPA hexamethylphosphoramide
[0171] TMEDA N,N,N',N'-tetramethylethylenediamine
[0172] Fmoc 9-fluorenylmethoxycarbonyl
Example Synthesis of Peptides
Example 1
Protection of the Carboxylic Acid of L-allylglycine
[0173] L-Allylglycine (0.600 g) was dissolved in dry methanol (7
mL) and cooled in an ice bath. Thionyl chloride (2 equivalents) was
added dropwise and the reaction warmed to room temperature and left
to stir for 3 hours at room temperature after which the solvent was
removed by rotary evaporation. The residue was redissolved in
methanol and re-evaporated several times to give a 90% yield of a
white low melting point solid.
[0174] MS ES 130 [RNH.sup.3].sup.+. .sup.1H NMR 400 MHz
(CDCl.sub.3) .delta.8.58, 3H, br s, NH.sub.3; 5.8, 1H, br s, H2;
5.32, 1H,d, J=15.6 Hz, H1; 5.26, 1H, d, J=6.8 Hz, H1'; 4.20, 1H, m,
H4; 3.80, 3H, s, OCH.sub.3; 2.88, 2H, m, H3,H3'. .sup.13C NMR 75
MHz .delta.169.2, CO.sub.2CH.sub.3; 130.1, C2; 121.5, C1; 53.3,
OCH.sub.3; 53.0, C4; 34.5, C3.
Example 2
Preparation of N.alpha.-Fmoc-N.epsilon.-Boc-D-Lysine-L-Allylglycine
Methyl Ester
##STR00005##
[0176] L-Allylglycine methyl ester HCl (0.706 g) was suspended in
dry dichloromethane (10 mL) and Fmoc-D-Lysine(Boc) OH (1 equiv.)
was added under N.sub.2 with stirring, followed by DMAP (0.1 equiv)
and diisopropylethyl amine (1.0 equiv). The mixture was cooled to
0.degree. C. and DCC (1.0 equiv) added. The reaction was left to
stir at ambient temperature over night. The suspension was filtered
through celite and the solids washed with cold DCM, the filtrate
and washings combined and washed twice with water then the solvent
was removed by rotary evaporation. The residue was then
chromatographed in 2% CH.sub.3OH/DCM to give 76% yield of a pale
cream flaky solid.
[0177] HRMS Calc. mass 580.3023, Found 580.3018 [M+H],
C.sub.32H.sub.42N.sub.3O.sub.7. .sup.1H NMR (CDCl.sub.3)
.delta.7.76, 2H, d, J=7.5 Hz, H17,17'; 7.59, 2H, d, J=6.9 Hz,
H20,20'; 7.40, 2H, t, J=7.2 Hz, H19,19'; 7.31, 2H, ddd, J=9.0, 7.2,
1.2 Hz, H18,18'; 6.7, 1H, br.d, J=6.6 Hz, NH; 5.63, 2H, br. m, NH,
H2; 5.10, 1H, d, J=5.4 Hz, H1; 5.05, 1H, s, H1'; 4.65, 2H, H4, NH;
4.38, 2H, d, J=6.6 Hz, H14, H14'; 4.21, 2H, H15, H8; 3.71, 3H, s,
OCH.sub.3; 3.11, 2H, d, J=6.0 Hz, H12,H12'; 2.52, 2H, m, H3,H3';
1.85, 2H, m; 1.68, 2H, m; 1.48-1.25, 2H, m; 1.43, 9H, s, t-Bu.
Example 3
Deprotection of the .alpha. Amino Group of
N.alpha.-Fmoc-N.epsilon.-Boc-D-Lysine-L-Allylglycine Methyl
Ester
##STR00006##
[0179] Fmoc-D-Lys(Boc)-L-Allylgly-methyl ester (0.631 g) was
dissolved in 10 mL dry acetonitrile and 20 mol % of piperidine in
acetonitrile was added. The flask was fitted with a condenser and
the reaction stirred under N.sub.2 at 30.degree. C. over night. The
solvent was then removed to give a pale cream oily semi solid which
was chromatographed on silica in 5% methanol in dichloromethane to
give the deprotected product (0.389 g (58% yield)) as a cream
oil.
[0180] MS ES 358.1 [M+H].sup.+ 1H NMR 300 MHz (CDCl.sub.3)
.delta.7.79, 1H, d, J=8.1 Hz, NH; 5.66, 1H, m, H2; 5.16, 1H, d,
J=5.7 Hz, H1; 5.11, 1H, d, J=0.9 Hz, H1'; 4.91, 1H, NH; 4.30, 1H,
m, H4; 3.74, 3H, s, OCH.sub.3; 3.33, 1H, br s, H8; 3.12, 2H, d,
J=6.0 Hz, H12, H12'; 2.56, 2H, m, H3, H3'; 1.87-1.26, 8H, m, H9,
H9', H10, H10', H11,H11', NH.sub.2; 1.43, 9H, s, 3CH.sub.3.
[0181] Compounds Based on a 3,3'-Substituted Binaphthyl Nucleus
Example 4
Preparation of (+/-)-2,2'-dimethoxy-1,1'-binaphthyl
##STR00007##
[0183] (+/-)-1,1'-Bi-2,2'-naphthol (10.13 g, 35 mmol) was dissolved
in acetone (300 mL, 0.12 M). Potassium carbonate (16.69 g, 121
mmol) and methyl iodide (22 mL, 353 mmol) were added and the
mixture heated to reflux under nitrogen for 48 h. The cooled
reaction mixture was evaporated to dryness, the residue taken up in
acetone (60 mL) and water (360 mL) then stirred for 7.5 h. The
solid was collected and dried under vacuum at 100.degree. C.
overnight yielding (+/-)-2,2'-dimethoxy-1,1'-binaphthyl as a
colourless solid (10.76 g, 97%), (lit..sup.10 224-225.degree.
C.).
[0184] .sup.1H NMR .delta.3.75, s, 6H, OCH.sub.3; 7.10, br d, J=8
Hz, 2H; 7.20, dt, J=1.5, 8 Hz, 2H; 7.30, ddd, J=1.5, 7, 8 Hz, 2H;
7.45, d, J=9 Hz, 2H; 7.86, d, J=7.5 Hz, 2H; 7.96, d, J=9 Hz, 2H,
ArH.
Example 5
Preparation of (+/-)-3,3'-diiodo-2,2'-dimethoxy-1,1'-binaphthyl
##STR00008##
[0186] To a solution of TMEDA (1.0 mL, 6.6 mmol) in diethyl ether
(50 mL) was added a solution of n-butyl lithium (1.6 M in hexanes,
4.4 mL, 7.0 mmol). The resulting solution was stirred for 15 min at
room temperature. (+/-)-2,2'-Dimethoxy-1,1'-binaphthyl (1.038 g,
3.3 mmol) was added as a solid to the reaction mixture which was
then stirred for 3 h at room temperature. The reaction mixture was
then cooled to -80.degree. C. and iodine (2.8 g, 11.0 mmol) was
added over several minutes using an addition tube. The reaction
mixture was allowed to gradually warm to room temperature and was
stirred overnight. The reaction mixture was stirred with a solution
of saturated aqueous sodium sulfite (added cautiously) for 4 h at
room temperature. The reaction mixture was partitioned between
dichloromethane (200 mL) and water (200 mL). The organic layer was
dried (MgSO.sub.4/Na.sub.2SO.sub.4), filtered and the filtrate
evaporated to dryness. The resulting deep yellow oil was purified
by flash column chromatography (5% ethyl acetate/hexane) to yield
(+/-)-3,3'-diiodo-2,2'-dimethoxy-1,1'-binaphthyl as a pale yellow
crystalline solid (0.954 g, 51%).
[0187] .sup.1H NMR .delta.3.41,s, 6H, 2.times.OCH.sub.3; 7.07, d,
J=8 Hz, 2H; 7.26, ddd, J=1.5, 7, 8 Hz, 2H; 7.40, ddd, J=1, 7, 8 Hz,
2H; 7.79, d, J=8 Hz, 2H, ArH; 8.53, s, 2H, ArH4, 4'. .sup.13C NMR
.delta.61.1, OCH3; 92.3, 125.3, 4.degree. ArC; 125.6, 125.75,
126.9, 127.05, 132.2, 4.degree. ArC; 133.8, 4.degree. ArC; 139.9,
154.5, 4.degree. ArC. m/z (CI, +ve) 567 (100%).
C.sub.22H.sub.16I.sub.2O.sub.2+H.sup.+ requires 567.
[0188] The by-product from this reaction is
(+/-)-3-iodo-2,2'-dimethoxy-1,1'-binaphthyl, which is separated
from (+/-)-3,3'-diiodo-2,2'-dimethoxy-1,1'-binaphthyl using
chromatography.
Example 6
Preparation of
(+/-)-3-iodo-2,2'-dimethoxy-3'-methyl-1,1'-binaphthyl
##STR00009##
[0190] To a -80.degree. C. solution of
(+/-)-3,3'-diiodo-2,2'-dimethoxy-1,1'-binaphthyl (2.016 g, 3.6
mmol) in THF (dry, distilled, 80 mL, 0.044 M) was added n-butyl
lithium (2.8 mL, 3.9 mmol) dropwise. The reaction mixture turned
yellow and was stirred for 1 h before the addition of methyl iodide
(dry, distilled, 0.35 mL, 5.6 mmol). The reaction mixture was
allowed to gradually warm to room temperature. After stirring for a
further 3 h saturated aqueous ammonium chloride solution (4 drops)
was added. The reaction mixture was evaporated to dryness, the
residue taken up in diethyl ether and washed with water. The
organic layer was dried (MgSO.sub.4), filtered and the filtrate
evaporated to dryness to give a pale yellow solid. Purification of
the crude material by flash column chromatography (4% ethyl
acetate/hexane) yielded
(+/-)-2,2'-dimethoxy-3-iodo-3'-methyl-1,1'-binaphthyl.
[0191] .sup.1H NMR .delta.2.55, s, 3H, CH.sub.3; 3.36, s, 6H,
OCH.sub.3; 7.06, d, J=8 Hz, 1H; 7.12, d, J=8 Hz, 1H; 7.16-7.42, m,
2H, ArH; 7.80, t, J=8 Hz, ArH; 7.81, s, 3H,ArH4''; 8.52, s,
ArH4.
[0192] The product also contained
(+/-)-3,3'-diiodo-2,2'-dimethoxy-1,1'-binaphthyl (10%) and
(+/-)-2,2'-dimethoxy-3,3'-dimethyl-1,1'-binaphthyl (8%).
[0193] Other reaction products seperated by chromatography were
(+/-)-2,2'-dimethoxy-3-iodo-1,1'-binaphthyl and
(+/-)-2,2'-dimethoxy-3-methyl-1,1'-binaphthyl.
Example 7
Preparation of
(+/-)-3-bromomethyl-3'-iodo-2,2'-dimethoxy-1,1'-binaphthyl
##STR00010##
[0195] (+/-)-3-Iodo-2,2'-dimethoxy-3'-methyl-1,1'-binaphthyl (1.737
g, 3.8 mmol) was dissolved in carbon tetrachloride (100 mL) and
N-bromosuccinimide (1.316 g, 7.4 mmol) was added. The mixture was
heated to reflux followed by external irradiation of the pyrex
flask with a 500 W mercury lamp for 1 h. The cooled reaction
mixture was filtered (to remove succinimide), the filtrate
evaporated to dryness to give a red solid. The residue was purified
by flash column chromatography (4% ethyl acetate/hexane) to yield a
colourless crystalline solid (1.130 g) that was a mixture
containing
(+/-)-3-bromomethyl-3'-iodo-2,2'-dimethoxy-1,1'-binaphthyl (0.942
g, 46%).
[0196] .sup.1H NMR .delta. 3.36, s, 3H, OCH.sub.3; 3.40, s, 3H,
OCH.sub.3; 4.72 d, J=9.9 Hz, 1H, CH.sub.2A; 4.91, d, J=9.9 Hz,
1H,CH.sub.2B; 7.08, d, J=8 Hz, 1H; 7.18, d, J=8 Hz, 1H; 7.23-7.44,
m, 4H; 7.80, d, J=8 Hz, 1H; 7.88, d, J=8 Hz, 1H, ArH; 8.07, s, 1H,
ArH4 and 8.54, s, 1H, ArH4'.
[0197] The other component was found to be
(+/-)-3-bromo-3'-bromomethyl-2,2'-dimethoxy-1,1'-binaphthyl (0.188
g, 10%).
Example 8
Preparation of ethyl
(+/-)-3-[3-(2,2'-dimethoxy-3'-iodo-1,1'-binaphthyl)]-2-[(diphenylmethylen-
e)amino]propanoate
##STR00011##
[0199] To a -10.degree. C. solution of HMPA (0.7 mL, 4.02 mmol) and
diisopropylamine (0.24 mL, 1.71 mmol) in THF (dry, distilled, 40
mL) was added n-butyllithium (1.32 M in hexanes, 1.4 mL, 1.85
mmol). The pale yellow solution was stirred for 10 min then cooled
to -78.degree. C. To this solution was added a solution of ethyl
N-(diphenylmethylene)glycinate (0.450 g, 1.68 mmol) in THF (dry,
distilled, 20 mL) using a cannula and precooling the addition
solution by running the drops down the side of the receiving flask.
The resulting mixture was stirred for 30 min then a solution of
3-bromomethyl-2,2'-dimethoxy-3'-iodo-(+/-)-1,1'-binaphthyl (0.895
g, 1.68 mmol) in THF (dry, distilled, 40 mL) was added using a
cannula. The reaction mixture was allowed to slowly warm to room
temperature and stirred over night. The yellow solution was
quenched with aqueous ammonium chloride solution (1 mL). The
reaction mixture was evaporated to dryness to give a yellow oil
that contained ethyl
(+/-)-3-[3-(2,2'-dimethoxy-3'-iodo-1,1'-binaphthyl)]-2-[(diphenylmethylen-
e)amino]propanoate. The residue was used without further
purification, due to the presence of HMPA.
[0200] .sup.1H NMR .delta.1.21, t, J=5 Hz, 3H, CH.sub.3; 3.00, s,
3H, OCH.sub.3; 3.20, s, 3H, OCH.sub.3; 3.40, dd, J=7, 10 Hz, 1H,
CH.sub.2A; 3.71, dd, J=3, 10 Hz, 1H, CH.sub.2B; 4.11-4.22, m, 2H,
OCH.sub.2; 4.50, q, J=3 Hz, 1H, .alpha.-CH; 6.82, d, J=5 Hz, 1H,
NH; 7.78-6.98, m, 19H, ArH; 8.49, s, 1H, ArH.
Example 9
Preparation of ethyl
(+/-)-2-amino-3-[3-(2,2'-dimethoxy-3'-iodo-1,1'-binaphthyl)]propanoate
hydrochloride salt
##STR00012##
[0202] To a solution of the crude alkylated product from Example 8
(1.208 g, 1.68 mmol) in diethyl ether (30 mL) was added 3% aqueous
hydrogen chloride solution (15 mL, 4.6 mmol). The mixture was
stirred at RT overnight and gave a yellow oil underneath the
aqueous layer underneath a yellow organic layer. The mixture was
evaporated to dryness, the sticky yellow residue was taken up in
ethanol and evaporated to dryness. This was repeated twice more.
The final residue was dried under high vacuum then freeze dried.
The crude product was used without further purification.
[0203] .sup.13C NMR .delta.13.8, 13.9, ArCH.sub.3; 33.0, 33.6,
ArCH.sub.2; 53.2, 53.7, OCH.sub.2; 61.0, 61.1, 61.2, 62.3,
OCH.sub.3; 92.3, .alpha.-CH; 117.4, 124.1, 124.2, 125.1, 125.3,
125.5, 125.6, 125.8, 126.0, 126.2, 126.5, 126.7, 126.75, 126.9,
127.05, 127.65, 127.85, 128.2, 130.0, 130.4, 131.3, 132.0, 132.1,
132.4, 132.8, 132.9, 133.3, 134.8, 133.9, 134.1, 139.7 (.times.2),
152.5, 154.4, 154.7, 154.9, ArC; 168.6, 169.0, C.dbd.O.
Example 10
Preparation of ethyl
(+/-)-2-acetylamino-3-[3-(2,2'-dimethoxy-3'-iodo-1,1'-binaphthyl)]propano-
ate
##STR00013##
[0205] The residue obtained after acid hydrolysis containing the
binaphthyl salt obtained in Example 9 (0.993 g, 1.68 mmol) was
dissolved in dichloromethane (dry, distilled, 100 mL). The solution
was stirred with MgSO.sub.4 (anhydrous) briefly then cooled in an
ice/salt bath. Triethylamine (0.70 mL, 5.02 mmol) was added,
followed by acetic anhydride (0.4 mL, 4.24 mmol) and DMAP, after
stirring for 5 min. The reaction mixture was allowed to warm to
room temperature and was stirred overnight. To the reaction mixture
was added a solution of 3% aqueous hydrochloric acid (50 mL) and
dichloromethane (50 mL). The aqueous layer was removed and
extracted with dichloromethane. The combined organic layers were
washed with a solution of 3% aqueous hydrochloric acid (.times.1),
a solution of 1:1 aqueous saturated lithium chloride and water
(.times.2) then water (.times.1). The solution was dried
(MgSO.sub.4) and the filtrate evaporated to dryness to give a
yellow liquid. The crude product was purified by squat column
chromatography (10% ethyl acetate/hexane.fwdarw.ethyl acetate) to
yield ethyl
(+/-)-2-acetylamino-3-[3-(2,2'-dimethoxy-3'-iodo-1,1'-binaphthyl)]propano-
ate as a pale yellow solid (0.75 g, 75% from
(+/-)-3-bromomethyl-3'-iodo-2,2'-dimethoxy-1,1'-binaphthyl)(ave.
91% yield per step).
[0206] .sup.1H NMR .delta.1.25, t, J=7 Hz, 3H, CH.sub.3; 1.98, s,
3H, COCH.sub.3; 3.26, s, OCH.sub.3; 3.28, s, 3H, OCH.sub.3;
3.30-3.42, m, ArCH.sub.2; 4.23, m, OCH.sub.2; 4.73, q, J=7 Hz, 1H,
.alpha.-CH; 6.79, d, J=7 Hz, 1H, NH; 7.05-7.82, ArH; 7.86, s, 1H,
ArH4; 8.535, s, 1H, ArH4'.
Example 11
Preparation of ethyl
(+/-)-2-acetylamino-3-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binaphthyl)]propan-
oate
##STR00014##
[0208] To a solution of the binaphthyl derivative obtained from
Example 10 (0.740 g, 1.24 mmol) in 1,4-dioxane (dry, 40 mL) was
added palladium chloride (0.025 g, 0.14 mmol) and
triphenylphosphine (0.136 g, 0.52 mmol). The solution was
deoxygenated with argon for 10 min then allyltributyltin (0.39 mL,
1.26 mmol) was added. The resulting mixture was heated at reflux
for 5 h. After cooling the solution was filtered through celite and
evaporated to dryness. The residue was purified by squat column
chromatography, to remove stannanes, then flash column
chromatography (50% ethyl acetate/hexane) to give a mixture that
contained ethyl
(+/-)-2-acetylamino-3-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binaphthyl)]propan-
oate as a clourless oil (0.54 g, 85%).
[0209] .sup.1H NMR .delta.0.92, t, J=7 Hz; 1.26, t, J=7 Hz,
3H,CH.sub.3; 1.98, s; 2.04, s, 3H; COCH.sub.3; 3.17, s, 3H,
OCH.sub.3; 3.235, s, 3H, OCH.sub.3; 3.25-3.33, m, 2H, CH.sub.2;
3.58-3.72, br m, 2H, CH.sub.2; 4.12, q, J=7 Hz, (OCH.sub.2); 4.21,
q, J=7 Hz, 2H, OCH.sub.2; 4.71, q, J=7 Hz, .alpha.-CH; 4.84, q, J=5
Hz, 1H, .alpha.-CH; 5.125-5.19, m, 2H, .dbd.CH.sub.2; 6.08-6.22, m,
1H, CH.dbd.; 6.78, d, J=7 Hz; 6.91, d, J=7 Hz, 1H, NH; 7.14-7.26,
m, 4H, ArH; 7.35-7.46, m, 2H, ArH; 7.81-7.85, m, 4H, ArH. m/z (CI,
+ve) 512 (100%). C.sub.32H.sub.33NO.sub.5+H.sup.+ requires 512.
[0210] The other product in this mixture is ethyl
(+/-)-2-acetylamino-3-[3-(3'-bromo-2,2'-dimethoxy-1,1'-binaphthyl)]propan-
oate.
Example 12
Preparation of
(+/-)-2-acetylamino-3-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binaphthyl)]propan-
oic acid
##STR00015##
[0212] The binaphthyl derivative obtained in Example 11 (0.522 g,
1.02 mmol) was dissolved in THF (22 mL) and cooled in an ice/water
bath. To this solution was added a solution of lithium hydroxide
monohydrate (0.196 g, 4.67 mmol) in water (9 mL). The mixture was
allowed to gradually warm to room temperature and was stirred for 5
h. To the reaction mixture was added diethyl ether, the aqueous
layer was washed with ether and the combined ether layers extracted
with water (.times.2). The combined aqueous layers were acidified
(3% aq. HCl), extracted with diethyl ether (.times.3) and dried
(MgSO.sub.4). The filtrate was evaporated to dryness to give
(+/-)-2-acetylamino-3-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binaphthyl)]propan-
oic acid as a white solid (0.462 g, 94%).
[0213] .sup.1H NMR .delta.2.07, s, 3H, COCH.sub.3; 3.07, s, 3H,
OCH.sub.3; 3.20, s, 3H, OCH.sub.3; 3.28-3.77, m, 2.times.CH.sub.2;
4.55, 2.times.t, J=5 Hz, 1H, .alpha.-CH; 5.11-5.19, m, 2H,
.dbd.CH.sub.2; 6.07-6.20, m, 1H, CH.dbd.; 7.16-7.56, m, 6H, ArH;
7.74, br s, 1H, NH; 7.84, d, J=8 Hz, ArH; 7.88, s, 4H, ArH4,
4'.
Example 13
methyl
(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3'-allyl-2,2'-dimethoxy-1,1'-
-binaphthyl}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxo-
nonanoate
##STR00016##
[0215] The binaphthyl derivative obtained from Example 12 (0.258 g,
0.53 mmol) was dissolved in dichloromethane (dry, 3 mL) and a
solution of the dipeptide obtained from Example 3 (freshly
deprotected) (0.22 g, 0.61 mmol) in dichloromethane (3 mL) was
added. To the resulting solution was added 4-dimethylaminopyridine
(crystal) and then the solution was cooled in an ice/water bath. To
the chilled solution was added 1,3-dicyclohexylcarbodiimide (0.111
g, 0.54 mmol). The reaction mixture was allowed to warm to room
temperature and was stirred overnight. To the reaction mixture was
added dichloromethane (10 mL) which was then filtered through
celite. The filtrate was evaporated to give the amide as a pale
yellow crystalline solid (0.404 g, 92%).
[0216] m/z (ES, +ve) 823 (M+H.sup.+, product, 32%), 723 (823-Boc,
8), 565 (11), 428 (19), 358 (21), 302 (26) and 225 (DCU+H.sup.+,
100). C.sub.47H.sub.58N.sub.4O.sub.9+H.sup.+ requires 823.
Example 13A
Preparation of benzyl
(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3'-allyl-2,2'-dimethoxy-1,1'-binap-
hthyl]}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononan-
oate
[0217] The corresponding allylglycine benzyl ester of the compound
of Example 13 was prepared by similar methods as described above
except that the appropriate benzyl precursor was used. The amino
group of the lysine side chain was deprotected according to the
procedure of Example 15 to give the target compound.
Example 13B
benzyl
(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3'-allyl-2,2'-dimethoxy-1,1'-
-binaphthyl]}-5-(4-aminobutyl)-3,6-diaza-4,7-dioxononanoate
hydrochloride
##STR00017##
[0219] Prepared from the product obtained from Example 13 (0.0226
g, 0.025 mmol) using the method as set out in Example 15. The
product was isolated as a pale yellow solid (0.014 g, 67%).
[0220] m/z (ES, +ve) 839 (M+CH.sub.3CN, 1%), 837 (M+K.sup.+, 1),
799 (M+H.sup.+, 19), 626 (2), 449 (4), 338 (6) and 225 (DCU+H,
100).
Example 14
Preparation of
(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(4-{[(tert-butoxy)carbonyl]amino}bu-
tyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocy-
clotetradecaphane-12-ene
##STR00018##
[0222] The binaphthyl derivative obtained in Example 13 (0.205 g,
0.25 mmol) was dissolved in dichloromethane (50 mL). The solution
was deoxygenated with argon gas for 10 min before the addition of
benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.022 g,
0.027 mmol). The reaction mixture was heated to reflux for 18
hours. The cooled reaction mixture was evaporated to dryness and
the resulting residue purified by flash column chromatography to
give three fractions each of which contained different
diasteriomeric cyclic products;
[0223] 1) Pale yellow glass like solid (0.038 g). m/z (ES, +ve) 817
(M+Na.sup.+, 4%), 795 (M+H.sup.+, 16), 593 (48) and 297
(O.dbd.P(C.sub.6H.sub.11).sub.3+H.sup.+, 100);
[0224] 2) Light brown solid (0.041 g). m/z (ES, +ve) 795
(M+H.sup.+, 54%), 593 (35), 297
(O.dbd.P(C.sub.6H.sub.11).sub.3+H.sup.+, 100), 145 (44), 104 (33)
and 86 (64);
[0225] 3) Very pale yellow glass like solid (0.073 g) (Total=0.152
g, 74%). m/z (ES, +ve) 795 (M+H.sup.+, 15%), 297
(O.dbd.P(C.sub.6H.sub.11).sub.3+H.sup.+, 29), 147 (32), 145 (66),
106 (16), 104 (52) and 86 (100).
C.sub.45H.sub.54N.sub.4O.sub.9+H.sup.+ requires 795.
Example 15
Preparation of
(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1-
(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene
hydrochloride
##STR00019##
[0227] The protected diasteriomeric cyclic peptoids prepared in
Example 14 (0.073 g, 0.09 mmol) were dissolved in dichloromethane
(2 mL) then trifluoroacetic acid (2 mL) was added. The mixture was
stirred at room temperature for 25 min. The mixture was evaporated
to dryness, the residue taken up in dichloromethane and evaporated
to dryness again. This was repeated twice more. The residue was
taken up in dichloromethane (3 mL) and a solution of 1.0 M hydrogen
chloride in diethyl ether (1 mL) was added. The resulting mixture
was stirred at room temperature for 10 min before being evaporated
to dryness. The residue was taken up in dichloromethane and
evaporated to dryness again. This was repeated twice more. The
deprotected product was crystallised from the residue with diethyl
ether and dichloromethane. The product was isolated using
centrifugation to yield the deprotected cyclic product as a pale
yellow crystalline solid (0.055 g, 82%).
[0228] m/z (ES, +ve) 696.5 (41%) and 695.8 (53) and 695.4
(M+H.sup.+, 73) (aggregates), 111 (48) and 60 (100).
C.sub.40H.sub.46N.sub.4O.sub.7+H.sup.+ requires m/z 695.3445. Found
695.3400
[0229] Similarly other diastereomers were also obtained--(0.021 g,
60%) m/z (ES, +ve) 697 (32%) and 696 (100) and 695 (M+H.sup.+, 96)
(aggregates), C.sub.40H.sub.46N.sub.4O.sub.7+H.sup.+ requires m/z
695.3445 found 695.3435; and (0.023 g, 60%), m/z (ES, +ve) 696
(9%), 695 (M+H.sup.+, 20); 111 (12) and 60 (100);
C.sub.40H.sub.46N.sub.4O.sub.7+H.sup.+ requires m/z 695.3445, found
695.3427.
Example 15A
(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(-
1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane
hydrochloride
##STR00020##
[0231] One of the isomers of the deprotected cyclized peptoid
obtained from Example 15 was dissolved in a mixture of
dichloromethane (0.2 mL), methanol (0.5 mL) and water (0.2 mL). To
this solution was added 10% Pd/C (0.001 g, 0.0009 mmol) and the
reaction vessel was sealed. The reaction mixture was stirred and
the atmosphere inside the reaction vessel removed and replaced with
an atmosphere of hydrogen. This procedure was repeat twice. The
reaction was stirred at room temperature for several days before
removal of all solid material by passing the reaction mixture
through a plug of celite (filter aid). The filtrate was evaporated
and gave the reduced deprotected cyclized peptoid as a white solid
(0.001 g, 33%).
[0232] m/z (ES, +ve) 697 (M+H.sup.+, 100%); 316 (51), 288 (74).
Example 15B
Preparation of
(aR/S,7R,10S)-4-acetamido-6,9-diaza-10-benzyloxycarbonyl-7-(4-{[(tert-but-
oxy)carbonyl]amino}butyl)-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxo-
cyclotetradecaphane-12-ene
##STR00021##
[0234] The corresponding benzyl ester of the compound of Example 15
was prepared by similar methods as described above except that the
appropriate benzyl precursor was used. Two isomers were isolated at
the protected cyclic peptide stage and these were seperately
deprotected to provide the desired products.
[0235] m/z (ES, +ve) 771 (M+H.sup.+, 100).
[0236] m/z (ES, +ve) 771 (M+H.sup.+, 72%), 699 (7), 59 (100)
respectively.
Example 16
Coupling of
(+/-)-2-acetylamino-3-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binaphthyl)]propan-
oic acid with N.epsilon.-Fmoc-L-lysine-L-allylglycine methyl
ester
##STR00022##
[0238] The binaphthyl derivative obtained in Example 12 (0.447 g,
0.92 mmol) was dissolved in dichloromethane (1 mL) and a solution
of the N.epsilon.-Fmoc-L-lysine-L-allylglycine methyl ester
(freshly deprotected) (0.450 g, 0.94 mmol) in dichloromethane (2
mL) was added. To the resulting solution was added
4-dimethylaminopyridine (crystal) and then the solution was cooled
in an ice/water bath. To the chilled solution was added
1,3-dicyclohexylcarbodiimide (0.195 g, 0.94 mmol). The reaction
mixture was allowed to warm to room temperature and was stirred
overnight. To the reaction mixture was added dichloromethane (10
mL) which was then filtered through celite. The filtrate was
evaporated to dryness and the residue purified by flash column
chromatography to give the coupled product as an off white
crystalline solid (0.474 g, 54%).
[0239] m/z (ES, +ve) 945 (M+H.sup.+, 36%) and 225 (DCU+H.sup.+,
100). C.sub.57H.sub.60N.sub.4O.sub.9+H.sup.+ requires 945.
Example 17
Preparation of the Protected Cyclic Peptoid
##STR00023##
[0241] The binaphthyl derivative obtained in Example 16 (0.470 g,
0.50 mmol) was dissolved in dichloromethane (120 mL). The solution
was deoxygenated with argon gas for 10 min before the addition of
benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.022 g,
0.027 mmol). The reaction mixture was heated to reflux for 18 h.
The cooled reaction mixture was evaporated to dryness the resulting
residue purified by flash column chromatography (4%
methanol/dichloromethane) to give the cyclic peptoid product as an
off white crystalline solid (0.329 g, 72%).
[0242] m/z (ES, +ve) 918 (4%), 917 (M+H.sup.+, 5), 593 (9), 522 (3)
and 297 (100). C.sub.55H.sub.56N.sub.4O.sub.9+H.sup.+ requires
917.
Example 18
Preparation of the Deprotected Cyclic Peptoid
##STR00024##
[0244] To the protected cyclic peptoid obtained in Example 17
(0.123 g, 0.13 mmol) was added dry acetonitrile (9 mL). The mixture
was warmed to 60.degree. C. in a sealed system and a solution of
0.02 M piperidine in acetonitrile (0.54 mL) was added. The reaction
mixture was heated at 60.degree. C. for 43 h. The cooled mixture
was filtered, and the filtrate evaporated to dryness to give a
white solid. The solid was purified by flash column chromatography
(10% methanol/dichloromethane, followed by 10%
methanol/dichloromethane containing 2% triethylamine). The isolated
product was dissolved in dichloromethane (5 mL) and 1.0 M hydrogen
chloride in diethyl ether (0.5 mL) was added. The solution was
stirred for 10 min then evaporated to dryness and dried under high
vacuum to give the deprotected cyclic peptoid product as a pale
yellow crystalline solid (0.048, 51%).
[0245] m/z (ES, +ve) 729 (30%), 695 (M+H.sup.+, 100) and 498 (25).
C.sub.40H.sub.46N.sub.4O.sub.7+H.sup.+ requires m/z 695.3445. Found
695.3419
Example 19
Coupling of
(+/-)-2-acetylamino-3-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binaphthyl)]propan-
oic acid with N.omega.-PMC-L-arginine-L-allylglycine methyl
ester
##STR00025##
[0247] The binaphthyl derivative obtained in Example 12 (0.127 g,
0.26 mmol) and N.omega.-PMC-L-arginine-L-allylglycine methyl ester
(freshly deprotected) (0.150 g, 0.27 mmol) were dissolved in
dichloromethane (dry, 1.5 mL). To the resulting solution was added
4-dimethylaminopyridine (crystal) and then the solution was cooled
in an ice/water bath. To the chilled solution was added
1,3-dicyclohexylcarbodiimide (0.053 g, 0.25 mmol). The reaction
mixture was allowed to warm to room temperature and was stirred
overnight. To the reaction mixture was added dichloromethane (10
mL) which was then filtered through celite. The filtrate was
evaporated to dryness and the residue purified by flash column
chromatography (4% methanol/dichloromethane) to give the protected
arginine derivative as a colourless solid (0.176 g, 68%).
[0248] m/z (ES, +ve) 1056 (M+K.sup.+, 4%), 1040 (M+Na.sup.+, 16),
1018 (M+H.sup.+, 64), 1017 (M.sup.+.cndot., 100), 920 (13), 624
(14) and 225 (24). C.sub.56H.sub.68N.sub.6O.sub.10S requires
1017.
Example 19A
Preparation of methyl
(aR/S,2S,5R)-8-acetamido-2-allyl-9-[3-(3'-allyl-2,2'-dimethoxy-1,1'-binap-
hthyl)]-3,6-diaza-5-(3-guanidinopropyl)-4,7-dioxononanoate
hydrochloride
##STR00026##
[0250] Similarly to the procedures described above the D-arginyl
version of Example 19 was prepared. This was deprotected according
to the procedure of Example 21 and isolated as a pale yellow
solid.
Example 20
Preparation of the Protected Cyclic Peptoid
##STR00027##
[0252] The binaphthyl derivative obtained in Example 19 (0.176 g,
0.17 mmol) was dissolved in dichloromethane (50 mL). The solution
was deoxygenated with argon gas for 10 min before the addition of
benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.015 g,
0.017 mmol). The reaction mixture was heated to reflux for 20 h.
The cooled reaction mixture was evaporated to dryness and the
resulting residue purified by flash column chromatography (4%
methanol/dichloromethane) to give the cyclic peptoid product as a
light brown glass (0.132 g, 77%).
[0253] m/z (ES, +ve) 1011 (M+Na.sup.+) and 989 (M+H.sup.+).
C.sub.54H.sub.64N.sub.6O.sub.10S+H.sup.+ requires 989.
Example 21
Preparation of
(aR/S,7S,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbo-
nyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-
-ene hydrochloride
##STR00028##
[0255] The cyclic peptoid obtained in Example 20 (0.047 g, 0.05
mmol) was dissolved in dichloromethane (2 mL) then trifluoroacetic
acid (2 mL) was added. The mixture was stirred at room temperature
for 25 min. The mixture was evaporated to dryness, the residue
taken up in dichloromethane and evaporated to dryness again. This
was repeated twice more. The residue was taken up in
dichloromethane (3 mL) and a solution of 1.0 M hydrogen chloride in
diethyl ether (1 mL) was added. The resulting mixture was stirred
at room temperature for 10 min before being evaporated to dryness.
The residue was taken up in dichloromethane and evaporated to
dryness again. This was repeated twice more. The deprotected
product was crystallised from the residue with diethyl ether and
dichloromethane. The deprotected product was isolated using
centrifugation and yielded an off white solid (0.021 g, 58%).
[0256] m/z (ES, +ve) 724 (100%).
C.sub.40H.sub.46N.sub.6O.sub.7+H.sup.+ requires m/z 723.3506. Found
723.3488.
Example 21A
Preparation of
(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbo-
nyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-
-ene hydrochloride
##STR00029##
[0258] Similarly to the procedures described above the D-arginyl
version of Example 21 was prepared and the isomers of the
deprotected cyclic peptoid that contains a D-arginine residue were
isolated as an off-white solid and a pale yellow solid
respectively.
[0259] m/z (ES, +ve) 723 (M+H.sup.+, 15), 316 (28), 288 (78), 217
(100), 199 (79), 111 (41) and m/z (ES, +ve) 723 (M+H.sup.+, 30),
316 (51), 288 (100), 217 (34) and 199 (45) respectively.
Example 21B
Preparation of
(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbo-
nyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane
hydrochloride
[0260] Preparation of a reduced cyclic peptoid that contains an
D-arginine residue
##STR00030##
[0261] The cyclized peptoid of Example 21A was dissolved in
methanol (2 mL). To this solution was added 10% Pd/C (0.012 g, 0.01
mmol) and the reaction vessel was sealed. The reaction mixture was
stirred and the atmosphere inside the reaction vessel removed and
replaced with an atmosphere of hydrogen. This procedure was repeat
twice. The reaction was stirred at room temperature for several
days before removal of all solid material by passing the reaction
mixture through a plug of celite (filter aid). The filtrate was
evaporated and gave the reduced cyclic peptoid as a light brown
solid.
[0262] m/z (ES, +ve) 725 (M+H.sup.+, 19%), 394 (13), 316 (71), 288
(100), 180 (37) and 111 (47).
Example 22
Preparation of Cyclic Tetra Peptoid
##STR00031##
[0264] This compound was prepared in a similar manner to the
compound of Example 18 but the aminoacyl moiety used in the
coupling reaction contained an additional alanine residue.
[0265] m/z (ES, +ve) 766.5 (100%), 767 (79) and 767.5 (58).
C.sub.43H.sub.51N.sub.5O.sub.8+H.sup.+ requires m/z 766.3816; found
766.3740.
[0266] Compounds Based on a 3,6-Substituted Carbazole Nucleus
[0267] The preparation of
6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,-
10-dioxo-[12](3,6)-1H-carbazolophane HCl described in Examples 23
to 35 is shown schematically in Scheme 1.
##STR00032## ##STR00033##
[0268] Nomenclature for Carbazole Based Cyclic Peptoids
6-acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-
-[12](3,6)-1H-carbazolophane
##STR00034##
[0270] These compounds are named as carbozolophanes with the
numbering of the cyclophane structure as shown above. The notation
[12] refers to the length of the atom chain attached to the
heteroaromatic scaffold and the notation (3,6) refers to where this
12-atom chain is attached to the parent 9H-carbazole unit.
[0271] Note: For examples 23-44, where samples exhibited several
isomers [diastereoisomers, (E) or (Z) isomers and/or rotamers], the
minor form is indicated by an asterisk in their NMR spectra.
Example 23
Preparation of 6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole
[0272] To a solution of 4-methylcyclohexanone (5.47 mL, 44.6 mmol),
cyclohexane (70 mL) and glacial acetic acid (50 mL) was added
4-bromophenylhydrazine hydrochloride (10.0 g, 44.6 mmol) and the
reaction mixture was refluxed for 23 h under a nitrogen atmosphere.
The cooled reaction mixture was filtered and the filtrate was
evaporated. Diethyl ether was added and the mixture was washed with
a saturated sodium bicarbonate solution and then water; the ether
solution was dried and evaporated. The crude product was
recrystallised from ethanol over an ice bath, filtered, washed with
cold PS and dried in vacuo to afford
6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole (8.73 g, 33.1 mmol,
74%) as an off-white solid, mp 108-110.degree. C.
[0273] .sup.1H NMR, 400 MHz, (D.sub.6) benzene, .delta.7.78, d, J=2
Hz, 1H, H-5; 7.41, dd, J=8, 2 Hz, 1H, H-7; 6.77, d, J=8 Hz, 1H,
H-8; 6.23, bs, 1H, NH; 2.53, dd, J=15, 5 Hz, 1H, H-4; 2.32-2.15, m,
2H, H-1, H-2; 2.01, dd, J=15, 9 Hz, 1H, H-4; 1.73-1.61, m, 2H, H-2,
H-3; 1.29, m, 1H, H-1; 0.99, d, J=7 Hz, 3H, CH.sub.3.
Example 24
Preparation of
6-bromo-9-tert-butoxycarbonyl-3-methyl-1,2,3,4-tetrahydrocarbazole
[0274] A solution of 6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole
obtained from Example 23 (7.0 g, 26.5 mmol) in dry THF (25 mL) was
added to sodium hydride (1.17 g, 29.2 mmol) under a nitrogen
atmosphere and the mixture was stirred for 0.5 h at room
temperature. A solution of di-tert-butyl-dicarbonate (8.67 g, 39.8
mmol) in dry THF (55 mL) was added and the reaction mixture was
stirred for 20.5 h. The reaction solvent was evaporated, ether was
added and the ether mixture was washed with water, dried and
evaporated. The crude product was dissolved in ethanol, the solvent
evaporated to a minimal volume and the product recrystallised over
an ice bath. The recrystallised solid was filtered, washed with
cold MeOH and dried in vacuo to afford
6-bromo-9-tert-butoxycarbonyl-3-methyl-1,2,3,4-tetrahydrocarbazole
(8.33 g, 22.9 mmol. 86%) as an off-white solid, mp 122.degree.
C.
[0275] .sup.1H NMR, (D.sub.6) benzene, .delta.8.27, d, J=8.7 Hz,
1H, H-8; 7.61, d, J=2.1 Hz, 1H, H-5; 7.44, dd, J=8.7, 2.1 Hz, 1H,
H-7; 3.06-2.94, m, 1H, H-1; 2.85-2.70, m, 1H, H-2; 2.36, dd, J=16,
5 Hz, 1H, H-4; 1.90-1.78, m, 1H, H-4; 1.65, m, 2H, H-2 and H-3;
1.38, s, 9H, C(CH.sub.3).sub.3; 1.30-1.16, m, 1H, H-1; 0.96, d,
J=6.6 Hz, 311, CHCH.sub.3.
Example 25
Preparation of 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole
[0276] To a mixture of
6-bromo-9-tert-butoxycarbonyl-3-methyl-1,2,3,4-tetrahydrocarbazole
obtained in Example 24 (2.0 g, 5.49 mmol),
2,3-dichloro-4,5-dicyano-1,4-benzoquinone (2.62 g, 11.5 mmol) and
activated 3 .ANG. molecular sieves was added anhydrous benzene (17
mL) under a nitrogen atmosphere, and the mixture was refluxed for
20 h. The cooled reaction mixture was filtered and the filtrate
evaporated. The crude product was chromatographed (PS with gradient
elution up to PS:DCM 3:1) to afford
3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole (1.64 g, 4.56 mmol,
83%) as a colourless solid. By-products were also
obtained--6-bromo-9-tent-butoxycarbonyl-4-ethoxy-3-methylcarbazole
(12 mg, 0.030 mmol, 0.5%) was obtained as a colourless oil, and
6-bromo-9-tert-butoxycarbonyl-1,2-dihydro-3-methylcarbazol-4-(3H)-one
(52 mg, 0.14 mmol, 2.5%) was obtained as a pale yellow solid.
[0277] 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole: mp
96.degree. C. Rf: 0.66 in PS:DCM (2:1). .sup.1H NMR, .delta.8.14,
d, J=9 Hz, 1H, H-1; 8.10, d, J=8.7 Hz, 1H, H-8; 7.99, d, J=2.1 Hz,
1H, H-4; 7.65, bs, W.sub.1/2 4 Hz, 1H, H-5; 7.50, dd, J=8.9, 2 Hz,
1H, H-2; 7.27, dd, J=8.4, 1.8 Hz, 1H, H-7; 2.48, s, 3H, ArCH.sub.3;
1.74, s, 9H, C(CH.sub.3).sub.3.
[0278] 6-bromo-9-tent-butoxycarbonyl-4-ethoxy-3-methylcarbazole:
Rf: 0.58 in PS:DCM (2:1). .sup.1H NMR, .delta.8.32, d, J=2.1 Hz,
1H, H-4; 8.16, d, J=9 Hz, 1H, H-1; 7.91, d, J=8.4 Hz, 1H, H-8;
7.51, dd, J=8.9, 2 Hz, 1H, H-2; 7.27, d, J=8.7 Hz, 1H, H-7; 4.06,
q, J=7.2 Hz, 2H, OCH.sub.2CH.sub.3; 2.40, s, 3H, ArCH.sub.3; 1.72,
s, 9H, C(CH.sub.3).sub.3; 1.55, t, J=7.2 Hz, 3H,
OCH.sub.2CH.sub.3.
[0279]
6-bromo-9-tert-butoxycarbonyl-1,2-dihydro-3-methylcarbazol-4-(3H)-o-
ne: mp 137.degree. C.
Example 26
Preparation of
3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole
[0280] A suspension of
3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole obtained from
Example 25 (653 mg, 1.81 mmol) and recrystallised
N-bromosuccinimide (355 mg, 2.00 mmol) in carbon tetrachloride was
refluxed under nitrogen with irradiation from a 150W halogen lamp
for 2.5 h. The reaction mixture was cooled over an ice bath and
filtered, and the filtrate evaporated. The crude product was
chromatographed (PS with gradient elution to PS:DCM 1:1) to afford
3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole (551 mg, 1.26
mmol, 69%) as a colourless solid, mp 150.degree. C. (dec).
[0281] .sup.1H NMR, 400 MHz, .delta.8.22, d, J=8.4 Hz, 1H, H-8;
8.16, d, J=8.8 Hz, 1H, H-1; 8.07, d, J=2Hz, 1H, H-4; 7.93, d, J=1.6
Hz, 1H, H-5; 7.54, dd, J=8.8, 2 Hz, 1H, H-2; 7.50, dd, J=8.8, 2 Hz,
1H, H-7; 4.66, s, 2H, CH.sub.2; 1.73, s, 9H, CH.sub.3.
Example 27
Preparation of diethyl
2-acetamido-2-[3'-(6'-bromo-9'-tert-butoxycarbonyl)-carbazolylmethyl]-pro-
panedioate
[0282] A solution of diethyl acetamidomalonate (225 mg, 1.04 mmol)
in anhydrous DMSO (6 mL) was added to sodium hydride (44 mg, 1.09
mmol) under a nitrogen atmosphere and the mixture was stirred at
room temperature for 1.5 h. After this period,
3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole obtained from
Example 26 (500 mg, 1.14 mmol) was added and the reaction mixture
was stirred at room temperature for 0.5 h. The reaction mixture was
diluted with diethyl ether, the ether mixture was washed with brine
and then water several times. The water layers were extracted with
diethyl ether, and the ether extracts were washed with water. Both
ether solutions were combined, dried and evaporated to afford
diethyl
2-acetamido-2-[3'-(6'-bromo-9'-tert-butoxycarbonyl)-carbazolylmethyl]-pro-
panedioate (448 mg, 0.78 mmol, 75%) as a yellow solid, mp
158.degree. C. .sup.1H NMR, 400 MHz, .delta.8.14, d, J=8 Hz, 2H,
H-1' and H-8' (direct overlap); 7.95, d, J=1.6 Hz, 1H, H-5'; 7.54,
d, J=2 Hz, 1H, H-4'; 7.53, dd, J=8.8, 2 Hz, 1H, H-7'; 7.10, dd,
J=8.6, 2 Hz, 1H, H-2'; 6.53, s, 1H, NH; 4.28, q, J=7.2 Hz, 4H,
OCH.sub.2CH.sub.3; 3.79, s, 2H, ArCH.sub.2; 2.05, s, 3H, COCH3;
1.72, s, 9H, C(CH.sub.3).sub.3; 1.31, t, J=7.2Hz, 6H,
OCH.sub.2CH.sub.3.
Example 28
Preparation of ethyl
2-acetamido-3-[3'-(6'-bromocarbazole)]propanoate
[0283] A suspension of diethyl
2-acetamido-2-[3'-(6'-bromo-9'-tert-butoxycarbonyl)-carbazylmethyl]-propa-
nedioate obtained from Example 27 (310 mg, 0.54 mmol), lithium
chloride (23 mg, 0.54 mmol), distilled water (0.02 mL, 1.08 mmol)
and DMSO (5 mL) was refluxed under a nitrogen atmosphere for 2 h.
The cooled reaction mixture was diluted with ether, the ether
mixture was washed with brine and then water. The ether layer was
dried and evaporated to afford ethyl
2-acetamido-3-[3'-(6'-bromocarbazole)]propanoate (181 mg, 0.45
mmol, 83%) as a yellow solid, mp 175.degree. C.
[0284] .sup.1H NMR, .delta.8.49, s, 1H, NH; 8.05, d, J=1.8 Hz, 1H,
H-5'; 7.69, s, W.sub.1/2 4 Hz, 1H, H-4'; 7.43, dd, J=8.6, 1.8 Hz,
1H, H-7'; 7.25, d, J=9 Hz, 1H, H-1'; 7.23, d, J=8.4 Hz, 1H, H-8';
7.12, dd, J=8.3, 1.5 Hz, 1H, H-2'; 6.05, d, J=7.5 Hz, 1H, NH; 4.90,
dt, J=7.8, 6 Hz, 1H, CHN; 4.16, q, J=7.2 Hz, 2H, OCH.sub.2CH.sub.3;
3.27, dd, J=14.1, 6.3 Hz, 1H, ArCH.sub.2; 3.20, dd, J=14, 5.9 Hz,
1H, ArCH.sub.2; 1.96, s, 3H, COCH.sub.3; 1.22, t, J=7.2 Hz, 3H,
OCH.sub.2CH.sub.3.
Example 29
Alternative One-Pot Preparation of Ethyl
2-acetamido-3-[3'-(6'-bromocarbazole)]propanoate
[0285] A solution of diethyl acetamidomalonate (368 mg, 1.70 mmol)
in anhydrous DMSO (10 mL) was added to sodium hydride (71 mg, 1.78
mmol) under a nitrogen atmosphere and the mixture was stirred at
room temperature for 1.5 h. After this period,
3-bromo-6-bromomethyl-9-tent-butoxycarbonylcarbazole obtained in
Example 26 (820 mg, 1.87 mmol) was added and the reaction mixture
was stirred at room temperature for 0.5 h. Lithium chloride (71 mg,
1.70 mmol) and distilled water (0.06 mL, 3.40 mmol) were added and
the reaction mixture was refluxed for 1.75 h. The reaction mixture
was diluted with ether, the ether mixture was washed with brine and
then water, the combined water layers were extracted with ether,
and these extracts were washed with wafer. The combined ether
layers were dried and evaporated and the crude product was
chromatographed (PS with gradient elution to DCM and finally EtOAc)
to afford ethyl 2-acetamido
(6'-bromo-9'-ethyl)-3-carbazolepropanoate (56 mg, 0.13 mmol, 8%) as
a dark yellow oil, and ethyl
2-acetamido-3-[3'-(6'-bromocarbazole)]propanoate (481 mg, 1.19
mmol, 70%) as a pale yellow solid.
[0286] Ethyl
2-acetamido-3-[3'-(6'-bromo-9'-ethylcarbazole)]propanoate: .sup.1H
NMR, .delta.8.11, d, J=1.8 Hz, 1H, H-5'; 7.73, s, W.sub.1/2 4.7 Hz,
1H, H-4'; 7.51, dd, J=8.5, 2 Hz, 1, H-7'; 7.30, d, J=8.4 Hz, 1H,
H-1'; 7.24, d, J=8.4 Hz, 1H, H-8'; 7.20, dd, J=8.4, 1.8 Hz, 1H,
H-2'; 5.98, d, J=7.5 Hz, 1H, NH; 4.91, dt, J=7.8, 6 Hz, 1H, CHN;
4.29, q, J=7.2 Hz, 2H, NCH.sub.2CH.sub.3; 4.18, q, J=7.2 Hz, 2H,
OCH.sub.2CH.sub.3; 3.27, d, J=5.7 Hz, 2H, ArCH.sub.2; 1.98, s, 3H,
COCH.sub.3; 1.38, t, J=7.2 Hz, 3H, NCH.sub.2CH.sub.3; 1.24, t,
J=7.2 Hz, 3H, OCH.sub.2CH.sub.3.
Example 30
Preparation of ethyl
2-acetamido-3-[3'-(6'-allylcarbazole)]propanoate
[0287] To a glass, high-pressure tube containing ethyl
2-acetamido-(6'-bromo)-3-carbazolepropanoate obtained in Examples
28 or 29 (1.0 g, 2.48 mmol), palladium chloride (22 mg, 0.124 mmol)
and triphenylphosphine (130 mg, 0.496 mmol) was added anhydrous DMF
(10 mL) followed by allyltributyltin (0.92 mL, 2.98 mmol). The tube
was sealed under nitrogen and the reaction mixture heated in a
110.degree. C. oil bath for 22 h. The cooled reaction mixture was
diluted with diethyl ether, the ether mixture was washed with brine
and then water, and the ether layer was dried and evaporated. The
crude product was chromatographed (PS with gradient elution to
DCM:EtOAc 2:1) to afford ethyl
2-acetamido-3-[3'-(6'-allylcarbazole)]propanoate (823 mg, 2.26
mmol, 91%) as a pale yellow solid, mp 100.degree. C.
[0288] .sup.1H NMR, .delta.8.13, bs, 1H, ArNH; 7.80, s, W.sub.1/2
4.8 Hz, 1H, H-5'; 7.76, s, W.sub.1/2 4.8 Hz, 1H, H-4'; 7.32, d,
J=8.7 Hz, 1H, H-8'; 7.29, d, J=8.4 Hz, 1H, H-1'; 7.22, dd, J=8.7,
1.2 Hz, 1H, H-7'; 7.10, dd, J=8.4, 1.5 Hz, 1H, H-2'; 6.05, ddt,
J=17, 10, 6.6 Hz, 1H, CH.sub.2CH.dbd.CH.sub.2; 5.96, d, J=8.4 Hz,
1H, NHAc; 5.11, dd, J=15, 1.8 Hz, 1H, CH.sub.2CH.dbd.CH.sub.2;
5.08, d, J=8.1 Hz, 1H, CH.sub.2CH=CH.sub.2; 4.90, dt, J=7.8, 6.3
Hz, 1H, CHN; 4.17, q, J=7.2 Hz, 2H, OCH.sub.2CH.sub.3; 3.54, d,
J=6.6 Hz, 2H, CH.sub.2CH.dbd.CH.sub.2; 3.26, d, J=5.7 Hz, 2H,
ArCH.sub.2; 1.97, s, 3H, COCH.sub.3; 1.23, t, J=7.2 Hz, 3H,
OCH.sub.2CH.sub.3.
Example 31
Preparation of ethyl
2-acetamido-3-[3'-(6'-allyl-9'-tert-butoxycarbonylcarbazole)]propanoate
[0289] A suspension of ethyl
2-acetamido-3-[3'-(6'-allylcarbazole)]propanoate obtained in
Example 30 (823 mg, 2.26 mmol) and cesium carbonate (1.47 g, 4.52
mmol) in anhydrous DMF (20 mL) was stirred at room temperature
under a nitrogen atmosphere for 15 min before a solution of
di-tert-butyl-dicarbonate (739 mg, 3.39 mmol) in anhydrous DMF (6
mL) was added. The reaction mixture was stirred at room temperature
for 20 h. After this period the reaction mixture was diluted with
ether, and the ether mixture was washed with brine followed by
water, and then dried and evaporated. The crude product was
chromatographed (PS with gradient elution to DCM:EtOAc 5:1) to
afford ethyl
2-acetamido-3-[3'-(6'-allyl-9'-tert-butoxycarbonylcarbazole)]propan-
oate (820 mg, 1.77 mmol, 78%) as a pale yellow solid, mp
125.degree. C.
[0290] .sup.1H NMR, .delta.8.18, d, J=8.1 Hz, 1H, H-8'; 8.16, d,
J=8.1 Hz, 1H, H-1'; 7.71, d, J=1.2 Hz, 1H, H-4'; 7.68, d, J=1.5 Hz,
1H, H-5'; 7.27, dd, J=8.5, 1.5 Hz, 1H, H-2'; 7.17, dd, J=8.5, 1.8
Hz, 1H, H-7'; 6.03, ddt, J=16.5, 9.9, 6.9 Hz, 1H,
CH.sub.2CH.dbd.CH.sub.2; 5.11, dd, J=17.7, 1.8 Hz, 1H,
CH.sub.2CH.dbd.CH.sub.2; 5.10, dd, J=10.2, 1.8 Hz, 1H,
CH.sub.2CH.dbd.CH.sub.2; 4.90, dt, J=7.5, 6 Hz, 1H, CHN; 4.17, q,
J=7.2 Hz, 2H, OCH.sub.2CH.sub.3; 3.52, d, J=6.6 Hz, 2H,
CH.sub.2CH.dbd.CH.sub.2; 3.28, dd, J=14, 5.7 Hz, 1H, ArCH.sub.2;
3.22, dd, J=14.1, 5.7 Hz, 1H, ArCH.sub.2; 1.98, s, 3H, COCH.sub.3;
1.72, s, 9H, C(CH.sub.3).sub.3; 1.23, t, J=7.2 Hz, 3H,
OCH.sub.2CH.sub.3.
Example 32
Preparation of
2-acetamido-3-[3'-[6'-allyl-9'-tert-butoxycarbonylcarbazole)]propanoic
acid
[0291] To an ice-cold solution of ethyl
2-acetamido-3-[3'-(6'-allyl-9'-tert-butoxycarbonylcarbazole)]propanoate
obtained in Example 31 (787 mg, 1.70 mmol) in THF (50 mL) was added
a solution of lithium hydroxide (440 mg, 10.5 mmol) in distilled
water (20 mL), and the reaction mixture was stirred at 0.degree. C.
for 3.5 h. After this period the THF portion of the solvent was
evaporated, the aqueous mixture remaining was diluted with
distilled water and washed with ether. The aqueous layer was
acidified to pH<2 with a 10% HCl solution and the product was
extracted with diethyl ether, after adding a sufficient amount of
solid sodium chloride to the acidified mixture to dissolve it.
Finally, the ether extracts were dried and evaporated to afford
2-acetamido-3-[3'-(6'-allyl-9'-tert-butoxycarbonylcarbazole)]propa-
noic acid (666 mg, 1.53 mmol, 90%) as a colourless solid, mp
177.degree. C.
[0292] .sup.1H NMR, (D.sub.6) acetone, .delta.8.21, d, J=8.4 Hz,
1H, H-8'; 8.20, d, J=8.7 Hz, 1H, H-1'; 7.96, d, J=1.2 Hz, 1H, H-4';
7.89, d, J=0.9 Hz, 1H, H-5'; 7.39, dd, J=8.4, 1.5 Hz, 2H, H-2' and
NH (concealed under ArH signal); 7.33, dd, J=8.5, 1.8 Hz, 1H, H-7';
6.07, ddt, J=16.9, 9.9, 6.9 Hz, 1H, CH.sub.2CH.dbd.CH.sub.2; 5.14,
dd, J=17.2, 1.5 Hz, 1H, CH.sub.2CH.dbd.CH.sub.2; 5.07, dd, J=9.9,
1.5 Hz, 1H, CH.sub.2CH.dbd.CH.sub.2; 4.80, m, 1H, CHN; 3.55, d,
J=6.9 Hz, 2H, CH.sub.2CH.dbd.CH.sub.2; 3.34, dd, J=13.8, 5.4 Hz,
1H, ArCH.sub.2; 3.15, dd, J=13.8, 8.1 Hz, 1H, ArCH.sub.2; 1.89, s,
3H, COCH.sub.3; 1.76, s, 9H, C(CH.sub.3).sub.3.
Example 33
Preparation of a Carbazole Peptoid Derivative
##STR00035##
[0294] To a mixture of
2-acetamido-3-[3'-(6'-allyl-9'-tert-butoxycarbonylcarbazole)]propanoic
acid (84 mg, 0.192 mmol), methyl L-arg(Pmc)allylglycinate (106 mg,
0.192 mmol) and 4-dimethylaminopyridine (1 crystal) was added dry
DCM (3 mL) and anhydrous acetonitrile (5 mL). The mixture was
warmed and stirred vigorously under nitrogen to give a translucent
solution before 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (37 mg, 0.192 mmol) was added. The reaction mixture
was stirred at room temperature under nitrogen for 19.5 h. After
this period the reaction solvent was evaporated, DCM was added and
the mixture was washed with brine followed by water. The DCM layer
was dried and evaporated and then chromatographed (PS with gradient
elution to DCM:MeOH 10:1). The purified product was triturated with
PS from DCM to give the carbazole peptoid derivative as a cream
solid, mp 141-143.degree. C. Rf: 0.60 in 10% MeOH in DCM.
[0295] .sup.1H NMR, .delta.8.12, d, J=8.4 Hz, 1H, ArH; 8.10, d,
J=8.4 Hz, 1H, ArH; 7.78, s, W.sub.1/2 6 Hz, 1H, ArH; 7.66, s,
W.sub.1/2 4 Hz, 1H, ArH; 7.59, d, J=7.5 Hz, 1H, NH; 7.29-7.19, m,
2H, ArH; 6.93, d, J=6.9 Hz, 1H, NH; 6.76, d, J=7.2 Hz, 1H, NH;
6.33, bs, 1H, NH; 6.26, bs, 1H, NH; 5.97, m, 1H,
ArCH.sub.2CH.dbd.CH.sub.2; 5.63, m, 1H, CH.sub.2CH.dbd.CH.sub.2;
5.14-4.95, m, 4H, CH.sub.2CH.dbd.CH.sub.2; 4.80, m, 1H, CHN; 4.71,
dt, J=7.2, 7.2 Hz, 1H, CHN; 4.56-4.40, m, 2H, NH and CHN; 3.62, s,
3H, OCH.sub.3; 3.46, d, J=8.1 Hz, 1H, ArCH.sub.2CH.dbd.CH.sub.2;
3.43, d, J=7.2 Hz, 1H, ArCH.sub.2CH.dbd.CH.sub.2; 3.32-2.94, m, 6H,
NHCH.sub.2CH.sub.2CH.sub.2 and ArCH.sub.2; 2.54, s, 3H, ArCH.sub.3
(ortho to SO.sub.2 attach); 2.51, s, 3H, ArCH.sub.3 (ortho to
SO.sub.2 attach); 2.44, m, 4H, CH.sub.2CH.dbd.CH.sub.2 and
ArCH.sub.2CH.sub.2; 2.06, s, 3H, ArCH.sub.3; 1.90, s, 3H,
COCH.sub.3; 1.74, t, J=6.3 Hz, 2H, ArCH.sub.2CH.sub.2; 1.68, s, 9H,
C(CH.sub.3).sub.3; 1.58, m, 2H, NHCH.sub.2CH.sub.2CH.sub.2, 1.26,
s, 6H, C(CH.sub.3).sub.2.
Example 34
Preparation of Protected Cyclised Carbazole Peptoid Product
##STR00036##
[0297] To a solution of the compound obtained in Example 33 (110
mg, 0.113 mmol) in dry DCM (28 mL) was added Grubbs' ruthenium
catalyst (9 mg, 0.0113 mmol) and the reaction mixture was refluxed
under a nitrogen atmosphere for 23 h. After this period the
reaction solvent was evaporated, and the crude product was
chromatographed (PS with gradient elution to DCM:MeOH 10:1) and
then triturated with diethyl ether/PS from DCM to give a cyclised
carbazole peptoid derivative (107 mg, 0.113 mmol, 100%) as a cream
solid, mp 190.degree. C. (dec). Rf: 0.37 in 10% MeOH in DCM. Mass
spectrum (ES.sup.+), m/z 942 (30%) [MH.sup.+].
Example 35
Preparation of
6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,-
10-dioxo-[12](3,6)-1H-carbazolophane HCl
##STR00037##
[0299] A solution of the cyclic carbazole derivative obtained in
Example 34 (20 mg, 0.0212 mmol) in TFA (2 mL) was stirred at room
temperature under a nitrogen atmosphere for 1.5 h. The TFA was
removed by co-evaporation with several portions of DCM. The crude
product was dissolved in MeOH, a 1M HCl-in-ether solution (0.04 mL,
0.0425 mmol) was added and the reaction mixture was stirred for 15
min. After this period the solvent was evaporated to a minimal
volume and the product recrystallised from ether/PS over an ice
bath to give
6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,-
10-dioxo-[12](3,6)-1H-carbazolophane HCl (12 mg, 0.0196 mmol, 92%)
as a pale brown solid, mp 222-224.degree. C. (dee). Mass spectrum
(ES.sup.+), m/z 576 (100%) [MH.sup.+]. HRMS calcd for
C.sub.30H.sub.37N.sub.7O.sub.5+H: 576.2934; found: 576.2902.
Example 36
##STR00038##
[0301]
6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,1-
0-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S) was prepared by
hydrogenation of the compound of Example 35.
Example 37
##STR00039##
[0303]
6-Acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbo-
nyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) was
prepared according to the procedure for Example 35 except the
precursor containing a D-arginyl residue was used.
Example 38
##STR00040##
[0305]
6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,1-
0-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) was prepared by
hydrogenation of the compound of Example 37.
Example 39
##STR00041##
[0307]
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-14-ene-12-methoxycarbonyl-7-
,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S) was prepared
similarly to Example 35 from the corresponding protected
Fmoc-Lys-Pmb protected carbozole derivative with the initial
deprotection using anisole/TFA followed by piperidine
Example 39A
##STR00042##
[0309]
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-en-
e-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl
(9S,12S) was prepared similarly to Example 39 but deprotection of
the lysine side chain was conducted using piperidine in dry THF at
room temperature. The free base was converted to its hydrochloride
salt using HCl in ether with the compound isolated as a cream
solid, nip ca 230.degree. C. (dec). .sup.1H NMR, [500 MHz,
(CD.sub.3).sub.2SO] .delta. 8.84*, br d, J 7.5 Hz, NH-11; 8.82*, br
d, J 8.0 Hz, NH-11; 8.70, br d, J 7.5 Hz, NH-11; 8.63, br d, J 7.5
Hz, NH-11; 8.49*, br d, J 10.0 Hz, NH-8; 8.47, br d, J 9.5 Hz,
NHAc; 8.41*, br d, J 8.5 Hz, NH-8; 8.38-8.28, m, NHAc; 8.24-8.16*,
m, NH-11; 8.14-7.93, m, 2H, ArH-2 and ArH-19; 8.04, br s, NH.sub.2;
7.97*, br s, NH.sub.2; 7.83-7.77*, m, NH-8; 7.69, br d, J 8.0 Hz,
NH-8; 7.57*, s, ArH-21; 7.55, s, ArH-20; 7.53, s, ArH-20; 7.50*, s,
ArH-20; 7.49*, br d, J 8.5 Hz, NHAc; 7.41, s, ArH-21; 7.38-7.30*,
m, ArH-3; 7.30, br d, J 8.0 Hz, ArH-18; 7.22, br d, J 6.5 Hz, NHAc;
7.16*, br d, J 8.0 Hz, ArH-3; 7.10, br d, J 8.0 Hz, ArH-3;
5.89-5.79, m, ArCH.sub.2CH.dbd.CH (E isomer); 5.81-5.70, m,
ArCH.sub.2CH.dbd.CH* (Z isomer) and CHCH.sub.2CH.dbd.CH; 5.72-5.62,
m, CHCH.sub.2CH.dbd.CH; 5.65-5.42, m, CHCH.sub.2CH.dbd.CH; 4.84*,
br s, NCH-6; 4.62*, br d, J 3.5 Hz, NCH-6 and NCH-9; 4.46, br d, J
3.5 Hz, NCH-9 and NCH-12; 4.31*, br d, J 8.0 Hz, NCH-12; 4.28*, br
d, J 7.5 Hz, NCH-12; 4.18, br s, NCH-6; 3.72-3.36, m,
ArCH.sub.2CH.dbd.CH; 3.65, s, OCH.sub.3; 3.60*, s, OCH.sub.3;
3.57*, s, OCH.sub.3; 3.22-2.84, m, 2H, ArCH.sub.2-5; 2.78-2.50, m,
2H, NCH.sub.2(CH.sub.2).sub.3; 2.59, br d, J 11.0 Hz,
CHCH.sub.2CH.dbd.CH; 2.42-2.28, m, CHCH.sub.2CH.dbd.CH; 2.33, br d,
J 11.0 Hz, CHCH.sub.2CH.dbd.CH; 1.90, s, COCH.sub.3; 1.87, s,
COCH.sub.3; 1.84-1.45, m, 2H, N(CH.sub.2).sub.3CH.sub.2; 1.77*, s,
COCH.sub.3; 1.73*, s, COCH.sub.3; 1.67, s, 9H, C(CH.sub.3).sub.3;
1.62-1.40, m, 2H, NCH.sub.2CH.sub.2(CH.sub.2).sub.2; 1.32, m,
N(CH.sub.2).sub.2CH.sub.2CH.sub.2; 1.21, m,
N(CH.sub.2).sub.2CH.sub.2CH.sub.2.
Example 40
[0310]
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dio-
xo[12](3,6)-1H-carbazolophane HCl (9S,12S) was prepared by
hydrogenation of the compound of Example 39.
Example 41
##STR00043##
[0312]
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-14-ene-12-methoxycarbonyl-7-
,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) was prepared in
the same manner as Example 39 except that an amino acyl moiety
containing a protected D-lysine residue was utilised.
Example 42
##STR00044##
[0314]
6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dio-
xo-[12](3,6)-1H-carbazolophane HCl (9R,12S) was prepared by
hydrogenation of the compound of Example 41
Example 43
##STR00045##
[0316] Methyl
8-acetamido-3,6-diaza-5-[3-guanidinopropyl]-4,7-dioxo-2-propyl-9-[3-(6-pr-
opyl)-9H-carbazole]nonanoate HCl (2S,5R) was prepared by
hydrogenation and deprotection of the ring opened diene precursor
of Example 37.
[0317] Hydrogenation of the compound obtained in Example 33 gave
the corresponding compound where the allyl groups had been reduced
to propyl groups. This was deprotected according to the procedure
of Example 35 to provide a cream solid, mp 210.degree. C. .sup.1H
NMR, [500 MHz, (CD.sub.3)2SO, isomer ratio 69:31] .delta. 11.16*,
br s, 0.3H, ArNH; 10.99, br s, 0.7H, ArNH; 8.33, br d, J 8.0 Hz,
0.7H, NH-6; 8.30, br d, J 6.5 Hz, 0.7H NHAc; 8.25*, br d, J 7.5 Hz,
0.3H, NH-3; 8.21-8.11*, m, 0.6H, NH-6 and NHAc; 8.07, br d, J 7.5
Hz, 0.7H, NH-3; 7.94, s, 1H, ArCH-4; 7.81, s, 1H, ArCH-5;
7.62-7.53*, m, 0.3H, NHCH.sub.2; 7.45, br s, 0.7 NHCH.sub.2; 7.35,
m, 2H, ArH-1 and ArH-8; 7.26, d, J 8.5 Hz, 1H, ArH-2; 7.17, d, J
8.0 Hz, 1H, ArH-7; 6.85, v br s, 3H, NH(C.dbd.NH)NH.sub.2; 4.56, m,
1H, NCH-8; 4.37*, dt, J 6.0, 7.5 Hz, 0.3H, NCH-5; 4.30-4.16, m,
1.7H, NCH-2 and NCH-5; 3.61, s, 3H, OCH.sub.3; 3.20-3.11*, m, 0.3H,
ArCHH-9; 3.15-3.05*, m, 0.6H, NCH.sub.2(CH.sub.2).sub.2; 3.11-3.03,
m, 0.7H, ArCHH-9; 2.98-2.88, m, 0.7H, ArCHH-9; 2.93-2.83, m, 1.4H,
NCH.sub.2(CH.sub.2).sub.2; 2.88-2.82*, m, 0.3H, ArCHH-9; 2.69, t, J
7.5 Hz, 2H, ArCH.sub.2CH.sub.2CH.sub.3; 1.77, s, 2.1H, COCH.sub.3;
1.75*, s, 0.9H, COCH.sub.3; 1.68-1.54, m, 2H,
CHCH.sub.2CH.sub.2CH.sub.3; 1.67-1.58*, m, 0.6H,
C(CH.sub.2).sub.2CH.sub.2; 1.65, m, 2H, ArCH.sub.2CH.sub.2CH.sub.3;
1.52-1.38*, m, 0.6H, NCH.sub.2CH.sub.2CH.sub.2; 1.48-1.36, m, 1.4H,
N(CH.sub.2).sub.2CH.sub.2; 1.34-1.17, m, 2H,
CHCH.sub.2CH.sub.2CH.sub.3; 1.25-1.13, m, 1.4H,
NCH.sub.2CH.sub.2CH.sub.2; 0.91, t, J 7.0 Hz, 3H,
Ar(CH.sub.2).sub.2CH.sub.3; 0.83, t, J 7.0 Hz, 3H,
CH(CH.sub.2).sub.2CH.sub.3.
Example 44
##STR00046##
[0319] Methyl
8-acetamido-5-[4-aminobutyl]-3,6-diaza-4,7-dioxo-2-propyl-9-[3-(6-propyl)-
-9H-carbazole]nonanoate HCl (2S,5R) was prepared by hydrogenation
and deprotection of the ring opened diene precursor of Example
41.
[0320] The uncyclised protected precursor to Example 41, was
reduced by hydrogenation and then deprotected in the usual manner
to yield a cream solid, mp 160-162.degree. C.
[0321] .sup.1H NMR, [500 MHz, (CD.sub.3).sub.2SO, isomer ratio
69:31] .delta. 11.16, br s, 0.7H, ArNH; 11.07*, br s, 0.3H, ArNH;
8.36, br d, J 6.5 Hz, 0.7H, NHAc; 8.32, br d, J 8.0 Hz, 0.7H, NH-6;
8.29*, br d, J 7.5 Hz, 0.3H, NH-3; 8.21*, br d, J 8.0 Hz, 0.3H,
NHAc; 8.21*, br d, J 8.5 Hz, 0.3H, NH-6; 8.06*, br s, 0.6H,
NH.sub.2; 8.02, br d, J 8.0 Hz, 0.7H, NH-3; 7.99, br s, 1.4H,
NH.sub.2; 7.96*, s, 0.3H, ArH-4; 7.93, s, 0.7H, ArH-4; 7.81, s,
0.7H, ArH-5; 7.79*, s, 0.3H, ArH-5; 7.37*, d, J 8.0 Hz, 0.3H,
ArH-8; 7.35, d, J 8.5 Hz, 1.4H, ArH-1 and ArH-8; 7.32*, d, J 8.5
Hz, 0.3H, ArH-1; 7.27*, d, J 8.5 Hz, 0.3H, ArH-2; 7.25, d, J 8.5
Hz, 0.7H, ArH-2; 7.17, d, J 8.0 Hz, 1H, ArCH-7; 4.57*, m, 0.3H,
NCH-8; 4.53, dt, J 7.0, 7.5 Hz, 0.7H, NCH-8; 4.34*, dt, J 5.5, 8.0
Hz, 0.3H, NCH-5; 4.22, m, 1H, NCH-2; 4.09, m, 0.7H, NCH-5; 3.60, s,
3H, OCH.sub.3; 3.18*, dd, J 13.5, 4.0 Hz, 0.3H, ArCHH-9; 3.05, dd,
J 13.2, 7.5 Hz, 0.7H, ArCHH-9; 2.96, dd, J 13.2, 8.5 Hz, 0.7H,
ArCHH-9; 2.89*, dd, J 13.2, 10.5 Hz, 0.3H, ArCHH-9; 2.73*, br d, J
5.5 Hz, 0.6H, NCH.sub.2(CH.sub.2).sub.3; 2.68, t, J 7.5 Hz, 2H,
ArCH.sub.2CH.sub.2CH.sub.3; 2.45, br s, 1.4H,
NCH.sub.2(CH.sub.2).sub.3; 1.79, s, 2.1H, COCH.sub.3; 1.76*, s,
0.9H, COCH.sub.3; 1.71-1.51, m, 2.6H, CHCH.sub.2CH.sub.2CH.sub.3
and N(CH.sub.2).sub.3CH.sub.2*; 1.69-1.58, m, 2H,
ArCH.sub.2CH.sub.2CH.sub.3; 1.61-1.52*, m, 0.6H,
NCH.sub.2CH.sub.2(CH.sub.2).sub.2; 1.61-1.48, m, 0.7H,
N(CH.sub.2).sub.3CH.sub.2; 1.41-1.26, m, 2.7H,
N(CH.sub.2).sub.3CH.sub.2, NCH.sub.2CH.sub.2(CH.sub.2).sub.2 and
N(CH.sub.2).sub.2CH.sub.2CH.sub.2*; 1.32-1.18, m, 2H,
CHCH.sub.2CH.sub.2CH.sub.3; 0.91, t, J 7.0 Hz, 3H,
Ar(CH.sub.2).sub.2CH.sub.3; 0.90-0.82, m, 1.4H,
N(CH.sub.2).sub.2CH.sub.2CH.sub.2; 0.82, t, J 7.0 Hz, 2.1H,
CH(CH.sub.2).sub.2CH.sub.3; 0.81*, t, J 7.0 Hz, 0.9H,
CH(CH.sub.2).sub.2CH.sub.3.
[0322] Compounds Based on a 1,4-Substituted Phenyl Nucleus
[0323] General Synthetic Procedures
[0324] N-Boc & Pmc Deprotection (Procedure A)
[0325] The N-Boc or Pmc protected amine (1 equiv.) was stirred for
3 hours in 1:1 DCM/TFA solution at room temperature. The solvent
was removed under reduced pressure, and the residue was resuspended
in a minimal volume of methanol. The solution was then treated with
an excess of 1M HCl/ether solution and the solvent again
evaporated. The crude product was purified by
recrystallization/precipitation from DCM &/or MeOH by addition
of ether.
[0326] Peptide Coupling (Procedure B)
[0327] To a solution of the acid (1 equiv.) in DMF at room
temperature was added HOBt (1.1 equiv.), EDCI (1 equiv.) and the
amine (1.2 equiv.). If the amine was a hydrochloride salt, DIPEA (1
equiv.) was also added. The mixture was allowed to stir for 16
hours before the reaction was quenched with water until
precipitation occurred. The solid was collected by vacuum
filtration, and washed thoroughly with water. The amorphous product
was dried over P.sub.2O.sub.5 to yield the desired peptide.
[0328] N-Fmoc Deprotection (Procedure C)
[0329] The Fmoc Protected amine (1 equiv.) was stirred in 1%
piperidine/acetonitrile for 3 hours at room temperature. The
solvent was removed under reduced pressure and the crude product
was purified by flash column chromatography (15:1, DCM/MeOH) to
yield the free amine.
[0330] Macrocyclization by Olefin Metathesis (Procedure D)
[0331] To a solution of the precursor tripeptide (1 equiv.) in DCM
(to 0.004 M) was added Grubb's ruthenium catalyst (15 mol %) and
the resulting solution was heated at reflux for 48 hours before the
solvent was removed by evaporation and the product isolated by
flash column chromatography (15:1, DCM/MeOH) to yield the
corresponding macrocycle.
Example 45
Methyl
(2S)-2{(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylca-
rboxamido]-5-tert-butoxycarboxamidopentylcarboxamido}-4-pentenoate
##STR00047##
[0333] To a solution of methyl
(2S)-2-[(1S)-1-amino-5-tert-butoxycarboxamido]-4-pentenoate (782
mg, 2.19 mmol) and
(2S)-3-(4-allyloxyphenyl)-2-methylcarboxamidopropanoic acid (576
mg, 2.19 mmol) in DCM (10 mL) was added EDCI (420 mg, 2.19 mmol)
and a catalytic quantity of DMAP. The resulting mixture was allowed
to stir at room temperature for 16 hours before the reaction was
quenched by the addition of DCM (25 mL). The organic layer was
washed with brine (2.times.25 mL) and water (2.times.25 mL) and
dried over MgSO.sub.4, before being concentrated by evaporation.
The crude product was purified by flash column chromatography (25:1
DCM/MeOH) to afford methyl
(2S)-2{(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxam-
ido]-5-tert-butoxycarboxamidopentylcarboxamido}-4-pentenoate (664
mg, 1.10 mmol, 50%) as a white solid. Mass Spectrum (ES, +ve) m/z
503.4 (100%) [MH.sup.+(less t-boc)], 603.4 (35%) [MH.sup.+]. HRMS
calcd for C.sub.31H.sub.47N.sub.4O.sub.8 603.3394, found
603.3397.
Example 46
(5S)-5-[(1S)-2-(4-Allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-[-
(1S)-1-methyloxycarbonyl-3-butenylcarbamoyl]pentylammonium
chloride
##STR00048##
[0335] This ammonium salt was synthesized using the general N-Boc
deprotection procedure (Procedure A), from methyl
(2S)-2{(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxam-
ido]-5-tert-butoxycarboxamidopentylcarboxamido}-4-pentenoate (104
mg, 0.170 mmol) to yield
(5S)-5-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5--
[(1S)-1-methyloxycarbonyl-3-butenylcarbamoyl]pentylammonium
chloride (55 mg, 0.10 mmol, 60%) as a yellow solid. Mass Spectrum
(ES, +ve) m/z 503.3 (100%) [M.sup.+ less Cl.sup.-]. HRMS calcd for
C.sub.26H.sub.39N.sub.4O.sub.6 503.2870, found 503.2894.
Example 47
Methyl
(7S,13S,10S)-10-(4-tert-butoxycarboxamidobutyl)-13-methylcarboxamid-
o-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraen-
e-7-carboxylate
##STR00049##
[0337] The macrocyclic peptide was prepared using the general
procedure for olefin metathesis (Procedure D) using methyl
(2S)-2{(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxam-
ido]-5-tert-butoxycarboxamidopentylcarboxamido}-4-pentenoate (311
mg, 0.52 mmol) to yield methyl
(7S,13S,10S)-10-(4-tert-butoxycarboxamidobutyl)-13-methylcarboxamido-9,12-
-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-7-ca-
rboxylate (228 mg, 0.40 mmol, 76%) as a brown solid. Mass Spectrum
(ES, +ve) m/z 475.3 (40%) [MH.sup.+(less t-boc)], 575.3 (25%)
[MH.sup.+].
Example 48
4-[(3S,9S,6S)-3-Methylcarboxamido-9-methyloxycarbonyl-4,7-dioxo-14-oxa-5,8-
-diazabicyclo[13.2.2]nonadeca-1(17),11,15,18-tetraen-6-yl]butylammmonium
chloride
##STR00050##
[0339] This ammonium salt was synthesized using the general N-Boc
deprotection procedure (Procedure A) using methyl
(7S,13S,10S)-10-(4-tert-butoxycarboxamidobutyl)-13-methylcarboxamido-9,12-
-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-7-ca-
rboxylate (220 mg, 0.380 mmol) to yield
4-[(3S,9S,6S)-3-methylcarboxamido-9-methyloxycarbonyl-4,7-dioxo-14-oxa-5,-
8-diazabicyclo[13.2.2]nonadeca-1(17),11,15,18-tetraen-6-yl]butylammmonium
chloride (152 mg, 0.300 mmol, 79%) as a dark yellow solid. Mass
Spectrum (ES, +ve) m/z 475.4 (100%) [M.sup.+ (less Cl.sup.-)].
Examples 49
Methyl
(2S)-2-[(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylc-
arboxamido]-5-di(tert-butoxycarboxamido)methyleneaminopentylcarboxamido]-4-
-pentenoate
##STR00051##
[0341] To a solution of
(5S)-5-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5--
[(1S)-1-methyloxycarbonyl-3-butenylcarbamoyl]pentylammonium
chloride (41 mg, 0.081 mmol) in DCM (2 mL) N,
N'-diBoc-N''-triflylguanidine (35 mg, 0.089 mmol), triethylamine
(0.1 mL) and DCM (2 mL). The resulting solution was allowed to stir
overnight in a nitrogen atmosphere. The solvent was evaporated and
the crude product was purified by flash column chromatography
(15:1, DCM/MeOH) to yield methyl
(2S)-2-[(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxa-
mido]-5-di(tert-butoxycarboxamido)methyleneaminopentylcarboxamido]-4-pente-
noate (45 mg, 0.060 mmole, 74%) as an orange/yellow solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz): .delta. 8.26 (bs, 1H); 7.08 (t, J 8.4
Hz, 2H); 6.97 (m, 1H); 6.83 (t, J 8.4 Hz, 2H); 6.73 (d, J 8.0 Hz,
1H); 6.57 (t, J 9.3 Hz, 1H); 6.03 (m, 1H); 5.66 (m, 1H); 5.39 (d, J
17.3 Hz, 1H); 5.26 (d, J 10.1 Hz, 1H); 5.10 (m, 2H); 4.51 (m, 5H);
3.74 (s, 3H); 3.33 (bs, 2H); 2.96 (ddd, J 6.7, 7.2, 14.0 Hz, 2H);
2.52 (m, 2H); 1.97 (s, 3H); 1.47 (m, 6H); 1.54 (s, 3H); 1.49 (s,
18H). .sup.13C NMR (CDCl.sub.3, 300 MHz): .delta. 171.7; 171.3;
171.2; 170.9; 170.6; 163.2; 157.5; 156.0; 153.1; 151.4; 133.1;
132.0; 130.1; 128.2; 119.2; 119.0; 117.5; 114.8; 83.2; 79.5; 68.7;
55.2; 53.1; 53.0; 52.4; 40.7; 40.5; 37.2; 36.1; 32.0; 28.6; 28.3;
22.9; Mass Spectrum (ES, +ve) m/z 745.2 (100%) [MH.sup.+]. HRMS
calcd for C.sub.37H.sub.57N.sub.6O.sub.10 745.4136, found
745.4105.
Example 50
(5S)-5-[(1S)-2-(4-Allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-[-
(1S)-1-methyloxycarbonyl-3-butenylcarbamoyl]pentylguanidinium
chloride
##STR00052##
[0343] This salt was synthesized using the general N-Boc
deprotection procedure (Procedure A) on the compound of Example 49.
Mass Spectrum (ES, +ve) m/z 545.3 (100%) [M.sup.+]. HRMS calcd for
C.sub.27H.sub.41N.sub.6O.sub.6 545.3088, found 545.3066.
Example 51
Methyl (7S, 13S,
10S)-10-[4-di(tert-butoxycarboxamido)methyleneaminobutyl]-13-methylcarbox-
amido-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tet-
raene-7-carboxylate
##STR00053##
[0345] In an anlogous manner to Example 49, the compound of Example
48 was converted to its protected guanidine analogue. Isolated as
an orange/yellow solid. Mass Spectrum (ES, +ve) m/z 717.4 (100%)
[MH.sup.+]. HRMS calcd for C.sub.35H.sub.53N.sub.6O.sub.10
717.3823, found 545.3806.
Example 52
Imino{4-[(3S,6S,9S)-3-methylcarboxamido-9-methyloxycarbonyl-4,7-dioxo-14-o-
xa-5,8-diazabicyclo[13.2.2]nondeca-1(17),11,15,18-tetraen-6-yl]butylamino}-
methylammonium chloride
##STR00054##
[0347] Deprotection procedure (Procedure A) of Example 51 gave the
desired compound as a yellow solid. Mass Spectrum (ES, +ve) m/z
517.4 (100%) [M.sup.+ (less Cl.sup.-)]. HRMS calcd for
C.sub.25H.sub.37N.sub.6O.sub.6 517.2775, found 517.2765.
Examples 53-60
[0348] In an analogous manner, the series of compounds
corresponding to the compounds of Examples 45-52 but where the
L-lysine was replaced with D-lysine were prepared.
Examples 61-64
[0349] A series of compounds corresponding to the compounds of
Examples 45-48 but where the L-allyl glycine was replaced with
D-allyl glycine, and L-lysine was replaced with D-arginine were
prepared in an analogous manner to the compounds of Examples 45-48.
The arginine was Pmc protected.
Examples 65-68
[0350] In an analogous manner, the series of compounds
corresponding to the compounds of Examples 61-64 but where the
D-arginine was replaced with L-arginine were prepared.
[0351] Compounds Based on a 1,3-Substituted Indole Nucleus
[0352] Nomenclature of cyclic peptoids based on a 1,3-substituted
indole nucleus. These compounds are named as bridged compounds with
the metheno bridge between the atoms 1 and 15. The macrocyle is
then label and numbered as illustrated below.
[0353] Methyl
1,2,5,6,7,9,10,12,13,14-octahydro-1,15-metheno-7,10-diaza-8,11-dioxo-9-4'-
(tert-butoxycarbonylamino)butyl-1-benzazacyclododecine-6-carboxylate
##STR00055##
Example 69
Preparation of 1-Prop-2-enyl 1-(1-prop-2-enyl)-indole-3-acetate and
1-Prop-2-enyl 1H-indole-3-acetate
##STR00056##
[0355] Sodium hydride (1.0 g, 25.1 mmol, 2.2 molar equiv., 60% in
paraffin) was washed with petroleum spirit twice under a N.sub.2
atmosphere before dry DMF was added. A solution of
1H-indole-3-acetic acid (2.0 g, 11.4 mmol) in DMF under N.sub.2 was
added to this suspension at room temperature and the mixture was
stirred for half an hour. Allyl bromide (2.5 mL, 28.6 mmol, 2.5
molar equiv) was added dropwise and the reaction mixture was
stirred overnight at room temperature. The DMF was evaporated and
the residue was partitioned between diethyl (20 mL) and water (20
mL). The diethyl layer was separated and the aqueous layer was
extracted further with diethyl ether. The combined diethyl ether
layers were washed with water, dried (Na.sub.2SO.sub.4) and
evaporated. The crude product was chromatographed on a flash silica
gel column (20% DCM in petroleum spirit as eluent) to produce the
diallyl derivative as an oil (1.9 g, 95%) and the allylester (90
mg) upon elution with 50% DCM in petroleum spirit. For 25: MS (CI)
m/z 256 (100% MH.sup.+). HRMS (CI) calcd for
C.sub.16H.sub.18NO.sub.2: 256.1338; found: 256.1338.
[0356] For the diallyl derivative: MS (CI) m/z 216 (100% MH.sup.+).
HRMS (CI) calcd for C.sub.13H.sub.14NO.sub.2: 216.1024; found:
216.1021.
Example 70
Preparation of 1-(1-prop-2-enyl)-1H-indole-3-acetic acid
##STR00057##
[0358] To a solution of the diallyl from example 69 (1.8 g, 7.2
mmol) was added lithium hydroxide (0.3 g, 0.15M) dissolved in a
ratio of 2.5:1 THF/water (35 mL). The reaction mixture was placed
in ice and stirred at 0.degree. C. for 3 hours. The solvent of THF
was evaporated and the crude was extracted with diethyl and water.
The aqueous layer was separated with diethyl layer and extracted
with water. The combined aqueous layers were acidified by 10%
hydrochloride acid to pH less than 2. The aqueous layer was then
saturated with sodium chloride and extracted with DCM (20 mL),
dried (Na.sub.2SO.sub.4) and evaporated. The titled compound (1.1
g, 74%) was obtained as an oil. .sup.1H NMR (CDCl.sub.3)
.delta.=7.60 (d, J=8 Hz, 1 H, ArH-4), 7.30 (d, J=8 Hz, 1H, ArH-7),
7.22 (dt, J=8, 1 Hz, 1H, ArH-6), 7.13 (dt, J=8, 1 Hz, 1H, ArH-5),
7.08 (s, 1H, ArH-2), 5.98 (ddt, J=17, 11, 5 Hz, 1H, CH=CH.sub.2),
5.20* (dd, J=9, 1 Hz, 2H, CH.dbd.CH.sub.2), 5.11 (dd, J=16, 1 Hz,
2H, CH=CH.sub.2), 4.68 (dd, J=5, 1 Hz, 2H,
NCH.sub.2CH.dbd.CH.sub.2), 3.80 (s, 2H, CH.sub.2C.dbd.O); .sup.13C
NMR .delta.=177.5 (C.dbd.O), 136.1 (ArC), 133.2 (CH.dbd.CH.sub.2),
127.6 (ArC), 126.8, 121.8 and 119.3 (ArCH), 118.9 (CH=CH.sub.2),
117.4 and 109.6 (ArCH), 106.4 (ArC), 48.8 (NCH.sub.2), 31.0
(CH.sub.2); MS (CI) m/z 216 (100% MH.sup.+). HRMS (CI) calcd for
C.sub.13H.sub.14NO.sub.2: 216.1024; found: 216.1039.
Example 71
Preparation of
N-[(1S)-1-[[[(1S)-1-methoxycarbonyl-3-butenyl]amino]carbonyl]-5(tert-buto-
xycarbonylamino)pentyl]-1-(1-prop-2-enyl)-1H-indole-3-acetamide
##STR00058##
[0360] The compound of Example 70 (0.05 g, 0.2 mmol) in DCM (3 mL)
was coupled to N-Boc-D-lysine-L-allylglycine methyl ester (0.08 g,
0.2 mmol) in the standard manner to produce the titled compound
(0.08 g, 100%) as a solid. .sup.1H NMR (CDCl.sub.3) .delta.=7.52
(d, J=8 Hz, 1H, ArH-4), 7.29 (d, J=8 Hz, 1H, ArH-7), 7.20 (t, J=8
Hz, 1H, ArH-6), 7.10 (t, J=8 Hz, 1H, ArH-5), 7.06 (s, 1H, ArH-2),
6.78 (d, J=8 Hz, 1H, NH-3'), 6.21 (d, J=8 Hz, 1H, NH-6'), 5.97
(ddt, J=17, 11, 5 Hz, 1H, NCH.sub.2CH.dbd.CH.sub.2), 5.61 (m, 1H,
CHCH.sub.2CH.dbd.CH.sub.2), 5.18 (d, J=10 Hz, 1H, CH.dbd.CHH),
5.09-5.04 (m, 3H, CH.dbd.CH.sub.2+CH.dbd.CHH), 4.69 (d, J=6 Hz, 2H,
NCH.sub.2--CH.dbd.CH.sub.2), 4.53 (m, 1H, .alpha.CH-2'), 4.43 (m,
1H .alpha.CH-5'), 3.72 (s, 2H, CH.sub.2-8'), 3.68 (s, 3H,
OCH.sub.3), 2.93 (d, J=5 Hz, 2H, NCH.sub.2(CH.sub.2).sub.3),
2.53-2.35 (m, 2H, CHCH.sub.2CH.dbd.CH.sub.2), 1.77-1.66 (m, 1H,
N(CH.sub.2).sub.3CH.sub.2) 1.41 (s, 9H, Boc), 1.45-1.27 (m, 4H,
N(CH.sub.2).sub.3CH.sub.2+NCH.sub.2CH.sub.2(CH.sub.2).sub.2),
1.15-1.08 (m, 2H, N(CH.sub.2).sub.2CH.sub.2CH.sub.2).
Example 72
Preparation of
N-[(1S)-1-[[[(1S)-1-methoxycarbonyl-3-butenyl]amino]carbonyl]-5'-amino-pe-
ntyl]-1-(1-prop-2-enyl)-1H-indole-3-acetamide
##STR00059##
[0362] The compound of Example 71, was deprotected in the standard
manner to provide the titled compound as a brown solid. mp
103-106.degree. C.; MS (ES) m/z 455 (100% MH.sup.+), 326 (79%
M.sup.+-(NHCH(CH.sub.2CH.dbd.CH.sub.2)COOCH.sub.3). HRMS (ES) calcd
for C.sub.25H.sub.35N.sub.4O.sub.4: 455.2658; found: 455.2663.
Example 73
Preparation of
methyl-1,2,5,6,7,9,10,12-octahydro-1,13-metheno-7,10-diaza-8,11-dioxo-9-4-
'(tert-butoxycarbonylamino)butyl-1-benzazacyclododecine-6-carboxylate
##STR00060##
[0364] Ring closure of the compound of Example 71 in the standard
manner gave the cyclic compound as a brown amorphous solid. MS (ES)
m/z 527 (45% MH.sup.+), 471 (56% MH.sup.+--CMe.sub.3), 453 (74%
M.sup.+-OC(CH.sub.3).sub.3), 427 (100% MH.sup.+-Boc). HRMS (ES)
calcd for C.sub.23H.sub.31N.sub.4O.sub.4: 527.2870; found:
527.2870.
Example 74
Preparation of
methyl-1,2,5,6,7,9,10,12-octahydro-1,13-metheno-7,10-diaza-8,11-dioxo-9-4-
'-aminobutyl-1-benzazacyclododecine-6-carboxylate
##STR00061##
[0366] Deprotection of the compound of Example 73 in the standard
manner gave the titled compound as a brown solid. mp
168-170.degree. C.; .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta.=7.39
(d, J=8 Hz, 1 H, ArH-14''), 7.27* (d, J=8 Hz, ArH-17''), 7.21 (d,
J=8 Hz, 1H, ArH-17''), 6.98 (t, J=8 Hz, 1H, ArH-16''), 6.93 (s, 1H,
ArH-18''), 6.88 (t, J=8 Hz, 1H, ArH-15''), 5.78* (dd, J=10, 5 Hz,
CH-3''), 5.52 (dt, J=15, 5 Hz, 1H, CH-3''), 5.40* (dd, J=10, 5 Hz,
CH-4''), 4.88-4.83 (dt, J=15, 8 Hz, 1H, CH-4''), 4.59 (dd, J=9, 3
Hz, 1H, CHH-2''), 4.36 (dd, J=9, 6 Hz, 1H, CHH-2''), 4.20 (t, J=7
Hz, 1H, CH-9''), 4.10 (dd, J=9, 5 Hz, 1H, CH-6''), 3.67 (d, J=9 Hz,
1H, CHH-12''), 3.51 (s, 3H, OCH.sub.3), 3.31 (d, J=9 Hz, 1H,
CHH-12''), 2.74 (dd, 2H, NCH.sub.2(CH.sub.2).sub.3), 2.51-2.42* (m,
CHH-5''), 2.41-2.34 (m, 1H, CHH-5''), 2.12 (ddd, J=14, 6 Hz, 1H,
CHH-5''), 1.69-1.49 (m, 2H, N(CH.sub.2).sub.3CH.sub.2), 1.58-1.48
(m, 2H, NCH.sub.2CH.sub.2(CH.sub.2).sub.2), 1.36-1.23 (m, 2H,
N(CH.sub.2).sub.2CH.sub.2CH.sub.2).
Example 75
Preparation of
methyl-1,2,5,6,7,9,10,12-1,13-metheno-7,10-diaza-8,11-dioxo-9-4'(ditert-b-
utoxycarbonylamino)pentylguanidine-1-benzazacyclododecine-6-carboxylate
##STR00062##
[0368] Guanidation of the compound of Example 74 according to the
general procedure of Example 49 gave the titled compound. MS (ES)
m/z 669 (27% MH.sup.+). HRMS (ES) calcd for
C.sub.34H.sub.49N.sub.6O.sub.8: 669.3612; found: 669.3624.
Example 76
Preparation of
methyl-1,2,5,6,7,9,10,12-octahydro-1,13-metheno-7,10-diaza-8,11-dioxo-9-4-
'-pentylguanidine-1-benzazacyclododecine-6-carboxylate
##STR00063##
[0370] Deprotection of the compound of Example 75 in the standard
manner produced the titled compound (0.06 g, 75%) as a brown solid.
mp 151-154.degree. C.
Examples 77-84
[0371] A series of compounds corresponding to the compounds of
Examples 69-76 but where a propanoate was attached at the
3-position of the indole rather than an acetate were prepared in an
analogous manner to the compounds of Examples 69-76.
Examples 85-92
[0372] A series of compounds corresponding to the compounds of
Examples 69-76 but where a butanoate was attached at the 3-position
of the indole rather than an acetate were prepared in an analogous
manner to the compounds of Examples 69-76.
[0373] Compounds Based on a 2,2'-Substituted Binaphthyl Nucleus
Example 93
Synthesis of (aR/S)-2'-allyloxy-1,1'-binaphth-2-ol
##STR00064##
[0375] 1,1'-binaphthol-2,2'-diol (4.8678 g, 17 mmol) in acetone (20
ml) was stirred with 3 g of anhydrous granules potassium carbonate
(3.0 g) and molecular sieve (5.0 g) 3 .ANG. for 1 h under nitrogen
prior to the slow addition of allyl bromide (2 ml). The reaction
mixture was refluxed for 24 h and then was left to cool. The
mixture was filtered off and the solid being washed with acetone
until colourless filtrate appeared. The combined filtrate was
evaporated to dryness and the residue was taken up in 50 ml of
dichloromethane and filtered to remove any remaining potassium
salts. The compound was purified by chromatography using
dichloromethane/hexane (1:2), R.sub.f=0.8. Yield 4.0 g, m. p.
111.degree. C. lit mp: 112.5-114, Nakamura et al., Helvetica
Chimica Acta, 58(7), (1975), 214-215.
Example 94
Synthesis of ethyl
(aR/S)-(2'-allyloxy-1,1'-binaphth-2-oxy)ethanoate
##STR00065##
[0377] Example 93 (3.631 g, 11.138 mmol) in dry acetone (10 ml) was
stirred with anhydrous potassium carbonate (2.35 g) for 1 h under
nitrogen prior to the addition of the ethyl bromoacetate (1.86 g,
11.138 mmol, 1.24 ml). After the reaction being stirred overnight
the reaction mixture was filtered. The solid being washed
repeatedly with acetone. The filtrate was evaporated to dryness and
the residue was taken up in chloroform (50 ml) then filtered. The
product isolated as a colourless semisolid by using column
chromatography chloroform/hexane 20% increase to 60%. Yield: 4.33
g. MS, m/z for C.sub.27H.sub.24O.sub.4: 413 (M+1) 100%; 339
(M.sup.+-COOC.sub.2H.sub.5) 11%.
Example 95
Synthesis of
(aR/S)-(2'-allyloxy-1,1'-binaphth-2-oxy)ethanoicacid
##STR00066##
[0379] Example 94 (0.1386 g, 0.336 mmol) was dissolved in THF
(0.047 M, 4 ml). To this ice-cooled solution was added a solution
of lithium hydroxide monohydrate (1.513 mmol, 0.063 g) in water (9
ml). The mixture was allowed to gradually warm to room temperature
and was stirred for 5 h. To the reaction mixture was added diethyl
ether. The aqueous layer was separated and washed with ether (20
ml.times.2) and the combined ether layers extracted with water (50
ml.times.2). The combined aqueous layers were acidified (dilute
hydrochloric acid) then extracted with diethyl ether (20
ml.times.3) then dried over anhydrous magnesium sulfate. The
filtrate was evaporated to dryness to afford the required product
as off white precipitate, m. p. 77-80.degree. C.
Example 96
##STR00067##
[0381] Example 95 (0.2689 g, 0.700 mmol) and
N.sub..epsilon.-Boc-D-lys-L-allylglycine methyl ester (0.25 g,
0.700 mmol) were coupled in the normal manner to give white solid,
m. p. 54-6.degree. C. Yield 0.3 g. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 8.015-7.982 (d, 1H, J=5.7 Hz), 7.982-7.955 (d, 1H,
J=5.7 Hz), 7.910-7.886 (d, 1H, J=4.2 Hz), 7.886-7.860 (d, 1H, J=4.2
Hz), 7.510-7.469 (d, 1H, J=9.3 Hz), 7.469-7.433 (d, 1H, J=9.0 Hz),
7.396-7.100 (m, 6H), 6.638-6.609 (d, 1H-N, J=7.5 Hz), 6.491-6.461
(d, 1H-N, J=7.8 Hz), 6.182 (dd, 1H, J.sub.1=7.8, J.sub.2=12.0 Hz),
5.699-5.520 (m, 2H, HC=allyl), 5.109-4.885 (m, 4H), 4.581-4.459 (m,
6H), 4.116-4.060 (m, 1H), 3.685 (s, 3H), 2.980-2.865 (m, 2H),
2.570-2.350 (m, 2H), 1.679 (br, 2H), 1.455 & 1.436 (s, 9H, R, S
isomers), 1.350-1.200 (m, 2H), 1.060-0.760 (m, 2H). MS, m/z for
C.sub.42H.sub.49N.sub.3O.sub.8: 723 (M.sup.+) 25%; 722 (M.sup.+-1)
100%; 348 18%.
Example 97
##STR00068##
[0383] Deprotection of Example 96 in the normal manner provided the
product. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.: 8.290-8.216
(m, 1H), 8.055-8.022 (m, 2H), 7.959-7.925 (m, 2H), 7.743 (br,
3H--N) 7.568-7.478 (m, 2H), 7.378-7.305 (m, 2H), 7.269-7.190 (m,
2H), 7.050-6.870 (m, 3H), 5.801-5.605 (m, 2H), 5.120-4.920 (m, 4H),
4.610-4.250 (m, 6H), 3.611, 3.602 (s, 3H, R & S), 2.637 (br,
2H), 2.450-2.310 (m, 2H), 1.500-0.860 (m, 6H). MS, m/z: 625
(M.sup.+1) 100%; 626, 19%; 737 (M.sup.-+TFA) 66%.
Example 98
##STR00069##
[0385] Cyclisation of Example 96 in the usual manner gave the
product.
[0386] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.: 8.103-7.810 (br,
1H), 8.04-7.97 (m, 2H), 7.930-7.875 (m, 2H), 7.502 (dd, 1H,
J.sub.1=4.2, J.sub.2=8.7 Hz), 7.390-7.315 (m, 3H), 7.285-7.090 (m,
4H), 6.512 (dd, 1H, J.sub.1=7.8, J.sub.2=38.7 Hz), 6.135 (dd, 1H,
J.sub.1=4.2, J.sub.2=7.5 Hz), 5.733-5.523 (m, 2H), 5.110-5.880 (m,
4H), 4.583-4.469 (m, 5H), 4.120-4.058 (m, 1H), 3.682 (s, 3H), 3.212
(dd, 2H, J.sub.1=7.2, J.sub.2=12.6 Hz), 2.577-2.363 (m, 2H), 1.502,
1.486 (2.times.s, 9H, Boc), 1.458-1.354 (m, 2H), 1.018-0.810 (m,
4H). MS m/z for C.sub.40H.sub.45N.sub.3O.sub.8: 696 (M.sup.++1)
52%; 695 (M.sup.+) 44%; 694 (M.sup.+-1) 100%.
Example 99
[0387] Deprotection of Example 98 in the usual manner the
product.
[0388] MS m/z for C.sub.35H.sub.38CIN.sub.3O.sub.6: 596 (M.sup.+)
100%; 597 40%.
Example 100
##STR00070##
[0390] The compound was prepared by guanidation of Example 97 in
the usual manner.
[0391] .sup.1HNMR (CDCl.sub.3, 300 MHz) .delta.: 8.273-8.212 (br,
1H), 8.04-7.97 (m, 2H), 7.930-7.875 (m, 2H), 7.502 (dd, 1H,
J.sub.1=4.2, J.sub.2=8.7 Hz), 7.390-7.315 (m, 3H), 7.285-7.090 (m,
4H), 6.512 (dd, 1H, J.sub.1=7.8, J.sub.2=38.7 Hz), 6.135 (dd, 1H,
J.sub.1=4.2, J.sub.2=7.5 Hz), 5.733-5.523 (m, 2H), 5.110-5.880 (m,
4H), 4.583-4.469 (m, 5H), 4.120-4.058 (m, 1H), 3.682 (s, 3H,
methyl), 3.212 (dd, 2H, J.sub.1=7.2, J.sub.2=12.6 Hz), 2.577-2.363
(m, 2H), 1.502 (s, 9H, Boc), 1.486 (s, 9H, Boc), 1.458-1.354 (m,
2H), 1.018-0.810 (m, 4H). MS, m/z for
C.sub.48H.sub.59N.sub.5O.sub.10: 867 (M.sup.++1) 100%; 867 67%; 868
67%.
Example 101
Preparation of methyl
(aR/S,2S,5R)-2-allyl-5-[2-({[(2'-allyloxy-1,1'-binaphthoxymethyl]carbonyl-
}amino)-3-aza-9-guanidino-4-oxononanoate hydrochloride
##STR00071##
[0393] The compound was prepared by deprotection of Example 100 in
the usual manner. MS, m/z for C.sub.38H.sub.44ClN.sub.5O.sub.6: 666
(M.sup.++1) 100%; 667 25%; 668 7%; 664 100%; 665 55%.
Example 102
##STR00072##
[0395] The compound was prepared by guanidation of Example 99 in
the usual manner, m. p. 108.degree. C.
Example 103
Preparation of (aR,S,7
R,10S)-6,9-diaza-3,15-dioxa-5,8-dioxo-7-(4-guanidinobutyl)-10-methoxycarb-
onyl-1(1,2),2(1,2)-dinaphthalenacyclopentadecaphane-12-ene
hydrochloride
##STR00073##
[0397] The compound was prepared by deprotection of Example 102 in
the usual manner. MS, m/z for C.sub.36H.sub.40ClN.sub.5O.sub.6: 638
(M.sup.++1) 100%; 639 55%.
Examples 104-113
[0398] A series of compounds corresponding to the compounds of
Examples 94-103 but where the corresponding butanoate was prepared
rather than an ethanoate were prepared in an analogous manner to
the compounds of Examples 94-103.
Example 104
Synthesis of ethyl
(aR/S)-(2'-allyloxy-1,1'-binaphth-2-oxy)butanoate
[0399] MS, for C.sub.29H.sub.28O.sub.4: 441 (M.sup.++1) 14.5%; 115
(CH.sub.2CH.sub.2CH.sub.2COOC.sub.2H.sub.5.sup.+) 100%.
Example 105
Synthesis of (aR/S)-(2'-allyloxy-1,1'-binaphth-2-oxy)butanoic
acid
[0400] MS, m/z for C.sub.27H.sub.24O.sub.4: 412 (M.sup.++1) 77.1%;
395 81.5%; 355 (M.sup.+-OCH.sub.2CHCH.sub.2) 12.8%; 87
(CH.sub.2CH.sub.2CH.sub.2COOH.sup.+) 100%.
Example 106
##STR00074##
[0402] m. p. 90.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.: 7.985-7.850 (m, 4H), 7.466-7.300 (m, 4H), 7.238-7.130 (m,
4H), 6.558 (t, 1H-N, J=7.5 Hz), 5.749-5.591 (m, 2H, HC=allyl),
5.451 (dd, 1H-N, J.sub.1=7.5, J.sub.2=19.2 Hz), 5.117-4.930 (m, 4H,
OCH.sub.2), 4.640-4.540 (m, 3H), 4.275-3.840 (m, 3H), 3.725, 3.693
(s, 3H 1:1), 3.08-2.950 (m, 2H), 2.578-2.450 (m, 2H), 1.965-1.570
(m, 10H), 1.442, 1.424 (s, 9H, Boc, 1:1), 1.363-1.080 (m, 2H).
Example 107
methyl
(aS/R,2S,5R)-2-allyl-10-(2'-allyloxy-1,1'-binaphth-2-oxy)-5-(4-amin-
obutyl)-3,6-diaza-4,7-dioxodecanoate hydrochloride
##STR00075##
[0404] MS, m/z for C.sub.39H.sub.46ClN.sub.3O.sub.6: 652
(M.sup.++1) 100%; 653 81%; 654 44%.
Example 108
##STR00076##
[0406] MS, m/z for C.sub.42H.sub.49N.sub.3O.sub.8: 724 (M.sup.++1)
76%; 725 40%; 768 100%; 624 (M.sup.+-Boc) 20%; 593 38%; 521
48%.
Example 109
##STR00077##
[0408] MS m/z for C.sub.37H.sub.42ClN.sub.3O.sub.6: 624 (M.sup.++1)
100%; 625 42%; 622 52%; 623 17%.
Example 110
##STR00078##
[0410] MS, m/z for C.sub.50H.sub.63N.sub.5O.sub.10: 894 (M.sup.++1)
100%; 895 70%; 896 20%.
Example 111
Preparation of methyl
(aS/R,2S,5R)-2-allyl-10-(2'-allyloxy-1,1'-binaphth-2-oxy)-3,6-diaza-5-(4--
guanidinobutyl)-4,7-dioxodecanoate hydrochloride
##STR00079##
[0412] MS, m/z for C.sub.40H.sub.48ClN.sub.5O.sub.6: 694
(M.sup.++1) 92%; 695 15%; 693 22%; 692 35%.
Example 112
##STR00080##
[0414] m. p. 95.degree. C. (d). MS, m/z for
C.sub.48H.sub.59N.sub.5O.sub.10: 866 (M.sup.++1) 100%; 867 45%.
Example 113
Preparation of
(aR/S,9R,12S)-8,11-diaza-9-(4-guanidinobutyl)-12-methoxycarbonyl-1(1,2),2-
(1,2)-dinaphthalena-3,17-dioxa-7,10-dioxoheptadecaphane-15-ene
hydrochloride
##STR00081##
[0416] MS, m/z for C.sub.38H.sub.44ClN.sub.5O.sub.6: 666
(M.sup.++1) 100%; 667 40%.
[0417] Biological Testing:
[0418] General Methods for Antibacterial Screens
[0419] Definitions
[0420] SA: Staphylococcus aureus
[0421] PA: Pseudomonas aeruginosa
[0422] KP: Klebsiella pneumoniae
[0423] SP: Streptococcus pneumoniae
[0424] Bacterial Strains Used:
[0425] Staphylococcus aureus (ATCC 6538P)
[0426] Pseudomonas aeruginosa (ATCC 27853)
[0427] Klebsiella pneumoniae (IP103623)
[0428] Streptococcus pneumoniae (IP53146)
[0429] Culture Media
[0430] Mueller-Hinton Broth Medium (MHB): MHB (Oxoid CM405) was
prepared with final concentrations of 1 .mu.g/mL MgCl.sub.2 and 2
.mu.g/mL CaCl.sub.2. Culture medium was pre-warmed for
approximately 2-3 hours at 37.degree. C. before use.
[0431] Mueller-Hinton Agar medium (MHA): MHB containing 1.5% Agar
(Merck Agar 1.01614).
[0432] Blood Agar (BA): Oxoid PP 2001.
[0433] Maintenance of Bacteria
[0434] From thawed cryovials, P. aeruginosa, K. pneumoniae and S.
aureus were streaked onto Mueller Hinton Agar (MHA), and S.
pneumoniae was streaked onto Blood Agar (BA), and plates were
incubated overnight at 37.degree. C. For each bacterial strain, 10
cryovials were prepared by looping several colonies into 0.5 mL of
20% glycerol solution. The cryovials were immediately stored at
-140.degree. C.
[0435] Preparation of Seed Cultures
[0436] A cryovial was removed from -140.degree. C. storage and
thawed at room temperature. An MHA plate was streaked with a
loopful of bacterial suspension and incubated overnight at
37.degree. C. to create a parent plate (P1). A daughter plate (D1)
was streaked from the parent plate and incubated overnight at
37.degree. C. The parent plate was stored at 4.degree. C. A loop of
colony from the daughter plate was used to inoculate a 125 mL flask
containing 20 mL of Mueller Hinton Broth (MHB) containing 25
.mu.g/mL CaCl.sub.2.2H.sub.20 and 12.5 .mu.g/mL
MgCl.sub.2.6H.sub.20. The flask was shaken at 260 rpm for 18 hours
at 37.degree. C. on an orbital incubator shaker. The parent plate
(P1) was reused within 9 days to generate another daughter plate
(D2), which, in turn, was used to inoculate a broth culture. Parent
plates were used twice (to generate D1 and D2 plates) before a new
one was prepared from the previously thawed cryovial. The second
parent plate (P2) was used to generate two additional daughter
plates using the procedure outlined above before being discarded.
Cryovials were used twice to prepare parent plates (P1 and P2)
before being discarded.
[0437] Preparation of Standardised Inocula for Assays
[0438] Prepare a 1/10 dilution of Seed Cultures by adding 250 .mu.l
of the cultures to 2,250 .mu.l of MHB in a disposable cuvette. Read
OD.sub.650 and multiply OD.sub.650 by a factor of 10 to calculate
the optical density of the undiluted culture. Calculate the
required dilution factor by dividing the observed OD.sub.650 by the
standard OD.sub.650 for each strain (previously determined in assay
optimisation studies).
TABLE-US-00001 Klebsiella pneumoniae standard OD.sub.650 = 6.16
Pseudomonas aeruginosa standard OD.sub.650 = 7.14 Staphylococcus
aureus standard OD.sub.650 = 4.75 Streptococcus pneumoniae standard
OD.sub.650 = 5.18
[0439] Prepare 10 mL of standardised inocula as illustrated by the
following example:
[0440] Sample calculation--Klebsiella pneumoniae
[0441] OD.sub.650=0.652 ( 1/10 dilution)
[0442] 10.times.0.652=6.52
[0443] .thrfore. 6.16/6.52=0.94
[0444] Add 0.94 mL of Klebsiella pneumoniae seed culture to 9.06 mL
of MHB as the first dilution.
[0445] Prepare sufficient volumes of the final inoculum cultures in
pre-warmed MHB (37.degree. C.) by diluting the standardised
cultures to the required final concentration. The final dilutions
used for each of the bacterial strains were as follows:
[0446] K. pneumoniae--10.sup.6 dilution;
[0447] P. aeruginosa--10.sup.6 dilution;
[0448] S. aureus--10.sup.8 dilution;
[0449] S. pneumoniae--10.sup.4 dilution.
[0450] Assay Procedure (for 96 Well Microtiter Plates)
[0451] Add 50 microlitres of liquid medium to each well of a 96
well microtitre plate. Dissolve test samples in liquid medium. Add
50 microlitres of test sample in triplicate to the top row of the
microtitre plate, and include a vancomycin control set. Also
include a compound negative control well set. Allow inoculated
culture medium to incubate at 37.degree. C. for 30 minutes, shaking
at 130 rpm. Using a multichannel pipette, mix the contents of the
first row and transfer 50 microlitres of mixed broth solutions to
the next row, change tips and repeat until the last row contains
diluted compound or control and discard 50 microlitres from the
last row. Each well should now contain 50 microlitres of diluted
compound or negative control medium. Using a multistepper pipette
add 50 microlitres of inoculum to each well of the plate, save for
one row containing the compound negative control, to this row add
50 microlitres of liquid broth. Incubate plates at 37.degree. C.
for 18 hours, shaking at 100 rpm in an environment of approximately
90% relative humidity. Results were recorded as the highest
dilution of compound that prevented bacterial growth (MIC).
[0452] The compounds of the invention showed MIC's of between 1 and
250 .mu.g per mL.
[0453] Results of certain compounds against S. aureus
TABLE-US-00002 Example MIC .mu.g/ml Example MIC .mu.g/ml 13A 4 44
32 (one isomer) 15 8 44 64 (one isomer) (another isomer) 15A 16 42
64 15B 16 97 4 19A 4 99 32 21A 16 101 8 (one isomer) 21A 64 103 8
(another isomer) 33A 32 107 16 36 32 109 64 37 64 111 8 38 32 113 8
39A 32 40 64
[0454] References [0455] 1. S. C. Stinson, Chem. & Eng. News,
1996, 75. [0456] 2. S. J. Brickner, Chemistry & Industry, 1997,
131. [0457] 3. T Kaneko, R G Linde II, W.-G. Su, Ann. Rep. Med.
Chem., 1999, 34, 169 [0458] 4. P. Groves, M. S. Scarle, I.
Chicarelli-Robertson, D. H. Williams, J. Chem. Soc. Perkin I, 1994,
659. [0459] 5. R. J. Dancer, A. C. Try, G. J. Sharman, D. H.
Williams, J. Chem. Soc. Chem. Commun., 1996, 1445. [0460] 6. D. H.
Williams, B Bardsley, Angew. Chem. 2.sup.nd Ed., 1999, 38, 1173.
[0461] 7. K. Nakamura et al., Tetrahedron Lett., 1995, 36, 8625 and
8629. [0462] 8. M. Ezaki et al., J. Antibiot., 1985, 38, 1453.
[0463] 9. P. H. Popieniek, P. R. Pratt, Anal. Biochem. 1987, 165,
108. [0464] 10. D. S. Lingerfelter, R. C. Helgeson, D. J. Cram, J.
Org. Chem., 1981, 46, 393
* * * * *