U.S. patent application number 16/619133 was filed with the patent office on 2021-12-30 for ring-fused thiazolino 2-pyridones, methods for preparation thereof and their use in the treatment and/or prevention of a disease involving gram-positive bacteria.
The applicant listed for this patent is QURETECH BIO AB, WASHINGTON UNIVERSITY IN ST. LOUIS. Invention is credited to Fredrik Almqvist, Michael Gordon Caparon, Jr., Scott Hultgren, Anders Lindgren, Aaron James Leonard Lynch, Ana Lidia Flores Mireles, Jerome S. Pinkner, Pardeep Singh.
Application Number | 20210401815 16/619133 |
Document ID | / |
Family ID | 1000005865642 |
Filed Date | 2021-12-30 |
United States Patent
Application |
20210401815 |
Kind Code |
A1 |
Hultgren; Scott ; et
al. |
December 30, 2021 |
RING-FUSED THIAZOLINO 2-PYRIDONES, METHODS FOR PREPARATION THEREOF
AND THEIR USE IN THE TREATMENT AND/OR PREVENTION OF A DISEASE
INVOLVING GRAM-POSITIVE BACTERIA
Abstract
The present disclosure provides a compound of Formula I, or a
pharmaceutically acceptable salt thereof, optionally in combination
with a drug against a disease involving gram-positive bacteria.
##STR00001##
Inventors: |
Hultgren; Scott; (Town and
Country, MO) ; Pinkner; Jerome S.; (St. Louis,
MO) ; Caparon, Jr.; Michael Gordon; (Chesterfield,
MO) ; Mireles; Ana Lidia Flores; (St. Louis, MO)
; Almqvist; Fredrik; (Umea, SE) ; Singh;
Pardeep; (Umea, SE) ; Lindgren; Anders; (Umea,
SE) ; Lynch; Aaron James Leonard; (Webster Grove,
MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
QURETECH BIO AB
WASHINGTON UNIVERSITY IN ST. LOUIS |
Umea
St. Louis |
MO |
SE
US |
|
|
Family ID: |
1000005865642 |
Appl. No.: |
16/619133 |
Filed: |
June 13, 2018 |
PCT Filed: |
June 13, 2018 |
PCT NO: |
PCT/EP2018/065681 |
371 Date: |
December 4, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62518680 |
Jun 13, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61K 9/0024 20130101; A61L 27/34 20130101; A61K 31/431 20130101;
A61P 31/04 20180101; A61L 27/54 20130101; A61K 31/4439 20130101;
A61L 29/085 20130101; A61K 38/14 20130101; A61K 31/4365 20130101;
A61K 38/12 20130101; A61L 29/16 20130101; C07D 513/04 20130101;
A61K 31/7036 20130101 |
International
Class: |
A61K 31/4365 20060101
A61K031/4365; A61K 9/00 20060101 A61K009/00; C07D 513/04 20060101
C07D513/04; A61K 38/14 20060101 A61K038/14; A61K 31/431 20060101
A61K031/431; A61K 38/12 20060101 A61K038/12; A61K 31/5377 20060101
A61K031/5377; A61K 31/7036 20060101 A61K031/7036; A61K 31/4439
20060101 A61K031/4439; A61P 31/04 20060101 A61P031/04; A61L 27/54
20060101 A61L027/54; A61L 29/16 20060101 A61L029/16; A61L 27/34
20060101 A61L027/34; A61L 29/08 20060101 A61L029/08 |
Claims
1. A compound of Formula III: ##STR00079## or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is selected from the
group consisting of: a) C(O)OH, b) tetrazolyl, c)
C(O)NHSO.sub.2R.sub.6, d) NH.sub.2, e) H, ##STR00080## R.sub.2 is
selected from the group consisting of: a) H, b) Cl, F, Br, or I, c)
CH.sub.2OH, d) C.sub.1-C.sub.4alkyl, and e) NZ.sub.1Z.sub.2,
R.sub.3 is selected from the group consisting of: a) 1-naphtyl,
2-naphtyl, 1-naphtyloxy, 9-anthryl and 9-anthryloxy each
independently substituted with 0, 1, 2 or 3 substituents selected
from the group consisting of methyl, fluoro, chloro, bromo, cyano
and methoxy, b) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or
4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro, cyano and trifluoromethyl, d) aminophenyl substituted with
0, 1, 2 or 3 substituents independently selected from the group
consisting of methyl, fluoro, chloro and trifluoromethyl e)
2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h)
2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i)
2-methyl-1-aza-2-bora-1H-naphth-5-yl, R.sub.4 is selected from the
group consisting of: a) C.sub.1-C.sub.4alkyl substituted with 0, 1,
2, 3 or 4 fluoro; b) C.sub.3-C.sub.6cycloalkyl, c)
C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d)
C.sub.3-C.sub.6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered
heterocycle, f) NZ.sub.1Z.sub.2, g) CH.sub.2NZ.sub.1Z.sub.2, i)
C(O)OH, and j) C(O)H, R.sub.5 is selected from the group consisting
of: ##STR00081## and in the above definitions: R.sub.6 is selected
from the group consisting of ethyl, vinyl, allyl, n-propyl,
isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl,
R.sub.7 is selected from the group consisting of F, Cl, Br, and
C.sub.1-C.sub.4alkyl, R.sub.8 is selected from the group consisting
of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy,
pentoxy, henoxy, pentoxy, octoxy, nonoxy, decoxy,
C.sub.1-C.sub.10alkenoxy, C.sub.1-C.sub.10alkynoxy and
O(CH.sub.2).sub.2OCH.sub.3, or R.sub.7 and R.sub.8 together form
O(CH.sub.2).sub.2O, R.sub.9 represents C.sub.1-C.sub.10 alkyl,
R.sub.10 represents C.sub.1-C.sub.4alkyl, R.sub.11 represents
C.sub.1-C.sub.4alkyl, or R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2, Y is O, S or N, Z.sub.1 and
Z.sub.2 each independently represents hydrogen, methyl,
CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, n is 0 or 1, m is 0 or 1,
p is 0, 1 or 2, q is 0 or 1, r is 1, and X is S, SO or SO.sub.2,
with the proviso that the compound of Formula III is not:
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or
5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-
-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid.
2. (canceled)
3. (canceled)
4. The compound according to claim 1, wherein: R.sub.1 is C(O)OH or
tetrazolyl, R.sub.2 is H; R.sub.3 is 1-naphtyl, 9-anthryl or
trifluoromethylphenyl, and R.sub.4 is C.sub.3-C.sub.6cycloalkyl,
C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, or
NZ.sub.1Z.sub.2, or a pharmaceutically acceptable salt thereof.
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. The compound according to claim 1, wherein R.sub.4 is
cyclopropyl or methoxy, or a pharmaceutically acceptable salt
thereof.
10. (canceled)
11. (canceled)
12. (canceled)
13. The compound according to claim 1, wherein R.sub.7 is methyl,
and/or R.sub.8 is selected form the group consisting of ethoxy,
propoxy, butoxy, pentoxy, hexoxy, heptoxy,
4-hydroxy-3-methyl-phenyl, 4-methoxy-3-methyl-phenyl,
4-ethoxy-3-methyl-phenyl, 4-propoxy-3-methyl-phenyl,
4-butoxy-3-methyl-phenyl, 4-pentoxy-3-methyl-phenyl,
4-hexoxy-3-methyl-phenyl, 4-heptoxy-3-methyl-phenyl,
4-butoxyphenyl, 4-pentyloxyphenyl,
4-(2-methoxyethoxy)-3-methyl-phenyl, 4-alloxy-3-methyl-phenyl,
5-hexynyloxy-3-methyl-phenyl, 4-isohexyloxy-3-methyl-phenyl,
4-(4'-methyl)-3'-pentenyloxy)-3-methyl-phenyl,
4-(5'-hexenyloxy)-3-methyl-phenyl and
1-hexyl-1H-1,2,3-triazol-4-yl, or a pharmaceutically acceptable
salt thereof.
14. The compound according to claim 1, wherein the compound is
selected from the group consisting of:
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-th-
ia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
8-(4-Butoxy-3-methyl-phenyl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thi-
a-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Methoxy-8-[4-(2-methoxyethoxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]--
2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid,
8-[4-(Allyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
8-[4-(5-Hexynyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-o-
xo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-ox-
o-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Methoxy-8-[4-(4-methyl-3-pentenyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)m-
ethyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid,
8-[4-(5-Hexenyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methy-
l]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid,
8-(1-Hexyl-1H-1,2,3-triazol-4-yl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
8(p-Butoxyphenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-aza-
bicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[p-(pentyloxy)phenyl]-7-thia-
-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-(4-methoxy-3-methyl-phenyl)-4-[(1-naphthyl)methyl]-2-oxo--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-(4-ethoxy-3-methyl-phenyl)-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phen-
yl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-o-
xo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-[4-(heptyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2--
oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-[4-(2-methoxyethoxy)-3-methyl-phenyl]-4-[(1-naphthyl)meth-
yl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid,
8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluoromethyl)p-
henyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid,
8-[4-(Cyclopropylmethoxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl-
)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid,
5-Amino-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-o-
xo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphtyl)methyl]-2-oxo-7--
thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid
imidazole salt,
8-(1-Hexyl-1H-1,2,3-triazol-4-yl)-5-methoxy-4-[(1-naphtyl)methyl]-2-
-oxo-7-thia-1-azabicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid
imidazole salt,
5-Cyclopropyl-8-(4-hydroxytolyl)-4-[(1-naphtyl)methyl]-2-oxo-7-thia-1-aza-
bicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid,
8-(dimethylamino)-2-(3-methyl-4-(pentyloxy)phenyl)-7-(naphtalen-1-ylmethy-
l)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid,
8-(dimethylamino)-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphthalen-1-ylmethy-
l)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylic,
8-(dimethylamino)-2-(4-(heptyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethy-
l)-5-oxo-thiazolo[3,2,a]pyridine-3-carbocylic acid,
8-(dimethylamino)-2-(3-methyl-4-((4-methylpentyl)oxy)phenyl)-7-(naphtalen-
-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid,
8-amino-2-(3-methyl-4-(pentyloxyphenyl)-7-naphtalen-1-ylmethyl)-5-oxo-thi-
azolo[3,2,a]pyridine-3-carboxylic acid,
8-amino-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-th-
iazolo[3,2,a]pyridine-3-caraboxylic acid,
8-amino-2-(4-heptyloxy)-3-methylphenyl)-7-8naphtalen-1-ylmethyl)-5-oxo-th-
iazolo[3,2,a]pyridine-3-carboxyic acid,
7-(anthracen-9-ylmethyl)-8-methoxy-2-(3-methyl-4-(pentyloxy)phenyl)-5-oxo-
-thiazolo[3,2,a]pyridine-3-carboxylic acid, and 1H-imidazol-1-ium
8-methoxy-2-(3-methyl-4((4-methylpentyl)oxy)phenyl)-7-(naphtalen-1-ylmeth-
yl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylate, or a
pharmaceutically acceptable salt of any of the foregoing
compounds.
15. (canceled)
16. A pharmaceutical composition comprising the compound according
to claim 1, or a pharmaceutically acceptable salt thereof, in
admixture with a pharmaceutically acceptable adjuvant, carrier or
excipient.
17. A combination comprising: (i) a composition comprising a drug
against a disease involving gram-positive bacteria, or a
pharmaceutically acceptable salt of said drug, and (ii) a
composition comprising a compound of Formula IV: ##STR00082## or a
pharmaceutically acceptable salt thereof, wherein: R.sub.1 is
selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c)
C(O)NHSO.sub.2R.sub.6, d) NH.sub.2, e) H, ##STR00083## R.sub.2 is
selected from the group consisting of: a) H, b) Cl, F, Br or I, c)
CH.sub.2OH, d) C.sub.1-C.sub.4alkyl, and e) NZ.sub.1Z.sub.2,
R.sub.3 is selected from the group consisting of: a) 1-naphtyl,
2-naphtyl, 1-naphtyloxy, 9-anthryl and 9-anthryloxy each
independently substituted with 0, 1, 2 or 3 substituents selected
from the group consisting of methyl, fluoro, chloro, bromo, cyano
and methoxy, b) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or
4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro, cyano and trifluoromethyl, d) aminophenyl substituted with
0, 1, 2 or 3 substituents independently selected from the group
consisting of methyl, fluoro, chloro and trifluoromethyl, e)
2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h)
2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i)
2-methyl-1-aza-2-bora-1H-naphth-5-yl, R.sub.4 is selected from the
group consisting of: a) C.sub.1-C.sub.4alkyl substituted with 0, 1,
2, 3 or 4 fluoro; b) C.sub.3-C.sub.6cycloalkyl, c)
C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d)
C.sub.3-C.sub.6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered
heterocycle, f) NZ.sub.1Z.sub.2, g) CH.sub.2NZ.sub.1Z.sub.2, i)
C(O)OH, j) C(O)H, k) 3-(trifluoromethyl)phenyl, and l)
benzo[d][1,3]dioxol-5-yl, R.sub.5 is selected from the group
consisting of: ##STR00084## and f) H and in the above definitions:
R.sub.6 is C.sub.1-C.sub.4alkyl or phenyl, R.sub.7 is selected from
the group consisting of F, Cl, Br, and C.sub.1-C.sub.4alkyl,
R.sub.8 is selected from the group consisting of OH,
C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10alkenoxy,
C.sub.1-C.sub.10alkynoxy and O(CH.sub.2).sub.2OCH.sub.3, or R.sub.7
and R.sub.8 together form O(CH).sub.2O, R.sub.9 is selected from
the group consisting of H and C.sub.1-C.sub.10 alkyl, R.sub.10
represents C.sub.1-C.sub.4alkyl, R.sub.11 represents
C.sub.1-C.sub.4alkyl, or R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2, Y is O, S or N, Z.sub.1 and
Z.sub.2 each independently represents hydrogen, methyl,
CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, n is 0 or 1, m is 0 or 1,
p is 0, 1 or 2, q is 0 or 1, r is 0 or 1, and X is S, SO or
SO.sub.2.
18. The combination according to claim 17, wherein said compound of
Formula IV is selected from the group consisting of:
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-(1H-indol-5-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-aza-
bicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-
-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicy-
clo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-(2-furyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-8-(3-furyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
6-[(9-Anthryl)methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-
-indancarboxylic acid,
6-[(Naphtyl)methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-i-
ndancarboxylic acid,
6-[(Naphtyloxy)methyl]-4-oxo-2-phenyl-7-(1,3-Dioxa-5-indanyl)-1-thia-3a-a-
za-3indancarboxylic acid,
(R)-7-(naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-tiazolo[3,2,a]pyridine-3,8-
-dicarboxylic acid, and
7-(anthracen-9-ylmethyl)-8-methoxy-5-oxo-2,3-dihydro-thiazolo[3,2,a]pyrid-
ine-3-carboxylic acid, or a pharmaceutically acceptable salt of any
of the foregoing compounds.
19. The combination according to claim 17, wherein the compound of
Formula IV is a compound of Formula III: ##STR00085## or a
pharmaceutically acceptable salt thereof, wherein: R.sub.1 is
selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c)
C(O)NHSO.sub.2R.sub.6, d) NH.sub.2, e) H, ##STR00086## R.sub.2 is
selected from the group consisting of: a) H, b) Cl, F, Br, or I, c)
CH.sub.2OH, d) C.sub.1-C.sub.4alkyl, and e) NZ.sub.1Z.sub.2,
R.sub.3 is selected from the group consisting of: a) 1-naphtyl,
2-naphtyl, 1-napthyloxy, 9-anthryl and 9-anthryloxy each
independently substituted with 0, 1, 2 or 3 substituents selected
from the group consisting of methyl, fluoro, chloro, bromo, cyano
and methoxy, b) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or
4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro, cyano and trifluoromethyl, d) aminophenyl substituted with
0, 1, 2 or 3 substituents independently selected from the group
consisting of methyl, fluoro, chloro and trifluoromethyl e)
2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h)
2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i)
2-methyl-1-aza-2-bora-1H-naphth-5-yl, R.sub.4 is selected from the
group consisting of: a) C.sub.1-C.sub.4alkyl substituted with 0, 1,
2, 3 or 4 fluoro: b) C.sub.3-C.sub.6cycloalkyl, c)
C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d)
C.sub.3-C.sub.6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered
heterocycle, f) NZ.sub.1Z.sub.2, g) CH.sub.2NZ.sub.1Z.sub.2, i)
C(O)OH, and j) C(O)H, R.sub.5 is selected from the group consisting
of: ##STR00087## and in the above definitions: R.sub.6 is selected
from the group consisting of ethyl, vinyl, allyl, n-propyl,
isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl,
R.sub.7 is selected from the group consisting of F, Cl, Br, and
C.sub.1-C.sub.4alkyl, R.sub.8 is selected from the group consisting
of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy,
pentoxy, hexoxy, pentoxy, octoxy, nonoxy, decoxy,
C.sub.1-C.sub.10alkenoxy, C.sub.1-C.sub.10alkenoxy and
O(CH.sub.2).sub.2OCH.sub.3, or R.sub.7 and R.sub.8 together form
O(CH.sub.2).sub.2O, R.sub.9 represents C.sub.1-C.sub.10 alkyl,
R.sub.10 represents C.sub.1-C.sub.4alkyl, R.sub.11 represents
C.sub.1-C.sub.4alkyl, or R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.6CH.sub.2, Y is O, S or N, Z.sub.1 and
Z.sub.2 each independently represents hydrogen, methyl,
CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, n is 0 or 1, m is 0 or 1,
p is 0, 1 or 2, q is 0 or 1, r is 1, and X is S, SO or SO.sub.2,
with the proviso that the compound of Formula III is not:
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3.5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4-
.3.0]nona-3.5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphtyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo-
[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicycl-
o[4,3,0]nona-3,5,8-triene-9-carboxylic acid, or
5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-
-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid.
20. The combination according to claim 17, wherein said combination
is provided as a single composition.
21. The combination according to claim 17, wherein said combination
is provided as a kit of parts.
22. The combination according to claim 17, wherein said combination
further comprises instructions for use.
23. The combination according to claim 17, wherein the drug against
a disease involving gram-positive bacteria is an antibiotic.
24. The combination according to claim 17, wherein the drug against
a disease involving gram-positive bacteria is selected from the
group consisting of vancomycin, oxacillin, dalbavancin,
oritavancin, teicoplanin, daptomycin, linezolid, tedizolid,
telavancin, gentamicin, tobramycin, amikacin, streptomycin,
neomycin, and paromomycin or any combination thereof.
25. The combination according to claim 17, wherein the drug against
a disease involving gram-positive bacteria is vancomycin, oxacillin
and/or gentamicin.
26.-36. (canceled)
37. A method for treatment and/or prevention of a disease involving
gram-positive bacteria comprising administering to a mammal, in
need thereof an effective amount of a compound of Formula III or an
effective amount of a compound of Formula IV: ##STR00088## or a
pharmaceutically acceptable salt thereof, wherein: R.sub.1 is
selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c)
C(O)NHSO.sub.2R.sub.6, d) NH.sub.2, e) H, ##STR00089## R.sub.2 is
selected from the group consisting of: a) H, b) Cl, F, Br, or I, c)
CH.sub.2OH, d) C.sub.1-C.sub.4alkyl, and e) NZ.sub.1Z.sub.2,
R.sub.3 is selected from the group consisting of: a) 1-naphtyl,
2-naphtyl, 1-napthyloxy, 9-anthryl and 9-anthryloxy each
independently substituted with 0, 1, 2 or 3 substituents selected
from the group consisting of methyl, fluoro, chloro, bromo, cyano
and methoxy, b) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or
4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro, cyano and trifluoromethyl, d) aminophenyl substituted with
0, 1, 2 or 3 substituents independently selected from the group
consisting of methyl, fluoro, chloro and trifluoromethyl e)
2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h)
2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i)
2-methyl-1-aza-2-bora-1H-naphth-5-yl, R.sub.4 is selected from the
group consisting of: a) C.sub.1-C.sub.4alkyl substituted with 0, 1,
2, 3 or 4 fluoro: b) C.sub.3-C.sub.6cycloalkyl, c)
C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d)
C.sub.3-C.sub.6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered
heterocycle, f) NZ.sub.1Z.sub.2, g) CH.sub.2NZ.sub.1Z.sub.2, i)
C(O)OH, and j) C(O)H, R.sub.5 is selected from the group consisting
of: ##STR00090## and in the above definitions: R.sub.6 is selected
from the group consisting of ethyl, vinyl, allyl, n-propyl,
isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl,
R.sub.7 is selected from the group consisting of F, Cl, Br, and
C.sub.1-C.sub.4alkyl, R.sub.8 is selected from the group consisting
of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy,
pentoxy, henoxy, pentoxy, octoxy, nonoxy, desoxy,
C.sub.1-C.sub.10alkenoxy, C.sub.1-C.sub.10alkynoxy and
O(CH.sub.2).sub.2OCH.sub.3, or R.sub.7 and R.sub.8 together form
O(CH.sub.2).sub.2O, R.sub.9 represents C.sub.1-C.sub.10 alkyl,
R.sub.10 represents C.sub.1-C.sub.4alkyl, R.sub.11 represents
C.sub.1-C.sub.4alkyl, or R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2, Y is O, S or N, Z.sub.1 and
Z.sub.2 each independently represents hydrogen, methyl,
CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, n is 0 or 1, m is 0 or 1,
p is 0, 1 or 2, q is 0 or 1, r is 1 and X is S, SO or SO.sub.2,
with the proviso that the compound of Formula III is not:
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4-
.3.0]nona-3.5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3.5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-1(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or
5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-
-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3.5,8-triene-9-carboxylic
acid: ##STR00091## or a pharmaceutically acceptable salt thereof,
wherein: R.sub.1 is selected from the group consisting of: a)
C(O)OH, b) tetrazolyl, c) C(O)NHSO.sub.2R.sub.6, d) NH.sub.2, e) H,
##STR00092## R.sub.2 is selected from the group consisting of: a)
H, b) Cl, F, Br or I, c) CH.sub.2OH, d) C.sub.1-C.sub.4alkyl, and
e) NZ.sub.1Z.sub.2, R.sub.3 is selected from the group consisting
of: a) 1-naphtyl, 2-naphtyl, 1-napthyloxy, 9-anthryl and
9-anthryloxy each independently substituted with 0, 1, 2 or 3
substituents selected from the group consisting of methyl, fluoro,
chloro, bromo, cyano and methoxy, b) C.sub.1-C.sub.4alkyl
substituted with 0, 1, 2, 3 or 4 fluoro, c) phenyl substituted with
0, 1, 2 or 3 substituents independently selected from the group
consisting of methyl, fluoro, chloro, cyano and trifluoromethyl, d)
aminophenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro and trifluoromethyl, e) 2-(3-methyl)phenylmethylene, f)
benzothiophen-2-yl, g) H, h)
2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i)
2-methyl-1-aza-2-bora-1H-naphth-5-yl, R.sub.4 is selected from the
group consisting of: a) C.sub.1-C.sub.4alkyl substituted with 0, 1,
2, 3 or 4 fluoro; b) C.sub.3-C.sub.6cycloalkyl, c)
C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d)
C.sub.3-C.sub.6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered
heterocycle, f) NZ.sub.1Z.sub.2, g) CH.sub.2NZ.sub.1Z.sub.2, i)
C(O)OH, j) C(O)H, k) 3-(trifluoromethyl)phenyl, and l)
benzo[d][1,3]dioxol-5-yl, R.sub.5 is selected from the group
consisting of: ##STR00093## and f) H and in the above definitions:
R.sub.6 is C.sub.1-C.sub.4alkyl or phenyl, R.sub.7 is selected from
the group consisting of F, Cl, Br, and C.sub.1-C.sub.4alkyl,
R.sub.8 is selected from the group consisting of OH,
C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10alkenoxy,
C.sub.1-C.sub.10alkynoxy and O(CH.sub.2).sub.2OCH.sub.3, or R.sub.7
and R.sub.8 together form O(CH).sub.2O, R.sub.9 is selected from
the group consisting of H and C.sub.1-C.sub.10 alkyl, R.sub.10
represents C.sub.1-C.sub.4alkyl, R.sub.11 represents
C.sub.1-C.sub.4alkyl, or R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2, Y is O, S or N, Z.sub.1 and
Z.sub.2 each independently represents hydrogen, methyl,
CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, n is 0 or 1, m is 0 or 1,
p is 0, 1 or 2, q is 0 or 1, r is 0 or 1, and X is S, SO or
SO.sub.2, or a combination according to claim 17.
38. The method according to claim 37, wherein said gram-positive
bacteria are selected from the group consisting of Staphylococcus
aureus, Methicillin-resistant Staphylococcus aureus (MRSA),
Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E.
faecalis), Enterococcus faecium, Vancomycin-Intermediate
Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus
aureus (VRSA), Clostridium difficile (C. difficile), Clostridium
tetani, Streptococcus pyogenes, Staphylococcus saphyticus, and
Bacillus subtilis or any combination thereof.
39. The method according to claim 37, wherein said disease is a
healthcare associated infection.
40. The method according to claim 37, wherein said disease is
selected from the group consisting of urinary tract infection
(UTI), catheter associated urinary tract infection, central line
associated bloodstream infection (CLABSI), pneumonia, wound
associated infection, surgical site infection, bacterial
endocarditis, and tetanus or any combination thereof.
41. (canceled)
42. (canceled)
43. A catheter or an implant treated with: a compound of Formula
III or Formula IV: ##STR00094## or a pharmaceutically acceptable
salt thereof, wherein: R.sub.1 is selected from the group
consisting of: a) C(O)OH, b) tetrazolyl, c) C(O)NHSO.sub.2R.sub.6,
d) NH.sub.2, e) H, ##STR00095## R.sub.2 is selected from the group
consisting of: a) H, b) Cl, F, Br, or I, c) CH.sub.2OH, d)
C.sub.1-C.sub.4alkyl, and e) NZ.sub.1Z.sub.2, R.sub.3 is selected
from the group consisting of: a) 1-naphtyl, 2-naphtyl,
1-napthyloxy, 9-anthryl and 9-anthryloxy each independently
substituted with 0, 1, 2 or 3 substituents selected from the group
consisting of methyl, fluoro, chloro, bromo, cyano and methoxy, b)
C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4 fluoro, c)
phenyl substituted with 0, 1, 2 or 3 substituents independently
selected from the group consisting of methyl, fluoro, chloro, cyano
and trifluoromethyl, d) aminophenyl substituted with 0, 1, 2 or 3
substituents independently selected from the group consisting of
methyl, fluoro, chloro and trifluoromethyl e)
2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h)
2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i)
2-methyl-1-aza-2-bora-1H-naphth-5-yl, R.sub.4 is selected from the
group consisting of: a) C.sub.1-C.sub.4alkyl substituted with 0, 1,
2, 3 or 4 fluoro; b) C.sub.3-C.sub.6cycloalkyl, c)
C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d)
C.sub.3-C.sub.6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered
heterocycle, f) NZ.sub.1Z.sub.2, g) CH.sub.2NZ.sub.1Z.sub.2, i)
C(O)OH, and j) C(O)H, R.sub.5 is selected from the group consisting
of: ##STR00096## and in the above definitions: R.sub.6 is selected
from the group consisting of ethyl, vinyl, allyl, n-propyl,
isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl,
R.sub.7 is selected from the group consisting of F, Cl, Br, and
C.sub.1-C.sub.4alkyl, R.sub.8 is selected from the group consisting
of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy,
pentoxy, hexoxy, pentoxy, octoxy, nonoxy, decoxy,
C.sub.1-C.sub.10alkenoxy, C.sub.1-C.sub.10alkynoxy and
O(CH.sub.2).sub.2OCH.sub.3, or R.sub.7 and R.sub.8 together form
O(CH.sub.2).sub.2O, R.sub.9 represents C.sub.1-C.sub.10 alkyl,
R.sub.10 represents C.sub.1-C.sub.4alkyl, R.sub.11 represents
C.sub.1-C.sub.4alkyl, or R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2, Y is O, S or N, Z.sub.1 and
Z.sub.2 each independently represents hydrogen, methyl,
CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, n is 0 or 1, m is 0 or 1,
p is 0, 1 or 2, q is 0 or 1, r is 1, and X is S, SO or SO.sub.2,
with the proviso that the compound of Formula III is not:
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4-
.3.0]nona-3.5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphtyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo-
[4.3.0]nona-3.5,8-triene-9-carboxylic acid,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or
5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-
-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, ##STR00097## or a pharmaceutically acceptable salt thereof,
wherein: R.sub.1 is selected from the group consisting of: a)
C(O)OH, b) tetrazolyl, c) C(O)NHSO.sub.2R.sub.6, d) NH.sub.2, e) H,
##STR00098## R.sub.2 is selected from the group consisting of: a)
H, b) Cl, F, Br or I, c) CH.sub.2OH, d) C.sub.1-C.sub.4alkyl, and
e) NZ.sub.1Z.sub.2, R.sub.3 is selected from the group consisting
of: a) 1-naphtyl, 2-naphtyl, 1-napthyloxy, 9-anthryl and
9-anthryloxy each independently substituted with 0, 1, 2 or 3
substituents selected from the group consisting of methyl, fluoro,
chloro, bromo, cyano and methoxy, b) C.sub.1-C.sub.4alkyl
substituted with 0, 1, 2, 3 or 4 fluoro, c) phenyl substituted with
0, 1, 2 or 3 substituents independently selected from the group
consisting of methyl, fluoro, chloro, cyano and trifluoromethyl, d)
aminophenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro and trifluoromethyl, e) 2-(3-methyl)phenylmethylene, f)
benzothiophen-2-yl, g) H, h)
2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i)
2-methyl-1-aza-2-bora-1H-naphth-5-yl, R.sub.4 is selected from the
group consisting of: a) C.sub.1-C.sub.4alkyl substituted with 0, 1,
2, 3 or 4 fluoro; b) C.sub.3-C.sub.6cycloalkyl, c)
C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d)
C.sub.3-C.sub.6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered
heterocycle, f) NZ.sub.1Z.sub.2, g) CH.sub.2NZ.sub.1Z.sub.2, i)
C(O)OH, j) C(O)H, k) 3-(trifluoromethyl)phenyl, and l)
benzo[d][1,3]dioxol-5-yl, R.sub.5 is selected from the group
consisting of: ##STR00099## and f) H and in the above definitions:
R.sub.6 is C.sub.1-C.sub.4alkyl or phenyl, R.sub.7 is selected from
the group consisting of F, Cl, Br, and C.sub.1-C.sub.4alkyl,
R.sub.8 is selected from the group consisting of OH,
C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10alkenoxy,
C.sub.1-C.sub.10alkynoxy and O(CH.sub.2).sub.2OCH.sub.3, or R.sub.7
and R.sub.8 together form O(CH).sub.2O, R.sub.9 is selected from
the group consisting of H and C.sub.1-C.sub.10 alkyl, R.sub.10
represents C.sub.1-C.sub.4alkyl, R.sub.11 represents
C.sub.1-C.sub.4alkyl, or R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2, Y is O, S or N, Z.sub.1 and
Z.sub.2 each independently represents hydrogen, methyl,
CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, n is 0 or 1, m is 0 or 1,
p is 0, 1 or 2, q is 0 or 1, r is 0 or 1, and X is S, SO or
SO.sub.2, or a combination as defined in claim 17.
44. (canceled)
45. (canceled)
Description
TECHNICAL FIELD
[0001] The present disclosure concerns novel ring-fused thiazolino
2-pyridones, methods for preparation thereof as well as their use
in the treatment and/or prevention of a disease involving
gram-positive bacteria. Further, the disclosure concerns a
combination of a ring-fused thiazolino 2-pyridone and a drug
against a disease involving gram-positive bacteria.
BACKGROUND
[0002] Infections and/or diseases that resist treatment with
currently available drugs is an increasing problem and a serious
threat to public health. Many of these infections and/or diseases
involve gram-positive bacteria such as Staphylococcus aureus,
Methicillin-resistant Staphylococcus aureus (MRSA),
Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E.
faecalis), Enterococcus faecium, Vancomycin-Intermediate
Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus
aureus (VRSA), Clostridium difficile (C. difficile), Clostridium
tetani, Streptococcus pyogenes and Staphylococcus saphyticus and
Bacillus subtilis.
[0003] The term gram-positive originates from a laboratory staining
technique named after the Danish scientist Hans Christian Gram. In
this staining technique, bacteria are divided into groups of
gram-positive bacteria and gram-negative bacteria depending on
their ability to take up crystal violet stain. The Gram staining
differentiates bacteria by the chemical and physical properties of
their cell walls by detecting peptidoglycan, which is present in
the cell wall of Gram-positive bacteria. Gram-positive bacteria
retain the crystal violet dye, and thus are stained violet, while
the Gram-negative bacteria do not. The Gram stain is almost always
the first step in the preliminary identification of a bacterial
organism. While Gram staining is a valuable diagnostic tool in both
clinical and research settings, not all bacteria can be
definitively classified by this technique. For instance,
tuberculosis bacteria are neither gram-positive or
gram-negative.
[0004] In addition to being classified by their staining in the
Gram staining technique, bacteria may be further classified by
their shape. For instance, the shapes include Cocci and Bacilli.
Cocci have a spherical shape and can be either Staphylococcus
(appearing like a bunch of grapes) or Streptococcus (forming a
chain). Bacilli have a rod shape and can be either spore forming or
non spore forming.
[0005] Examples of infection and/or disease involving gram-positive
bacteria include urinary tract infection (UTI), catheter associated
urinary tract infection, central line associated bloodstream
infection (CLABSI), pneumonia, wound associated infection, surgical
site infection, bacterial endocarditis, and tetanus. An important
reason for the increase of these infections and/or diseases appears
to be the increasing number of healthcare-associated infections
(HCAI), i.e. infections acquired in or in connection with a
health-care setting such as a hospital. For instance, the use of
catheters and other intravascular devices frequently lead to
diseases and/or infections involving gram-positive bacteria such as
Staphylococcus aureus. The World Health Organization has reported
that hundreds of millions of patients are affected by
healthcare-associated infections worldwide each year, leading to
significant mortality and financial losses for health systems.
Thus, healthcare-associated infections are a widespread and
significant problem that needs to be addressed.
[0006] WO 2014/185852 discloses substituted ring-fused 2-pyridones
which are shown to reduce the infectivity of Chlamydia. However,
the bacteria involved in Chlamydia are gram-negative.
[0007] WO2016075296 discloses ring-fused thiazolino 2-pyridones and
use thereof in the treatment of a Chlamydia infection. However, the
bacteria involved in Chlamydia are gram-negative.
[0008] PCT/IB2017/051999 discloses ring-fused thiazolino
2-pyridones and use thereof in the treatment of tuberculosis.
However, the bacteria involved in are neither gram-positive nor
gram-negative.
[0009] Many of the diseases and/or infections involving
gram-positive bacteria are severe and/or drug-resistant making them
a serious threat to public health. Therefore, there is a need for
alternative and/or improved treatments of infections and/or
diseases involving gram-positive bacteria.
[0010] It is an object of the present disclosure to provide
compounds useful in the treatment and/or prevention of infections
and/or diseases involving gram-positive bacteria. Further, it is an
object of the present disclosure to provide compounds that may be
used in combination with current therapeutic agents such as
vancomycin to improve treatment and/or prevention of infections
and/or diseases involving gram-positive bacteria.
SUMMARY
[0011] There is provided a compound of Formula I:
##STR00002##
[0012] or a pharmaceutically acceptable salt thereof,
[0013] wherein:
[0014] R.sub.1 is selected from the group consisting of:
[0015] a) C(O)OH,
[0016] b) tetrazolyl,
[0017] c) C(O)NHSO.sub.2R.sub.6,
[0018] d) NH.sub.2,
[0019] e) H,
##STR00003##
[0020] R.sub.2 is selected from the group consisting of:
[0021] a) H,
[0022] b) Cl, F, Br, or I,
[0023] c) CH.sub.2OH,
[0024] d) C.sub.1-C.sub.4alkyl, and
[0025] e) NZ.sub.1Z.sub.2,
[0026] R.sub.3 is selected from the group consisting of:
[0027] a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and
9-anthryloxy each independently substituted with 0, 1, 2 or 3
substituents selected from the group consisting of methyl, fluoro,
chloro, bromo, cyano and methoxy,
[0028] b) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4
fluoro,
[0029] c) phenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro, cyano and trifluoromethyl,
[0030] d) aminophenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro and trifluoromethyl
[0031] e) 2-(3-methyl)phenylmethylene,
[0032] f) benzothiophen-2-yl,
[0033] g) H,
[0034] h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
[0035] i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
[0036] R.sub.4 is selected from the group consisting of:
[0037] a) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4
fluoro;
[0038] b) C.sub.3-C.sub.6cycloalkyl,
[0039] c) C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4
fluoro,
[0040] d) C.sub.3-C.sub.6cycloalkoxy,
[0041] e) a 3-, 4-, 5-, or 6-membered heterocycle,
[0042] f) NZ.sub.1Z.sub.2,
[0043] g) CH.sub.2NZ.sub.1Z.sub.2,
[0044] i) C(O)OH, and
[0045] j) C(O)H,
[0046] R.sub.5 is selected from the group consisting of:
##STR00004##
[0047] and in the above definitions:
[0048] R.sub.6 is C.sub.1-C.sub.4alkyl or phenyl,
[0049] R.sub.7 is selected from the group consisting of F, Cl, Br,
and C.sub.1-C.sub.4alkyl,
[0050] R.sub.8 is selected from the group consisting of OH,
C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10alkenoxy,
C.sub.1-C.sub.10alkynoxy and O(CH.sub.2).sub.2OCH.sub.3, or
[0051] R.sub.7 and R.sub.8 together form O(CH).sub.2O,
[0052] R.sub.9 represents C.sub.1-C.sub.10 alkyl,
[0053] R.sub.10 represents C.sub.1-C.sub.4alkyl,
[0054] R.sub.11 represents C.sub.1-C.sub.4alkyl, or
[0055] R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2,
[0056] Y is O, S or N,
[0057] Z.sub.1 and Z.sub.2 each independently represents hydrogen,
methyl, CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2,
[0058] n is 0 or 1,
[0059] m is 0 or 1,
[0060] p is 0, 1 or 2,
[0061] q is 0 or 1,
[0062] r is 1, and
[0063] X is S, SO or SO.sub.2,
[0064] with the proviso that the compound of Formula I is not:
[0065]
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid, [0066]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid, [0067]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0068]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or [0069]
5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-
-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid.
[0070] There is also provided a pharmaceutical composition
comprising a compound of Formula I as described herein, or a
pharmaceutically acceptable salt thereof, in admixture with a
pharmaceutically acceptable adjuvant, carrier or excipient.
[0071] Further, the present disclosure provides a compound of
Formula as described herein, or a pharmaceutically acceptable salt
thereof, for use as a medicament in therapy.
[0072] There is also provided a compound of Formula I or Formula IV
as described herein, or a pharmaceutically acceptable salt thereof,
for use in the treatment and/or prevention of a disease involving
gram-positive bacteria.
[0073] There is also provided use of a compound of Formula I or
Formula IV as described herein, or a pharmaceutically acceptable
salt thereof, for the manufacture of a medicament for the treatment
and/or prevention of a disease involving gram-positive
bacteria.
[0074] There is also provided a method for treatment and/or
prevention of a disease involving gram-positive bacteria comprising
administering to a mammal, such as a human or an animal, in need
thereof an effective amount of a compound of Formula I or Formula
IV as described herein, or a pharmaceutically acceptable salt
thereof.
[0075] Further, there is provided a combination comprising:
[0076] (i) a composition comprising or consisting of a drug against
a disease involving gram-positive bacteria, or a pharmaceutically
acceptable salt of said drug, and
[0077] (ii) a composition comprising or consisting of a compound of
Formula IV:
##STR00005##
[0078] or a pharmaceutically acceptable salt thereof,
[0079] wherein:
[0080] R.sub.1 is selected from the group consisting of:
[0081] a) C(O)OH,
[0082] b) tetrazolyl,
[0083] c) C(O)NHSO.sub.2R.sub.6,
[0084] d) NH.sub.2,
[0085] e) H,
##STR00006##
[0086] R.sub.2 is selected from the group consisting of:
[0087] a) H,
[0088] b) Cl, F, Br, or I,
[0089] c) CH.sub.2OH,
[0090] d) C.sub.1-C.sub.4alkyl, and
[0091] e) NZ.sub.1Z.sub.2,
[0092] R.sub.3 is selected from the group consisting of:
[0093] a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and
9-anthryloxy each independently substituted with 0, 1, 2 or 3
substituents selected from the group consisting of methyl, fluoro,
chloro, bromo, cyano and methoxy,
[0094] b) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4
fluoro,
[0095] c) phenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro, cyano and trifluoromethyl,
[0096] d) aminophenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro and trifluoromethyl,
[0097] e) 2-(3-methyl)phenylmethylene,
[0098] f) benzothiophen-2-yl,
[0099] g) H,
[0100] h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
[0101] i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
[0102] R.sub.4 is selected from the group consisting of:
[0103] a) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4
fluoro;
[0104] b) C.sub.3-C.sub.6cycloalkyl,
[0105] c) C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4
fluoro,
[0106] d) C.sub.3-C.sub.6cycloalkoxy,
[0107] e) a 3-, 4-, 5-, or 6-membered heterocycle,
[0108] f) NZ.sub.1Z.sub.2,
[0109] g) CH.sub.2NZ.sub.1Z.sub.2,
[0110] i) C(O)OH,
[0111] j) C(O)H,
[0112] k) 3-(trifluoromethyl)phenyl, and
[0113] l) benzo[d][1,3]dioxol-5-yl,
[0114] R.sub.5 is selected from the group consisting of:
##STR00007##
and
[0115] f) H,
[0116] and in the above definitions:
[0117] R.sub.6 is C.sub.1-C.sub.4alkyl or phenyl,
[0118] R.sub.7 is selected from the group consisting of F, Cl, Br,
and C.sub.I-C.sub.4alkyl,
[0119] R.sub.8 is selected from the group consisting of OH,
C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10alkenoxy,
C.sub.1-C.sub.10alkynoxy and O(CH.sub.2).sub.2OCH.sub.3, or
[0120] R.sub.7 and R.sub.8 together form O(CH).sub.2O,
[0121] R.sub.9 is selected from the group consisting of H and
C.sub.1-C.sub.10 alkyl,
[0122] R.sub.10 represents C.sub.1-C.sub.4alkyl,
[0123] R.sub.11 represents C.sub.1-C.sub.4alkyl, or
[0124] R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2,
[0125] Y is O, S or N,
[0126] Z.sub.1 and Z.sub.2 each independently represents hydrogen,
methyl, CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2,
[0127] n is 0 or 1,
[0128] m is 0 or 1,
[0129] p is 0, 1 or 2,
[0130] q is 0 or 1,
[0131] r is 0 or 1, and
[0132] X is S, SO or SO.sub.2.
[0133] There is also described a combination as described herein
for use as a medicament in therapy.
[0134] There is also provided a combination as described herein for
use in the treatment and/or prevention of a disease involving
gram-positive bacteria.
[0135] There is also provided use of a combination as described
herein for the manufacture of a medicament for the treatment and/or
prevention of a disease involving gram-positive bacteria.
[0136] There is also provided a method for treatment and/or
prevention of a disease involving gram-positive bacteria comprising
administering to a mammal, such as a human or an animal, in need
thereof an effective amount of a combination as described
herein
BRIEF DESCRIPTION OF THE DRAWINGS
[0137] FIG. 1a shows the chemical structure of vancomycin.
[0138] FIG. 1b shows the chemical structure of oxacillin.
[0139] FIG. 2a shows the chemical structure of dalbavancin.
[0140] FIG. 2b shows the chemical structure of oritavancin.
[0141] FIG. 3a shows the chemical structure of teicoplanin.
[0142] FIG. 3b shows the chemical structure of daptomycin.
[0143] FIG. 4a shows the chemical structure of linezolid.
[0144] FIG. 4b shows the chemical structure of tedizolid.
[0145] FIG. 5 shows the chemical structure of telavancin.
[0146] FIG. 6 shows the chemical structure of gentamicin.
[0147] FIG. 7 shows the effect of a combination of gentamicin and
the compound of Example 11 described herein on E. faecalis OG1RF in
vitro.
[0148] FIG. 8a shows the effect of the compounds of Example 28 and
Example 30 against E. faecalis OG1RF bladder colonization in a
mouse model of catheter-associated urinary tract infection
(CAUTI).
[0149] FIG. 8b shows the effect of the compounds of Example 28 and
Example 30 against E. faecalis OG1RF catheter colonization in a
mouse model of CAUTI.
[0150] FIG. 9a shows the effect of the compounds of Example 14,
Example 49, Example 23, and Example 50 against E. faecalis OG1RF
bladder colonization in a mouse model of catheter-associated
urinary tract infection (CAUTI).
[0151] FIG. 9b shows the effect of the compounds of Example 14,
Example 49, Example 23, and Example 50 against E. faecalis OG1RF
catheter colonization in a mouse model of CAUTI.
[0152] FIG. 10a shows the effect of a combination of vancomycin and
the compound of Example 49 against E. faecalis OG1RF bladder
colonization in a mouse model of CAUTI.
[0153] FIG. 10b shows the effect of a combination of vancomycin and
the compound of Example 49 against E. faecalis OG1RF catheter
colonization in a mouse model of CAUTI.
[0154] FIG. 11a shows the effect of a combination of vancomycin and
the compound of Example 49 against vancomycin-resistant E. faecalis
V583 bladder colonization in a mouse model of CAUTI.
[0155] FIG. 11b shows the effect of a combination of vancomycin and
the compound of Example 49 against vancomycin-resistant E. faecalis
V583 catheter colonization in a mouse model of CAUTI.
[0156] FIG. 12a shows the effect of a combination of gentamicin and
the compound of Example 49 against E. faecalis OG1RF bladder
colonization in a mouse model of CAUTI.
[0157] FIG. 12b shows the effect of a combination of gentamicin and
the compound of Example 49 against E. faecalis OG1RF catheter
colonization in a mouse model of CAUTI.
[0158] The chemical structures depicted in FIGS. 1-6 have not been
drawn with the program Chem Doodle.
DETAILED DESCRIPTION
[0159] The present disclosure provides a compound of Formula I:
##STR00008##
[0160] or a pharmaceutically acceptable salt thereof,
[0161] wherein:
[0162] R.sub.1 is selected from the group consisting of:
[0163] a) C(O)OH,
[0164] b) tetrazolyl,
[0165] c) C(O)NHSO.sub.2R.sub.6,
[0166] d) NH.sub.2,
[0167] e) H,
##STR00009##
[0168] R.sub.2 is selected from the group consisting of:
[0169] a) H,
[0170] b) Cl, F, Br, or I,
[0171] c) CH.sub.2OH,
[0172] d) C.sub.1-C.sub.4alkyl, and
[0173] e) NZ.sub.1Z.sub.2,
[0174] R.sub.3 is selected from the group consisting of:
[0175] a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and
9-anthryloxy each independently substituted with 0, 1, 2 or 3
substituents selected from the group consisting of methyl, fluoro,
chloro, bromo, cyano and methoxy,
[0176] b) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4
fluoro,
[0177] c) phenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro, cyano and trifluoromethyl,
[0178] d) aminophenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro and trifluoromethyl
[0179] e) 2-(3-methyl)phenylmethylene,
[0180] f) benzothiophen-2-yl,
[0181] g) H,
[0182] h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
[0183] i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
[0184] R.sub.4 is selected from the group consisting of:
[0185] a) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4
fluoro;
[0186] b) C.sub.3-C.sub.6cycloalkyl,
[0187] c) C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4
fluoro,
[0188] d) C.sub.3-C.sub.6cycloalkoxy,
[0189] e) a 3-, 4-, 5-, or 6-membered heterocycle,
[0190] f) NZ.sub.1Z.sub.2,
[0191] g) CH.sub.2NZ.sub.1Z.sub.2,
[0192] i) C(O)OH, and
[0193] j) C(O)H,
[0194] R.sub.5 is selected from the group consisting of:
##STR00010##
[0195] and in the above definitions:
[0196] R.sub.6 is C.sub.1-C.sub.4alkyl or phenyl,
[0197] R.sub.7 is selected from the group consisting of F, Cl, Br,
and C.sub.1-C.sub.4alkyl, R.sub.8 is selected from the group
consisting of OH, C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10alkenoxy,
C.sub.1-C.sub.10alkynoxy and O(CH.sub.2).sub.2OCH.sub.3, or
[0198] R.sub.7 and R.sub.8 together form O(CH.sub.2).sub.2O,
[0199] R.sub.9 represents C.sub.1-C.sub.10 alkyl,
[0200] R.sub.10 represents C.sub.1-C.sub.4alkyl,
[0201] R.sub.11 represents C.sub.1-C.sub.4alkyl, or
[0202] R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2,
[0203] Y is O, S or N,
[0204] Z.sub.1 and Z.sub.2 each independently represents hydrogen,
methyl, CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2,
[0205] n is 0 or 1,
[0206] m is 0 or 1,
[0207] p is 0, 1 or 2,
[0208] q is 0 or 1,
[0209] r is 1, and
[0210] X is S, SO or SO.sub.2,
[0211] with the proviso that the compound of Formula I is not:
[0212]
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid, [0213]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid, [0214]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0215]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or [0216]
5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-
-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid.
[0217] The term "C.sub.1-C.sub.4alkyl" denotes a straight or
branched, saturated or unsaturated alkyl group of one to four
carbon atoms. Examples of "C.sub.1-C.sub.4alkyl" include, but are
not limited to, methyl, ethyl, vinyl, allyl, n-propyl, isopropyl,
n-butyl, sec-butyl, iso-butyl and tert-butyl.
[0218] The term "C.sub.1-C.sub.4alkoxy" denotes a
C.sub.1-C.sub.4alkyl group as described herein which is linked to
an oxygen atom. Examples of "C.sub.1-C.sub.4alkoxy" include, but
are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy and
butoxy.
[0219] The term "C.sub.1-C.sub.10alkoxy" denotes a
C.sub.1-C.sub.10alkyl group which is linked to an oxygen atom. The
C.sub.1-C.sub.10alkyl group may be straight, branched and/or
include a cycloalkyl group. The Examples of
"C.sub.1-C.sub.10alkoxy" include, but are not limited to, methoxy,
ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy,
pentoxy, hexoxy, pentoxy, octoxy, nonony, and decoxy.
[0220] The term "C.sub.3-C.sub.6cycloalkyl" denotes a saturated or
unsaturated non-aromatic monocyclic ring composed of three, four,
five or six carbon atoms. Examples of "C.sub.3-C.sub.6cycloalkyl"
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
[0221] The term "C.sub.3-C.sub.6cycloalkoxy" denotes a saturated or
unsaturated non-aromatic monocyclic ring composed of three, four,
five or six carbon atoms which is linked to an oxygen atom.
Examples of "C.sub.3-C.sub.6cycloalkoxy" include, but are not
limited to, cyclopropyloxy, cyclopropoxymethylene, cyclobutyloxy,
cyclobutyloxymethylene, cyclopentyloxy, cyclopentyloxymethylene,
cyclohexyloxy and cyclohexyloxymethylene.
[0222] The term "C.sub.1-C.sub.10alkenoxy" denotes a
C.sub.1-C.sub.10alkenyl group which is linked to an oxygen atom.
The C.sub.1-C.sub.10alkenyl group may be straight or branched. The
Examples of C.sub.1-C.sub.10alkenoxy include, but are not limited
to, allyloxy, 5-hexenyloxy or 4-methyl-3-pentenyloxy,
(E)-2-heptenyloxy, (E)-2-hexenyloxy, (E)-2-pentenyloxy,
(E)-2-butenyloxy, (Z)-2-heptenyloxy, (Z)-2-hexenyloxy and
(Z)-2-pentenyloxy.
[0223] The term "C.sub.1-C.sub.10alkynoxy" denotes a
C.sub.1-C.sub.10alkynyl group which is linked to an oxygen atom.
The C.sub.1-C.sub.10alkynyl group may be straight or branched. The
Examples of C.sub.1-C.sub.10alkynoxy include, but are not limited
to, 5-hexynyloxy, (Z)-2-Butenyloxy 2-heptynyloxy, 2-hexynyloxy,
2-pentynyloxy, 2-butynyloxy, 3-heptynyloxy, 3-hexynyloxy,
3-pentynyloxy, 3-butynyloxy, 4-heptynyloxy, 4-hexynyloxy and
4-pentynyloxy.
[0224] The term "3-membered heterocycle" denotes a 3-membered
saturated or unsaturated heterocycle. Examples of a 3-membered
saturated heterocycle include, but are not limited to, aziridine,
oxirane and thiirane. Examples of 3-membered unsaturated
heterocycles include, but are not limited to, azirine, oxirene and
thiirene.
[0225] The term "4-membered heterocycle" denotes a 4-membered
saturated or unsaturated heterocycle. Examples of a 4-membered
heterocycle include, but are not limited to, azetidine, oxethane
and thietane.
[0226] The term "5-membered heterocycle" denotes a 5-membered
saturated or unsaturated heterocycle. Examples of a 5-membered
heterocycles include, but are not limited to pyrrolidine,
tetrahydrofurane, thiolane, pyrrole, furane, thiophene,
imidazolidine, pyrazolidine, pxazolidine, isoxazolidine,
thiazolidine, isothiazolidine, dioxolane, dithiolane, imidazole,
pyrazole, oxazole, isoxazole, thiazole, and isothiazole.
[0227] The term "6-membered heterocycle" denotes a 6-membered
saturated or unsaturated heterocycle. Examples of a 6-membered
heterocycles include, but are not limited to piperidine, pyridine,
piperazine, morpholine, and thiomorpholine.
[0228] The drug against a disease involving gram-positive bacteria
is to be understood as a drug that counteracts gram-positive
bacteria. The against a disease involving gram-positive bacteria
may reduce, substantially eliminate or eradicate gram-positive
bacteria. The drug against a disease involving gram-positive
bacteria may also be denominated a drug to treat a disease
involving gram-positive bacteria.
[0229] The term infection intends a condition wherein gram-positive
bacteria have entered into a mammal such as a human. The term
disease is understood to be an abnormal condition of a part, organ,
or system of a mammal such as a human resulting from various
causes, such as infection, inflammation, environmental factors, or
genetic defect, and characterized by an identifiable group of
signs, symptoms, or both. The skilled person understands that there
is an overlap of the terms. In this document, the term disease is
understood to encompass both disease and infection. Thus, when the
term disease is used it may intend disease and/or infection.
[0230] The compound of Formula I may be a compound of Formula II or
Formula III:
##STR00011##
[0231] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and X
are as defined for the compound of Formula I, or a pharmaceutically
acceptable salt thereof.
[0232] The compound of Formula I may be a compound of Formula IIa,
Formula IIb, Formula IIc and/or Formula IId:
##STR00012##
[0233] wherein
[0234] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and X are as
defined for the compound of Formula I, or a pharmaceutically
acceptable salt thereof.
[0235] Further values of wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, n, m, p, q, r and X will now follow. It will be
appreciated that these values may be applied to any compound of
Formula I, Formula II or Formula III of the present disclosure.
[0236] R.sub.1 may be C(O)OH or tetrazolyl.
[0237] In a further example, R.sub.1 is a combination C(O)OH,
tetrazolyl or C(O)NHSO.sub.2R.sub.6 with imidazole. Thus, R.sub.1
may be selected from:
##STR00013##
[0238] wherein R.sub.6 is as defined herein.
[0239] R.sub.2 may be H.
[0240] R.sub.3 may be 1-naphtyl, 9-anthryl or
trifluoromethylphenyl.
[0241] R.sub.4 may be selected from:
[0242] C.sub.3-C.sub.6cycloalkyl,
[0243] C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4
fluoro, or
[0244] NZ.sub.1Z.sub.2,
[0245] wherein Z.sub.1 and Z.sub.2 are as defined herein. For
instance, R.sub.4 may be cyclopropyl or methoxy.
[0246] X may be S or SO.
[0247] R.sub.5 may be:
##STR00014##
[0248] wherein R.sub.7 and R.sub.8 are as defined herein. For
instance, R.sub.5 may be:
##STR00015##
[0249] wherein R.sub.7 and R.sub.8 are as defined herein. In an
example, R.sub.7 may be H or methyl and/or R.sub.8 is selected form
the group consisting of methoxy, ethoxy, propoxy, butoxy, pentoxy,
hexoxy, heptoxy, 4-hydroxy-3-methyl-phenyl,
4-methoxy-3-methyl-phenyl, 4-ethoxy-3-methyl-phenyl,
4-propoxy-3-methyl-phenyl, 4-butoxy-3-methyl-phenyl,
4-pentoxy-3-methyl-phenyl, 4-hexoxy-3-methyl-phenyl,
4-heptoxy-3-methyl-phenyl, 4-Butoxyphenyl, 4-pentyloxyphenyl,
4-(2-methoxyethoxy-3-methyl-phenyl, 4-alloxy-3-methyl-phenyl,
5-Hexynyloxy-3-methyl-phenyl, 4-Isohexyloxy-3-methyl-phenyl,
4-(4'-methyl)-3'-pentenyloxy)-3-methyl-phenyl,
4-(5'-Hexenyloxy)-3-methyl-phenyl and
1-Hexyl-1H-1,2,3-triazol-4-yl.
[0250] The compound of Formula I described herein may be selected
from Examples 1-27, 41-47, 49 and 50 of Table 1 of this
document.
[0251] For instance, the compound of Formula I described herein may
be selected from: [0252]
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-th-
ia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0253]
8-(4-Butoxy-3-methyl-phenyl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thi-
a-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0254]
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0255]
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0256]
5-Methoxy-8-[4-(2-methoxyethoxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]--
2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0257]
8-[4-(Allyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]--
2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0258]
8-[4-(5-Hexynyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)meth-
yl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0259]
8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methy-
l]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0260]
5-Methoxy-8-[4-(4-methyl-3-pentenyloxy)-3-methyl-phenyl]-4-[(1-nap-
hthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxyl-
ic acid, [0261]
8-[4-(5-Hexenyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-o-
xo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0262]
8-(1-Hexyl-1H-1,2,3-triazol-4-yl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0263]
8-(p-Butoxyphenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-az-
abicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0264]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[p-(pentyloxy)phenyl]-7-thia-
-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0265]
5-Cyclopropyl-8-(4-methoxy-3-methyl-phenyl)-4-[(1-naphthyl)methyl]-2-oxo--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0266]
5-Cyclopropyl-8-(4-ethoxy-3-methyl-phenyl)-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0267]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0268]
8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0269]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phen-
yl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0270]
5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-o-
xo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0271]
5-Cyclopropyl-8-[4-(heptyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2--
oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0272]
5-Cyclopropyl-8-[4-(2-methoxyethoxy)-3-methyl-phenyl]-4-[(1-naphthyl)meth-
yl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0273]
8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluorom-
ethyl)phenyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxy-
lic acid, [0274]
8-[4-(Cyclopropylmethoxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methy-
l]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0275]
5-Amino-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2--
oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0276]
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphtyl)methyl]-2-oxo-7--
thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid
imidazole salt, [0277]
8-(1-Hexyl-1H-1,2,3-triazol-4-yl)-5-methoxy-4-[(1-naphtyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid
imidazole salt, [0278]
5-Cyclopropyl-8-(4-hydroxytolyl)-4-[(1-naphtyl)methyl]-2-oxo-7-thia-1-aza-
bicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid, [0279]
8-(dimethylamino)-2-(3-methyl-4-(pentyloxy)phenyl)-7-(naphtalen-1ylmethyl-
)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid, [0280]
8-(dimethylamino)-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphthalen-1-ylmethy-
l)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylic, [0281]
8-(dimethylamino)-2-(4-(heptyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethy-
l)-5-oxo-thiazolo[3,2,a]pyridine-3-carbocylic acid, [0282]
8-(dimethylamino)-2-(3-methyl-4-((4-methylpentyl)oxy)phenyl)-7-(naphtalen-
-1ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid, [0283]
8-amino-2-(3-methyl-4-(pentyloxyphenyl)-7-naphtalen-1ylmethyl)-5-oxo-thia-
zolo[3,2,a]pyridine-3-carboxylic acid, [0284]
8-amino-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-th-
iazolo[3,2,a]pyridine-3-caraboxylic acid, [0285]
8-amino-2-(4-heptyloxy)-3-methylphenyl)-7-8naphtalen-1-ylmethyl)-5-oxo-th-
iazolo[3,2,a]pyridine-3-carboxyic acid, [0286]
7-(anthracen-9-ylmethyl)-8-methoxy-2-(3-methyl-4-(pentyloxy)phenyl)Y5-oxo-
-thiazolo[3,2,a]pyridine-3-carboxylic acid, or [0287]
1H-imidazol-1-ium
8-methoxy-2-(3-methyl-4((4-methylpentyl)oxy)phenyl)-7-(naphtalen-1-ylmeth-
yl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylate,
[0288] a pharmaceutically acceptable salt of any of the foregoing
compounds.
[0289] Further, the compound of Formula I as described herein may
be selected from: [0290]
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0291]
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0292]
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-th-
ia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0293]
8-(4-Butoxy-3-methyl-phenyl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thi-
a-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0294]
5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-o-
xo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0295]
8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0296]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0297]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phen-
yl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0298]
8-[4-(Cyclopropylmethoxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methy-
l]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0299]
8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methy-
l]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0300]
8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluorom-
ethyl)phenyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxy-
lic acid, or [0301] 1H-imidazol-1-ium
8-methoxy-2-(3-methyl-4((4-methylpentyl)oxy)phenyl)-7-(naphtalen-1-ylmeth-
yl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylate,
[0302] a pharmaceutically acceptable salt of any of the foregoing
compounds.
[0303] Further, the compound of Formula I as described herein may
be selected from: [0304]
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0305]
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0306]
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-th-
ia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0307]
5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-o-
xo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0308]
8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-ox-
o-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0309]
8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluoromethyl)p-
henyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, or
[0310] a pharmaceutically acceptable salt of any of the foregoing
compounds.
[0311] There is also provided a compound of Formula I as described,
wherein:
[0312] R.sub.1 is selected from the group consisting of carboxylic
acid and 1H-imidazol-1-ium carboxylate,
[0313] R.sub.2 is hydrogen,
[0314] R.sub.3 is selected from the group consisting of
naphthalen-1-yl, 3-(trifluoromethyl)phenyl, anthracen-9-yl and
naphthalen-1-yloxy,
[0315] R.sub.4 is selected from the group consisting of:
cyclopropyl, methoxy, amino, dimethylamino,
3-(trifluoromethyl)phenyl, benzo[d][1,3]dioxol-5-yl, and carboxylic
acid, and
[0316] R.sub.5 is selected from the group consisting of
4-(hexyloxy)-3-methylphenyl, 3-methyl-4-propoxyphenyl,
4-(heptyloxy)-3-methylphenyl, 4-methoxy-3-methylphenyl,
4-ethoxy-3-methylphenyl, 3-methyl-4-(pentyloxy)phenyl,
4-butoxy-3-methylphenyl, 4-(pentyloxy)phenyl, 4-butoxyphenyl,
1-hexyl-1H-1,2,3-triazol-4-yl, 4-(2-methoxyethoxy)-3-methylphenyl,
4-hydroxy-3-methylphenyl, 4-(allyloxy)-3-methylphenyl,
4-(hex-5-yn-1-yloxy)-3-methylphenyl,
3-methyl-4-((4-methylpentyl)oxy)phenyl,
3-methyl-4-((4-methylpent-3-en-1-yl)oxy)phenyl,
4-(hex-5-en-1-yloxy)-3-methylphenyl,
4-(cyclopropylmethoxy)-3-methylphenyl, benzyl, phenyl, 2-(m-tolyl),
2-(p-tolyl), and 2,3-dihydrobenzo[b][1,4]dioxin-6-yl,
[0317] or a pharmaceutically acceptable salt thereof.
[0318] Further, there is provided a compound of Formula I as
described herein for use as a medicament in therapy.
[0319] There is also provided a compound of Formula I or Formula IV
as described herein for use in the treatment and/or prevention of a
disease involving gram-positive bacteria. The gram-positive
bacteria may be selected from the group consisting of
Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus
(MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus
faecalis (E. faecalis), Enterococcus faecium,
Vancomycin-Intermediate Staphylococcus aureus (VISA),
Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium
difficile (C. difficile), Clostridium tetani, Streptococcus
pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any
combination thereof. The disease may be a healthcare-associated
infection. Examples of the disease, which may or may not be
healthcare-associated, include diseases selected from the group
consisting of urinary tract infection (UTI), catheter associated
urinary tract infection, central line associated bloodstream
infection (CLABSI), pneumonia, wound associated infection, surgical
site infection, bacterial endocarditis, tetanus and any combination
thereof. The central line associated bloodstream infection may be
bacteremia or sepsis. Further, the disease may be drug-resistant
such as resistant to drugs frequently used to treat diseases
involving gram-positive bacteria.
[0320] There is also provided a use of a compound of Formula I or
Formula IV as described herein for use in the manufacture of a
medicament for the treatment and/or prevention of a disease
involving gram-positive bacteria. The gram-positive bacteria may be
selected from the group consisting of Staphylococcus aureus,
Methicillin-resistant Staphylococcus aureus (MRSA),
Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E.
faecalis), Enterococcus faecium, Vancomycin-Intermediate
Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus
aureus (VRSA), Clostridium difficile (C. difficile), Clostridium
tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus
subtilis and any combination thereof. The disease may be a
healthcare-associated infection. Examples of the disease, which may
or may not be healthcare-associated, include diseases selected from
the group consisting of urinary tract infection (UTI), catheter
associated urinary tract infection, central line associated
bloodstream infection (CLABSI), pneumonia, wound associated
infection, surgical site infection, bacterial endocarditis, tetanus
and any combination thereof. The central line associated
bloodstream infection may be bacteremia or sepsis. Further, the
disease may be drug-resistant such as resistant to drugs frequently
used to treat diseases involving gram-positive bacteria.
[0321] There is also a method for treatment and/or prevention of a
disease involving gram-positive bacteria comprising administering
to a mammal, such as a human or an animal, in need thereof an
effective amount of a compound of Formula I or Formula IV as
described herein. The gram-positive bacteria may be selected from
the group consisting of Staphylococcus aureus,
Methicillin-resistant Staphylococcus aureus (MRSA),
Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E.
faecalis), Enterococcus faecium, Vancomycin-Intermediate
Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus
aureus (VRSA), Clostridium difficile (C. difficile), Clostridium
tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus
subtilis and any combination thereof. The disease may be a
healthcare-associated infection. Examples of the disease, which may
or may not be healthcare-associated, include diseases selected from
the group consisting of urinary tract infection (UTI), catheter
associated urinary tract infection, central line associated
bloodstream infection (CLABSI), pneumonia, wound associated
infection, surgical site infection, bacterial endocarditis, tetanus
and any combination thereof. The central line associated
bloodstream infection may be bacteremia or sepsis. Further, the
disease may be drug-resistant such as resistant to drugs frequently
used to treat diseases involving gram-positive bacteria.
[0322] The compound of Formula I may be provided in admixture with
a pharmaceutically acceptable adjuvant, carrier or excipient
thereby forming a pharmaceutical composition. Thus, the present
disclosure provides a pharmaceutical composition comprising a
compound of Formula I as described herein, or a pharmaceutically
acceptable salt thereof, in admixture with a pharmaceutically
acceptable adjuvant, carrier or excipient.
[0323] The compounds of the present disclosure may possess
bactericidal activity against gram-positive bacteria. Additionally
or alternatively, the compounds of the present disclosure may
sensitize gram-positive bacteria to treatment with a drug against
gram-positive bacteria. In the latter case, the gram-positive
bacteria may be affected to a little extent or no extent by
treatment with the compounds of the present disclosure alone or by
treatment by the drug against gram-positive bacteria alone.
However, when a combination of the compounds of the present
disclosure and a drug against gram-positive bacteria as described
herein is used a significant bactericidal effect is achieved.
[0324] Thus, there is provided a compound as disclosed herein for
use in sensitizing gram-positive bacteria to treatment with a drug
against a disease involving gram-positive bacteria. There is also
provided a use of a compound as described herein for the
manufacture of a medicament for sensitizing gram-positive bacteria
to treatment with a drug against a disease involving gram-positive
bacteria. There is also provided a method for sensitizing
gram-positive bacteria to treatment with a drug against a disease
involving gram-positive bacteria, said method comprising
administering to a patient such as a human or an animal in need
thereof an effective amount of a compound as described herein.
[0325] The compound of Formula I or Formula IV as described herein
may be provided in combination with a drug against a disease
involving gram-positive bacteria. The combination may be provided
in admixture with a pharmaceutically acceptable adjuvant, carrier
or excipient thereby forming a pharmaceutical composition. It is
believed that this combination will provide an alternative and/or
improved way of treating a disease involving gram-positive
bacteria. This alternative and/or improved way may involve lowering
the dose of the drug compared to use of the drug alone when
treating the disease involving gram-positive bacteria.
Alternatively or additionally, this alternative and/or improved way
may mitigate or at least partly overcome problems associated with
drug-resistance.
[0326] Thus, there is provided a combination comprising:
[0327] (i) a composition comprising or consisting of a drug against
a disease involving gram-positive bacteria, or a pharmaceutically
acceptable salt of said drug, and
[0328] (ii) a composition comprising or consisting of a compound of
Formula IV:
##STR00016##
[0329] or a pharmaceutically acceptable salt thereof,
[0330] wherein:
[0331] R.sub.1 is selected from the group consisting of:
[0332] a) C(O)OH,
[0333] b) tetrazolyl,
[0334] c) C(O)NHSO.sub.2R.sub.6,
[0335] d) NH.sub.2,
[0336] e) H,
##STR00017##
[0337] R.sub.2 is selected from the group consisting of:
[0338] a) H,
[0339] b) Cl, F, Br or I,
[0340] c) CH.sub.2OH,
[0341] d) C.sub.1-C.sub.4alkyl, and
[0342] e) NZ.sub.1Z.sub.2,
[0343] R.sub.3 is selected from the group consisting of:
[0344] a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and
9-anthryloxy each independently substituted with 0, 1, 2 or 3
substituents selected from the group consisting of methyl, fluoro,
chloro, bromo, cyano and methoxy,
[0345] b) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4
fluoro,
[0346] c) phenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro, cyano and trifluoromethyl,
[0347] d) aminophenyl substituted with 0, 1, 2 or 3 substituents
independently selected from the group consisting of methyl, fluoro,
chloro and trifluoromethyl
[0348] e) 2-(3-methyl)phenylmethylene,
[0349] f) benzothiophen-2-yl,
[0350] g) H,
[0351] h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
[0352] i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
[0353] R.sub.4 is selected from the group consisting of:
[0354] a) C.sub.1-C.sub.4alkyl substituted with 0, 1, 2, 3 or 4
fluoro;
[0355] b) C.sub.3-C.sub.6cycloalkyl,
[0356] c) C.sub.1-C.sub.4alkoxy substituted with 0, 1, 2, 3 or 4
fluoro,
[0357] d) C.sub.3-C.sub.6cycloalkoxy,
[0358] e) a 3-, 4-, 5-, or 6-membered heterocycle,
[0359] f) NZ.sub.1Z.sub.2,
[0360] g) CH.sub.2NZ.sub.1Z.sub.2,
[0361] i) C(O)OH,
[0362] j) C(O)H,
[0363] k) 3-(trifluoromethyl)phenyl, and
[0364] l) benzo[d][1,3]dioxol-5-yl,
[0365] R.sub.5 is selected from the group consisting of:
##STR00018##
and
[0366] f) H,
[0367] and in the above definitions:
[0368] R.sub.6 is C.sub.1-C.sub.4alkyl or phenyl,
[0369] R.sub.7 is selected from the group consisting of F, Cl, Br,
and C.sub.1-C.sub.4alkyl,
[0370] R.sub.8 is selected from the group consisting of OH,
C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10alkenoxy,
C.sub.1-C.sub.10alkynoxy and O(CH.sub.2).sub.2OCH.sub.3, or
[0371] R.sub.7 and R.sub.8 together form O(CH).sub.2O,
[0372] R.sub.9 is selected from the group consisting of H and
C.sub.1-C.sub.10 alkyl,
[0373] R.sub.10 represents C.sub.1-C.sub.4alkyl,
[0374] R.sub.11 represents C.sub.1-C.sub.4alkyl, or
[0375] R.sub.10 and R.sub.11 together form
CH.sub.2(CH.sub.2).sub.mCH.sub.2,
[0376] Y is O, S or N,
[0377] Z.sub.1 and Z.sub.2 each independently represents hydrogen,
methyl, CH.sub.3S(O).sub.2, C(O)OR.sub.10, C(O)NR.sub.10R.sub.11 or
C(O)R.sub.10, or Z.sub.1 and Z.sub.2 together form
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2,
[0378] n is 0 or 1,
[0379] m is 0 or 1,
[0380] p is 0, 1 or 2,
[0381] q is 0 or 1,
[0382] r is 0 or 1, and
[0383] X is S, SO or SO.sub.2.
[0384] Further, there is provided a combination as described herein
wherein the compound of Formula IV is as described herein except
that R.sub.5 is not hydrogen (H).
[0385] The compound of Formula IV may be a compound of Formula IVa
or Formula IVb:
##STR00019##
[0386] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and X
are as described herein for the compound of Formula IV.
[0387] In an example, the compound of Formula IV may be selected
from Examples 28-39, 40 and 48 of Table 1 of this document.
[0388] For instance, the compound of Formula IV may be selected
from: [0389]
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabi-
cyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0390]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid, [0391]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0392]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0393]
5-Cyclopropyl-8-(1H-indol-5-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-aza-
bicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0394]
5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-
-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, [0395]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1--
azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0396]
5-Cyclopropyl-8-(2-furyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0397]
5-Cyclopropyl-8-(3-furyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0398]
6-[(9-Anthryl)methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-
-indancarboxylic acid, [0399] 6-[(Naphtyl)
methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-indancarboxyl-
ic acid, [0400]
6-[(Naphtyloxy)methyl]-4-oxo-2-phenyl-7-(1,3-Dioxa-5-indanyl)-1-thia-3a-a-
za-3indancarboxylic acid, [0401]
(R)-7-(naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-tiazolo[3,2,a]pyridine-3,8-
-dicarboxylic acid, or [0402]
7-(anthracen-9-ylmethyl)-8-methoxy-5-oxo-2,3-dihydro-thiazolo[3,2,a]pyrid-
ine-3-carboxylic acid,
[0403] a pharmaceutically acceptable salt of any one of the
foregoing compounds.
[0404] In a further example, the compound described herein may be
selected from: [0405]
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0406]
6-[(9-Anthryl)methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-
-indancarboxylic acid, [0407]
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0408]
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]--
7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0409]
5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-th-
ia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, [0410]
5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-o-
xo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0411]
8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-ox-
o-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
[0412]
8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluoromethyl)p-
henyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid, or
[0413] a pharmaceutically acceptable salt of any of the foregoing
compounds.
[0414] For instance, the compound of Formula IV may be a compound
of Formula I as described herein.
[0415] The combination described herein may be provided as a single
composition.
[0416] Alternatively, the combination may be provided as a kit of
parts.
[0417] The combination described herein may further comprise
instructions for use. For instance, the instructions for use may
include instructions for separate, sequential or simultaneous use
of (i) and (ii) of the combination as described herein.
[0418] The drug of the combination described herein may be an
antibiotic such as an antibiotic selected from the group consisting
of glycopeptide antibiotics, lipoglycopeptide antibiotics,
lipopeptide antibiotics, penicillin antibiotics, oxazolidinone
antibiotics, aminoglycoside antibiotics and any combination
thereof. The glycopeptide antibiotics may be a semisynthetic
glycopeptide antibiotics. The glycopeptide antibiotics may be
vancomycin and/or teicoplanin. The lipoglycopeptide antibiotics may
be telavancin. The lipopeptide antibiotics may be daptomycin. The
penicillin antibiotics may be oxacillin. The oxazolidinone
antibiotics may be linezolide and/or teidizolide. The semisynthetic
antibiotics may be orbactiv. The aminoglycoside antibiotics may be
gentamicin, tobramycin, amikacin, streptomycin, neomycin, and/or
paromomycin.
[0419] It will be appreciated that teicoplanin is a mixture of
several compounds, namely five major compounds (named teicoplanin
A.sub.2-1 through A.sub.2-5) and four minor (named teicoplanin
R.sub.S-1 through R.sub.S-4). All teicoplanins share a same
glycopeptide core, termed teicoplanin A.sub.3-1--a fused ring
structure to which two carbohydrates (mannose and
N-acetylglucosamine) are attached. The major and minor components
also contain a third carbohydrate moiety--.beta.-D-glucosamine--and
differ only by the length and conformation of a side-chain attached
to it. The present disclosure encompasses all teicoplanin
mixtures.
[0420] For instance, the drug of the combination described herein
may be selected from the group consisting of vancomycin, oxacillin,
dalbavancin, oritavancin, teicoplanin, daptomycin, linezolid,
tedizolid, telavancin, gentamicin, tobramycin, amikacin,
streptomycin, neomycin, and paromomycin and any combination
thereof. In an example, the drug may be vancomycin, oxacillin
and/or gentamicin.
[0421] The chemical structures of vancomycin, oxacillin,
dalbavancin, oritavancin, teicoplanin, daptomycin, linezolid,
tedizolid, telavancin, gentamicin are as described in the figures
of this document.
[0422] It will be appreciated that the drug against a disease
involving gram-positive bacteria as described herein may or may not
also be a drug against tuberculosis bacteria such as rifampin
and/or linezolid.
[0423] There is also provided a combination as described herein for
use as a medicament in therapy.
[0424] There is also provided a combination as described herein for
use in the treatment and/or prevention of a disease involving
gram-positive bacteria. The gram-positive bacteria may be selected
from the group consisting of Staphylococcus aureus,
Methicillin-resistant Staphylococcus aureus (MRSA),
Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E.
faecalis), Enterococcus faecium, Vancomycin-Intermediate
Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus
aureus (VRSA), Clostridium difficile (C. difficile), Clostridium
tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus
subtilis and any combination thereof. The disease may be a
healthcare-associated infection. Examples of the disease, which may
or may not be healthcare-associated, include diseases selected from
the group consisting of urinary tract infection (UTI), catheter
associated urinary tract infection, central line associated
bloodstream infection (CLABSI), pneumonia, wound associated
infection, surgical site infection, bacterial endocarditis, tetanus
and any combination thereof. The central line associated
bloodstream infection may be bacteremia or sepsis. Further, the
disease may be drug-resistant such as resistant to drugs frequently
used to treat diseases involving gram-positive bacteria.
[0425] There is also provided a use of a combination as described
herein for the manufacture of a medicament for the treatment and/or
prevention of a disease involving gram-positive bacteria. The
gram-positive bacteria may be selected from the group consisting of
Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus
(MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus
faecalis (E. faecalis), Enterococcus faecium,
Vancomycin-Intermediate Staphylococcus aureus (VISA),
Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium
difficile (C. difficile), Clostridium tetani, Streptococcus
pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any
combination thereof. The disease may be a healthcare-associated
infection. Examples of the disease, which may or may not be
healthcare-associated, include diseases selected from the group
consisting of urinary tract infection (UTI), catheter associated
urinary tract infection, central line associated bloodstream
infection (CLABSI), pneumonia, wound associated infection, surgical
site infection, bacterial endocarditis, tetanus and any combination
thereof. The central line associated bloodstream infection may be
bacteremia or sepsis. Further, the disease may be drug-resistant
such as resistant to drugs frequently used to treat diseases
involving gram-positive bacteria.
[0426] There is also provided a method for treatment and/or
prevention of a disease involving gram-positive bacteria comprising
administering to a mammal, such as a human or an animal, in need
thereof an effective amount of a combination as described herein.
The gram-positive bacteria may be selected from the group
consisting of Staphylococcus aureus, Methicillin-resistant
Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci
(VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium,
Vancomycin-Intermediate Staphylococcus aureus (VISA),
Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium
difficile (C. difficile), Clostridium tetani, Streptococcus
pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any
combination thereof. The disease may be a healthcare-associated
infection. Examples of the disease, which may or may not be
healthcare-associated, include diseases selected from the group
consisting of urinary tract infection (UTI), catheter associated
urinary tract infection, central line associated bloodstream
infection (CLABSI), pneumonia, wound associated infection, surgical
site infection, bacterial endocarditis, tetanus and any combination
thereof. The central line associated bloodstream infection may be
bacteremia or sepsis. Further, the disease may be drug-resistant
such as resistant to drugs frequently used to treat diseases
involving gram-positive bacteria.
[0427] The present disclosure provides an article treated with a
compound as described herein or a combination as described herein.
The article may be a medical device or a cosmetic device. Thus,
there is also provided a medical device or cosmetic device such as
an implant treated with a compound as described herein or a
combination as described herein. The medical device or cosmetic
device may be a catheter or an implant such as a dental implant,
cochlear implant, breast implant, nose prosthesis, heart valve,
pacemaker, ocular prosthesis or an injectable filler.
[0428] Further, the present disclosure provides the following
compounds: [0429]
(R)-7-(naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-tiazolo[3,2,a]pyrid-
ine-3,8-dicarboxylic acid, or [0430]
7-(anthracen-9-ylmethyl)-8-methoxy-5-oxo-2,3-dihydro-thiazolo[3,2,a]pyrid-
ine-3-carboxylic acid,
[0431] or a pharmaceutically acceptable salt of any of the
foregoing compounds.
[0432] Salts
[0433] The compounds of the present disclosure may be provided as a
pharmaceutically acceptable salt. A suitable pharmaceutically
acceptable salt of a compound of the present disclosure may be, for
example, a base-addition salt of a compound of the present
disclosure which is sufficiently acidic, for example, a metal salt,
for example, lithium, sodium, potassium, calcium, magnesium, zinc
or aluminum, an ammonium salt, a salt with an organic base which
affords a physiologically acceptable cation, which includes
quartenary ammonium hydroxides, for example methylamine,
ethylamine, diethylamine, trimethylamine, tert-butylamine,
triethylamine, dibenzylamine, N,N-dibenzylethylamine,
cyclohexylethylamine, tris-(2-hydroxyethyl)amine, hydroxyethyl
diethylamine, (IR, 2S)-2-hydroxyinden-1-amine, morpholine,
N-methylpiperidine, N-ethylpipeidine, imidazole, piperazine,
methylpiperazine, adamantylamine, choline hydroxide,
tetrabutylammonium hydroxide, tris-(hydroxymethyl)methylamine
hydroxide, L-arginine, N-methyl D-glucamine, lysine or
arginine.
[0434] In an example, there is provided an imidazole salt of the
compounds of the present disclosure such as a compound of the
present disclosure wherein R.sub.1 is C(O)OH, tetrazolyl or
C(O)NHSO.sub.2R.sub.6. It will be appreciated that the imidazole
salt is a combination of a compound of the present disclosure and
imidazole.
[0435] As described herein, proton transfer may occur between the
active pharmaceutical ingredient such as the compounds described
herein and the counter ion of the salt. The proton transfer may
take place to a varying extent.
[0436] For instance, when the R.sub.1 group of the compounds
described herein is C(O)OH it may combine with imidazole to form a
salt which may be depicted as shown below:
##STR00020##
[0437] In a further example, when the R.sub.1 group of the
compounds described herein is tetrazolyl it may combine with
imidazole to form a salt which may be depicted as shown below:
##STR00021##
[0438] In still a further example, when the R.sub.1 group of the
compounds described herein is C(O)NHSO.sub.2R.sub.6 it may combine
with imidazole to form a salt which may be depicted as shown
below:
##STR00022##
[0439] It will be appreciated that the imidazole salts of the
compounds described herein wherein R.sub.1 is C(O)OH, tetrazolyl or
C(O)NHSO.sub.2R.sub.6 may be depicted as shown above regardless of
the extent of proton transfer.
[0440] Solvates or Hydrates
[0441] Certain compounds of the present disclosure may exist as
solvates or hydrates. It is to be understood that the present
disclosure encompasses all such solvates or hydrates. Compounds of
the present disclosure may also contain unnatural proportions of
atomic isotopes at one or more of the atoms that constitute such
compounds. For example, the compounds may be radiolabeled with
radioactive isotopes, such as for example tritium (.sup.3H),
iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All isotopic
variations of the compounds of the present disclosure, whether
radioactive or not, are intended to be encompassed within the scope
of the present disclosure.
[0442] Co-Crystals
[0443] In a salt, proton transfer may occur between the active
pharmaceutical ingredient and the counter ion of the salt. However,
in some cases there is no or only partial proton transfer and the
solid is therefore not a true salt. It is accepted that the proton
transfer is in fact a continuum, and can change with temperature,
and therefore the point at which a salt is better described as a
"co-crystal" may be subjective. The term "co-crystal" as used
herein refers to multicomponent system in which there exists a host
molecule or molecules (active pharmaceutical ingredient) and a
guest (or co-former) molecule or molecules. The guest or co-former
molecule is defined as existing as a solid at room temperature in
order to distinguish the co-crystal from solvates. However, a
co-crystal may itself form solvates. In a co-crystal there is
generally predominance for interaction through non-ionic forces,
such as hydrogen bonding. It will be appreciated that all
co-crystals are included within the scope of the compounds
described herein.
[0444] Polymorphs
[0445] Compounds of the present disclosure may exist in a continuum
of solid states ranging from fully amorphous to fully crystalline.
Thus, it is to be understood that all polymorphs, such as mixtures
of different polymorphs, are included within the scope of the
compounds described herein.
[0446] Prodrugs
[0447] In addition, compounds of the present disclosure may be
administered in the form of a prodrug. A prodrug is a compound
which may have little or no pharmacological activity itself, but
when such compound is administered into or onto the body of a
patient, it is converted into a compound of Formula II. The prodrug
may contain a metabolically or chemically labile acyl function such
as a carboxylate ester or carbamate.
[0448] Methods of Preparation
[0449] Compounds of the present disclosure may be prepared as
described in WO 2014/185833 and/or in schemes 1 to 4 below. In
schemes 1 to 4, R may be an alkyl group and Ar may be an aryl such
as phenyl. The aryl may optionally be substituted with one or more
alkyl groups such as a methyl group. The compounds may also be
prepared as described for structurally related compounds. The
reactions may be carried out as in standard procedures or as
described in the experimental section of this document. The sulfide
of the compounds of Formula I or Formula IV may be oxidized with
the aid of meta-chloroperoxybenzoic acid (mCPBA) to sulphoxide and
sulphone, respectively.
##STR00023##
##STR00024##
##STR00025## ##STR00026##
##STR00027## ##STR00028##
[0450] It will be appreciated that some of the compounds of the
present disclosure may also serve as intermediates for preparing
further compounds of Formula I or Formula IV. For instance,
compounds wherein R.sub.1 is C(O)OH or tetrazolyl may be used in
the synthesis of a pharmaceutically acceptable salt of a compound
of Formula I or Formula IV as described herein. In a further
example, when R.sub.8 is OH it may be transformed into an alkoxy
group.
[0451] The disclosure is further illustrated by the following
non-limitative Examples.
EXAMPLES
Abbreviations
[0452] BHI Brain Heart Infusion plates supplied from Fischer
Scientific
[0453] calcd. calculated
[0454] CAUTI Catheter-Associated Urinary Tract Infection
[0455] C. difficile Clostridium difficile
[0456] CLABSI central line associated bloodstream infection
[0457] DCM dichloromethane
[0458] DMF dimethylformamide
[0459] DMSO dimethylsulphoxide
[0460] EA Ethyl Acetate
[0461] EtOAc Ethyl Acetate
[0462] ESI-TOF Electrospray Ionization Time of Flight Mass
Spectroscopy
[0463] Gen Gentamicin
[0464] HCAI HealthCare-Associated Infection
[0465] HRMS High Resolution Mass Spectroscopy
[0466] IR infrared
[0467] MBC Minimum Bactericidal Concentration
[0468] MIC Minimum Inhibitory Concentration
[0469] ml milliliter
[0470] MRSA Methicillin-resistant Staphylococcus aureus
[0471] MW microwave
[0472] NMR Nuclear Magnetic Resonance
[0473] nd no data
[0474] nm nanometer
[0475] ns not statistically different
[0476] OD Optical density
[0477] OD.sub.600 Optical density at 600 nm
[0478] PBS Phosphate-Buffered Saline buffer
[0479] ppm part per million
[0480] Van Vancomycin
[0481] VISA Vancomycin-Intermediate Staphylococcus aureus
[0482] VRE Vancomycin-Resistant Enterococci
[0483] VRSA Vancomycin-Resistant Staphylococcus aureus
[0484] TBAF tetra-n-butylammonium fluoride
[0485] TFA trifluoroacetic acid
[0486] THF tetrahydrofurane
[0487] TLC Thin Layer Chromatography
[0488] TMS trimethylsilyl
[0489] UTI urinary tract infection
[0490] .mu.l microliter
[0491] LOD Bacterial limit of detection
[0492] In this document, unless otherwise stated, the naming and
the drawing of the chemical compounds and radicals have been made
using the program Chem Doodle version 7.0.1 or version 7.0.2, or
the program ChemDraw Ultra 12.0.2.1076. If the name and drawing are
inconsistent, the chemical structure shall be considered to be
correct.
[0493] Chemistry
[0494] General
[0495] Unless otherwise stated, all reagents and solvents were used
as received from commercial suppliers. Microwave reactions were
performed in sealed vessels using a Biotage.RTM. Initiator
microwave synthesizer; temperatures were monitored by an internal
IR probe. Automated flash column chromatography was performed using
a Biotage.RTM. Isolera One system and purchased pre-packed silica
gel cartridges (Biotage.RTM. SNAP Cartridge, KP-Sil). .sup.1H- and
.sup.13C-NMR spectra were recorded, depending on instrument
availability, on a Bruker Avance III 400 MHz spectrometer with a
BBO-F/H Smartprobe.TM., a Bruker Avance III HD 600 MHz spectrometer
with a CP BBO-H/F, 5 mm cryoprobe at 298 K. All spectrometers were
operated by Topspin 3.5.7. Resonances are given in ppm relative to
TMS, and calibrated to solvent residual signals (CDCl.sub.3:
.delta..sub.H=7.26 ppm; .delta..sub.C=77.16 ppm.
(CD.sub.3).sub.2SO: .delta..sub.H=2.50 ppm; .delta..sub.C=39.51
ppm. CD.sub.3OD .delta..sub.H=3.31 ppm; .delta..sub.C=49.00 ppm).
The following abbreviations are used to indicate splitting
patterns: s=singlet; d=doublet; dd=double doublet; t=triplet;
m=multiplet; bs=broad singlet. HRMS was performed on a mass
spectrometer with ESI-TOF (ES+).
[0496] Synthesis of Compounds
[0497] The compounds of the Examples were synthesized in accordance
or analogy with Schemes 1-4 disclosed herein. For instance, the
compounds of the Examples were synthesized as follows.
[0498]
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-ind-
ancarboxylic acid and
(3R)-7-Methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxyl-
ic acid was prepared according to WO2016075296.
[0499]
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-ind-
ancarboxylic acid (17.42 mmol) was suspended in dichloromethane
(190 ml) and cooled to 0.degree. C. Oxalyl chloride (19.16 mmol,
1.70 ml) and dimethylformamide (19.16 mmol, 1.50 ml) were added at
0.degree. C. The mixture was then stirred at room temperature for
12 minutes. 2-(trimethylsilyl)ethanol (49.53 mmol, 7.10 ml) was
added slowly and the reaction was stirred for 3 hours. Completion
of the reaction was confirmed by TLC. The reaction mixture was then
diluted with DCM, washed with NaHCO.sub.3 (saturated, aqueous),
dried (Na.sub.2SO.sub.4) and concentrated until about 200 ml
dichloromethane remained. The organic layer was washed with water
and the aqueous layer was extracted with DCM. The organic layers
were combined, dried with Na.sub.2SO.sub.4 and concentrated. Crude
product was purified on silica gel (ethyl acetate:heptane 1:1) to
give TMS-ethyl ester.
[0500] NaH (3.06 mmol) was added slowly to a solution of the
TMS-ethyl ester (1.70 mmol) in dry acetonitrile (15 ml) at
0.degree. C. After 10 minutes, BrCCl.sub.3(5.11 mmol) was added
dropwise. After stirring for 30 minutes, the reaction mixture was
allowed to reach room temperature and stirred for further 30
minutes. 2-(TMS)ethanol (3.40 mmol) was added dropwise, and
stirring was continued overnight. After completion reaction was
quenched with an aqueous solution of 6 wt % KHSO.sub.4 (10 ml),
diluted with H.sub.2O (10 ml) and acidified with 1 M HCl (10 ml).
Aqueous layer extracted with EtOAc (20 ml.times.3), combined
organic layers were washed with brine, dried over anhydrous sodium
sulphate and evaporated under reduced pressure to yield crude
brominated product which was purified by flash column
chromatography (Biotage, 100 g column) eluting with 10-60% EtOAc in
heptane.
[0501] A microwave vial was charged with bromo compound (0.90
mmol), added MeOH (6 ml) and degassed with nitrogen for 10 minutes.
Boronic ester (1.44 mmol), K.sub.2CO.sub.3(1.62 mmol) and
Pd(OAc).sub.2 (0.09 mmol) were added. The microwave vial was sealed
and the reaction mixture heated under MWI at 120.degree. C. for 10
minutes. Diluted with dichloromethane (30 ml) and acidified with 1N
HCl. Organic layer was separated, dried over anhydrous sodium
sulphate and evaporated to yield crude aryl alcohol product which
was purified by flash column chromatography (Biotage 100 g column)
eluting with 0-100% EtOAc in heptane.
[0502] Aryl alcohol compound (0.27 mmol) was dissolved in dry DMF
(2 ml). Added K.sub.2CO.sub.3 (1.11 mmol) and alkyl bromide (1.11
mmol). Reaction mixture was stirred under heating at 80.degree. C.
for 2 hours. Cooled to room temperature and added EtOAc (10 ml).
Washed with brine (10 ml.times.4) 4. Organic layer dried over
anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to
yield crude silyl ester product which was used in next step without
further purification.
[0503] Silyl Ester (0.23 mmol) was dissolved in dry THF (4 ml) and
added TBAF (0.47 mmol). Reaction mixture was stirred at room
temperature for 2 hours. Added H.sub.2O and extracted with EtOAc
(10 ml.times.2). Combined organic layers were dried over anhydrous
sodium sulphate and evaporated to yield crude product which was
purified by flash column chromatography (Biotage 10 g column)
eluting with 20% MeOH in DCM. Pure compound was lyophilized from
acetonitrile:water (1:3) mixture.
[0504] Example 36 was prepared from the known compound Methyl
(3R)-5-bromo-7-iodo-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancar-
boxylate as described in J. Org. Chem (2010), 75(3), 972-975 and/or
according to Scheme 3.
[0505] Imidazole Salt
[0506] An imidazole salt was prepared as follows.
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7--
thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic Acid
Imidazole Salt
[0507]
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-
-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
(0.11 mmol) was taken in a round bottom flask and MeOH (2 ml) was
added thereby providing a suspension. Then imidazole (0.11 mmol)
was added. Allowed to stir for about 2 hours. A clear reaction
mixture was obtained. Solvent evaporated and the crude product was
lyophilized from acetonitrile:water (3:1).
Examples 1-50
TABLE-US-00001 [0508] TABLE 1 Example Chemical name Number Chemical
structure. NMR and HRMS 1 ##STR00029##
5-Cyclopropyl-8-[4-(hexyloxy)- 3-methyl-phenyl]-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid .sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO):
.delta. 7.97 (dd, J 2.0, 7.2 Hz, 1H), 7.85-7.89 (m, 2H), 7.45-7.57
(m, 5H), 7.32 (d, J 6.8 Hz, 1H), 6.93 (d, J 8.4 Hz, 1H), 5.46 (s,
1H), 4.54 (s, 2H), 3.99 (t, J 6.4 Hz, 2H), 2.16 (s, 3H), 1.87 (bs,
1H), 1.70-1.77 (m, 2H), 1.41-1.46 (m, 2H), 1.28-1.36 (m, 4H),
1.02-1.04 (m, 2H), 0.88 (t, J 6.8 Hz, 3H), 0.74 (bs, 2H). HRMS
(ESI) calcd (M + Na).sup.+ C.sub.35H.sub.35NNaO.sub.4S.sup.+
588.2179 observed 588.2174. 2 ##STR00030## 5-Cyclopropyl-4-[(1-
naphthyl)methyl]-2-oxo-8-(4- propoxy-3-methyl-phenyl)-7-
thia-1-azabicyclo[4.3.0]nona- 3,5,8-triene-9-carboxylic acid
.sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO): .delta. 7.98 (dd, J 2.4,
9.2 Hz, 1H), 7.86-7.90 (m, 2H), 7.46-7.61 (m, 5H), 7.34 (d, J 7.2
Hz, 1H), 6.94 (d, J 8.8 Hz, 1H), 5.46 (s, 1H), 4.55 (s, 2H), 3.97
(t, J 6.4 Hz, 2H), 2.17 (s, 3H), 1.87-1.88 (m, 1H), 1.72-1.81 (m,
2H), 0.91- 1.05 (m, 5H), 0.76-0.77 (m, 2H). HRMS (ESI) calcd (M +
Na).sup.+ C.sub.32H.sub.29NNaO.sub.4S.sup.+ 546.1710 observed
546.1705. 3 ##STR00031## 5-Cyclopropyl-8-[4-
(heptyloxy)-3-methyl-phenyl]- 4-[(1-naphthyl)methyl]-2-oxo-
7-thia-1- azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid
.sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO): .delta. 7.96 (dd, J 2.0,
7.2 Hz, 1H), 7.85-7.89 (m, 2H), 7.45-7.56 (m, 5H), 7.32 (d, J 6.4
Hz, 1H), 6.93 (d, J 7.6 Hz, 1H), 5.46 (s, 1H), 4.55 (s, 2H) 3.99
(t, J 6.4 Hz, 2H), 2.15 (s, 3H), 1.88 (bs, 1H), 1.70-1.77 (m, 2H),
1.40-1.47 (m, 2H), 1.28-1.37 (m, 6H), 1.02-1.04 (m, 2H), 0.87 (t, J
6.4 Hz, 3H), 0.74 (bs, 2H). HRMS (ESI) calcd (M + Na).sup.+
C.sub.36H.sub.37NNaO.sub.4S.sup.+ 602.2336 observed 602.2328. 4
##STR00032## 5-Cyclopropyl-8-(4-methoxy- 3-methyl-phenyl)-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid .sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO):
.delta. 8.42 (bs, 1H), 7.96 (dd, J 2.0, 6.0 Hz, 1H), 7.86-7.91 (m,
2H), 7.64 (dd, J 1.6, 8.4 Hz, 1H) 7.47-7.56 (m, 4H), 7.36 (d, J 7.2
Hz, 1H), 6.97 (d, J 8.8 Hz, 1H), 5.46 (s, 1H), 4.56 (s, 2H), 3.82
(s, 3H), 2.17 (s, 3H), 1.88-1.91 (m, 1H), 1.02-1.05 (m, 2H), 0.78-
0.79 (m, 2H). HRMS (ESI) calcd (M + H).sup.+
C.sub.30H.sub.26NO.sub.4S.sup.+ 496.1577 observed 496.1574. 5
##STR00033## 5-Cyclopropyl-8-(4-ethoxy-3- methyl-phenyl)-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid .sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO):
.delta. 7.96 (dd, J 2.0, 9.2 Hz, 1H), 7.85-7.88 (m, 2H), 7.46-7.58
(m, 5H), 7.31 (d, J 6.8 Hz, 1H), 6.93 (d, J 8.8 Hz, 1H), 5.45 (s,
1H), 4.54 (s, 2H), 4.06 (q, J 6.8, 13.6 Hz, 2H), 2.16 (s, 3H), 1.91
(bs, 1H), 1.36 (t, J 6.8 Hz, 3H), 1.02-1.04 (m, 2H), 0.73 (bs, 2H).
HRMS (ESI) calcd (M + H).sup.+ C.sub.31H.sub.28NO.sub.4S.sup.+
510.1734 observed 510.1727. 6 ##STR00034## 5-Cyclopropyl-4-[(1-
naphthyl)methyl]-2-oxo-8-[4- (pentyloxy)-3-methyl-phenyl]-
7-thia-1- azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid
.sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO): .delta. 7.97 (dd, J 4.4,
9.6 Hz, 1H), 7.87-7.91 (m, 2H), 7.48-7.59 (m, 5H), 7.37 (d, J 6.4
Hz, 1H), 6.96 (d, J 8.8 Hz, 1H), 5.45 (s, 1H), 4.56 (s, 2H), 4.01
(t, J 6.4 Hz, 2H), 2.17 (s, 3H), 1.89 (bs, 1H), 1.72-1.79 (m, 2H),
1.32-1.47 (m, 4H), 1.03-1.05 (m, 2H), 0.91 (t, J 7.2 Hz, 3H), 0.78
(bs, 2H). HRMS (ESI) calcd (M + Na).sup.+
C.sub.34H.sub.33NNaO.sub.4S.sup.+ 574.2023 observed 574.2019. 7
##STR00035## 8-(4-Butoxy-3-methyl-phenyl)- 5-cyclopropyl-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid .sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO):
.delta. 7.98 (dd, J 3.6, 7.2 Hz, 1H), 7.88-7.92 (m, 2H), 7.49-7.55
(m, 3H), 7.3- 7.46 (m, 3H), 7.0 (d, J 8.4 Hz, 1H), 5.53 (s, 1H),
4.59 (s, 2H), 4.04 (t, J 6.4 Hz, 2H), 2.19 (s, 3H), 1.88-1.94 (m,
1H), 1.70- 1.77 (m, 2H), 1.43-1.52 (m, 2H), 1.03-1.05 (m, 2H), 0.95
(t, J 7.2 Hz, 3H), 0.81-0.82 (m, 2H). HRMS (ESI) calcd (M +
Na).sup.+ C.sub.33H.sub.31NNaO.sub.4S.sup.+ 560.1866 observed
560.1857. 8 ##STR00036## 5-Methoxy-4-[(1-
naphthyl)methyl]-2-oxo-8-[4- (pentyloxy)-3-methyl-phenyl]-
7-thia-1- azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid
.sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO): .delta. 7.86-7.97 (m,
3H), 7.42-7.58 (m, 6H), 6.94 (d, J 8.8 Hz, 1H), 5.46 (s, 1H), 4.41
(s, 2H), 3.99 (t, J 6.4 Hz, 2H), 3.82 (s, 3H), 2.15 (s, 3H),
1.71-1.78 (m, 2H), 1.33-1.46 (m, 4H), 0.91 (t, J 7.2 Hz, 3H). HRMS
(ESI) calcd (M + Na).sup.+ C.sub.32H.sub.31NNaO.sub.5S.sup.+
564.1815 observed 564.1813. 9 ##STR00037##
8-(4-Butoxy-3-methyl-phenyl)- 5-methoxy-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid .sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO):
.delta. 7.86-7.97 (m, 3H), 7.43-7.59 (m, 6H), 6.96 (d, J 8.8 Hz,
1H), 5.47 (s, 1H), 4.41 (s, 2H), 4.01 (t, J 6.4 Hz, 2H), 3.83 (s,
3H), 2.16 (s, 3H), 1.69-1.76 (m, 2H), 1.42-1.51 (m, 2H), 0.95 (t, J
7.2 Hz, 3H). HRMS (ESI) calcd (M + Na).sup.+
C.sub.31H.sub.29NNaO.sub.5S.sup.+ 550.1659 observed 550.1649. 10
##STR00038## 5-Methoxy-4-[(1- naphthyl)methyl]-2-oxo-8-(4-
propoxy-3-methyl-phenyl)-7- thia-1-azabicyclo[4.3.0]nona-
3,5,8-triene-9-carboxylic acid .sup.1H-NMR (400 MHz,
(CD.sub.3).sub.2SO): .delta. 7.95-7.98 (m, 2H), 7.89 (d, J 8.0 Hz,
1H) 7.41-7.56 (m, 6H), 7.06 (d, J 8.4 Hz, 1H), 5.61 (s, 1H), 4.45
(s, 2H), 4.00 (t, J 6.4 Hz, 2H), 3.85 (s, 3H), 2.19 (s, 3H),
1.72-1.79 (m, 2H), 1.01 (t, J 7.6 Hz, 3H). HRMS (ESI) calcd (M +
Na).sup.+ C.sub.30H.sub.27NNaO.sub.5S.sup.+ 536.1502 observed
536.1503. 11 ##STR00039## 8-[4-(Hexyloxy)-3-methyl-
phenyl]-5-methoxy-4-[(1- naphthyl)methyl]-2-oxo-7-thia-
1-azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid .sup.1H-NMR
(400 MHz, (CD.sub.3).sub.2SO): .delta. 7.95-7.98 (m, 2H), 7.89 (d,
J 8.4 Hz, 1H), 7.41-7.55 (m, 6H), 7.07 (d, J 8.8 Hz, 1H), 5.61 (s,
1H), 4.45 (s, 2H), 4.03 (t, J 6.4 Hz, 2H), 3.85 (s, 3H), 2.18 (s,
3H), 1.71-1.78 (m, 2H), 1.41-1.47 (m, 2H), 1.31-1.34 (m, 4H), 0.88
(t, J 7.2 Hz, 3H). HRMS (ESI) calcd (M + Na).sup.+
C.sub.33H.sub.33NNaO.sub.5S.sup.+ 578.1972 observed 578.1964. 12
##STR00040## 5-Cyclopropyl-4-[(1- naphthyl)methyl]-2-oxo-8-[p-
(pentyloxy)phenyl]-7-thia-1- azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid .sup.1H-NMR (600 MHz, (CD.sub.3).sub.2SO):
.delta. 7.97 (dd, J 1.2, 8.4 Hz, 1H), 7.87-7.90 (m, 2H), 7.69 (bs,
2H), 7.47-7.53 (m, 3H), 7.35 (d, J 5.4 Hz, 1H), 6.96 (d, J 8.4 Hz,
2H), 5.45 (s, 1H), 4.56 (s, 2H), 3.99 (t, J 6.6 Hz, 2H), 1.89 (bs,
1H), 1.70-1.75 (m, 2H), 1.32-1.43 (m, 4H), 1.04 (bs, 2H), 0.90 (t,
J 7.2 Hz, 3H), 0.77 (bs, 2H). HRMS (ESI) calcd (M + Na).sup.+
C.sub.33H.sub.31NNaO.sub.4S.sup.+ 560.1866 observed 560.1861. 13
##STR00041## 8-(p-Butoxyphenyl)-5- cyclopropyl-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid .sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO):
.delta. 7.88-7.98 (m, 3H), 7.49-7.58 (m, 5H), 7.38 (d, J 6.8 Hz
1H), 7.07 (d, J 8.4 Hz, 2H), 5.53 (s, 1H), 4.59 (s, 2H), 4.03 (t, J
6.0 Hz, 2H), 1.92 (bs, 1H), 1.70-1.73 (m, 2H), 1.42-1.47 (m, 2H),
1.03- 1.05 (m, 2H), 0.94 (t, J 7.2 Hz, 3H), 0.82 (bs, 2H). HRMS
(ESI) calcd (M + Na).sup.+ C.sub.32H.sub.29NNaO.sub.4S.sup.+
546.1710 observed 546.1703. 14 ##STR00042##
8-[4-(Hexyloxy)-3-methyl- phenyl]-5-methoxy-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid imidazole salt .sup.1H-NMR (600 MHz,
CD.sub.3OD): .delta. 8.69 (s, 1H), 7.89-7.93 (m, 2H), 7.83 (d, J
7.8 Hz, 1H), 7.57 (d, J 6.0 Hz, 2H), 7.44- 7.48 (m, 6H), 6.95 (d, J
9.0 Hz, 1H), 5.76 (s, 1H), 4.48 (s, 2H), 4.03 (t, J 6.6 Hz, 2H),
3.92 (s, 3H), 2.24 (s, 3H), 1.80-1.85 (m, 2H), 1.52-1.54 (m, 2H),
1.38-1.39 (m, 4H), 0.95 (t, J 7.2 Hz, 3H). .sup.11H- NMR (151 MHz,
CD.sub.3OD): .delta. 167.44, 159.98, 159.81, 148.50, 141.50,
137.43, 135.69, 135.63, 133.38, 133.16, 131.54, 129.95, 129.09,
128.98, 128.63, 128.56, 127.44, 126.98, 126.73, 125.74, 125.15,
122.71, 120.81, 112.36, 110.53, 69.33, 61.12, 33.57, 32.88, 30.45,
27.08, 23.83, 16.49, 14.51. 15 ##STR00043##
8-(1-Hexyl-1H-1,2,3-triazol-4- yl)-5-methoxy-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid .sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO):
.delta. 8.39 (s, 1H), 7.96-7.99 (m, 2H), 7.89 (d, J 8.0 Hz, 1H),
7.46-7.57 (m, 4H), 5.62 (s, 1H), 4.45-4.49 (m, 4H), 3.87 (s, 3H)
1.81- 1.84 (m, 2H), 1.26 (bs, 6H), 0.84 (t, J 6.4 Hz, 3H). HRMS
(ESI) calcd (M + Na).sup.+ C.sub.28H.sub.28N.sub.4NaO.sub.4S.sup.+
539.1723 observed 539.1722 16 ##STR00044##
8-(1-Hexyl-1H-1,2,3-triazol-4- yl)-5-methoxy-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid imidazole salt, .sup.1H-NMR (400 MHz,
(CD.sub.3).sub.2SO): .delta. 8.50 (bs, 1H), 8.32 (s, 1H), 7.86-7.93
(m, 2H), 7.82 (dd, J 1.6, 9.2 Hz, 1H), 7.42-7.49 (m, 4H), 7.40 (bs,
2H), 5.74 (s, 1H), 4.43- 4.48 (m, 4H), 3.92 (s, 3H) 1.91-1.94 (m,
2H), 1.32-133 (m, 6H), 0.90 (t, J 6.8 Hz, 3H) 17 ##STR00045##
5-Methoxy-8-[4-(2- methoxyethoxy)-3-methyl- phenyl]-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid, .sup.1H-NMR (600 MHz,
(CD.sub.3).sub.2SO): .delta. 7.95-7.98 (m, 2H), 7.89 (d, J 7.8 Hz,
1H), 7.40-7.56 (m, 3H), 7.42-7.47 (m, 3H), 7.95 (d, J 8.4 Hz, 1H),
5.61 (s, 1H), 4.45 (s, 2H), 4.17 (t, J 4.2 Hz, 2H), 3.85 (s, 3H),
3.70 (t, J 4.2 Hz, 2H), 3.34 (s, 3H), 2.19 (s, 3H). HRMS (ESI)
calcd (M + Na).sup.+ C.sub.30H.sub.27NNaO.sub.6S.sup.+ 552.1451
observed 552.1442 18 ##STR00046## 5-Cyclopropyl-8-[4-(2-
methoxyethoxy)-3-methyl- phenyl]-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid, .sup.1H-NMR (400 MHz,
(CD.sub.3).sub.2SO): .delta. 7.97-7.99 (m, 1H), 7.88-7.92 (m, 2H),
7.43- 7.56 (m, 5H), 7.38 (d, J 6.8 Hz, 1H), 7.90 (d, J 8.4 Hz, 1H),
5.52 (s, 1H), 4.59 (s, 2H), 4.17 (t, J 4.8 Hz, 2H), 3.70 (t, J 4.8
Hz, 2H), 3.33 (s, 3H), 2.20 (s, 3H), 1.88-1.95 (m, 1H), 1.02-1.06
(m, 2H), 0.80- 0.84 (m, 2H). HRMS (ESI)
calcd (M + H).sup.+ C.sub.32H.sub.30NO.sub.5S.sup.+ 540.1839
observed 540.1824 19 ##STR00047## 5-Cyclopropyl-8-(4-
hydroxytolyl)-4-[(1- naphthyl)methyl]-2-oxo-7-thia-
1-azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid 20
##STR00048## 8-(4-Butoxy-3-methyl-phenyl)-
5-cyclopropyl-2-oxo-4-{[m- (trifluoromethyl)phenyl]
methyl}-7-thia-1- azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic
acid, .sup.1H-NMR (400 MHz, (CD.sub.3).sub.2SO): .delta. 7.50-7.61
(m, 6H), 6.95 (d, J 8.8 Hz, 1H), 5.88 (s, 1H), 4.20 (s, 2H), 4.00
(t, J 6.4 Hz, 2H), 2.15 (s, 3H), 1.69-1.76 (m, 2H), 1.56- 1.58 (m,
1H), 1.44-1.51 (m, 2H), 0.99-1.01 (m, 2H), 0.95 (t, 7.2 Hz, 3H),
0.66 (bs, 2H). HRMS (ESI) calcd (M + Na).sup.+
C.sub.30H.sub.28F.sub.3NNaO.sub.4S.sup.+ 578.1583 observed 578.1579
21 ##STR00049## 8-[4-(Allyloxy)-3-methyl- phenyl]-5-methoxy-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid, .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. = 7.96 (sext , J = 4.44 Hz, 2H), 7.88 (d, J = 8.07 Hz, 1H),
7.56-7.42 (m, 6H), 7.06 (d, J = 8.59 Hz, 1H), 6.07 (tdd, J = 4.94,
10.57, 17.32 Hz, 1H), 5.59 (s, 1H), 5.43 (qd, J = 1.75, 17.36 Hz,
1H), 5.28 (qd, J = 1.7, 10.61 Hz, 1H), 4.64 (td, J = 1.68, 5.02 Hz,
2H), 4.44 (s, 2H), 3.84 (s, 3H), 2.21 (s, 3H) 22 ##STR00050##
8-[4-(5-Hexynyloxy)-3-methyl- phenyl]-5-methoxy-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid, .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. = 7.98-7.91 (m, 2H), 7.88 (d, J = 7.40 Hz, 1H), 7.58-7.42
(m, 6H), 6.99 (dd, J = 1.48, 8.70 Hz, 1H), 5.51 (s, 1H), 4.42 (s,
2H), 4.04 (t, J = 6.62 Hz, 2H), 3.83 (s, 3H), 2.79 (t, J = 2.6 Hz,
1H), 2.25 (dt, J = 2.77, 6.99 Hz, 2H), 2.17 (s, 3H), 1.84 (quint, J
= 7.22 Hz, 2H), 1.63 (quint, J = 7.15 Hz, 2H) ppm 23 ##STR00051##
8-[4-(Isohexyloxy)-3-methyl- phenyl]-5-methoxy-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid, .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. = 7.96 (quint t, J = 2.39, 6.89 Hz, 2H), 7.88 (d, J = 7.64
Hz, 1H), 7.56-7.40 (m, 6H), 7.88 (d, J = 7.64 Hz, 1H), 5.58 (s,
1H), 4.44 (s, 2H), 4.01 (t, J = 6.19 Hz, 2H), 3.84 (s, 3H), 2.18
(s, 3H), 1.79-1.70 (m, 2H), 1.66-1.53 (m, 1H), 1.33 (dqt, J = 2.3,
6.51, 8.81 Hz, 2H), 0.91 (s, 3H), 0.89 (s, 3H) ppm. .sup.13C NMR
(100 MHz, CDCl.sub.3): .delta. = 161.37, 158.09, 156.54, 146.98,
138.16, 134.63, 134.21, 133.49, 131.39, 130.02, 128.66, 127.63,
127.45, 127.11, 126.80, 126.41, 125.86, 125.69, 123.87, 111.73,
109.16, 68.05, 60.30, 34.77, 31.96, 27.20, 26.52, 22.49, 15.93 ppm
24 ##STR00052## 5-Methoxy-8-[4-(4-methyl-3- pentenyloxy)-3-methyl-
phenyl]-4-[(1- naphthyl)methyl]-2-oxo-7-thia-
1-azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid,
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. = 7.96 (sext, J = Hz,
2H), 7.88 (d, J = 7.86 Hz, 1H), 7.56-7.40 (m, 6H), 7.05 (d, J =
8.49 Hz, 1H), 5.59 (s, 1H), 5.22 (tt, J = 1.79, 7.14 Hz, 1H), 4.44
(s, 2H), 5.22 (tt, J = 1.79, 7.14 Hz, 2H), 3.84 (s, 3H), 2.44 (dq,
J = 1.94, 7.29 Hz, 2H), 2.17 (s, 3H), 1.69 (s, 3H), 1.63 (s, 3H)
ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. = 161.36, 157.98,
156.52, 147.06, 138.11, 134.18, 133.48, 133.40, 131.38, 130.04,
128.65, 127.63, 127.45, 127.10, 126.87, 126.40, 125.86, 125.68,
123.86, 120.10, 111.82, 109.16, 67.58, 60.31, 31.97, 27.74, 25.58,
17.72, 15.93 ppm. 25 ##STR00053## 8-[4-(5-Hexenyloxy)-3-methyl-
phenyl]-5-methoxy-4-[(1- naphthyl)methyl]-2-oxo-7-thia-
1-azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid 26
##STR00054## 8-[4-(Cyclopropylmethoxy)-3-
methyl-phenyl]-5-methoxy-4- [(1-naphthyl)methyl]-2-oxo-7-
thia-1-azabicyclo[4.3.0]nona- 3,5,8-triene-9-carboxylic acid 27
##STR00055## 5-Amino-8-[4-(hexyloxy)-3- methyl-phenyl]-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid, .sup.1H NMR (600 MHz, SO(CD.sub.3).sub.2)
.delta. 8.01-7.92 (m, 1H), 7.91-7.82 (m, 2H), 7.55-7.36 (m, 6H),
7.02 (d, J = 8.9 Hz, 1H), 5.36 (s, 1H), 4.40 (s, 2H), 4.01 (t, J =
6.4 Hz, 2H), 2.17 (s, 3H), 1.79-1.68 (m, 2H), 1.52-1.39 (m, 2H),
1.38-1.25 (m, 4H), 0.94-0.81 (m, 3H); .sup.13C NMR (150 MHz,
SO(CD.sub.3).sub.2) .delta. 165.3, 165.2, 162.6, 133.9, 133.0,
131.1, 129.3, 128.1, 127.0, 126.8, 126.3, 125.9, 125.7, 125.3,
125.2, 123.7, 111.1, 108.9, 67.2, 33.1, 30.4, 28.1, 24.7, 21.5,
15.5, 13.4. 28 ##STR00056## 8-Benzyl-5-cyclopropyl-4-[(1-
naphthyl)methyl]-2-oxo-7-thia- 1-azabicyclo[4.3.0]nona-3,5,8-
triene-9-carboxylic acid 29 ##STR00057## 5-Cyclopropyl-4-[(1-
naphthyl)methyl]-2-oxo-8- phenyl-7-thia-1-
azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid 30
##STR00058## 5-Cyclopropyl-4-[(1- naphthyl)methyl]-2-oxo-8-(m-
tolyl)-7-thia-1- azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic
acid 31 ##STR00059## 5-Cyclopropyl-4-[(1-
naphthyl)methyl]-2-oxo-8-(p- tolyl)-7-thia-1-
azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid 32
##STR00060## 5-Cyclopropyl-8-(1H-indol-5-
yl)-4-[(1-naphthyl)methyl]-2- oxo-7-thia-1-
azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid 33
##STR00061## 5-Cyclopropyl-8-(1,4-dioxa-
2,3-dihydronaphth-6-yl)-4-[(1- naphthyl)methyl]-2-oxo-7-thia-
1-azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic acid 34
##STR00062## 5-Cyclopropyl-4-[(1- naphthyl)methyl]-2-oxo-8-(3-
thienyl)-7-thia-1- azabicyclo[4.3.0]nona-3,5,8- triene-9-carboxylic
acid, 35 ##STR00063## 5-Cyclopropyl-8-(2-furyl)-4-
[(1-naphthyl)methyl]-2-oxo-7- thia-1-azabicyclo[4.3.0]nona-
3,5,8-triene-9-carboxylic acid 36 ##STR00064##
5-Cyclopropyl-8-(3-furyl)-4- [(1-naphthyl)methyl]-2-oxo-7-
thia-1-azabicyclo[4.3.0]nona- 3,5,8-triene-9-carboxylic acid 37
##STR00065## 6-[(9-Anthryl)methyl]-4-oxo-7-
[m-(trifluoromethyl)phenyl]-1- thia-3a-aza-3-indancarboxylic acid
38 ##STR00066## 6-[(1-Naphthyl)methyl]-4-oxo-
7-[m-(trifluoromethyl)phenyl]- 1-thia-3a-aza-3- indancarboxylic
acid 39 ##STR00067## 6-[(1-Naphthyloxy)methyl]-4-
oxo-2-phenyl-7-(1,3-Dioxa-5- indanyl)-1-thia-3a-aza-3-
indancarboxylic acid 40 ##STR00068## (R)-7-(naphthalen-1-ylmethyl)-
5-oxo-2,3-dihydro- thiazolo[3,2-a]pyridine-3,8- dicarboxylic acid
.sup.1H NMR (400 MHz, SO(CD.sub.3).sub.2) 513.38 (br s, 1H), 13.26
(br s, 1H), 7.99-7.90 (m, 2H), 7.85 (d, J = 7.9 Hz, 1H), 7.56-7.51
(m, 2H), 7.47 (dd, J = 8.4, 7.0 Hz, 1H), 7.25 (dd, J = 7.2, 1.4 Hz,
1H), 5.50 (s, 1H), 5.45 (dd, J = 9.7, 1.8 Hz, 1H), 4.70 (d, J =
17.5 Hz, 1H), 4.60 (d, J = 17.5 Hz, 1H), 3.72 (dd, J = 12.0, 9.8
Hz, 1H), 3.42 (dd, J = 12.0, 1.8 Hz, 1H); .sup.13C NMR (100 MHz,
SO(CD.sub.3).sub.2) .delta. 169.5, 166.7, 159.6, 159.0, 154.2,
135.1, 133.4, 131.5, 128.6, 127.7, 126.7, 126.3, 125.8, 125.7,
123.8, 114.9, 105.1, 62.5, 36.8, 30.7. 41 ##STR00069##
8-(dimethylamino)-2-(3- methyl-4-(pentyloxy)phenyl)-
7-(naphthalen-1-ylmethyl)-5- oxo-thiazolo[3,2-a]pyridine-3-
carboxylic acid .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.77 (br
s, 1H), 7.93-7.87 (m, 1H), 7.84-7.74 (m, 2H), 7.53- 7.46 (m, 2H),
7.46-7.41 (m, 1H), 7.34 (dd, J = 8.4, 2.4 Hz, 1H), 7.31-7.27 (m,
2H), 6.83 (d, J = 8.6 Hz, 1H), 6.03 (s, 1H), 4.46 (s, 2H), 3.99 (t,
J = 6.4 Hz, 2H), 2.92 (s, 6H), 2.23 (s, 3H), 1.88-1.75 (m, 2H),
1.52-1.35 (m, 4H), 0.95 (t, J = 7.1 Hz, 3H); .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 159.9, 159.2, 158.8, 152.6, 148.2, 142.7,
134.1, 133.2, 131.8, 131.2, 129.1, 128.2, 128.1, 128.1, 127.9,
127.6, 127.3, 126.5, 125.9, 125.6, 123.5, 121.8, 111.8, 110.7,
68.1, 42.5 (2C), 34.8, 29.0, 28.3, 22.5, 16.3, 14.1. 42
##STR00070## 8-(dimethylamino)-2-(4- (hexyloxy)-3-methylphenyl)-7-
(naphthalen-1-ylmethyl)-5- oxo-thiazolo[3,2-a]pyridine-3-
carboxylic acid .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.77 (br
s, 1H), 7.94-7.86 (m, 1H), 7.86-7.74 (m, 2H), 7.54- 7.46 (m, 2H),
7.46-7.40 (m, 1H), 7.34 (dd, J = 8.4, 2.4 Hz, 1H), 7.31-7.27 (m,
2H), 6.83 (d, J = 8.6 Hz, 1H), 6.03 (s, 1H), 4.46 (s, 2H), 3.99 (t,
J = 6.4 Hz, 2H), 2.92 (s, 6H), 2.23 (s, 3H), 1.88-1.75 (m, 2H),
1.56-1.43 (m, 2H), 1.41-1.30 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H);
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 160.0, 159.3, 158.9,
152.7, 148.3, 142.7, 134.2, 133.3, 131.9, 131.3, 129.2, 128.2,
128.2, 128.2, 128.0, 127.7, 127.4, 126.6, 126.0, 125.7, 123.6,
121.9, 111.9, 110.8, 68.2, 42.6 (2C), 34.9, 31.7, 29.3, 25.9, 22.8,
16.4, 14.2. 43 ##STR00071## 8-(dimethylamino)-2-(4-
(heptyloxy)-3-methylphenyl)- 7-(naphthalen-1-ylmethyl)-5-
oxo-thiazolo[3,2-a]pyridine-3- carboxylic acid .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.30 (br s, 1H), 7.94-7.86 (m, 1H),
7.86-7.74 (m, 2H), 7.54- 7.46 (m, 2H), 7.46-7.40 (m, 1H), 7.35 (dd,
J = 8.4, 2.4 Hz, 1H), 7.32-7.27 (m, 2H), 6.82 (d, J = 8.6 Hz, 1H),
6.02 (s, 1H), 4.45 (s, 2H), 3.98 (t, J = 6.4 Hz, 2H), 2.92 (s, 6H),
2.23 (s, 3H), 1.87-1.75 (m, 2H), 1.55-1.43 (m, 2H), 1.43-1.24 (m,
6H), 0.91 (t, J = 7.1 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 159.9, 159.5, 158.9, 152.7, 148.1, 141.9, 134.2, 133.4,
131.9, 131.3, 129.1, 128.2, 128.2, 128.1, 128.0, 127.6, 127.4,
126.6, 126.0, 125.7, 123.7, 121.8, 111.9, 110.8, 68.2, 42.6 (2C),
34.9, 31.9, 29.4, 29.2, 26.2, 22.8, 16.4, 14.3. 44 ##STR00072##
8-(dimethylamino)-2-(3- methyl-4-((4- methylpentypoxy)phenyl)-7-
(naphthalen-1-ylmethyl)-5- oxo-thiazolo[3,2-a]pyridine-3-
carboxylic acid .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 13.45 (br
s, 1H), 7.92-7.86 (m, 1H), 7.84-7.76 (m, 2H), 7.53- 7.45 (m, 2H),
7.45-7.40 (m, 1H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H), 7.33-7.26 (m,
2H), 6.81 (d, J = 8.6 Hz, 1H), 6.02 (s, 1H), 4.45 (s, 2H), 3.97 (t,
J = 6.4 Hz, 2H), 2.90 (s, 6H), 2.23 (s, 3H), 1.87-1.76 (m, 2H),
1.71-1.57 (m, 1H), 1.41-1.33 (m, 2H), 0.95 (d, J = 6.6 Hz,
6H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 159.7, 159.6,
158.9, 152.6, 147.9, 140.4, 134.1, 133.5, 131.9, 131.2, 129.1,
128.1, 128.1, 128.0, 127.9, 127.4, 127.4, 126.5, 126.0, 125.6,
123.7, 121.6, 111.8, 110.9, 68.5, 42.6 (2C), 35.4, 34.8, 27.9,
27.2, 22.7 (2C), 16.4 45 ##STR00073## 8-amino-2-(3-methyl-4-
(pentyloxy)phenyl)-7- (naphthalen-1-ylmethyl)-5-
oxo-thiazolo[3,2-a]pyridine-3- carboxylic acid .sup.1H NMR (600
MHz, SO(CD.sub.3).sub.2) .delta. 8.00-7.94 (m, 1H), 7.89 (d, J =
8.4 Hz, 1H), 7.88-7.83 (m, 1H), 7.57-7.47 (m, 3H), 7.44- 7.39 (m,
2H), 7.39-7.35 (m, 1H), 7.06 (d, J = 8.6 Hz, 1H), 5.40 (s, 1H),
4.41 (s, 2H), 4.03 (t, J = 6.4 Hz, 2H), 2.18 (s, 3H), 1.78-1.71 (m,
2H), 1.46-1.39 (m, 2H), 1.39-1.31 (m, 2H), 0.90 (d, J = 7.2 Hz,
3H); .sup.13C NMR (150 MHz, SO(CD.sub.3).sub.2) .delta. 161.6,
157.9, 155.9, 144.7, 134.2, 133.5, 131.5, 131.2, 129.9, 128.6,
127.6, 127.4, 127.1, 126.8, 126.3, 126.2, 126.1, 125.8, 125.8,
124.2, 121.2, 120.4, 111.7, 109.5, 67.7, 33.7, 28.3, 27.8, 21.8,
16.0, 13.9. 46 ##STR00074## 8-amino-2-(4-(hexyloxy)-3-
methylphenyl)-7-(naphthalen- 1-ylmethyl)-5-oxo-
thiazolo[3,2-a]pyridine-3- carboxylic acid .sup.1H NMR (600 MHz,
SO(CD.sub.3).sub.2) .delta. 8.02-7.93 (m, 1H), 7.89 (d, J = 8.4 Hz,
1H), 7.88-7.83 (m, 1H), 7.56-7.47 (m, 3H), 7.45- 7.39 (m, 2H),
7.39-7.35 (m, 1H), 7.06 (d, J = 8.6 Hz, 1H), 5.40 (s, 1H), 4.41 (s,
2H), 4.03 (t, J = 6.4 Hz, 2H), 2.18 (s, 3H), 1.78-1.69 (m, 2H),
1.49-1.39 (m, 2H), 1.37-1.26 (m, 4H), 0.88 (d, J = 7.2 Hz, 3H);
.sup.13C NMR (150 MHz, SO(CD.sub.3).sub.2) .delta. 161.6, 157.9,
155.9, 144.7, 134.2, 133.5, 131.5, 131.2, 129.9, 128.6, 127.6,
127.4, 127.1, 126.8, 126.3, 126.2, 126.0, 125.8, 125.8, 124.2,
121.2, 120.4, 111.7, 109.5, 67.7, 33.7, 30.9, 28.6, 25.2, 22.1,
16.0, 13.9. 47 ##STR00075## 8-amino-2-(4-(heptyloxy)-3-
methylphenyl)-7-(naphthalen- 1-ylmethyl)-5-oxo-
thiazolo[3,2-a]pyridine-3- carboxylic acid .sup.1H NMR (600 MHz,
SO(CD.sub.3).sub.2) .delta. 8.03-7.94 (m, 1H), 7.89 (d, J = 8.4 Hz,
1H), 7.88-7.83 (m, 1H), 7.56-7.47 (m, 3H), 7.45- 7.39 (m, 2H),
7.39-7.35 (m, 1H), 7.06 (d, J = 8.6 Hz, 1H), 5.40 (s, 1H), 4.41 (s,
2H), 4.03 (t, J = 6.4 Hz, 2H), 2.18 (s, 3H), 1.79-1.68 (m, 2H),
1.49-1.38 (m, 2H), 1.38-1.18 (m, 6H), 0.87 (d, J = 7.2 Hz, 3H);
.sup.13C NMR (150 MHz, SO(CD.sub.3).sub.2) .delta. 161.6, 158.0,
155.9, 144.7, 134.2, 133.5, 131.5, 131.2, 129.9, 128.6, 127.6,
127.4, 127.1, 126.8, 126.3, 126.2, 126.1, 125.8, 125.8, 124.2,
121.2, 120.4, 111.7, 109.5, 67.8, 33.7, 31.3, 28.6, 28.4, 25.5,
22.1, 16.0, 14.0.0 48 ##STR00076## 7-(anthracen-9-ylmethyl)-8-
methoxy-5-oxo-2,3-dihydro- thiazolo[3,2-a]pyridine-3- carboxylic
acid .sup.1H-NMR (400 MHz, SO(CD.sub.3).sub.2): .delta. 13.4 (bs
1H), 8.65 (s,1H), 8.15-8.17 (m, 4H), 7.53-7.65 (m, 4H), 5.29 (dd, J
= 1.6, 8.8 Hz, 1H), 4.81-4.93 (m, 2H), 4.78 (s, 1H), 3.98 (s, 3H),
3.91 (dd, J = 8.9, 11.9 Hz, 1H), 3.61 (dd, J = 1.6, 11.9 Hz, 1H);
.sup.13C- NMR (100 MHz, SO(CD.sub.3).sub.2): .delta. 169.2, 158.7,
151.1, 139.8, 135.2, 131.0, 129.9, 129.4, 129.1, 126.8, 126.5,
125.2, 124.2, 112.3, 62.7, 60.6, 32.0, 26.5. 49 ##STR00077##
7-(anthracen-9-ylmethyl)-8- methoxy-2-(3-methyl-4-
(pentyloxy)phenyl)-5-oxo- thiazolo[3,2-a]pyridine-3- carboxylic
acid .sup.1H-NMR (600 MHz, SO(CD.sub.3).sub.2): .delta. 13.7 (bs,
1H), 8.66 (s, 1H), 8.16-8.21 (m, 4H), 7.54-7.59 (m, 4H), 7.42- 7.45
(m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 5.01 (s, 2H), 4.97 (s, 1H), 4.07
(s, 3H), 4.03 (t, J = 6.2 Hz, 2H), 2.18 (s, 3H), 1.73-1.77 (m, 2H),
1.34-1.45 (m, 4H), 0.90 (t J = 7.1 Hz, 3H); .sup.13C-NMR (150 MHz,
SO(CD.sub.3).sub.2) .delta. 161.2, 158.1, 156.3, 138.0, 134.5,
131.1, 130.0, 129.5, 129.1, 127.1, 126.9, 126.8, 126.5, 125.2,
124.2, 111.7, 108.0, 67.7, 60.5, 28.2, 27.7, 26.5, 21.8, 15.8,
13.9. 50 ##STR00078## 1H-imidazol-1-ium 8-methoxy-
2-(3-methyl-4((4- methylpentypoxy)phenyl)-7-
(naphtalen-1-ylmethyl)-5-oxo- thiazolo[3,2-a]pyridine-3-
carboxylate .sup.1H NMR (600 MHz, SO(CD.sub.3).sub.2) .delta.
7.99-7.901 (m, 3H), 7.88 (d, J = 8.1 Hz, 1H), 7.56-7.41 (m, 6H),
7.14 (s, 2H), 7.02 (d, J = 8.5 Hz, 1H), 5.58 (s, 1H), 4.43 (s, 2H),
4.00 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 2.17 (s, 3H), 1.78-1.70 (m,
2H), 1.63-1.55 (m, 1H), 1.36-1.29 (m, 2H), 0.89 (d, J = 6.6 Hz,
6H); .sup.13C NMR (150 MHz, SO(CD.sub.3).sub.2) .delta. 161.6,
157.9, 156.6, 146.8, 138.3, 135.0, 134.6, 134.2, 133.5, 131.4,
130.0, 128.7, 128.3, 127.6, 127.4, 127.1, 126.7, 126.4, 125.8,
125.7, 124.7, 123.9, 121.2, 120.2, 111.7, 109.1, 68.0, 60.3, 34.8,
32.0, 27.2, 26.5, 22.5 (2C), 15.9.
[0509] Examples 28-36 are described in J. Med Chem (2010), 53(15),
5690-5695, example 37 and 39 are described in Bioorg. Med Chem
(2012), 20(9), 3128-3142, example 38 is described in Chem&Biol
(2013), 20, (10), 1245-1254.
[0510] Biology
[0511] Minimum Inhibitory Concentration (MIC) and Minimum
Bactericidal Concentration (MBC) Assays
[0512] To define the MIC, bacterial cultures at starting OD=0.001
at OD.sub.600 were incubated in the presence of different
increasing concentrations of each compound of Examples 1-39 as
described herein, or a combination of each compound of Examples
1-39 as described herein with an antibiotic overnight (18 hrs). MIC
was defined by the lowest concentration of the test compound that
inhibits visible growth of pathogen of interest. The optical
density of the pathogen of interest culture was measured by
OD.sub.600.
[0513] The MBC was defined by the lowest concentration of each
compound of Examples 1-39, or a combination of each compound of
Example 1-36 with an antibiotic that results in pathogen of
interest death from the same cultures as MIC assay. MBC was
determined colony forming units (CFUs) enumeration by serially
diluting and plating bacterial cultures on BHI plates.
[0514] MIC and MBC data for each compound of examples 1-39 is
provided in Table 2. The values provided in Table 2 result from the
use of the compounds of Examples 1-39 alone. Thus, no antibiotic
was used in Table 2.
TABLE-US-00002 TABLE 2 Pathogen Staph. E. Strep. Staph. MRSA aureus
faecalis pyogenes saphyticus C. diff Streptococcus MIC/MBC MIC/MBC
MIC/MBC MIC/MBC MIC/MBC MIC/MBC MIC/MBC Example uM uM uM uM uM uM
uM 1 20/25 67/25 nd/9 2 27/50+ 250/nd nd/5 3 167/nd 183/100 nd/50 4
200/nd 250/nd nd/9 5 150/nd 250/nd nd/10 6 69/37 200/100 nd/23 7
25/32 95/19 nd/7 8 12/13 .sup. 25/12.5 nd/7 9 17/37 .sup. 39/12.5
nd/8 10 17/17 188/50 nd/5 11 10/6 49/50 .sup. nd/2.5 12 70/25
300/nd nd/2 13 31/25 300/nd nd/3 14 3/nd 6/nd 15 100/nd 16 200/nd
17 >25/nd 18 >25/nd 20 10/nd 21 19/nd >100/nd 22 6/nd
>100/nd 23 45/nd >100/nd 24 45/nd >100/nd 25 45/nd
>100/nd 26 12/nd >100/nd 27 25/nd 28 25/50 25/50 25/100
12.5/25.sup. 100/25 50/50 29 250/200 100/200 25/25 30 25/50 50/50
50/100 .sup. 25/12.5 .sup. 100/12.5 50/50 nd/19 31 50/100 50/100
nd/50 32 200/>400 nd/>400 nd/50 33 nd/400 >400/nd nd/20 34
nd/250 nd/400 nd/25 35 nd/50 36 nd/25 37 25/25 50/50 100/400
12.5/12.5 >500/25 50/50 38 200/250 200/250 200/250 50/50 250/50
200/200 39 50/50 50/200 400/900 12.5/25.sup. >500/25 100/100
[0515] Method for Determining the Effect of Each Compound of
Examples 8, 9 and 11 on MRSA, and Also the Effect on MRSA of a
Combination of Oxacillin with Each Compound of Examples 8, 9 and 11
on MRSA
[0516] The test compound of interest, i.e. the compound of Example
8, 9 or 11, was added to the bacterial inoculum MRSA (190 .mu.l)
with an OD 1, 0.1 or 0.001. The mixture (200 .mu.L) was incubated
at 37.degree. C. for 18 h. A control without the test compound was
performed in the same way. The results are shown in Table 3a.
[0517] The test compound of interest, i.e. the compound of Example
8, 9 or 11, (25 .mu.M, 5 .mu.L in DMSO) was added to the bacterial
inoculum MRSA (190 .mu.l) with an OD 1, 0.1 or 0.001 along with
Oxacillin (9 .mu.M, 5 .mu.L in water). The mixture (200 .mu.L) was
incubated at 37.degree. C. for 18 h. A control without the test
compound was performed in the same way. The results are shown in
Table 3b.
[0518] The effect was determined by CFU counts and is summarized in
Tables 3a and 3b, respectively.
[0519] Table 3a shows the results obtained for each compound of
Examples 8, 9 and 11 described herein compared with a DMSO
control.
[0520] Table 3b shows the results obtained for the combination of
Oxacillin with each of compound of Examples 8, 9 and 11 compared
with a DMSO control also containing oxacillin.
TABLE-US-00003 TABLE 3a Example 8 Example 9 Example 11 MRSA DMSO 25
.mu.M 25 .mu.M 25 .mu.M OD CFUs/ml CFUs/ml CFUs/ml CFUs/ml 1
6.0E+09 6.0E+07 5.0E+07 2.0E+09 0.1 2.0E+09 6.0E+06 4.4E+06 3.3E+06
0.001 3.7E+09 4.0E+05 8.0E+04 5.0E+05
TABLE-US-00004 TABLE 3b Oxacillin 9 .mu.M and Example 8 Example 9
Example 11 MRSA DMSO 25 .mu.M 25 .mu.M 25 .mu.M OD CFUs/ml CFUs/ml
CFUs/ml CFUs/ml 1 2.2E+09 1E+06 3E+06 1.3E+06 0.1 1.6E+10 1.7E+04
2.6E+04 0 0.001 600 0 0 0
[0521] Table 3a shows that for each OD value use of the compound of
Examples 8, Example 9 and Example 11, respectively, resulted in a
decrease of the number of CFUs/ml as compared to the DMSO
control.
[0522] Table 3b shows that for each OD value use of a combination
of oxacillin and the compound of Example 8, Example 9 or Example 11
resulted in a larger decrease in the number of CFUs/ml as compared
to the control containing DMSO and oxacillin. No CFUs/ml were
detected when a combination of oxacillin and the compound of
Example 11 was used at OD 0.1. Further, no CFUs/ml were detected at
OD 0.001 when oxacillin was used in combination with the compounds
of Examples 8, 9 and 11, respectively.
[0523] A comparison of the results of Tables 3a and 3b reveals that
a larger decrease in the number of detected CFUs/ml was observed
for the combination of oxacillin with the compounds of Examples 8,
9 and 11, respectively, as compared to use of each of these
compounds alone or use of oxacillin alone.
[0524] In this document, E+n stands for 10.sup.n. For instance, E+6
means 10.sup.6.
[0525] Method for Determining the Effect of a Combination of
Example 11 and Vancomycin on VRE (V583)
[0526] Compound of Example 11 (2.5 .mu.M, 5 .mu.L in DMSO) was
added to the bacterial inoculum (190 ul) with OD 0,001 along with
increasing doses of Vancomycin (in water) at increasing
concentrations of the Vancomycin ranging from 1-64 .mu.g/ml. The
mixture (200 .mu.L) was incubated at 37.degree. C. for 18 h
Controls were performed without bacteria-vehicle (DMSO), Vancomycin
vehicle (water) and BHI controls that use those as treatment to the
inoculum, to ensure no previous bacterial contamination in the
reagents. Bacterial CFU were counted as standard methods using
serial dilution plated on BHI plates to determine the effect of
each treatment. Additionally, the initial bacterial inoculum was
counted to determine whether the treatment had a bacteriostatic or
a bacteriocidal effect. Bacterial CFU of each treatment were
summarized in Table 4
[0527] Table 4 shows the results obtained for a combination of
Example 11 with Vancomycin for eradication of a Vancomycin
Resistant Enterococcus (VRE) strain V583.
TABLE-US-00005 TABLE 4 Experiment 1 Experiment 2 Treatment Example
11 Example 11 Vancomycin Control 2.5 .mu.M Control 2.5 .mu.M conc.
.mu.g/ml avg. CFU avg. CFU avg. CFU avg. CFU 0 (DMSO) 1.65E+09
5.00E+08 1.20E+09 7.50E+08 1 1.20E+09 5.50E+08 1.70E+09 3.50E+08 2
1.35E+09 2.50E+08 1.40E+09 5.65E+05 4 5.00E+08 5.65E+06 8.50E+08
4.50E+03 8 4.00E+08 6.00E+05 8.50E+08 2.15E+04 16 3.00E+08 3.15E+05
4.50E+08 1.75E+04 32 5.50E+08 3.50E+05 1.95E+06 8.00E+03 64
4.00E+07 1.09E+05 6.00E+04 4.50E+03 Control BHI 1.35E+09 1.35E+09
Control H.sub.2O 1.55E+09 1.50E+09 Initial 6.50E+05 4.00E+05
bacteria Inoculum
[0528] It was observed that use of Vancomycin at a concentration
below 64 .mu.g/ml had no or no substantial effect on the bacterial
growth and nor the use of only the compound of Example 11 at 2.5
.mu.M. However, the combination of Example 11 (2.5 .mu.M) and
Vancomycin had a large effect on the number of CFU's from 2
.mu.g/mL of Vancomycin and above.
[0529] Effect of a Combination of Gentamicin and the Compound of
Example 11 on E. faecalis OG1RF
[0530] In this example, gentamicin was used in combination with the
compound of Example 11, i.e.
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid. FIG.
7 shows that use of Gentamicin alone or the compound of Example 11
alone did not result in a decrease of the number of observed
bacterial CFUs/ml. However, use of a combination of Gentamicin and
the compound of Example 11 resulted in a large decrease of the
number of counted CFUs/ml up to the bacterial limit of detection
(LOD). Thus, there is a synergistic effect when Gentamicin and the
compound of Example 11 are combined."
[0531] Stand Alone Activity In Vivo Against Enterococcus Faecalis
in a Mouse Model of Catheter-Associated Urinary Tract Infection
(CAUTI)
[0532] Mice used in this study were six-week-old female wild-type
C57BL/6Ncr mice. Mice were anesthetized by inhalation of isoflurane
and implanted with a 5-mm length of platinum-cured silicone
catheter. Then, mice were infected immediately following catheter
implantation with 50 .mu.l of .about.2.times.10.sup.7 CFU of E.
faecalis OG1RF in PBS (1 mL) was introduced in the bladder lumen by
transurethral inoculation. 24 hours post-infection, 100 .mu.L, 10
mg/kg of
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid (Example 30) or
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid (Example 28) in DMSO was
administrated via intraperitoneally injection. Mice were sacrificed
at 48 hours post-infection by cervical dislocation after
anaesthesia inhalation, and the bladders were aseptically
harvested. Subsequently, the silicone implant was retrieved from
the bladder. Catheters were placed in 1.times.PBS (1 mL), sonicated
for 10 min, to detach E. faecalis and bladders were homogenized in
1.times.PBS (1 mL). For bacterial enumeration on catheters and
bladders, samples were serially diluted and plated on BHI for CFU
enumeration FIG. 8a shows that
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid was able to reduce
bacterial titers about 1.5 log units in the bladder.
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid was able to reduce
bacterial titers about 0.5 log units (FIG. 8a). On the catheters,
5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicycl-
o[4.3.0]nona-3,5,8-triene-9-carboxylic acid (EC305) reduced
bacterial titers about 1 log unit and
8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4-
.3.0]nona-3,5,8-triene-9-carboxylic acid reduced about 0.4 log unit
(FIG. 8b).
[0533] Additionally, the compounds of Example 14, Example 49,
Example 23, and Example 50 were tested in the mouse model of E.
faecalis CAUTI (FIG. 9). Mice used in this study were six-week-old
female wild-type C57BL/6Ncr mice. Mice were anesthetized by
inhalation of isoflurane and implanted with a 5-mm length of
platinum-cured silicone catheter. Then, mice were infected
immediately following catheter implantation with 50 .mu.l of
.about. 2.times.10.sup.7 CFU of E. faecalis OG1RF in PBS (1 mL) was
introduced in the bladder lumen by transurethral inoculation. 24
hours post-infection, 100 .mu.L, 10 mg/kg of
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-
-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid
imidazole salt (Example 14);
7-(anthracen-9-ylmethyl)-8-methoxy-2-(3-methyl-4-(pentyloxy)phenyl)-5-oxo-
-thiazolo[3,2-a]pyridine-3-carboxylic acid (Example 49);
8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-ox-
o-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid
(Example 23), or
8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)meth-
yl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic
acid imidazole salt (Example 50) in DMSO was administrated via
intraperitoneally injection. Mice were sacrificed at 48 hours
post-infection by cervical dislocation after anaesthesia
inhalation, and the bladders were aseptically harvested.
Subsequently, the silicone implant was retrieved from the bladder.
Catheters were placed in 1.times.PBS (1 mL), sonicated for 10 min,
to detach E. faecalis and bladders were homogenized in 1.times.PBS
(1 mL). For bacterial enumeration on catheters and bladder, samples
were serially diluted and plated on BHI for CFU enumeration. It was
found that compounds of Example 49 and Example 23 were able to
reduce bacterial titers about 1.5 log units in the bladder (FIG.
9a). Compounds of Example 14 and Example 50 were able to reduce
bacterial titers about 0.5 log units (bladders). On the catheters,
compounds of Example 14 and Example 49 reduced bacterial titers
about 1.5 log units and compound of Example 23 and Example 50
reduced about 0.4 log unit (FIG. 9b).
[0534] Activity of a Combination of Vancomycin and the Compound of
Example 49 In Vivo Against Two Enterococcus Faecalis Strains OG1RF
(Vancomycin Sensitive) and V583 (Vancomycin Resistant) in a Mouse
Model of Catheter-Associated Urinary Tract Infection (CAUTI)
[0535] Mice used in this study were six-week-old female wild-type
C57BL/6Ncr mice. Mice were anesthetized by inhalation of isoflurane
and implanted with a 5-mm length of platinum-cured silicone
catheter. Then, mice were infected immediately following catheter
implantation with 50 .mu.l of.about.2.times.10.sup.7 CFU of E.
faecalis OG1RF (FIG. 10) or V583 (FIG. 11) in PBS (1 mL) was
introduced in the bladder lumen by transurethral inoculation. 24
hours post-infection, 100 .mu.L, 3 mg/kg of Vancomycin or
7-(anthracen-9-ylmethyl)-8-methoxy-2-(3-methyl-4-(pentyloxy)phenyl)-5-oxo-
-thiazolo[3,2-a]pyridine-3-carboxylic acid (Example 49) or in
combination in DMSO was administrated via intraperitoneally
injection. Mice were sacrificed at 48 hours post-infection by
cervical dislocation after anaesthesia inhalation, and the bladders
were aseptically harvested. Subsequently, the silicone implant was
retrieved from the bladder. Catheters were placed in 1.times.PBS (1
mL), sonicated for 10 min, to detach E. faecalis and bladders were
homogenized in 1.times.PBS (1 mL). For bacterial enumeration on
catheters and bladder, samples were serially diluted and plated on
BHI for CFU enumeration.
[0536] FIG. 10a shows that Vancomycin alone did not result in
reduction of the number of E. faecalis OG1RF bacterial titers on
the bladders and catheters. Compound of Example 49 alone was able
to reduce about 1 log unit in the bladders and catheters. However,
use of a combination of Vancomycin and compound of Example 49
resulted in about 2 log units in the bladder and catheters. Thus,
there is a synergistic effect when Vancomycin and the compound of
Example 49 are combined in vivo.
[0537] FIG. 11a and FIG. 11b shows that Vancomycin alone resulted
in reduction of the vancomycin resistant E. faecalis V583 bacterial
titers of 0.3 log units in the bladder and no effect on the
catheter. The compound of Example 49 alone did resulted in
reduction of bacterial titers of about 0.5 log units on bladders
and no effect on catheters. However, use of a combination of
Vancomycin and compound of Example 49 against the vancomycin
resistant E. faecalis V583 resulted in reduction of bacterial
titers of about 2 log units in the bladder (FIG. 11a) and about 1
log unit on the catheter (FIG. 11b). Thus, there is a synergistic
effect when Vancomycin and the compound of Example 49 are combined
against a vancomycin resistant strain in vivo.
[0538] Activity of a Combination of Gentamicin and the Compound of
Example 49 In Vivo Against Enterococcus Faecalis Strains OG1RF in a
Mouse Model of Catheter-Associated Urinary Tract Infection
(CAUTI)
[0539] Mice used in this study were six-week-old female wild-type
C57BL/6Ncr mice. Mice were anesthetized by inhalation of isoflurane
and implanted with a 5-mm length of platinum-cured silicone
catheter. Then, mice were infected immediately following catheter
implantation with 50 .mu.l of .about.2.times.10.sup.7 CFU of E.
faecalis OG1RF in PBS (1 mL) was introduced in the bladder lumen by
transurethral inoculation. 24 hours post-infection, 100 .mu.L, 2
mg/kg of Vancomycin or Example 49
(7-(anthracen-9-ylmethyl)-8-methoxy-2-(3-methyl-4-(pentyloxy)phenyl)-5-ox-
o-thiazolo[3,2-a]pyridine-3-carboxylic acid) or in combination in
DMSO was administrated via intraperitoneally injection. Mice were
sacrificed at 48 hours post-infection by cervical dislocation after
anaesthesia inhalation, and the bladders were aseptically
harvested. Subsequently, the silicone implant was retrieved from
the bladder. Catheters were placed in 1.times.PBS (1 mL), sonicated
for 10 min, to detach E. faecalis and bladders were homogenized in
1.times.PBS (1 mL). For bacterial enumeration on catheters and
bladder, samples were serially diluted and plated on BHI for CFU
enumeration.
[0540] FIG. 12a and FIG. 12b shows that Gentamicin alone did not
result in reduction of the number of E. faecalis OG1RF bacterial
titers on the bladders and catheters. Compound of Example 49 alone
was able to reduce about 0.2 log units in the bladders and 0.5 log
units on catheters. However, use of a combination of Gentamicin and
compound of Example 49 resulted in reduction of bacterial titers of
about 2 log units in the bladder and about 1.5 log units on
catheters. Thus, there is a synergistic effect when Gentamicin and
the compound of Example 49 are combined in vivo.
[0541] In this document, to evaluate significance the .Mann-Whitney
U test was used for mouse experiments, p<0.05 was considered
statistically significant.*, p<0.05; *, p<0.005; *,
p<0.0005; ns, values were not statistically different.
* * * * *