US2021401815A1PendingUtilityA1
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
Est. expiryJun 13, 2037(~10.9 yrs left)· nominal 20-yr term from priority
Inventors:Scott HultgrenJerome S. PinknerMichael G. CaparonAna Lidia Flores MirelesFredrik AlmqvistPardeep SinghAnders LindgrenAaron James Leonard Lynch
C07D 233/56C07D 513/04A61L 29/16A61L 29/085A61L 27/54A61L 27/34A61K 38/14A61K 38/12A61K 31/7036A61K 31/5377A61K 31/4439A61K 31/431A61K 9/0024A61P 31/04A61K 31/4365A61F 2250/0067
47
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Claims
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.
Claims
exact text as granted — not AI-modified1 . A compound of Formula III:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO 2 R 6 ,
d) NH 2 ,
e) H,
R 2 is selected from the group consisting of:
a) H,
b) Cl, F, Br, or I,
c) CH 2 OH,
d) C 1 -C 4 alkyl, and
e) NZ 1 Z 2 ,
R 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 1 -C 4 alkyl 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 4 is selected from the group consisting of:
a) C 1 -C 4 alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ 1 Z 2 ,
g) CH 2 NZ 1 Z 2 ,
i) C(O)OH, and
j) C(O)H,
R 5 is selected from the group consisting of:
and in the above definitions:
R 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 7 is selected from the group consisting of F, Cl, Br, and C 1 -C 4 alkyl,
R 8 is selected from the group consisting of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, henoxy, pentoxy, octoxy, nonoxy, decoxy, C 1 -C 10 alkenoxy, C 1 -C 10 alkynoxy and O(CH 2 ) 2 OCH 3 , or
R 7 and R 8 together form O(CH 2 ) 2 O,
R 9 represents C 1 -C 10 alkyl,
R 10 represents C 1 -C 4 alkyl,
R 11 represents C 1 -C 4 alkyl, or
R 10 and R 11 together form CH 2 (CH 2 ) m CH 2 ,
Y is O, S or N,
Z 1 and Z 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 , C(O)OR 10 , C(O)NR 10 R 11 or C(O)R 10 , or Z 1 and Z 2 together form CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , or CH 2 CH 2 CH 2 CH 2 CH 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 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-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-azabicyclo[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 1 is C(O)OH or tetrazolyl, R 2 is H; R 3 is 1-naphtyl, 9-anthryl or trifluoromethylphenyl, and R 4 is C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, or NZ 1 Z 2 , or a pharmaceutically acceptable salt thereof.
5 . (canceled)
6 . (canceled)
7 . (canceled)
8 . (canceled)
9 . The compound according to claim 1 , wherein R 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 7 is methyl, and/or R 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-thia-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-thia-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-oxo-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-oxo-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)methyl]-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)methyl]-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-azabicyclo[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-phenyl]-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-oxo-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)methyl]-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)phenyl]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-oxo-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-azabicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid, 8-(dimethylamino)-2-(3-methyl-4-(pentyloxy)phenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid, 8-(dimethylamino)-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphthalen-1-ylmethyl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylic, 8-(dimethylamino)-2-(4-(heptyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethyl)-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-thiazolo[3,2,a]pyridine-3-carboxylic acid, 8-amino-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-caraboxylic acid, 8-amino-2-(4-heptyloxy)-3-methylphenyl)-7-8naphtalen-1-ylmethyl)-5-oxo-thiazolo[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-ylmethyl)-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:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO 2 R 6 ,
d) NH 2 ,
e) H,
R 2 is selected from the group consisting of:
a) H,
b) Cl, F, Br or I,
c) CH 2 OH,
d) C 1 -C 4 alkyl, and
e) NZ 1 Z 2 ,
R 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 1 -C 4 alkyl 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 4 is selected from the group consisting of:
a) C 1 -C 4 alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ 1 Z 2 ,
g) CH 2 NZ 1 Z 2 ,
i) C(O)OH,
j) C(O)H,
k) 3-(trifluoromethyl)phenyl, and
l) benzo[d][1,3]dioxol-5-yl,
R 5 is selected from the group consisting of:
and
f) H
and in the above definitions:
R 6 is C 1 -C 4 alkyl or phenyl,
R 7 is selected from the group consisting of F, Cl, Br, and C 1 -C 4 alkyl,
R 8 is selected from the group consisting of OH, C 1 -C 10 alkoxy, C 1 -C 10 alkenoxy, C 1 -C 10 alkynoxy and O(CH 2 ) 2 OCH 3 , or
R 7 and R 8 together form O(CH) 2 O,
R 9 is selected from the group consisting of H and C 1 -C 10 alkyl,
R 10 represents C 1 -C 4 alkyl,
R 11 represents C 1 -C 4 alkyl, or
R 10 and R 11 together form CH 2 (CH 2 ) m CH 2 ,
Y is O, S or N,
Z 1 and Z 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 , C(O)OR 10 , C(O)NR 10 R 11 or C(O)R 10 , or Z 1 and Z 2 together form CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , or CH 2 CH 2 CH 2 CH 2 CH 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 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-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-azabicyclo[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-azabicyclo[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-azabicyclo[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-azabicyclo[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-azabicyclo[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-indancarboxylic acid, 6-[(Naphtyloxy)methyl]-4-oxo-2-phenyl-7-(1,3-Dioxa-5-indanyl)-1-thia-3a-aza-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]pyridine-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:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO 2 R 6 ,
d) NH 2 ,
e) H,
R 2 is selected from the group consisting of:
a) H,
b) Cl, F, Br, or I,
c) CH 2 OH,
d) C 1 -C 4 alkyl, and
e) NZ 1 Z 2 ,
R 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 1 -C 4 alkyl 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 4 is selected from the group consisting of:
a) C 1 -C 4 alkyl substituted with 0, 1, 2, 3 or 4 fluoro:
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ 1 Z 2 ,
g) CH 2 NZ 1 Z 2 ,
i) C(O)OH, and
j) C(O)H,
R 5 is selected from the group consisting of:
and in the above definitions:
R 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 7 is selected from the group consisting of F, Cl, Br, and C 1 -C 4 alkyl,
R 8 is selected from the group consisting of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, hexoxy, pentoxy, octoxy, nonoxy, decoxy, C 1 -C 10 alkenoxy, C 1 -C 10 alkenoxy and O(CH 2 ) 2 OCH 3 , or
R 7 and R 8 together form O(CH 2 ) 2 O,
R 9 represents C 1 -C 10 alkyl,
R 10 represents C 1 -C 4 alkyl,
R 11 represents C 1 -C 4 alkyl, or
R 10 and R 11 together form CH 2 (CH 2 ) 6 CH 2 ,
Y is O, S or N,
Z 1 and Z 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 , C(O)OR 10 , C(O)NR 10 R 11 or C(O)R 10 , or Z 1 and Z 2 together form CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , or CH 2 CH 2 CH 2 CH 2 CH 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 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-azabicyclo[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:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO 2 R 6 ,
d) NH 2 ,
e) H,
R 2 is selected from the group consisting of:
a) H,
b) Cl, F, Br, or I,
c) CH 2 OH,
d) C 1 -C 4 alkyl, and
e) NZ 1 Z 2 ,
R 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 1 -C 4 alkyl 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 4 is selected from the group consisting of:
a) C 1 -C 4 alkyl substituted with 0, 1, 2, 3 or 4 fluoro:
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ 1 Z 2 ,
g) CH 2 NZ 1 Z 2 ,
i) C(O)OH, and
j) C(O)H,
R 5 is selected from the group consisting of:
and in the above definitions:
R 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 7 is selected from the group consisting of F, Cl, Br, and C 1 -C 4 alkyl,
R 8 is selected from the group consisting of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, henoxy, pentoxy, octoxy, nonoxy, desoxy, C 1 -C 10 alkenoxy, C 1 -C 10 alkynoxy and O(CH 2 ) 2 OCH 3 , or
R 7 and R 8 together form O(CH 2 ) 2 O,
R 9 represents C 1 -C 10 alkyl,
R 10 represents C 1 -C 4 alkyl,
R 11 represents C 1 -C 4 alkyl, or
R 10 and R 11 together form CH 2 (CH 2 ) m CH 2 ,
Y is O, S or N,
Z 1 and Z 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 , C(O)OR 10 , C(O)NR 10 R 11 or C(O)R 10 , or Z 1 and Z 2 together form CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , or CH 2 CH 2 CH 2 CH 2 CH 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 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-azabicyclo[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-azabicyclo[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:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO 2 R 6 ,
d) NH 2 ,
e) H,
R 2 is selected from the group consisting of:
a) H,
b) Cl, F, Br or I,
c) CH 2 OH,
d) C 1 -C 4 alkyl, and
e) NZ 1 Z 2 ,
R 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 1 -C 4 alkyl 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 4 is selected from the group consisting of:
a) C 1 -C 4 alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ 1 Z 2 ,
g) CH 2 NZ 1 Z 2 ,
i) C(O)OH,
j) C(O)H,
k) 3-(trifluoromethyl)phenyl, and
l) benzo[d][1,3]dioxol-5-yl,
R 5 is selected from the group consisting of:
and
f) H
and in the above definitions:
R 6 is C 1 -C 4 alkyl or phenyl,
R 7 is selected from the group consisting of F, Cl, Br, and C 1 -C 4 alkyl,
R 8 is selected from the group consisting of OH, C 1 -C 10 alkoxy, C 1 -C 10 alkenoxy, C 1 -C 10 alkynoxy and O(CH 2 ) 2 OCH 3 , or
R 7 and R 8 together form O(CH) 2 O,
R 9 is selected from the group consisting of H and C 1 -C 10 alkyl,
R 10 represents C 1 -C 4 alkyl,
R 11 represents C 1 -C 4 alkyl, or
R 10 and R 11 together form CH 2 (CH 2 ) m CH 2 ,
Y is O, S or N,
Z 1 and Z 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 , C(O)OR 10 , C(O)NR 10 R 11 or C(O)R 10 , or Z 1 and Z 2 together form CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , or CH 2 CH 2 CH 2 CH 2 CH 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 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:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO 2 R 6 ,
d) NH 2 ,
e) H,
R 2 is selected from the group consisting of:
a) H,
b) Cl, F, Br, or I,
c) CH 2 OH,
d) C 1 -C 4 alkyl, and
e) NZ 1 Z 2 ,
R 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 1 -C 4 alkyl 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 4 is selected from the group consisting of:
a) C 1 -C 4 alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ 1 Z 2 ,
g) CH 2 NZ 1 Z 2 ,
i) C(O)OH, and
j) C(O)H,
R 5 is selected from the group consisting of:
and in the above definitions:
R 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 7 is selected from the group consisting of F, Cl, Br, and C 1 -C 4 alkyl,
R 8 is selected from the group consisting of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, hexoxy, pentoxy, octoxy, nonoxy, decoxy, C 1 -C 10 alkenoxy, C 1 -C 10 alkynoxy and O(CH 2 ) 2 OCH 3 , or
R 7 and R 8 together form O(CH 2 ) 2 O,
R 9 represents C 1 -C 10 alkyl,
R 10 represents C 1 -C 4 alkyl,
R 11 represents C 1 -C 4 alkyl, or
R 10 and R 11 together form CH 2 (CH 2 ) m CH 2 ,
Y is O, S or N,
Z 1 and Z 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 , C(O)OR 10 , C(O)NR 10 R 11 or C(O)R 10 , or Z 1 and Z 2 together form CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , or CH 2 CH 2 CH 2 CH 2 CH 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 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-azabicyclo[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,
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO 2 R 6 ,
d) NH 2 ,
e) H,
R 2 is selected from the group consisting of:
a) H,
b) Cl, F, Br or I,
c) CH 2 OH,
d) C 1 -C 4 alkyl, and
e) NZ 1 Z 2 ,
R 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 1 -C 4 alkyl 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 4 is selected from the group consisting of:
a) C 1 -C 4 alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ 1 Z 2 ,
g) CH 2 NZ 1 Z 2 ,
i) C(O)OH,
j) C(O)H,
k) 3-(trifluoromethyl)phenyl, and
l) benzo[d][1,3]dioxol-5-yl,
R 5 is selected from the group consisting of:
and
f) H
and in the above definitions:
R 6 is C 1 -C 4 alkyl or phenyl,
R 7 is selected from the group consisting of F, Cl, Br, and C 1 -C 4 alkyl,
R 8 is selected from the group consisting of OH, C 1 -C 10 alkoxy, C 1 -C 10 alkenoxy, C 1 -C 10 alkynoxy and O(CH 2 ) 2 OCH 3 , or
R 7 and R 8 together form O(CH) 2 O,
R 9 is selected from the group consisting of H and C 1 -C 10 alkyl,
R 10 represents C 1 -C 4 alkyl,
R 11 represents C 1 -C 4 alkyl, or
R 10 and R 11 together form CH 2 (CH 2 ) m CH 2 ,
Y is O, S or N,
Z 1 and Z 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 , C(O)OR 10 , C(O)NR 10 R 11 or C(O)R 10 , or Z 1 and Z 2 together form CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , or CH 2 CH 2 CH 2 CH 2 CH 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 2 , or
a combination as defined in claim 17 .
44 . (canceled)
45 . (canceled)Join the waitlist — get patent alerts
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