US2020352919A1PendingUtilityA1
Ring-fused thiazolino 2-pyridones, methods for preparation thereof and their use in the treatment and/or prevention of tuberculosis
Est. expiryApr 8, 2036(~9.7 yrs left)· nominal 20-yr term from priority
A61K 31/69A61K 31/444A61K 31/437A61P 31/06A61K 45/06A61K 31/4409A61K 31/47A61K 31/4365A61K 2300/00
59
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Claims
Abstract
or a pharmaceutically acceptable salt thereof. The composition is useful in the treatment of tuberculosis.
Claims
exact text as granted — not AI-modified1 . A composition comprising:
(i) a drug against tuberculosis, or a pharmaceutically acceptable salt thereof; and (ii) a compound of Formula II
or a pharmaceutically acceptable salt thereof,
wherein
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) CH 2 OH,
d) C(O)NR 6a R 6b ,
e) C(O)NHSO 2 R 7 ,
f) C(O)OR 8 ,
g) NH 2 ,
h) H,
i)
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) NY 1 Y 2 ,
R 3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, and 1-naphtyloxy, each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano, and methoxy,
b) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano, and trifluoromethyl,
c) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, and trifluoromethyl,
d) 2-(3-methyl)phenylmethylene,
e) benzothiophen-2-yl,
f) H or C 1 -C 4 -alkyl,
i) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
j) 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 by 0, 1, 2, 3 or 4 fluoro;
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted by 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5- or 6-membered heterocycle,
f) N-methyl 3-indolyl, and
h) NR 9 R 10 ,
R 5 is selected from the group consisting of:
a) H,
b) phenyl substituted with 0, 1, 2 or 3 methyl group(s),
c) benzyl,
d) thienyl,
e) C 1 -C 4 alkoxy, and
f) 3-, 4-, 5- or 6-membered heterocycle,
and in the above definitions:
R 6a is selected from the group consisting of H and C 1 -C 4 alkyl,
R 6b is selected from the group consisting of H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and isonicotinoylamino;
R 7 is C 1 -C 4 alkyl or phenyl,
R 8 represents 2-{2-[1-(hydroxymethyl)propylamino]ethylamino}butyl),
R 9a represents C 1 -C 4 alkyl,
R 9b represents C 1 -C 4 alkyl,
R 10 represents C 1 -C 4 alkyl, or R 9 and R 10 together form CH 2 (CH 2 ) m CH 2 ,
Y 1 and Y 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 or C(O)CH 3 , or
Y 1 and Y 2 together form CH 2 CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 CH 2 ,
m is 1, 2 or 3, and
X is S, SO or SO 2 .
2 . The composition according to claim 1 , wherein the compound of Formula II is a compound of Formula IIa or Formula IIb:
wherein R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined in claim 1 ,
or a pharmaceutically acceptable salt thereof.
3 . The composition according to claim 1 , wherein the compound of Formula II is a compound of Formula IIa51:
wherein
R 1 , R 2 , R 3 , R 4 and X are as defined in claim 1 ,
or a pharmaceutically acceptable salt thereof.
4 .- 7 . (canceled)
8 . The composition according to claim 1 , wherein X is S or SO.
9 . The composition according to claim 1 , wherein R 1 is C(O)OH, tetrazolyl, or C(O)NHSO 2 R 7 .
10 . The composition according to claim 1 , wherein R 2 is H.
11 . The composition according to claim 1 , wherein R 3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, and 1-naphtyloxy, each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, cyano, and methoxy, and b) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano, and trifluoromethyl.
12 . The composition according to claim 1 , wherein R 3 is selected from the group consisting of: 1-naphtyl, 2-naphtyl, 4-methyl-1-naphtyl, 4-fluoro-1-naphtyl, 4-bromo-1-naphtyl, 4-methoxy-1-naphtyl, 2-methoxy-1-naphtyl, 2-methoxy-1-naphtyl, 1-naphtyloxy, 3-methylphenyl, 2,3-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,3-dichlorophenyl, 2-(3-methyl)phenylmethylene; 2,3-xylylamine, 3-trifluoromethylphenyl, and benzothipohene-2-yl
13 . The composition according to claim 1 , wherein R 3 is 1-naphtyl.
14 . (canceled)
15 . The composition according to claim 14 , wherein R 4 is cyclopropyl.
16 . The composition according to claim 1 , wherein R 5 is H or phenyl substituted with 0, 1, 2 or 3 methyl group(s).
17 . The composition combination according to claim 1 , wherein the compound of Formula II is selected from:
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-6-[(4-fluoro-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-6-[(4-methyl-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3S)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic 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, (3R)-7-Cyclopropyl-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-6-[(2-fluoro-5-methyl-phenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylyl)methyl]-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Methyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (N-Methylmethoxyamino){(3R)-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}formaldehyde, (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-3-(1H-1,2,3,4-tetrazol-5-yl)-1-thia-3a-aza-4-indanone, 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, (3R)-7-Cyclopropyl-6-[(2-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-3-(hydroxymethyl)-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone, (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(2-thienyl)-1-thia-3a-aza-3-indancarboxylic acid, 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(1H-1,2,3-triazol-4-yl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, 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, (3R)-7-Cyclopropyl-6-[(2,3-dichlorophenyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxamide, {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(phenylsulfonylamino)formaldehyde, (3R)-7-Isopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-6-methyl-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-6-[(p-Chlorophenyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, {(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(methylsulfonylamino)formaldehyde, (3R)-7-Cyclopropyl-4-oxo-6-[(m-tolyl)methyl]-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Isopropyl-4-oxo-6-[2-(m-tolyl)ethyl]-1-thia-3a-aza-3-indancarboxylic acid, 7-(1-Methyl-1H-indol-3-yl)-6-[(1-naphthyloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-6-[(4-Bromo-1-naphthyl)methyl]-7-cyclopropyl-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone, (3R)-7-Cyclopropyl-5-(hydroxymethyl)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3S)-3-Amino-7-cyclopropyl-6-[(1-naphthyl)methyl]-1-thia-3a-aza-4-indanone, (2R,3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-2-phenyl-1-thia-3a-aza-3-indancarboxylic acid, (2S,3R)-7-Cyclopropyl-2-methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic acid, 2-{2-[1-(Hydroxymethyl)propylamino]ethylamino}butyl 7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate, {7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde, 7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-(Dimethylamino)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-5-Bromo-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(1-naphthyl)methyl]-1,1-dioxo-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylidino)methyl]-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Ethoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-6-[(1-Naphthyl)methyl]-4-oxo-7-(trifluoromethyl)-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Isobutoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-6-[(2-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-(Cyclopropylmethoxy)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-5-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-5-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-8-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-8-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, or a pharmaceutically acceptable salt of any of the foregoing compounds.
18 . (canceled)
19 . (canceled)
20 . The composition according to claim 1 , wherein the compound of Formula II is selected from the group consisting of:
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic acid, and (3R)-7-Cyclopropyl-4-oxo-6-{(7-thiabicyclo[4.3.0]nona-1,3,5,8-tetraen-8-yl)methyl}-1-thia-3a-aza-3-indancarboxylic, or a pharmaceutically acceptable salt of any of the foregoing compounds.
21 . (canceled)
22 . (canceled)
23 . (canceled)
24 . The composition according to claim 1 , wherein the drug against tuberculosis is at least one of the following: isonicotinylhydrazide, bedaquiline, ethionamide, pretomanid, 4-aminosalisalicylic acid, rifampicin, pyrazinamide, or ethambutol.
25 . (canceled)
26 . The composition according to claim 24 , wherein the drug against tuberculosis is isonicotinylhydrazide and/or bedaquiline.
27 .- 57 . (canceled)
58 . A compound which is selected from:
7-Cyclopropyl-4-oxo-6-{[m-(trifluoromethyl)phenyl]methyl}-1-thia-3a-aza-3-indancarboxylic acid, 2-{2-[1-(Hydroxymethyl)propylamino]ethylamino}butyl 7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate, {7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indanyl}(2-isonicotinoylhydrazino)formaldehyde, 7-Cyclopropyl-6-[(4-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-5-Bromo-7-cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(1-naphthyl)methyl]-1,1-dioxo-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-4-oxo-6-[(2,3-xylidino)methyl]-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(1-naphthyl)methyl]-1-oxo-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Ethoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-Cyclopropyl-6-[(2-methoxy-1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, (3R)-7-(Cyclopropylmethoxy)-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(2-methyl-)-aza-2-bora-H-naphth-5-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-5-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, 7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-8-yl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, or 7-Cyclopropyl-6-[(2-methyl-1-aza-2-bora-TH-naphth-8-yloxy)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid, or a pharmaceutically acceptable salt of any of the foregoing compounds.
59 .- 61 . (canceled)
62 . A kit comprising:
i) an effective amount of a drug against tuberculosis,
or a pharmaceutically acceptable salt thereof;
ii) an effective amount of a compound of Formula II
or a pharmaceutically acceptable salt thereof,
wherein
R 1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) CH 2 OH,
d) C(O)NR 6a R 6b ,
e) C(O)NHSO 2 R 7 ,
f) C(O)OR 8 ,
g) NH 2 ,
h) 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) NY 1 Y 2 ,
R 3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, and 1-naphtyloxy, each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano, and methoxy,
b) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano, and trifluoromethyl,
c) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, and trifluoromethyl,
d) 2-(3-methyl)phenylmethylene,
e) benzothiophen-2-yl,
f) H or C 1 -C 4 -alkyl,
i) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
j) 2-methyl-1-aza-2-bora-H-naphth-5-yl,
R 4 is selected from the group consisting of:
a) C 1 -C 4 alkyl substituted by 0, 1, 2, 3 or 4 fluoro;
b) C 3 -C 6 cycloalkyl,
c) C 1 -C 4 alkoxy substituted by 0, 1, 2, 3 or 4 fluoro,
d) C 3 -C 6 cycloalkoxy,
e) a 3-, 4-, 5- or 6-membered heterocycle,
f) N-methyl 3-indolyl, and
h) NR 9 R 10 ,
R 5 is selected from the group consisting of:
a) H,
b) phenyl substituted with 0, 1, 2 or 3 methyl group(s),
c) benzyl,
d) thienyl,
e) C 1 -C 4 alkoxy, and
f) 3-, 4-, 5- or 6-membered heterocycle,
and in the above definitions:
R 6a is selected from the group consisting of H and C 1 -C 4 alkyl,
R 6b is selected from the group consisting of H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and isonicotinoylamino;
R 7 is C 1 -C 4 alkyl or phenyl,
R 8 represents 2-{2-[1-(hydroxymethyl)propylamino]ethylamino}butyl),
R 9a represents C 1 -C 4 alkyl,
R 9b represents C 1 -C 4 alkyl,
R 10 represents C 1 -C 4 alkyl, or
R 9 and R 10 together form CH 2 (CH 2 ) m CH 2 ,
Y 1 and Y 2 each independently represents hydrogen, methyl, CH 3 S(O) 2 or C(O)CH 3 , or Y 1 and Y 2 together form CH 2 CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 CH 2 ,
m is 1, 2 or 3, and
X is S, SO or SO 2 : and
iii) optionally instructions of use.
63 . The kit of claim 62 , wherein the kit comprises instructions for use.
64 . A kit comprising:
i) an effective amount of the composition of claim 1 ; and ii) optionally instructions of use.
65 . The kit of claim 64 , wherein the kit comprises instructions for use.Cited by (0)
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