IL-8 RECEPTOR ANTAGONISTS
This invention relates to novel compounds and compositions thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
1 . A compound according to Formula (I):
wherein
X is selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, cyano, CF 3 , and OCF 3 ;
R2 is selected from the group consisting of C 3-6 cycloalkyl, phenyl and heteroaryl, wherein the phenyl or heteroaryl moieties are optionally substituted, once or twice, independently, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, CF 3 , OCF 3 , phenyloxy and benzyloxy; or
R2 is phenyl substituted by methylenedioxy or phenyl substituted by (di-halo-substituted)-methylenedioxy;
R1 is a C 4-8 heterocyclyl(CH 2 ) n — moiety wherein the C 4-8 heterocyclyl is an optionally substituted pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, or azetidin-3-yl, the heterocyclyl moieties being optionally substituted independently, once or twice, by a substituent selected from the group consisting of C 1-3 alkyl, C(O)OR4 and C(O)R5; or
R1 is selected from the following ring systems (a-k):
R4 and R5 are, independently, C 1-3 alkyl;
n is 0 or 1; and
R3 is H or C 1-3 alkyl;
or a pharmaceutically acceptable salt thereof.
2 . A compound according to claim 1 wherein X is halogen.
3 . A compound according to claim 1 wherein X is chlorine.
4 . A compound according to claim 1 wherein R2 is phenyl optionally substituted, independently once or twice, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, OCF 3 and phenyloxy.
5 . A compound according to claim 4 wherein R2 is selected from the group consisting of 3-fluoro-2-methylphenyl, 2-trifluoromethyloxyphenyl, 2-chloro-3-fluorophenyl, 2-ethylphenyl and 2-phenyloxyphenyl.
6 . A compound according to claim 1 wherein R2 is 3-fluoro-2-methylphenyl or 2-chloro-3-fluorophenyl.
7 . A compound according to claim 1 wherein R2 is pyridyl, optionally substituted once by halogen.
8 . A compound according to claim 7 wherein R2 is 2-chloro-3-pyridyl.
9 . A compound according to claim 1 wherein n is 0.
10 . A compound according to claim 1 wherein n is 0 and R1 is a piperidine-3-yl or piperidine-4-yl moiety.
11 . A compound according to claim 1 wherein n is 1, and R1 is a pyrrolidin-3-yl or a ethyl-1-pyrrolidinylcarboxylate moiety.
12 . A compound according to claim 1 wherein R1 is 3-exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl or 3-exo-8-azabicyclo[3.2.1]oct-3-yl.
13 . A compound according to claim 1 wherein the pharmaceutically acceptable salt is a hydrochloride salt.
14 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
15 . A compound according to claim 1 selected from the group consisting of
N-(4-chloro-2-hydroxy-3-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]sulfonyl}phenyl)-N′-(3-fluoro-2-methylphenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′-{2-[(trifluoromethyl)oxy]phenyl}urea;
N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-chloro-3-pyridinyl)urea;
N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea;
N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-chloro-3-fluorophenyl)urea;
N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(2,2-difluoro-1,3-benzodioxol-4-yl)urea;
N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(3-fluoro-2-methylphenyl)urea;
N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(2-chloro-3-pyridinyl)urea;
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-pyridinyl)urea;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}urea;
N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(2-ethylphenyl)urea;
N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-{2-[(trifluoromethyl)oxy]phenyl}urea;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-ethylphenyl)urea;
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(3-fluoro-2-methylphenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2,2-difluoro-1,3-benzodioxol-4-yl)urea;
N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(3-fluoro-2-methylphenyl)urea;
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2-ethylphenyl)urea;
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2-chloro-3-pyridinyl)urea;
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-{2-[(trifluoromethyl)oxy]phenyl}urea;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-{2-[(trifluoromethyl)oxy]phenyl}urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea;
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-[2-(phenyloxy)phenyl]urea;
N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-[2-(phenyloxy)phenyl]urea;
ethyl 4-{[6-chloro-3-({[(3-fluoro-2-methylphenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate;
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-fluorophenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea;
ethyl 4-({6-chloro-2-hydroxy-3-[({[2-(phenyloxy)phenyl]amino}carbonyl)amino]-phenyl}sulfonyl)-1-piperidinecarboxylate;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-[2-(phenyloxy)phenyl]urea;
N-(2-chloro-3-fluorophenyl)-N′-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]urea;
ethyl 4-{[6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea;
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(3-fluoro-2-methylphenyl)urea;
N-(2-chloro-3-fluorophenyl)-N′-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]urea; and
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea;
or a pharmaceutically acceptable salt thereof.
16 . A compound according to claim 1 selected from the group consisting of:
N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(3-fluoro-2-methylphenyl)urea;
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2-chloro-3-pyridinyl)urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea;
N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-[2-(phenyloxy)phenyl]urea;
ethyl 4-{[6-chloro-3-({[(3-fluoro-2-methylphenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate;
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-fluorophenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea;
ethyl 4-({6-chloro-2-hydroxy-3-[({[2-(phenyloxy)phenyl]amino}carbonyl)amino]phenyl}sulfonyl)-1-piperidinecarboxylate;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-[2-(phenyloxy)phenyl]urea;
N-(2-chloro-3-fluorophenyl)-N′-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]urea;
ethyl 4-{[6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea;
N-(2-chloro-3-fluorophenyl)-N′-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]urea; and
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea;
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-fluorophenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea;
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea;
or a pharmaceutically acceptable salt thereof.
17 . A method of synthesizing a compound according to Formula (I):
wherein
X is selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, cyano, CF 3 , and OCF 3 ;
R2 is selected from the group consisting of C 3-6 cycloalkyl, phenyl and heteroaryl, wherein the phenyl or heteroaryl moieties are optionally substituted, once or twice, independently, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, CF 3 , OCF 3 , phenyloxy and benzyloxy; or
R2 is phenyl substituted by methylenedioxy or phenyl substituted by (di-halo-substituted)-methylenedioxy;
R1 is a C 4-8 heterocyclyl(CH 2 ) n — moiety wherein the C 4-8 heterocyclyl is an optionally substituted pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, or azetidin-3-yl, the heterocyclyl moieties being optionally substituted independently, once or twice, by a substituent selected from the group consisting of C 1-3 alkyl, C(O)OR4 and C(O)R5; or
R1 is selected from the following ring systems (a-k):
R4 and R5 are, independently, C 1-3 alkyl;
n is 0 or 1; and
R3 is H or C 1-3 alkyl;
or a pharmaceutically acceptable salt thereof,
comprising the steps of:
a) oxidizing a sulfide according to Formula (II):
wherein R1 and X are as defined according to Formula (I), to a sulfone according to Formula (III):
b) hydrolyzing the sulfone to an aminophenol according to Formula (IV):
and
c) exposing the aminophenol to an isocyanate or isocyanate precursor having the formula
R2C═N═O or R2CON 3 ,
to yield the final product, and wherein R2 is as defined for Formula (I); and protecting and de-protecting the R1 moiety by an acid labile protecting group as necessary.
18 . The process according to claim 17 wherein the compound of Formula (I) is
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-pyridinyl)urea;
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(3-fluoro-2-methylphenyl)urea;
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-[2-(phenyloxy)phenyl]urea; or
N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-fluorophenyl)urea; or a pharmaceutically acceptable salt thereof.
19 . The process according to claim 17 wherein the compound of Formula (I) is
N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′-{2-[(trifluoromethyl)oxy]phenyl}urea;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}urea;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-ethylphenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2,2-difluoro-1,3-benzodioxol-4-yl)urea;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-{2-[(trifluoromethyl)oxy]phenyl}urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea;
N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-[2-(phenyloxy)phenyl]urea;
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea; or
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea; or a pharmaceutically acceptable salt thereof.
20 . The process according to claim 17 wherein the compound of Formula (I) is
N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea;
N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea, or
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)-phenyl]-N′-(3-fluoro-2-methylphenyl)urea,
or a pharmaceutically acceptable salt thereof.
21 . The process according to claim 17 wherein the compound of Formula (I) is
N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea, or
N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)-phenyl]-N′-(3-fluoro-2-methylphenyl)urea,
or a pharmaceutically acceptable salt thereof.
22 . The process according to claim 17 wherein n is 0 and R1 is a piperidine-3-yl or piperidine-4-yl moiety.
23 . The process according to claim 17 wherein R2 is phenyl optionally substituted, independently once or twice, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, OCF 3 and phenyloxy.
24 . The process according to claim 17 wherein R2 is selected from the group consisting of 3-fluoro-2-methylphenyl, 2-trifluoromethyloxyphenyl, 2-chloro-3-fluorophenyl, 2-ethylphenyl and 2-phenyloxyphenyl.
25 . The process according to claim 17 wherein n=0 and R1 is a 3-azetidinyl, 4-piperidinyl, 3-piperidinyl, 3-pyrrolidinyl or ethyl-1-pyrrolidinylcarboxylate.
26 . The process according to claim 17 wherein R1 is an optionally substituted piperidine-3-yl.
27 . The process according to claim 26 wherein X is halogen.
28 . The process according to claim 27 wherein R2 is a phenyl substituted, once or twice, independently, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, CF 3 , OCF 3 , phenyloxy and benzyloxy.
29 . A compound which is
N-(4-chloro-2-hydroxy-3-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]sulfonyl}phenyl)-N′-(3-fluoro-2-methylphenyl)urea;
N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-chloro-3-pyridinyl)urea;
N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-chloro-3-fluorophenyl)urea; or
N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(3-fluoro-2-methylphenyl)urea; or a pharmaceutically acceptable salt thereof.
30 . A compound selected from the group consisting of:
31 . A method of treating a chemokine mediated disease, wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which method comprises administering to said mammal an effective amount of a compound according to claim 1 .