Inhibitors of leukotriene A4 hydrolase
View Patent ↗The present invention is directed to compounds encompassed by the Formula (I), pharmaceutical compositions thereof, methods for inhibiting LTA-4 hydrolase, and methods for the treatment of a disease and disorder which is ameliorated by the inhibition of LTA4-h activity. Non-limiting examples of such diseases and conditions include inflammatory and autoimmune diseases and disorders.
1. A compound having the Formula (I):
wherein:
R is
r is 0 to 4;
R 1a is selected from the group consisting of C(O)OR 10 , C(O)R 10 , C(O)NR 10 R 11 , optionally substituted C 1 -C 12 alkyl, halo, optionally substituted phenyl, and optionally substituted heteroaryl;
R 1b , R 1c , R 1d and R 1e are each hydrogen;
R 3 is —O—;
R 4 is methylene;
R 5a and R 6a are each independently hydrogen or optionally substituted C 1 to C 12 alkyl;
R 7 is hydrogen, C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
each R 9 is independently —OR 10 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, halo, optionally substituted aryl, or optionally substituted heteroaryl;
each R 10 and R 11 is independently hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
or R 10 and R 11 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;
each R 13 is independently a direct bond, an optionally substituted straight or branched C 1 to C 12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 3 to C 12 alkynylene chain; and
R 15 is
R 16 is the group:
z is an integer from 1 to 5;
at least one R 18 is C(O)OR 10 and the other R 18 , if present, are independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR 10 , NO 2 , C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , NR 10 R 11 , and N(R 10 )C(O)R 10 ;
as a single stereoisomer or as a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 15 is:
3. The compound of claim 1 , wherein R 16 has the structure:
4. The compound of claim 1 , wherein R 5a and R 6a are each independently hydrogen, C 1 -C 12 alkyl, halo-C 1 -C 12 -alkyl, or hydroxy-C 1 -C 12 -alkyl.
5. The compound of claim 1 , wherein R 1a is selected from the group consisting of C(O)OR 10 , C(O)R 10 , C(O)NR 10 R 11 , optionally substituted C 1 -C 12 alkyl, halo, optionally substituted phenyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted thiazolyl, and optionally substituted oxazolyl.
6. The compound of claim 5 , wherein R 1a is halo.
7. The compound of claim 5 , wherein R 1a is oxazolyl or thiazolyl.
8. The compound of claim 1 , wherein R 7 is hydrogen or optionally substituted C 1 -C 6 alkyl.
9. The compound of claim 1 selected from the compounds in the Table below, or a pharmaceutically acceptable salt thereof:
X =
Y =
10. The compound of claim 3 selected from the compounds in the following Table, or a pharmaceutically acceptable salt thereof:
X
Y
H
CH 2 CH 2 —OMe
Me
H
Me
Me
H.
11. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.