PENDANT AMINES AND DERIVATIVES AS INHIBITORS OF LEUKOTRIENE A4 HYDROLASE
This present disclosure is directed to compounds of formula (I): where R 1a , R 1b , R 1c , R 1d , R 1c , R 3 , R 4a , R 4c , R 4d , R 6 , R 7 , and R 8 are described herein as , single stereoisomers or as mixtures of stereoisomers, or pharmaceutically acceptable salts, solvates, clathrates, polymorphs, ammonium ions, N-oxides or prodrugs thereof; which are leukotriene A 4 hydrolase inhibitors and therefore useful in treating inflammatory disorders. Pharmaceutical compositions including the compounds described herein and methods of preparing the compounds described herein are also provided.
1 . A compound having the following formula (I):
wherein
R 1a , R 1b , R 1c , R 1d and R 1e are independently hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 13 —OR 10 , —R 13 —C(═O)OR 10 , or —R 13 —C(═O)R 10 ;
R 3 is a direct bond, —O—, —R 12 —O—, —O—R 12 —, —O—R 12 —O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain, —R 13 — 0 C(═O)R 13 , —R 13 —O—R 13 —C(═O)R 13 , —R 13 C(═O)R 13 —O—R 13 , —R 13 —O—R 13 C(OH) —R 13 , —R 13 C(OH)—R 13 —O—R 13 , or —R 13 —N(R 10 )—R 13 —;
R 4a is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;
R 4b is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;
R 4c is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;
R 4d is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, an optionally substituted straight or branched alkynylene chain, or —R 13 —N(R 10 )—R 13 —;
R 6 is hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;
R 7 is hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;
R 8 is halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; —R 13 —N(R 10 )(R 14 ), —R 13 —NH—O(R 14 ), or —R 13 —OR 10 ;
or R 8 is R 13 —NH 2 when R 3 is —O—, —R 13 —N(R 10 )—R 13 —, or an optionally substituted straight or branched alkylene chain;
or R 8 is R 13 —NH—OH when R 4c is a direct bond, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;
each R 10 is independently hydrogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;
each R 12 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;
each R 13 is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and
each R 14 is independently hydrogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;
as a single stereoisomer or as a mixture of stereoisomers;
or a pharmaceutically acceptable salt, ammonium ion, or N-oxide thereof.
2 . A compound according to claim 1 wherein R 8 is —R 13 —N(R 10 )(R 14 ).
3 . A compound according to claim 2 wherein R 13 is a direct bond or optionally substituted straight or branched alkylene, R 13 is hydrogen or optionally substituted straight or branched alkylene, and R 14 is optionally substituted alkyl, haloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl.
4 . A compound according to claim 1 wherein R 8 is —R 13 —OR 10 .
5 . A compound according to claim 4 wherein R 13 is a direct bond and R 10 is optionally substituted alkyl.
6 . A compound according to claim 1 wherein R 8 is R 13 —NH 2 when R 3 is —O—, —R 13 —N(R 10 )—R 13 —, or an optionally substituted straight or branched alkylene chain.
7 . A compound according to claim 1 wherein R 8 is R 13 —NH—OH when R 4c is a direct bond, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain.
8 . A compound according to claim 1 wherein R 4d is —R 13 —N(R 10 )—R 13 —.
9 . A compound according to claim 1 wherein R 4 a, R 4b , and R 4c are independently a direct bond or an optionally substituted straight or branched alkenylene chain.
10 . A compound according to claim 1 wherein R 3 is —O—, —R 12 —O—, —O— R 12 —, an optionally substituted straight or branched alkylene chain, R 13 —C(═O)R 13 , —R 13 —O—R 13 —(═O)R 13 , —R 13 —C(═O)R 13 —O—R 13 , —R 13 —O—R 13 —C(OH)—R 13 , —R 13 —C(OH)—R 13 —O—R 13 or —R 13 —N(R 10 )—R 13 —.
11 . A compound according to claim 10 wherein R 3 is —O—.
12 . A compound according to claim 10 wherein R 3 is —R 13 —C(═O)R 13 .
13 . A compound according to claim 10 wherein R 3 is —R 13 —N(R 10 )—R 13 .
14 . A compound according to claim 10 wherein R 3 is —R 13 —C(OH)—R 13 —O—R 13 .
15 . A compound according to claim 10 wherein R 3 is —R 13 —C(═O)R 13 —O—R 13 .
16 . A compound according to claim 10 wherein R 3 is an optionally substituted alkylene chain.
17 . A compound according to claim 1 comprising a formula of any of the compounds in the Table below:
Compound Formula
Compound Name
2-amino-N 5 -(4-(benzyloxy)phenyl)- N 1 -methylpentanediamide
4-amino-N 1 -(4- phenoxyphenyl)pentanediamide
2-amino-N 1 -(2-chloroethyl)-N 5 -(4- phenoxyphenyl)pentanediamide
methyl N 5 -(4-(4-(1H-pyrrol-1- yl)phenoxy)phenyl)glutaminate
(2S)-2-amino-N-(4- benzylphenyl)pentanediamide
methyl (2S)-2-amino-4-({4-[4-(1H- pyrrol-1-yl)phenoxy]phenyl} carbamoyl)butanoate
methyl 3-{[(2R)-2-amino-4-[(4- phenoxyphenyl)carbamoyl]butyl}car- bamoyl}propanoate
(2R)-2-amino-N-{4-[4-(1H-pyrrol-1- yl)phenoxy]phenyl}-N′-[2-(pyrrolidin- 1-yl)ethyl]pentanediamide
(2S)-2-amino-N-[2-(pyridin-2- yl)ethyl]-N′-{4-[4-(1H-pyrrol-1- yl)phenoxy]phenyl}pentanediamide
(2R)-2-amino-N-[2-(1H-imidazol-5- yl)ethyl]-N′-{4-[4-(1H-pyrrol-1- yl)phenoxy]phenyl}pentanediamide
(2S)-2-amino-N-(2-chloroethyl)-N′- (4-phenoxyphenyl)pentanediamide
ethyl 3-[(2R)-2-amino-4-[(4- phenoxyphenyl)carbamoyl]butana- mido]propanoate
(2R)-2-amino-N-(4- phenoxyphenyl)pentanediamide
(2S)-2-amino-N-[4- (benzyloxy)phenyl]-N′- hydroxypentanediamide
(2S)-2-amino-N-benzyl-N′-[4- (benzyloxy)phenyl]pentanediamide
(2S)-2-amino-N-[4- (benzyloxy)phenyl]-N′,N′- dimethylpentanediamide
(2S)-2-amio-N-[4- (benzyloxy)phenyl]-N′- methylpentanediamide
methyl (2S)-2-amino-4-{[4-(2- hydroxy-2- phenylethoxy)phen- yl]carbamoyl}butanoate
methyl (2S)-2-amino-4-{[4- (phenylamino)phen- yl]carbamoyl}butanoate