Patent ID: 6306881
Filing Date: 2001-10-23
Classification: A61K,A61P

Abstract:
A method of treatment of mammals suffering diseases responsive to inhibition of intracellular leukotriene-A.sub.4 hydrolase activity, comprising administering to the mammal suffering such disease an amount of a compound of formula (I) or a pharmaceutically accepted salt hydrate or solvate thereof to inhibit such activity ##STR53##whereinR is hydrogen or (C.sub.1 -C.sub.6)alkyl;R.sub.1 is hydrogen;(C.sub.1 -C.sub.6)allkyl;(C.sub.2 -C.sub.6)alkenyl;phenyl or substituted phenyl;phenyl (C.sub.1 -C.sub.6)alkyl or substituted phenyl(C.sub.1 -C.sub.6)alkyl;phenyl (C.sub.2 -C.sub.6)alkenyl or substituted phenyl(C.sub.2 -C.sub.6)alkenylheterocyclyl or substituted heterocyclyl;heterocyclyl(C.sub.1 -C.sub.8)alkyl or substituted heterocyclyl (C.sub.1 -C.sub.6)alkyl;a group BSO.sub.n A- wherein n is 0, 1 or 2 and B is hydrogen or a (C.sub.1 -C.sub.6)alkyl,phenyl, substituted phenyl, heterocyclyl substituted heterocyclyl, (C.sub.1 -C.sub.6)acyl, phenacyl or substituted phenacyl group, and A represents (C.sub.1 -C.sub.6)alkylene;hydroxy or (C.sub.1 -C.sub.6)alkoxy;amino, protected amino, acylamino, (C.sub.1 -C.sub.6)alkylamino or di-(C.sub.1 -C.sub.6)alkylamino;mercapto or (C.sub.1 -C.sub.6)alkylthio;amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, di-(C.sub.1 -C.sub.6) alkylamino(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, mercapto(C.sub.1 -C.sub.6)alkyl or carboxy(C.sub.1 -C.sub.6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated;lower alkyl substituted by carbamoyl, mono(C.sub.1 -C.sub.6 alkyl) carbamoyl, di(C.sub.1 -C.sub.6 alkyl)carbamoyl, di-(C.sub.1 -C.sub.6 alkyl)amino, or carboxy-C.sub.1 -C.sub.6 alkanoylamino; ora cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, cyano (--CN), --CO.sub.2 H, --CO.sub.2 R, --CONH.sub.2, --CONHR, --CON(R).sub.2, --OH, --OR, oxo-, --SH, --SR, --NHCOR, and --NHCO.sub.2 R.sup.A wherein R.sup.A is C.sub.1 -C.sub.6 alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;R.sub.2 is a C.sub.1 -C.sub.12 alkyl,C.sub.2 -C.sub.12 alkenyl,C.sub.2 -C.sub.12 alkynyl,phenyl(C.sub.1 -C.sub.6 alkyl)-,heteroaryl(C.sub.1 -C.sub.6 alkyl)-,phenyl(C.sub.2 -C.sub.6 alkenyl)-,heteroaryl(C.sub.2 -C.sub.6 alkenyl)-,phenyl(C.sub.2 -C.sub.6 alkynyl)-,heteroaryl(C.sub.2 -C.sub.6 alkynyl)-,cycloalkyl(C.sub.1 -C.sub.6 alkyl)-,cycloalkyl(C.sub.2 -C.sub.6 alkenyl)-,cycloalkyl(C.sub.2 -C.sub.6 alkynyl)-,cycloalkenyl(C.sub.1 -C.sub.6 alkyl)-,cycloalkenyl(C.sub.2 -C.sub.6 alkenyl)-,cycloalkenyl(C.sub.2 -C.sub.6 alkynyl)-,phenyl(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)-, orheteroaryl(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)- group,any one of which may be optionally substituted by C.sub.1 -C.sub.6 alkyl,C.sub.1 -C.sub.6 alkoxy, halo, cyano (--CN), phenyl or heteroaryl, or phenyl or heteroaryl substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halo, or cyano (--CN);R.sub.3 is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, phenyl, 2,- 3-, and 4-hydroxyphenyl, 2,- 3-, and 4-methoxyphenyl, 2- and 3-thienyl, 2,- 3-, and 4-pyridylmethyl, benzyl, 2,- 3-, and 4-hydroxybenzyl, 2,- 3-, and 4-benzyloxybenzyl, 2,- 3-, and 4-C.sub.1 -C.sub.6 alkoxybenzyl, benzyloxy(C.sub.1 -C.sub.6 alkyl)-, a group -(Alk).sub.n R.sub.6 where Alk is a (C.sub.1 -C.sub.6)alkyl or (C.sub.2 -C.sub.6)alkenyl group, optionally interrupted by one or more --O--, --S-- atoms or --N(R.sub.7)- groups, where R.sub.7 is a hydrogen atom or a (C.sub.1 -C.sub.6)alkyl group, n is 0 or 1, and R.sub.6 is an optionally substituted cycloalkyl or cycloalkenyl group, a benzyl group substituted in the phenyl ring by a group of formula --OCH.sub.2 COR.sub.8 where R.sub.8 is hydroxyl, amino, (C.sub.1 -C.sub.6)alkoxy, phenyl(C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylamino, di((C.sub.1 -C.sub.6)alkyl)amino, phenyl(C.sub.1 -C.sub.6)alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from the group consisting of glycine, .alpha. or .beta. alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid, a heterocyclic(C.sub.1 -C.sub.6)alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C.sub.1 -C.sub.6)alkoxy, cyano, (C.sub.1 -C.sub.6)alkanoyl, trifluoromethyl (C.sub.1 -C.sub.6)alkyl, hydroxy, formyl, amino, (C.sub.1 -C.sub.6)alkylamino, di-(C.sub.1 -C.sub.6)alkylamino, mercapto, (C.sub.1 -C.sub.6)alkylthio, hydroxy(C.sub.1 -C.sub.6)alkyl, mercapto(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkylphenylmethyl, and a group-CR.sub.a R.sub.b R.sub.c in which:each of R.sub.a, R.sub.b and R.sub.c is independently hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.8)cycloalkyl; orR.sub.c is hydrogen and R.sub.a and R.sub.b are independently phenyl or heteroaryl; orR.sub.c is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, or (C.sub.3 -C.sub.8)cycloalkyl, and R.sub.a and R.sub.b together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; orR.sub.a, R.sub.b and R.sub.c together with the carbon atom to which they are attached form a tricyclic ring; orR.sub.a and R.sub.b are each independently (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, or a group as defined for R.sub.c below other than hydrogen, or R.sub.a and R.sub.b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and R.sub.c is hydrogen, --OH, --SH, halogen, --CN, --CO.sub.2 H, (C.sub.1 -C.sub.4)perfluoroalkyl, --CH.sub.2 OH, --CO.sub.2 (C.sub.1 -C.sub.6)alkyl, --O(C.sub.1 -C.sub.6)alkyl, --O(C.sub.2 -C.sub.6)alkenyl, --S(C.sub.1 -C.sub.6)alkyl, --SO(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 (C.sub.1 -C.sub.6) alkyl, --S(C.sub.2 -C.sub.6)alkenyl, --SO(C.sub.2 -C.sub.6)alkenyl, --SO.sub.2 (C.sub.2 -C.sub.6)alkenyl or a group -Q-W wherein Q represents a bond or --O--, --S--, --SO-- or --SO.sub.2 - and W represents a phenyl, phenylalkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.3 -C.sub.8)cycloalkylalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (C.sub.4 -C.sub.8)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 (C.sub.1 -C.sub.6)alkyl, --CONH.sub.2, --CONH(C.sub.1 -C.sub.6)alkyl, --CONH(C.sub.1 -C.sub.6 alkyl).sub.2, --CHO, --CH.sub.2 OH, (C.sub.1 -C.sub.4)perfluoroalkyl, --O(C.sub.1 -C.sub.6)alkyl, --S(C.sub.1 -C.sub.6)alkyl, --SO(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 (C.sub.1 -C.sub.6)alkyl, --NO.sub.2, --NH.sub.2, --NH(C.sub.1 -.sub.6)alkyl, --N((C.sub.1 -C.sub.6)alkyl).sub.2, --NHCO(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, phenyl or benzyl; andR.sub.4 is an ester or thioester group.