Anti-inflammatory agents

A method of treatment of mammals suffering diseases responsive to inhibition of intracellular leukotriene-A4 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

• wherein
• R is hydrogen or (C1-C6)alkyl;
• R1 is hydrogen;
• (C1-C6)allkyl;
• (C2-C6)alkenyl;
• phenyl or substituted phenyl;
• phenyl (C1-C6)alkyl or substituted phenyl(C1-C6)alkyl;
• phenyl (C2-C6)alkenyl or substituted phenyl(C2-C6)alkenyl
• heterocyclyl or substituted heterocyclyl;
• heterocyclyl(C1-C8)alkyl or substituted heterocyclyl (C1-C6)alkyl;
• a group BSOnA- wherein n is 0, 1 or 2 and B is hydrogen or a (C1-C6)alkyl,
• phenyl, substituted phenyl, heterocyclyl substituted heterocyclyl, (C1-C6)acyl, phenacyl or substituted phenacyl group, and A represents (C1-C6)alkylene;
• hydroxy or (C1-C6)alkoxy;
• amino, protected amino, acylamino, (C1-C6)alkylamino or di-(C1-C6)alkylamino;
• mercapto or (C1-C6)alkylthio;
• amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di-(C1-C6) alkylamino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, mercapto(C1-C6)alkyl or carboxy(C1-C6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated;
• lower alkyl substituted by carbamoyl, mono(C1-C6 alkyl) carbamoyl, di(C1-C6 alkyl)carbamoyl, di-(C1-C6 alkyl)amino, or carboxy-C1-C6 alkanoylamino;
• or
• a 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 C1-C6 alkyl, C2-C6 alkenyl, halo, cyano (—CN), —CO2H, —CO2R, —CONH2, —CONHR, —CON(R)2, —OH, —OR, oxo-, —SH, —SR, —NHCOR, and —NHCO2RA wherein RA is C1-C6 alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;
• R2 is a C1-C12 alkyl,
• C2-C12 alkenyl,
• C2-C12 alkynyl,
• phenyl(C1-C6 alkyl)-,
• heteroaryl(C1-C6 alkyl)-,
• phenyl(C2-C6 alkenyl)-,
• heteroaryl(C2-C6 alkenyl)-,
• phenyl(C2-C6 alkynyl)-,
• heteroaryl(C2-C6 alkynyl)-,
• cycloalkyl(C1-C6 alkyl)-,
• cycloalkyl(C2-C6 alkenyl)-,
• cycloalkyl(C2-C6 alkynyl)-,
• cycloalkenyl(C1-C6 alkyl)-,
• cycloalkenyl(C2-C6 alkenyl)-,
• cycloalkenyl(C2-C6 alkynyl)-,
• phenyl(C1-C6 alkyl)O(C1-C6 alkyl)-, or
• heteroaryl(C1-C6 alkyl)O(C1-C6 alkyl)- group,
• any one of which may be optionally substituted by C1-C6 alkyl,
• C1-C6 alkoxy, halo, cyano (—CN), phenyl or heteroaryl, or phenyl or heteroaryl substituted by C1-C6 alkyl, C1-C6 alkoxy, halo, or cyano (—CN);
• R3 is selected from the group consisting of C1-C6 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-C1-C6 alkoxybenzyl, benzyloxy(C1-C6alkyl)-, a group -(Alk)nR6 where Alk is a (C1-C6)alkyl or (C2-C6)alkenyl group, optionally interrupted by one or more —O—, —S— atoms or —N(R7)- groups, where R7 is a hydrogen atom or a (C1-C6)alkyl group, n is 0 or 1, and R6 is an optionally substituted cycloalkyl or cycloalkenyl group, a benzyl group substituted in the phenyl ring by a group of formula —OCH2COR8 where R8 is hydroxyl, amino, (C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, phenyl(C1-C6)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, α or β alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid, a heterocyclic(C1-C6)alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C1-C6)alkoxy, cyano, (C1-C6)alkanoyl, trifluoromethyl (C1-C6)alkyl, hydroxy, formyl, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, mercapto, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, mercapto(C1-C6)alkyl or (C1-C6)alkylphenylmethyl, and a group-CRaRbRc in which:
• each of Ra, Rb and Rc is independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, (C3-C8)cycloalkyl;
• or
• Rc is hydrogen and Ra and Rb are independently phenyl or heteroaryl;
• or
• Rc is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, or (C3-C8)cycloalkyl, and Ra and Rb 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;
• or
• Ra, Rb and Rc together with the carbon atom to which they are attached form a tricyclic ring;
• or
• Ra and Rb are each independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, or a group as defined for Rc below other than hydrogen, or Ra and Rb together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and Rc is hydrogen, —OH, —SH, halogen, —CN, —CO2H, (C1-C4)perfluoroalkyl, —CH2OH, —CO2(C1-C6)alkyl, —O(C1-C6)alkyl, —O(C2-C6)alkenyl, —S(C1-C6)alkyl, —SO(C1-C6)alkyl, —SO2(C1-C6) alkyl, —S(C2-C6)alkenyl, —SO(C2-C6)alkenyl, —SO2(C2-C6)alkenyl or a group -Q-W wherein Q represents a bond or —O—, —S—, —SO— or —SO2- and W represents a phenyl, phenylalkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkylalkyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, —CN, —CO2H, —CO2(C1-C6)alkyl, —CONH2, —CONH(C1-C6)alkyl, —CONH(C1-C6alkyl)2, —CHO, —CH2OH, (C1-C4)perfluoroalkyl, —O(C1-C6)alkyl, —S(C1-C6)alkyl, —SO(C1-C6)alkyl, —SO2(C1-C6)alkyl, —NO2, —NH2, —NH(C1-6)alkyl, —N((C1-C6)alkyl)2, —NHCO(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, phenyl or benzyl;
• and
• R4 is an ester or thioester group.