Piperazine derivatives and their use as anti-inflammatory agents

A method of treating an inflammatory disorder selected from the group consisting of multiple sclerosis and encephalomyelitis in a human, which method comprises administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (Ia):

• wherein:
• R1a is a substituent selected from the group consisting of alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, monoalkylaminoalkyl, monoalkylureidoalkyl, and azidoalkyl;
• or R1a is two substituents, wherein one substituent is an alkyl radical and the other substituent is selected from the group consisting of alkyl, aryloxyalkylcarbonyloxyalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkenyl, cyanoalkyl, triazol-2-ylalkyl and tetrazolylalkyl;
• R2 is fluoro in the 4-position;
• R3 is phenyl substituted by one to three substituents independently selected from the group consisting of hydroxy, halo, alkyl, alkoxy, hydroxyalkoxy, formyl, nitro, cyano, hydroxyalkyl, (monoalkylamino)aralkyl, amino, monoalkylamino, dialkylamino, monoaralkylamino, alkylcarbonylamino, alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, furan-2-ylcarbonylamino, dialkylaminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl, (cycloalkylalkyl)aminoalkyl, monoarylaminoalkyl, oxazol-2-ylaminoalkyl, alkoxycarbonylalkylcarbonlylaminoalkyl, (arylsulfonyl)(alkyl)aminOalkYl, carboxy, alkoxycarbonyl, alkylcarbonyl, (hydroxyalkoxy)carbonyl, aminocarbonyl, (hydroxyalkyl)aminocarbonyl, ureido, monoarylureido, monoaralkylureido, dialkylureidoalkyl, monoarylureidoalkyl, monohaloalkylureidoalkyl, (alkoxycarbonylalkyl)ureidoalkyl, (alkoxycarbonylalkylcarbOnyl)(alkYl)glyciflamido, arylcarbonylglycinanhido, (arylcarbonyl)(alkyl)glycinamido, (monoaralkylaminocarbonyl)(alkyl)glycinamido, (monoarylaminocarbonyl)glycinamido, phthalimido, maleimido, morpholin-4-ylalkyl, and piperazin-4-ylalkyl (wherein the piperazinyl radical is optionally substituted by alkoxycarbonyl, benzylcarbonyl, or phenylaminocarbonyl);
• R4 is —O—;
• R5 is methylene;
• and
• R6 is —C(O)—;
• as a single stereoisomer or a mixture thereof;
• or a pharmaceutically acceptable salt thereof.

A method of treating an inflammatory disorder selected from the group consisting of multiple sclerosis and encephalomyelitis in a human, which method comprises administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (Ia):

• wherein:
• R1a is a substituent selected from the group consisting of alkyl and hydroxyalkyl;
• or R1a is two substituents wherein one substituent is an alkyl radical and the other substituent is selected from the group consisting of alkyl and hydroxyalkyl;
• R2 is fluoro in the 4-position;
• R3 is phenyl substituted by one to three substituents independently selected from the group consisting of hydroxy, halo, alkyl, alkoxy, formyl, nitro, hydroxyalkyl, amino, aminocarbonyl, (aminocarbonylalkyl)aminocarbonyl, (aminoalkyl)aminocarbonyl, monoarylaminocarbonyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, cycloalkylaminoalkyl, (alkylsulfonyl)(alkyl)aminoalkyl, alkylcarbonylamino, haloalkylcarbonylamino, alkenylcarbonylamino, alkoxycarbonylalkylcarbonylamino, alkoxyalkylcarbonylamino, monoalkylaminocarbonyl, alkylcarbonyl, hydroxyamidino, alkylsulfonylamino, glycinamido, monoalkylglycinamido, aminocarbonylglycinamido, (aminocarbonyl)(alkyl)glycinamido, (alkoxyalkylcarbonyl)glycinamido, (alkoxycarbonylaminocarbonyl)glycinamido, alaninamido, ureido, monoalkylureido, ureidoalkyl, (haloalkylcarbonyl)ureido, imidazol-1 -ylalkyl, 1,2,4-triazol-1 -yl, tetrazol-1-yl, morpholin-4-yl, and piperazin-4-ylalkyl (wherein the piperazinyl radical is optionally substituted by alkyl or alkoxycarbonyl);
• R4 is —O—;
• R5 is methylene;
• and
• R6 is —C(O)—;
• as a single stereoisomer or a mixture thereof;
• or a pharmaceutically acceptable salt thereof.