Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents

A compound of the general formula (Ia) or a salts or a physiologically functional derivatives thereof,

• wherein
• A is a non-heterocyclic non-aromatic ring system containing 4, 5, 6, 7 or 8 carbon atoms, wherein the ring system comprises at least one double bond and wherein one or more of the carbon atoms in the ring represented X may be carbonyl (C═O);
• D is O, S, SO2, NR4, or CH2;
• z1 and z2 are independent from each other O, S, or NR5;
• R1 is independently H, halogen, haloalkyl, haloalkyloxy —CO2R″, —SO3H, —OH, —CONR*R″, —CR″O, —SO2—NR*R″, —NO2, —SO2—R″, SO—R*, —CN, alkoxy, alkylthio, aryl, —NR″—CO2—R′, —NR″—CO—R*, —NR″—SO2—R′, —O—CO—R*, —O—CO2—R*, —O—CO—NR*R″;
• cycloalkyl, alkylamino, hydroxyalkylamino, —SH, heteroaryl, or alkyl;
• R* is independently H, alkyl, cycloalkyl aminoalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
• R′ is independently H, —CO2R″, —CONHR″, —CR″O, —SO2NR″, —NR″—CO-haloalkyl, —NO2, —NR″—SO2-haloalkyl, —NR″—SO2-alkyl, —SO2-alkyl, —NR″—CO-alkyl, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl arylalkyl or heteroaryl;
• R″ is independently hydrogen, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
• R2 is NHOH or R2 together with the nitrogen atom which is attached to R8 form a 5 or 6 membered heterocyclic ring with the proviso that R2 is —[CH2]8 and R8 is absent;
• R3 is H, alkyl, cycloalkyl, aryl, alkoxy, O-aryl;
• O-cycloalkyl, halogen, aminoalkyl, alkylamino, hydroxylamino, hydroxylalkyl, haloalkyloxy, heteroaryl, alkylthio, S-aryl;
• S-cycloalkyl, arylalkyl, or haloalkyl;
• R4 is H, alkyl, cycloalkyl, aryl or heteroaryl;
• R5 is H, OH, alkoxy, O-aryl, alkyl or aryl;
• R8 is hydrogen, or alkyl;
• E is an alkyl or cycloalkyl group which is substituted by [Dm-(CHR3)n]qY or a monocyclic or polycyclic substituted or unsubstituted ring system which contains at least one aromatic ring;
• Y is hydrogen, halogen, haloalkyl, haloalkyloxy, alkyl cycloalkyl, a monocyclic or polycyclic substituted or unsubstituted ring system which contains at least one aromatic ring or
• m is 0 or 1;
• n is 0 or 1;
• p is 0 or 1;
• r is 0 or 1;
• q is 0 or 1;
• s is 0 to 2;
• and
• t is 0 to 3;
• with the proviso at the following compounds are excluded:
• compounds wherein ring A is an unsubstituted carbocycle containing six carbon atoms and one double bond between the CZ1 and CZ2-substituents, z1=z2=O, and s is 0;
• 1,3,5-Tribenzyl-2,4,6-trioxopyrrolo[3,4-d]imidazole, 1,3-Dibenzyl-5-(4-methoxy-benzyl)-2,4,6-trioxopyrrolo[3,4-d]imidazole, 1,3-Bis-(methoxybenzyl)-5-benzyl-2,4,6-trioxopyrrolo[3,4-d]imidazole, and 1,3-Tris-(4-methoxybenzyl)-2,4,6-trioxo-pyrrolo[3,4-d]imidazole.

A compound of the general formula (IV) or a salts or physiologically functional derivative thereof,

• wherein
• A is a non-heterocyclic, non-aromatic ring system containing 4, 5, 6, 7 or 8 carbon atoms, wherein the ring system comprises at least one double bond and wherein one or more of the carbon atoms in the ring represented by X may be carbonyl (C═O);
• D is O, S, SO2, NR4, or CH2;
• z1 and z2 are independent from each other O, S, or NR5;
• R1 is independently H, halogen, haloalkyl, haloalkyloxy —CO2R″, —SO3H, —OH, —CONR*R″, —CR″O, —SO1NR*R″, —NO2, —SO2—R″, —SO—R*, —CN, alkoxy, alkylthio, aryl, —NR″—CO2—R′, NR″—CO—R*, —NR″—SO2—R′, —O—CO—R*, —O—OC2—R*, —O—CO—NR*R″;
• cycloalkyl, alkylamino, hydroxyalkylamino, heteroaryl, —SH;
• or alkyl;
• R* is independently H, alkyl, cycloalkyl, aminoalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
• R′ is independently H, —CO2R″, —CONHR″, —CR″O, —SO2NR″, —NR″—CO-haloalkyl, —NO2, —NR″—SO2-haloalkyl, —NR″—SO2-alkyl, —SO2-alkyl, —NR″—CO-alkyl, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl arylalkyl or heteroaryl;
• R″ is independently hydrogen, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
• R2 is H or OR6, NHR7, NR7OR7 or R2 together with the nitrogen atom which is attached to R8 form a 6 membered hetercyclic ring with the proviso that R2 is —[CH2]8 and R8 is absent;
• R3 is H, alkyl, cycloalkyl, aryl, alkoxy, O-aryl;
• O-cycloalkyl, halogen, aminoalkyl, alkylamino, hydroxylamino, hydroxylalkyl, haloalkyloxy, heteroaryl alkylthio, S-aryl;
• S-cycloalkyl, arylalkyl, or haloalkyl;
• R4 is H, alkyl, cycloalkyl aryl or heteroaryl;
• R5 is H, OH, alkoxy, O-aryl, alkyl or aryl;
• R6 is H, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkylaryl, alkoxyalkyl, acylmethyl, (acyloxy)alkyl, non-symmetrical (acyloxy)alkyldiester, or dialkylphosphate;
• R7 is H, OH, alkyl, aryl, alkoxy, O-aryl, cycloalkyl or O-cycloalkyl;
• R8 is hydrogen, or alkyl;
• E is an alkyl or cycloalkyl group which is substituted by [Dm-(CHR3)n]qY or a monocyclic or polycyclic substituted or unsubstituted ring system which contains at least one aromatic ring;
• Y is hydrogen, halogen, haloalkyl, haloalkyloxy, alkyl, cycloalkyl, a monocyclic or polycyclic substituted or unsubstituted ring system which contains at least one aromatic ring or
• m is 0 or 1;
• n is 0 or 1;
• p is 0 or 1;
• q is 0 or 1;
• s is 0 to 2;
• and
• t is 0 to 3;
• with the proviso that the following compounds are excluded:
• 5,5-Dimethyl-4-phenyl-2-(3-phenyl-ureido-4,5-dihydro-furan-3-carboxylic acid methyl ester, 2[3-(4-Chlorophenyl-ureido)]-5,5-dimethyl-4-phenyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 2[3-(4-Methoxylphenyl-ureido)]-5,5-dimethyl-4-phenyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 2[3-(4-Methylphenyl-ureido)]-5,5-dimethyl-4-phenyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 2[3-(4-Nitrophenyl-ureido)]-5,5-dimethyl-4-phenyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 4-(4-Chlorophenyl)-5,5-dimethyl-2-(3-phenyl-ureido)-4,5-dihydro-furan-3-carboxylic acid methyl ester, 4-(4-Chlorophenyl)-2[3-(4-chlorophenyl-ureido)]-5,5-dimethyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 4-(4-Chlorophenyl)-2[3-(4-nitrophenyl-ureido)]-5,5-dimethyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 4-(4-Chlorophenyl)-2[3-(4-methoxyphenyl-ureido)]-5,5-dimethyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, or 4-(4-Chlorophenyl)-2[3-(4-nitrophenyl-ureido)]-5,5-dimethyl-4,5-dihydro-furan-3-carboxylic acid methyl ester.