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

1. A compound of the general formula (I) or a salt or a physiologically functional derivative thereof:

wherein

A is a non-heterocyclic non-aromatic ring system containing 4 to 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 optionally be carbonyl (C═O);

D is O, S, SO 2 , NR 4 or CH 2 ;

z 1 and z 2 are independent from each other O, S, or NR 5 ;

R 1 is independently —CO 2 R″, —SO 3 H, —CONR*R″, —CR″O, —SO 2 —NR*R″, —NO 2 , —SO 2 —R″, —SO—R*, —CN, alkoxy, —OH, —SH, alkylthio, —NR″—CO 2 —R′, —NR″—CO—R*, —NR″—SO 2 —R′, —O—CO—R*, —O—CO 2 —R*, —O—CO—NR*R″; cycloalkyl, alkylamino, hydroxyalkylamino, aryl, or heteroaryl;

R 9 is independently H, halogen, haloalkyl, haloalkyloxy or alkyl;

R* is independently H, alkyl, cycloalkyl, aminoalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R′ is independently H, —CO 2 R″, —CONHR″, —CR″O, —SO 2 NR″, —NR″—CO-haloalkyl, —NO 2 , —NR″—SO 2 -haloalkyl, —NR″—SO 2 -alkyl, —SO 2 -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;

R 2 is H, OR 6 , or NHR 7 ;

R 3 is H, alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, O-aryl, O-cycloalkyl, halogen, aminoalkyl, alkylamino, hydroxylamino, hydroxylalkyl, haloalkyl, haloalkyloxy, heteroaryl, alkylthio, S-aryl, or S-cycloalkyl;

R 4 is H, alkyl, cycloalkyl, aryl, or heteroaryl;

R 5 is H, OH, alkoxy, O-aryl, alkyl, or aryl;

R 6 is H, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylaryl, alkoxyalkyl, acylmethyl, (acyloxy)alkyl, non-symmetrical (acyloxy)alkyldiester, or dialkylphosphate;

R 7 is H, alkyl, aryl, alkoxy, O-aryl, cycloalkyl, or O-cycloalkyl;

R 8 is hydrogen or alkyl;

E is an alkyl or cycloalkyl group which is substituted by [D m -(CHR 3 ) n ] q Y 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 and 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;

t is 1 to 3; and

v is 0 to 3.

2. 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, SO 2 , NR 4 , or CH 2 ;

z 1 and z 2 are independent from each other O, S, or NR 5 ;

R 1 is independently H, halogen, haloalkyl, haloalkyloxy —CO 2 R″, —SO 3 H, —OH, —CONR*R″, —CR″O, —SO 2 —NR*R″, —NO 2 , —SO 2 —R″, SO—R*, —CN, alkoxy, alkylthio, aryl, —NR″—CO 2 —R′, —NR″—CO—R*, —NR″—SO 2 —R′, —O—CO—R*, —O—CO 2 —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, —CO 2 R″, —CONHR″, —CR″O, —SO 2 NR″, —NR″—CO-haloalkyl, —NO 2 , —NR″—SO 2 -haloalkyl, —NR″—SO 2 -alkyl, —SO 2 -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;

R 2 is NHOH or R 2 together with the nitrogen atom which is attached to R 8 form a 5 or 6 membered heterocyclic ring with the proviso that R 2 is —[CH 2 ] 8 and R 8 is absent;

R 3 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;

R 4 is H, alkyl, cycloalkyl, aryl or heteroaryl;

R 5 is H, OH, alkoxy, O-aryl, alkyl or aryl;

R 8 is hydrogen, or alkyl;

E is an alkyl or cycloalkyl group which is substituted by [D m -(CHR 3 ) n ] q Y 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 CZ 1 and CZ 2 -substituents, z 1 =z 2 =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.

3. 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, SO 2 , NR 4 , or CH 2 ;

z 1 and z 2 are independent from each other O, S, or NR 5 ;

R 1 is independently H, halogen, haloalkyl, haloalkyloxy —CO 2 R″, —SO 3 H, —OH, —CONR*R″, —CR″O, —SO 1 NR*R″, —NO 2 , —SO 2 —R″, —SO—R*, —CN, alkoxy, alkylthio, aryl, —NR″—CO 2 —R′, NR″—CO—R*, —NR″—SO 2 —R′, —O—CO—R*, —O—OC 2 —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, —CO 2 R″, —CONHR″, —CR″O, —SO 2 NR″, —NR″—CO-haloalkyl, —NO 2 , —NR″—SO 2 -haloalkyl, —NR″—SO 2 -alkyl, —SO 2 -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;

R 2 is H or OR 6 , NHR 7 , NR 7 OR 7 or R 2 together with the nitrogen atom which is attached to R 8 form a 6 membered hetercyclic ring with the proviso that R 2 is —[CH 2 ] 8 and R 8 is absent;

R 3 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;

R 4 is H, alkyl, cycloalkyl aryl or heteroaryl;

R 5 is H, OH, alkoxy, O-aryl, alkyl or aryl;

R 6 is H, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, alkylaryl, alkoxyalkyl, acylmethyl, (acyloxy)alkyl, non-symmetrical (acyloxy)alkyldiester, or dialkylphosphate;

R 7 is H, OH, alkyl, aryl, alkoxy, O-aryl, cycloalkyl or O-cycloalkyl;

R 8 is hydrogen, or alkyl;

E is an alkyl or cycloalkyl group which is substituted by [D m -(CHR 3 ) n ] q Y 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.

4. A pharmaceutical composition comprising:

the compound as defined in claim 1 ; and

a pharmaceutically acceptable diluent or carrier.

5. A pharmaceutical composition comprising:

the compound as defined in claim 2 ; and

a pharmaceutically acceptable diluent or carrier.

6. A method for treating a disease associated with the expression of dihydroorotate dehydrogenase (“DHODHD”) comprising administering an amount of the compound of claim 1 effective to inhibit the activity of DHODH to a subject in need thereof.

7. A method for treating a disease associated with the expression of DHODH comprising administering an amount of the compound of claim 2 effective to inhibit the activity of DHODH to a subject in need thereof.

8. The method of claim 6 , wherein the disease is selected from the group consisting of rheumatism, an acute immunological disorder, an autoimmune disease, a disease caused by malignant cell proliferation, an inflammatory disease, a disease that is caused by a protozoal infestation, a disease that is caused by a viral infection, Pneurnocystis carinii , fibrosis, uveitis, rhinitis, asthma and athropathy.

9. The method of claim 6 , comprising administering a compound of the general formula (I) or a salt thereof.

10. The compound of claim 1 , which is compound of the general formula (I) in free form.

11. The compound of claim 1 , which is a salt of a compound of general formula (I).

12. The compound of claim 1 , which is a physiologically functional derivative of a compound of general formula (I).

13. The compound of claim 1 , wherein ring A contains five carbon atoms.

14. The compound of claim 1 , wherein ring A contains a single double bond between the carbon atoms carrying substituents Cz 1 and Cz 2 .

15. The compound of claim 1 , wherein ring A contains a single X group which is carbonyl (C═O).

16. The compound of claim 1 , wherein none of the carbon atoms is replaced by X, which is carbonyl.

17. The compound of claim 1 , wherein R 1 is OH, OCH 3 , SH, CO 2 H, SO 3 H or tetrazole.

18. The compound of claim 1 , wherein R 9 is H.

19. The compound of claim 1 , wherein R 2 is OH or OR 6 .

20. The compound of claim 1 , wherein R 8 is H or methyl.

21. The compound of claim 1 , wherein Y is optionally substituted phenyl.

22. The compound of claim 1 , wherein D is S or O and m=1.

23. The compound of claim 1 , wherein z 1 and z 2 are both O.