Diebenzofuran derivatives as inhibitors of PDE-4 and PDE-10

1. A compound of formula

and its tautomers, stereoisomers, enantiomers, diastereomers, and pharmaceutically acceptable salts wherein

R 1 is

X 1 is selected from hydrogen, optionally substituted alkyl, optionally substituted N,N-dimethylaminoalkenyl, carboxy, ═CH—NR 5 R 6 , COOR 6 ;

X 2 is selected from optionally halo, cyano, carboxy, COOR 6 , substituted alkyl, NR 5 R 6 , —NR 5 S(O) m R 6 ;

X 4 represents O, S, NR 5 , N—OR 5 , ═N—OCH 2 COOH, ═N—O-Me;

when X 1 and X 2 or X 1 and X 4 ; are ortho to each other, they may together form a 4 to 7 membered ring system selected from an alicyclic or heterocyclic ring;

r is 0 or 1;

R 2 represents optionally substituted groups selected from alkyl, haloalkyl, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

R 5 represents hydrogen, alkoxy, R′COOR 6 , optionally substituted alkyl or optionally substituted aryl;

R 6 represents hydrogen, optionally substituted alkyl or optionally substituted aryl;

R 5 and R 6 may together form a 3 to 12 membered mono or polycyclic ring;

R′ represents a direct bond or an optionally substituted alkylene;

m is an integer represented by 0, 1 or 2.

2. The compound of claim 1 wherein R 1 is

; X 1 is COOR 6 ; X 4 is O; r=1; and R 2 and R 6 are methyl.

3. The compound of claim 1 wherein the 4 to 7 membered ring system selected form an alicyclic or heterocyclic ring is optionally mono- or di-substituted with oxo, carboxy, R′COOR 6 , R′NR 5 R 6 , OR 5 , alkyl or aryl, wherein R′ is a direct bond or an optionally substituted alkylene.

4. The compound according to claim 1 , wherein X 1 is COOR 6 .

5. The compound according to claim 1 , wherein X 1 is N,N-dimethylaminoalkenyl.

6. The compound according to claim 1 , wherein X 2 is COOR 6 .

7. The compound according to claim 1 , wherein X 2 is NR 5 S(O) m R 6 .

8. The compound according to claim 7 , wherein R 5 is hydrogen, m is 2 and R 6 is methyl.

9. The compound according to claim 1 , wherein X 1 and X 2 or X 1 and X 4 are ortho to each other and together fog n a 4 to 7 membered ring system selected from an alicyclic or heterocyclic ring.

10. The compound according to claim 1 or 9 , wherein the 4 to 7 membered ring system is selected from

11. The compound according to claim 1 , wherein X 4 is O.

12. The compound according to claim 1 , wherein X 4 is N—OR 5 wherein R 5 is alkoxy.

13. The compound according to claim 1 , wherein X 4 is ═N—OCH 2 COOH.

14. The compound according to claim 1 , wherein R 2 is methyl.

15. A compound according to claim 1 , wherein the compound is selected from

Methyl-5-cyano-5-(4-methoxydibenzo[b,d]furan-1-yl)-2-oxocyclohexane carboxylate,

1-(4-Methoxydibenzo[b,d]furan-1-yl)-4-oxocyclohexanecarbonitrile,

4-Cyano-4-(4-methoxydibenzo[b,d]furan-1-yl)cyclohexanecarboxylic acid,

5-(4-Methoxydibenzo[b,d]furan-1-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carbonitrile,

N-[4-Cyano-4-(4-methoxydibenzo[b,d]furan-1-yl)cyclohexyl]methanesulfonamide,

(3E)-3-[(Dimethylamino)methylene]-1-(4-methoxydibenzo[b,d]furan-1-yl)-4-oxocyclohexanecarbonitrile,

Ethyl 6-cyano-6-(4-methoxydibenzo[b,d]furan-1-yl)-2-methyl-5,6,7,8-tetrahydro quinoline-3-carboxylate,

5-(4-Methoxydibenzo[b,d]furan-1-yl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carbonitrile,

5-(4-Methoxydibenzo[b,d]furan-1-yl)-2-phenyl-4,5,6,7-tetrahydro-2H-indazole-5-carbonitrile,

6-Cyano-6-(4-methoxydibenzo[b,d]furan-1-yl)-2-methyl-5,6,7,8-tetrahydro quinoline-3-carboxylic acid,

5-(4Ethoxydibenzo[b,d]furan-1-yl)-4,5,6,7-tetrahydro-2,1-benzisoxazole-5-carbonitrile,

5-(4-Methoxydibenzo[b,d]furan-1-yl)-3-oxo-3,3a,4,5,6,7-hexahydro-2H-indazole-5-carbonitrile,

6-(4-Methoxydibenzo[b,d]furan-1-yl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile,

6-(4-Methoxydibenzo[b,d]furan-1-yl)-3-methyl-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile,

6-(4-Methoxydibenzo[b,d]furan-1-yl)-5,6,7,8-tetrahydroquinazoline-6-carbonitrile,

2-Amino-6-(4-methoxydibenzo[b,d]furan-1-yl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile,

2-Amino-6-(4-methoxydibenzo[b,d]furan-1-yl)-5,6,7,8-tetrahydroquinazoline-6-carbonitrile,

{[6-Cyano-6-(4-methoxydibenzo[b,d]furan-1-yl)-5,6,7,8-tetrahydroquinazolin-2-yl]amino}acetic acid,

Ethyl [6-cyano-6-(4-methoxydibenzo[b,d]furan-1-yl)-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl]acetate,

[6-Cyano-6-(4-methoxydibenzo[b,d]furan-1-yl)-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl]acetic acid,

6-(4-Methoxydibenzo[b,d]furan-1-yl)-2-methyl-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile,

Ethyl [6-cyano-6-(4-methoxydibenzo[b,d]furan-1-yl)-2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl]acetate,

Ethyl {[6-cyano-6-(4-methoxydibenzo[b,d]furan-1-yl)-2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl]oxy}acetate,

1-(4-Methoxydibenzo[b,d]furan-1-yl)-4-(methoxyimino)cyclohexanecarbonitrile,

({[4-Cyano-4-(4-methoxydibenzo[b,d]furan-1-yl)cyclohexylidene]amino}oxy)acetic acid and pharmaceutically acceptable salts thereof.

16. A compound according to claim 15 , wherein the compound is Methyl-5-cyano-5-(4-methoxydibenzo[b,d]furan-1-yl)-2-oxocyclohexane carboxylate.

17. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a Phosphodiesterase 4 (PDE IV) inhibitor.

18. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a Phosphodiesterase 10 (PDE 10) inhibitor.

19. A pharmaceutical composition comprising, as an active ingredient, a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or a diluent.

20. A process for preparing a compound according to claim 1 or a pharmaceutically acceptable salt, pharmaceutically acceptable enantiomer, diastereomer or N-oxide thereof comprising at least one of the steps a-e

a. alkylating the compound of formula 3 wherein X is O, and Y is O

with a suitable alkylating agent to produce compound of formula 4

b. formulation of a compound of formula 4 using dichloromethyl methyl ether in the presence of a suitable Lewis acid to produce compound of formula 5

c. reduction of a compound of formula 5, followed by chlorination and cyanation to produce a compound of formula 6

d. reaction of formula 6 with a suitable alkyl acrylate to form compound of formula 7

e. cyclisation and de-esterification of a compound of formula 7.