Granted Patent B2

US 7,932,250 · App. 11/630,757 · Granted Apr 26, 2011

Abstract

Claims (98)

1. Thienopyrazole compounds represented by the following formula (I):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted, or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

R 5 and R 6 are, same or different from each other, a hydrogen atom; C 1 -C 6 alkyl group which may be substituted by a halogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted cycloalkyl group, a group —NR 7 COR 8 , —COR 8 , —NR 9 R 10 ; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5 and R 6 ;

R 7 is a hydrogen atom, or substituted or unsubstituted C 1 -C 3 alkyl group;

R 8 is a substituted or unsubstituted heterocycloalkyl group, or a group —OH, —OR 7 or —NR 9 R 10 ;

R 9 and R 10 are, same or different from each other, a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted acyl group; a group —SO 2 R 7 , or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5 and R 6 or pharmaceutically acceptable salts or solvates thereof.

2. The compound according to claim 1 , wherein R 1 is a substituted or unsubstituted cycloalkyl group.

3. The compound according to claim 1 , wherein R 1 is a substituted or unsubstituted heterocycloalkyl group.

4. The compound according to claim 1 , wherein R 1 is a substituted or unsubstituted cyclohexyl group.

5. The compound according to claim 1 , wherein R 1 is a substituted or unsubstituted tetrahydropyranyl group.

6. The compound according to claim 1 , wherein R 2 is a methyl group.

7. The compound according to claim 1 , wherein R 3 is a hydrogen atom.

8. The compound according to claim 1 , wherein R 4 is —CONR 5 R 6 .

9. The compound according to claim 8 , wherein any one of R 5 and R 6 is a hydrogen atom.

10. The compound according to claim 8 , wherein any one of R 5 and R 6 is a substituted or unsubstituted cycloalkyl group.

11. The compound according to claim 8 , wherein any one of R 5 and R 6 is a cycloalkyl group which is substituted by a heterocycloalkyl group which may be substituted.

12. The compound according to claim 8 , wherein any one of R 5 and R 6 is an aryl group which may be substituted.

13. The compound according to claim 8 , wherein any one of R 5 and R 6 is an aryl group which is substituted by a heterocycloalkyl group which may be substituted.

14. The compound according to claim 8 , wherein any one of R 5 and R 6 is a substituted or unsubstituted heteroaryl group.

15. A pharmaceutical composition containing a compound according to claim 1 , or a pharmaceutical acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable diluent or exipient.

16. A method of inhibiting PDE 7 in a subject in need thereof comprising administering a compound according to claim 1 , or a pharmaceutical acceptable salt thereof, to the subject to inhibit PDE 7.

17. A method for preparing the thienopyrazole compounds represented by the formula (I):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom,

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

comprising chlorinating the pyrazole-5-one derivative represented by the formula (VI):

wherein

R 1 is substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group; and then, undergoing an electrophilic substitution reaction of the resulting compound without separation to give the pyrazole derivative of the formula (IV):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group,

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

then, reacting the resulting pyrazole derivative of formula (IV) with the compound of the formula (III) in the presence of base:

wherein

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group or a group —CONR 5 R 6 or —CO 2 R 7 ,

to give the compound of the formula (II):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

and then, treating the resulting compound of formula (II) with base to give the thienopyrazole compound of the formula (I).

18. A method for preparing the thienopyrazole compounds represented by the formula (I):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

comprising undergoing an electrophilic substitution reaction of the chloropyrazole derivative of the formula (V):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

to give the pyrazole derivative of the formula (IV):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 3 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

then, reacting the resulting pyrazole derivative of formula (IV) with the compound of the formula (III) in the presence of base:

wherein

R 4 is a substituted or unsubstituted aryl group substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

to give the compound of the formula (II):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

and then, treating the resulting compound of formula (II) with base to give the thienopyrazole compound of the formula (I).

19. A method for preparing the thienopyrazole compounds represented by the formula (I):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

comprising reacting the pyrazole derivative of formula (IV):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

with the compound of the formula (III) in the presence of base:

wherein

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

to give the compound of the formula (II):

wherein

R 1 is a substituted or unsubstituted C 3 -C 8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;

R 2 is a hydrogen atom or substituted or unsubstituted C 1 -C 3 alkyl group;

R 3 is a hydrogen atom, substituted or unsubstituted C 1 -C 3 alkyl group, or a halogen atom;

R 4 is a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR 5 R 6 or —CO 2 R 7 ;

and then, treating the resulting compound of formula (II) with base to give the thienopyrazole compound of the formula (I).

20. The method for preparing thienopyrazole compound according to claim 19 ,

wherein the conversion of the compound of formula (IV) to the compound of formula (I) is carried out in one pot synthesis without separation of the compound of the formula (II).

21. The method according to claim 17 , wherein the group R 3 is a hydrogen atom.

Assignments (6)