3,7-dihydro-purine-2,6-dione derivatives as CRF receptor ligands

1. A method of treating a subject afflicted with a disorder characterized by over expression of corticotropin releasing factor (CRF), which method comprises administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt form thereof, wherein:

R 1 is selected from the group consisting of HC 1-4 alkyl, CN, and CF 3 ;

alternatively R 1 is —OR 1a , wherein R 1a is C 1 –C 4 alkyl;

R 2 is selected from the group consisting of C 1 –C 6 alkyl and C 3 –C 7 cycloalkyl;

R 3 is selected from the group consisting of aryl and heteroaryl;

R 4 is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 3-8 cycloalkyl and benzyl;

R 4 is optionally substituted with 0–1 1-naphthalenyl groups;

alternatively R 4 is optionally substituted with 0–3 substituents independently selected at each occurrence from the group consisting of aryl, C 1-6 alkyl, C 2-8 alkenyl, —OR 10 , —NR 10 R 12 , CF 3 , C 1-4 alkoxy-C 1-4 alkyl and C 3-8 cycloalkyl;

R 10 is selected from the group consisting of H and benzyl;

R 12 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 1-6 alkyl;

R 13 is selected from the group consisting of C 1-6 alkyl and C 1-4 haloalkyl;

aryl is phenyl optionally substituted with 0–5 substituents independently selected at each occurrence from the group consisting of phenyl, C 1-6 alkyl, —OR 13 , Br, Cl, F, I and C 1-4 haloalkyl; and

heteroaryl is pyridyl optionally substituted with 0–4 substituents independently selected at each occurrence from the group consisting of C 1-6 alkyl and —OR 13 .

2. The method of claim 1 wherein R 1 is ethyl.

3. The method of claim 1 wherein R 1 is methoxy.

4. The method of claim 1 wherein R 2 is selected from the group consisting of methyl, ethyl, propyl and cyclopropyl.

5. The method of claim 1 wherein the compound of formula (I) is selected from the group consisting of:

3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-7-(3-pentyl)-3,7-dihydro-1H-purine-2,6-dione;

3-(2,4-dichlorophenyl)-8-ethyl-7-(4-heptyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;

7-benzyloxymethyl-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione;

7-(1-allyl-3-butenyl)-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione;

3-(2,4-dichlorophenyl)-1-methyl-7-(3-pentyl)-3,7-dihydro-1H-purine-2,6-dione;

3-(2,4-dichlorophenyl)-7-(4-heptyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;

3-(2,4-dichlorophenyl)-8-ethyl-7-(4-methoxybenzyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;

3-[2-chloro-4-(isopropylphenyl)]-8-ethyl-1-methyl-7-(3-pentyl)-3,7-dihydro-1H-purine-2,6-dione;

3-[2-chloro-4-(isopropylphenyl)]-8-ethyl-7-(4-heptyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;

3-[2-chloro-4-(isopropylphenyl)]-1-methyl-7-(3-pentyl)-3,7-dihydro-1H-purine-2,6-dione;

3-[2-chloro-4-(isopropylphenyl)]-7-(4-heptyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;

8-ethyl-7-(4-heptyl)-1-methyl-3-(2,4,6-trimethylphenyl)-3,7-dihydro-1H-purine-2,6-dione;

8-ethyl-7-(4-heptyl)-3-(4-methoxy-2-methylpyrid-3-yl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;

or a pharmaceutically acceptable salt form thereof.

6. The method of claim 1 wherein said disorder is anxiety or depression.

7. The method of claim 1 wherein said disorder is irritable bowel syndrome.