3-monosubstituted tropane derivatives as nociceptin receptor ligands
View Patent ↗Compounds of the formula or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl, all optionally substituted; R 2 is H; or aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl, all optionally substituted; R 3 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, all optionally substituted; X is a bond, —(CH 2 ) m —N(R 7 )—(CH 2 ) n —, —(CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —S—CH 2 ) n —, —C(O)—, —CH(OH)—, —C(O)N(R 7 )—, —C(O)N(R 7 )-alkylene or —N(R 7 )C(O)—; R 7 is H or alkyl; and m and n are each 0-6, provided that the sum of m and n is 0-6; or a pharmaceutically acceptable salt or solvate thereof, pharmaceutical compositions thereof, and the use of said compounds in the treatment of cough, pain, anxiety, asthma, depression, alcohol abuse, urinary incontinence and overactive bladder are disclosed.
1. A compound represented by the formula
or a pharmaceutically acceptable salt thereof, wherein
R 1 is R 4 -aryl-, R 4 -arylalkyl-, R 4 -heteroaryl-, R 4 -heteroarylalkyl-, R 4 -cycloalkyl-, R 4 -cycloalkylalkyl-, R 4 -heterocycloalkyl-, R 4 -heterocycloalkylalkyl-;
R 2 is R 5 -aryl-, R 5 -arylalkyl-, R 5 -heteroaryl-, R 5 -heteroarylalkyl-, R 5 -cycloalkyl-, R 5 -cycloalkylalkyl-, R 5 -heterocycloalkyl-, R 5 -heterocycloalkylalkyl-;
R 3 is R 6 -alkyl-, R 6 -aryl-, R 6 -heteroaryl-, R 6 -cycloalkyl-, R 6 -heterocycloalkyl-;
X is a bond, (C 1 -C 3 )alkylene, —(CH 2 ) m —N(R 7 )—(CH 2 ) n —, —(CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —S—(CH 2 ) n —, —C(O)—, —CH(OH)—, —C(O)N(R 7 )—, —C(O)N(R 7 )-alkylene or —N(R 7 )C(O)—;
n is 0, 1, 2, 3; 4, 5 or 6; m is 0, 1, 2, 3; 4, 5 or 6; provided that the sum of m and n is 0, 1, 2, 3; 4, 5 or 6;
each R 4 and R 5 is 1 to 3 substituents independently selected from the group consisting of H, halo, alkyl, cycloalkyl, —CN, —CF 3 , —(CH 2 ) p —OR 8 , —N(R 10 ) 2 and —(CH 2 ) n —N(R 10 ) 2 ;
R 6 is 1 to 3 substituents independently selected from the group consisting of H, halo, alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, —CN, cyanoalkyl, —CF 3 , —C(O)alkyl, —(CH 2 ) p —OR 8 , —COOR 8 , —N(R 10 ) 2 , —(CH 2 ) n —N(R 10 ) 2 and —C(O)N(R 10 ) 2 ;
p is 0, 1, 2, 3; 4, 5 or 6;
R 7 is H or alkyl;
R 8 and R 9 are independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkyl-C(O)— and alkyl-C(O)—N(R 7 )—C(O)—; and
R 10 is independently selected from the group consisting of H and alkyl.
2. A compound of claim 1 wherein R 1 is R 4 -phenyl and R 2 is R 5 -phenyl, wherein R 4 and R 5 are independently selected from the group consisting of H, halo and alkyl.
3. A compound of claim 2 wherein R 1 is R 4 -phenyl wherein R 4 is one halo atom, and R 2 is R 5 -phenyl wherein R 5 is one halo atom.
4. A compound of claim 3 wherein R 4 and R 5 are chlorine.
5. A compound of claim 1 wherein X is a bond, —N(R 7 )—(CH 2 ) n — wherein R 7 is H and n is 0 or 1, or —C(O)N(R 7 )— wherein R 7 is H.
6. A compound of claim 5 wherein X is a bond.
7. A compound of claim 1 wherein R 3 is R 6 -aryl, R 6 -heteroaryl or R 6 -heterocycloalkyl.
8. A compound of claim 7 wherein R 3 is R 6 -phenyl, R 6 -pyridyl, R 6 -pyrimidyl, R 6 -imidazolyl, R 6 -benzimidazolyl, R 6 -piperidinyl or R 6 -morpholinyl.
9. A compound of claim 8 wherein R 6 is one substituent selected from the group consisting of H, halo, alkyl, OH and —OCH 3 .
10. A compound of claim 1 selected from the group consisting of
11. The compound having the formula
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.