Substituted n-aryl amidines as selective D
View Patent ↗The present invention provides compounds, which, are novel antagonists for D 1 receptors as well as methods for preparing such compounds. In another embodiment, the invention provides pharmaceutical compositions comprising such D 1 receptor antagonists as well as methods of using them to treat CNS disorders, obesity, metabolic disorders, eating disorders such as hyperphagia, and diabetes.
1. A compound having the structural formula I:
or a pharmaceutically acceptable salt thereof, wherein
A is phenyl optionally substituted with 1 to 4 moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —OR ll , —(CR 4 R 5 ) p OR 11 , —NR 5 R 6 , —CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 11 , —C(O)R 11 , —C(O)NR 5 R 6 , —SR 11 , —S(O 2 )R 11 , —S(O 2 ) NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
m is 0 or 1;
p is 1 to 4;
R 1 is 1 to 5 moieties independently selected from hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, alkoxy, —NR 5 R 6 , —SR 11 , —CF 3 , —OCF 3 , —CN, —NO 2 and alkyl, or two adjacent R 1 moieties can be linked to form
R 2 is 1 to 5 moieties independently selected from halogen, aryl, heteroaryl,
wherein each of said aryl or heteroaryl for R 2 can be optionally substituted with 1 to 4 moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, alkylenyl, aralkyl, —C(O)H, —C(O)OH, —C(R 4 )═NOR 11 , —CF 3 , —CN, —OCF 3 , —OR 11 , —(CR 4 R 5 ) p OR 11 ,—NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 11 , —C(O)R 11 , —C(O)NR 5 R 6, —SR 11 , —S(O 2 )R 11 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2)R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 3 is hydrogen, alkyl, —C(O)R 11 , —SO 2 R 11 , —C(O)alkoxy, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclylalkyl, heteroaralkyl or aralkyl, wherein each of said alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclylalkyl, heteroaralkyl or aralkyl for R 3 can be optionally substituted with 1 to 4 moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —OR 11 , —(CR 4 R 5 ) p OR 11 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 11 , —C(O)R 11 , —C(O)NR 5 R 6 , —SR 11 , —S(O 2 )R 11, —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is hydrogen or alkyl;
R 5 is hydrogen, alkyl or aryl, wherein each of said alkyl or aryl for R 5 can be unsubstituted or substituted with 1 to 4 moieties which can be the same or different, each moiety being independently selected from the group consisting of —CN, —NO 2 , halogen, vinyl, alkoxy, —OCF 3 , alkoxyalkyl, —C(O)OH, —C(O)O-alkyl, —CF 3 and alkyl;
R 6 is hydrogen, alkyl or aryl, wherein each of said alkyl or aryl for R 6 can be unsubstituted or substituted with 1 to 4 moieties which can be the same or different, each moiety being independently selected from the group consisting of —CN, —NO 2 , halogen, vinyl, alkoxy, —OCF 3 , alkoxyalkyl, —C(O)OH, —C(O)O-alkyl, —CF 3 and alkyl;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, —CF 3 , —OCF 3 , aralkyl and heteroaralkyl wherein each of said alkyl, cycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl for R 7 can be unsubstituted or substituted with 1 to 4 moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl. —CF 3 , —OCF 3 , —CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R8 is alkyl, aryl, heteroaryl, —NR 3 R 4 ,
R 9 is hydrogen. alkyl, —C(O)R 11 , —SO 2 R 11 , aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, heteroaralkyl or aralkyl, wherein each of said aryl, cycloalkyl, cycloalkylalkyl, heteroaralkyl or aralkyl for R 9 can be unsubstituted or substituted with 1 to 4 moieties which can be the same or different, each moiety being independently selected from the group consisting of —CN, —NO 2 , halogen, vinyl, alkoxy, —OCF 3 , alkoxyalkyl, —C(O)OH, —C(O)O-alkyl, —CF 3 and alkyl:
R 10 is hydrogen, alkyl or aryl, wherein each of said alkyl or aryl for R 10 can be unsubstituted or substituted with 1 to 4 moieties which can be the same or different; each moiety being independently selected from the group consisting of —CN, —NO 2 , halogen, vinyl, alkoxy, —OCF 3 , alkoxyalkyl, —C(O)OH, —C(O)O-alkyl, —CF 3 and alkyl; and
R 11 is alkyl or aryl, wherein each of said alkyl or aryl for R 11 can be unsubstituted or substituted with 1 to 4 moieties which can be the same or different, each moiety being independently selected from the group consisting of —CN, —NO 2 . halogen, vinyl, alkoxy, —OCF 3 , alkoxyalkyl, —C(O)OH, —C(O)O-alkyl, —CF 3 and alkyl.
2. The compound of claim l wherein
R 3 is hydrogen or alkyl; and
R 5 is hydrogen or alkyl.
3. The compound of claim 2 wherein
R 3 is methyl or hydrogen; and
R 5 is methyl or hydrogen.
4. A compound of formula I selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
5. A compound of formula I selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim l in combination with at least one pharmaceutically acceptable carrier.
7. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 4 in combination with at least one pharmaceutically acceptable carrier.