Tri-and tetraaza-acenaphthylen derivatives as CRF receptor antagonists
View Patent ↗CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure: including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, R 1 , R 2 , R 4 , R 5 , R 6 , A, X, and Y are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
1. A compound having the following structure:
wherein
R 1 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 2 is hydrogen, alkyl, substituted alkyl, alkoxy, thioalkyl, halo, cyano, or haloalkyl;
R 4 is hydrogen, alkyl, substituted alkyl or C(O)R 1 ;
R 5 is hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl, C(O)R 1 , NR 10 R 11 or cyano;
R 6 is hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl, C(O)alkyl, NR 10 R 11 or cyano;
R 8 is hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl, C(O)alkyl, NR 10 R 11 or cyano; and
R 10 , R 11 are the same or different and are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt thereof.
2. A compound having the following structure:
wherein
R 1 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 2 is hydrogen, alkyl, substituted alkyl, alkoxy, thioalkyl, halo, cyano, or haloalkyl;
R 3 is hydrogen, alkyl, substituted alkyl, halo or haloalkyl;
R 4 is hydrogen, alkyl, substituted alkyl, C(O)R 1 , aryl, substituted aryl, heterocycle or substituted heterocycle;
R 5 is hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl, C(O)R 1 , NR 10 R 11 or cyano;
R 6 is hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl, C(O)R 1 , NR 10 R 11 or cyano;
R 8 is hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl, C(O)alkyl, NR 10 R 11 or cyano; and
R 10 , R 11 are the same or different and are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt thereof.
3. A compound selected from the group consisting of:
7-methyl-1-(1-propyl-butyl)-5-[4-(1,1,2-trifluoro-ethyl)-2-trifluoromethylphenyl]-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene;
3-methyl-4-[7-methyl-1-(1-propyl-butyl)-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile;
4-[1-(1-ethyl-propyl)-7-methyl-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-3-methyl-benzonitrile;
3-chloro-4-[7-methyl-1-(1-propyl-butyl)-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile;
3-chloro-4-[1-(1-ethyl-propyl)-7-methyl-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile;
5-(2,4-bis-trifluoromethyl-phenyl)-1-(1-ethyl-propyl)-7-methyl-1,3,4,5-tetrahydro-1,5,6,8-tetraaza-acenaphthylene; and
8-[2,4-bis(trifluoromethyl)phenyl]-4,6,7,8-tetrahydro-2-methyl-4-(1-propylbutyl)-pyrrolo[2,3,4-de]-1,8-naphthyridine; or a pharmaceutically acceptable salt thereof.
4. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or diluent.
5. A composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or diluent.