NICOTINE RECEPTOR TARGETED COMPOUNDS AND COMPOSITIONS

摘要

The invention relates to the design and synthesis of novel anabaseine-based compounds, which are useful in treating or preventing a wide variety of conditions, including nervous system diseases or disorders, such as, schizophrenia, Alzheimer's disease, Parkinson's disease, drug dependence, and substance addiction, and compositions, kits, and methods thereof. The invention also provides novel anabaseine-based compounds, compositions, kits, and methods thereof for treating or preventing non-nerve system diseases or disorders (such as, inflammation and cancer) in a subject identified in need thereof. Certain enantiomeric compounds of the invention exhibited enhanced selectivity toward α7 nAChRs relative to alpha4beta2 nAChRs. Other enantiomeric compounds of the invention exhibited enhanced selectivity for alpha4beta2 nAChRs relative to α7 nAChRs.

主权项

1. A compound of Formula (I): wherein , independently, stands for a single bond or a double bond; R1, on each occurrence, independently is (C1-C3)alkyl, hydroxy(C1-C3)alkyl, (C1-C3)alkoxy, cyano, halogen, aryl-O—, aryl, or a 5- to 6-membered heteroaryl; or two R1 groups, together with the bonds they are attached to, form a 5 to 8 membered cyclic ring; n is 0, 1, 2, 3, or 4; Each of a1, a2, and a3 is 0 or 1, wherein two of a1, a2, and a3 are 0, and the other is 1; R2 is hydrogen, (C1-C3)alkyl, hydroxy(C1-C3)alkyl, or (C1-C3)alkoxy; E and G, each independently, are absent, -hetero(C0-C3)alkyl-, (C1-C3)alkylene, or (C2-C3)alkenylene, wherein E and G cannot be both absent at the same time; A is a bond or n′ is 0, 1, or 2; R4 and R5, on each occurrence, independently are hydrogen, (C1-C3)alkyl, hydroxy(C1-C3)alkyl, or (C1-C3)alkoxy; X is aryl or heteroaryl, wherein said aryl and said heteroaryl are optionally substituted by one to five R3 groups and/or one Rc group; R3, on each occurrence, independently is hydrogen, halogen, (C1-C3)alkyl-C(O)O—, (C1-C3)alkyl-C(O)—, (C1-C3)alkyl-C(O)N(R6), N(R6)2—, (R6)2NC(O)—, (R6)2N(C1-C5)alkoxy, (R6)3N⊕ (C1-C5) alkoxy, hydroxyl, cyano, a sugar moiety or derivative thereof, (C1-C3)alkoxy optionally substituted by one or more same or different halogen or thio groups, or (C1-C3)alkyl optionally substituted by one or more same or different halogen or hydroxyl groups; R6, on each occurrence, independently is hydrogen, (C1-C3)alkyl, hydroxy(C1-C3)alkyl, or (C1-C3)alkoxy; Ra on each occurrence, independently is hydrogen, (C1-C3)alkyl, hydroxy(C1-C3)alkyl, (C1-C3)alkoxy, cyano, halogen, aryl, or aryl-O—; Rc is hydrogen, (C1-C5)alkoxy, or (C1-C5)alkyl, wherein said (C1-C5)alkoxy and said (C1-C5)alkyl are optionally substituted by one or more same or different substituents selected from the group of hydroxyl, (C1-C3)alkoxy, halogen, and thio; and b is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, stereoisomer, enantiomer, or combination thereof.