Patent
Provided are bis-quaternary ammonium cyclophane compounds which are modulators of nicotinic acetylcholine receptors. Also provided are methods of using the compounds for modulating the function of a nicotinic acetylcholine receptor, and for the prevention and/or treatment of central nervous system disorders, substance use and/or abuse, and or gastrointestinal tract disorders.
1. A compound of Formula (I)
wherein
X 1Θ and X 2Θ are each independently an organic or inorganic anion;
Q and T are each independently attached to R 1 and R 2 ;
Q is alkyl;
T is alkynyl;
R 1 and R 2 are each six membered rings as shown in formula (IIA);
R 8 or R 12 is replaced by one attachment to T in R 1 and R 2 ;
R 4 is replaced by one attachment to Q in R 1 and R 2 ;
R 6 , R 8 , R 10 , R 12 , and R 14 , when present, are each independently selected from the group consisting of hydrogen, lower alkyl, halo, cyano, nitro, trifluoromethyl, hydroxymethyl, hydroxyethyl and hydroxypropyl.
2. The compound of claim 1 , wherein Q is —(CH 2 ) 4 —, —(CH 2 ) 6 —, —(CH 2 ) 8 —, —(CH 2 ) 9 —, —(CH 2 ) 10 —, —(CH 2 ) 11 — or —(CH 2 ) 12 —; and T is —C≡C—(CH 2 ) 6 —C≡C—.
3. The compound of claim 2 , wherein
X 1Θ and X 2Θ are bromide or iodide.
4. The compound of claim 1 selected from the group consisting of:
N,N′-(1,6-hexanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;
N,N′-(1,8-octananediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;
N,N′-(1,9-nonanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;
N,N′-(1,10-decanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide; and
N,N′-(1,11′-undecanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide.
5. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .
6. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 2 .
7. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 3 .
8. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 4 .
9. N,N′-(1,4-butanediyl)-3,3′-(1,12-dodecanediyl)-bis-pyridinium diiodide.