Mono quaternary ammonium salts and methods for modulating neuronal nicotinic acetylcholine receptors

Patent metadata

Field	Value
Publication number	US-9550753-B2
Application number	US-201414470715-A
Country	US
Kind code	B2
Filing date	Aug 27, 2014
Priority date	Jun 16, 2006
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

Provided are monoquaternary ammonium 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 gastrointestinal tract disorders.

First claim

We claim:

1. A compound of Formula (I):

wherein A 1 , A 2 , A 3 , A 4 , and A 5 are each carbon;
wherein three of R 1 , R 3 , R 4 , and R 5 are hydrogen, alkyl, or substituted alkyl, and
R 1 and R 2 or R 2 and R 3 together with the carbons to which they are attached independently form a three- to eight-member cycloalkane, cycloalkene, aryl, heterocycle with one to three hetero atoms in the ring, or substituted heterocycle with one to three hetero atoms in the ring;
wherein Z 1 is absent or is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, alkenyl, alkynyl, phenylene, and alkoxy;
wherein Z 2 is selected from the group consisting of substituted alkyl, cycloalkyl, alkenyl, alkynyl, arylene, heterocycle, substituted heterocycle, and alkoxy;
wherein Z 3 is selected from propyl, butyl, hexyl, substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocycle, and substituted heterocycle;
wherein X − is an inorganic or organic anion,
wherein substituted alkyl is an alkyl substituted with one or more substituents selected from the group consisting of hydroxy, lower-alkyl alkoxy, lower-alkyl mercapto, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbamate, sulfonyl, sulfonamide, an aryl group, and a heterocyclic group, and
wherein substituted heterocycle is a heterocycle substituted with one or more substituents selected from the group consisting of hydroxy, lower-alkyl alkoxy, lower-alkyl mercapto, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbamate, sulfonyl, sulfonamide, an aryl group, and a heterocyclic group.

2. The compound of claim 1 , wherein A 1 , A 2 , A 3 , A 4 , and A 5 are carbon;
wherein R 1 is hydrogen, methyl, forms a six membered ring with A 1 , A 2 and R 2 and with R 1 and R 2 providing four saturated carbon atoms, or forms a phenyl group with A 1 , A 2 and R 2 ;
wherein R 2 is hydrogen, methyl, ethyl, butyl, phenyl, 3-hydroxypropyl, forms a six membered ring with A 1 , A 2 and R 1 and with R 1 and R 2 providing four saturated carbon atoms, forms a phenyl group with A 1 , A 2 and R 1 , forms a six membered ring with A 2 , A 3 and R 3 and with R 2 and R 3 providing four saturated carbon atoms, or forms a phenyl group with A 2 , A 3 and R 3 ;
wherein R 3 is hydrogen, methyl, forms a six membered ring with A 2 , A 3 and R 2 and with R 2 and R 3 providing four saturated carbon atoms, or forms a phenyl group with A 2 , A 3 and R 2 ;
wherein R 4 is hydrogen or methyl;
wherein R 5 is hydrogen;
wherein Z 1 is absent, butyl, but-3-ynyl, pentyl, pent-4-ynyl or 2-ethoxy;
wherein Z 2 is para-phenylene, or 2-ethoxy;
wherein Z 3 is propyl, butyl, but-1-ynyl, hex-1-ynyl, phenyl, or 3-pyridinyl;

and wherein X is chloride, bromide or iodide.

3. The compound of claim 1 , wherein A 1 , A 2 , A 3 , A 4 , and A 5 are carbon;
wherein R 1 is hydrogen, methyl, forms a six membered ring with A 1 , A 2 and R 2 and with R 1 and R 2 providing four saturated carbon atoms, or forms a phenyl group with A 1 , A 2 and R 2 ;
wherein R 2 is hydrogen, methyl, ethyl, 3-hydroxypropyl, forms a six membered ring with A 1 , A 2 and R 1 and with R 1 and R 2 providing four saturated carbon atoms, forms a phenyl group with A 1 , A 2 and R 1 , forms a six membered ring with A 2 , A 3 and R 3 and with R 2 and R 3 providing four saturated carbon atoms, or forms a phenyl group with A 2 , A 3 and R 3 ;
wherein R 3 is hydrogen, methyl, forms a six membered ring with A 2 , A 3 and R 2 and with R 2 and R 3 providing four saturated carbon atoms, or forms a phenyl group with A 2 , A 3 and R 2 ;
wherein R 4 is hydrogen or methyl;
wherein R 5 is hydrogen;
wherein Z 1 is absent, butyl, but-3-ynyl, pent-4-ynyl or 2-ethoxy;
wherein Z 2 is para-phenylene, or 2-ethoxy;
wherein Z 3 is propyl, butyl, but-1-ynyl, hex-1-ynyl, phenyl, or 3-pyridinyl; and

wherein X is chloride, bromide or iodide.

4. The compound of claim 1 , wherein A 1 , A 2 , A 3 , A 4 , and A 5 are carbon;
wherein R 1 is hydrogen, methyl, or forms a phenyl group with A 1 , A 2 and R 2 ;
wherein R 2 is hydrogen, methyl, butyl, forms a phenyl group with A 1 , A 2 and R 1 , or forms a phenyl group with A 2 , A 3 and R 3 ;
wherein R 3 is hydrogen, methyl, or forms a phenyl group with A 2 , A 3 and R 2 ;
wherein R 4 is hydrogen or methyl;
wherein R 5 is hydrogen;
wherein Z 1 is pentyl or pent-4-ynyl;
wherein Z 2 is para-phenylene;
wherein Z 3 is phenyl; and
wherein X is bromide.

5. The compound of claim 1 selected from the group consisting of:
2-[4-(4-butyl-phenyl)-butyl]-5,6,7,8-tetrahydro-isoquinolinium bromide;
2-[4-(4-butyl-phenyl)-but-3-ynyl]-5,6,7,8-tetrahydro-isoquinolinium bromide;
2-[13-(3-pyridinyl)-tridecyl]-5,6,7,8-tetrahydro-isoquinolinium bromide;
1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-quinolinium bromide;
2-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-isoquinolinium bromide;
1-[5-(1,1′-biphenyl-4-yl)-pentyl]-quinolinium bromide;
2-[5-(1,1′-biphenyl-4-yl)-pentyl]-isoquinolinium bromide;
2-[4-(4-propyl-phenyl)-pent-4-ynyl]-5,6,7,8-tetrahydro-isoquinolinium bromide;
1-[2-(2-hexoxy-ethoxy)-ethyl]-5,6,7,8-tetrahydro-quinolinium chloride; and
2-[2-(2-hexoxy-ethoxy)-ethyl]-5,6,7,8-tetrahydro-isoquinolinium chloride.

6. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

7. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 2 .

8. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 3 .

9. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 4 .

10. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 5 .

Assignees

• Univ Kentucky Res Found

Inventors

• Crooks Peter
• Dwoskin Linda P
• Zheng Guangrong
• Sumithran Sangeetha
• Zhang Zhenfa

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D217/10

  Quaternary compounds · CPC title

• C07C17/16

  of hydroxyl groups · CPC title

• C07D213/30

  Oxygen atoms · CPC title