Bis-quaternary ammonium salts as pain modulating agents

Patent metadata

Field	Value
Publication number	US-9499518-B2
Application number	US-88059110-A
Country	US
Kind code	B2
Filing date	Sep 13, 2010
Priority date	Jun 16, 2006
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

Provided are methods for using bis-quaternary ammonium compounds to treat inflammatory pain, neuropathic pain and nociceptive pain.

First claim

We claim the following:

1. A method of blocking the nicotinic acetylcholine receptor α9α10nAChR, comprising administering to a mammalian subject in need thereof a pharmaceutically acceptable amount of a compound-of Formula (I)
X 2 ⊖⊕R 1 —H 2 C-L 1 -Q-L 2 -CH 2 —R 2 ⊕⊖X 1   (I)

wherein X 1⊖′ and X 2⊖′ are each independently an organic or inorganic anion; and
wherein -L 1 -Q-L 2 - is —(CH 2 ) 4 -1,2-phenyl-(CH 2 ) 4 —; R 1⊕ and R 2⊕ are rings represented by the formula

wherein R 3 is hydrogen or methyl; R 5 is hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl; R 7 is hydrogen or methyl; R 9 is hydrogen; and R 11 is hydrogen; or R 1⊕ and R 2⊕ are

or
wherein -L 1 -Q-L 2 - is —(CH 2 ) 4 -1,3-phenyl-(CH 2 ) 4 —; R 1⊕ and R 2⊕ are rings represented by the formula

wherein R 3 is hydrogen or methyl; R 5 is hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl; R 7 is hydrogen or methyl; R 9 is hydrogen or methyl; and R 11 is hydrogen; or R 1⊕ and R 2⊕ are

or
wherein -L 1 -Q-L 2 - is —(CH 2 ) 3 -1,4-phenyl-(CH 2 ) 3 —; R 1⊕ and R 2⊕ are rings represented by the formula

wherein R 3 is hydrogen or methyl; R 5 is hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl; R 7 is hydrogen or methyl; R 9 is hydrogen; and R 11 is hydrogen; or R 1⊕ and R 2⊕ are

or
wherein -L 1 -Q-L 2 - is —(CH 2 ) 2 -4,4′-biphenyl-(CH 2 ) 2 —; R 1⊕ and R 2⊕ are rings represented by the formula

wherein R 3 is hydrogen or methyl; R 5 is hydrogen, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl; R 7 is hydrogen or methyl; R 9 is hydrogen or methyl; and R 11 is hydrogen; or R 1⊕ and R 2⊕ are

or
wherein -L 1 -Q-L 2 - is —(CH 2 ) 2 —C≡C-1,2-phenyl-C≡C—(CH 2 ) 2 —; R 1⊕ and R 2⊕ are rings represented by the formula

wherein R 3 is hydrogen or methyl; R 5 is hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl; R 7 is hydrogen or methyl; R 9 is hydrogen or methyl; and R 11 is hydrogen; or R 1⊕ and R 2⊕ are

or
wherein -L 1 -Q-L 2 - is —(CH 2 ) 2 —C≡C-1,3-phenyl-C≡C—(CH 2 ) 2 —; R 1⊕ and R 2⊕ are rings represented by the formula

wherein R 3 is hydrogen or methyl; R 5 is hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl; R 7 is hydrogen or methyl; R 9 is hydrogen or methyl; and R 11 is hydrogen; or R 1⊕ and R 2⊕ are

or
wherein -L 1 -Q-L 2 - is —CH 2 —C≡C-1,4-phenyl-C≡C—CH 2 —; R 1⊕ and R 2⊕ are rings represented by the formula

wherein R 3 is hydrogen or methyl; R 5 is hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl; R 7 is hydrogen or methyl; R 9 is hydrogen or methyl; and R 11 is hydrogen; or R 1⊕ and R 2⊕ are

or
wherein -L 1 -Q-L 2 - is —C≡C-4,4′-biphenyl-C≡C—; R 1⊕ and R 2⊕ are rings represented by the formula

wherein R 3 is hydrogen or methyl; R 5 is hydrogen, methyl, ethyl, butyl, phenyl, 1-methyl-2-pyrrolidinyl, bromo, hydroxymethyl or hydroxypropyl; R 7 is hydrogen or methyl; R 9 is hydrogen or methyl; and R 11 is hydrogen; or R 1⊕ and R 2⊕ are

2. A method of blocking the nicotinic acetylcholine receptor α9α10nAChR, comprising administering to a mammalian subject in need thereof a pharmaceutically acceptable amount of a compound selected from the group consisting of:
N,N′[1,4-phenylenedi-(4-butanyl)]-bis-(3,4-dimethylpyridinium) dibromide;
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,2-bis-[5-(3,5-dimethyl-pyridinium)-pent-1-ynyl]-benzene dibromide;
1,2-bis-[5-isoquinolinium-pent-1-ynyl)-benzene dibromide;
1,2-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,2-bis-[5-isoquinolinium-pentyl)-benzene dibromide;
1,3-bis-[5-(3,4-dimethyl-pyridiniiim)-pent-1-ynyl]-benzene dibromide;
1,3-bis-(5-quinolinium-pent-1-ynyl)-benzene dibromide;
1,3-bis-[5-(3,4-dimethyl-pyridinium)-pentyl]-benzene dibromide;
1,3-bis-(5-isoquinolinium-pentyl)-benzene dibromide;
N,N′-[(1,1′-biphenyl)-4,4′-di-(3-propanyl)]-bis-[3-(3-hydroxy-propyl)-pyridinium] dibromide;
N,N′-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,4-dimethyl-pyridinium) dibromide;
N,N′-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,5-dimethyl-pyridinium) dibromide; and
N,N′-[(1,1′-biphenyl)-4,4′-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridinium) dibromide.

3. The method of claim 2 , wherein the compound is N,N′-[(1,1′-biphenyl)-4,4′-di-(1-propyn-3-yl)]-bis-(3,4-dimethylpyridinium) dibromide.

4. The method of claim 2 , wherein the compound is N,N′-[(1,4-phenylene)-bis-(4-butynyl)]-bis-(3,4-dimethyl-pyridinium) dibromide.

5. The method of claim 1 , wherein -L 1 -Q-L 2 - is —(CH 2 ) 4 -1,2-phenyl-(CH 2 ) 4 — and R 1⊕ and R 2⊕ are each

6. The method of claim 1 , wherein X 1⊖i and X 2⊖i are each bromide, -L 1 -Q-L 2 - is —(CH 2 ) 4 -1,2-phenyl-(CH 2 ) 4 —, and R 1⊕ and R 2⊕ are each

Assignees

• Holtman Joseph R
• Crooks Peter A
• Dwoskin Linda P
• Mcintosh J Michael
• Wala Elzbieta Pogonowska
• Univ Kentucky Res Found
• Univ Utah

Inventors

• Holtman Joseph R
• Crooks Peter A
• Dwoskin Linda P
• Mcintosh J Michael
• Wala Elzbieta Pogonowska

Classifications

• A61K31/4425

  Pyridinium derivatives, e.g. pralidoxime, pyridostigmine · CPC title

• A61K31/472

  Non-condensed isoquinolines, e.g. papaverine · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title