Nicotinic desensitizers and methods of selecting, testing, and using them

• US 8,642,612 B2
• Filed: 07/18/2007
• Issued: 02/04/2014
• Est. Priority Date: 07/18/2006
• Status: Active Grant

• Current Assignee: Potomac Pharmaceuticals Incorporated
• Original Assignee: Potomac Pharmaceuticals Incorporated
• Inventors: Xiao, Yingxian, Kellar, Kenneth J.
• Primary Examiner(s): CHONG, YONG SOO
• Application Number:
  US12/374,172
• Publication Number:
  US 20100129291A1
• Time in Patent Office: 2,393 Days
• Field of Search: 514/219, 514/277
• US Class Current: 514/277
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/18 Bridged systems
• CPC Class Codes: G01N 2500/02 Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 33/9406 Neurotransmitters
• CPC Class Codes: G01N 33/944 Acetylcholine

Abstract

The present invention discloses nicotinic desensitizers and methods of selecting, testing, and using them. The present invention provides methods for selecting nicotinic desensitizers from one or more compounds by using receptor, cell, and tissue models; and methods for testing one or more nicotinic desensitizers for their therapeutic utility by using animal models. The present invention also provides compounds of formula (I) and (II) as nicotinic desensitizers. Nicotinic desensitizers of the present invention are useful for the treatment of a wide range of conditions, diseases, and disorders.

Claims

1. A pharmaceutical composition comprising a compound of formula (I):

2. The pharmaceutical composition of claim 1, further comprising at least one additional active agent.

3. The pharmaceutical composition of claim 1, wherein R¹ is halo, amino, N-alkyl amino, N,N-dialkyl amino, amido, nitro, cyano, hydroxyl, or alkoxy, or an optionally substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl;

and R² and R⁴ are H.

4. The pharmaceutical composition of claim 1, wherein R³ is an optionally substituted C₂-C₁₂ alkynyl.

5. The pharmaceutical composition of claim 1, wherein Het is a 4- to 7-membered monocyclic fully-saturated heterocyclic ring containing at least one hetero atom selected from the group consisting of N, O, and S.

6. The pharmaceutical composition of claim 1, wherein

R¹ is halo, amino, N-alkyl amino, N,N-dialkyl amino, amido, nitro, cyano, hydroxyl, or alkoxy, or an optionally substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, N-alkyl amino, N,N-dialkyl amino, —

NH—

C(O)—

R⁶, —

NH—

C(O)—

OR⁶, —

O—

C(O)—

R⁶, —

O—

C(O)—

OR⁶, nitro, and alkoxy;

R² and R⁴ are H;

R³ is an optionally substituted C₂-C₁₂ alkynyl; and

Het is a 4- to 7-membered monocyclic fully-saturated heterocyclic ring containing at least one hetero atom selected from the group consisting of N, O, and S.

7. A compound of formula (I):

8. The compound of claim 7, wherein R¹ is halo, amino, N-alkyl amino, N,N-dialkyl amino, amido, nitro, cyano, or an optionally substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, N-alkyl amino, N,N-dialkyl amino, —

NH—

C(O)—

R⁶, —

NH—

C(O)—

OR⁶, —

O—

C(O)—

R⁶, —

O—

C(O)—

OR⁶, nitro, and alkoxy;

R² and R⁴ are H.

9. The compound of claim 7, wherein R³ is an optionally substituted C₂-C₁₂ alkynyl.

10. The compound of claim 7, wherein Het is a 4- to 7-membered monocyclic fully-saturated heterocyclic ring containing at least one hetero atom selected from the group consisting of N, O, and S.

11. The compound of claim 7, wherein

R¹ is halo, amino, N-alkyl amino, N,N-dialkyl amino, amido, nitro, cyano, or an optionally substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, N-alkyl amino, N,N-dialkyl amino, —

NH—

C(O)—

R⁶, —

NH—

C(O)—

OR⁶, —

O—

C(O)—

R⁶, —

O—

C(O)—

OR⁶, nitro, and alkoxy;

R² and R⁴ are H;

R³ is an optionally substituted C₂-C₁₂ alkynyl; and

Het is a 4- to 7-membered monocyclic fully-saturated heterocyclic ring containing at least one hetero atom selected from the group consisting of N, O, and S.

12. A compound of formula (I):

14. A pharmaceutical composition comprising a compound of formula (I) as described in claim 12, or a pharmaceutically acceptable tautomer, salt, or solvate thereof;

and a pharmaceutically acceptable carrier or excipient.

13. A compound of