2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase

• US 9,878,996 B2
• Filed: 05/23/2017
• Issued: 01/30/2018
• Est. Priority Date: 07/11/2014
• Status: Active Grant

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Silverman, Richard B., Mukherjee, Paramita, Nguyen, Hien M.
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US15/602,833
• Publication Number:
  US 20170260165A1
• Time in Patent Office: 252 Days
• Field of Search: 544331, 514275
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond

Abstract

Imidazolyl-pyrimidine and related compounds, as can utilize heme-iron coordination in the selective inhibition of neuronal nitric oxide synthase.

Claims

1. A method of inhibiting a nitric oxide synthase, said method comprising:

(a) providing a compound of a formula

2. The method of claim 1 wherein Ar is selected from fluoro-, chloro- and cyano-substituted phenyl moieties;

and E₅ is N.

3. The method of claim 2 wherein E₆ is a CCH₃ moiety.

8. The method of claim 1 wherein L₁ is selected from (CH₂)_n moieties, where n is an integer selected from 1-3, CH(R₄)CH(R₅)CH(R₆) moieties where each of R₄-R₆ is independently selected from H, fluoro, and alkyl substituents and moieties where R₄ and R₅ together and R₅ and R₆ together form methylene substituents and cyclopropyl moieties.

9. The method of claim 1 wherein L₂ is selected from (CH₂)_m, CH(R₇)CH(R₈), (_CH2)_mNH and (CH₂)_mNR₂ moieties, where m is an integer selected from 1-3 and each of R₇-R₈ is independently selected from H and fluoro substituents, and moieties where R₁ and R₂ together form a divalent C₁-C₂ alkylene substituent and a diazacycloalkyl moiety.

10. The method of claim 1 wherein L₁ is selected from (CH₂)_n moieties, where n is an integer selected from 1-3, and CH(R₄)CH(R₅)CH(R₆) moieties where each of R₄-R₆ is independently selected from H and fluoro substituents.

11. The method of claim 1 wherein L₂ is selected from (CH₂)_m and CH(R₇)CH(R₈), moieties, where m is an integer selected from 1-3 and each of R₇-R₈ is independently selected from H and fluoro substituents.

12. The method of claim 1 wherein said compound is an ammonium salt, and said salt has a counter ion that is a conjugate base of a protic acid.

4. A method of inhibiting a nitric oxide synthase, said method comprising:

(a) providing a compound of a formula

5. The method of claim 4 wherein E₅ is N.

6. The method of claim 5 wherein E₆ is a CCH₃ moiety.

7. The method of claim 4 wherein neuronal nitric oxide synthase is selectively inhibited over inducible and endothelial isoforms.

13. The method of claim 4 wherein L₁ is selected from (CH₂)_n moieties, where n is an integer selected from 1-3, and CH(R₄)CH(R₅)CH(R₆) moieties where each of R₄-R₆ is independently selected from H and fluoro substituents.

14. The method of claim 4 wherein said compound is an ammonium salt, and said salt has a counter ion that is a conjugate base of a protic acid.

15. A method of inhibiting a nitric oxide synthase, said method comprising:

(a) providing a compound of a formula

16. The compound of claim 15 wherein L₁ is selected from (CH₂)_n moieties, where n is an integer selected from 1-3, CH(R₄)CH(R₅)CH(R₆) moieties where each of R₄-R₆ is independently selected from H and fluoro substituents, and moieties where R₄ and R₅ together and R₅ and R₆ together form methylene substituents and cyclopropyl moieties.

17. The compound of claim 15 wherein L₂ is selected from (CH₂)_m, CH(R₇)CH(R₈), (_CH2)_mNH and (CH₂)_mNR₂ moieties, where m is an integer selected from 1-3 and each of R₇-R₈ is independently selected from H and fluoro substituents, and moieties where R₁ and R₂ together form a divalent C₁-C₂ alkylene substituent and a diazacycloalkyl moiety.

18. The compound of claim 15 wherein E₅ is N.

19. The compound of claim 15 wherein L₁ is selected from (CH₂)_n moieties, where n is an integer selected from 1-3, and CH(R₄)CH(R₅)CH(R₆) moieties where each of R₄-R₆ is independently selected from H and fluoro substituents;

.

20. The compound of claim 15 wherein L₂ is selected from (CH₂)_m and CH(R₇)CH(R₈), moieties, where m is an integer selected from 1-3 and each of R₇-R₈ is independently selected from H and fluoro substituents.