Mammalian and Bacterial Nitric Oxide Synthase Inhibitors

Patent metadata

Field	Value
Publication number	US-2016122302-A1
Application number	US-201514932587-A
Country	US
Kind code	A1
Filing date	Nov 4, 2015
Priority date	Nov 4, 2014
Publication date	May 5, 2016
Grant date	—

Abstract

Compounds and related methods for inhibition of mammalian and bacterial nitric oxide synthase.

First claim

We claim:

1 . A compound of a formula

wherein R 1 is selected from H, alkyl and amino moieties; L 1 is a divalent linker moiety selected from a covalent bond, alkylene and substituted alkylene moieties, said alkylene substituents selected from hydroxy, amino, aminoalkyl, oxa (—O—) aza (—NH—), alkyl (R) substituted aza (—NR—) and amino substituents and combinations thereof; R 3 is selected from H, alkyl, halo, haloalkyl, cyano and amino moieties and combinations thereof; X is selected from CH, CR 3 and N; L 2 is a divalent linker moiety selected from alkylene and substituted alkylene moieties, said alkylene substituents selected from aza (—NH—) or (—N—), alkyl and cycloalkyl (R) and substituted aza (—NR—) substituents; and R 2 is selected from amino, substituted amino and optionally-substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties, said substituents selected from amino, halo, alkyl, cycloalkyl and heterocycloalkyl substituents and divalent alkylene and heteroatom-substituted alkylene substituents, or a salt thereof.

2 . The compound of claim 1 of a formula

wherein n is 1-3.

3 . The compound of claim 2 wherein n is 2, L 2 is selected from —(CH 2 ) m —, —NH(CH 2 ) m — and N(R)(CH 2 ) m — moieties, where m is 0-4; R is selected from alkyl and cycloalkyl moieties; and R 2 is selected from amine, alkyl- and cycloalkyl-substituted amine moieties and optionally-substituted aryl and heteroaryl moieties.

4 . The compound of claim 3 of a formula

wherein R 1 is selected from H and methyl moieties; X and Y are independently selected from CH, CR 3 and N, providing both X and Y are not N; Z is selected from N and NH; m is an integer selected from 0-3; and R 4 is selected from H, alkyl, cycloalkyl and divalent alkylene moieties; and R 5 and R 6 are independently selected from H, alkyl, cycloalkyl, optionally substituted aryl and heteroaryl moieties and divalent alkylene moieties, providing where m is 0, R 6 is selected from H and alkyl and R 4 and R 5 are independently selected from divalent alkylene moieties to provide together with NR 6 and Z, respectively, a heterocycloalkyl moiety.

5 . The compound of claim 4 wherein Z is selected from N and NH; m is 0; and R 4 and R 5 are independently divalent alkylene moieties to provide a said heterocycloalkyl moiety.

6 . The compound of claim 5 wherein Z is N and said heterocycloalkyl moiety is a piperazinyl moiety.

7 . The compound of claim 5 wherein Z is NH and said heterocycloalkyl moiety is a piperidinyl moiety.

8 . The compound of claim 4 wherein one of X and Y is N; R 3 is H; Z is N; R 4 is selected from H, alkyl and cycloalkyl; m is 2-3; R 5 and R 6 are independently selected from H, alkyl and cycloalkyl moieties.

9 . The compound of claim 4 wherein X is CH and Y is CR 3 , where R 3 is selected from fluoro, trifluoromethyl and cyano substituents; R 4 is selected from H and alkyl; m is 2-3; R 5 and R 6 are independently selected from H, alkyl and cycloalkyl moieties.

10 . The compound of claim 3 wherein n is 2; L 2 is —NH(CH 2 ) m —, where m is selected from 1 and 2; and R 2 is selected from pyridinyl and substituted phenyl moieties.

11 . The compound of claim 1 wherein L 1 is a covalent bond and R 3 is H, said compound of a formula

12 . The compound of claim 11 of a formula

wherein L 2 is an aza-substituted alkylene moiety, said substituent selected from —NH— and —NR— where R is alkyl; and R 2 is selected from halo-substituted phenyl and alkyl-substituted amino moieties.

13 . The compound of claim 12 wherein said aza-substituted alkylene moiety is selected from —CH 2 NH(CH 2 ) 2 —, CH 2 N(CH 3 )(CH 2 ) 2 —, —CH 2 NH(CH 2 ) 3 —, —CH 2 NHCH 2 — and N(CH 3 )(CH 2 ) 2 — moieties.

14 . The compound of claim 1 wherein L 1 is selected from alkylene moieties; X is N; L 2 is selected from alkylene and aza-substituted alkylene moieties; and R 2 is selected from alkyl-substituted amino moieties.

15 . The compound of claim 14 wherein said aza-substituted alkylene moiety is selected from —CH 2 NH(CH 2 ) 2 —, CH 2 N(CH 3 )(CH 2 ) 2 —, —CH 2 NH(CH 2 ) 3 —, CH 2 N(CH 3 )(CH 2 ) 3 —, —CH 2 NHCH 2 — and N(CH 3 )(CH 2 ) 2 — moieties.

16 . The compound of claim 1 wherein L 1 is selected from substituted alkylene moieties, said substituents selected from hydroxy, amino and aminoalkyl substituents; L 2 is selected from alkylene moieties; and R 2 is selected from substituted pyridinyl moieties, said R 2 substituents selected from alkyl and amino substituents and combinations thereof.

17 . A method of affecting a human nitric oxide synthase, said method comprising:
providing a compound of claim 1 ; and contacting said compound with a human nitric oxide synthase, said compound in an amount sufficient to affect human neuronal nitric oxide synthase binding affinity.

18 . The method of claim 17 providing a compound of claim 4 .

19 . The method of claim 17 providing a compound of claim 9 .

20 . The method of claim 17 wherein said contact selectively inhibits human neuronal nitric oxide synthase over inducible and endothelial isoforms.

21 . A method of affecting bacterial nitric oxide synthase, said method comprising:
providing a cellular medium comprising a gram-positive bacterium expressing a nitric oxide synthase; and contacting said bacterium with a compound selected from compounds of claims 12 and 14 .

22 . The method of claim 21 comprising induction of oxidative stress in said bacterium.

23 . The method of claim 22 wherein said oxidative stress is induced by an antimicrobial agent.

24 . The method of claim 23 wherein said antimicrobial agent is acriflavine.

25 . The method of claim 21 wherein said bacterium is selected from S. aureus and a methicillin-resistant strain thereof.

26 . A method of affecting a bacterial nitric oxide synthase, said method comprising:
providing a gram-positive bacterium expressing a nitric oxide synthase; and contacting said bacterium with a compound selected from compounds of a formula

wherein R 1 is selected from H, alkyl and amino moieties; L is a divalent linker moiety selected from substituted and unsubstituted alkylene, alkylenearylalkylene, alkyleneheteroarylalkylene, alkylenepyrrolidinylalkylene moieties, said alkylene component substituents independently selected from alkyl, hydroxy, amino, aminoalkyl, oxa (—O—), aza (—NH—) and alkyl and cycloalkyl (R)-substituted aza (—NR—) substituents and combinations thereof; and said aryl, heteroaryl and pyrrolidinyl component substituents independently selected from alkyl, amino, aminoalkyl and cyano substituents and combinations thereof; R 2 and R 8 are independently selected from aryl, substituted aryl, heteroaryl, substituted

Assignees

• Univ Northwestern

Inventors

• Silverman Richard B
• Jing Qing
• Kang Soosung
• Wang Heng-Yen

Classifications

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D213/73 Primary

  Unsubstituted amino or imino radicals · CPC title