Azasteroids for treatment of tuberculosis

Patent metadata

Field	Value
Publication number	US-11072633-B2
Application number	US-201716097558-A
Country	US
Kind code	B2
Filing date	Apr 28, 2017
Priority date	Apr 29, 2016
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

The present invention provides a compound having the structure:for use in combination with an anti-tuberculosis drug for treating a subject infected with M. tuberculosis.

First claim

What is claimed is:

1. A compound having the structure:

wherein
α is absent or present and when present is a bond,
wherein when R 3 and R 4 combine to form a cycloalkyl group, then α is absent;

X is —NH—, —NH—NH—, —NH—C(O)—, —NH—C(S)—, —NH—NHC(O)— or —NH—NHC(S)—;
R 1 is —H, alkyl, alkenyl, alkynyl, aryl, C(O)-alkyl, C(O)-haloalkyl, C(O)-cycloalkyl, C(O)-alkenyl, C(O)-alkynyl, C(O)-aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 , SO 2 -alkyl, SO 2 -haloalkyl, SO 2 -cycloalkyl, SO 2 -alkenyl, SO 2 -alkynyl, SO 2 -aryl, or L-(anti-tuberculosis drug),
wherein the anti-tuberculosis drug is any one of isoniazid, ethionamide, pretomanid (PA-824), pyrazinamide, ethambutol, rifabutin, kanamycin, amikacin, capreomycin, streptomycin, levofloxacin, moxifloxacin, ofloxacin, para-aminosalicylic acid, cycloserine, terizidone, thionamide, protionamide, delamanid, bedaquiline, or rifampicin;

R 2 is H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 or alkyl-N(alkyl) 2 ;
R 3 is —H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 or alkyl-N(alkyl) 2 , and
R 4 is —H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 , or alkyl-N(alkyl) 2 , or
R 3 and R 4 combine to form a cycloalkyl group;
R 5 is a substituted pyridyl
wherein the substituted pyridyl is substituted with halo, —CN, —CF 3 , —OCF 3 , -alkyl, -alkenyl, -alkynyl, -aryl, -heteroaryl, —NH 2 , —NH-alkyl, —NH-alkenyl, —NH-alkynyl, —NH-aryl, —NH-heteroaryl, —OH, —OAc, —O—C(O)alkyl, —O-alkyl, —O-alkylaryl, —O-alkenyl, —O-alkynyl, —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), —SO 2 -(heteroaryl), alkyl-OH, alkyl-O-alkyl, alkyl-NH 2 , alkyl-NH-alkyl, alkyl-N(alkyl) 2 , cycloalkyl or alkyl-cycloalkyl,

wherein L is a chemical linker comprising a functional group capable of forming a bond with an anti-tuberculosis drug;
or a salt thereof.

2. The compound of claim 1 having the structure:

wherein
α is absent or present and when present is a bond,
wherein when R 3 and R 4 combine to form a cycloalkyl group, then α is absent;

X is —NH—, —NH—NH—, —NH—C(O)—, —NH—C(S)—, —NH—NHC(O)— or —NH—NHC(S)—;
R 1 is —H, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 , or L-(anti-tuberculosis drug),
wherein the anti-tuberculosis drug is any one of isoniazid, ethionamide, pretomanid (PA-824), pyrazinamide, ethambutol, rifabutin, kanamycin, amikacin, capreomycin, streptomycin, levofloxacin, moxifloxacin, ofloxacin, para-aminosalicylic acid, cycloserine, terizidone, thionamide, protionamide, delamanid, bedaquiline, or rifampicin;

R 2 is H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 or alkyl-N(alkyl) 2 ;
R 3 is —H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 or alkyl-N(alkyl) 2 , and
R 4 is —H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 , or alkyl-N(alkyl) 2 , or
R 3 and R 4 combine to form a cycloalkyl group;
R 5 is a substituted pyridyl
wherein the substituted pyridyl is substituted with halo, —CN, —CF 3 , —OCF 3 , -alkyl, -alkenyl, -alkynyl, -aryl, -heteroaryl, —NH 2 , —NH-alkyl, —NH-alkenyl, —NH-alkynyl, —NH-aryl, —NH-heteroaryl, —OH, —OAc, —O—C(O)alkyl, —O-alkyl, —O-alkylaryl, —O-alkenyl, —O-alkynyl, —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), —SO 2 -(heteroaryl), alkyl-OH, alkyl-O-alkyl, alkyl-NH 2 , alkyl-NH-alkyl, alkyl-N(alkyl) 2 , cycloalkyl or alkyl-cycloalkyl,

wherein L is a chemical linker comprising a functional group capable of forming a bond with an anti-tuberculosis drug;
or a salt thereof.

3. The compound of claim 1 ,
wherein
α is absent or present and when present is a bond,
wherein when R 3 and R 4 combine to form a cycloalkyl group, then α is absent;

X is —NH—;
R 1 is —H, alkyl, alkenyl, alkynyl, aryl, C(O)-alkyl, C(O)-haloalkyl, C(O)-cycloalkyl, C(O)-alkenyl, C(O)-alkynyl, C(O)-aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 , SO 2 -alkyl, SO 2 -haloalkyl, SO 2 -cycloalkyl, SO 2 -alkenyl, SO 2 -alkynyl, SO 2 -aryl,
R 2 is H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 or alkyl-N(alkyl) 2 ;
R 3 is —H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 or alkyl-N(alkyl) 2 , and
R 4 is —H, halo, alkyl, alkenyl, alkynyl, aryl, CO 2 -alkyl, CO 2 -alkenyl, CO 2 -alkynyl, CO 2 -aryl, cycloalkyl, alkyl-OH, alkyl-NH 2 , or alkyl-N(alkyl) 2 , or
R 3 and R 4 combine to form a cycloalkyl group;
R 5 is a substituted pyridyl
wherein the substituted pyridyl is substituted with halo, —CN, —CF 3 , —OCF 3 , -alkyl, -alkenyl, -alkynyl, -aryl, -heteroaryl, —NH 2 , —NH-alkyl, —NH-alkenyl, —NH-alkynyl, —NH-aryl, —NH-heteroaryl, —OH, —OAc, —O—C(O)alkyl, —O-alkyl, —O-alkylaryl, —O-alkenyl, —O-alkynyl, —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), —SO 2 -(heteroaryl), alkyl-OH, alkyl-O-alkyl, alkyl-NH 2 , alkyl-NH-alkyl, alkyl-N(alkyl) 2 , cycloalkyl or alkyl-cycloalkyl,

or a salt thereof.

4. The compound of claim 1 , wherein the alkyl group in R 1 , R 2 , R 3 , R 4 , and R 5 is a t-butyl group.

5. The compound of claim 1 , wherein R 5 is

6. The compound of claim 1 , wherein R 5 is

7. The compound of claim 1 , wherein the pyridyl in R 5 is trisubstituted.

8. The compound of claim 1 , wherein R 5 has the structure:

wherein R 6 , R 7 , R 8 , R 9 and R 10 are each, independently, —H, halo, —CN, —CF 3 , —OCF 3 , -alkyl, -alkenyl, -alkynyl, -aryl, —NH 2 , —NH-alkyl, —NH-alkenyl, —NH-alkynyl, —NH-aryl, —OH, —OAc, —O—C(O)alkyl, —O-alkyl, —O-alkylaryl, —O-alkenyl, —O-alkynyl, —O-(aryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S(O)-(alkyl), —S(O)-(aryl), —SO 2 -(alkyl), —SO 2 -(aryl), alkyl-OH, alkyl-O-alkyl, alkyl-NH 2 , alkyl-NH-alkyl, alkyl-N(alkyl) 2 , cycloalkyl or alkyl-cycloalkyl.

9. The compound of claim 8 , wherein R 5 has the structure:

wherein R 7 , R 8 and R 10 are each, independently, halo, —CN, —CF 3 , —OCF 3 , -alkyl, -alkenyl, -alkynyl, -aryl, —NH 2 , —NH-al

Assignees

• Univ New York State Res Found

Inventors

• Sampson Nicole
• Yang Xinxin
• Yuan Tianao

Classifications

• A61K31/58

  containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P31/06

  for tuberculosis · CPC title

• C07J73/005 Primary

  by nitrogen as hetero atom · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title