Use of Inhibitor of Apoptosis Protein (IAP) Antagonists in HIV Therapy

Patent metadata

Field	Value
Publication number	US-2017196879-A1
Application number	US-201515313286-A
Country	US
Kind code	A1
Filing date	Jun 4, 2015
Priority date	Jun 4, 2014
Publication date	Jul 13, 2017
Grant date	—

Abstract

Provided herein is the use of compounds that modulate the activity of inhibitor of apoptosis proteins (1APs), alone or in combination with other therapeutic agents, in the treatment of human immunodeficiency virus (HIV). Described herein is the use of IAP antagonists in the treatment of human immunodeficiency virus (HIV) in a mammal, alone or in combination with other therapeutic agents used in HIV therapy. In one aspect, provided herein is a method of treating human immunodeficiency virus (HIV) in an individual in need thereof comprising administering a therapeutically effective amount of at least one inhibitor of apoptosis proteins (IAP) antagonist.

First claim

What is claimed is:

1 . A method of treating human immunodeficiency virus (HIV) in an individual in need thereof comprising administering a therapeutically effective amount of at least one inhibitor of apoptosis proteins (IAP) antagonist.

2 . A method of reducing dormant, replication competent human immunodeficiency virus (HIV) in an individual in need thereof, or making dormant, replication competent human immunodeficiency virus (HIV) susceptible to immune system clearance in an individual in need thereof, or making dormant, replication competent human immunodeficiency virus (HIV) susceptible to the effects of antiretroviral therapy in an individual in need thereof, or eliminating replication competent human immunodeficiency virus (HIV) in an individual in need thereof, or inducing long term control of human immunodeficiency virus (HIV) replication and growth in the absence of antiretroviral therapy in an individual in need thereof, or activating human immunodeficiency virus (HIV) transcription in latently infected cells in an individual in need thereof, or reducing human immunodeficiency virus (HIV) reservoirs of latently infected cells in an individual in need thereof, comprising administering a therapeutically effective amount of at least one inhibitor of apoptosis proteins (IAP) antagonist.

3 . The method of claim 1 , wherein the individual in need is on concomitant antiretroviral therapy.

4 . The method of claim 3 , wherein the IAP antagonist activates HIV transcription in latently infected cells.

5 . The method of claim 4 , wherein the latently infected cells are CD4 + T cells.

6 . The method of any one of claims 1 - 5 , wherein the IAP antagonist is a small molecule.

7 . The method of claim 6 , wherein the IAP antagonist is a small molecule comprising a fused bicyclic, non-aromatic lactam containing a six-five, seven-five, eight-five, seven-six, or eight-six ring system.

8 . The method of claim 7 , wherein the IAP antagonist is a small molecule that has the following structure of Formula B-I, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:

wherein,
R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
when X 1 is selected from N—R A , then X 2 is C═O, or CR 2c R 2d , and X 3 is CR 2a R 2b ;
or
when X 1 is selected from S, S(O) and S(O) 2 , then X 2 is CR 2c R 2d , and X 3 is CR 2a R 2b ;
or
when X 1 is O, then X 2 is selected from CR 2c R 2d and N—R A , and X 3 is CR 2a R 2b ;
or:
when X 1 is CH 2 , then X 2 is selected from O, N—R A , S, S(O), and S(O) 2 , and X 3 is CR 2a R 2b ;
or:
X 1 is CR 2e R 2f and X 2 is CR 2c R 2d , and R 2e and R 2c together form a bond, and X 3 is CR 2a R 2b ;
or:
X 1 and X 3 are both CH 2 and X 2 is C═O, C═C(R C ) 2 , or C═NR C ; where each R C is independently selected from H, —CN, —OH, alkoxy, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
or:
X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 is CR 2a R 2b ;
or:
X 2 and X 3 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 is CR 2e R 2f ;
R A is H, C 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
W 1 is O, S, N—R A , or C(R 8a )(R 8b );
W 2 is O, S, N—R A , or C(R 8c )(R 8d ) provided that W 1 and W 2 are not both O, or both S;
R 2a , R 2b , R 2c , R 2d R 2e , and R 2f are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl) and —C(═O)R B ;
R B is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), or —NR D R E ;
R D and R E are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
m is 0, 1 or 2;
—U— is —NHC(═O)—, —C(═O)NH—, —NHS(═O) 2 —, —S(═O) 2 NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O) 2 NH—;
R 3 is C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl;
R 4 is —NHR 5 , —N(R 5 ) 2 , —N + (R 5 ) 3 or —OR 5 ;
each R 5 is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 heteroalkyl and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);
or:
R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
or:
R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
R 6 is —NHC(═O)R 7 , —C(═O)NHR 7 , —NHS(═O) 2 R 7 , —S(═O) 2 NHR 7 ; —NHC(═O)NHR 7 , —NHS(═O) 2 NHR 7 , —(C 1 -C 3 alkyl)-NHC(═O)R 7 , —(C 1 -C 3 alkyl)-C(═O)NHR 5 , —(C 1 -C 3 alkyl)-NHS(═O) 2 R 7 , —(C 1 -C 3 alkyl)-S(═O) 2 NHR 7 ; —(C 1 -C 3 alkyl)-NHC(═O)NHR 7 , —(C 1 -C 3 alkyl)-NHS(═O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl

Assignees

• Sanford-Burnham Medical Res Inst
• Salk Inst For Biological Studi

Inventors

• Pache Lars
• Chanda Sumit K
• Vamos Mitchell Dennis
• Cosford Nicholas David Peter
• Teriete Peter
• Marlett John
• Diaz Arturo
• Young John A T

Classifications

• A61K31/27

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/5365

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · CPC title