Anti-fungal compounds

Patent metadata

Field	Value
Publication number	US-10980754-B2
Application number	US-201716094682-A
Country	US
Kind code	B2
Filing date	Apr 19, 2017
Priority date	Apr 19, 2016
Publication date	Apr 20, 2021
Grant date	Apr 20, 2021

Abstract

The present disclosure provides compounds of the formula (I), (II), (III), wherein the variables are as defined herein for use in the treatment of fungal infections. In some embodiments, the fungal infection is an infection of Cryptococcus neojormans fungus. Also provided herein are compositions comprising a compound of formula I, II, or III and a second anti-fungal agent.

First claim

What is claimed:

1. A method of treating a fungal infection in a patient comprising administering to the patient a therapeutically effective amount of a compound of the formula:

wherein:
R 1 and R 6 are each independently hydrogen, halo, or a group of the formula: —X—Y 1 , wherein:
X is C(O), O, S, or NR 1 ′, wherein:
R 1 ′ is hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , aryl (C≤8) , or substituted aryl (C≤8) ; and

Y 1 is hydrogen, hydroxy, or alkyl (C≤12) , aryl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , alkylsulfonyl (C≤12) , arylsulfonyl (C≤12) , or a substituted version of any of these groups;

R 2 and R 5 are each independently hydrogen, hydroxy, halo, alkyl (C≤12) , substituted alkyl (C≤12) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , alkenyl (C≤12) , substituted alkenyl (C≤12) , aryl (C≤12) , substituted aryl (C≤12) , aralkyl (C≤12) , substituted aralkyl (C≤12) , heteroaryl (C≤12) , substituted heteroaryl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , or a group of the formula: —C(O)Y 2 R 2 1 , wherein:
Y 2 is alkenediyl (C≤8) or substituted alkenediyl (C≤8) ; and
R 2 ′ is aryl (C≤12) , heteroaryl (C≤12) , arenediyl (C≤12) -O-aryl (C≤12) , or a substituted version of any of these groups; and

R 3 and R 4 are each independently hydrogen, hydroxy, halo, nitroso, alkyl (C≤12) , substituted alkyl (C≤12) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , alkenyl (C≤12) , substituted alkenyl (C≤12) , aryl (C≤18) , substituted aryl (C≤18) , heteroaryl (C≤18) , substituted heteroaryl (C≤18) , acyl (C≤18) , substituted acyl (C≤18) , amido (C≤18) , substituted amido (C≤18) , or C(O)R a or S(O) 2 R a wherein:
R a is alkyl (C≤18) , cycloalkyl (C≤18) , aryl (C≤18) , heteroaryl (C≤18) , alkoxy (C≤18) , aryloxy (C≤18) , -alkanediyl (C≤6) -cycloalkyl (C≤12) ; or a substituted version of any of these groups; or
R 2 and R 3 are taken together and are a compound of the formula:

wherein:
R b , R c , R d , and R e are each independently hydrogen, hydroxy, or alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , or a substituted version of any of these groups; or -alkanediyl (C≤6) -alkylamino (C≤8) , -alkane-diyl (C≤6) -dialkylamino (C≤8) , or a substituted version of either of these groups; or

R 1 and R 2 are taken together and are a compound of the formula:

wherein:
R f , R g , R h , and R i are each independently hydrogen, hydroxy, or alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , or a substituted version of any of these groups; or -alkanediyl (C≤6) -alkylamino (C≤8) , -alkane-diyl (C≤6) -dialkylamino (C≤8) , or a substituted version of either of these groups; or
R 3 and R 4 are taken together and are a compound of the formula:

wherein:
R j is hydrogen, hydroxy, halo, or alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , or a substituted version of any of these groups; or -alkanediyl (C≤6) -alkylamino (C≤8) , -alkane-diyl (C≤6) -dialkylamino (C≤8) , or a substituted version of either of these groups; or

a compound of the formula:

wherein:
R 7 is alkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups;
R 8 is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and
R 9 is hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;

a compound of the formula:

wherein:
R 10 is amino, hydroxy, or aryl (C≤18) , aralkyl (C≤18) , aryloxy (C≤18) , cycloalkylamino (C≤18) , aralkoxy (C≤18) , arylamino (C≤18) , aralkamino (C≤18) , diarylamino (C≤18) , diaralkamino (C≤18) , or a substituted version of any of these groups;
R 11 is hydrogen, acyl (C≤12) , or substituted acyl (C≤12) , or —C(O)R a ; wherein:
R a is amino, hydroxy, alkoxy (C≤8) , substituted alkoxy (C≤8) , alkylamino (C≤8) , substituted alkylamino (C≤8) , dialkylamino (C≤8) , or substituted dialkylamino (C≤8) ;

R 12 is hydrogen, alkoxy (C≤8) , or substituted alkoxy (C≤8) ;
R 13 is amino, cyano, halo, hydroxy, nitro, alkyl (C≤8) , substituted alkyl (C≤8) , acyl (C≤8) , substituted acyl (C≤8) , alkoxy (C≤8) , substituted alkoxy (C≤8) , acyloxy (C≤8) , substituted acyloxy (C≤8) , alkylamino (C≤8) , substituted alkylamino (C≤8) , dialkylamino (C≤8) , substituted dialkylamino (C≤8) , amido (C≤8) , or substituted amido (C≤8) ; and
n is 1, 2, or 3;

or a pharmaceutically acceptable salt or tautomer thereof;
wherein the compound is formulated as a pharmaceutical composition comprising the compound and an excipient, further wherein the pharmaceutical composition is formulated for oral administration, intraarterial administration, intravenous administration, parenteral administration, or for administration to the lungs;
provided that the compound is not thujaplicin when the fungal infection is a Candida albicans infection.

2. The method of claim 1 , wherein the compound is further defined as:

wherein:
R 1 and R 6 are each independently hydrogen, halo, or a group of the formula: —X—Y 1 , wherein:
X is O, S, or NR 1 ′, wherein:
R 1 ′ is hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , aryl (C≤8) , or substituted aryl (C≤8) ; and

Y 1 is hydrogen, or alkyl (C≤12) , aryl (C≤12) , acyl (C≤12) , alkylsulfonyl (C≤12) , arylsulfonyl (C≤12) , or a substituted version of any of these groups;

R 2 and R 5 are each independently hydrogen, hydroxy, halo, alkyl (C≤12) , substituted alkyl (C≤12) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C≤12) , substituted aryl (C≤12) , aralkyl (C≤12) , substituted aralkyl (C≤12) , heteroaryl (C≤12) , substituted heteroaryl (C≤12) , alkoxy (C≤12) , substituted alkoxy (C≤12) , acyl (C≤12) , substituted acyl (C≤12) ; and
R 3 and R 4 are each independently hydrogen, hydroxy, halo, nitroso, alkyl (C≤12) , substituted alkyl (C≤12) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , alkenyl (C≤12) , substituted alkenyl (C≤12) , aryl (C≤18) , substituted aryl (C≤18) , heteroaryl (C≤18) , substituted heteroaryl (C≤18) , acyl (C≤18) , substituted acyl (C≤18) , amido (C≤18) , substituted amido (C≤18) , or —C(O)R a , wherein:
R a is alkyl (C≤18) , cycloalkyl (C≤18) , aryl (C≤18) , heteroaryl (C≤18) , alkoxy (C≤18) , aryloxy (C≤18) , -alkanediyl (C≤6) -cycloalkyl (C≤12) ; or a substituted version of any of these groups; or
R 2 and R 3 are taken together and are a compound of the formula:

wherein:
R b , R c , R d , and R e are each independently hydrogen, hydroxy, or alkyl (C≤8) , cycloalkyl (C≤8) , alkenyl (C≤8) , or a substituted version of any of these groups; or -alkanediyl (C≤6) -alkylamino (C≤8) , -alkane-diyl (C≤6) -dialkylamino (C≤8) , or a substituted version of either of these groups; or

R 1 and R 2 are taken together and are a compound of the formula:

Assignees

• Univ Saint Louis
• Univ City New York Res Found

Inventors

• Donlin Maureen J
• Tavis John Edwin
• Murelli Ryan
• Meyers Marvin J

Classifications

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• A61K31/4409

  only substituted in position 4, e.g. isoniazid, iproniazid · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• C07C49/723

  polycyclic · CPC title

• A61P31/10

  Antimycotics · CPC title