Anti-fungals compounds targeting the synthesis of fungal sphingolipids

Patent metadata

Field	Value
Publication number	US-11414378-B2
Application number	US-201816622431-A
Country	US
Kind code	B2
Filing date	Jun 15, 2018
Priority date	Jun 16, 2017
Publication date	Aug 16, 2022
Grant date	Aug 16, 2022

Abstract

The present invention provides a compound having the structure:

and use of the compound for inhibiting the growth of or killing a fungus.

First claim

What is claimed is:

1. A compound having the structure:

wherein
R 1 is —H, alkyl, alkenyl, or alkynyl;
R 2 is —H, alkyl, alkenyl, or alkynyl;
R 6 is —H, halogen, C 1 -C 6 alkyl, —OH, —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 ;
R 3 , R 4 , and R 5 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 , or
R 3 and R 4 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 , and R 5 and R 6 combine to form a fused aryl or fused heteroaryl, which are each unsubstituted or substituted, or
R 3 and R 6 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 , and R 4 and R 5 combine to form a fused aryl or fused heteroaryl, which are each unsubstituted or substitute, or
R 5 and R 6 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 , and R 3 and R 4 combine to form a fused aryl or fused heteroaryl, which are each unsubstituted or substituted; and
A is a substituted monocyclic aryl or a substituted monocyclic heteroaryl, wherein the substitution is with halogen, alkynyl, alkoxy, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 , —OCF 3 , —CN, —CH 2 OCH 3 , —N(CH 3 ) 2 , —CH 2 F, —N 3 or —CCH, or an unsubstituted or substituted bicyclic aryl or bicyclic heteroaryl, or

wherein when R 3 , R 4 and R 6 are each —H and R 5 is —OH or —OCH 3 , or R 3 , R 5 and R 6 are each —H and R 4 is —Br, then A is other than ortho-tolyl or meta-bromophenyl,
or a pharmaceutically acceptable salt or ester thereof.

2. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt or ester thereof.

3. A method of inhibiting the growth of a fungus, or inhibiting fungal sphingolipid synthesis in a fungus, or inhibiting fungal sphingolipid synthesis in a fungus in a mammal without substantially inhibiting mammalian sphingolipid synthesis, comprising contacting the fungus with an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or ester thereof, so as to thereby inhibit the growth of the fungus, or inhibit fungal sphingolipid synthesis in a fungus, or inhibit fungal sphingolipid synthesis in a fungus in a mammal without substantially inhibiting mammalian sphingolipid synthesis.

4. The method of claim 3 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

5. The method of claim 3 , wherein the amount of the compound and the amount of the anti-fungal agent when taken together is more effective to inhibit the growth of the fungus than the anti-fungal agent alone, more effective to inhibit fungal sphingolipid synthesis than the anti-fungal agent alone, or more effective to inhibit fungal sphingolipid synthesis without substantially inhibiting mammalian sphingolipid synthesis in the mammal than the anti-fungal agent alone.

6. A method of inhibiting the growth of or killing a fungus in a subject or treating a subject afflicted with a fungal infection comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or ester thereof, so as to thereby inhibiting the growth of or kill the fungus in the subject or treat the subject afflicted with the fungal infection.

7. The compound of claim 1 having the structure:

wherein
R 1 is —H, alkenyl, or alkynyl;
R 2 is —H, alkyl, alkenyl, or alkynyl;
R 5 is halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 ;
R 6 is —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 ;
R 3 and R 4 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 , or
R 3 and R 4 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 , and R 5 and R 6 combine to form a fused aryl or fused heteroaryl, which are each unsubstituted or substituted, or
R 3 and R 6 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 , and R 4 and R 5 combine to form a fused aryl or fused heteroaryl, which are each unsubstituted or substitute, or
R 5 and R 6 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 , and R 3 and R 4 combine to form a fused aryl or fused heteroaryl, which are each unsubstituted or substituted; and
A is a substituted monocyclic aryl or a substituted monocyclic heteroaryl, wherein the substitution is with alkynyl, alkoxy, —O—(C 1 -C 6 alkyl), —CHF 2 , —OCHF 2 , —OCF 3 , —CN, —CH 2 OCH 3 , —N(CH 3 ) 2 , —CH 2 F, —N 3 or —CCH, or an unsubstituted or substituted bicyclic aryl or bicyclic heteroaryl, wherein the substitution is with halogen, alkynyl, alkoxy, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 , —OCF 3 , —CN, —CH 2 OCH 3 , —N(CH 3 ) 2 , —CH 2 F, —N 3 or —CCH; or A is

wherein when R 3 , R 4 and R 6 are each —H and R 5 is —OH or —OCH 3 , then A is other than ortho-tolyl or meta-bromophenyl,
or a pharmaceutically acceptable salt or ester thereof.

8. The compound of claim 7 ,
wherein the monocyclic or bicyclic aryl or heteroaryl is substituted with —O—(C 1 -C 6 alkyl), —CHF 2 , —OCHF 2 or —OCF 3 ; or
wherein the fused aryl or fused heteroaryl is substituted with halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 ; or
wherein one of R 3 -R 6 is other than —H; or
wherein two of R 3 -R 6 is other than —H.

9. The compound of claim 7 ,
wherein R 3 , R 4 and R 6 are each independently —H, halogen, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl), —CHF 2 , —CF 3 , —OCHF 2 or —OCF 3 ; or
wherein R 3 , R 4 and R 6 are each independently halogen, —O—

Assignees

• Univ New York State Res Found

Inventors

• Ojima Iwao
• Del Poeta Maurizio
• Lazzarini Cristina
• Haranahalli Krupanandan
• Sun Yi

Classifications

• A61K31/195

  having an amino group · CPC title

• A01N37/28

  containing the group [IMAGE cpc-sch-A01N-0937.gif]; Thio analogues thereof · CPC title

• C07C251/86 Primary

  having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07D213/86

  Hydrazides; Thio or imino analogues thereof · CPC title

• C07D239/30

  Halogen atoms or nitro radicals · CPC title