Derivatives of amphotericin B

Patent metadata

Field	Value
Publication number	US-9957290-B2
Application number	US-201615099837-A
Country	US
Kind code	B2
Filing date	Apr 15, 2016
Priority date	Apr 15, 2015
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

Disclosed are derivatives of amphotericin B (AmB) characterized by improved therapeutic index compared to AmB. The AmB derivatives include C16 ureas, carbamates, and amides according to Formula (I); C3′-substituted C16 ureas, carbamates, and amides according to Formula (II); C16 acyls according to Formula (III); C2′epi-C16 ureas, carbamates, and amides according to Formula (IV); and C16 oxazolidinone derivatives according to Formula (V). Also disclosed are pharmaceutical compositions comprising the AmB derivatives, and therapeutic methods of using the AmB derivatives.

First claim

We claim:

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:
X is —N(R 2 )—, —C(R 3 )(R 3 )—, or —O—;
R 2 is hydrogen or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl;
R 3 is hydrogen, halogen, hydroxyl, sulfhydryl, nitro, cyano, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, carboxyl, acyl, acyloxy, amino, amido, azido, aminoalkyl, and alkoxyl;
R 5 is selected from the group consisting of hydrogen, alkyl, and haloalkyl;
when X is —N(R 2 )—, R 1 is a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl; or R 1 and R 2 , together with the nitrogen to which they are attached, may form a substituted or unsubstituted 3- to 10-membered heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic;
when X is —C(R 3 )(R 3 )—, R 1 is hydrogen, halogen, hydroxyl, sulfhydryl, nitro, cyano, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, carboxyl, acyl, acyloxy, amino, amido, azido, aminoalkyl, and alkoxyl; or the two instances of R 3 , together with the carbon to which they are attached, may form a substituted or unsubstituted 3- to 10-membered aliphatic or heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic; and
when X is —O—, R 1 is a substituted or unsubstituted group selected from the group consisting of alkyl, alkenyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, and aminoalkyl;
provided that when R 5 is hydrogen, —XR 1 is not —N(H)CH 3 , —N(H)(CH 2 ) 2 NH 2 , —N(H)(CH 2 ) 2 COOH, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH(CH 3 ) 2 ) 2 ,

2. The compound of claim 1 , wherein X is —N(R 2 )—.

3. A compound represented by Formula (II) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:
X is —N(R 2 )—, —C(R 3 )(R 3 )—, or —O—;
R 2 is hydrogen or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl;
R 3 is hydrogen, halogen, hydroxyl, sulfhydryl, nitro, cyano, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, carboxyl, acyl, acyloxy, amino, amido, azido, aminoalkyl, and alkoxyl;
when X is —N(R 2 )—, R 1 is a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl; or R 1 and R 2 , together with the nitrogen to which they are attached, may form a substituted or unsubstituted 3- to 10-membered heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic;
when X is —C(R 3 )(R 3 )—, R 1 is hydrogen, halogen, hydroxyl, sulfhydryl, nitro, cyano, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, carboxyl, acyl, acyloxy, amino, amido, azido, aminoalkyl, and alkoxyl; or the two instances of R 3 , together with the carbon to which they are attached, may form a substituted or unsubstituted 3- to 10-membered aliphatic or heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic;
when X is —O—, R 1 is a substituted or unsubstituted group selected from the group consisting of alkyl, alkenyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, and aminoalkyl;
R 4 is secondary amino, tertiary amino, amido, azido, isonitrile, nitro, urea, isocyanate, carbamate, or guanidinyl; and
R 5 is selected from the group consisting of hydrogen, alkyl, and haloalkyl.

4. The compound of claim 3 , wherein X is —N(R 2 )—.

5. The compound of claim 3 , wherein R 4 is selected from the group consisting of

wherein
R a is hydrogen or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl.

6. A compound represented by Formula (III) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:
X 1 is —N(R 6 )(R 7 ), —OR 8 , or —R 9 ;
R 6 and R 7 are independently hydrogen or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl; or, R 6 and R 7 , together with the nitrogen to which they are attached, may form a substituted or unsubstituted 3- to 10-membered heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic;
R 8 is a substituted or unsubstituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, and aminoalkyl;
R 9 is hydrogen, halogen, hydroxyl, sulfhydryl, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, carboxyl, acyl, acyloxy, amino, amido, aminoalkyl, and alkoxyl; and
R 4 is secondary amino, tertiary amino, amido, azido, isonitrile, nitro, urea, isocyanate, carbamate, or guanidinyl; and
R 5 is selected from the group consisting of hydrogen, alkyl, and haloalkyl.

7. The compound of claim 6 , wherein R 4 is selected from the group consisting of

wherein
R a is hydrogen or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl.

8. The compound of claim 6 , wherein X 1 is —N(R 6 )(R 7 ); and R 7 is hydrogen.

9. A compound represented by Formula (IV) or a pharmaceutically acceptable salt thereof:

Assignees

• Revolution Medicines Inc
• Sfunga Therapeutics Inc

Inventors

• Burke Martin D
• Thottumkara Arun P
• Mellem Kevin T
• Sweeney Zachary K
• Koltun Elena S

Classifications

• A61P31/10

  Antimycotics · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07H17/08 Primary

  Hetero rings containing eight or more ring members, e.g. erythromycins · CPC title

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• A61K31/7034

  attached to a carbocyclic compound, e.g. phloridzin · CPC title