Hybrid Amphotericin B derivatives with reduced toxicity

Patent metadata

Field	Value
Publication number	US-11198705-B2
Application number	US-201916563243-A
Country	US
Kind code	B2
Filing date	Sep 6, 2019
Priority date	Sep 7, 2018
Publication date	Dec 14, 2021
Grant date	Dec 14, 2021

Abstract

Disclosed are derivatives of amphotericin B (AmB) characterized by improved clinical efficacy with reduced toxicity compared to AmB. Also disclosed are pharmaceutical compositions comprising the AmB derivatives, therapeutic methods of using the AmB derivatives and methods of making 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 )—;
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;
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 4 is selected from the group consisting of secondary amino, tertiary amino, amido, azido, isonitrile, nitro, urea, isocyanate, carbamate, and guanidinyl; and
R 5 is selected from the group consisting of hydrogen, alkyl, and haloalkyl.

2. The compound of claim 1 , wherein the compound is represented by Formula (IV) or a pharmaceutically acceptable salt thereof:

wherein:
R 6 is C(O)OR f ; and
R f is selected from the group consisting of 2-alken-l-yl, tert-butyl, benzyl and fluorenylmethyl.

3. The compound of claim 1 , wherein:
—XR 1 is selected from the group consisting of

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

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

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

7. The compound of claim 1 , wherein —XR 1 is

8. The compound of claim 1 , wherein R 5 is hydrogen; and —XR 1 is

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

wherein, independently for each occurrence:
R 4 is selected from the group consisting of primary amino, secondary amino, tertiary amino, amido, azido, isonitrile, nitro, urea, isocyanate, carbamate, and guanidinyl; and
R 5 is selected from the group consisting of hydrogen, alkyl, and haloalkyl.

10. The compound of claim 9 , wherein the compound is represented by Formula (III) or a pharmaceutically acceptable salt thereof:

wherein:
R 6 is —C(O)OR f ; and
R f is selected from the group consisting of 2-alken-l-yl, tert-butyl, benzyl and fluorenylmethyl.

11. A pharmaceutical composition, comprising a compound of claim 1 ;
and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is an intravenous dosage form.

13. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is an oral dosage form.

14. A method of treating a fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , thereby treating the fungal infection.

15. The method of claim 14 , wherein the compound is administered intravenously.

16. The method of claim 14 , wherein the compound is administered orally.

17. A method of making a C16 urea derivative of C2′epi-Amphotericin B according to any one of the four transformations shown in Scheme 1:

wherein 1 represents

and
each instance of R is independently selected from the group consisting of hydrogen, halogen, straight- and branched-chain alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyl, sulfhydryl, carboxyl, amino, amido, azido, nitro, cyano, aminoalkyl, and alkoxyl.

Assignees

• Univ Illinois

Inventors

• Burke Martin D
• Khandelwal Anuj
• Zhang Jiabao
• Santamaria Anna

Classifications

• A61P31/10

  Antimycotics · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• C07H17/08

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

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• C07H17/00 Primary

  Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals · CPC title