Amphotericin B derivatives

Patent metadata

Field	Value
Publication number	US-9925275-B2
Application number	US-201715657649-A
Country	US
Kind code	B2
Filing date	Jul 24, 2017
Priority date	Aug 13, 2015
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

Embodiments of the invention provide derivatives of Amphotericin B having increased solubility and reduced toxicity relative to AMB, while retaining antifungal activity against multiple clinical fungal isolates. Derivatives of AMB are provided comprising a polymer group having an amine group, the polymer linked to mycosamine via a relatively stable linker such as an amide linker. The derivatives may be of the general formula [I]:

wherein R is H, C 1-4 alkyl or phenyl; R 2 is (CH 2 ) m wherein m is between 0 and 4; R 3 and R 4 are each independently H or C 1-4 alkyl, R 5 is or OH, R 6 is selected from a group consisting of: amide and alkyl, and R 7 is a water-soluble polymer, and pharmaceutically acceptable salts, solvates, hydrates, diastereomers, and prodrugs of the compound of Formula [I].

First claim

The invention claimed is:

1. A pharmaceutical composition comprising:
at least one compound according to Formula [I]

wherein R is H, C 1-4 alkyl or phenyl; R 2 is (CH 2 ) m wherein m is between 0 and 4; R 3 and R 4 are each independently H or C 1-4 alkyl, R 5 is H or OH, R 6 is selected from a group consisting of: amide and alkyl, and R 7 is a water-soluble PEG polymer having p PEG monomers, wherein p is from 6 to 40, or pharmaceutically acceptable salts, solvates, hydrates, and diastereomers thereof, including mixtures thereof in all ratios, and
a pharmaceutically acceptable carrier or diluent.

2. The pharmaceutical composition of claim 1 , wherein the diluent comprises at least 50% v/v water and the concentration of the at least one compound according to Formula [I] is at least 0.01 mg/ml.

3. A method for the treatment of a disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula [I]

wherein R is H, C 1-4 alkyl or phenyl; R 2 is (CH 2 ) m wherein m is between 0 and 4; R 3 and R 4 are each independently H or C 1-4 alkyl, R 5 is H or OH, R 6 is selected from a group consisting of: amide and alkyl, and R 7 is a water-soluble PEG polymer having p PEG monomers, wherein p is from 6 to 40, or pharmaceutically acceptable salts, solvates, hydrates, and diastereomers thereof, including mixtures thereof in all ratios.

4. The method according to claim 3 , wherein the disease is selected from the group consisting of: a fungal disease, a protozoan disease, a viral disease and a prion disease.

5. The method of claim 3 , wherein the disease is a fungal disease.

6. The method of claim 5 , wherein the fungal disease is of a fungus selected from the group consisting of Aspergillus, Candida, Cryptococcus and Pneumocystis.

7. The method of claim 3 , wherein the compound of Formula I is administered at a dosage of between 0.5 milligrams per kilogram bodyweight (mg/kg) and 10.0 mg/kg per day.

8. The method of claim 7 , wherein the daily dosage is between 0.5 mg/kg and 4.0 mg/kg daily.

9. The pharmaceutical composition according to claim 1 , wherein the amide is selected from a group consisting of: organic amide, sulfonamide, sulfenyl amide and phosphoramide.

10. The pharmaceutical composition according to claim 1 , wherein p is from 6 to 10.

11. The method of claim 3 , wherein the disease is a protozoan disease.

12. The method of claim 11 , wherein the protozoan disease is leishmaniasis.

Assignees

• Univ Ramot
• Technion Res & Dev Foundation

Inventors

• Benhar Itai
• Osherov Nir
• DERGACHEV Vladimir
• SZPILMAN Alex Martin

Classifications

• C08G65/333

  containing nitrogen · CPC title

• C08G65/08

  Saturated oxiranes · CPC title

• C08G65/3322

  acyclic · CPC title

• C08G65/3314

  cyclic · CPC title

• C07H17/08

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