Amphotericin B derivatives

Patent metadata

Field	Value
Publication number	US-9750817-B2
Application number	US-201615236875-A
Country	US
Kind code	B2
Filing date	Aug 15, 2016
Priority date	Aug 13, 2015
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

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 H 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 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, and pharmaceutically acceptable salts, solvates, hydrates, and diastereomers of the compound of Formula [I].

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

3. The compound according to claim 1 , wherein p is from 6 to 10.

4. The compound according to claim 1 , the compound being according to formula [II]:

wherein R is H, C 1-4 alkyl or phenyl; R 2 is (CH 2 ) m , wherein m is between 1 and 4; R 3 and R 4 are each independently H or C 1-4 alkyl, R 5 is H or OH, and n is between 5 and 39, and pharmaceutically acceptable salts, solvates, hydrates, and diastereomers of the compound of Formula [II].

5. The compound according to claim 4 , wherein n is between 5 and 9.

6. The compound according to claim 4 , wherein R is H, R 2 is ethyl; R 3 and R 4 are each H, R 5 is OH and n is 7.

7. The compound according to claim 4 , wherein R is methyl, R 2 is ethyl; R 3 and R 4 are each H, R 5 is OH and n is 7.

8. A process for the preparation of the compound according to claim 4 , the process comprising:
reacting Amphotericin B with a protected N-hydroxysuccinimide ester of PEG, and
removing the protection.

9. The process of claim 8 , wherein the reaction is performed under one or more of the following conditions:
the N-hydroxysuccinimide ester of PEG is protected by a FMOC group;
reactants Amphotericin B and/or the protected N-hydroxysuccinimide ester of PEG are solutes in a non-aqueous solvent;
the reaction is performed in the presence of a tertiary amine;
the reaction is performed under an inert atmosphere;
the reaction is performed in a light-free environment;
a reaction mixture comprising Amphotericin B and the protected N-hydroxysuccinimide ester of PEG is stirred for at least an hour; and
a reaction product is isolated from the reaction mixture; by passing the reaction mixture via a chromatographic column.

10. The process of claim 9 , wherein the removal of the protecting group is by hydrolysis.

11. The process of claim 10 , wherein the removal is carried out in the presence of a weak base.

12. A pharmaceutical composition comprising:
at least one compound according to formula [II]

wherein R is H, C 1-4 alkyl or phenyl; R 2 is (CH 2 ) m wherein m is between 1 and 4; R 3 and R 4 are each independently H or C 1-4 alkyl, R 5 is H or OH, and n is between 5 and 39, and pharmaceutically acceptable salts, solvates, hydrates, and diastereomers thereof, including mixtures thereof in all ratios, and
a pharmaceutically acceptable carrier or diluent.

13. The pharmaceutical composition of claim 12 , wherein the diluent comprises at least 50% v/v water and the concentration of the at least one compound according to formula [II] is at least 0.01 mg/ml.

14. 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 according to formula [II]

wherein R is H, C 1-4 alkyl or phenyl; R 2 is (CH 2 ) m wherein m is between 1 and 4; R 3 and R 4 are each independently H or C 1-4 alkyl, R 5 is H or OH, and n is between 5 and 39, and pharmaceutically acceptable salts, solvates, hydrates, and diastereomers thereof, including mixtures thereof in all ratios.

15. The method according to claim 14 , wherein the disease is selected from the group consisting of: a fungal disease, a protozoan disease, a viral disease and a prion disease.

16. The method of claim 14 , wherein the disease is a fungal disease.

17. The method of claim 16 , wherein the fungal disease is of a fungus selected from the group consisting of one or two or more of: Aspergillus, Candida, Cryptococcus and Pneumocystis.

18. The method of claim 14 , wherein the compound of formula II is administered at a dosage of between 0.5 milligrams per kilogram bodyweight (mg/kg) and 10.0 mg/kg per day.

19. The method of claim 18 , wherein the daily dosage is between 0.5 mg/kg and 4.0 mg/kg daily.

Assignees

• Ramot At Tel-Aviv Univ Ltd
• Technion Res & Dev Foundation

Inventors

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

Classifications

• C08G65/3314

  cyclic · CPC title

• C08G65/3322

  acyclic · CPC title

• A61K47/48215 Primary

  Human Necessities · mapped topic

• C08G65/08

  Saturated oxiranes · CPC title

• C08G65/333

  containing nitrogen · CPC title