# US 9,750,817 B2 · Amphotericin B derivatives

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,750,817 B2
- Document ID: US9750817B2
- Status: Granted
- Kind: B2
- Application number: 15/236,875
- Filed: 2016-08-15
- Published: 2017-02-16
- Granted: 2017-09-05
- Earliest claimed: 2015-08-13
- Assignees: Ramot at Tel-Aviv University Ltd.; Technion Research & Development Foundation Limited
- Applicants: Ramot at Tel-Aviv University Ltd.; Technion Research & Development Foundation Ltd.
- Inventors: Itai Benhar; Nir Osherov; Vladimir Dergachev; Alex Martin Szpilman
- Web page: https://patentgrep.com/patent/US9750817B2

## CPC

- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- C07H 17/08: Hetero rings containing eight or more ring members, e.g. erythromycins
- C08G 65/08: Saturated oxiranes
- C08G 65/329: with organic compounds
- C08G 65/3312: {acyclic}
- C08G 65/3314: {cyclic}
- C08G 65/3322: {acyclic}
- C08G 65/333: containing nitrogen
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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, C1-4 alkyl or phenyl; R2 is (CH2)m wherein m is between 0 and 4; R3 and R4 are each independently H or C1-4 alkyl, R5 is H or OH, R6 is selected from a group consisting of: amide and alkyl, and R7 is a water-soluble polymer, and pharmaceutically acceptable salts, solvates, hydrates, diastereomers, and prodrugs of the compound of Formula [I].

## Claims

### Claim 1

A compound according to formula [I]:
wherein R is H, C1-4 alkyl or phenyl; R2 is (CH2)m wherein m is between 0 and 4; R3 and R4 are each independently H or C1-4 alkyl, R5 is H or OH, R6 is selected from a group consisting of: amide and alkyl, and R7 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].

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

The compound according to claim 1, the compound being according to formula [II]:
wherein R is H, C1-4 alkyl or phenyl; R2 is (CH2)m, wherein m is between 1 and 4; R3 and R4 are each independently H or C1-4 alkyl, R5 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].

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 4)

The compound according to claim 4, wherein R is H, R2 is ethyl; R3 and R4 are each H, R5 is OH and n is 7.

### Claim 7 (depends on 4)

The compound according to claim 4, wherein R is methyl, R2 is ethyl; R3 and R4 are each H, R5 is OH and n is 7.

### Claim 8 (depends on 4)

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.

### Claim 9 (depends on 8)

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.

### Claim 10 (depends on 9)

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

### Claim 11 (depends on 10)

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

### Claim 12

A pharmaceutical composition comprising:
at least one compound according to formula [II]
wherein R is H, C1-4 alkyl or phenyl; R2 is (CH2)m wherein m is between 1 and 4; R3 and R4 are each independently H or C1-4 alkyl, R5 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.

### Claim 13 (depends on 12)

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.

### Claim 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, C1-4 alkyl or phenyl; R2 is (CH2)m wherein m is between 1 and 4; R3 and R4 are each independently H or C1-4 alkyl, R5 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.

### Claim 15 (depends on 14)

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.

### Claim 16 (depends on 14)

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

### Claim 17 (depends on 16)

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.

### Claim 18 (depends on 14)

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.

### Claim 19 (depends on 18)

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