# US 2014/0155348 A1 · Inclusion Compounds of Fumagillol Derivative or its Salt, and Pharmaceutical Compositions Comprising the Same

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- Number: US 2014/0155348 A1
- Document ID: US20140155348A1
- Status: Published application
- Kind: A1
- Application number: 13/924,768
- Filed: 2013-06-24
- Published: 2014-06-05
- Earliest claimed: 2002-03-28
- Assignees: Zafgen, Inc.
- Inventors: Jae Hyun Kim; Su Kyung Lee; Won Kyu Choi; Jong Lae Lim; Soon Kil Ahn; Hee Jong Shin; Chung Il Hong
- Web page: https://patentgrep.com/patent/US20140155348A1

## CPC

- A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)}
- A61K 9/0019: {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)}
- A61K 31/336: having three-membered rings, e.g. oxirane, fumagillin
- A61K 47/02: Inorganic compounds
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- C07D 303/16: by esterified hydroxyl radicals
- C07D 303/20: Ethers with hydroxy compounds containing no oxirane rings
- C07D 303/28: Ethers with hydroxy compounds containing oxirane rings
- C07D 407/14: containing three or more hetero rings
- C08B 37/0015: {Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes}
- C08L 5/16: Cyclodextrin; Derivatives thereof
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

The present invention relates to an inclusion compound of fumagillol derivative or its salt with hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin, and pharmaceutical compositions comprising the same. The inclusion compound according to the present invention has superior water solubility and stability while exhibiting low toxicity, rendering it valuable as an anticancer agent or inhibitor of tumor metastasis.

## Claims

### Claim 1

An inclusion compound of fumagillol derivative of the following Formula 1 or its salt with hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin
Wherein,
X is hydroxy, Y is halogen, or X and Y together forms oxirane ring;
B is O or H2; and
R1, R2, R3, R4 and R5 independently represent hydrogen, hydroxy, acetoxy, C1-C6 alkyl, C1-C6 alkoxy, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, halogen, cyano, trifluoromethyl, nitro, formyl, acetamido, methyleneoxycarboxy, methylenedioxy or ethylenedioxy group,
provided that R1, R2, R3, R4 and R5 cannot be hydrogen at the same time.

### Claim 2 (depends on 1)

The inclusion compound in claim 1 characterized in that said fumagillol derivative or its salt is the following compounds:
O-(4-chlorocinnamoyl)fumagillol;
O-(4-aminocinnamoyl)fumagillol;
O-(4-dimethylaminoethoxycinnamoyl)fumagillol;
O-(4-methoxycinnamoyl)fumagillol;
O-(4-dimethylaminocinnamoyl)fumagillol;
O-(4-hydroxycinnamoyl)fumagillol;
O-(3,4-dimethoxycinnamoyl)fumagillol;
O-(3,4-methylenedioxycinnamoyl)fumagillol;
O-(3,4,5-trimethoxycinnamoyl)fumagillol;
O-(4-nitrocinnamoyl)fumagillol;
O-(3,4-dimethoxy-6-aminocinnamoyl)fumagillol;
O-(4-acetoxy-3,5-dimethoxycinnamoyl)fumagillol;
O-(4-ethylaminocinnamoyl)fumagillol;
O-(4-ethylaminoethoxycinnamoyl)fumagillol;
O-(3-dimethylaminomethyl-4-methoxycinnamoyl)fumagillol;
O-(4-trifluoromethylcinnamoyl)fumagillol;
O-(3,4-dimethoxy-6-nitrocinnamoyl)fumagillol;
O-(4-acetoxycinnamoyl)fumagillol;
O-(4-cyanocinnamoyl)fumagillol;
4-(4-methoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
O-(3,4,5-trimethoxycinnamyl)fumagillol;
O-(4-dimethylaminocinnamyl)fumagillol;
O-(3,4,5-trimethoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
O-(4-dimethylaminocinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
O-(3,5-dimethoxy-4-hydroxycinnamoyl)fumagillol; or a salt thereof.

### Claim 3 (depends on 1)

The inclusion compound in claim 1 characterized in that said fumagillol derivative or its salt is the following compounds:
(4-methoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
O-(4-methoxycinnamoyl)fumagillol;
O-(3,5-dimethoxy-4-hydroxycinnamoyl)fumagillol;
O-(4-dimethylaminoethoxycinnamoyl)fumagillol;
O-(3,4,5-trimethoxycinnamoyl)fumagillol;
O-(3,4-dimethoxy-6-aminocinnamoyl)fumagillol; or a salt thereof.

### Claim 4 (depends on 1)

The inclusion compound in claim 1 characterized in that said fumagillol derivative or its salt is O-(4-dimethylaminoethoxycinnamoyl)fumagillol or O-(3,4,5-trimethoxycinnamoyl)fumagillol.

### Claim 5 (depends on 1)

The inclusion compound of claim 1 characterized in that said fumagillol derivative salt is selected from a group consisting of salts of fumagillol derivative with hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, fumaric acid, tartaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid.

### Claim 6 (depends on 1)

The inclusion compound in claim 1 characterized in preparing by dissolving hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin in distilled water, and adding fumagillol derivative or its salt under stirring.

### Claim 7 (depends on 1)

The inclusion compound in claim 1 characterized in that the inclusion compound is prepared by dissolving hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin in distilled water, and adding fumagillol derivative or its salt under stirring after adjusting the solution pH in a range of 6-8 with dilute hydrochloric acid or sodium hydroxide solution.

### Claim 8 (depends on 1)

The inclusion compound in claim 1 characterized in that the inclusion compound is prepared by dissolving hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin in buffer solution which pH was pre-adjusted in a range of 6-8 with phosphate, and adding fumagillol derivative or its salt under stirring.

### Claim 9 (depends on 6)

The inclusion compound in claim 6 characterized in that the inclusion compound is obtained by further lyophilization step for the final solution obtained after stirring.

### Claim 10 (depends on 6)

The inclusion compound in claim 6 characterized in that molar ratio of fumagillol derivative or its salt to hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin is 1:1 to 1:10.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the inclusion compound in claim 1 and pharmaceutically acceptable additives.

### Claim 12 (depends on 11)

The pharmaceutical composition in claim 11 characterized in that the pharmaceutically acceptable additive is at least one selected from a group consisting of pharmaceutically acceptable diluents, buffers, flavors, binders, thickening agent, lubricants and preservatives.

### Claim 13 (depends on 12)

The pharmaceutical composition in claim 12 characterized in that said buffer is phosphate buffer.

### Claim 14 (depends on 11)

The pharmaceutical composition in claim 11 characterized in that it is formulated in oral or parenteral preparation.

### Claim 15 (depends on 14)

The pharmaceutical composition in claim 14 characterized in that said parenteral preparation is injection.

### Claim 16 (depends on 11)

The pharmaceutical composition in claim 11 characterized in that it is formulated in sustained-release dosage form.

### Claim 17 (depends on 1)

An anti-tumor agent comprising the inclusion compound of claim 1 as active component.

### Claim 18 (depends on 1)

A tumor metastasis inhibitor comprising the inclusion compound of claim 1 as active component.