# US 10,370,404 B2 · Protoescigenin derivative, process of its preparation, use of said compound and pharmaceutical composition comprising that compound

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

- Number: US 10,370,404 B2
- Document ID: US10370404B2
- Status: Granted
- Kind: B2
- Application number: 15/553,301
- Filed: 2016-02-26
- Published: 2018-08-30
- Granted: 2019-08-06
- Earliest claimed: 2015-02-27
- Assignees: Warszawski Uniwersytet Medyczny
- Applicants: Warszawski Uniwersytet Medyczny
- Inventors: Katarzyna Koziak; Krzysztof Bojakowski; Magdalena Kowalewska; Dorota Maciejko; Oliwia Zegrocka-Stendel; Iwona Grabowska; Grzegorz Grynkiewicz; Mariusz Marek Gruza; Kamil Jatczak; Katarzyna Filip; Piotr Cmoch; Marta Laszcz; Malgorzata Dutkiewicz
- Web page: https://patentgrep.com/patent/US10370404B2

## CPC

- C07J 63/008: {Expansion of ring D by one atom, e.g. D homo steroids}
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C07J: STEROIDS (seco-steroids C07C)
- 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

## Abstract

Described herein is compound including a protoescigenin derivative having pharmacological properties. Also described are a process of its preparation, and the use of such a compound as a medicament, especially for treating vascular disorders. A pharmaceutical composition comprising such compound is further described.

## Claims

### Claim 1

A compound of formula (I)
and its salts.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein a salt of the compound of formula (I) is a sodium salt.

### Claim 3 (depends on 1)

A process for preparation of the compound according to claim 1, comprising:
a) coupling of 3,24; 16,22-O, O-diisopropylidene-28-O-propargylprotoescigenin of formula (II)
with 4-azidobenzoic acid of formula (III)
in presence of copper (I) cations generated in situ from copper (II) cation in
tetrahydrofuran or its mixtures with water,
b) isolation of 28-O-[(1-(4-carboxyphenyl)-1H[1,2,3]triazol-4-yl)methyl]-3,24; 16,22-O,O-diisopropylideneprotoescigenin of formula (IV)
from the reaction mixture,
c) purification of 28-O-[(1-(4-carboxyphenyl)-1H[1,2,3]triazol-4-yl)methyl]-3,24; 16,22-O,O-diisopropylideneprotoescigenin,
d) preparation of solution or suspension of 28-O-[(1-(4-carboxyphenyl)-1H[1,2,3]triazol-4-yl)methyl]-3,24;16,22-O,O-diisopropylideneprotoescigenin in solvent selected from group comprising C1-C3 alcohol and acetone,
e) reaction with organic acid or inorganic acid and obtaining the compound of formula (I),
f) isolation of the compound of formula (I),
g) optional purification of the compound of formula (I), and/or optional transformation of the compound of formula (I) into its salt.

### Claim 4 (depends on 3)

The process according to claim 3, wherein copper (I) cations generated in situ from copper (II) cations are obtained by reduction reaction using sodium ascorbate.

### Claim 5 (depends on 4)

The process according to claim 4, wherein CuSO4 is used as source of copper (II) cations.

### Claim 6 (depends on 4)

The process according to claim 4, wherein the purification of 28-O-[(1-(4-carboxyphenyl)-1H[1,2,3]triazol-4-yl)methyl]-3,24;16,22-O,O-diisopropylideneprotoescigenin in step c) is carried out by maceration of said compound in methanol at a temperature ranging from 15° C. to 40° C.

### Claim 7 (depends on 3)

The process according to claim 3, wherein methanol is used in step d) and p-toluenesulfonic acid is used in step e).

### Claim 8 (depends on 3)

The process according to claim 3, wherein step e) is carried out at a temperature ranging from 15° C. to 60° C.

### Claim 9 (depends on 3)

The process according to claim 3, wherein the optional purification in step g) is carried out in MeOH, THF, acetone or mixtures thereof.

### Claim 10 (depends on 1)

The compound of claim 1, for use as a medicament.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1.

### Claim 12 (depends on 11)

The pharmaceutical composition according to claim 11, in a formulation suitable for intravenous, oral, rectal or transdermal administration.

### Claim 13 (depends on 11)

The pharmaceutical composition according to claim 11, further comprising an additional active agent.

### Claim 14 (depends on 4)

The process according to claim 4, wherein the purification of 28-O-[(1-(4-carboxyphenyl)-1H[1,2,3]triazol-4-yl)methyl]-3,24;16,22-O,O-diisopropylideneprotoescigenin in step c) is carried out by maceration of said compound in methanol at a temperature ranging from 20° C. to 25° C.

### Claim 15 (depends on 3)

The process according to claim 3, wherein step e) is carried out at a temperature ranging from 20° C. to 25° C.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, further comprising auxiliary agents.

### Claim 17 (depends on 1)

A method for treating a vascular disorder in a subject, the method comprising administering to the subject the compound of claim 1.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the vascular disorder is selected from the group consisting of venous insufficiency, edema, consequences of ischemia or muscles ischemia/reperfusion, pathological consequences of the presence of arteriovenous fistulas and vascular malformations.