# US 10,245,270 B2 · Salt of 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, its preparation, and formulations containing it

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- Number: US 10,245,270 B2
- Document ID: US10245270B2
- Status: Granted
- Kind: B2
- Application number: 16/120,797
- Filed: 2018-09-04
- Published: 2018-12-27
- Granted: 2019-04-02
- Earliest claimed: 2013-07-12
- Assignees: Les Laboratoires Servier
- Applicants: Les Laboratoires Servier
- Inventors: Alexandre Le Flohic; Jérôme Guidotti; Philippe Letellier
- Web page: https://patentgrep.com/patent/US10245270B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 417/14: containing three or more hetero rings
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione methanesulphonate of formula (II): Medicinal products containing the same which are useful in treating cancer.

## Claims

### Claim 1

E isomer of 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione methanesulphonate of formula (II):
having an X-ray powder diffractogram which exhibits the Bragg's angles 2 theta (expressed in terms of °+0.2) 7.55; 10.42; 14.84; 15.06; 15.25; 15.80; 16.81; 17.01; 17.95; 19.06; 20.00; 20.29; 21.88; 23.87; 24.31; 24.64; 26.13; 26.59.

### Claim 2 (depends on 1)

A process for obtaining the compound of formula (II) according to claim 1, wherein 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione is dissolved in a binary system of solvent/water, to which solution from 1 to 2 molar equivalents of methanesulphonic acid are added, stirring until the methanesulphonate precipitates out, which precipitate is filtered off.

### Claim 3 (depends on 1)

A process for obtaining the compound of formula (II) according to claim 1, wherein 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione hydrochloride is dissolved in a binary system of solvent/water, the pH of which solution is brought to 8 by adding a base, the resulting salt is removed by filtration, the filtrate is then heated and the methanesulphonic acid added, and the medium is stirred and cooled until the methanesulphonate precipitates out, which precipitate is filtered off.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising the compound of formula (II) according to claim 1 in combination with one or more pharmaceutically acceptable excipients.

### Claim 5 (depends on 1)

A method of treating a condition selected from cancers of the colon, breast, liver, kidneys, brain and esophagus, melanomas, myelomas, ovarian cancers, non-small-cell lung cancers, small-cell lung cancers, prostate and pancreatic cancers, and sarcomas in a subject in need thereof, comprising administration of a compound of formula II according to claim 1 to said subject, optionally in combination with one or more pharmaceutically acceptable excipients.

### Claim 6 (depends on 1)

A combination of the compound of formula (II) according to claim 1 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors and kinase inhibitors.

### Claim 7 (depends on 6)

A method of treating cancer in a subject in need thereof, comprising administration of the combination according to claim 6 to said subject.

### Claim 8 (depends on 1)

A method of treating cancer in a subject in need thereof, comprising administration of the compound of formula (II) according to claim 1 to said subject in combination with radiotherapy.