WO2018047131A1

WO2018047131A1 - Amorphous eluxadoline

Info

Publication number: WO2018047131A1
Application number: PCT/IB2017/055467
Authority: WO
Inventors: Sriram Hari MOHAN; Anu Arya; Ketan HIRPARA; Mukesh Kumar Madhra
Original assignee: Sun Pharmaceutical Industries Limited
Priority date: 2016-09-09
Filing date: 2017-09-11
Publication date: 2018-03-15

Abstract

The present invention relates to amorphous eluxadoline, processes for its preparation, a pharmaceutical composition comprising the amorphous eluxadoline, and its use for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

Description

AMORPHOUS ELUXADOLINE

Field of the Invention

Background of the Invention

Eluxadoline chemically is 5-[[[(25)-2-amino-3-[4-(aminocarbonyl)-2,6- dimethylphenyl] - 1 -oxopropyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino]methyl]-2- methoxybenzoic acid, represented by Formula I.

Formula I

Eluxadoline is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

U.S. Patent No. 7,741,356 describes a process for the preparation of eluxadoline.

U.S. Patent Nos. 7,629,488 and 8,710,256 describe processes for the preparation of intermediates of eluxadoline.

PCT Publication No. WO2009/009480 allegedly discloses Form a and Form β crystals of eluxadoline and processes thereof.

There is a need in the art to develop a new polymorphic form of eluxadoline.

Summary of the Invention

The present invention relates to amorphous eluxadoline, processes for its preparation, a pharmaceutical composition comprising the amorphous eluxadoline, and its use for the treatment of irritable bowel syndrome with diarrhea (IBS-D). The amorphous eluxadoline obtained by the process of the present invention is stable.

Brief Description of the Drawings

Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of amorphous eluxadoline.

Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of amorphous eluxadoline.

Figure 3 depicts an Infra-red (IR) spectrum of amorphous eluxadoline.

Detailed Description of the Invention

The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

The term "room temperature," as used herein, refers to the temperature in the range of 25°C to 35°C.

The term "contacting," as used herein, refers to dissolving, slurrying, stirring, suspending, or combinations thereof.

The term "stable," as used herein, refers to amorphous eluxadoline for which no change was observed in an X-ray powder diffraction (XRPD) pattern, when placed under conditions of 25±2°C/70±5% relative humidity (RH) or 25±2°C/8±5% RH or

25±2°C/40±5% RH or 30±2°C/65±5% RH.

A first aspect of the present invention provides amorphous eluxadoline.

In an embodiment, the amorphous eluxadoline is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks at about 86.7°C and 178. PC.

Amorphous eluxadoline is characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, or an IR absorption spectrum substantially as depicted in Figure 3.

A second aspect of the present invention provides a process for the preparation of amorphous eluxadoline comprising contacting eluxadoline with a solvent optionally in the presence of an additive. Eluxadoline used herein may be prepared by any method known in the art, for example, the method described in U.S. Patent No. 7,741,356.

The additive is an organic or an inorganic salt of ammonium, alkali metals, and alkaline earth metals. The additive is selected from the group consisting of ammonium formate, sodium formate, potassium formate, ammonium acetate, sodium acetate, potassium acetate, triammonium citrate, trisodium citrate, and tripotassium citrate.

The solvent is selected from the group consisting of nitriles, ketones, alcohols, ethers, aromatic hydrocarbons, esters, amides, sulfoxides, water, and mixtures thereof. An example of nitrile is acetonitrile. Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of alcohols include methanol, ethanol, propanol, iso-propanol, n-butanol, and iso-butanol. Examples of ethers include methyl fert-butyl ether, tetrahydrofuran, 1,4-dioxane, ethyl methyl ether, diethyl ether, and diisopropyl ether. Examples of aromatic hydrocarbons include toluene and xylene.

Examples of esters include methyl acetate, ethyl acetate, isopropyl acetate, and isobutyl acetate. Examples of amides include hexamethylphosphorous triamide,

hexamethylphosphoramide, and N,N-dimethylformamide. An example of sulfoxide is dimethylsulfoxide .

The preparation of amorphous eluxadoline is carried out for about one hour to about 20 hours, for example, for about 2 hours to about 12 hours.

The preparation of amorphous eluxadoline is carried out at about 15°C to about

75°C, for example, at about 20°C to about 65°C.

Amorphous eluxadoline may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. An anti-solvent may be used for the isolation of amorphous eluxadoline, for example, acetone.

Amorphous eluxadoline may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.

A third aspect of the present invention provides a process for the preparation of amorphous eluxadoline comprising acid base treatment of lithium 5-({[N-(fert- butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-Z-phenylalanyl] [( \S)- 1 -(4-phenyl- 1H- imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoate in a solvent. Lithium 5-({ [N-(fert-butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-Z- phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate used herein is prepared by the method as disclosed herein.

An example of acid is hydrochloric acid. An example of base is sodium hydroxide.

The solvent is selected from the group consisting of esters, ethers, ketones, water, and mixtures thereof. Examples of esters include methyl acetate, ethyl acetate, isopropyl acetate, and isobutyl acetate. Examples of ethers include tetrahydrofuran, methyl tert- butyl ether, 1,4 dioxan, and diisopropyl ether. Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.

The acid base treatment of lithium 5-({ [N-(fert-butoxycarbonyl)-4-carbamoyl-2,6- dimethyl-Z-phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate is carried out for about one hour to about 20 hours, for example, for about 2 hours to about 12 hours.

The acid base treatment of lithium 5-({ [N-(fert-butoxycarbonyl)-4-carbamoyl-2,6- dimethyl-Z-phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate is carried out at about 10°C to about 60°C, for example, at about 20°C to about 55°C.

A fourth aspect of the present invention provides a pharmaceutical composition comprising amorphous eluxadoline, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

A fifth aspect of the present invention provides a method of treating irritable bowel syndrome with diarrhea (IBS-D) comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising amorphous eluxadoline. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.

Method

XRPD of samples were determined using Rigaku Instrument; Model:

MiniFlex600; Detector: D/teX Ultra; Power: 40 kV, 15 mA; Scanning speed: 10 deg/min; step: 0.0200 deg; Wave length: 1.541862 A.

IR of the samples was recorded using a PerkinElmer® instrument, potassium bromide pellet method.

DSC of the samples was recorded using a Mettler-Toledo® 82 le instrument.

The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1 : Preparation of lithium 5-( N-(fer^butoxycarbonyl)-4-carbamoyl-2.6- dimethyl -Z-phenylalanyll Γ( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyllamino}methyl)-2- methoxybenzoate

Methyl 5-({ [N-(teri-butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-Z- phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate (75 g) was added to a mixture of tetrahydrofuran (375 mL) and methanol ( 187.5 mL) at 25°C. Lithium hydroxide monohydrate (6.89 g) and de-ionized water (75 mL) were added to the mixture. The reaction mixture was heated to 35°C and then stirred for 18 hours at 35°C to 40°C. The reaction mixture was cooled to 30°C. The product was filtered, suck dried and then washed with a mixture of tetrahydrofuran (57 mL) and methanol (19 mL) to obtain a solid. The solid was air dried at 50°C to 55°C for 12 hours to obtain the title compound.

Yield: 29.3 g

Chromatographic purity: 99.17%

Example 2: Preparation of amorphous eluxadoline

Method A: Eluxadoline (1 g) was added to methanol (4 mL) at room temperature to obtain a mixture. The mixture was heated to 60°C to obtain a clear solution. The solution was cooled to 25 °C and then acetone (10 mL) was added drop-wise. The precipitate so obtained was stirred for 10 minutes and then filtered and air dried for 12 hours at 50°C to 55°C to obtain the title compound.

Yield: 0.52 g

Method B: Eluxadoline (0.5 g) was added to acetone (10 mL) at room temperature to obtain a reaction mass. The reaction mass was heated to 50°C and then cooled to 40°C. The product so obtained was filtered, suck dried for 5 minutes and then air dried for 12 hours at 50°C to 55°C to obtain the title compound.

Yield: 0.30 g

Method C: Eluxadoline (0.5 g) was added to acetonitrile (10 mL) at room temperature to obtain a reaction mass. The reaction mass was heated to 60°C and then cooled to 40°C. The product so obtained was filtered, suck dried for 5 minutes and then air dried for 12 hours at 50°C to 55°C to obtain the title compound.

Yield: 0.36 g

Method D: Eluxadoline (0.5 g) was added to ethyl acetate (10 mL) at room temperature to obtain a reaction mass. The reaction mass was heated to 60°C and then cooled to 40°C. The product so obtained was filtered, suck dried for 5 minutes and then air dried for 12 hours at 50°C to 55°C to obtain the title compound.

Yield: 0.42 g

Example 3 : Preparation of amorphous eluxadoline

Method A: Lithium 5-({ [N-(fert-butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-Z- phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate (30 g; as obtained in Example 1) was added to a mixture of ethyl acetate (420 mL) and tetrahydrofuran (60 mL) at 23°C to 24°C to obtain a mixture. Hydrogen chloride gas (generated by addition of concentrated H2SO4 (50 mL) into sodium chloride (200 g)) was purged into the reaction mixture over a period of 60 minutes. The reaction mixture was stirred for 15 hours at 30°C to 35°C. The reaction mixture was filtered, washed with a mixture of ethyl acetate (240 mL) and tetrahydrofuran (30 mL), and then suck dried for 5 minutes to obtain a solid. The solid was dissolved in deionized water (240 mL), filtered through a 0.45μπι filter and then washed with deionized water (60 mL). This solution was added dropwise to a solution of sodium hydroxide (4 g) and deionized water (900 mL) at 40°C to 42°C over a period of 15 minutes. Hydrochloric acid solution (5 mL) in deionized water (5 mL) was added to the mixture to adjust the pH to 6.58. The reaction mixture was stirred for 5 minutes and then filtered at 40°C to 45°C. The filtrate was washed with deionized water (30 mL) and then air dried for 12 hours at 40°C to 45°C to obtain the title compound.

Yield: 12.1 g

Chromatographic purity: 93.44%

Method B: Lithium 5 -( { [N-(teri-butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-Z- phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate (5.0 g; as obtained in Example 1) was added to a solution of concentrated hydrogen chloride (25 mL) at 5°C to 10°C to obtain a mixture. The mixture was stirred for 30 minutes at 10°C to 15°C. A solution of sodium hydroxide (9.3 g in 50 mL of deionized water) was added to the mixture at 10°C to 40°C. Sodium hydroxide solution (20%, 8 mL) was further added to the mixture and then hydrochloric acid solution (6Ν, 3 mL) was added to adjust the pH to 6.5. The reaction mixture was stirred for one hour at 15°C to 20°C. The product was filtered, suck dried and then washed with deionized water ( 10 mL) to obtain a solid. The solid was air dried at 45°C to 50°C for 12 hours to obtain the title compound.

Yield: 3.6 g

Chromatographic purity: 99.64%

Method C: Lithium 5-({ [N-(teri-butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-Z- phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate (5.0 g; as obtained in Example 1) was added to a solution of concentrated hydrogen chloride (20 mL) at 0°C to 5°C to obtain a mixture. The mixture was stirred for 8 hours at 0°C to 5°C. This solution was added to a solution of sodium hydroxide (8 g of sodium hydroxide in 100 mL of deionized water) at 10°C. Hydrogen chloride solution (6Ν, 2 mL) was further added to adjust the pH to 6.52. The reaction mixture was stirred for 60 minutes at 10°C to 15°C. The reaction mixture was filtered, washed with deionized water (10 mL), suck dried for 15 minutes and then air dried at 45°C to 50°C for 12 hours to obtain the title compound.

Yield: 2.1 g

Chromatographic purity: 99.64% Method D: Lithium 5-({ [N-(fert-butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-Z- phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate (25 g; as obtained in Example 1) was added to acetone (250 mL) at 25°C to 27°C to obtain a mixture. Concentrated hydrochloric acid (16.36 g) was added drop-wise to the mixture over a period of 10 minutes at 25 °C to 30°C. The reaction mixture was heated to 45°C and then stirred for 3 hours. The reaction mixture was cooled to 25 °C and then concentrated hydrochloric acid (8.19 g) was added over a period of 5 minutes at 25°C to 27°C. The reaction mixture was again heated to 45°C and stirred for 2 hours. Acetone (250 mL) was added drop wise to the reaction mixture over a period of 60 minutes at 45°C to 50°C. The solvent was decanted and then acetone (250 mL) was again added. The reaction mixture was stirred for 15 minutes and the product obtained was filtered. The product was washed with acetone (50 mL) and then dissolved in de-ionized water (100 mL). The product was filtered through a 0.45μπι filter and washed with de- ionized water (25 mL). This solution was added drop wise to a solution of sodium hydroxide (7.4 g) and de-ionized water (92.5 mL) (taken in another flask) over a period of 20 minutes at 25°C to 30°C till a clear solution was obtained. Hydrochloric acid (6Ν, 15 mL) was added and the product was precipitated at pH 4.2. Sodium hydroxide (20%, 5 mL) was added to the solution to adjust the pH to 6.52 to obtain a solid and then stirred for 15 minutes. The solid was filtered, suck dried, and then washed with de-ionized water (50 mL). The solid obtained was air dried at 50°C to 55°C for 12 hours and then under vacuum at 50°C to 55°C for 5 hours to obtain the title compound.

Yield: 18.1 g

Chromatographic purity: 97.56%

Claims

Claims: 1. Amorphous eluxadoline.

2. The amorphous eluxadoline according to claim 1, characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks at about 86.7°C and l78.rC.

3. The amorphous eluxadoline according to claim 1 , characterized by an XRPD pattern substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in Figure 2, or an IR absorption spectrum substantially as depicted in Figure 3.

4. A process for the preparation of amorphous eluxadoline comprising contacting eluxadoline with a solvent optionally in the presence of an additive.

5. The process according to claim 4, wherein the additive is selected from the group consisting of an organic or an inorganic salt of ammonium, alkali metals, and alkaline earth metals.

6. The process according to claim 4, wherein the additive is selected from the group consisting of ammonium formate, sodium formate, potassium formate, ammonium acetate, sodium acetate, potassium acetate, triammonium citrate, trisodium citrate, and tripotassium citrate.

7. The process according to claim 4, wherein the solvent is selected from the group consisting of nitriles, ketones, alcohols, ethers, aromatic hydrocarbons, esters, amides, sulfoxides, water, and mixtures thereof.

8. The process according to claim 4, wherein the process further comprises isolation of the amorphous eluxadoline from the solution thereof using technique selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.

9. The process according to claim 4, wherein the process further comprises isolation of the amorphous eluxadoline from the solution thereof using an anti-solvent.

10. A process for the preparation of amorphous eluxadoline comprising acid base treatment of lithium 5-({ [N-(teri-butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-Z- phenylalanyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino}methyl)-2- methoxybenzoate in a solvent.

1 1. The process according to claim 10, wherein the acid selected is hydrochloric acid.

12. The process according to claim 10, wherein the base selected is sodium hydroxide.

13. The process according to claim 10, wherein the solvent is selected from the group consisting of esters, ethers, ketones, water, and mixtures thereof.

14. The process according to claim 10, wherein the process further comprises isolation of the amorphous eluxadoline from the solution thereof using technique selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.

15. The process according to claim 10, wherein the process further comprises isolation of the amorphous eluxadoline from the solution thereof using an anti-solvent.