Finerenone benzene sulfonic acid salt, salt polymorphs and process for the preparation thereof

Abstract

The present invention relates to Finerenone benzenesulfonic acid salt represented by the following structural Formula-(1). The present invention also relates to the 1:1 ratio of Finerenone to its benzenesulfonic acid salt. The present invention further relates to a process for the preparation of Finerenone benzenesulfonic acid salt of Formula-(1).

Description

[0001] “FINERENONE BENZENESULFONIC ACID SALT, SALT POLYMORPHS AND PROCESS FOR THE PREPARATION THEREOF”

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to Finerenone benzenesulfonic acid salt represented by the following structural Formula- 1.

[0004] Formula-1

[0005] The present invention also relates to the 1:1 ratio of Finerenone to its benzenesulfonic acid salt.

[0006] The present invention further relates to a process for the preparation of Finerenone benzenesulfonic acid salt of Formula- 1.

[0007] BACKGROUND OF THE INVENTION

[0008] Finerenone is a potent, selective, and orally available nonsteroidal mineralocorticoid receptor (MR) antagonist to control deleterious effects on the kidneys, blood vessels, and heart for the management of cardiovascular and renal diseases such as heart failure and diabetic nephropathy (Chem. Med. Chem. 2012, 7(8), 1385-1403). Finerenone is approved by USFDA under the brand name of Kerendia in the year of 2021 and by EU and IN in the following year, 2022. Finerenone’s chemical name is (4S) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2, 8-dimethyl-l, 4-dihydro-l, 6-naphthyridine- 3 -carboxamide, and has the following chemical structure. Bayer’s US 8,436,180 B2 discloses different acceptable salts for example acid addition salts of mineral acids, carboxylic acids and Sulfonic acids, e.g. salts of wherein benzenesulfonic acid is mentioned one among them. Benzenesulfonic acid salt is not specifically taught in this patent.

[0009] US 10,336,749 B2 discloses / claims crystalline form of polymorph I of Finerenone free base.

[0010] IN 201911048297 also discloses different pharmaceutically acceptable salts covering benzenesulfonic acid as one of the lists of acids used to form a salt. In this application again, Benzenesulfonic acid salt is not specifically taught.

[0011] None of the prior-art discloses Finerenone benzenesulfonic acid salt.

[0012] Finerenone is a BCS class II Molecule with solubility issue. Low solubility and dissolution rate (physicochemical properties) of BCS class II active pharmaceutical ingredients (API molecules) is a biggest problem for oral solid dosage forms in the market and pipeline. Therefore, to enhance solubility alternate solid form strategy has to adopt. To address the Finerenone existing solid form solubility issue the inventors of the present invention has tried many pharmaceutically accepted salts.

[0013] Vigorous experimentation trials could not yield viable salts and / or salt formation. Surprisingly salt of Finerenone with pharmaceutically acceptable Bezenesulfonic acid counter ion formed. The inventors of the present invention found that Finerenone Benzenesulfonic acid salt is stable over shelf life and does not convert into any other forms.

[0014] OBJECTIVE OF THE INVENTION

[0015] The principle objective of the present invention provides Finerenone benzenesulfonic acid salt of Formula- 1 In another objective, the present invention provides Finerenone benzenesulfonic acid salt of Formula- 1 is in crystalline form, herein after designated as Form-L.

[0016] In another objective, the present invention provides a process for the preparation of Finerenone benzene sulfonic acid salt of Formula- 1.

[0017] In further objective of the present invention provides a pharmaceutical composition comprising Finerenone benzenesulfonic acid salt of Formula- 1 and a pharmaceutically acceptable excipient.

[0018] SUMMARY OF THE INVENTION

[0019] Accordingly, the present invention provides Finerenone benzenesulfonic acid salt of Formula- 1.

[0020] In another aspect, the present invention provides Finerenone benzenesulfonic acid salt of Formula- 1 in a crystalline form, herein after designated as Form-L.

[0021] In another aspect, the present invention provides crystalline Form-L of Finerenone benzenesulfonic acid salt of Formula- 1 , in a hydrated crystalline form.

[0022] In another aspect, the present invention provides the ratio of Finerenone to benzenesulfonic acid ranging from approximately 1:0.5 to 1:5, preferably 1:1.

[0023] In another aspect, the present invention provides the Finerenone benzenesulfonic acid salt of Formula- 1, which is characterized by X-ray powder diffraction (XRPD) pattern as illustrated in Figure 1.

[0024] In another aspect, the present invention provides the Finerenone benzenesulfonic acid salt of Formula- 1, which is characterized by a powder X-ray diffraction (PXRD) pattern exhibiting characteristic peaks at 4.38+0.2, 6.65+0.2, 6.96+0.2, 9.6+0.2, 10.88+0.2, 12.1+0.2, and 12.6+0.2° 2 theta. In another aspect, the present invention provides the Finerenone benzenesulfonic acid salt of Formula- 1, which is characterized by differential scanning calorimetry thermogram (DSC thermogram) as illustrated in Figure 3.

[0025] In another aspect, the present invention provides the Finerenone benzenesulfonic acid salt of Formula- 1, which is characterized by Thermogravimetric analysis (TGA) as illustrated in Figure 5.

[0026] In another aspect, the present invention provides a process for the preparation of Finerenone benzenesulfonic acid salt of Formula- 1, comprising the steps of: i). providing a solution of benzenesulfonic acid in a suitable solvent, ii). adding Finerenone to the solution obtained in step i), iii). adding acetic acid to the reaction mass obtained in step ii), iv). adding an anti-solvent to the reaction mass obtained in step iii), and v). isolating Finerenone benzenesulfonic acid salt of Formula- 1.

[0027] In another aspect, the present invention provides a process for the preparation of Finerenone benzenesulfonic acid salt of Formula- 1, comprising the steps of: a) reacting (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- l,6-naphthyridine-3-carboxylic acid of Formula-3

[0028] Formula-3 with l,l'-Carbonyldiimidazole in a suitable solvent to obtain (S)-4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3-carboxylic IH-imidazole-l -carboxylic anhydride of Formula-2

[0029] Formula-2 b) reacting the compound of formula-2 in-situ with aqueous ammonia to obtain crude Finerenone of formula- la c) dissolving the crude Finerenone of formula- la in a suitable solvent, d) adding a solution of benzenesulfonic acid in a suitable solvent, e) adding acetic acid to the reaction mass obtained in step d), f) adding an anti-solvent to the reaction mass obtained in step e), and g) isolating Finerenone benzenesulfonic acid salt of Formula- 1. wherein the process involves without isolation of Finerenone in crystalline form.

[0030] In further aspect, the present invention provides a pharmaceutical composition comprising the Finerenone benzenesulfonic acid salt of Formula- 1 and a pharmaceutically acceptable excipient.

[0031] BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1: Illustrates the PXRD pattern of crystalline Form-L Finerenone benzenesulfonic acid salt.

[0033] Figure 2: Illustrates the PXRD pattern of crystalline Form-L Finerenone benzenesulfonic acid salt (middle pattern), Finerenone reported Form I (bottom) and benzenesulfonic acid (Top).

[0034] Figure 3: Illustrates the DSC thermogram of crystalline Form-L of Finerenone benzenesulfonic acid salt

[0035] Figure 4: Illustrates the DSC thermogram of crystalline Form-L of Finerenone benzenesulfonic acid salt (middle pattern), Finerenone reported Form I (bottom) and benzenesulfonic acid (Top). Figure 5: Illustrates the TGA of crystalline Form-L of Finerenone benzenesulfonic acid salt

[0036] Figure 6: Illustrates the TGA of crystalline Form-L of Finerenone benzenesulfonic acid salt (Bottom) and Finerenone Form I (Top).

[0037] DETAILED DESCRIPTION OF THE INVENTION

[0038] The main embodiment of the present invention provides Finerenone benzenesulfonic acid salt of Formula- 1.

[0039] In another embodiment, the present invention provides Finerenone benzenesulfonic acid salt of Formula- 1 is in crystalline form, herein after designated as Form-L.

[0040] In another embodiment, the present invention provides crystalline Form-L of Finerenone benzenesulfonic acid salt of Formula- 1 , in a hydrated crystalline form.

[0041] In another embodiment, the present invention provides the ratio of Finerenone to benzenesulfonic acid ranging from approximately 1:0.5 to 1:5, preferably 1:1.

[0042] In another embodiment, the present invention provides the Finerenone benzenesulfonic acid salt of Formula- 1, which is characterized by X-ray powder diffraction (XRPD) pattern as illustrated in Figure 1.

[0043] The PXRD overlay of Finerenone benzenesulfonic acid, Finerenone and benzenesulfonic acid indicates absence of input benzenesulfonic acid peaks in salt at the same time the XRD indicates absence of Finerenone input form peaks in Finerenone benzenesulfonic acid salt.

[0044] In another embodiment, the present invention provides the Finerenone benzenesulfonic acid salt of Formula- 1, which is characterized by a powder X-ray diffraction (PXRD) pattern exhibiting characteristic peaks at 4.38+0.2, 6.65+0.2, 6.96+0.2, 9.6+0.2, 10.88+0.2, 12.1+0.2, and 12.6+0.2° 2 theta.

[0045] In another embodiment, the present invention provides the Finerenone benzenesulfonic acid salt of Formula- 1, which is characterized by differential scanning calorimetry thermogram (DSC thermogram) as illustrated in Figure 3.

[0046] In another embodiment, the Finerenone benzenesulfonic acid salt prepared by the process of the present invention melts around 213.76 °C whereas the API Form I melting is at -253 °C. Further salt has shown monohydrate (3.5%) related water loss endotherm from 60 to 125°C. Hence, it is another evidence salt hydrate formation.

[0047] In another embodiment, the present invention provides the Finerenone benzenesulfonic acid salt of Formula- 1, which is characterized by Thermogravimetric analysis (TGA) as illustrated in Figure 5.

[0048] In another embodiment, the Finerenone benzenesulfonic acid salt so obtained is having water content less than 5.0% (w / w), preferably less than 4.0% and more preferably less than 3.5%.

[0049] In another embodiment, the present invention relates to a process for the preparation of Finerenone benzenesulfonic acid salt of Formula- 1, comprising the steps of: i). providing a solution of benzenesulfonic acid in a suitable solvent, ii). adding Finerenone to the solution obtained in step i), iii). adding acetic acid to the reaction mass obtained in step ii), iv). adding an anti-solvent to the reaction mass obtained in step iii), and v). isolating Finerenone benzenesulfonic acid salt of Formula- 1.

[0050] The term "solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" selected from dimethyl ether, di isopropyl ether, diethyl ether, methyl tert-butyl ether (MTBE), 1 ,2-dimethoxy ethane, tetrahydrofuran, Trifluoroacetic anhydride, 1,4-dioxane and the like; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone and the like; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) and the like; "nitrile solvents" selected from acetonitrile, propionitrile, iso butyro nitrile and the like; “alcohol solvents” selected from methanol, ethanol, n- propanol, isopropanol, n-butanol, iso butanol, t-butanol, n-pentanol, iso pentanol, 2-nitroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol mono ethyl ether, benzyl alcohol, phenol, or glycerol and the like; “polar-aprotic solvents" selected from dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; "polar solvents" selected from water or mixtures thereof.

[0051] In an embodiment, the suitable solvent in step c) and step d) is selected from “ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) and the like.

[0052] In an embodiment, the anti-solvent in step f) is selected from "ether solvents" selected from dimethyl ether, di isopropyl ether, diethyl ether, methyl tert-butyl ether (MTBE), 1 ,2-dimethoxy ethane, tetrahydrofuran, Trifluoroacetic anhydride, 1,4-dioxane and the like.

[0053] In another embodiment, the present invention provides a process for the preparation of Finerenone benzenesulfonic acid salt of Formula- 1, comprising the steps of: a) reacting (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6- naphthyridine-3-carboxylic acid of Formula-3

[0054] Formula-3 with 1 J '-Carbonyldiimidazole in a suitable solvent to obtain (S)-4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3-carboxylic IH-imidazole-l -carboxylic anhydride of Formula-2 b) reacting the compound of formula-2 in-situ with aqueous ammonia to obtain crude Finerenone of formula- la c) dissolving the crude Finerenone of formula- la in a suitable solvent, d) adding a solution of benzenesulfonic acid in a suitable solvent, e) adding acetic acid to the reaction mass obtained in step d), f) adding an anti-solvent to the reaction mass obtained in step e), and g) isolating Finerenone benzenesulfonic acid salt of Formula- 1. wherein the process involves without isolation of Finerenone in crystalline form.

[0055] In an embodiment, the suitable solvent is selected from "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; “ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) and the like. In an embodiment, the anti-solvent is selected from "ether solvents" selected from dimethyl ether, di isopropyl ether, diethyl ether, methyl tert-butyl ether (MTBE), 1,2-dimethoxy ethane, tetrahydrofuran, Trifluoroacetic anhydride, 1,4-dioxane and the like.

[0056] The Finerenone benzenesulfonic acid salt of the present invention is stable over the shelf life under different stability conditions, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling. The Finerenone benzenesulfonic acid salt of the present invention is also suitable for formulating into different dosage forms.

[0057] In pharmaceutical products both thermal stability and polymorphic stability is very important. Otherwise one solid state form converts into other solid-state form. Further there is no control on the conversion rate at different time intervals and in different storage conditions. This means at different time points during shelf life the product might have mixture of two different solid states in different ratios. It is clearly reported in the literature that this has impact on the solubility and bioavailability of the product. This has direct impact on the efficacy of the product. Hence, it is very important to have polymorphic stability.

[0058] In a preferred embodiment, the present invention provides a pharmaceutical composition comprising Finerenone benzenesulfonic acid salt along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrates, glidant, lubricants and or anti- adherents.

[0059] The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

[0060] The pharmaceutical compositions comprising Finerenone benzenesulfonic acid salt may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using procedures such as direct blending, dry granulation, wet granulation, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.

[0061] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. 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.

[0062] PXRD:

[0063] DSC: TGA:

[0064] The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.

[0065] Examples

[0066] Example 1: Preparation of Finerenone benzenesulfonic acid salt of Formula- 1. Benzenesulfonic acid (4.17 gm) was dissolved in methyl ethyl ketone (MEK) (210 ml) at 25-30 °C. Finerenone (10 gm) was added into the above clear solution and the reaction temperature was raised to 50 °C. To this reaction mass, acetic acid (57 ml) was added, then clear solution was observed. Methyl tert-butyl ether (MTBE) (560 ml) was added to the above clear solution at 25-30 °C and precipitation was observed and stirred. Filtered the solid and dried under vacuum to get the title compound. Yield: -85%. The obtained compound is characterized by PXRD pattern as illustrated in Figure 1.

[0067] Example 2: Preparation of Finerenone benzenesulfonic acid salt of Formula-1.

[0068] Benzenesulfonic acid (41.7 gm) was dissolved in methyl ethyl ketone (MEK) (2140 ml) at 25-30 °C. Finerenone (100 gm) was added into above clear solution and reaction temperature was raised to 50 °C. To this reaction mass, acetic acid (570 ml) was added, then clear solution was observed. Methyl tert-butyl ether (MTBE) (5600 ml) was added to the above clear solution at 25-30 °C and precipitation was observed and stirred. Filtered the solid and dried under vacuum to get the title compound. Yield: -85%. The obtained compound is characterized by PXRD pattern as illustrated in Figure 1.

[0069] Example 3: Preparation of Finerenone benzenesulfonic acid salt of Formula- 1. (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6- naphthyridine-3-carboxylic acid (1.46 g) was added to ethyl acetate (22 ml) at room temperature. To this reaction mass, l,l'-carbonyldiimidazole (930 mg) was added and stirred at room temperature. After completion of the reaction, the residue was taken up in DMF (22 ml), then ammonia (18% by weight solution in water, 56.2 mmol) are added, and the reaction mixture is heated at 100° C. for 30 min. The solvent is distilled out under reduced pressure. The residue was dissolved in 17.5 ml of ethyl acetate and filtered through hyflo after carbon treatment. Methyl ethyl ketone (MEK) (7.5 ml) was added to the concentrated crude at 25-30 °C. To this a solution of benzenesulfonic acid (0.61 gm) in methyl ethyl ketone (MEK) (30.5 ml) was added. The reaction temperature was raised to 50 °C. To this reaction mass, acetic acid (8.3 ml) was added, then clear solution was observed. Methyl tert-butyl ether (MTBE) (77 ml) was added to the above clear solution at 25-30 °C and precipitation was observed and stirred. Filtered the solid and dried under vacuum to get the title compound. Yield: -55%. The obtained compound is characterized by PXRD pattern as illustrated in Figure 1.

Claims

WE CLAIM:

1. A Finerenone benzenesulfonic acid salt of Formula- 1Formula-12. The Finerenone benzenesulfonic acid salt of Formula- 1, as claimed in claim 1, in a crystalline form.

3. The Finerenone benzenesulfonic acid salt of Formula- 1 as claimed in claim 1, is a crystalline hydrate.

4. The Finerenone benzenesulfonic acid salt of Formula- 1 in crystalline form as claimed in claims 2 and 3, is characterized by a powder X-ray diffraction (PXRD) pattern that is substantially the same as the one shown in Figure- 1.

5. A Finerenone benzenesulfonic acid salt of Formula- 1 is characterized by a powder X-ray diffraction (PXRD) pattern exhibiting characteristic peaks at 4.38+0.2, 6.65+0.2, 6.96+0.2, 9.6+0.2, 10.88+0.2, 12.1+0.2, and 12.6+0.2° 2 theta.

6. A process for the preparation of Finerenone benzenesulfonic acid salt of Formula- 1, comprising the steps of: i). providing a solution of benzenesulfonic acid in a suitable solvent, ii). adding Finerenone to the solution obtained in step i), iii). adding acetic acid to the reaction mass obtained in step ii), iv). adding an anti-solvent to the reaction mass obtained in step iii), and v). isolating Finerenone benzenesulfonic acid salt of Formula- 1.

7. A process for the preparation of Finerenone benzenesulfonic acid salt of Formula- 1,comprising the steps of: a) reacting (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- l,6-naphthyridine-3-carboxylic acid of Formula-3Formula-3 with 1 J '-Carbonyldiimidazole in a suitable solvent to obtain (S)-4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3- carboxylic IH-imidazole-l -carboxylic anhydride of Formula-2b) reacting the compound of formula-2 in-situ with aqueous ammonia to obtain crude Finerenone of formula- la c) dissolving the crude Finerenone of formula- la in a suitable solvent, d) adding a solution of benzenesulfonic acid in a suitable solvent e) adding acetic acid to the reaction mass obtained in step d), f) adding an anti-solvent to the reaction mass obtained in step e), and g) isolating Finerenone benzenesulfonic acid salt of Formula- 1.wherein the process involves without isolation of Finerenone in crystalline form.

8. The process as claimed in claim 6 and 7, wherein the suitable solvent is selected from "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; “ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) and the like; the antisolvent is selected from "ether solvents" selected from dimethyl ether, di isopropyl ether, diethyl ether, methyl tert-butyl ether (MTBE), 1 ,2-dimethoxy ethane, tetrahydrofuran, Trifluoroacetic anhydride, 1,4-dioxane and the like.

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