DESC:FIELD OF THE INVENTION
Present invention provides novel salts of Mavacamten, its hydrates, solvates and polymorphic forms thereof, its preparation and its use in the preparation of Mavacamten.
BACKGROUND OF THE INVENTION
Mavacamten, a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.
Mavacamten has the chemical name: (S)-3-isopropyl-6-((1-phenylethyl) amino) pyrimidine-2,4(1H,3H)-dione. The structural formula is as follows:

The physicochemical and biological properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development. Several salts of APIs also help in the purification, crystallization and salt exchange of APIs.
The present invention provides novel salts of Mavacamten that provides improved pharmacological and/or physiological and/or physicochemical properties. Further present inventors found that these salts help in improving purity of Mavacamten by effective removal of impurities.
OBJECT OF THE INVENTION
Main object of the present invention is to provide solid form of Mavacamten compound of formula I or salt thereof.
Another object of the present invention is to provide novel salts of Mavacamten compound of formula I.
Another object of the present invention is to provide a process for the preparation of novel salts of Mavacamten.
Another object of the present invention is to provide a pure novel salt of Mavacamten.
Another object of the present invention provides a process for purification of novel salt of Mavacamten.
Another object of the present invention is to provide a process for the preparation of Mavacamten by using novel salts of Mavacamten.
SUMMARY OF THE INVENTION
Main aspect of the present invention is to provide solid form of Mavacamten compound of formula I,

or salt thereof.
Another aspect of the present invention provides novel salts of Mavacamten compound of formula I.
Another aspect of the present invention provides process for preparation of novel salts of Mavacamten compound of formula I.
Another aspect of the present invention provides novel salts of Mavacamten, its hydrates, solvates and polymorphic forms.
Another aspect of the present invention provides novel salts of Mavacamten compound of formula I, wherein the said salt of Mavacamten is prepared by treating Mavacamten with acid or base. Acid used include organic as well as inorganic acid. Base used include organic and inorganic base.
Another aspect of the present invention provides novel salts of Mavacamten compound of formula I,

comprises, compounds of formulae I-a, II & III,
, , and
wherein M is selected from monovalent or bivalent metal and X is selected from organic/inorganic acid or base.
Another aspect of the present invention provides a process for the preparation of novel salt of Mavacamten compound of formula II,
;
comprising treating Mavacamten compound of formula I with monovalent metal source to form compound of formula II, wherein M is selected from monovalent metal.
Another aspect of the present invention provides a process for the preparation of novel salt of Mavacamten compound of formula III,
,
comprising treating the compound of formula I with bivalent metal source to form compound of formula III, wherein M is selected from bivalent metal.
Another aspect of the present invention provides a process for the preparation of novel salt of Mavacamten compound of formula III,
;
comprising treating the alkaline metal salt of compound of formula II with bivalent metal source to form compound of formula III, wherein M is selected from calcium, magnesium, barium, zinc, strontium, copper and Iron.
Another aspect of the present invention provides a process for the preparation of novel salt of Mavacamten compound of formula III, comprising the steps of:
i) treating Mavacamten compound of formula I with monovalent metal source/alkali metal source to form compound of formula II, wherein M is selected from sodium, potassium, cesium and lithium
, and
ii) treating the alkaline metal salt of compound of formula II with bivalent metal source to form compound of formula III, wherein M is selected from calcium, magnesium, barium, zinc, strontium, copper and Iron,
.
Another aspect of the present invention provides a process for the preparation of Mavacamten compound of formula I, using Mavacamten salts.
Another aspect of the present invention provides a pure novel salt of Mavacamten.
Another aspect of the present invention provides a process for purification of novel salt of Mavacamten.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Represents the X-Ray Powder Diffraction (XRPD) pattern of Mavacamten of the present invention.
Figure 2: Represents the Differential Scanning Calorimetry (DSC) of Mavacamten of the present invention.
Figure 3: Represents the X-Ray Powder Diffraction (XRPD) pattern of amorphous form of sodium salt of Mavacamten of the present invention.
Figure 4: Represents the Thermogravimetric Analysis (TGA) of amorphous form of sodium salt of Mavacamten of the present invention.
Figure 5: Represents the X-Ray Powder Diffraction (XRPD) pattern of amorphous form of potassium salt of Mavacamten of the present invention.
Figure 6: Represents the Thermogravimetric Analysis (TGA) of amorphous form of potassium salt of Mavacamten of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, the terms “amorphous or stable amorphous “is interchangeable and indicate that the Mavacamten is present in substantially amorphous state and is substantially free from any other form. It may be present in the form of solid dispersion, adsorbate or pharmaceutical composition. "Substantially pure amorphous” denotes that at least 90%, preferably at least 95%, more preferably at least 99% of the Mavacamten is amorphous. In other words, “substantially free from any other form” preferably means that the amorphous form does not contain detectable amounts, of any other portions of Mavacamten e.g. measurable upon X-ray powder diffraction analysis and/or Differential scanning calorimetry, and preferably the any other form is less than about 5% w/w of the amorphous form.
The term crystalline form refers to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline Form of Mavacamten refers to unique crystalline form that can be identified by characterization techniques including, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (TGA).
The term “stable” as used herein refers to physical stability and/or chemical stability of the active agent in the composition, wherein changes in the drug assay values and/or impurities content are less than about 10%, during stability study storage of the composition at 25° C. and 60% relative humidity (RH), or 30° C. and 65% RH, or 40° C. and 75% RH, for durations such as initial, 1, 3, 6, 12, 18, or 24 months.
The term “room temperature” refers to a temperature in the range of 20°C to 25°C.
The term “pharmaceutically acceptable excipient” means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.
Analytical Methods:
Differential scanning calorimetry (DSC) was performed using instrument Perkin Elmer, Model: DSC 8000. Sample was placed into the respective sample position in DSC and blank pan at the reference position and scan was run in the scanning temperature range of 30oC to 250oC (10oC per minute) using given instrumental parameter and data was collected. Thermogram was recorded by integrating the endothermic peak.
Powder X-ray Diffraction was recorded on an X-Ray powder diffractometer PANalytical X’Pert3; K-Alpha1 [Å] (l = 1.54060 Å); X'Celerator detector. Prior to analysis, sufficient quantity of powder sample was grinded gently in a mortar with pestle. Finally, grinded simple was filled in to the groove of the sample holder uniformly and the XRPD graph was recorded within the 2? range of 3 to 40.
Thermogravimetric analysis was performed on Perkin Elmer Pyris 1 TGA and platinum sample pan was loaded onto the hang down wire and waited till the balance become stable and TGA curve was recorded in the temperature range of 30oC to 400oC (100 oC/minute) with air flow 50mL/minute.
Active pharmaceutical ingredients exhibit different properties in its salt form when compared to non-salified form. The properties can be crystallinity, solubility, intrinsic dissolution rate, stability under storage, and stability in aqueous media.
In one embodiment, the present invention is to provide solid form of Mavacamten compound of formula I,

or salt thereof.
Another embodiment of the present invention provides novel salts of Mavacamten compound of formula I.
Another embodiment of the present invention provides novel salts of Mavacamten, its hydrates, solvates and polymorphic forms.
Another embodiment of the present invention provides process for preparation of novel salts of Mavacamten compound of formula I.
Another embodiment of the present invention provides novel salts of Mavacamten compound of formula I, wherein the said salt of Mavacamten is prepared by treating Mavacamten with acid or base. Acid used include organic as well as inorganic acid. Base used include organic and inorganic base.
Another embodiment of the present invention provides novel salts of Mavacamten compound of formula I, wherein the said novel salts of Mavacamten comprises organic acid or base salts; inorganic acid or base salt; monovalent or divalent metal salt.
Another embodiment of the present invention provides novel salts of Mavacamten compound of formula I,

comprises, compounds of formulae I-a, II & III
, , and
wherein M is selected from monovalent or divalent metal; X is selected from organic/inorganic acid or base.
In another embodiment of the present invention provides novel salts of Mavacamten compound of formula I, wherein the salt of Mavacamten is prepared by treating with inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid and sulphuric acid; organic acids such as but not limited to sulphonic acids such as methanesulfonic acid, benzenesulphonic acid, toluenesulphonic acid, dodecylbenzene sulfonic Acid, cyclamic acid, and naphthalene-1,5-disulphonic acid; monocarboxylic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, (+)-L-lactic acid, DL-lactic acid, DL-mandelic acid, gluconic acid, cinnamic acid, salicylic acid, and gentisic acid; dicarboxylic acids such as oxalic acid, 2-oxo-glutaric acid, malonic acid, succinic acid, (-)-L-malic acid, (+)-L-tartaric acid, fumaric acid, maleic acid and terephthalic acid; tricarboxylic acids, such as citric acid; aromatic sulphonimides such as saccharin; ascorbic acid; organic or inorganic bases such as but not limited to amines such as trimethylamine, triethylamine, diethylmethyl amine, dicyclohexylamine, dipropylamine, diisopropylamine, diisopropylethylamine, a-methylbenzylamine, cyclohexylethylamine, t-butyl amine, ammonia, and the like; carbonates, bicarbonates, hydroxides, hydrides and alkoxides of alkali or alkaline earth metals selected from lithium, sodium, potassium, cesium, magnesium, calcium, strontium, zinc, copper, iron, barium and the like.
In another embodiment, the present invention provides salts of Mavacamten of compounds of formulae II and III,
,
wherein M is selected from sodium, potassium, cesium and lithium;
,
wherein M is selected from calcium, magnesium, barium, zinc, strontium, copper and iron; and are interconvertible.
Another embodiment of the present invention provides a process for the preparation of novel salt of Mavacamten compound of formula II,
,
comprising treating Mavacamten compound of formula I with monovalent metal source to form compound of formula II, wherein M is selected from monovalent metal.
Another embodiment of the present invention provides monovalent metal source/alkali metal source comprises hydrides, hydroxides, bicarbonates, carbonates of alkali metals selected from lithium, sodium, potassium or cesium.
Another embodiment of the present invention provides a process for the preparation of novel salts of Mavacamten compound of formula II, comprising the steps of:
;
treating Mavacamten compound of formula I with monovalent metal source/alkali metal source to form compound of formula II, wherein M is selected from lithium, sodium, potassium or cesium.
Another embodiment of the present invention provides a process for the preparation of novel salts of Mavacamten compound of formula III,
,
comprising, treating the compound of formula I with bivalent metal source to form compound of formula III, wherein M is selected from bivalent metal.
Another embodiment of the present invention provides bivalent metal source comprises hydrides, hydroxides, bicarbonates, carbonates of bivalent metals selected from calcium, magnesium, barium, zinc, strontium, copper and iron.
Another embodiment of the present invention provides a process for the preparation of novel salts of Mavacamten compound of formula III,
,
comprising treating the alkaline metal salt of compound of formula II with bivalent metal source to form compound of formula III, wherein M is selected from calcium, magnesium, barium, zinc, strontium, copper and Iron.
Another embodiment of the present invention provides a process for the preparation of novel salt of Mavacamten compound of formula III, comprising the steps of:
i) treating Mavacamten compound of formula I with monovalent metal source/alkali metal source to form compound of formula II, wherein M is selected from sodium, potassium, cesium and lithium,
, and
ii) treating the alkaline metal salt of compound of formula II with bivalent metal source to form compound of formula III, wherein M is selected from calcium, magnesium, barium, zinc, strontium, copper and Iron.
.
Another embodiment of the present invention provides a process for the preparation of Mavacamten compound of formula I using novel salts of Mavacamten compound of formula I.
Another embodiment of the present invention provides a process for the preparation of Mavacamten compound of formula I, comprising the steps of;
i) providing a solution of salt of Mavacamten compound of formula I in one or more solvents;
ii) adding suitable acid or base to the above solution; and
iii) isolating the Mavacamten compound of formula I.
In another embodiment, the present invention provides a process for the preparation of Mavacamten compound of formula I, comprising, converting the compound of formula II to Mavacamten compound of formula I.
Another embodiment of the present invention provides a process for the preparation of Mavacamten compound of formula I, comprising the steps of;
i) providing a solution of salt of Mavacamten compound of formula II in one or more solvents;
ii) adding suitable acid to the above solution; and
iii) isolating the Mavacamten compound of formula I.
In another embodiment, the present invention provides a process for the preparation of Mavacamten compound of formula I, comprising, converting the compound of formula III to Mavacamten compound of formula I.
Another embodiment of the present invention provides a process for the preparation of Mavacamten compound of formula I, comprising the steps of;
i) providing a solution of salts of Mavacamten compound of formula III in one or more solvent;
ii) adding suitable acid to the above solution; and
iii) isolating the Mavacamten compound of formula I.
Another embodiment of the present invention provides a process for the preparation of salt of Mavacamten compound of formula I-a, comprising the steps of;
i) providing a solution of Mavacamten compound of formula I in one or more solvents;
ii) adding suitable acid or base to the above solution; and
iii) isolating the salt of Mavacamten compound of formula I-a.
Another embodiment of the present invention provides a pure novel salt of Mavacamten.
Another embodiment of the present invention provides a process for purification of compound of formula II or III of Mavacamten, comprising the steps of;
i) providing a solution of salt of Mavacamten compound of formula II or III in DM water;
ii) adjusting the pH of <2 with concentrated HCl; and
iii) stirring the slurry for 2-3h at RT, after filtering the slurry, dried in air oven at 50oC.
In one another embodiment, solvent as used in the context of the present invention is selected from but not limited to, the group comprising of alcohol such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; ester solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.
Another embodiment of the present invention provides a process for the purification of Mavacamten compound of formula I, comprising: treating Mavacamten compound of formula I with a mixture of alcoholic solvent and water.
In another embodiment, alcoholic solvent is selected from methanol, ethanol, isopropyl alcohol or mixtures thereof.
Another embodiment of the present invention provides Mavacamten compound of Formula I or salt thereof in solid form & preparation thereof.
Another embodiment of the present invention provides salts of Mavacamten compound of Formula I in solid form & preparation thereof.
In another embodiment, the present invention provides novel solid forms of Mavacamten compound of formula II & preparation thereof.
In another embodiment, the present invention provides novel solid forms of Mavacamten compound of formula III & preparation thereof.
Another embodiment of the solid form of Mavacamten compound of Formula I or salt thereof comprises crystalline, amorphous, solid dispersion and premix of Mavacamten.
In another embodiment, the present invention provides a crystalline form of compound of Formula I, characterized by its X-Ray Powder Diffraction (XRPD) pattern comprises peaks (2? values) at about 11.6, 18.7, and 20 ±0.2 ° 2?.
In another embodiment, the present invention provides a crystalline form of compound of Formula I (Mavacamten), characterized by its X-Ray Powder Diffraction (XRPD) pattern comprises peaks (2? values) having one or more peaks at about 10.0, 11.6, 14.6, 15.7, 16.2, 17.3, 18.7, 20, 22.3, 25.6, 29.0 ±0.2 ° 2? and one or more additional peaks selected from 13.7, 23.3, 24.1 and 31.6 ±0.2 ° 2?.
In another embodiment, the present invention provides a crystalline form of compound of Formula I (Mavacamten), characterized by its X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1.
In another embodiment, the present invention provides a crystalline form of compound of Formula I, characterized by its Differential Scanning Calorimetry (DSC) comprises endothermic peaks at about 216°C, and 252 °C.
In another embodiment, the present invention provides a crystalline form of compound of Formula I, characterized by its Differential Scanning Calorimetry (DSC) as depicted in Figure 2.
In another embodiment, the present invention provides a crystalline form of sodium salt of Mavacamten.
In another embodiment, the present invention provides an amorphous form of sodium salt of Mavacamten.
In another embodiment, the present invention provides an amorphous form of sodium salt of Mavacamten, characterized by its X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 3.
In another embodiment, the present invention provides an amorphous form of sodium salt of Mavacamten, characterized by weight loss about 8.4% up to temperature of 230 ±3 °C as measured by thermogravimetric analysis (TGA).
In another embodiment, the present invention provides an amorphous form of sodium salt of Mavacamten, characterized by its Thermogravimetric Analysis (TGA) as depicted in Figure 4.
In another embodiment, the present invention provides a crystalline form of potassium salt of Mavacamten.
In another embodiment, the present invention provides an amorphous form of potassium salt of Mavacamten.
In another embodiment, the present invention provides an amorphous form of potassium salt of Mavacamten, characterized by its X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 5.
In another embodiment, the present invention provides an amorphous form of potassium salt of Mavacamten, characterized by weight loss about 7.4 % up to temperature of 210 ±3 °C as measured by thermogravimetric analysis (TGA).
In another embodiment, the present invention provides an amorphous form of potassium salt of Mavacamten, characterized by its Thermogravimetric Analysis (TGA) as depicted in Figure 6.
In another embodiment, the present invention provides a crystalline form of calcium salt of Mavacamten.
In another embodiment, the present invention provides an amorphous form of calcium salt of Mavacamten.
In another embodiment, the present invention provides a crystalline form of magnesium salt of Mavacamten.
In another embodiment, the present invention provides an amorphous form of magnesium salt of Mavacamten.
In another embodiment, the novel salts of Mavacamten prepared above helps in the purification of Mavacamten with controlled/minimized impurity levels.
In another embodiment, the present invention provides a process for the preparation of an amorphous form of Mavacamten compound of Formula I or salt thereof, comprising the steps of:
a) providing a solution of compound of Formula I or salt thereof in one or more suitable solvent; and
b) isolating the amorphous Mavacamten compound of Formula I or salt thereof.
In another embodiment, the present invention provides a process for the preparation of crystalline form of Mavacamten compound of Formula I or salt thereof, comprising the steps of:
a) providing a solution of compound of Formula I or salt thereof in one or more suitable solvent; and
b) isolating the crystalline Mavacamten compound of Formula I or salt thereof.
In another embodiment, the present invention provides a stable solid Form includes crystalline or amorphous Form of Mavacamten compound of Formula I or salt thereof that after exposure to 40°C /75% RH for a period of six months or 25°C /60% RH, for a period of at least 12 months contains less than about 0.5% (wt/wt) total impurities and doesn't change to any other solid forms.
In another embodiment, the present invention provides premix of Mavacamten compound of Formula I and their preparation method.
In another embodiment, the present invention provides premix of Mavacamten compound of Formula I with one or more pharmaceutically acceptable excipients.
In another embodiments, the suitable pharmaceutically acceptable excipient(s) includes but not limited to diluents, lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures thereof.
In another embodiments, the suitable pharmaceutically acceptable excipient(s) includes but not limited to polyvinylpyrrolidone (also called povidone), copovidone, polyvinyl alcohol, polyethylene glycol, polyol(Lactose, Mannitol), sodium starch glycolate, colloidal silicon dioxide (aerosil), hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, sugars, silicates such as magnesium aluminometasilicate and combinations comprising one or more of the foregoing agents, Preferably selected from copovidone, lactose, magnesium aluminometasilicate, polyethylene glycol (PEG) and aerosol 200.
In preferred embodiments, removal of solvent or isolation of Mavacamten compound of Formula I or salt thereof may include, but not limited to, centrifugation, crystallization, filtration, extraction, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, flash evaporation, rotational dying, agitated nutsche filter drying, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization, and the like.
In preferred embodiment, the solvent may be removed under reduced pressures and at a temperature of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In another embodiment, the Mavacamten compound of Formula I or salt thereof used as input (starting material) for the preparation of any of the solid form is either a crude mass, reaction mixture, an amorphous form, one or more crystalline form or mixture thereof in any proportion.
In another embodiment, the present invention provides the chemical purity of the Mavacamten compound of Formula I or salt thereof as measured by high pressure liquid chromatography (HPLC) is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9%.
In another embodiment, the present invention provides the solid form of the Mavacamten compound of Formula I or salt thereof is about 99.9% pure as measured by high pressure liquid chromatography.
In another embodiment, the present invention provides, the Mavacamten compound of Formula I or salt thereof has less than about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, or about 0.009% of any one impurity introduced, obtained or produced as a result of the chemical synthesis or degradation, as measured by high pressure liquid chromatography.
In another embodiment, the solid form of the Mavacamten compound of Formula I or salt thereof of the present invention comprises mixture of one or more other crystalline form or amorphous form is not more than about 20%, about 10%, about 5.0%, about 2%, about 1.0%, about 0.5%, about 0.1% or not detectable based on the total volume or weight of the crystalline form.
In another embodiment, the present invention provides a stable amorphous/crystalline form of the compound of Formula I or salt thereof.
In another embodiment, the present invention provides the Mavacamten compound of Formula I or salt thereof that is characterized by particle size distribution wherein, d90 is 0.1µm to 200µm.
In another embodiment, the present invention provides the Mavacamten compound of Formula I or salt thereof that is characterized by particle size distribution wherein, d90 is 2.0 µm to 150µm.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
EXAMPLES
Example 1: Preparation of Mavacamten sodium salt.
Added Mavacamten (545 mg), dichloromethane (5.45 ml) and methanol (5.45 ml) to a dry single neck 25 mL RBF at 20-25°C. Charged NaOH solution (0.33 gm of NaOH in 3.3 mL DM water) into the reaction mass at 20-25°C. Stirred the reaction mass overnight at 20-25°C. Distilled out reaction mass completely at 45°C. Strip out the reaction mass with 10 mL of methanol at 45°C. Degas the reaction mass well 1-2 hrs at 45°C. Unloaded and dried under vacuum at 45°C for 12 hours to get title compound. Purity: 99.8% by HPLC.
Example 2: Preparation of Mavacamten Potassium salt.
Added Mavacamten (API) 545 mg, methanol 5.45 mL and dichloromethane 5.45 mL dry single neck 25mL RBF at 20-25°C. Added KOH solution (0.33 gm KOH + 3.3 mL water) into the reaction mass at 20-25°C. Stirred the reaction mass overnight at 20-25°C. Distilled out reaction mass completely at 45°C. Strip out the reaction mass with 10 mL of Methanol at 45°C. Degassed the reaction mass well 1-2 hrs at 45°C. Unloaded and dried under vacuum at 45°C for 12 hours to get title compound.
Purity: 99.6% by HPLC.
Example 3: Preparation of Mavacamten Calcium salt.
To Mavacamten (545 g) in RBF was added 5.45 ml water, 5.45 ml methanol and calcium hydroxide (0.33 gm CaOH + 3.3 mL water) at 20-25°C and the solution was stirred overnight at room temperature. The solvents were evaporated and the crude was dried over high vacuum to give solid calcium salt of Mavacamten (8 g).
Purity: 99.4 % by HPLC.
Example 4: Preparation of Mavacamten compound of formula I from sodium salt of Mavacamten compound of formula II.
Charged 10g sodium salt of Mavacamten compound of II (Example 1) in a 500mL vessel followed by 100mL of DM water. pH of <2 is adjusted with concentrated HCl. Stirred the slurry for 2-3h at RT. Filtered the slurry, suck dried and dried in air oven at 50oC to get compound of formula I. Purity: 99.6 % by HPLC.
Example 5: Preparation of Mavacamten compound of formula I from calcium salt of Mavacamten compound of formula III.
10g of Calcium salt of Mavacamten compound of III (Example 3) is charged in a 500mL vessel followed by the addition of 100mL of DM water. pH of <2 is adjusted with concentrated HCl. Stirred the slurry for 2-3h at RT. Filtered the slurry, suck dried and dried in air oven at 50oC to get compound of formula I. Purity: 99.4 % by HPLC.
Example 6: Purification of Potassium salt of Mavacamten compound of formula II.
10g Potassium salt of Mavacamten compound of II is charged in a 500mL vessel followed by the addition of 100mL of DM water. pH of <2 is adjusted with concentrated HCl. Stirred the slurry for 2-3h at RT. Filtered the slurry, suck dried and dried in air oven at 50oC to get purified potassium salt of Mavacamten. Purity: 99.7 % by HPLC.
Example 7: Purification of magnesium salt of Mavacamten compound of formula III.
10g Magnesium salt of Mavacamten compound of III is charged in a 500mL vessel followed by the addition of 100mL of DM water. pH of <2 is adjusted with concentrated HCl. Stirred the slurry for 2-3h at RT. Filtered the slurry, suck dried and dried in air oven at 50oC to get purified magnesium salt of Mavacamten.
Purity: 99.4 % by HPLC.
Example 8: Purification of Mavacamten compound of formula I.
Mavacamten compound of formula I is purified in a mixture of alcoholic solvents (isopropyl alcohol, ethanol, methanol or mixture thereof) and water at RT, higher or lower temperature. Filter the slurry, suck dried and dried in air oven at 50oC.
,CLAIMS:We claim:
1. Salts of Mavacamten compound of formula I,

comprising compounds of formulae I-a, II & III,
, , and
wherein M is selected from monovalent or bivalent metal and X is selected from organic/inorganic acid or base.
2. The salts of Mavacamten as claimed in claim 1, comprising compound of formula II and compound of formula III, wherein monovalent metal is selected from sodium, potassium, cesium or lithium and bivalent metal is selected from calcium, magnesium, barium, zinc, strontium, copper or Iron.
3. The salts of Mavacamten as claimed in claim 1 or 2, wherein the said salts comprising:
(i) the sodium salt of Mavacamten, wherein said salt further characterized by data selected from one or more of the following:
a) an X ray powder diffraction spectrum (XRPD) as depicted in Figure 3; or
b) a Thermogravimetric Analysis (TGA) characterized by weight loss about 8.4% up to temperature of 230 ±3 °C or as depicted in Figure 4; or
c) combinations of the above data;
(ii) the potassium salt of Mavacamten, wherein said salt further characterized by data selected from one or more of the following:
a) an X ray powder diffraction spectrum (XRPD) as depicted in Figure 5; or
b) a Thermogravimetric Analysis (TGA) characterized by weight loss about 7.4 % up to temperature of 210 ±3 °C as depicted in Figure 6; or
c) combinations of the above data.
4. The salts as claimed in claim 1, wherein the process for the preparation of salt of Mavacamten compound of formula II or III, comprising the step of:
i) treating Mavacamten compound of formula I with monovalent source to form compound of formula II,

wherein M is monovalent metal selected from sodium, potassium, cesium or lithium; or
ii) treating Mavacamten compound of formula I with bivalent source to form compound of formula III,
,
wherein M is bivalent metal selected from calcium, magnesium, barium, zinc, strontium, copper or Iron.
5. The salts as claimed in claim 1, wherein the process for the preparation of salt of Mavacamten compound of formula III comprising the steps of:
i) treating Mavacamten compound of formula I with monovalent source to form compound of formula II,

wherein M is monovalent metal selected from sodium, potassium, cesium or lithium; and
ii) treating the alkaline metal salt of compound of formula II with bivalent metal source to form compound of formula III,

wherein M is bivalent metal selected from calcium, magnesium, barium, zinc, strontium, copper or Iron.
6. A process for the preparation of Mavacamten freebase compound of formula I from its acceptable salts, comprising the steps of;
i) providing a solution of salts of Mavacamten compound of formula I in one or more solvents;
ii) adding suitable acid to the above solution; and
iii) isolating the Mavacamten compound of formula I.
7. The process as claimed in claim 6, wherein Mavacamten compound of formula I, isolated as crystalline or amorphous solid having purity of 99.5% as measured by HPLC.
8. The process as claimed in claim 6, wherein Mavacamten compound of formula I, isolated as crystalline, characterized by one or more of the following:
a) an X ray powder diffraction spectrum (XRPD) comprising one or more peaks at 2? angle values of 10.0, 11.6, 14.6, 15.7, 16.2, 17.3, 18.7, 20, 22.3, 25.6, 29.0 ±0.2° as depicted in Figure 1; or
b) a Differential Scanning Calorimetry (DSC) plot comprising endothermic peaks at about 216°C, and 252 °C as depicted in Figure 2; or
c) combinations of the above data.

Dated 11th Day of Sept, 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer