Highly soluble salts

Abstract

The present invention relates to a compound selected from the group consisting of a lactate, hydrochloride, tartrate, succinate, citrate and maleate salt of a compound of formula (I). The present invention also relates to certain formulations comprising said compound. (I)

Description

Technical Field

[0001] This invention relates to novel salts and crystalline forms of compounds of formula (I). Furthermore, this invention relates to compounds of formula (I) in solution or solid form for use in pharmaceutical compositions for treating mammals, such as human subjects, who have or are diagnosed with, for example, atrial fibrillation. Background Technology

[0002] The heart is a muscle that pumps circulating blood by contracting 1-3 times per second. A heartbeat is caused by the simultaneous contraction of individual cardiac muscle cells (myocardium). The synchronization of these cell contractions is controlled by cardiac electrical impulses (cardiac action potentials), which are generated in the pacemaker cells of the sinoatrial node and rapidly propagate to the heart via a specific conduction system.

[0003] Disorders in pulse generation and conduction can result from illness, medication, or electrolyte imbalances. These pulse disturbances are called arrhythmias or rhythm disorders, and they can lead to anxiety, embolism, syncope, or sudden death. In its simplest form, arrhythmias include anything that deviates from the normal sinus rhythm of the heart. Disorders can range from simple palpitations to devastating ventricular fibrillation, including bradycardia and tachycardia.

[0004] At the molecular level, a group of proteins called ion channels are fundamental to cardiac electrical activity because they are able to conduct electrical currents across cell membranes. Therefore, different types of ion channels play a role in the generation and conduction of cardiac action potentials, the regulation of heart rate by the autonomic nervous system, and the contraction of individual heart cells. Consequently, different types of ion channels are obvious targets for antiarrhythmic cardiac drugs, and many antiarrhythmic drugs on the market do indeed exert their effects by interacting with ion channels.

[0005] According to the so-called Singh Vaughan Williams classification, antiarrhythmic drugs are generally divided into four classes: Class I compounds all inhibit cardiac voltage-dependent sodium channels. Some Class I compounds do have additional effects affecting cardiac action potentials, which forms the basis for further subdivision into three subclasses: Class IA compounds are sodium channel inhibitors, such as quinidine, procainamide, or disopyramid, which prolong the action potential; Class IB compounds are sodium channel inhibitors, such as lidocaine, mexiletine, tocarneline, or phenytoin, which shorten action potentials; and Class IC compounds are sodium channel inhibitors, such as flecainide, moricizine, or propafenone, which do not alter the duration of action potentials.

[0006] Class II compounds are β-adrenergic receptor inhibitors, including drugs such as atenolol, metamizole, timolol, or propranolol. β-adrenergic receptor inhibitors are selective for cardiac β1 receptors or have affinity for both β1 and β2 receptors.

[0007] Class III compounds are potassium channel inhibitors, such as amiodarone, dronedarone, sotalol, ibutilide, and dofetilide, which can prolong action potentials.

[0008] Class IV compounds are L-type calcium channel inhibitors, such as verapamil.

[0009] Small-conductance calcium-activated potassium (SK) channels belong to the Ca2+ family. 2+ Activate K + Channel family. Three SK channel subtypes have been cloned: SK1, SK2, and SK3 (corresponding to KCNN1-3 using genomic nomenclature). The activity of these channels is mediated by free intracellular calcium ([Ca]) via calmodulin. 2+ The concentration of calmodulin (SK) determines the constitutive binding of the channel. SK channels are widely expressed in the central nervous system (CNS) and peripheral tissues, including the heart.

[0010] SK channel inhibitors are a type of inhibitor that weakens potassium ions (K+). + ) via Ca 2+ Activated small conductance K + Drugs that regulate the conduction of SK channels. Reviews of SK channels and their modulators can be found in Wulff H et al.: “Modulators of Small-and Intermediate-Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications”, Current Medicinal Chemistry 2007 14 1437-1457; and Liegeois JF et al.: “Modulation of small conductance calcium-activated potato (SK) channels: a new challenge in medicinal chemistry”, Current Medicinal Chemistry 2003 10 625-647.

[0011] Based on the SK channel in connecting [Ca 2+ Given their important role in membrane potential and function, SK channels are an interesting target for developing novel therapeutics, and the potential of SK channel inhibitors for antiarrhythmic therapy has been identified, see, for example, Nattel S; J. Physiol. 2009 587 1385-1386; Diness JG, Sørensen US, Nissen JD, Al-Shahib B, Jespersen T, Grunnet M, Hansen RS; Circ. Arrhythm. Electrophysiol. 2010 3 380-90; and Diness et al; Hypertension 2011 57 1129-1135.

[0012] International patent application WO2017 / 144183 describes inhibitors or negative regulators of low-conductivity calcium-activated potassium (SK) channels. Some of these compounds also possess physicochemical properties suitable for pharmaceuticals and are important for the preparation of pharmaceutical formulations. Furthermore, some of these compounds possess pharmacokinetic properties, making them suitable for use as drugs. Example 56 of WO2017 / 144183 describes a particularly useful compound, namely compound (I):

[0013] (I). Summary of the Invention

[0014] This invention relates to a compound selected from lactate, hydrochloride, tartrate, succinate, citrate, and maleate salts of formula (I).

[0015] (I).

[0016] The salts are highly soluble in water and / or mixtures of water and lactic acid. Specifically, at room temperature, the solubility of lactate, hydrochloride, succinate, citrate, and maleate in water is at least 1 mg / mL, and some even at least 4 mg / mL. At room temperature, the free base of compound (I) has relatively low solubility in water, less than 0.5 mg / mL; however, when lactic acid is added, whether alone or as a lactate of compound (I), the solubility increases significantly. When lactic acid is added alone or as a lactate of compound (I), the solubility of hydrochloride, tartrate, succinate, citrate, and / or maleate of compound (I) in water increases at room temperature, with some increases exceeding 50%.

[0017] In one embodiment, the compound is in solid form, such as amorphous, semi-amorphous, semi-crystalline, or crystalline. In another embodiment, the compound is in crystalline form.

[0018] In another embodiment, the compound is selected from salts that can be obtained by reacting a compound of formula (I) with an acid, wherein the acid is selected from lactic acid, HCl, tartaric acid, succinic acid, citric acid and maleic acid.

[0019] In another embodiment, the compound is selected from lactate, hydrochloride, hemitartaric acid, hemisuccinate, hemicitrate, and hemimaleate.

[0020] In another embodiment, the compound is a lactate in solid form, preferably in a crystalline form having the following XRPD peaks: 3.2200 [°2θ], 5.6248 [°2θ], 19.2321 [°2θ], and 25.3221 [°2θ].

[0021] In another embodiment, the compound is a crystalline HCl salt, preferably having the following XRPD peaks: 5.5121 [°2θ], 6.3516 [°2θ], 7.1200 [°2θ], 7.6005 [°2θ], 8.9006 [°2θ], 9.5707 [°2θ], 10.8783 [°2θ], and 12.6826 [°2θ]. [°2θ], 13.5397 position [°2θ], 14.7076 position [°2θ], 15.3655 position [°2θ], 15.6498 position [°2θ], 16.1771 position [°2θ], 16.3977 position [°2θ], 16.7038 position [°2θ], 17.7137 position [°2θ], 17.9872 position [°2θ], 18.4715 position [° [2θ], 19.1970 position [°2θ], 19.3342 position [°2θ], 19.8371 position [°2θ], 20.1291 position [°2θ], 20.6847 position [°2θ], 21.5920 position [°2θ], 22.1415 position [°2θ], 22.9190 position [°2θ], 24.3724 position [°2θ], 25.0984 position [°2θ] ]、25.4518 position [°2θ]、26.0917 position [°2θ]、26.4768 position [°2θ]、27.0813 position [°2θ]、27.3489 position [°2θ]、28.3910 position [°2θ]、30.0421 position [°2θ]、31.3214 position [°2θ]、31.9249 position [°2θ]、33.1039 position [°2θ].

[0022] In another embodiment, the compound is a crystalline hemitaritate, preferably having the following XRPD peaks: 5.4038 [°2θ], 6.1493 [°2θ], 7.3131 [°2θ], 9.1195 [°2θ], 10.0257 [°2θ], 11.1230 [°2θ], 12.7984 [°2θ]. 2θ], 13.8675 position [°2θ], 14.6409 position [°2θ], 15.4125 position [°2θ], 16.1065 position [°2θ], 17.3943 position [°2θ], 18.3377 position [°2θ], 18.6233 position [°2θ], 19.1123 position [°2θ], 19.3903 position [°2θ], 19 0.6856 position [°2θ], 20.1147 position [°2θ], 20.5016 position [°2θ], 20.8607 position [°2θ], 21.8794 position [°2θ], 22.4461 position [°2θ], 23.9178 position [°2θ], 24.3693 position [°2θ], 24.9312 position [°2θ], 25.5910 position Positions [°2θ], 26.7010, 28.0426, 29.3745, 29.7308, 30.7073, 31.2874, 32.6855, 33.6562, and 34.2587 are [°2θ].

[0023] In another embodiment, the compound is a crystalline hemisuccinate, preferably having the following XRPD peaks: 5.6580 [°2θ], 7.3357 [°2θ], 8.1986 [°2θ], 10.7259 [°2θ], 11.6171 [°2θ], 12.2091 [°2θ], 12.4728 [°2θ], 12.9965 [°2θ], 13.766 Position 3 [°2θ], Position 14.7434 [°2θ], Position 15.8677 [°2θ], Position 16.4811 [°2θ], Position 17.0683 [°2θ], Position 18.0981 [°2θ], Position 18.4433 [°2θ], Position 18.8245 [°2θ], Position 19.0046 [°2θ], Position 19.9192 [°2θ], Position 21.0571 [°2θ], Position 21.4078 [°2θ], 22.3724 position [°2θ], 22.9593 position [°2θ], 23.8409 position [°2θ], 24.1665 position [°2θ], 24.5771 position [°2θ], 24.8406 position [°2θ], 25.1205 position [°2θ], 25.5645 position [°2θ], 25.8133 position [°2θ], 26.2217 position [°2θ], 26.4674 position [°2θ] θ], 26.5978 position [°2θ], 27.7801 position [°2θ], 27.9340 position [°2θ], 29.7462 position [°2θ], 30.3368 position [°2θ], 30.9059 position [°2θ], 31.1610 position [°2θ], 32.0284 position [°2θ], 32.4917 position [°2θ], 33.0368 position [°2θ], 34.7039 position [°2θ].

[0024] In another embodiment, the compound is a crystalline hemicitrate, preferably having the following XRPD peaks: 5.5866 [°2θ], 7.1866 [°2θ], 8.6152 [°2θ], 9.5965 [°2θ], 11.0629 [°2θ], 14.4306 [°2θ], 16.0686 [°2θ], 16.6580 [°2θ], 17 .7791 position [°2θ], 18.3213 position [°2θ], 19.4935 position [°2θ], 20.3765 position [°2θ], 21.0489 position [°2θ], 21.7831 position [°2θ], 23.9648 position [°2θ], 26.3998 position [°2θ], 26.6610 position [°2θ], 27.1403 position [°2θ], 28.0543 position [°2θ].

[0025] In another embodiment, the compound is a crystalline form of hemamaleate, preferably having the following XRPD peaks: 5.6099, 6.7751, 8.2693, 14.0558, 17.7186, 18.9592, 20.2532, 22.6761, 24.4336, 24.9746, 26.2849, 28.0237, and 29.7648.

[0026] In yet another embodiment, the compound is a salt that can be obtained by a method comprising the following steps: a) Adding lactic acid, HCl, tartaric acid, succinic acid, citric acid, or maleic acid in solution or suspension form to a compound of formula (I) in the form of a free base or its salt to provide a solution or suspension of the corresponding salt; the free base or its salt form of compound (I) is, for example, a solid, solution, or suspension. b) Obtain the salt as a solid by precipitation or crystallization, for example by cooling, evaporating the solvent, adding an antisolvent or adding to an antisolvent, or by adding a co-crystallizing agent, followed by filtration or centrifugation and optionally purifying the salt.

[0027] In another embodiment, the compound is a salt that can be obtained by the method described in the experimental section of this document.

[0028] In yet another embodiment, the compound has a solubility of at least 5 mg / mL, for example 5-20 mg / mL, in a solution mixture of water and lactic acid at room temperature.

[0029] In another respect, the present invention relates to compounds of formula (I),

[0030] (I) The compound of formula (I) is selected from crystal form B having the following XRPD peaks: Positions 5.4583 [°2θ], 8.6494 [°2θ], 9.4935 [°2θ], and 9.9758 [°2θ] Positions at 11.0201 [°2θ], 11.6273 [°2θ], 12.2790 [°2θ], and 13.2330 [°2θ] are also mentioned. Positions at 14.5131 [°2θ], 14.6913 [°2θ], 16.0913 [°2θ], and 16.6654 [°2θ] Positions at 17.3892°2θ, 17.8785°2θ, 20.0832°2θ, and 20.7572°2θ. Positions at 21.1411 [°2θ], 21.8912 [°2θ], 22.9346 [°2θ], and 23.3471 [°2θ] are also mentioned. Positions at 23.7332°2θ, 24.4525°2θ, 25.4370°2θ, and 25.6615°2θ are also mentioned. Positions 26.7014 [°2θ], 27.3638 [°2θ], 27.8805 [°2θ], and 30.2132 [°2θ].

[0031] In another aspect, the present invention relates to pharmaceutical compositions comprising compounds selected from lactates, hydrochlorides, tartrates, succinates, citrates, and maleates of formula (I), as well as any of the above-described embodiments of the compounds of the present invention, and optional pharmaceutically acceptable additives, such as carriers or excipients.

[0032] In another embodiment, the pharmaceutical composition is in a solid oral form, such as a tablet. In some embodiments, the solid oral composition is a tablet containing 10 mg to 100 mg of a compound of formula (I) or any salt described herein, for example 20-80 mg, preferably 30-70 mg, such as 50 mg of a compound of formula (I).

[0033] In another embodiment, the pharmaceutical composition is a liquid solution, such as an intravenous (IV) solution.

[0034] In another aspect, the present invention relates to liquid compositions, such as intravenous (IV) solutions, comprising a compound of formula (I) and lactic acid, and optionally an acid selected from HCl, tartaric acid, succinic acid, citric acid and maleic acid, and optionally a water-soluble PEG, such as PEG400.

[0035] (I).

[0036] In one embodiment, the composition is an IV solution for infusion containing 1 mg / mL to 10 mg / mL, for example 2-8 mg / mL, preferably 5-8 mg / mL, more preferably 8-10 mg / mL of the compound of formula (I).

[0037] In another embodiment, the composition is a liquid concentrate for infusion solution containing 10 mg / mL to 200 mg / mL, for example 10-50 mg / mL, preferably 50-100 mg / mL, more preferably 100-200 mg / mL of the compound of formula (I).

[0038] In another aspect, the present invention relates to compounds selected from the compounds of formula (I) such as lactates, hydrochlorides, tartrates, succinates, citrates, and maleates, as well as any of the above-described embodiments of the compounds of the present invention, for use in methods of treating heart diseases, disorders, or conditions in mammals such as humans.

[0039] In another aspect, the present invention relates to a composition comprising a compound selected from lactate, hydrochloride, tartrate, succinate, citrate and maleate of formula (I), and any of the above embodiments of the composition of the present invention, for use in a method of treating heart disease, disorder or ailment in mammals such as humans.

[0040] In another aspect, the present invention relates to compounds selected from the compounds of formula (I) such as lactates, hydrochlorides, tartrates, succinates, citrates and maleates, and any of the above embodiments of the compounds of the present invention, in a method for treating a heart disease, disorder or condition, wherein the disease, disorder or condition is related to a heart rhythm abnormality.

[0041] In another aspect, the present invention relates to a composition comprising a compound selected from the compounds of formula (I) including lactate, hydrochloride, tartrate, succinate, citrate and maleate, and any of the above embodiments of the composition of the present invention, for a method of treating a heart disease, disorder or condition, wherein the disease, disorder or condition is related to a heart rhythm abnormality.

[0042] In another aspect, the present invention relates to compounds selected from the lactate, hydrochloride, tartrate, succinate, citrate and maleate of formula (I), and any of the above embodiments of the compounds of the present invention, for the treatment of arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal rhythms occurring after cardiac surgery or cardiac ablation.

[0043] In other respects, the present invention relates to a composition comprising a compound selected from lactate, hydrochloride, tartrate, succinate, citrate, and maleate of formula (I), and any of the above-described embodiments of the composition of the present invention, for use in the treatment of a heart disease, disorder, or condition selected from arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradycardia, and abnormal rhythms occurring after cardiac surgery or cardiac ablation. Detailed Implementation

[0044] This invention relates to compounds selected from lactates, hydrochlorides, tartrates, succinates, citrates and maleates of formula (I), and stable polymorphs of free bases of formula (I) compounds referred to as type B.

[0045]

[0046] (I); Type B and its salts are highly soluble in water and / or mixtures of water and lactic acid, which provides the unique formulation options described herein.

[0047] In another embodiment, the compound is a lactate in solid form, preferably a crystalline form having the following XRPD peaks:

[0048] The XRPD details described above identify the specific salt; however, as described herein, the salt is not only crystalline but also has an amorphous composition.

[0049] In another embodiment, the compound is a crystalline form of an HCl salt, preferably a crystalline form having the following XRPD peaks:

[0050] The above XRPD details identify the specific salt; however, in some implementations, the XRPD peaks characterizing the salt are selected from the 10 peaks with the highest relative intensity (Rel. Int%).

[0051] In yet another embodiment, the compound is a crystalline hemitaritate, preferably a crystalline form having the following XRPD peaks:

[0052] The above XRPD details identify the specific salt; however, in some implementations, the XRPD peaks characterizing the salt are selected from the 10 peaks with the highest relative intensity (Rel. Int%).

[0053] In another embodiment, the compound is a crystalline hemisuccinate, preferably a crystalline form having the following XRPD peaks:

[0054] The above XRPD details identify the specific salt; however, in some implementations, the XRPD peaks characterizing the salt are selected from the 10 peaks with the highest relative intensity (Rel. Int%).

[0055] In another embodiment, the compound is a crystalline form of hemicitrate, preferably a crystalline form having the following XRPD peaks:

[0056] The above XRPD details identify the specific salt; however, in some implementations, the XRPD peaks characterizing the salts are selected from the 10 peaks with the highest relative intensities (Rel. Int%).

[0057] In another embodiment, the compound is a crystalline form of hemimaleate, preferably a crystalline form having the following XRPD peaks:

[0058] The above XRPD details identify the specific salt; however, in some implementations, the XRPD peaks characterizing the salt are selected from the 10 peaks with the highest relative intensity (Rel. Int%).

[0059] In another respect, the present invention relates to compounds of formula (I):

[0060] (II) The compound of formula (I) is selected from crystal form B having the following XRPD peaks:

[0061] The above XRPD details identify the specific salt; however, in some implementations, the XRPD peaks characterizing the salt are selected from the 10 peaks with the highest relative intensity (Rel. Int%).

[0062] Throughout this document and throughout the specification and claims, XRPD details are described in the following section on analytical methods, where the specific wavelength type is Kα1 1.540598 Å.

[0063] Unless otherwise stated or clearly contradicted by the context, in X-ray powder diffraction (XRPD), “compound of formula (I)” or “compound of formula (I)” (which may be used interchangeably) as used herein refers to a compound of formula (I) in its free base form.

[0064]

[0065] Compounds of formula (I) may be in solid form, such as amorphous or crystalline, or in liquid form.

[0066] As used herein, the terms "treatment" and "treating" refer to the management and care of a patient in order to combat a condition (e.g., disease or disorder). The term is intended to encompass all treatment of a given condition suffered by a patient, such as the administration of active compounds to alleviate symptoms or complications, slow the progression of the disease, disorder, or symptom, reduce or alleviate symptoms and complications, and / or cure or eliminate the disease, disorder, or symptom, as well as prevention of the condition. Prevention should be understood as the management and care of a patient for the purpose of combating a disease, symptom, or disorder, and includes the administration of active compounds to prevent the onset of symptoms or complications. Treatment can be carried out in an acute or chronic manner. Patients to be treated are preferably mammals; particularly humans, but may also include animals such as dogs, cats, cattle, sheep, and pigs.

[0067] The term “pharmaceutically acceptable salt” as used herein is used to describe a salt suitable for human or animal use. Examples of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, PH Stahl and CG Wermuth, editors, Weinheim / Zurich:Wiley-VCH / VHCA, 2002. Pharmaceutically acceptable salts of compounds of formula (I) include salts formed in the human or animal body after administration of the compound.

[0068] As used herein, the term "therapeutic effective amount" for compounds of formula (I) of this invention refers to an amount sufficient to cure, alleviate, or partially suppress the clinical manifestations of a given disease and its complications. An amount sufficient to achieve this purpose is defined as a "therapeutic effective amount." The effective amount for each purpose will depend on the severity of the disease or injury, as well as the subject's weight and general condition. It should be understood that appropriate dosages can be determined using standard experimental methods, by constructing a numerical matrix and testing the differences in the matrix, within the scope of the common skill of a trained physician or veterinarian.

[0069] As used herein, “pharmaceuticalally acceptable additives” are intended, but are not limited to, carriers, excipients, diluents, adjuvants, colorants, fragrances, preservatives, etc., that a person skilled in the art would consider using when formulating the compounds of the present invention to prepare pharmaceutical compositions.

[0070] The adjuvants, diluents, excipients, and / or carriers that can be used in the compositions of the present invention must be pharmaceutically acceptable, i.e., compatible with the compound of formula (I) and other components of the pharmaceutical composition, and harmless to the recipient. Preferably, the composition should not contain any substances that may cause adverse reactions (e.g., allergic reactions). The adjuvants, diluents, excipients, and carriers that can be used in the pharmaceutical compositions of the present invention are well known to those skilled in the art.

[0071] As described above, in addition to the compounds disclosed herein, the compositions disclosed herein, particularly pharmaceutical compositions, may also contain at least one pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% by weight of the at least one pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier, and 0.1% to 99.9% by weight of the compounds disclosed herein. The total amount of the active ingredient and the pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier does not exceed 100% by weight of the composition, particularly the pharmaceutical composition.

[0072] In some implementations, only one compound disclosed herein is used for the above purposes.

[0073] In some embodiments, two or more compounds disclosed herein are combined for the above-described purposes.

[0074] This composition, particularly pharmaceutical compositions comprising the compounds described herein, may be suitable for oral, intravenous, topical, intraperitoneal, intranasal, oral, sublingual, or subcutaneous administration, or for administration via the respiratory tract, for example, in the form of an aerosol or air-suspended fine powder. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches, or suppositories.

[0075] Other implementations of the method are described in the experimental section of this paper, and each individual method and each starting material constitutes an implementation that can form part of the implementation.

[0076] The above embodiments should be considered as relating to any aspect described herein (e.g., "treatment method", "pharmaceutical composition", "compound used as a medicine" or "compound used in a method"), and any embodiment described herein, unless specifically stated that the embodiments relate to one or more aspects of the invention.

[0077] All references cited in this article, including publications, patent applications and patents, are incorporated herein by reference as if each reference were individually and specifically indicated as incorporated herein by reference and are fully elaborated in this article.

[0078] All headings and subheadings used herein are for convenience only and should not be construed as limiting the invention in any way.

[0079] This invention includes any combination of the above-described elements in all possible variations, unless otherwise stated herein or obviously contradicted by the context.

[0080] The terms “a,” “an,” and “the,” as used in the context of describing this invention, and similar indicators, shall be construed as encompassing both the singular and plural, unless otherwise stated herein or clearly contradicted by the context. In particular, the terms “a,” “an,” and “the” may be used interchangeably with “at least one” or “one or more,” and have such meanings, unless clearly contradicted by the context.

[0081] Unless otherwise stated herein, the descriptions of numerical ranges herein are intended only as a shorthand for individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were described separately herein. Unless otherwise stated, all precise values ​​provided herein represent corresponding approximations (e.g., all precise exemplary values ​​provided with respect to a specific factor or measurement may also be considered as providing corresponding approximate measurements, modified with "about" where appropriate).

[0082] Unless otherwise stated in this document or clearly contradicted by the context, all methods described herein may be performed in any suitable order.

[0083] Unless otherwise stated, the use of any and all embodiments or exemplary language (e.g., “such as”) provided herein is merely for the purpose of better illustrating the invention and does not constitute a limitation on the scope of the invention. No language in the specification should be construed as indicating that any element is essential to the implementation of the invention unless equally expressly stated otherwise.

[0084] The references and associations to patent documents in this article are for convenience only and do not reflect any opinion on the validity, patentability and / or enforceability of such patent documents.

[0085] The description of any aspect or embodiment of the invention uses terms relating to one or more elements, such as “comprising,” “having,” “including,” or “containing,” intended to support similar aspects or embodiments of the invention, namely “consisting of the particular one or more elements,” “substantially consisting of the particular one or more elements,” or “substantially comprising the particular one or more elements,” unless otherwise stated or clearly contradicted by the context (e.g., a composition described herein as including a particular element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by the context).

[0086] To the fullest extent permitted by applicable law, this invention includes all modifications and equivalents of the subject matter set forth herein or in the claims.

[0087] The invention is further illustrated by the following embodiments; however, these embodiments should not be construed as limiting the scope of protection. The features disclosed in the foregoing description and the following embodiments, whether individually or in any combination, are important for implementing the invention in different forms.

[0088] Example General Experiment Information Common Abbreviations CPME cyclopentyl methyl ether DSC Differential Scanning Calorimeter Eq equivalent Et Ethyl L-level M Moore m milligrams TBME methyl tert-butyl ether TGA thermogravimetric analysis THF tetrahydrofuran IPA isopropyl alcohol PEG 400 (Polyethylene Glycol 400) RT room temperature XRPDX Powder Diffraction Analytical methods X-ray powder diffraction (XRPD) X-ray powder diffraction patterns were collected on a PANalytical diffractometer using Cu Kα radiation (45 kV, 40 mA), an θ–θ goniometer, a focusing lens, a diverging slit (1 / 2”), a Soller slit (4 mm) at the incident and diverging beams, and a PIXcel detector. In this study, the specific wavelength type was Kα1 1.540598 Å. The software used for data collection was X'Pert Data Collector, version 2.2f, and the data were displayed using X'Pert Data Viewer, version 1.2d. XRPD patterns were obtained under ambient conditions using PANalytical X'Pert PRO through a transmission foil sample stage (polyimide-Kapton, 12.7 μm thick film). The data collection range was 2.994–35°2θ, with a continuous scan rate of 0.202004ºs. -1 .

[0089] Differential scanning calorimetry (DSC) DSC data were collected on a PerkinElmer Pyris 6000 DSC equipped with a 45° sample holder. The instrument was calibrated for energy and temperature using certified indium. Pre-calculated sample volumes (0.5–3.0 mg) were placed in a pinhole aluminum dish and heated from 30°C to 350°C at a rate of 20°C / min, or as required by the experiment. The sample was purged with dry nitrogen at a rate of 20 mL / min. Instrument control, data acquisition, and analysis were performed using Pyris software v11.1.1 (Revision H).

[0090] Thermogravimetric analysis (TGA) TGA data were collected on a PerkinElmer Pyris 1 TGA instrument equipped with a 20° position autosampler. The instrument was calibrated using certified weights and certified aluminum alloys and Perkalloy for temperature control. Pre-weighed samples (1–5 mg) were loaded onto pre-weighed aluminum crucibles and heated from ambient temperature to 400°C at a rate of 20°C / min. The samples were purged with nitrogen at a rate of 20 mL / min. Instrument control, data acquisition, and analysis were performed using Pyris software v11.1.1 (Revision H).

[0091] Example 1: Preparation of the compound of the present invention Preliminary screening for salt formation and crystallization Based on solubility information obtained from in-house chemical development, ethyl acetate, ethanol, and acetonitrile / water (4:1) were selected as solvents for salt screening. The range of acid counterions was selected based on the estimated pKa values ​​of the compounds of formula (I) and their acceptability / use in commercially available drugs. The free base of the compound of formula (I) (50 mg) was loaded into 36 crystallization tubes, followed by the addition of the relevant solvent (1 mL / 20 volumes). The reaction mixture was heated to 60 °C to dissolve the compound. The relevant acid, either a 1 M ethanol solution or a solid charge, was added to these solutions. The mixture was held at 60 °C for 1 hour, then gradually cooled to room temperature and equilibrated for 16 hours. For each resulting suspension, the solid was separated by vacuum filtration and dried under vacuum at 40 °C for 16 hours, analyzed by XRPD. For the mixture remaining in solution, the solvent volume was reduced by slow evaporation under nitrogen; if no precipitation occurred after approximately 50% reduction of the solvent volume, complete evaporation was permitted, and diethyl ether or heptane (20 volumes) was added. The solid was separated by vacuum filtration and dried under vacuum at 40°C for 16 hours, and then analyzed by XRPD.

[0092] Large-scale selective salt formation Initial salt screening identified several crystalline and amorphous salts that exhibited favorable properties regarding water solubility and pH. Experiments were conducted to demonstrate that the formation of each salt could be successfully replicated on a large scale. The formation of each salt was carried out on 150 mg of the free base of compound (I), reflecting the successful conditions employed in the initial salt screening.

[0093] Quantitative solubility study in various aqueous media The solubility of the compounds of formula (I) in HCl, hemisuccinate, hemimaleate, hemicitrate, and hemitartrate, as well as the free base of formula (I), in water containing an equivalent of 50 mM lactic acid, with and without PEG 400, was evaluated. The stability of the compounds in aqueous media at room temperature was also evaluated after a period of aging. Each salt (15 mg) was stirred in an aqueous medium (A: water / 50 mM lactic acid, B: water / 50 mM lactic acid / 2% w / v PEG 400) (1 mL) at 25 °C for 24 hours. Any solids were separated by vacuum filtration. The content of the compounds of formula (I) in the filtrate was determined by HPLC. The filtrate was aged for one week, with periodic observation for any redeposition and assessment of chemical purity. The filtrate was aged for another two weeks and reassessed.

[0094] The results of the solubility assessment are shown below:

[0095] Example 2: Preparation of the crystalline form of the free base of compound (I) Crystallization of saturated solution upon cooling The solid compound of formula (I) (30 mg) was loaded into a 12× crystallizer tube. Solvent (1 mL) was added. Items 1-8 (see table below) were heated to 70°C to obtain a solution, clarified into a preheated test tube, slowly cooled to 25°C, and equilibrated for 24 hours. When the material did not dissolve, the suspension was hot-filtered to separate the solid. Items 9-12 were heated to 40°C and held for 15 minutes to achieve dissolution, and the solution was clarified into a preheated test tube, cooled, and equilibrated at 25°C for 24 hours. With the obtained suspension, the solid was separated by vacuum filtration. The solution was cooled to -5°C, and the solvent volume was reduced by 50% to induce precipitation. The solid was vacuum-dried at 55°C for 24 hours. The results and observations of cooling crystallization of saturated solutions in various solvents and solvent mixtures are as follows:

[0096] The solids separated from THF (Table, Item 3) have an XRPD pattern corresponding to type A, with the following peaks:

[0097] As with previously observed thermal patterns, DSC thermal images of type A solids contain numerous thermal events.

[0098] Two representative solids, designated as type B by XRPD, were also subjected to thermal analysis by DSC. These solids were isolated from IPA and ethanol / water cooling crystallization.

[0099] These thermal data indicate a single solid phase. The thermal spectra of these type B solids, with much higher melting temperatures, are more favorable than those of type A, suggesting that this is the preferred solid form of the compound of formula (I).

[0100] Mixed solvent cooling crystallization Stock solutions of compound (I) (150 mg) in ethyl acetate (A) (5.63 mL), ethanol (B) (5.63 mL), acetonitrile (1.88 mL), and 3-methyl-2-butanone (5.63 mL) were prepared at 55 °C. The solutions were clarified through a 0.45 μm syringe filter, and aliquots (approximately 25 mg of active ingredient) were placed into preheated test tubes. The solutions were equilibrated to 55 °C, and the antisolvent (0.25 mL) was slowly added. The mixture was slowly cooled to 25 °C and equilibrated for 24 hours. A suspension was obtained, and the solid was separated by vacuum filtration. The solution was cooled to -5 °C, and the solvent volume was reduced by 50% to induce precipitation. The solid was vacuum dried at 55 °C for 24 hours. The results and observations of crystallization from the mixed solvent and antisolvent mixtures are as follows:

[0101] All solids obtained by cooling and crystallizing from a mixed solvent of ethyl acetate and ethanol were XRPD type B (I) compounds. Notably, the solids returned by crystallization from ethyl acetate and heptane via XRPD and DSC were single-phase type B.

[0102] formal hierarchical balance To establish a hierarchical classification of the various forms / versions of compound (I), competitive equilibrations were performed in numerous solvents to reveal the preferred form and metastable version at a given temperature. Competitive equilibrations were performed on mixtures containing equal amounts of compound (I) (types A and B) in water, IPA, toluene, ethyl acetate, 2-chlorobutane, trifluorotoluene, and CPME. The solids were suspended by stirring and equilibrated at 25 °C for 24 hours. The solids were then separated and dried under vacuum at 55 °C. The table below lists the hierarchical equilibration results for types A and B in various solvents at 25 °C. In summary, type B predominates, further supporting its position as the thermodynamically preferred form.

[0103]

[0104] Example 3: Preparation of solid dosage form of the compound of the present invention.

[0105] Examples of solid dosage forms are described in the table below, which outlines three compositions. The formulation was prepared by dissolving a compound of formula (I) in a molten medium and slowly pouring the mixture onto a carrier in a high-shear mixer equipped with a 1-liter bowl, then cooling with ice. The resulting granules were sieved through a Comil 2388 sieve, mixed with an excipient, and subsequently pressed.

[0106]

[0107] Example 4: Preparation of a 200 mg / mL concentrate for infusion solution In one embodiment, appropriate amounts of propylene glycol (3500 mL) and lactic acid (315 g) are added to a manufacturing vessel and mixed until the mixture appears homogeneous. While stirring, compound (I) (700 g) is added to the mixture and mixed until all substances are dissolved, resulting in a clear yellow solution. The bulk solution is filtered through two sterile 0.22 μm membrane filters and aseptically filled into sterile 10 mL injection vials and sealed. This concentrated formulation of 200 mg / mL compound (I) for infusion is a pale yellow viscous solution, diluted with 5% glucose prior to administration to provide a final 10 mg / mL solution.

Claims

1. A compound selected from lactate, hydrochloride, tartrate, succinate, citrate, and maleate salts of compounds of formula (I), （I）。 2. The compound according to claim 1, wherein the compound is in solid form.

3. The compound according to claim 1 or 2, wherein the compound is in crystalline form.

4. The compound according to any one of claims 1-3, wherein the compound is selected from salts obtained by reacting a compound of formula (I) with an acid, wherein the acid is selected from lactic acid, HCl, tartaric acid, succinic acid, citric acid and maleic acid.

5. The compound according to any one of claims 1-4, wherein the compound is selected from lactate, hydrochloride, hemitartaric acid salt, hemisuccinate, hemicitrate and hemimaleate.

6. The compound according to any one of claims 1-5, wherein the compound is a lactate in solid form, preferably having the following XRPD peaks, wherein the specific wavelength types are Kα1 1.540598 Å: 3.2200 position [°2θ], 5.6248 position [°2θ], 19.2321 position [°2θ] and 25.3221 position [°2θ].

7. The compound according to any one of claims 1-5, wherein the compound is a crystalline HCl salt, preferably having the following XRPD peaks, specifically the wavelength type Kα1 1.540598 Å: 5.5121 [°2θ], 6.3516 [°2θ], 7.1200 [°2θ], 7.6005 [°2θ], 8.9006 [°2θ], 9.5707 [°2θ], 10.8783 [°2θ], 12.6826 [°2θ], 13.5397 [°2θ], 14.7 076 position [°2θ], 15.3655 position [°2θ], 15.6498 position [°2θ], 16.1771 position [°2θ], 16.3977 position [°2θ], 16.7038 position [°2θ], 17.7137 position [°2θ], 17.9872 position [°2θ], 18.4715 position [°2θ], 19.1970 position [°2θ] ]、19.3342 position [°2θ]、19.8371 position [°2θ]、20.1291 position [°2θ]、20.6847 position [°2θ]、21.5920 position [°2θ]、22.1415 position [°2θ]、22.9190 position [°2θ]、24.3724 position [°2θ]、25.0984 position [°2θ]、25.451 Position 8 [°2θ], Position 26.0917 [°2θ], Position 26.4768 [°2θ], Position 27.0813 [°2θ], Position 27.3489 [°2θ], Position 28.3910 [°2θ], Position 30.0421 [°2θ], Position 31.3214 [°2θ], Position 31.9249 [°2θ], Position 33.1039 [°2θ].

8. The compound according to any one of claims 1-5, wherein the compound is a crystalline hemitaritate, preferably having the following XRPD peaks, wherein the specific wavelength type is Kα1 1.540598 Å: 5.4038 [°2θ], 6.1493 [°2θ], 7.3131 [°2θ], 9.1195 [°2θ], 10.0257 [°2θ], 11.1230 [°2θ], 12.7984 [°2θ], 13.8675 [°2θ], 14.640 Position 9 [°2θ], Position 15.4125 [°2θ], Position 16.1065 [°2θ], Position 17.3943 [°2θ], Position 18.3377 [°2θ], Position 18.6233 [°2θ], Position 19.1123 [°2θ], Position 19.3903 [°2θ], Position 19.6856 [°2θ], 20.1 Position 147 [°2θ], Position 20.5016 [°2θ], Position 20.8607 [°2θ], Position 21.8794 [°2θ], Position 22.4461 [°2θ], Position 23.9178 [°2θ], Position 24.3693 [°2θ], Position 24.9312 [°2θ], Position 25.5910 [°2θ], Position 26 .7010 position [°2θ], 28.0426 position [°2θ], 29.3745 position [°2θ], 29.7308 position [°2θ], 30.7073 position [°2θ], 31.2874 position [°2θ], 32.6855 position [°2θ], 33.6562 position [°2θ], 34.2587 position [°2θ].

9. The compound according to any one of claims 1-5, wherein the compound is a crystalline hemisuccinate, preferably having the following XRPD peaks, wherein the specific wavelength type is Kα1 1.540598 Å: 5.6580 position [°2θ], 7.3357 position [°2θ], 8.1986 position [°2θ], 10.7259 position [°2θ], 11.6171 position [°2θ], 12.2091 position [°2θ], 12.4728 position [°2θ], 12.9965 position [°2θ], 13.7663 position [°2θ], 14.7434 position [°2θ], 15 0.8677 position [°2θ], 16.4811 position [°2θ], 17.0683 position [°2θ], 18.0981 position [°2θ], 18.4433 position [°2θ], 18.8245 position [°2θ], 19.0046 position [°2θ], 19.9192 position [°2θ], 21.0571 position [°2θ], 21.4078 position [°2θ], 22.3724 position [°2θ] 2θ], 22.9593 position [°2θ], 23.8409 position [°2θ], 24.1665 position [°2θ], 24.5771 position [°2θ], 24.8406 position [°2θ], 25.1205 position [°2θ], 25.5645 position [°2θ], 25.8133 position [°2θ], 26.2217 position [°2θ], 26.4674 position [°2θ], 26.59 Position 78 [°2θ], Position 27.7801 [°2θ], Position 27.9340 [°2θ], Position 29.7462 [°2θ], Position 30.3368 [°2θ], Position 30.9059 [°2θ], Position 31.1610 [°2θ], Position 32.0284 [°2θ], Position 32.4917 [°2θ], Position 33.0368 [°2θ], Position 34.7039 [°2θ].

10. The compound according to any one of claims 1-5, wherein the compound is a crystalline hemicitrate, preferably having the following XRPD peaks, wherein the specific wavelength type is Kα1 1.540598 Å: 5.5866 [°2θ], 7.1866 [°2θ], 8.6152 [°2θ], 9.5965 [°2θ], 11.0629 [°2θ], 14.4306 [°2θ], 16.0686 [°2θ], 16.6580 [°2θ], 17.7791 [°2θ], 18.3 Position 213 [°2θ], Position 19.4935 [°2θ], Position 20.3765 [°2θ], Position 21.0489 [°2θ], Position 21.7831 [°2θ], Position 23.9648 [°2θ], Position 26.3998 [°2θ], Position 26.6610 [°2θ], Position 27.1403 [°2θ], Position 28.0543 [°2θ].

11. The compound according to any one of claims 1-5, wherein the compound is a crystalline hemamaleate, preferably having the following XRPD peaks, wherein the specific wavelength type is Kα1 1.540598 Å: 5.6099, 6.7751, 8.2693, 14.0558, 17.7186, 18.9592, 20.2532, 22.6761, 24.4336, 24.9746, 26.2849, 28.0237, and 29.7648.

12. The compound according to any one of claims 1-11, wherein the compound is a salt obtained by a method comprising the following steps: c) Adding lactic acid, HCl, tartaric acid, succinic acid, citric acid, or maleic acid in solution or suspension form to a free base or salt thereof of compound (I) to provide a solution or suspension of the corresponding salt; said free base or salt thereof of compound (I) is, for example, a solid, solution, or suspension. d) Obtaining the salt as a solid by precipitation or crystallization, for example by cooling, evaporating the solvent, adding an antisolvent or adding to an antisolvent, or by adding a co-crystallizing agent, followed by filtration or centrifugation and optionally purifying the salt.

13. The compound according to any one of claims 1-12, wherein the compound is a salt obtained by the method described in the experimental section herein.

14. The compound according to any one of claims 1-13, wherein at room temperature, the compound has a solubility of at least 5 mg / mL, for example 5-20 mg / mL, in a mixed solution of water and lactic acid.

15. A compound of formula (I), （I） The compound of formula (I) is selected from crystal form B having the following XRPD peaks, specifically wavelength type Kα1 1.540598 Å: Positions 5.4583 [°2θ], 8.6494 [°2θ], 9.4935 [°2θ], and 9.9758 [°2θ] Positions at 11.0201 [°2θ], 11.6273 [°2θ], 12.2790 [°2θ], and 13.2330 [°2θ] are also mentioned. Positions at 14.5131 [°2θ], 14.6913 [°2θ], 16.0913 [°2θ], and 16.6654 [°2θ] Positions at 17.3892°2θ, 17.8785°2θ, 20.0832°2θ, and 20.7572°2θ. Positions at 21.1411 [°2θ], 21.8912 [°2θ], 22.9346 [°2θ], and 23.3471 [°2θ] are also mentioned. Positions at 23.7332°2θ, 24.4525°2θ, 25.4370°2θ, and 25.6615°2θ are also mentioned. Positions at 26.7014 [°2θ], 27.3638 [°2θ], 27.8805 [°2θ], and 30.2132 [°2θ].

16. A pharmaceutical composition comprising the compound of any one of claims 1-15, and optionally a pharmaceutically acceptable additive, such as a carrier or excipient.

17. The pharmaceutical composition of claim 16, wherein the composition is in a solid oral form, such as a tablet.

18. The pharmaceutical composition according to claim 16, wherein the composition is a liquid solution, such as IV solution.

19. A liquid composition, such as a solution of formula (IV), comprising a compound of formula (I) and lactic acid, and optionally an acid selected from HCl, tartaric acid, succinic acid, citric acid and maleic acid, and optionally a water-soluble PEG, such as PEG400. （I）。 20. The liquid composition according to claim 19, wherein the composition is an IV solution containing a compound of formula (I) at a concentration of 1 mg / mL to 10 mg / mL, for example 2-8 mg / mL, preferably 5-8 mg / mL, more preferably 8-10 mg / mL.

21. The liquid composition according to claim 19, wherein the composition is a liquid concentrate of a solution for infusion, the liquid concentrate comprising 10 mg / mL to 200 mg / mL, for example 10-50 mg / mL, preferably 50-100 mg / mL, more preferably 100-200 mg / mL of a compound of formula (I).

22. The compound according to any one of claims 1-15 or the composition according to any one of claims 16-21, in a method of treating a heart disease, disorder or ailment in a mammal, such as a human.

23. A method of treating a heart disease, disorder, or condition with respect to any one of the compounds of claims 1-15 or any one of the compositions of claims 16-21, wherein the disease, disorder, or condition is associated with an abnormal rhythm of the heart.

24. A method of treating a heart disease, disorder, or condition using a compound according to any one of claims 1-15 or a composition according to any one of claims 16-21, wherein the heart disease, disorder, or condition is selected from arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradycardia, and abnormal rhythms occurring after cardiac surgery or cardiac ablation.

Images