Choline salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid

Abstract

The present invention relates to the choline salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid (choline salt). In particular, the present invention relates to a compound according to formula (II) [Formula 1] TIFF2024524531000029.tif57170 or a tautomer, solvate or hydrate thereof, and the medical use of a choline salt according to the invention.

Description

[Technical field]

[0001] The present invention relates to the choline salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid (choline salt). 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid is a compound of formula (I).

[0002] [ka]

[0003] In particular, the present invention relates to a compound of formula (I) which is a choline salt, or a solvate or hydrate thereof.

[0004] The present invention relates to 2-hydroxy-N,N,N-trimethylethanaminium-2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate (hereinafter also referred to as "the choline salt of the present invention" or "the choline salt of the present invention"). The choline salt of the present invention is a compound according to formula (II):

[0005] [ka]

[0006] or a tautomer, solvate or hydrate thereof.

[0007] Furthermore, the present invention relates to a method for producing a - a crystalline choline salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid (a choline salt according to the invention), preferably a crystalline choline salt of Form A; - a process for preparing the choline salt according to the invention; said choline salts according to the invention for the treatment and / or prevention of diseases; - the use of said choline salt according to the invention for the preparation of a medicament for the treatment and / or prevention of a disease; a pharmaceutical composition comprising the choline salt according to the invention; and - a pharmaceutical combination comprising the choline salt according to the invention and one or more further pharmaceutical agents. Regarding. [Background technology]

[0008] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid is a compound of formula (I)

[0009] [ka]

[0010] (hereinafter referred to as "compound of formula (I)" or "free acid"), is a proprietary antagonist of the human bradykinin B1 receptor (gene name BDKRB1, gene ID 623; see Example 3 of International Patent Application WO 2018 / 114786(A1), filed December 18, 2017). The bradykinin B1 receptor is a membrane-bound G protein-coupled receptor and is linked to a second messenger system that causes an increase in intracellular calcium concentration. The main signaling pathway is associated with Gq protein and phospholipase C (Leeb-Lundberg, LM et al. (2005), Pharmacol Rev 57(1): 27-77). The compound of formula (I) exhibits a broad spectrum of activity both in vitro and in vivo against bradykinin B1 receptor-associated disorders and diseases, such as endometriosis, neuropathic pain, and overactive bladder.

[0011] Said compound of formula (I) can be synthesized according to the methods set out in International Patent Application WO 2018 / 114786(A1), filed on December 18, 2017, which is incorporated herein by reference in its entirety, for example on page 113 et seq., in particular the methods disclosed for Example 3 of WO 2018 / 114786(A1).

[0012] Experiments required for pharmaceutical development include toxicity testing. To this end, it is desirable to have good pharmacokinetic properties, i.e., bioavailability, over a wide dose range to provide sufficient exposure for reliable toxicity testing in vivo. However, it has surprisingly been found that free acids do not provide sufficient bioavailability at higher doses that would allow the compound to be further tested for toxicity. Furthermore, throughout the development of a compound for pharmaceutical use, it is desirable to have good pharmacokinetic properties, i.e., bioavailability, to provide sufficient exposure in the treated patient. Since such sufficient exposure, i.e., sufficient exposure to ameliorate or cure the disease, is unknown prior to each test, it is desirable to provide the compound in a form that provides said good pharmacokinetic properties over a wide dose range.

[0013] Attempts to increase the bioavailability of compounds by producing salts have revealed that the majority of salts tested are at least partially amorphous. For a salt to be suitable for pharmaceutical development, it is desirable for it to be in crystalline form. Amorphous salts are difficult to handle because they are not usually free-flowing under pharmaceutical processing conditions.

[0014] Thus, there is a need for a form of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid that has sufficient bioavailability over a wide dosage range, has a crystalline form that can be advantageously used in pharmaceutical processes and compositions, and is not hygroscopic. Summary of the Invention

[0015] The inventors of the present invention have surprisingly found that the choline salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl) 5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid allows both good bioavailability and crystallinity of the compound over a wide dosage range, i.e. even at high dosages.

[0016] Moreover, the inventors of the present invention have unexpectedly discovered that the choline salt according to the present invention is the only salt that exhibits a fully crystallized form with reasonable efforts, and as shown in the Examples section of this specification, salts other than the choline salt according to the present invention appear amorphous, or only partially crystallize, or in yields far below any reasonable expectation.

[0017] Surprisingly, the choline salt exhibited higher solubility than either the amorphous or partially crystalline salts.

[0018] Moreover, the choline salt according to the invention is less hygroscopic than other salts, especially in the range of normal atmospheric relative humidity, which improves, for example, storage stability. Moreover, the crystalline choline salt dissolves not only faster than the free acid, but also faster than other salts of the compound obtained in partially crystalline or amorphous form.

[0019] The present invention therefore not only solves the problem of providing a salt having the advantages outlined above, but also provides a process for obtaining said salt in a manner suitable in time and yield for industrial application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Thus, the present invention relates to the choline salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid.

[0021] The terms "choline salts", "choline salts" and "2-hydroxy-N,N,N-trimethylethanaminium salts" are used interchangeably herein. They refer to salts having 2-hydroxy-N,N,N-trimethylethanaminium as the counterion.

[0022] Thus, in the context of the present invention, the terms "choline salt", "choline salt" and "2-hydroxy-N,N,N-trimethylethanaminium salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid" or "choline salt", "choline salt" and "2-hydroxy-N,N,N-trimethylethanaminium salt of a compound of formula (I)", as well as "choline salt according to the invention", "choline salt according to the invention" and "2-hydroxy-N,N,N-trimethylethanaminium salt according to the invention" are used interchangeably herein and are meant to refer to "2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate".

[0023] The present invention therefore particularly relates to 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate.

[0024] In a particular embodiment of the present invention, 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate is represented by the formula (II):

[0025] [ka]

[0026] or a tautomer, solvate or hydrate thereof.

[0027] It has been found that the choline salt according to the invention, unlike other salts of the compound of formula (I), can be obtained in crystalline form with sufficient time, effort and yield and exhibits polymorphism / pseudopolymorphism.

[0028] Form A has been found to be the most stable form well suited for use in pharmaceutical applications. Thus, the present invention also relates to a crystalline form of the choline salt according to the invention, preferably a crystalline form of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate. Preferably, the present invention relates to polymorphic Form A of the choline salt according to the invention, a process for its preparation, pharmaceutical compositions comprising it, and its use in combating disorders.

[0029] The following crystalline forms of the choline salt according to the invention have been revealed, which are polymorphic: Form A and anhydrous Form C, as well as mono 2-propanol solvate (Form B) and hexafluoro-2-propanol solvate (Form D). In this context, modification, polymorphic form and polymorph have the same meaning. In addition, amorphous forms also exist. Polymorphic forms, pseudopolymorphic forms and amorphous forms are all different solid forms of the choline salt according to the invention.

[0030] Polymorphic Form A of the crystalline choline salt according to the present invention is thermodynamically stable at room temperature and up to at least 35°C.

[0031] Polymorphic form A is therefore more suitable and preferred for use in the pharmaceutical field than other solid or crystalline forms of the choline salt according to the invention, and is particularly suitable for pharmaceutical compositions.

[0032] In particular, polymorphic Form A of the choline salt according to the invention reliably prevents the undesired conversion of the choline salt of the invention into other forms and the associated changes in the properties mentioned above, thereby improving the safety and quality of preparations and formulations comprising the choline salt of the invention and reducing the risks to patients.

[0033] The different crystalline forms of the choline salts according to the invention can be distinguished by X-ray powder diffraction, differential scanning calorimetry (DSC), and IR spectroscopy.

[0034] The polymorphic form A of the choline salt according to the invention has an X-ray powder diffractogram (at 25° C., using Cu-Kα1 as radiation source) showing at least the following reflections at 12.99°, 20.42°, and 20.64°, preferably at least the following reflections at 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°, more preferably at least the following reflections at 2θ values ​​of ±0.2: Polymorphic form A of the choline salt according to the present invention can be clearly characterized by exhibiting the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°, most preferably at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, 20.75°, 24.42°, 17.62°, and 18.41°. Polymorphic form A of the choline salt according to the present invention can also be clearly characterized by the X-ray powder diffraction pattern shown in Figure 1 (at 25°C, using Cu-Kα1 as radiation source).

[0035] The polymorphic form A of the choline salt according to the invention can be determined by measuring the IR pattern (at room temperature, 2 cm using an FT-IR spectrophotometer with a Bruker Tensor 37 instrument) -1 resolution), in cm -1 and preferably in cm -1 and more preferably, in cm -1and exhibiting at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874; most preferably, in cm -1 The choline salt of the present invention in polymorphic form A is clearly characterized by exhibiting at least the following bands, as shown by peak maxima at 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. The IR pattern of the choline salt of the present invention is shown in FIG. 2 (at room temperature, 2 cm using an FT-IR spectrophotometer with a Bruker Tensor 37 instrument). -1 The chromatic aberration can also be clearly characterized by the chromatic aberration (recorded at a resolution of 100 kHz).

[0036] Process for preparing the choline salt according to the present invention The present invention further relates to a method for preparing 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoate (also called choline salt according to the invention), said method comprising adding 2-hydroxy-N,N,N-trimethylethanaminium hydroxide to 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid in a suitable solvent, preferably toluene, ethanol, acetonitrile or mixtures thereof, preferably a mixture of ethanol and acetonitrile, preferably a mixture of ethanol and acetonitrile (7:100), thereby forming said choline salt of the compound of formula (I). The choline salt according to the invention can be isolated as a solid at this stage by filtering and / or drying.

[0037] The present invention further relates to a process for preparing the choline salt according to the invention in a crystalline form, preferably crystalline form A, which comprises dissolving the obtained solid in a suitable solvent, such as a solvent selected from the group consisting of acetonitrile, ethanol, methyl tert-butyl ether, ethyl acetate, heptane, toluene, tetrahydrofuran, butanol, acetone, water and mixtures thereof, at a suitable temperature, followed by cooling the solution to a temperature allowing the precipitation of salt crystals, preferably to 4° C. (+ / −2° C.).

[0038] In certain embodiments, the method for preparing a choline salt according to the present invention comprises reacting a compound of formula (I)

[0039] [ka]

[0040] In addition to the compound of formula (III)

[0041] [ka]

[0042] Thereby forming 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate according to formula (II):

[0043] [ka] The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0044] In a preferred embodiment, the method comprises the steps of:

[0045] [ka]

[0046] To a compound of formula (III)

[0047] [ka] In addition,

[0048] Thereby forming the choline salt according to formula (II)

[0049] [ka] The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0050] The mixing of the compounds of formula (I) and (III) can be carried out in a suitable medium, which can be selected by one skilled in the art, but is preferably an alcohol, preferably a C1-C4 alcohol, most preferably tert-butanol or isobutanol (2-methylpropan-1-ol).

[0051] Preferably, the adding step comprises mixing the compounds of formula (I) and (III) to obtain the choline salt according to the invention.

[0052] Furthermore, the skilled person can select suitable conditions for addition and / or mixing, for example with respect to temperature. Preferably, the addition temperature of said compounds is between the freezing point of the mixture and the boiling point of the mixture, more preferably room temperature, for example 22° C. (+ / - 2° C.).

[0053] In a preferred embodiment, the resulting mixture is stirred at a temperature between the freezing point of the mixture and the boiling point of the mixture, preferably at room temperature, e.g., 22°C (+ / - 2°C), for a period of 1 to 48 hours, preferably 12 to 36 hours, more preferably 14 to 20 hours, such as 18 hours.

[0054] In a further preferred embodiment, the obtained choline salt according to the present invention can be dried, preferably by evaporating the solvent. If deemed necessary, the obtained choline salt according to the present invention can be washed once or twice. The washing solvent can be selected by those skilled in the art and is preferably water-immiscible. Preferably, the obtained choline salt is washed once or twice with toluene.

[0055] It may be desirable to (re)crystallize the obtained solid choline salt according to the invention, in particular to obtain Form A. Thus, in a preferred embodiment, the method for preparing a choline salt according to the invention, preferably in crystalline form, more preferably in Form A, comprises the following steps: - dissolving the resulting solid in a solvent, such as a solvent selected from the group consisting of acetonitrile, ethanol, methyl tert-butyl ether, ethyl acetate, heptane, toluene, tetrahydrofuran, butanol, acetone, water and mixtures thereof, by stirring for a period of time at a temperature sufficient to dissolve the solid; - cooling the solution with stirring to a temperature that allows precipitation of salt crystals, such as 4°C (± 2°C); and, optionally, Stir further at a temperature of -4°C (+ / -2°C) for a period of time, e.g. 1 hour, and optionally filter off the resulting choline salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid, optionally washing with acetonitrile, ethanol, methyl tert-butyl ether, ethyl acetate, heptane, toluene, tetrahydrofuran, butanol, acetone, or water or mixtures thereof; preferably washing with the solvent used to dissolve the initial solid, and optionally drying, e.g. under reduced pressure (e.g. 200 mbar), e.g. at a temperature between 20°C and 60°C; resulting in crystalline 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate of Form A.

[0056] Those skilled in the art know how to provide the compound of formula (I). In particular, a method for the synthesis of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid is disclosed in Example 3 of WO 2018 / 114786(A1) (herein incorporated by reference).

[0057] Those skilled in the art can adapt the method for synthesizing 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid disclosed in Example 3 of WO 2018 / 114786(A1). For example, one can choose to exchange the reactivity of the nucleophile and electrophile in the Suzuki cross-coupling reaction by changing the boronic ester group of one adduct to a bromide group and the bromide group of the other adduct to a boronic ester group, as compared to that disclosed for "Intermediate 29A" in WO 2018 / 114786(A1). The respective alternative methods are disclosed in the Examples section of this specification.

[0058] Pharmaceutical Compositions The present invention also relates to a pharmaceutical composition comprising a choline salt according to the invention, in particular 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate, preferably in a crystalline form thereof (more preferably Form A), and optionally one or more pharma- ceutically acceptable excipients.

[0059] A preferred pharmaceutical composition according to the invention comprises a choline salt according to formula (II) and optionally one or more further pharma- ceutically acceptable excipients.

[0060] A preferred embodiment of the present invention is a pharmaceutical composition comprising polymorphic Form A of the choline salt according to formula (II), and even more preferred is a composition mainly comprising the choline salt according to formula (II) in Form A and not containing significant fractions of other forms of the choline salt according to formula (II), optionally comprising one or more further pharma- ceutically acceptable excipients. More preferably, the pharmaceutical composition contains more than 85% by weight, more preferably more than 90% by weight, and most preferably more than 95% by weight of the polymorphic Form A of the choline salt according to formula (II), relative to the total amount of all forms of the choline salt according to formula (II) present in the composition.

[0061] The choline salts according to the invention can be systemically and / or locally active and for this purpose can be administered in any suitable manner, for example orally, parenterally, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, cutaneous, transdermal, conjunctival, auricular, or as an implant or stent.

[0062] For these routes of administration, the choline salts according to the invention can be administered in suitable dosage forms.

[0063] Oral administration is preferred, for which the choline salts according to the invention can be formulated into dosage forms known in the art that deliver the compounds of the invention in a rapid and / or modified manner, such as tablets (uncoated or coated, e.g. with a delayed dissolving or insoluble enteric or release-controlling coating), orally disintegrating tablets, films / wafers, films / lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. The choline salts according to the invention can be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved form, preferably in crystalline form.

[0064] Parenteral administration can be performed by avoiding the absorption step (e.g., intravenously, intraarterially, intracardially, intraspinally or intraumbilically) or by including absorption (e.g., intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable dosage forms for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0065] Examples of suitable for other administration routes are pharmaceutical forms for inhalation (especially powder inhalers, nebulizers), nose drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae, lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), emulsions, pastes, foams, dusting powders, implants or stents.

[0066] The choline salts of the invention can be incorporated into the described dosage forms. This can be done in a manner known per se by mixing with pharma- ceutical suitable excipients, which include, inter alia: Fillers and carriers (e.g. cellulose, microcrystalline cellulose (e.g. Avicel®), lactose, mannitol, starch, calcium phosphates (e.g. Di-Cafos®), Ointment bases (e.g., petrolatum, paraffin, triglycerides, wax, wool wax, wool wax alcohol, lanolin, hydrophilic ointments, polyethylene glycols), Suppository bases (e.g. polyethylene glycol, cocoa butter, hard fats), Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycols, paraffin), surfactants, emulsifiers, dispersing agents or wetting agents (e.g. sodium dodecyl sulfate), lecithins, phospholipids, fatty alcohols (e.g. Lanette®, etc.), sorbitan fatty acid esters (e.g. Span®, etc.), polyoxyethylene sorbitan fatty acid esters (e.g. Tween®, etc.), polyoxyethylene fatty acid glycerides (e.g. Cremophor®, etc.), polyoxyethylene fatty acid esters, polyoxyethylene fatty acid ethers, glycerol fatty acid esters, poloxamers (e.g. Pluronic®, etc.), Buffers, acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine) Isotonic agents (e.g., glucose, sodium chloride), Adsorbents (e.g. highly dispersed silica), viscosity increasing agents, gel forming agents, thickening agents and / or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g. Carbopol®, etc.); alginic acid, gelatin), Disintegrants (e.g. modified starch, sodium carboxymethylcellulose, sodium starch glycolate (e.g. Explotab®, etc.), cross-linked polyvinylpyrrolidone, croscarmellose sodium (e.g. AcDiSol®, etc.), flow regulators, lubricants, gliders and release agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silica (e.g. Aerosil®, etc.)); coating materials for rapidly dissolving or dissolving modified films or diffusion membranes (e.g. sugar, shellac) and film formers (e.g. polyvinylpyrrolidones (e.g. Kollidon®, polyvinyl alcohols, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, e.g. polymethacrylates such as Eudragit®), · Capsule materials (e.g. gelatin, hydroxypropyl methylcellulose) synthetic polymers (e.g. polylactides, polyglycolides, polyacrylates, polymethacrylates (e.g. Eudragit®, etc.), polyvinylpyrrolidones (e.g. Kollidon®, etc.), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers); Plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), Penetration enhancers, Stabilizers (e.g. antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, and propyl gallate), Preservatives (e.g., parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), Colorants (e.g. inorganic pigments such as iron oxide, titanium dioxide, etc.), Flavoring, sweetening, flavoring and / or odoriferous agents.

[0067] The present invention further relates to pharmaceutical compositions comprising a choline salt according to the invention, conventionally together with one or more pharma- ceutically suitable excipient(s), and to their use according to the invention.

[0068] Treatment methods The present invention relates to methods of using choline salts and compositions thereof according to the present invention to inhibit the bradykinin B1 receptor.The present invention relates to methods of using choline salts and compositions thereof according to the present invention to treat, but are not limited to, the following mammalian disorders and diseases:

[0069] In particular, diseases associated with pain and / or inflammation selected from the group consisting of: Visceral pain, for example associated with pancreatitis, interstitial cystitis, bladder pain syndrome, renal colic, or prostatitis, chronic pelvic pain, or infiltrative endometriotic pain; Neuropathic pain such as postherpetic neuralgia, acute zoster pain, pain associated with nerve injury, pain including vulvodynia, phantom limb pain, pain associated with nerve root avulsion, pain associated with radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, pain associated with carpal tunnel syndrome, ulnar neuropathy, pain associated with tarsal tunnel syndrome, painful diabetic neuropathy, diabetic neuropathy pain, painful polyneuropathy, trigeminal neuralgia, or pain associated with familial amyloid polyneuropathy; · Central pain syndromes, which may be caused by virtually any lesion at any level of the nervous system, including, but not limited to, pain associated with stroke, multiple sclerosis, and spinal cord injury; postoperative pain syndromes (including post-mastectomy pain syndrome, post-thoracotomy pain syndrome, stump pain), bone and joint pain (osteoarthritis), spinal pain (including acute and chronic low back pain, neck pain, pain associated with spinal stenosis), shoulder pain, repetitive motion pain, toothache, pain associated with sore throat, cancer pain, pain from burns including sunburn, myofascial pain (pain associated with muscle injury, fibromyalgia), postoperative and perioperative pain (including but not limited to general surgery, orthopedic surgery, and gynecologic surgery); and Acute and chronic pain, chronic pelvic pain, endometriosis-related pain, dysmenorrhea-related pain (primary and secondary), uterine fibroid-related pain, vulvodynia-related pain, and angina-related pain, bladder pain syndromes, or inflammatory pain of various origins (including, but not limited to, pain associated with osteoarthritis, rheumatoid arthritis, rheumatic diseases, tendonitis, gout, ankylosing spondylitis, and bursitis); and A disease similar to or related to a disease selected from the group consisting of or related to: ·Gynaecological disorders and / or diseases or effects and / or symptoms that adversely impact women's health, including endometriosis, uterine fibroids, pre-eclampsia, hormone deficiencies, uterine cramps, or heavy menstrual bleeding; Inflammatory hyperresponsive airways, inflammation Inflammatory events associated with airway diseases such as chronic obstructive pulmonary disease, asthma including allergic asthma (atopic or non-atopic) and exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbations of asthma, other non-allergic asthma and wheezing infant syndromes, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, pulmonary fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (hereditary angioedema and omapatrilat (omep the respiratory or excretory system including any of the following: drug-induced angioedema including that caused by angiotensin-converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors such as atrilat), pneumoconiosis including aluminum pulmonary disease, anthracosis, asbestosis, stone lung disease, ptilosis, siderosis, silicosis, tobacco poisoning and byssinosis, intestinal diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis, interstitial cystitis / bladder pain syndrome, renal fibrosis, renal failure, hyperactive bladder, and overactive bladder; Dermatology, including pruritus, itch, psoriasis, eczema, and inflammatory skin diseases including atopic dermatitis; · joint or bone diseases, including rheumatoid arthritis, gout, osteoporosis, osteoarthritis, and ankylosing spondylitis; · Neurodegenerative diseases including Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head injury, and diseases of the central and peripheral nervous system including multiple sclerosis; · Infectious diseases, including HIV infection and tuberculosis; · Trauma with edema, including cerebral edema, burns, sunburn, and sprains or fractures; Poisoning, including aluminum pulmonary disease, anthracosis, asbestosis, stone lung disease, trichiasis, siderosis, silicosis, tobacco poisoning, and byssinosis uveitis; · diabetic clusters or metabolism such as type 1 diabetes, type 2 diabetes, diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, diabetic symptoms associated with postcapillary resistance or insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased urinary excretion of nitrite and kallikrein), diabetic macular edema, metabolic syndrome, insulin resistance, obesity, or fat or muscle metabolism; · Cachexia associated with or induced by any of the following: cancer, AIDS, celiac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acromonychia), and hormone deficiencies; Cardiovascular system, including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarction, and cardiac fibrosis; and Other conditions including septic shock, sepsis, muscle wasting, gastrointestinal spasms, benign prostatic hyperplasia, and liver disease such as nonalcoholic and alcoholic fatty liver disease, nonalcoholic and alcoholic steatohepatitis, liver fibrosis, or cirrhosis.

[0070] Preferred embodiments of the invention relate to methods of using a choline salt or composition thereof according to the invention for treating gynecological disorders, preferably endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms; diabetic neuropathic pain, interstitial cystitis and bladder pain syndrome (also called interstitial cystitis / bladder pain syndrome (IC / BPS)), and endometriosis.

[0071] Further preferred is a method of using a choline salt according to the invention or a composition thereof for the treatment of a disease selected from the group consisting of diabetic neuropathic pain, interstitial cystitis, bladder pain syndrome, and endometriosis. In a particular preferred embodiment, the present invention relates to a method of using a choline salt according to the invention or a composition comprising a choline salt according to the invention for the treatment of a disease selected from the group consisting of diabetic neuropathic pain, interstitial cystitis, bladder pain syndrome, and endometriosis.

[0072] Additionally, the present invention relates to methods of using the compounds of the present invention and compositions thereof to treat osteoarthritis, rheumatoid arthritis, gout, neuropathic pain, diabetic neuropathic pain, asthma, cough, lung injury, pulmonary fibrosis, pneumonia, renal fibrosis, renal failure pruritus, irritable bowel disease, overactive bladder, type 1 diabetes, type 2 diabetes, diabetic neuropathy, diabetic retinopathy, diabetic macular edema, metabolic syndrome, obesity, cardiac fibrosis, cachexia, muscle atrophy, Alzheimer's disease, bladder pain syndrome, and interstitial cystitis.

[0073] In a particular preferred embodiment, the present invention relates to a method of use of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate or a composition comprising same for the treatment of a disease, preferably a disease associated with pain and / or inflammation. Thus, the present invention also relates to 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate or a composition comprising same for use for the treatment of a disease, preferably a disease associated with pain and / or inflammation.

[0074] Although these diseases are well characterized in humans, they exist in other mammals with similar etiology and can be treated by administering a choline salt or pharmaceutical composition of the invention. As used throughout this specification, the terms "treat" or "treatment" are used conventionally and refer to the management or care of a subject for the purpose of combating, alleviating, relieving, ameliorating, etc., the condition of a disease or disorder, e.g., a gynecological disorder.

[0075] Dosage and Administration Based on standard laboratory techniques known for evaluating compounds useful in the treatment of disorders and / or diseases mediated by the bradykinin B1 receptor, by standard toxicity tests and standard pharmacological assays for determining the treatment of the above-identified conditions in mammals, and by comparing the results with those of known pharmaceuticals used to treat these conditions, the effective dosage of the choline salts according to the invention can be easily determined for the treatment of each desired indication. The amount of active ingredient administered in the treatment of one of these conditions can vary depending on such considerations as the dosage unit used, the method of administration, the duration of the treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

[0076] A person skilled in the art will recognize that the dosage of a pharma- ceutical active compound is important with respect to dosage. The choline salt according to the present invention is a salt of a pharma- ceutical active compound, namely, 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid. 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid (also called "active ingredient"). Thus, dosage preferably refers to the amount of this free acid administered. The total amount of active ingredient administered will generally be in the range of about 0.001 mg / kg to about 100 mg / kg body weight of the free acid, preferably about 0.01 mg / kg to about 20 mg / kg body weight per day. Preferred dosages of the compounds of the invention include, but are not limited to, 0.1 mg / kg to about 10 mg / kg body weight per day. Clinically useful dosing schedules will range from 1-3 times per day to once every 4 weeks.

[0077] Furthermore, "drug holidays", during which a patient receives no drug for a period of time, can be beneficial to the overall balance between pharmacological effect and tolerability.

[0078] The total daily dosage can range from about 0.5 mg to about 2000 mg of the active ingredient, administered in one or more doses per day or less than once per day.

[0079] The choline salts according to the invention have resulted in surprisingly good bioavailability of the active ingredient, especially when administered orally. Therefore, the dosage form is preferably an oral dosage form.

[0080] A preferred daily dose of the active ingredient is in the range of 0.5 mg to 2000 mg, preferably 100 mg to 1600 mg, for example 100 mg, 150 mg, 200 mg, 400 mg, 450 mg, 600 mg, 800 mg, 1600 mg, etc.

[0081] Those skilled in the art will recognize that to achieve such a dosage of active ingredient, a dosage of the choline salt according to the invention should be used that takes into account the mass of the choline salt added. To provide, for example, a 1 mg dosage of active ingredient, a dosage of about 1.2 mg (e.g., 1.20 mg to 1.25 mg, or 1.21 mg or 1.24 mg) of the choline salt of the invention should be used, i.e., about 1.2 times the respective amount (1.20 to 1.25 times, or 1.209 times, or 1.24 times, etc.).

[0082] Thus, in a preferred embodiment, the daily dosage of the choline salt according to the invention is from about 0.6 mg to about 2480 mg, preferably from about 124 mg to about 1984 mg, for example, a daily dosage of about 124 mg, about 186 mg, about 248 mg, about 496 mg, about 558 mg, about 744 mg, about 992 mg, about 1984 mg, etc. of the choline salt according to the invention. The term "about" means an amount acceptable for pharmaceutical use, preferably within + / - 10% or + / - 5% of the respective given amount / dosage, preferably within -10% and +5%.

[0083] The desired daily dosage can be achieved by administering a single dosage unit per day comprising the amount of the desired daily dosage, or by administering single dosage units comprising a portion of the desired daily dosage at times that add up to the desired daily dosage. For example, to administer a daily dose of 150 mg, a single dosage unit comprising 150 mg of active ingredient can be administered, or three single dosage units each comprising 50 mg of active ingredient can be administered.

[0084] The amount of active ingredient in a single dosage unit may vary depending on the desired daily dosage. Preferably, a single dosage unit comprises 10 mg to 1600 mg of active ingredient (or about 12.4 mg to about 1984 mg of the choline salt according to the present invention), preferably 50 mg to 450 mg of active ingredient, more preferably 50 mg to 150 mg of active ingredient (about 62 mg to about 186 mg of the choline salt according to the present invention). In certain preferred embodiments, a single dosage unit comprises 50 mg or 150 mg of active ingredient (about 62 mg or about 186 mg of the choline salt according to the present invention).

[0085] Of course, the specific initial and subsequent dosing regimens for each patient will vary depending on the nature and severity of the condition as determined by the attending diagnostician, the activity of the particular compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, drug combinations, etc. The desired mode of treatment and frequency of administration of the choline salt of the invention or compositions thereof can be ascertained by one of skill in the art using conventional therapeutic trials.

[0086] Combination therapy The term "combination" in the present invention is used as known to those skilled in the art and may exist as a fixed combination, a non fixed combination, or a kit of parts.

[0087] "Fixed combination" in the present invention is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present together in one unit dosage or in a single entity.One example of "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in a mixture for simultaneous administration, such as a pharmaceutical preparation.Another example of "fixed combination" is a pharmaceutical combination in which the first active ingredient and the second active ingredient are present in one unit, not in a mixture.

[0088] Non-fixed combination or "kit of parts" in the present invention is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present in two or more units.An example of non-fixed combination or kit of parts is a combination in which the first active ingredient and the second active ingredient are present separately.The components of non-fixed combination or kit of parts can be administered separately, sequentially, simultaneously, concurrently, or chronologically staggered.

[0089] The choline salts according to the invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination does not cause unacceptable adverse effects, and the invention also relates to such combinations.

[0090] The choline salts according to the invention can be combined with therapeutic agents or active ingredients already approved or currently under development for the treatment and / or prevention of diseases associated with or mediated by the bradykinin B1 receptor.

[0091] For the treatment and / or prevention of urinary tract disorders, the choline salts according to the invention may be administered in combination or combination therapy with any substance applicable as a treatment for the following indications: urinary tract disease conditions associated with bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased urination frequency, urge incontinence, stress incontinence or bladder hypersensitivity; benign prostatic hyperplasia; benign prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive bladder and symptoms associated with overactive bladder, said symptoms being in particular urinary frequency, nocturia, urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatic pain; cystitis, in particular interstitial cystitis / painful bladder syndrome (IC / BPS); idiopathic bladder hypersensitivity.

[0092] For the treatment and / or prevention of overactive bladder and symptoms associated with overactive bladder, the compounds of the invention can be administered in combination and as a combination therapy with anticholinergics such as oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterdine; beta3 agonists such as mirabegron; neurotoxins such as onabutolinumtoxin A; or antidepressants such as imipramine, duloxetine, in addition to diet, lifestyle, or behavioral therapies such as bladder training.

[0093] For the treatment and / or prevention of interstitial cystitis, the compounds of the present invention can be administered in combination with or as a combination therapy with pentosans such as Elmiron; antidepressants such as amitriptyline, imipramine; or antihistamines such as loratadine, in addition to dietary, lifestyle, or behavioral therapies such as bladder training.

[0094] For the treatment and / or prevention of gynecological disorders, the compounds of the invention may be administered in combination or as a combined therapy with any substance applicable as a therapeutic agent for the following indications: dysmenorrhea (including primary and secondary); dyspareunia; endometriosis; endometriosis-associated pain; endometriosis-associated symptoms, in particular dysmenorrhea, dyspareunia, urinary or defecation disorders, etc.

[0095] For the treatment and / or prevention of dysmenorrhea (including primary and secondary); dyspareunia; endometriosis and endometriosis associated pain, the compounds of the invention may be administered in combination with ovulation suppression therapy, in particular COCs as mentioned above, contraceptive patches such as Ortho-Evra or Apleek (Lisvy); or progestin genes such as dienogest (Visanne); or GnRH analogues, in particular GnRH agonists and antagonists, e.g. leuprorelin, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; or androgens such as danazol.

[0096] For the treatment and / or prevention of diseases associated with pain or pain syndromes, the choline salts according to the invention can be administered in combination or combination therapy with any substance applicable as a treatment for the following indications: pain-related diseases or disorders such as hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sports injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, viral trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, diabetic neuropathic pain, chronic arthritis and associated neuralgia, HIV and HIV treatment induced neuropathy.

[0097] Choline salts according to the invention may be combined with other pharmacological agents and compounds intended to treat inflammatory diseases, inflammatory pain or general pain conditions.

[0098] In addition to well-known pharmaceutical agents already approved and on the market, choline salts according to the invention can be administered in combination with inhibitors of the P2X purinergic receptor family (P2X3, P2X4), inhibitors of IRAK4, and antagonists of the prostanoid EP4 receptor.

[0099] In particular, choline salts according to the invention may be administered in combination with pharmacological endometriosis treatments intended to treat inflammatory diseases, inflammatory pain or general pain conditions and / or suppress endometrial proliferation and symptoms associated with endometriosis, specifically inhibitors of aldo-keto-reductase 1C3 (AKR1C3) and functional blocking antibodies of the prolactin receptor.

[0100] The choline salts according to the invention can be combined with other pharmacological agents and compounds intended for the treatment, prevention or management of cancer.

[0101] In particular, the choline salts according to the invention are useful in the treatment of various conditions, including but not limited to: 131I-chTNT, abarelix, abiraterone, aclarubicin, adotrastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anetholedithiolthione, angiotensin II, antithrombin III, aprepitant, architumomab, aruglavin, arsenic trioxide, alemtuzumab, arsenic trioxide, arsenic triphosphate ... Sparaginases, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, setumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chloramphenicol Mubucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, decreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, docetaxel, Racetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, etrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epithiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone,Floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoterate meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxime, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seed, lansoprazole, iband sirolimus acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alpha, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, lanreotide, lapatinib, iasocolin, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamizole ol, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, meptiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methyl aminolevulinate, methylprednisolone, methyltestosterone, metyrosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamul. Lizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximol, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumab pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, octamumab, omecetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin,Oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palifermin, palladium 103 seed, palonosetron, pamidronate, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alpha 2b, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin pixantrone, plerixafor, plicamycin, poliglusum, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refame Tinib, regorafenib, risedronate, rhenium 186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipulcel-T, sizofiran, sobuzoxane, glycidazole sodium, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentane, 9 9mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alpha, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib,It may be administered in combination with trofosfamide, thrombopoietin, tryptophan, ubenimex, baratinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, or zorubicin.

[0102] Additionally, the choline salts according to the invention can be combined with active ingredients known for the treatment of cancer-related pain and chronic pain. Such combinations include, but are not limited to, step II opioids such as codeine phosphate, dextropropoxyphene, dihydrocodeine, tramadol, step III opioids such as morphine, fentanyl, buprenorphine, oxymorphone, oxycodone and hydromorphone; other drugs used to treat cancer pain such as steroids such as dexamethasone and methylprednisolone; bisphosphonates such as etidronate, clodronate, alendronate, risedronate, and zoledronate; tricyclic antidepressants such as amitriptyline, clomipramine, desipramine, imipramine and doxepin; class I antiarrhythmics such as mexiletine and lidocaine; and anticonvulsants such as carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, topiramate, alprazolam, diazepam, flurazepam, pentobarbital and phenobarbital.

[0103] In addition to the above, the inventive choline salts according to the invention may also be combined with any of the following active ingredients: active ingredients for the treatment of Alzheimer's, such as acetylcholinesterase inhibitors (e.g. donepezil, rivastigmine, galantamine, tacrine), NMDA (N-methyl-D-aspartate) receptor antagonists (e.g. memantine); L-DOPA / carbidopa (L-3,4-dihydroxyphenylalanine), COMT (catechol-O-methyltransferase) inhibitors (e.g. entacapone), dopamine agonists (e.g. ropinol, pramipexole, bromocriptine), MAO-B (monoaminooxidase-B) inhibitors (e.g. selegiline), anticholinergics (e.g. trihexyphenidyl) and NMDA antagonists (e.g. amantadine) for the treatment of multiple sclerosis; beta-interferon (IFN-beta) for the treatment of multiple sclerosis. immunosuppressants such as IFN beta-1b, IFN beta-1a Avonex® and Betaferon®, glatiramer acetate, immunoglobulins, natalizumab, fingolimod and mitoxantrone, as well as azathioprine, cyclophosphamide; substances for the treatment of lung disorders, such as beta2 sympathomimetics (e.g. salbutamol), anticholinergics (e.g. glycopyrronium), methylxanthines (e.g. theophylline), leukotriene receptor antagonists (e.g. montelukast), PDE-4 (phosphodiesterase type 4) inhibitors (e.g. roflumilast), methotrexate, IgE antibodies, azathioprine and cyclophosphamide, cortisol-containing preparations; substances for the treatment of osteoarthritis, such as nonsteroidal anti-inflammatory substances (NSAIDs). For rheumatic disorders such as rheumatoid arthritis and juvenile idiopathic arthritis, in addition to the two aforementioned treatments, methotrexate and biologics directed against B and T cells (e.g. rituximab, abatacept) should also be mentioned.Neurotrophic substances such as acetylcholinesterase inhibitors (e.g. donepezil), MAO (monoaminooxidase) inhibitors (e.g. selegiline), interferons, anticonvulsants (e.g. gabapentin); active ingredients for the treatment of cardiovascular disorders such as beta-blockers (e.g. metoprolol), ACE inhibitors (e.g. benazepril), diuretics (e.g. hydrochlorothiazide), calcium channel blockers (e.g. nifedipine), statins (e.g. simvastatin); antidiabetic drugs such as metformin and glibenclamide, sulfonylureas (e.g. tolbutamide), and insulin therapy for the treatment of diabetes and metabolic syndrome. Active ingredients such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL#3®, Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917), antibiotics such as ciprofloxacin and metronidazole, antidiarrheal drugs such as loperamide, or laxatives (bisacodyl) for the treatment of chronic inflammatory bowel disease. Immunosuppressants such as glucocorticoids and nonsteroidal anti-inflammatory substances (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, and cyclophosphamide for the treatment of lupus erythematosus.Examples include, but are not limited to, calcineurin inhibitors (e.g., tacrolimus and cyclosporine), cytostatics (e.g., azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus), rapamycin, basiliximab, daclizumab, anti-CD3 antibodies, anti-T lymphocyte globulin / antilymphocyte globulin for organ transplants, vitamin D3 analogues such as calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, cyclosporine, methotrexate, efalizumab for skin disorders.

[0104] The present invention is further illustrated by the following figures and examples which should not be construed as limiting the invention but are merely exemplary in nature. [Brief description of the drawings]

[0105] [Figure 1] FIG. 1: XRPD pattern of polymorphic form A of the choline salt according to the invention. [Diagram 2] FIG. 2: FT-IR spectrum of polymorphic form A of the choline salt according to the invention. [Diagram 3] Figure 3: XRPD pattern of amorphous sodium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate [Figure 4] Figure 4: XRPD pattern of partially crystalline sodium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate [Diagram 5] Figure 5: XRPD pattern of crystalline sodium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate [Figure 6]Figure 6: XRPD pattern of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate mono 2-propanol solvate (Form B). [Figure 7] Figure 7: XRPD pattern of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate (Form C). [Figure 8] Figure 8: XRPD pattern of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate (Form D). [Figure 9] Figure 9: Exposure (AUC) of the free acid (circles) and choline salt (squares) in rats after intragastric administration of different doses. [Figure 10] Figure 10: Plasma exposure (AUC, kg*L / h normalized for dose) of the free acid in rats after intragastric administration of different doses of either the free acid (circles) or the choline salt (squares) [Figure 11A] FIG. 11A: Isotherm plot of DVS measurements: Choline salt. [Figure 11B] FIG. 11B: Isotherm plot of DVS measurements: sodium salt [Figure 11C] FIG. 11C: Isotherm plot of DVS measurements: Potassium salt [Figure 11D] FIG. 11D: Isotherm plot of DVS measurements: Arginine salt [Figure 11E] FIG. 11E: Isotherm plot of DVS measurements: free acid [Figure 12A] FIG. 12A: Dissolution curves measured in FeSSIF and FaSSIF solutions: free acid [Figure 12B]FIG. 12B: Dissolution curves measured in FeSSIF and FaSSIF solutions: choline salts [Figure 12C] FIG. 12C: Dissolution curves measured in FeSSIF and FaSSIF solutions: sodium salt [Figure 12D] FIG. 12D: Dissolution curves measured in FeSSIF and FaSSIF solutions: potassium salts [Figure 12E] FIG. 12E: Dissolution curves measured in FeSSIF and FaSSIF solutions: Arginine salts [Figure 13A] Figure 13A: Overlay of the dissolution curves of the free acid and various salt forms: in FeSSIF solution. [Figure 13B] FIG. 13B: Overlay of the dissolution curves of the free acid and various salt forms: in FassiF solution. EXAMPLES

[0106] Common methods: DSC / TG DSC thermograms were recorded using a PerkinElmer differential scanning calorimeter (models DSC7, Pyris-1 or Diamond). Non-hermetic aluminum pans were used for 20 K min. -1 The measurements were performed at a heating rate of 1000 s. The flow gas was nitrogen. There was no sample preparation.

[0107] TGA thermograms were recorded using PerkinElmer thermobalances (models TGA7 and Pyris1). -1 The measurements were performed at a heating rate of 1000 s. The flow gas was nitrogen. There was no sample preparation.

[0108] XRPD X-ray diffraction patterns were recorded at room temperature using an XRD diffractometer X`Pert PRO (PANalytical). No sample preparation was performed. All X-ray reflections are given in °2θ (theta) values ​​(peak maximum) with a resolution of ±0.2°.

[0109] Analytical LCMS method Method 1: Instrument: Waters Acquity Platform ZQ4000; Column: Waters BEHC18, 50 mm x 2.1 mm, 1.7 μm; Eluent A: water / 0.05% formic acid, Eluent B: acetonitrile / 0.05% formic acid; Gradient: 0.0 min 98% A → 0.2 min: 98% A → 1.7 min: 10% A → 1.9 min: 10% A → 2 min: 98% A → 2.5 min: 98% A; Flow rate: 1.3 ml / min; Column temperature: 60 °C; UV detection 200-400 nm

[0110] Method 2: Instrument: Agilent 1200 HPLC system; Column: Nucleodur C18 HTEC silica / C18, 50 mm x 2 mm, 2.0 μm; Eluent A: Phosphate buffer pH 2.4, Eluent B: Acetonitrile; Gradient: 0.0 min 95% A → 3 min: 60% A → 3.5 min: 55% A → 4.0 min: 50% A → 4.5 min: 45% A → 5.0 min: 20% A → 6.0 min: 20% A → 6.01 min: 95% A → 7.0 min: 95% A; Flow rate: 1.0 ml / min; Column temperature: 40 °C; UV detection: 220 nm

[0111] Solubility measurements were performed by Method 2. All other measurements were performed by Method 1.

[0112] Alternative Suzuki cross-coupling method to generate methyl-5-amino-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoate: Scheme

[0113] [ka]

[0114] Reactor A was charged with methyl-5-amino-2-bromobenzoate (1.00 wt, 1.0 equiv; CAS number: 6942-37-6), followed by methanol (8.0 vol) at a temperature between 15 °C and 25 °C. The resulting solution was purged with nitrogen. Reactor B was charged with bis(pinacolato)diboron (1.4 wt, 1.3 equiv; CAS number: 73183-34-3), and [Pd(cinnamyl)Cl]2 dimer (0.02 wt; CAS 12131-44-1), and meCgPPh (0.05 wt, 0.04 equiv). Reactor B was also purged with nitrogen. The solution in Reactor A was then mixed into Reactor B, followed by the addition of methanol (2.0 vol, 1.6 wt) as a line / vessel rinse. N,N-Diisopropylethylamine was added (2.3 vol, 3.0 equiv.), pre-purged with nitrogen and maintained at a temperature between 15° C. and 45° C. The solution was heated to a temperature between 40° C. and 45° C. and stirred for 2-4 hours until the reaction was complete, as confirmed by 1H NMR analysis.

[0115] This solution is then heated and held at a temperature between 55°C and 65°C for 10 minutes, charged with a pre-nitrogen sparged solution of 4-bromo-1-cyclobutylpyrazole (1.14 wt, 1.3 equiv; CAS number: 1002309-50-3) dissolved in methanol (2.0 vol), and then mixed with a pre-nitrogen sparged 5.2 M K2HPO4 (aq) solution (5.0 vol, 6.0 equiv) while maintaining the temperature at 55-65°C for 30 minutes.

[0116] The reaction mixture was heated to 70°C-75°C and stirred for 16-20 hours. The reaction mixture was then cooled to 15°C-25°C and purified water (3.7 vol) was charged while maintaining the temperature at 15°C-25°C. The two phases were separated and the organic phase was clarified using a 1 μm filter and the vessel / filter was washed with methanol (1.0 vol).

[0117] The clarified organic layer was concentrated to 12.0 vol by evaporation at a temperature of 50° C.-60° C. Isopropyl acetate (12.0 vol) was added and the mixture was then concentrated to 12 vol at 50-60° C. for four consecutive times or 1Repeated until H NMR analysis showed residual methanol was ≦3.0% (w / w) relative to (methyl 5-amino-2-(1-cyclobutylpyrazol-4-yl)benzoate).

[0118] The reaction mixture was cooled to 15°C-25°C and charged with purified water (10.0 vol) and isopropyl acetate (10.0 vol) while maintaining the temperature at 15°C-25°C. The mixture in the reaction vessel was stirred for 10-20 minutes. The two phases were then separated. The organic layer was heated to 40°C-45°C and charged with SiliaMetS (0.2 wt; Silicycle; R1030B). The reaction mixture was stirred at 40°C-45°C for at least 1 hour. The reaction mixture was then filtered to remove the silica and washed twice successively with isopropyl acetate (2.0 vol) at 40°C-45°C. The filtrates were combined and then heated to 50°C-60°C and concentrated to 3.0 vol by evaporation.

[0119] n-Heptane (6.0 vol) was added to the concentrated clarified filtrate over at least 30 min while maintaining the temperature at 50°C-60°C. The mixture was then cooled to 0°C-5°C over at least 90 min and then stirred for >4 h. The mixture was then filtered through 20 μm cloth at 0°C-5°C and the filter cake was washed with premixed isopropyl acetate (0.66 vol) and n-heptane (1.34 vol) at 0°C-5°C. The filter cake was slurry washed with purified water (2.0 vol) at 15°C-25°C for at least 20 min, followed by slurry washing the filter cake with n-heptane (2.0 vol) at 15°C-25°C for at least 20 min. The filter cake was then washed again with n-heptane (2.0 vol, 1.4 wt). For comparison with the product (methyl 5-amino-2-(1-cyclobutylpyrazol-4-yl)benzoate), the material was run under vacuum with a nitrogen flow at 50 °C for at least 6 hours or until the water content was ≦1.5% wt / wt, isopropyl acetate ≦1.0% wt / wt, and n-heptane ≦1.0% wt / wt. Methyl 5-amino-2-(1-cyclobutylpyrazol-4-yl)benzoate was obtained as a solid in 50%-70% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 0.7 Hz, 1H), 7.37 (d, J = 0.7 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.70 (dd, J = 8.4 Hz, 1H), 5.32 (bs, 2H), 4.79 (quint, 1H), 3.69 (s, 3H), 2-48-2.42 (m, 1H), 2.41-2.32 (m, 2H), 1.81-1.72 (m, 2H)

[0120] Example 1: The choline salt according to the invention was obtained in Form A by two alternative approaches described as Examples 1 a) and b). a) 2-Hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate Form A

[0121] [ka]

[0122] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid was prepared as disclosed in WO 2018 / 114786 A1, Example 3.

[0123] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid (10.0 g, 20.5 mmol) was suspended in 98 mL of isobutanol, choline hydroxide solution (CAS123-41-1, 46 wt% in water, 5.45 g, 20.5 mmol) was added, and after stirring at 22 °C for 10 min the mixture became clear. The clear solution was stirred at 22 °C for 18 h, after which the solvent was evaporated by co-distillation of 2 × 50 mL of toluene. The resulting solid was dissolved in 170 mL of refluxing acetonitrile over 3 h. The solution was cooled with gentle stirring and precipitation was observed at 48 °C. The mixture was then cooled to 5 °C and stirred for 1 h. The formed crystals were isolated by filtration, washed with 2×10 mL of acetonitrile at the same temperature and dried overnight in a drying cabinet (40° C., 200 mBar) to give 11.2 g (91.9% yield) of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl) 5-[({1-[2-fluoro-4(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate as a colourless crystalline solid, crystallised as Form A. 1 H NMR (600 MHz, DMSO-d6) δ [ppm] 1.15 - 1.17 (m, 2H), 1.59 - 1.60 (m, 2H), 1.72 - 1.80 (m, 2H), 2.33 - 2.40 (m, 2H), 2.41 - 2.52 (m, 2H), 3.09 (s, 9H), 3.38 - 3.39 (m, 2H), 3.82 (s, br, 2H), 4.75 (quint, 1H), 5.66 (s, br, 1H), 7.09 (d, 1H), 7.20 (d, 1H), 7.30 (dd, 1H), 7.58 (d, 1H), 7.65 - 7.70 (m, 2H), 7.72 (s, 1H), 8.04 (s, 1H), 8.78 (s, 1H)

[0124] b) 2-Hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate Form A 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid was prepared as disclosed in WO 2018 / 114786 A1, Example 3.

[0125] As an alternative to example 1b), a further process of salt formation was used. Thus, 487 mg of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid was dissolved in 200 mL of acetonitrile at 70° C. After clarification, 242 mg of aqueous choline hydroxide solution (CAS123-41-1, ca. 50%) was added and the clarified solution was stirred at room temperature for 1 hour. The solvent was then slowly evaporated at room temperature to obtain a dry solid. The solid corresponded to form A of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate.

[0126] Example 2: Crystallization of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate mono 2-propanol solvate (Form B) 25.27 mg of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate obtained according to Example 1 was suspended in 40 times the amount of 2-propanol at room temperature. Upon heating to 80° C., the solid was completely dissolved at 50° C. (clearing point). Upon cooling to −15° C., crystallization was observed at 25° C. The suspension was filtered to obtain 17.74 mg of a solid. The XRPD pattern corresponds to a 2-propanol solvate. This solvate is also called “Form B”.

[0127] Example 3: 2-Hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate Form C 150 mg of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate obtained according to Example 1 was dissolved in 5 mL of a 2-propanol / water mixture (9:1 vol:vol). The solution was clarified by filtration through a 2 μm PTFE syringe filter and then placed at 20° C. in a scintillation vial sealed with a twice-pierced aluminum cap until the solvent had completely evaporated. The resulting solid corresponds to Form C.

[0128] Example 4: 2-Hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate 125.48 mg of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate obtained according to Example 1 was dissolved in 0.5 mL of hexafluoropropan-2-ol in a small vessel. The smaller vessel was placed open in the larger vessel containing diethyl ether. The vessel setup was left undisturbed at room temperature to allow the solvent to diffuse throughout the small vessel and promote the crystallization of 125.48 mg of 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate. After several days, 92.18 mg of a solid was isolated by filtration and dried under reduced pressure at 40° C. for approximately 20 hours. This solid was also designated Form D. However, it was found to be a hexafluoropropan-2-ol solvate.

[0129] Example 5: Amorphous Sodium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate 487 mg of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid were dissolved in 300 mL of acetonitrile at 70° C. Then 1 mL of a molar aqueous solution of sodium hydroxide was added. The solvent was then evaporated at room temperature to give a solid, which corresponds to amorphous sodium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate.

[0130] Example 6: Partially crystalline sodium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate

[0131] [ka]

[0132] 2-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid (540 mg, 1.12 mmol) and sodium hydroxide (44.3 mg, 1.12 mmol) were stirred in 11 mL of water at 80° C. until a clear solution was formed. The mixture was evaporated to dryness. Residual water was removed by repeated azeotropic distillation with toluene (20 mL). The resulting solid was amorphous as evidenced by XRPD measurements (data not shown). The solid was dissolved in acetone (5 mL) and stored in the freezer (−18° C.) for 6 weeks. The amorphous solid formed was filtered off and dried in a drying cabinet (40° C.) to give 140 mg (25% yield) of sodium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate as a solid, which turned out to be only partially crystallized. See FIG. 5. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 1.15 - 1.18 (m, 2H), 1.58 - 1.60 (m, 2H), 1.72 - 1.81 (m, 2H), 2.32 - 2.48 (m, 4H), 4.75 (quint, 1H), 7.11 (d, 1H), 7.20 (d, 1H), 7.29 (dd, 1H), 7.56 - 7.58 (m, 1H), 7.64 - 7.70 (m, 2H), 7.72 (s, 1H), 8.04 (s, 1H), 8.78 (s, 1H) LCMS: Rt = 1.24 min; MS (ESIPos) m / z = 488 (M+H acid) +

[0133] Example 7: Crystalline sodium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate 0.1165 g of the solid obtained in Example 6 was suspended in 0.669 g of acetone to obtain a thin suspension. The solvent was then slowly evaporated at room temperature for more than one week until a solid was obtained. The crystallinity of the sample was evaluated by XPRD; see Example 10.

[0134] Example 8: Amorphous potassium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate 487 mg of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid, prepared as disclosed in WO 2018 / 114786(A1), Example 3, was dissolved in 300 mL of acetonitrile at 70° C. After clarification, 1 mL of a molar aqueous solution of potassium hydroxide was added. The solvent was then slowly evaporated at room temperature until a dry solid was obtained. XPRD analysis of the resulting solid was characteristic of an amorphous material.

[0135] Example 9: Amorphous arginine salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate 487 mg of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid, prepared as disclosed in WO 2018 / 114786(A1), Example 3, was dissolved in 200 mL of acetonitrile at 70° C. After clarification, 174 mg of arginine was added. The solvent was then slowly evaporated at room temperature until a dry solid was obtained. XPRD analysis of the resulting solid was characteristic of an amorphous material.

[0136] Example 10: XRPD characterization of polymorphic and pseudopolymorphic salts of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid X-ray diffraction patterns of the polymorphic form A of the choline salt and the solids obtained in Examples 5-7, i.e. the sodium salt, were recorded at room temperature using an XRD diffractometer X`Pert PRO (PANalytical) (Cu Kα1 radiation, wavelength 1.5406 Å). There was no further preparation of the samples. All X-ray reflections are given in °2θ (theta) values ​​(peak maximum) with a resolution of ±0.2°.

[0137] X-ray powder diffraction (XRPD) analysis of the choline salt Forms B, C, and D was performed using a Bruker D2 Phaser powder diffractometer equipped with a LynxEye detector. Samples underwent minimal preparation, but if necessary were lightly ground with a pestle and mortar prior to acquisition. Samples were placed (approximately 5-10 mg) in the center of a 5 mm pocket silicon sample holder.

[0138] [Table 1]

[0139] Example 11: IR data of the choline salt according to the invention in Form A IR The IR-ATR-spectrum of the choline salt according to the invention in Form A, prepared as outlined in Example 1, was recorded at room temperature using an FT-IR-spectrophotometer with a Tensor37 instrument from Bruker. The resolution was 2 cm -1 It was.

[0140] [Table 2] [Table 2-2]

[0141] Example 12: Solubility Free Acid vs. Salt The solubilities of crystalline 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid (free acid), prepared as described in Example 3 of WO 2018 / 114786 A1, and the choline salt Form A were measured according to the shake flask method (1 mL scale, stirring overnight) at 25 °C.

[0142] [Table 3]

[0143] Example 13: Measurement of exposure in rats after intragastric administration method Exposure following intragastric administration of test compounds was measured in awake female rats weighing 0.2 kg (min) to 0.25 kg (max). Test compounds were applied as a bolus via an intragastric probe to unfed female rats in solution or suspension in the vehicle ethanol / solvent / water (vol / vol / vol 10 / 40 / 50).

[0144] At the indicated time points between 8 min and 24 h after dosing, 150 μl of blood was collected via a catheter from the jugular vein. Samples were treated with K-EDTA as an anticoagulant and stored chilled (refrigerator, 4 °C) until further processing. Samples were centrifuged (15 min, 3000 rpm) and then 100 μL aliquots were taken from the supernatant (plasma), precipitated by adding 400 μL of cold acetonitrile or methanol (abs.) and frozen overnight at -20 °C. Samples were centrifuged (15 min, 3000 rpm) and then 150 μL of the clear supernatant was taken for analytical testing. Analysis was performed using an Agilent 1200 HPLC system with LCMS / MS detection.

[0145] Calculation of PK parameters (by PK calculation software, e.g. WinNonLin®): AUC (0-tlast) : Area under the plasma concentration-time profile from time zero to the final time point 24 hours (unit kg * L / hour); AUC (0-tlast)norm : The integral area of ​​the plasma concentration-time profile from time zero to the final time point 24 hours (units kg * L / h); C max : maximum concentration of test compound in plasma (unit: μg / L); C max , norm : Maximum concentration of test compound in plasma divided by the dose normalized to body weight (units: kg / L)

[0146] result The rat plasma exposure of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)amino]benzoic acid (free acid) was measured after application of various doses of either the free acid itself or 2-hydroxy-N,N,N-trimethylethanaminium 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate (choline salt). The applied dose of the choline salt according to the invention was adjusted according to the difference in molecular weight compared to the free acid. The resulting equivalent doses were used for comparison.

[0147] The obtained AUC or AUC norm were compared as a function of dose.

[0148] [Table 4]

[0149] As shown in FIG. 4, the exposure of free acid in rat plasma after administration of the free acid itself or the choline salt according to the present invention to rats was observed to be similar at low doses up to 30 mg / kg. After administration of high doses of free acid, the increase in exposure was observed to be much smaller than the dose-proportional increase. In contrast, surprisingly, after application of the choline salt, the plasma exposure of the free acid as an active pharmaceutical ingredient showed a dose-proportional increase in exposure up to a dose of about 100 mg / kg. Also, even at high doses (249 and 495 mg / kg), a non-dose-proportional increase in exposure was observed after administration of the choline salt. However, compared to the exposure after administration of 100 mg / kg of free acid, the exposure was still significantly higher in terms of absolute value and dose-normalized AUC (see Table 4 and FIG. 9 and FIG. 10). Thus, for the choline salt, it was surprisingly possible to achieve a high enough concentration of exposure in rats for toxicity testing, whereas administration of the free acid reached a plateau in plasma exposure at a level not suitable for toxicity testing.

[0150] Example 14: Solubility of choline salts (in mg) versus the free acid and other salts 遊離酸 / L) method The solubility of each salt was investigated as follows. The solubilities of crystalline 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid (free acid) prepared as described in Example 3 of WO 2018 / 114786 A1, choline salt form A prepared according to Example 1b herein, the partially crystalline sodium salt obtained as described in Example 6 herein, the amorphous potassium salt according to Example 8 herein and the amorphous arginine salt according to Example 9 herein were measured at 25° C. according to the shake flask method (according to the European Pharmacopoeia, 1 mL scale, stirring overnight) unless otherwise stated.

[0151] Preparation of FaSSIF (Fasted Simulated Intestinal Fluid) blank solution: 4.2 g NaOH, 44.7 g NaH2PO4 * 2 H2O, and 61.86 g of NaCl were dissolved in approximately 9.5 L of demineralized water. The pH of this solution was then adjusted to 6.50 + / - 0.05 using HCl or NaOH, respectively. In the last step, the final volume was adjusted to 10.0 L by adding demineralized water.

[0152] Preparation of final FaSSIF solution: 4.48 g of SIF (simulated intestinal fluid) powder (supplier: biorelevant.com, product code: FFF01 (May 2022)) was dissolved in approximately 500 mL of FaSSIF blank solution, then FaSSIF blank solution was added to adjust the final volume to 2.0 L. After 2 h, the solution was deemed ready for use and was used within 48 h.

[0153] Preparation of FeSSIF (Fed Simulated Intestinal Fluid) blank solution: 40.4 g NaOH, 118.74 g NaCl, and 82.4 mL glacial acetic acid were dissolved in approximately 9.5 L of demineralized water. The pH of this solution was then adjusted to 5.00 + / - 0.05 using HCl or NaOH, respectively. In the last step, the final volume was adjusted to 10.0 L by adding demineralized water.

[0154] Preparation of the final FeSSIF solution: 22.4 g of SIF powder (supplier: biorelevant.com, product code: FFF01 (May 2022)) was dissolved in approximately 500 mL of FeSSIF blank solution, then FeSSIF blank solution was added to adjust the final volume to 2.0 L. The solution was deemed ready for use immediately after production and was used within 48 hours.

[0155] result

[0156] [Table 5]

[0157] The aqueous solubility of the salt was observed to be significantly higher than that of the free acid, including measurements at pH 4.5 and above and in biorelevant media (FeSSIF and FaSSIF).

[0158] Surprisingly, the choline salt, the only fully crystallized salt, showed higher solubility than the amorphous and partially crystalline salts in most aqueous media tested, especially in FaSSIF.

[0159] It was surprising that the crystalline form of the salt was more soluble than the amorphous salt.

[0160] Example 15 Hygroscopicity of Choline Salts Versus the Free Acid and Other Salts method Water sorption isotherms were measured using a DVS Resolution gravimetric sorption analyzer (London, UK) or a DVS Intrinsic instrument (Surface measurement Systems). Samples were dried at 0% relative humidity (RH) for 1000 min. The dry weight was then recorded. Humidity was increased in 10% steps to 90%, then to 95%, and finally decreased again following the same steps to 0% RH. The equilibrium criterion for each relative humidity set point was 0.002% relative mass change per minute as a function of time. Dynamic vapor sorption isotherms are shown in Figures 11a-11e.

[0161] [Table 6]

[0162] [Table 7]

[0163] result Isotherm plots of the DVS measurements are shown in Figure 11a-e. Comparing these salts, the choline salt was less hygroscopic than the other salts, especially in the normal atmospheric relative humidity range (30-50%). The choline salt also showed a less significant increase in hygroscopicity at high relative humidity (>80%) compared to the other salts.

[0164] Example 16: Dissolution Profile of Choline Salts Versus Free Acid and Other Salts method Prior to the measurement, the sample was pulverized into fine particles using a jet mill (MC DECJET30) under a nitrogen atmosphere at an injector pressure of 4.5 Bar and a grinding pressure of 4.0 Bar.

[0165] The dissolution rate of the drug was then measured using a Sotax flow-through cell (FTC). All experiments were performed in triplicate.

[0166] For the experiment, the cell was loaded with an amount of solid equivalent to 1 mg of free acid (+ / - 2% with respect to free acid). The respective medium (FaSSIF or FeSSIF) was then pumped through the cell at a pump rate of 2 mL / min for a total of 14 minutes, resulting in a total volume of 28 mL. This volume was collected at 2 minute time increments, resulting in seven fractions of 4 mL each. The drug substance concentration of each fraction was measured by HPLC (external standard). From the collected data, a time-dependent concentration profile was obtained and used to compare the salts.

[0167] result The dissolution curves measured in FeSSIF and FaSSIF are shown in Figure 12a–e.

[0168] Figure 13a shows the overlay of the dissolution curves of the free acid and various salt forms in FeSSIF. The free acid dissolved significantly slower and had a lower cumulative dissolution amount after 14 min compared to the salt forms. With the exception of the potassium salt, the salt forms showed similar dissolution profiles in FeSSIF.

[0169] Figure 13b shows the overlay of the dissolution curves of the free acid and various salt forms in FaSSIF. Again, the free acid dissolved significantly slower and had a lower cumulative dissolution amount after 14 minutes compared to the salt forms. Surprisingly, despite being crystalline, the choline salt showed a better dissolution profile than the other salts.

[0170] There was no difference in the dissolution profile of the sodium salt, which is partially crystalline, and the potassium and arginine salts, which are amorphous.

[0171] Surprisingly, the crystalline choline salt not only dissolved faster than the free acid, but also faster than other salt compounds that were only available in partially crystalline or amorphous forms.

Claims

1. The choline salt of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]-cyclopropyl}carbonyl)amino]benzoic acid.

2. The choline salt according to Claim 1, according to formula (II) [Chemical 1] or a solvate, hydrate or tautomer thereof.

3. The choline salt according to Claim 1, which is in crystalline form.

4. The choline salt according to Claim 2, which is in crystalline form.

5. The crystalline choline salt according to Claim 3, which is polymorphic form A.

6. The crystalline choline salt according to Claim 4, which is polymorphic form A.

7. The crystalline choline salt according to Claim 3, characterized by an X-ray powder diffraction (XRPD) pattern that is substantially the same as that of Figure 1.

8. The crystalline choline salt according to Claim 4, characterized by an X-ray powder diffraction (XRPD) pattern that is substantially the same as that of Figure 1.

9. The crystalline choline salt according to Claim 5, characterized by an X-ray powder diffraction (XRPD) pattern that is substantially the same as that of Figure 1.

10. The crystalline choline salt according to Claim 6, characterized by an X-ray powder diffraction (XRPD) pattern that is substantially the same as that of Figure 1.

11. The crystalline choline salt according to Claim 3, characterized in that the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, and 20.64°.

12. The crystalline choline salt according to Claim 4, characterized in that the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, and 20.64°.

13. The crystalline choline salt according to Claim 5, characterized in that the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, and 20.64°.

14. The crystalline choline salt according to Claim 6, characterized in that the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, and 20.64°. **Claim 15**: The crystalline choline salt according to claim 7, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, and 20.64°. **Claim 16**: The crystalline choline salt according to claim 8, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, and 20.64°. **Claim 17**: The crystalline choline salt according to claim 9, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, and 20.64°. **Claim 18**: The crystalline choline salt according to claim 10, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, and 20.64°. **Claim 19** The crystalline choline salt according to claim 3, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 20**: The crystalline choline salt according to claim 4, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 21**: The crystalline choline salt according to claim 5, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 22**: The crystalline choline salt according to claim 6, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. Claim 23: The crystalline choline salt according to claim 7, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. Claim 24: The crystalline choline salt according to claim 8, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. Claim 25: The crystalline choline salt according to claim 9, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. Claim 26: The crystalline choline salt according to claim 10, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. Claim 27: The crystalline choline salt according to claim 11, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. Claim 28: The crystalline choline salt according to claim 12, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. Claim 29: The crystalline choline salt according to claim 13, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ±0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 30**: The crystalline choline salt according to claim 14, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 31**: The crystalline choline salt according to claim 15, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 32**: The crystalline choline salt according to claim 16, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 33**: The crystalline choline salt according to claim 17, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 34**: The crystalline choline salt according to claim 18, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values ± 0.2°, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, and 22.32°. **Claim 35** The crystalline choline salt according to claim 3, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 36**: The crystalline choline salt according to claim 4, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, at 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 37**: The crystalline choline salt according to claim 5, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 38**: The crystalline choline salt according to claim 6, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 39**: The crystalline choline salt according to claim 7, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 40**: The crystalline choline salt according to claim 8, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 41**: The crystalline choline salt according to claim 9, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 42**: The crystalline choline salt according to claim 10, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 43**: The crystalline choline salt according to claim 11, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 44**: The crystalline choline salt according to claim 12, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 45**: The crystalline choline salt according to claim 13, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 46**: The crystalline choline salt according to claim 14, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 47**: The crystalline choline salt according to claim 15, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 48**: The crystalline choline salt according to claim 16, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 49**: The crystalline choline salt according to claim 17, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. **Claim 50**: The crystalline choline salt according to claim 18, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 51: The crystalline choline salt according to claim 19, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 52: The crystalline choline salt according to claim 20, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 53: The crystalline choline salt according to claim 21, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 54: The crystalline choline salt according to claim 22, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 55: The crystalline choline salt according to claim 23, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 56: The crystalline choline salt according to claim 24, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 57: The crystalline choline salt according to claim 25, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°.

58. The crystalline choline salt according to claim 26, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°.

59. The crystalline choline salt according to claim 27, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°.

60. The crystalline choline salt according to claim 28, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°.

61. The crystalline choline salt according to claim 29, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°.

62. The crystalline choline salt according to claim 30, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°.

63. The crystalline choline salt according to claim 31, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°.

64. The crystalline choline salt according to claim 32, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows, in terms of 2θ values, at least the following reflections: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 65: The crystalline choline salt according to claim 33, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 66: The crystalline choline salt according to claim 34, wherein the X-ray powder diffraction pattern measured at 25 °C using Cu-Kα1 as the radiation source shows at least the following reflections in terms of 2θ values: 12.99°, 20.42°, 20.64°, 18.84°, 22.32°, 15.74°, and 20.75°. Claim 67 The crystalline choline salt according to claim 3, characterized by an IR pattern substantially the same as that of FIG.

2. Claim 68: The crystalline choline salt according to claim 4, characterized by an IR pattern substantially the same as that of FIG.

2. Claim 69: The crystalline choline salt according to claim 5, characterized by an IR pattern substantially the same as that of FIG.

2. Claim 70: The crystalline choline salt according to claim 6, characterized by an IR pattern substantially the same as that of FIG.

2. Claim 71 The IR pattern is shown by the peak maximum value in units of cm －１ The crystalline choline salt according to claim 3, characterized in that it shows at least the following bands: 1123, 1309, 1083. Claim 72: The crystalline choline salt according to claim 4, wherein the IR pattern shows at least the following bands in terms of peak maximum values per cm-1: 1123, 1309, 1083. Claim 73: The crystalline choline salt according to claim 5, wherein the IR pattern shows at least the following bands in terms of peak maximum values per cm-1: 1123, 1309, 1083. Claim 74: The crystalline choline salt according to claim 6, wherein the IR pattern shows at least the following bands in terms of peak maximum values per cm-1: 1123, 1309, 1083. Claim 75: The crystalline choline salt according to claim 67, wherein the IR pattern shows at least the following bands in terms of peak maximum values per cm-1: 1123, 1309, 1083. Claim 76: The crystalline choline salt according to claim 68, wherein the IR pattern shows at least the following bands in terms of peak maximum values per cm-1: 1123, 1309, 1083. Claim 77: The crystalline choline salt according to claim 69, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083. Claim 78: The crystalline choline salt according to claim 70, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083. Claim 79 The IR pattern is shown in peak maximum values per cm －１ and shows at least the following bands: 1123, 1309, 1083, 1324, and 808, the crystalline choline salt according to claim 3. Claim 80: The crystalline choline salt according to claim 4, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 81: The crystalline choline salt according to claim 5, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 82: The crystalline choline salt according to claim 6, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 83: The crystalline choline salt according to claim 67, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 84: The crystalline choline salt according to claim 68, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 85: The crystalline choline salt according to claim 69, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 86: The crystalline choline salt according to claim 70, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 87: The crystalline choline salt according to claim 71, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 88: The crystalline choline salt according to claim 72, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 89: The crystalline choline salt according to claim 73, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 90: The crystalline choline salt according to claim 74, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 91: The crystalline choline salt according to claim 75, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 92: The crystalline choline salt according to claim 76, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 93: The crystalline choline salt according to claim 77, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 94: The crystalline choline salt according to claim 78, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, and 808. Claim 95 The IR pattern is shown at the peak maximum value in units of cm －１ The crystalline choline salt according to claim 3, characterized in that it shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, as shown by the peak maximum value of －１ . Claim 96: The crystalline choline salt according to claim 4, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 97: The crystalline choline salt according to claim 5, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 98: The crystalline choline salt according to claim 6, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 99: The crystalline choline salt according to claim 67, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 100: The crystalline choline salt according to claim 68, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 101: The crystalline choline salt according to claim 69, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 102: The crystalline choline salt according to claim 70, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 103: The crystalline choline salt according to claim 71, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 104: The crystalline choline salt according to claim 72, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 105: The crystalline choline salt according to claim 73, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 106: The crystalline choline salt according to claim 74, characterized in that the IR pattern shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, shown as the peak maximum value in units of cm-1. Claim 107: The crystalline choline salt according to claim 75, characterized in that the IR pattern shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, shown as the peak maximum value in units of cm-1. Claim 108: The crystalline choline salt according to claim 76, characterized in that the IR pattern shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, shown as the peak maximum value in units of cm-1. Claim 109: The crystalline choline salt according to claim 77, characterized in that the IR pattern shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, shown as the peak maximum value in units of cm-1. Claim 110: The crystalline choline salt according to claim 78, characterized in that the IR pattern shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, shown as the peak maximum value in units of cm-1. Claim 111: The crystalline choline salt according to claim 79, characterized in that the IR pattern shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, shown as the peak maximum value in units of cm-1. Claim 112: The crystalline choline salt according to claim 80, characterized in that the IR pattern shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, shown as the peak maximum value in units of cm-1. Claim 113: The crystalline choline salt according to claim 81, characterized in that the IR pattern shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874, shown as the peak maximum value in units of cm-1. Claim 114: The crystalline choline salt according to claim 82, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 115: The crystalline choline salt according to claim 83, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 116: The crystalline choline salt according to claim 84, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 117: The crystalline choline salt according to claim 85, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 118 Claim 118: The crystalline choline salt according to claim 86, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 119: The crystalline choline salt according to claim 87, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 120: The crystalline choline salt according to claim 88, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 121: The crystalline choline salt according to claim 89, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 122: The crystalline choline salt according to claim 90, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 123: The crystalline choline salt according to claim 91, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 124: The crystalline choline salt according to claim 92, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 125: The crystalline choline salt according to claim 93, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 126: The crystalline choline salt according to claim 94, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, and 874. Claim 127 The IR pattern is in units of cm －１ characterized in that it exhibits at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835, shown as peak maximum values of Claim 128: The crystalline choline salt according to claim 4, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 129: The crystalline choline salt according to claim 5, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 130: The crystalline choline salt according to claim 6, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 131: The crystalline choline salt according to claim 67, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 132: The crystalline choline salt according to claim 68, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 133: The crystalline choline salt according to claim 69, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 134: The crystalline choline salt according to claim 70, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 135: The crystalline choline salt according to claim 71, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 136: The crystalline choline salt according to claim 72, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 137: The crystalline choline salt according to claim 73, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 138: The crystalline choline salt according to claim 74, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 139: The crystalline choline salt according to claim 75, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 140: The crystalline choline salt according to claim 76, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 141: The crystalline choline salt according to claim 77, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 142: The crystalline choline salt according to claim 78, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 143: The crystalline choline salt according to claim 79, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 144: The crystalline choline salt according to claim 80, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 145: The crystalline choline salt according to claim 81, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 146: The crystalline choline salt according to claim 82, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. **Claim 147**: The crystalline choline salt according to claim 83, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. **Claim 148**: The crystalline choline salt according to claim 84, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. **Claim 149**: The crystalline choline salt according to claim 85, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. **Claim 150**: The crystalline choline salt according to claim 86, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. **Claim 151**: The crystalline choline salt according to claim 87, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. **Claim 152**: The crystalline choline salt according to claim 88, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. **Claim 153**: The crystalline choline salt according to claim 89, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. **Claim 154**: The crystalline choline salt according to claim 90, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

155. The crystalline choline salt according to claim 91, wherein the IR pattern is shown by the peak maximum value per unit cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

156. The crystalline choline salt according to claim 92, wherein the IR pattern is shown by the peak maximum value per unit cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

157. The crystalline choline salt according to claim 93, wherein the IR pattern is shown by the peak maximum value per unit cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

158. The crystalline choline salt according to claim 94, wherein the IR pattern is shown by the peak maximum value per unit cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

159. The crystalline choline salt according to claim 95, wherein the IR pattern is shown by the peak maximum value per unit cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

160. The crystalline choline salt according to claim 96, wherein the IR pattern is shown by the peak maximum value per unit cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

161. The crystalline choline salt according to claim 97, wherein the IR pattern is shown by the peak maximum value per unit cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

162. The crystalline choline salt according to claim 98, wherein the IR pattern is shown by the peak maximum value per unit cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 163: The crystalline choline salt according to claim 99, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 164: The crystalline choline salt according to claim 100, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 165: The crystalline choline salt according to claim 101, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 166: The crystalline choline salt according to claim 102, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 167: The crystalline choline salt according to claim 103, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 168: The crystalline choline salt according to claim 104, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835. Claim 169: The crystalline choline salt according to claim 105, wherein the IR pattern is shown as peak maximum values per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

170. The crystalline choline salt according to claim 106, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

171. The crystalline choline salt according to claim 107, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

172. The crystalline choline salt according to claim 108, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

173. The crystalline choline salt according to claim 109, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

174. The crystalline choline salt according to claim 110, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

175. The crystalline choline salt according to claim 111, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

176. The crystalline choline salt according to claim 112, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

177. The crystalline choline salt according to claim 113, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

178. The crystalline choline salt according to claim 114, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

179. The crystalline choline salt according to claim 115, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

180. The crystalline choline salt according to claim 116, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

181. The crystalline choline salt according to claim 117, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

182. The crystalline choline salt according to claim 118, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

183. The crystalline choline salt according to claim 119, wherein the IR pattern is shown by the peak maximum value in units of cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

184. The crystalline choline salt according to claim 120, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

185. The crystalline choline salt according to claim 121, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

186. The crystalline choline salt according to claim 122, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

187. The crystalline choline salt according to claim 123, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

188. The crystalline choline salt according to claim 124, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

189. The crystalline choline salt according to claim 125, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

190. The crystalline choline salt according to claim 126, wherein the IR pattern is shown by the peak maximum value per cm-1 and shows at least the following bands: 1123, 1309, 1083, 1324, 808, 1091, 874, 1530, 954, and 835.

191. A method for preparing the choline salt according to any one of claims 1 to 190, comprising adding a compound of formula (III) to a compound of formula (I), ​ thereby forming the choline salt of formula (II). [Chemical Formula 3] The method comprising the step of 【Chemical 4】 forming the choline salt of formula (II).

192. The following steps: - drying the obtained choline salt to form a solid, and optionally washing the obtained solid; - dissolving the obtained solid in a solvent such as a solvent selected from the group consisting of acetonitrile, ethanol, methyl tert-butyl ether, ethyl acetate, heptane, toluene, tetrahydrofuran, butanol, acetone, water and mixtures thereof; - cooling the solution with stirring to a temperature that allows precipitation of the salt crystals, such as 48 °C (+ / - 2 °C); and - optionally, further cooling at a temperature of 4 °C (+ / - 1 °C) for a certain period of time, such as 1 hour; - optionally, filtering off the resulting choline salt and optionally washing with acetonitrile, ethanol, methyl tert-butyl ether, ethyl acetate, heptane, toluene, tetrahydrofuran, butanol, acetone, or water, or mixtures thereof, - optionally, drying the obtained solid further comprising: obtaining the crystalline choline salt according to formula (II) in such a way The method according to claim 191.

193. Use of a compound of formula (I) for 【Chemical Formula 5】 the preparation of a choline salt according to formula (II) 【Chemical Formula 6】 for use.

194. A pharmaceutical composition comprising a choline salt according to any one of claims 1 to 190 and a pharmaceutically acceptable diluent or carrier.

195. Use of a choline salt according to any one of claims 1 to 190 or a pharmaceutical composition according to claim 17 for the preparation of a medicament.

196. Use of a choline salt according to any one of claims 1 to 190 or a pharmaceutical composition according to claim 17 for use in the treatment or prevention of a disease or disease syndrome, condition, or symptom.

197. A choline salt for use according to claim 196, wherein the disease or disease syndrome, condition, or symptom is related to pain and / or inflammation.

198. The disease or disease syndrome, condition, or symptom is - visceral pain associated with, for example, pancreatitis, interstitial cystitis, painful bladder syndrome, nephralgia, or prostatitis, chronic pelvic pain, or infiltrative endometriosis pain; Neuropathic pain such as postherpetic neuralgia, acute herpetic pain, pain associated with nerve injury, pain including vulvar pain, phantom limb pain, pain associated with nerve root avulsion, pain associated with radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, pain associated with carpal tunnel syndrome, ulnar neuropathy, pain associated with tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia, or pain associated with familial amyloid polyneuropathy; Central pain syndromes that can be caused by virtually any lesion at any level of the nervous system, including but not limited to pain associated with stroke, multiple sclerosis, and spinal cord injury; Postoperative pain syndromes (including postmastectomy pain syndrome, postthoracotomy pain syndrome, stump pain), pain of bone and joints (osteoarthritis), spinal pain (including acute and chronic low back pain, neck pain, pain associated with spinal stenosis), shoulder pain, repetitive motion pain, dental pain, pain associated with pharyngitis, cancer pain, pain due to burns including sunburn, myofascial pain (pain associated with muscle injury, fibromyalgia), postoperative and perioperative pain (including but not limited to general surgery, plastic surgery, and gynecological surgery); and Acute and chronic pain, chronic pelvic pain, pain associated with endometriosis, pain associated with dysmenorrhea (primary and secondary), pain associated with uterine fibroids, pain associated with vulvar pain, and pain associated with angina, or inflammatory pain due to various causes (including but not limited to pain associated with osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis, gout, ankylosing spondylitis, and bursitis) A choline salt for use according to claim 196, related to pain selected from the group consisting of

199. The disease or disease syndrome, condition, or symptom is Visceral pain associated with, for example, pancreatitis, interstitial cystitis, painful bladder syndrome, pyelonephritis, or prostatitis, chronic pelvic pain, or pain of infiltrative endometriosis; Neuropathic pain such as postherpetic neuralgia, acute herpetic pain, pain associated with nerve injury, pain including vulvar pain, phantom limb pain, pain associated with nerve root avulsion, pain associated with radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, pain associated with carpal tunnel syndrome, ulnar neuropathy, pain associated with tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia, or pain associated with familial amyloid polyneuropathy; Central pain syndrome, which can be caused by virtually any lesion at any level of the nervous system, including but not limited to pain associated with stroke, multiple sclerosis, and spinal cord injury; Postoperative pain syndromes (including postmastectomy pain syndrome, postthoracotomy pain syndrome, stump pain), pain of bones and joints (osteoarthritis), spinal pain (including acute and chronic low back pain, neck pain, pain associated with spinal stenosis), shoulder pain, repetitive motion pain, dental pain, pain associated with pharyngitis, cancer pain, pain due to burns including sunburn, myofascial pain (pain associated with muscle injury, fibromyalgia), postoperative and perioperative pain (including but not limited to general surgery, orthopedic surgery, and gynecological surgery); and Acute and chronic pain, chronic pelvic pain, pain associated with endometriosis, pain associated with dysmenorrhea (primary and secondary), pain associated with uterine fibroids, pain associated with vulvodynia, and pain associated with angina, or inflammatory pain due to various causes (including but not limited to pain associated with osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis, gout, ankylosing spondylitis, and bursitis). The choline salt for use according to claim 197, which is related to pain selected from the group consisting of

200. Wherein the disease or disease syndrome, condition, or symptom is Gynecological disorders and / or diseases or effects and / or symptoms that have an adverse effect on women's health, including endometriosis, uterine fibroids, preeclampsia, hormonal deficiency, uterine spasms, or menorrhagia. Respiratory or excretory systems including any of the following: inflammatory allergic airway, inflammatory events associated with airway diseases such as chronic obstructive pulmonary disease, asthma including allergic asthma (atopic or non-atopic), exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbation of asthma, other non-allergic asthma and wheezing syndromes in infants, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, pulmonary fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema such as that caused by angiotensin-converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors like omapatrilat), aluminum pneumoconiosis, anthracosis, asbestosis, silicosis, madarosis, siderosis, silicosis, tobacco poisoning, and cotton pneumoconiosis, bowel diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis, interstitial cystitis / bladder pain syndrome, renal fibrosis, renal insufficiency, overactive bladder, and hyperactive bladder; Dermatology including inflammatory skin diseases including pruritus, itching, psoriasis, eczema, and atopic dermatitis; Joint or bone diseases including rheumatoid arthritis, gout, osteoporosis, osteoarthritis, and ankylosing spondylitis; Central and peripheral nervous system diseases including neurodegenerative diseases including Parkinson's disease and Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head injury, and multiple sclerosis; Infectious diseases including HIV infection and tuberculosis; Trauma with edema including cerebral edema, burns, sunburn, and contusion or fracture; Poisoning including aluminum pneumoconiosis, anthracosis, asbestosis, silicosis, madarosis, siderosis, silicosis, tobacco poisoning, and cotton pneumoconiosis meningitis; Diabetes classes or metabolisms including type 1 diabetes, type 2 diabetes, diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, diabetic symptoms associated with postcapillary resistance or insulitis (e.g., hyperglycemia, diuresis, proteinuria, and increased urinary excretion of nitrite and kallikrein), diabetic macular edema, metabolic syndrome, insulin resistance, obesity, or fat or muscle metabolism; Cachexia associated with, or induced by, any one of cancer, AIDS, celiac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia), and hormonal deficiencies; The cardiovascular system including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarction, and cardiac fibrosis; and Other conditions including hepatic diseases including primary peritonitis, secondary peritonitis, septic shock, sepsis, muscle atrophy, gastrointestinal spasms, benign prostatic hyperplasia, and non-alcoholic and alcoholic fatty liver diseases, non-alcoholic and alcoholic steatohepatitis, hepatic fibrosis, or cirrhosis A choline salt for use according to claim 196, selected from, or related to, any one of the groups consisting of

201. Wherein the disease or disease syndrome, condition, or symptom is Gynecological disorders and / or diseases or effects and / or symptoms that have an adverse effect on women's health, including endometriosis, uterine fibroids, pre-eclampsia, hormonal deficiencies, uterine spasms, or menorrhagia; Respiratory or excretory systems including inflammatory hypersensitive airways, inflammatory events associated with airway diseases such as chronic obstructive pulmonary disease, asthma including allergic asthma (atopic or non-atopic) and exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbations of asthma, other non-allergic asthma and wheezing syndromes in infants, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, pulmonary fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin-converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors such as omapatrilat), aluminum pneumoconiosis, anthracosis, asbestosis, silicosis, madarosis, siderosis, silicosis, tobacco poisoning, and byssinosis, bowel diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis, interstitial cystitis / bladder pain syndrome, renal fibrosis, renal insufficiency, overactive bladder, and hyperactive bladder; Dermatology including inflammatory skin diseases including pruritus, itching, psoriasis, eczema, and atopic dermatitis; Joint or bone diseases including rheumatoid arthritis, gout, osteoporosis, osteoarthritis, and ankylosing spondylitis Diseases of the central and peripheral nervous systems, including neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headaches including cluster headache, migraine including prophylactic and acute use, stroke, closed head injury, and multiple sclerosis; Infectious diseases including HIV infection and tuberculosis; Trauma with edema including cerebral edema, burns, sunburn, and contusion or fracture; Poisonings including aluminosis, anthracosis, asbestosis, silicosis, madarosis, siderosis, silicosis, tobacco poisoning, and cotton lung pleurisy; Type 1 diabetes, type 2 diabetes, diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, diabetic symptoms associated with postcapillary resistance or insulitis (e.g., hyperglycemia, diuresis, proteinuria, and increased urinary excretion of nitrite and kallikrein), diabetic macular edema, metabolic syndrome, insulin resistance, obesity, or diabetes clusters or metabolism such as fat or muscle metabolism; Cachexia associated with or induced by any of cancer, AIDS, celiac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia), and hormonal deficiency; Cardiovascular systems including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarction, and cardiac fibrosis; and Other conditions including primary peritonitis, secondary peritonitis, septic shock, sepsis, muscle atrophy, gastrointestinal spasm, benign prostatic hyperplasia, and liver diseases including non-alcoholic and alcoholic fatty liver disease, non-alcoholic and alcoholic steatohepatitis, liver fibrosis, or cirrhosis A choline salt for use according to claim 197, selected from or related to any one of the groups consisting of.

202. The disease or disease syndrome, condition, or symptom is Gynecological disorders and / or diseases or effects and / or symptoms that have an adverse effect on women's health, including endometriosis, uterine fibroids, preeclampsia, hormonal deficiency, uterine spasm, or menorrhagia. - Respiratory or excretory systems including inflammatory allergic airway, inflammatory events associated with airway diseases such as chronic obstructive pulmonary disease, asthma and exercise-induced bronchoconstriction including allergic asthma (atopic or non-atopic), occupational asthma, viral or bacterial exacerbations of asthma, other non-allergic asthma and wheezing syndromes in infants, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, pulmonary fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema such as that caused by angiotensin-converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors like omapatrilat), aluminum pneumoconiosis, anthracosis, asbestosis, silicosis, madarosis, siderosis, silicosis, tobacco poisoning and byssinosis including pneumoconiosis, bowel diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis, interstitial cystitis / bladder pain syndrome, renal fibrosis, renal insufficiency, overactive bladder, and hyperactive bladder; - Dermatology including inflammatory skin diseases including pruritus, itching, psoriasis, eczema, and atopic dermatitis; - Joint or bone diseases including rheumatoid arthritis, gout, osteoporosis, osteoarthritis, and ankylosing spondylitis; - Central and peripheral nervous system diseases including neurodegenerative diseases including Parkinson's disease and Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head injury, and multiple sclerosis; - Infectious diseases including HIV infection and tuberculosis; - Trauma with edema including cerebral edema, burns, sunburn, and contusion or fracture; - Poisoning including aluminum pneumoconiosis, anthracosis, asbestosis, silicosis, madarosis, siderosis, silicosis, tobacco poisoning, and byssinosis including meningitis; - Type 1 diabetes, type 2 diabetes, diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, diabetic symptoms associated with post-capillary resistance or insulitis (e.g., hyperglycemia, diuresis, proteinuria and increased urinary excretion of nitrite and kallikrein), diabetic macular edema, metabolic syndrome, insulin resistance, obesity, or diabetes clusters or metabolism such as fat or muscle metabolism; Cachexia associated with or induced by any one of cancer, AIDS, celiac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia), and hormonal deficiency; The cardiovascular system including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarction, and cardiac fibrosis; and Other conditions including hepatic diseases including primary peritonitis, secondary peritonitis, septic shock, sepsis, muscle atrophy, gastrointestinal spasm, benign prostatic hyperplasia, and non-alcoholic and alcoholic fatty liver disease, non-alcoholic and alcoholic steatohepatitis, liver fibrosis, or cirrhosis A choline salt for use according to claim 198, selected from or related to any one of the groups consisting of

203. Wherein the disease or disease syndrome, condition, or symptom is - Gynecological disorders and / or diseases or effects and / or symptoms that have an adverse effect on women's health, including endometriosis, uterine fibroids, preeclampsia, hormonal deficiency, uterine spasm, or menorrhagia; - Inflammatory allergic airway, inflammatory events associated with airway diseases such as chronic obstructive pulmonary disease, asthma including allergic asthma (atopic or non-atopic) and exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbation of asthma, other non-allergic asthma and wheezing syndrome in infants, chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, pulmonary fibrosis, allergic rhinitis (seasonal and perennial), vasomotor rhinitis, angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin-converting enzyme (ACE) or ACE / neutral endopeptidase inhibitors such as omapatrilat), aluminum pneumoconiosis, anthracosis, asbestosis, silicosis, madarosis, siderosis, silicosis, tobacco poisoning, and cotton pneumoconiosis, bowel diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis, interstitial cystitis / painful bladder syndrome, renal fibrosis, renal insufficiency, overactive bladder, and any of overactive bladder, including the respiratory or excretory system; - Dermatology including inflammatory skin diseases including pruritus, itching, psoriasis, eczema, and atopic dermatitis; - Joint or bone diseases including rheumatoid arthritis, gout, osteoporosis, osteoarthritis, and ankylosing spondylitis - Diseases of the central and peripheral nervous systems, including neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, headache including migraine, stroke, closed head injury, and multiple sclerosis; - Infectious diseases, including HIV infection and tuberculosis; - Trauma with edema, including cerebral edema, burns, sunburn, and contusion or fracture; - Poisonings, including aluminosis, anthracosis, asbestosis, silicosis, madarosis, siderosis, silicosis, tobacco poisoning, and cotton lung pleurisy; - Type 1 diabetes, type 2 diabetes, diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, diabetic symptoms associated with postcapillary resistance or insulitis (e.g., hyperglycemia, diuresis, proteinuria, and increased urinary excretion of nitrite and kallikrein), diabetic macular edema, metabolic syndrome, insulin resistance, obesity, or diabetes clusters or metabolism such as fat or muscle metabolism; - Cachexia associated with or induced by any of cancer, AIDS, celiac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia), and hormonal deficiency; - The cardiovascular system, including congestive heart failure, atherosclerosis, congestive heart failure, myocardial infarction, and cardiac fibrosis; and - Other conditions including primary peritonitis, secondary peritonitis, septic shock, sepsis, muscle atrophy, gastrointestinal spasm, benign prostatic hyperplasia, and liver diseases including non-alcoholic and alcoholic fatty liver disease, non-alcoholic and alcoholic steatohepatitis, liver fibrosis, or cirrhosis The choline salt for use according to claim 199, selected from or related to any one of the groups consisting of.

204. The choline salt for use according to claim 196, wherein the disease or disease syndrome, condition, or symptom is related to painful diabetic neuropathy, interstitial cystitis / bladder pain syndrome, endometriosis or endometriosis-related pain.

205. The choline salt for use according to claim 197, wherein the disease or disease syndrome, condition, or symptom is related to painful diabetic neuropathy, interstitial cystitis / bladder pain syndrome, endometriosis or endometriosis-related pain.

206. The choline salt for use according to claim 198, wherein the disease or disease syndrome, pathological condition, or symptom is related to painful diabetic neuropathy, interstitial cystitis / bladder pain syndrome, endometriosis or endometriosis-related pain.

207. The choline salt for use according to claim 199, wherein the disease or disease syndrome, pathological condition, or symptom is related to painful diabetic neuropathy, interstitial cystitis / bladder pain syndrome, endometriosis or endometriosis-related pain.

208. The choline salt for use according to claim 200, wherein the disease or disease syndrome, pathological condition, or symptom is related to painful diabetic neuropathy, interstitial cystitis / bladder pain syndrome, endometriosis or endometriosis-related pain.

209. The choline salt for use according to claim 201, wherein the disease or disease syndrome, pathological condition, or symptom is related to painful diabetic neuropathy, interstitial cystitis / bladder pain syndrome, endometriosis or endometriosis-related pain.

210. The choline salt for use according to claim 202, wherein the disease or disease syndrome, pathological condition, or symptom is related to painful diabetic neuropathy, interstitial cystitis / bladder pain syndrome, endometriosis or endometriosis-related pain.

211. The choline salt for use according to claim 203, wherein the disease or disease syndrome, pathological condition, or symptom is related to painful diabetic neuropathy, interstitial cystitis / bladder pain syndrome, endometriosis or endometriosis-related pain.

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