Aqueous formulations of cardiac P2X receptor agonists and their use in the treatment of diseases

Abstract

The present invention provides aqueous formulations containing compounds that stimulate the activity of cardiac P2X receptors, and methods for using them to stimulate the activity of cardiac P2X receptors and treat diseases such as heart failure.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests and priority of patent application PCT / CN2023 / 108594, filed on 21 July 2023, the contents of which are incorporated herein by reference.

[0002] The present invention provides aqueous formulations containing compounds that stimulate the activity of cardiac P2X receptors, and methods for using them to stimulate the activity of cardiac P2X receptors and treat diseases such as heart failure. [Background technology]

[0003] Heart failure affects a significant number of people worldwide and is characterized by impaired ability of the heart to pump blood. Typical symptoms of heart failure include shortness of breath, excessive fatigue, and leg swelling. Coronary artery disease, heart attack, hypertension, atrial fibrillation, valvular heart disease, excessive alcohol consumption, infections, and cardiomyopathy are factors that increase a person's risk of developing heart failure.

[0004] Stimulation of cardiac P2X receptors has been reported to be beneficial in patients with heart failure. See, for example, the work of Zhou et al. in J. Pharmacol. Exp. Ther. (2010) vol. 333(3), pp. 920-928. P2X receptors are expressed in cardiac tissue, and stimulation of cardiac P2X receptors increases nitric oxide and cyclic GMP (cGMP) in cardiomyocyte cells. Additional compounds and therapeutic methods using cardiac P2X receptor agonists are described in U.S. Patents 9,303,053 and 9,526,739.

[0005] In the treatment of heart failure, there is a need for a new formulation that is stable and readily available when combined with an intravenous diluent, and such a formulation could be beneficial to patients. This invention addresses this need and also provides other relevant advantages. [Overview of the Initiative]

[0006] The present invention provides aqueous formulations containing compounds that stimulate the activity of cardiac P2X receptors, and methods for using them to stimulate the activity of cardiac P2X receptors and treat diseases such as heart failure. The aqueous formulations exhibit excellent storage stability and can be prepared immediately for use by mixing with a diluent for intravenous administration to provide an aqueous injectable formulation. The aqueous injectable formulation can be administered to a patient by intravenous injection. These and other embodiments of the aqueous formulations and aqueous injectable formulations of the present invention, as well as their medical applications, are described below.

[0007] Therefore, one aspect of the present invention is an aqueous formulation, (a) Formula I below for 0.25%(w / v) to 0.75%(w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.03% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, pharmaceutically acceptable salts of ethylenediaminetetraacetic acid, or mixtures thereof; (c) A buffering agent containing citric acid and pharmaceutically acceptable salts of citric acid, in a concentration of 10 mM to 30 mM; (d) 3.5% (w / v) to 11% (w / v) isotonic modifier; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.5 to 8.5.

[0008] Another aspect of the present invention is an aqueous formulation, (a) The following formula I for approximately 0.5% (w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) Approximately 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A buffering agent of approximately 20 mM containing citric acid and pharmaceutically acceptable salts of citric acid; (d) Approximately 6.9% (w / v) of isotonic agent; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH of approximately 8.

[0009] Further descriptions of additional aqueous formulations are provided in the "Detailed Description". For example, another aspect of the present invention is an aqueous formulation, (a) Formula I below for 0.25%(w / v) to 0.75%(w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.06% (w / v) chelating agent; (c) buffering agent; and (d) containing at least 85% (w / v) water The present invention provides an aqueous formulation with a pH in the range of 7.0 to 8.5.

[0010] Another aspect of the present invention provides an aqueous injectable formulation comprising the aqueous formulation described herein and a diluent for intravenous administration. Examples of diluents for intravenous administration include physiological saline and Ringer's lactate solution. Another aspect of the present invention provides an aqueous injectable formulation produced by mixing the formulation described herein with a diluent for intravenous administration. Another aspect of the present invention provides a method for preparing an aqueous injectable formulation, comprising mixing the formulation described herein with a diluent for intravenous administration.

[0011] Another aspect of the present invention provides a method for treating heart disease, which includes administering a therapeutically effective amount of the aqueous injectable formulation described herein to a subject in need of treatment to treat heart disease.

[0012] Another aspect of the present invention provides a method for improving myocardial contractility in a subject, the method comprising administering an effective amount of the aqueous injectable formulation described herein to a subject in need of improvement, thereby improving myocardial contractility.

[0013] Another aspect of the present invention provides a method for improving cardiac function in a subject, the method comprising administering an effective amount of the aqueous injectable formulation described herein to a subject in need of improvement, thereby improving cardiac function.

[0014] Another aspect of the present invention provides a method for stimulating the activity of cardiac P2X receptors in a subject, the method comprising stimulating the activity of the cardiac P2X receptors by administering an effective amount of the aqueous injectable formulation described herein to a subject requiring stimulation. [Modes for carrying out the invention]

[0015] The present invention provides aqueous formulations containing compounds that stimulate the activity of cardiac P2X receptors, and methods for using them to stimulate the activity of cardiac P2X receptors and treat diseases such as heart failure. The aqueous formulations have excellent storage stability and can be prepared at the time of use by mixing with a diluent for intravenous administration to provide an aqueous injectable formulation. The aqueous injectable formulation can be administered to a patient by intravenous injection. These and other embodiments of the aqueous formulations and aqueous injectable formulations of the present invention and their medical uses are described below. In carrying out the present invention, unless otherwise specified, prior art in the fields of organic chemistry, pharmacology, molecular biology (including recombinant technology), cell biology, biochemistry, and immunology is used. These techniques are described in literature such as Comprehensive Organic Synthesis (BMTrost & I. Fleming, eds., 1991-1992), Handbook of experimental immunology (DMWeir & C.C. Blackwell, eds.), Current protocols in molecular biology (FMAusubel et al, eds., 1987, and subsequent periodic revisions), and Current protocols in immunology (JEColigan et al, eds., 1991), the contents of each of these publications are incorporated herein by reference in their entirety.

[0016] Various aspects of the present invention are shown in several sections below, but an aspect of the present invention described in one particular section is not limited to any particular section. Furthermore, where a variable is not defined, the prior definition of that variable shall apply.

[0017] definition The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. Where used herein, unless otherwise specified, the following definitions apply. These definitions apply whether the terms are used alone or in combination with other terms, unless otherwise specified. Therefore, the definition of "alkyl" applies not only to "alkyl" but also to alkyl portions such as "-O-alkyl". For the purposes of the present invention, chemical elements are defined as those in the CAS periodic table, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry are identified according to Ed., Thomas Sorrell, *Organic Chemistry*, University Science Books, Sausalito: 1999, and March's *Advanced Organic Chemistry*, 5 th This is described in Ed.,M. Smith and March, J., John Wiley & Sons, New York: 2001, and its entirety is incorporated herein by reference.

[0018] As used herein, the terms “aliphatic” or “aliphatic group” mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as “alicyclic”), having a single bond site to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In certain embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In certain embodiments, “alicyclic” means 、Monocyclic carbon atoms are either fully saturated or contain one or more unsaturated units but are not aromatic, and have a single bond site for the remainder of the molecule. 3- This refers to C6 hydrocarbons. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrid groups thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0019] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., a carbocyclic or heterocyclic ring, having saturated or one or more unsaturated units and having one or more common atoms between the two rings of the ring system. Thus, this term includes any acceptable ring condensation, such as ortho condensation and spirocyclic rings. As used herein, the term “heterobicyclic” is a subset of “bicyclic” and requires the presence of one or more heteroatoms in one or both rings of the bicyclic ring. Such heteroatoms are located at the junction of the rings, are optionally substituted, and can be selected from nitrogen (including N-oxide), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In certain embodiments, the bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one “bridge” portion. According to the IUPAC definition, a “bridge” is an unbranched atomic chain, or an atom or valence bond connecting two bridgeheads. Here, a “bridgehead” refers to any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen). In certain embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the following groups, each of which is bonded to the rest of the molecule by any substituteable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any substituteable nitrogen in a bridged bicyclic group is optionally substituted. Examples of bicyclic rings include: [ka]

[0020] Examples of two-ring bridges include the following: [ka]

[0021] The term "lower alkyl" refers to a straight-chain or branched alkyl group of C 1-4 Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0022] The term "lower haloalkyl" refers to a straight-chain or branched alkyl group of C 1-4 substituted with one or more halogen atoms.

[0023] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, any quaternized form of any basic nitrogen, or any replaceable nitrogen in a heterocyclic ring, such as N (in the case of 3,4-dihydro-2H-pyrrolyl), NH (in the case of pyrrolidinyl) or NR[[ID=I9]] + (in the case of N-substituted pyrrolidinyl)).

[0024] As used herein, the term "unsaturated" means that the moiety has one or more unsaturated units.

[0025] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight-chain or branched hydrocarbon chain" refers to a divalent alkylene chain, alkenylene chain, and alkynylene chain that is straight-chain or branched as defined herein.

[0026] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Examples of suitable substituents are listed below for substituted aliphatic groups.

[0027] The term "-(C0 alkylene)-" refers to a bond. Therefore, "-(C 0-3 The term "alkylene)-" refers to the bond (i.e., C0) and -(C 1-3 It includes an alkylene group.

[0028] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Examples of appropriate substituents include those listed below for substituted aliphatic groups.

[0029] The term "halogen" refers to F, Cl, Br, or I.

[0030] The term "aryl" is used alone or as part of a larger phrase such as "aralkyl," "aralkoxy," or "aryloxyalkyl," and refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that includes, non-limitingly, phenyl, biphenyl, naphthyl, anthrasyl, etc., which may have one or more substituents. The scope of the term "aryl" as used herein also includes groups in which an aromatic ring, such as indanyl, phthaliumidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl, is fused to one or more non-aromatic rings. The term "phenylene" refers to a polyvalent phenyl group having an appropriate number of open valencies, taking into account the groups bonded to it.

[0031] The terms "heteroaryl" and "heteroar-" are used alone or as part of a larger group such as heteroaralkyl or heteroaralkoxy, and refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, 6, 10, or 14 π electrons shared in the cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen. Examples of heteroaryl groups, but not limited to these, include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “heteroar-” further include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the radical or bond is located on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxadinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with heteroaryl ring, heteroaryl group, or heteroaromatic group, all of which include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl portions can be independently and optionally substituted.

[0032] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are interchangeable and refer to stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moieties that are saturated or partially unsaturated and have one or more, preferably 1 to 4, heteroatoms as defined above, in addition to carbon atoms. When used in relation to the ring atoms of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen is N (in the case of 3,4-dihydro-2H-pyrrolyl), NH (in the case of pyrrolidinyl), or + This results in NR (in the case of N-substituted pyrrolidinyl).

[0033] The heterocyclic ring may be bonded to its pendant group at any heteroatom or carbon atom, and any ring atom may be optionally substituted, as long as it results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. In this specification, the terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably, and include groups in which a heterocyclyl ring, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl, is fused to one or more aryl rings, heteroaryl rings, or alicyclic rings. The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, and the alkyl and heterocyclyl moieties may be independently and arbitrarily substituted. The term "oxo-heterocyclyl" refers to a heterocyclyl substituted with an oxo group. The term "heterocyclylene" refers to a polyvalent heterocyclyl group that has an appropriate number of open valencies, taking into account the groups bonded to it. For example, a heterocyclylene is a divalent heterocyclyl group when two groups are bonded to it, and a trivalent heterocyclyl group when three groups are bonded to it.

[0034] As used herein, the term “partially unsaturated” refers to a ring moiety containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moies, but not to include aryl or heteroaryl moies as defined herein.

[0035] As described herein, the compounds of the present invention may include “optionally substituted” moieties. Generally, the term “substituted,” whether preceded by the term “optionally,” means that one or more hydrogens of a given moiety are replaced with appropriate substituents. Unless otherwise specified, an “optionally substituted” group may have appropriate substituents at each substitutedable position of the group, and the substituents may be the same or different at all positions if multiple positions in any given structure can be replaced with multiple substituents selected from a specified group. The substituent combinations envisioned by the present invention preferably result in the formation of a stable or chemically feasible compound. As used herein, “stable” means that a compound remains substantially unchanged when exposed to conditions that enable its production, detection, and, in particular embodiments, its recovery, purification, and use in one or more of the purposes disclosed herein.

[0036] Each optional substituent on the carbon that can be substituted is a halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph (may be substituted with R°), -(CH2) 0-4 O(CH2) 0-1 Ph (may be substituted with R°), -CH = CHPh (may be substituted with R°), -(CH2) 0-4 O(CH2) 0-1-Pyridyl (may be substituted with R°), -NO2, -CN, -N3, -(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR-, SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-S(O)(NR°)R°;-S(O)2N=C(NR°2)2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1-4 Linear or branched alkylenes)ON(R°)2; or -(C 1-4 A monovalent substituent independently selected from linear or branched alkylene (C(O)ON(R°)2).

[0037] Each R° independently contains hydrogen and C. 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 member heteroaryl ring), or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R° together with their intervening atoms to form a monocyclic or bicyclic 3-12 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, the ring may be substituted by divalent substituents on the saturated carbon atoms of R° selected from =O and =S, or each R° may be a halogen, -(CH2) 0-2 R ● ,-(Haro R● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2, -O(HaroR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● ,-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● ,-(CH2) 0-2 SR ● ,-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● ,-(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● 、 -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● It may be substituted with a monovalent substituent selected independently of it.

[0038] Each R ●is C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or independently selected from 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens. Alternatively, any substituent on a saturated carbon is =O, =S, =NNR * 2, =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR *、 -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- or is a divalent substituent independently selected from, or the divalent substituent attached to the adjacent replaceable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, and each independent occurrence of R * is selected from hydrogen, C 1-6 aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] <00 supposing RR * is C 1-6 aliphatic, R * is optionally substituted with halogen, -R ● 、-(haloR ● )、-OH、-OR ● 、-O(haloR ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2, or -NO2, and each R ● is C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur, and each R ● It is either not substituted, or if a halo precedes it, it is substituted with only one or more halogens.

[0040] Any substitutionable substituent on nitrogen is independently -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † Here, each R † Hydrogen and C are independent of each other. 1-6 An aliphatic, unsubstituted-OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independent R groups. † The appearance of these atoms, together with the intervening atoms, forms an unsubstituted monocyclic or bicyclic 3-12 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Here, R † C 1-6 If it is aliphatic, R † Halogen, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or optionally substituted with -NO2, where each R ● C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur, where each R ● It is either not substituted, or if a halo precedes it, it is substituted with only one or more halogens.

[0041] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, or allergic reactions, within the normal range of reasonable medical judgment, and that balances with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, describe pharmaceutically acceptable salts in detail, which are incorporated herein by reference. Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethansulfate. Examples include honate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0042] Furthermore, for acids generally considered suitable for forming medicinally useful salts from basic pharmaceutical compounds, see, for example, P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977). 66 (1)1-19;P.Gould, International J.of Pharmaceutics(1986) 33 ,21-217;Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York;and The Orange Book (Food & Drug Administration, Washington, DC website version). These disclosures are incorporated herein by reference.

[0043] Examples of salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and N. + (C 1-4 Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Furthermore, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0044] Unless otherwise specified, the structures described herein are intended to include all isomeric forms of that structure (e.g., enantiomers, diastereomers, and geometric (or conformational) forms), examples of which include the R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers of the compounds of the present invention, as well as enantiomer mixtures, diastereomer mixtures, and geometric (or conformational) mixtures, are within the scope of the present invention. Unless otherwise specified, all tautomers of the compounds of the present invention are within the scope of the present invention.

[0045] Diastereomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscherate), separating the diastereomers, and converting the individual diastereomers into their corresponding pure enantiomers (e.g., by hydrolysis). Alternatively, specific enantiomers of the compounds of the present invention can also be prepared by asymmetric synthesis. Furthermore, if the molecules contain basic functional groups (such as amino acids) or acidic functional groups (such as carboxylic acids), diastereomer salts can be formed with a suitable optically active acid or base, and the formed diastereomers can then be separated by fractional crystallization or chromatographic means known in the art, followed by the recovery of the pure enantiomers.

[0046] The individual stereoisomers of the compounds of the present invention may not substantially contain other isomers, for example, or may be mixed, for example, as a racemate, or with all other or other selected stereoisomers. The chiral centers in the compounds of the present invention may have an S or R configuration as defined by the IUPAC 1974 Recommendations. Furthermore, to the extent that the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of the present invention.

[0047] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is mentioned using both its chemical structure and chemical name, and there is ambiguity between the structure and the name, the structure shall prevail. Note that any carbon and heteroatoms with insufficient valence in the text, schemes, examples, and tables of this specification are assumed to have a sufficient number of hydrogen atoms to satisfy their valence.

[0048] Unless otherwise stated, the term "approximately" refers to a value within ±10% of the stated value. The present invention encompasses embodiments in which the value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0049] As used herein, the terms "a" and "an" mean "one or more" and include the plural form unless the context is appropriate.

[0050] The term "alkyl" refers to saturated linear or branched hydrocarbons, such as linear or branched groups of 1 to 12, 1 to 10, or 1 to 6 carbon atoms, respectively, as used herein. 12 Alkyl, C1-C 10These are called alkyl groups and C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0051] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridging cyclic hydrocarbon group (e.g., adamantyl) having 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbon atoms, and is referred herein, for example, to "C3-C6 cycloalkyl" and is derived from cycloalkanes. Examples of cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.

[0052] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, and -CF2CF3. The term "haloalkylene" refers to a divalent haloalkyl group.

[0053] The terms "alkenyl" and "alkynyl" are recognized in the art and refer to unsaturated aliphatic groups that are similar to alkyl groups in length and possible substitutions, but each contains at least one double or triple bond.

[0054] The terms "alkoxyl" or "alkoxy" are recognized in the art and refer to alkyl groups defined above, to which an oxygen radical is bonded. Typical alkoxyl groups include methoxy, ethoxy, propyroxy, and tert-butoxy. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Examples of haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, and -OCF2CF3. The term "hydroxyalkoxyl" refers to an alkoxyl group substituted with at least one hydroxyl. Examples of hydroxyalkoxyl groups include -OCH2CH2OH and -OCH2C(H)(OH)CH2CH2OH. The term "alkoxylene" refers to a divalent alkoxyl group.

[0055] The term "oxo" is recognized in the relevant technical field and refers to an "=O" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0056] symbol [ka] The symbol indicates a connection point.

[0057] If a substituent or variable appears multiple times in a component or compound of the present invention, unless otherwise specified, the definition of that substituent in each appearance shall be independent of the definition of that substituent in all other appearances.

[0058] As used herein, the terms “subject” and “patient” are interchangeable and refer to the organism treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., rodents, primates, equids, bovines, pigs, canines, felines, etc.), and most preferably include, humans.

[0059] As used herein, the term “compound” refers to a quantity of a molecule that has been weighed, whose structural identity has been tested, and which is sufficient to have demonstrable applications (e.g., an amount that can be shown to be active in an assay, in vitro test, or in vivo test, or an amount that can be administered to a patient and produce a therapeutic effect).

[0060] As used herein, the term “effective dose” means the amount of a compound sufficient to produce a beneficial or desired outcome (e.g., a therapeutic, ameliorative, inhibitory, or prophylactic outcome). An effective dose may be administered in one or more doses, applications, or prescriptions and is not intended to be limited to a specific prescription or route of administration.

[0061] As used herein, the term “treat” includes any effect that may result in improvement of a medical condition, disease, disorder, etc., such as reduction, reduction, regulation, improvement, or elimination, or improvement of their symptoms.

[0062] As used herein, the term “pharmaceutical composition” refers to a combination of an activator and an inactive or active carrier, which makes the composition particularly suitable for use in in vivo or ex vivo diagnostic or therapeutic applications.

[0063] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0064] Throughout this specification, where a composition is described as having, including, or comprising specific components, or where a process and method is described as having, including, or comprising specific steps, it is assumed that there are compositions of the present invention that consist of or essentially consist of the listed components, and that there are processes and methods described in the present invention that consist of or essentially consist of the listed processing steps.

[0065] Generally, percentages of a composition are given by weight unless otherwise specified.

[0066] I. Aqueous formulations The present invention provides aqueous formulations comprising cardiac P2X receptor agonists. These aqueous formulations can be combined with diluents for intravenous administration, and the resulting aqueous injectable formulations can be used in the therapeutic methods described herein. Examples of aqueous formulations are described in the following sections.

[0067] Part A - First Aqueous Formulation One aspect of the present invention is an aqueous formulation, (a) Formula I below for 0.25%(w / v) to 0.75%(w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.03% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, pharmaceutically acceptable salts of ethylenediaminetetraacetic acid, or mixtures thereof; (c) A buffering agent containing citric acid and pharmaceutically acceptable salts of citric acid, in a concentration of 10 mM to 30 mM; (d) 3.5% (w / v) to 11% (w / v) isotonic agent; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.5 to 8.5.

[0068] The first aqueous formulation can be further described according to additional characteristics such as the amount and type of components in the formulation. A more detailed description of these functions is given below. The present invention encompasses all permutations and combinations of these characteristics.

[0069] In certain embodiments, the compound of formula I is present in the formulation at an amount of 0.4% (w / v) to 0.6% (w / v). In certain embodiments, the compound of formula I is present in the formulation at an amount of approximately 0.5% (w / v). In certain embodiments, the compound of formula I is present in the formulation at an amount of 0.5% (w / v).

[0070] In yet another embodiment, the formulation is 0.25%~0.75%(w / v), 0.25%~0.70%(w / v), 0.25%~0.65%(w / v), 0.25%~0.60%(w / v), 0.25%~0.55%(w / v), 0.25%~0.50%(w / v), 0.25%~0.45%(w / v), 0.25%~0.40%(w / v), 0.25%~0.35%(w / v), 0.25%~0.30%(w / v), 0.30%~0.75%(w / v), 0.30%~0.70%(w / v), 0.30%~0.65%(w / v), 0.30 %~0.60%(w / v), 0.30%~0.55%(w / v), 0.30%~0.50%(w / v), 0.30%~0.45%(w / v), 0.30%~0.40%(w / v), 0.30%~0.35%(w / v), 0.35%~0.75%(w / v), 0.35% ~0.70%(w / v), 0.35%~0.65%(w / v), 0.35%~0.60%(w / v), 0.35%~0.55%(w / v), 0.35%~0.50%(w / v), 0.35%~0.45%(w / v), 0.35%~0.40%(w / v), 0.40%~0 .75%(w / v), 0.40%~0.70%(w / v), 0.40%~0.65%(w / v), 0.40%~0.60%(w / v) , 0.40%~0.55%(w / v), 0.40%~0.50%(w / v), 0.40%~0.45%(w / v), 0.45%~0. 75%(w / v), 0.45%~0.70%(w / v), 0.45%~0.65%(w / v), 0.45%~0.60%(w / v), 0.45%~0.55%(w / v), 0.45%~0.50%(w / v), 0.50%~0.75%(w / v), 0.50%~0.70 It contains compounds of formula I in the following concentrations: %(w / v), 0.50%~0.65%(w / v), 0.50%~0.60%(w / v), 0.50%~0.55%(w / v), 0.55%~0.75%(w / v), 0.55%~0.70%(w / v), 0.55%~0.65%(w / v), 0.55%~0.60%(w / v), 0.60%~0.75%(w / v), 0.60%~0.70%(w / v), 0.60%~0.65%(w / v), 0.65%~0.75%(w / v), 0.65%~0.70%(w / v), or 0.70%~0.75%(w / v).

[0071] In certain embodiments, the formulation contains about 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, or 0.75% (w / v) of the compound of formula I. In certain embodiments of the formulation, the compound of formula I is present in amounts of 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, or 0.75% (w / v).

[0072] In a particular embodiment of the formulation, the compound of formula I is [ka] It is a pharmaceutically acceptable salt of a metal. For example, the compound of formula I may be a pharmaceutically acceptable salt of an alkali metal or an alkaline earth metal. In certain embodiments, the compound of formula I is a sodium salt.

[0073] The formulation may be characterized according to the chelating agent. For example, the chelating agent may be ethylenediaminetetraacetic acid (EDTA), a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof. In certain embodiments, the chelating agent is EDTA. In certain embodiments, the chelating agent is a pharmaceutically acceptable salt of EDTA. In certain embodiments, the chelating agent is a mixture of EDTA and a pharmaceutically acceptable salt of EDTA.

[0074] In certain embodiments, the formulation contains 0.01% to 0.03% (w / v) of a chelating agent. For example, in certain embodiments, the formulation contains 0.015% (w / v) to 0.025% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof. In certain embodiments, the formulation contains about 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof. In certain embodiments, the formulation contains 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof.

[0075] In certain embodiments, the formulation contains 0.01% to 0.03% (w / v), 0.01% to 0.025% (w / v), 0.01% to 0.02% (w / v), 0.01% to 0.015% (w / v), 0.015% to 0.03% (w / v), 0.015% to 0.025% (w / v), 0.015% to 0.02% (w / v), 0.02% to 0.03% (w / v), 0.02% to 0.025% (w / v), or 0.025% to 0.03% (w / v) of a chelating agent. In certain embodiments, the formulation contains about 0.01%, 0.015%, 0.02%, 0.025%, or 0.03% (w / v) of a chelating agent. In certain embodiments, the formulation contains 0.01%, 0.015%, 0.02%, 0.025%, or 0.03% (w / v) of a chelating agent.

[0076] The formulation may be characterized based on the buffer. In certain embodiments, the formulation comprises 15 mM to 25 mM of a buffer containing citric acid and a pharmaceutically acceptable salt of citric acid. In certain embodiments, the formulation comprises 18 mM to 22 mM of a buffer containing citric acid and a pharmaceutically acceptable salt of citric acid. In certain embodiments, the formulation comprises about 20 mM of a buffer containing citric acid and a pharmaceutically acceptable salt of citric acid. In certain embodiments, the formulation comprises 20 mM of a buffer containing citric acid and a pharmaceutically acceptable salt of citric acid. In certain embodiments, the formulation comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mM of a buffer containing citric acid and a pharmaceutically acceptable salt of citric acid.

[0077] In certain embodiments, the formulation contains 0.25% (w / v) to 0.75% (w / v) of a buffering agent comprising citric acid and a pharmaceutically acceptable salt of citric acid.For example, in certain embodiments, the formulation contains citric acid and pharmaceutically acceptable salts of citric acid, in concentrations of 0.25%~0.75% (w / v), 0.25%~0.70% (w / v), 0.25%~0.65% (w / v), 0.25%~0.60% (w / v), 0.25%~0.55% (w / v), 0.25%~0.50% (w / v), 0.25%~0.45% (w / v), 0.25%~0.40% (w / v), 0.25%~0.35% (w / v), 0.25%~0.30% (w / v), 0.30%~0.75% (w / v), 0.30%~0.70% (w / v), 0.30%~0.65%(w / v), 0.30%~0.60%(w / v), 0.30%~0.55%(w / v), 0.30%~0.50 %(w / v), 0.30%~0.45%(w / v), 0.30%~0.40%(w / v), 0.30%~0.35%(w / v), 0.35 %~0.75%(w / v), 0.35%~0.70%(w / v), 0.35%~0.65%(w / v), 0.35%~0.60%(w / v ), 0.35%~0.55%(w / v), 0.35%~0.50%(w / v), 0.35%~0.45%(w / v), 0.35%~0.4 0%(w / v), 0.40%~0.75%(w / v), 0.40%~0.70%(w / v), 0.40%~0.65%(w / v), 0. 40%~0.60%(w / v), 0.40%~0.55%(w / v), 0.40%~0.50%(w / v), 0.40%~0.45%(w / v), 0.45%~0.75%(w / v), 0.45%~0.70%(w / v), 0.45%~0.65%(w / v), 0.45%~0.60%(w / v), 0.45%~0.55%(w / v), 0.45%~0.50%(w / v), 0.50%~0.75%(w / v), 0 Contains buffering in the following proportions: 0.50%~0.70%(w / v), 0.50%~0.65%(w / v), 0.50%~0.60%(w / v), 0.50%~0.55%(w / v), 0.55%~0.75%(w / v), 0.55%~0.70%(w / v), 0.55%~0.65%(w / v), 0.55%~0.60%(w / v), 0.60%~0.75%(w / v), 0.60%~0.70%(w / v), 0.60%~0.65%(w / v), 0.65%~0.75%(w / v), 0.65%~0.70%(w / v), or 0.70%~0.75%(w / v).

[0078] In certain embodiments, the formulation contains a buffer in about 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, or 0.75% (w / v) of a buffer containing citric acid and pharmaceutically acceptable salts of citric acid. In certain embodiments of the formulation, the buffer containing citric acid and pharmaceutically acceptable salts of citric acid is present in amounts of 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, or 0.75% (w / v). In certain embodiments, the formulation contains a buffer in 0.56% or about 0.56% (w / v) of a buffer containing citric acid and pharmaceutically acceptable salts of citric acid.

[0079] These formulations may be further characterized based on the isotonic agent. For example, in certain embodiments, the formulation contains 3.5% to 11% (w / v) of the isotonic agent. In certain embodiments, the formulation contains 3.5% to 9% (w / v) of the isotonic agent. In certain embodiments, the formulation contains 4% to 9% (w / v) of the isotonic agent. In certain embodiments, the formulation contains 5% to 9% (w / v) of the isotonic agent. In certain embodiments, the formulation contains 6% to 8% (w / v) of the isotonic agent. In certain embodiments, the formulation contains about 6.9% (w / v) of the isotonic agent. In certain embodiments, the formulation contains 6.9% (w / v) of the isotonic agent.

[0080] In certain embodiments, the formulation contains an isotonic agent in concentrations of 3.5%~11%, 3.5%~10.5%, 3.5%~10%, 3.5%~9.5%, 3.5%~9%, 3.5%~8.5%, 3.5%~8%, 3.5%~7.5%, 3.5%~7%, 3.5%~6.5%, 3.5%~6%, 3.5%~5.5%, 3.5%~5%, 3.5%~4.5%, 3.5%~4%, 4%~11%, 4%~10.5%, 4%~10%, 4%~9.5%, 4%~9%, 4%~8.5%, 4%~8%, 4%~7.5%, 4%~7%, 4%~6.5%, 4%~6%, 4%~5.5%, and 4%~5%. , 4%~4.5%, 4.5%~11%, 4.5%~10.5%, 4.5%~10%, 4.5%~9.5%, 4.5%~9%, 4.5%~8.5%, 4.5%~8%, 4.5%~7.5%, 4.5%~7%, 4.5%~6.5%, 4.5%~6%, 4.5%~5.5%, 4.5%~ 5%, 5%~11%, 5%~10.5%, 5%~10%, 5%~9.5%, 5%~9%, 5%~8.5%, 5%~8%, 5%~7.5%, 5%~7%, 5%~6.5%, 5%~6%, 5%~5.5%, 5.5%~11%, 5.5%~10.5%, 5.5%~10%, 5.5%~9 0.5%, 5.5%~9%, 5.5%~8.5%, 5.5%~8%, 5.5%~7.5%, 5.5%~7%, 5.5%~6.5%, 5.5%~6%, 6%~11%, 6%~10.5%, 6%~10%, 6%~9.5%, 6%~9%, 6%~8.5%, 6%~8%, 6%~7.5%, 6%~7%, 6%~6.5%, 6.5%~11%, 6.5%~10.5%, 6.5%~10%, 6.5%~9.5%, 6.5%~9%, 6.5%~8.5%, 6.5%~8%, 6.5%~7.5%, 6.5%~7%, 7%~11%, 7%~10.5%, 7%~10%, 7%~9. 5%, 7%~9%, 7%~8.5%, 7%~8%, 7%~7.5%, 7.5%~11%, 7.5%~10.5%, 7.5%~10%, 7.5%~9.5%, 7.5%~9%, 7.5%~8.5%, 7.5%~8%, 8%~11%, 8%~10.5%, 8%~10%, 8%~9.5% %, 8%~9%, 8%~8.5%, 8.5%~11%, 8.5%~10.5%, 8.5%~10%, 8.5%~9.5%, 8.5%~9%, 8%~11%, 8%~10.5%, 8%~10%, 8%~9.5%, 8.5%~11%, 8.5%~10.5%, 8.5%~10%, 8.Includes percentages of 5%-9%, 9%-11%, 9%-10.5%, 9%-10%, %, 9.5%-11%, 9.5%-10.5%, 9.5%-10%, 10%-11%, 10%-10.5%, or 10.5%-11% (w / v).

[0081] In certain embodiments, the formulation contains about 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, or 11% (w / v) of an isotonic agent. In certain embodiments of the formulation, the isotonic agent is present in amounts of 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, or 11% (w / v). In certain embodiments, the formulation contains 6.9% or about 6.9% of an isotonic agent.

[0082] In certain embodiments, the isotonic agent is a disaccharide. In certain embodiments, the isotonic agent is sucrose.

[0083] The formulation may be further characterized based on its pH. In certain embodiments, the formulation has a pH in the range of 7.8 to 8.2. In certain embodiments, the formulation has a pH of 8.0. In certain embodiments, the pH range is 7.5~8.5, 7.5~8.4, 7.5~8.3, 7.5~8.2, 7.5~8.1, 7.5~8, 7.5~7.9, 7.5~7.8, 7.5~7.7, 7.5~7.6, 7.6~8.5, 7.6~8.4, 7.6~8.3, 7.6~8.2, 7.6~8.1, 7.6~8, 7.6~7.9, 7.6~7.8, 7.6~7.7, 7.7~8.5, 7.7~8.4, 7.7~8.3, 7.7~8.2, 7.7~8.1, 7.7~8, 7.7~7.9, 7.7~7. The ranges are 0.8, 7.8~8.5, 7.8~8.4, 7.8~8.3, 7.8~8.2, 7.8~8.1, 7.8~8, 7.8~7.9, 7.9~8.5, 7.9~8.4, 7.9~8.3, 7.9~8.2, 7.9~8.1, 7.9~8, 8~8.5, 8~8.4, 8~8.3, 8~8.2, 8~8.1, 8.1~8.5, 8.1~8.4, 8.1~8.3, 8.1~8.2, 8.2~8.5, 8.2~8.4, 8.2~8.3, 8.3~8.5, 8.3~8.4, or 8.4~8.5. In certain embodiments, the formulation has a pH of 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5.

[0084] Adjusting the pH of aqueous formulations is beneficial. Therefore, in certain embodiments, the formulation includes one or more pH adjusters. In certain embodiments, the pH adjuster is one or more alkali metal hydroxides or hydrochloric acid. In certain embodiments, the pH adjuster is one or more sodium hydroxide or hydrochloric acid. In certain embodiments, the pH adjuster is sodium hydroxide. In certain embodiments, the pH adjuster is hydrochloric acid.

[0085] The formulation may be further characterized based on the amount of water in the formulation. In certain embodiments, the formulation contains at least 90% or 91% (w / v) water. In certain embodiments, the formulation contains at least 91% (w / v) water. In certain embodiments, the formulation contains 90% or 91% (w / v) water.

[0086] Part B - Second aqueous formulation Another aspect of the present invention is an aqueous formulation, (a) The following formula I for approximately 0.5% (w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) Approximately 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A buffering agent of approximately 20 mM containing citric acid and pharmaceutically acceptable salts of citric acid; (d) Approximately 6.9% (w / v) of isotonic agent; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH of approximately 8.

[0087] The second aqueous formulation can be further described according to additional characteristics such as the amount and type of components in the formulation. A more detailed description of these functions is given below. The present invention encompasses all permutations and combinations of these characteristics.

[0088] For example, in a particular embodiment, the compound of formula I is [ka] It is a pharmaceutically acceptable salt of a metal. For example, the compound of formula I may be a pharmaceutically acceptable salt of an alkali metal or an alkaline earth metal. In certain embodiments, the compound of formula I is a sodium salt.

[0089] The formulation may also contain approximately 0.02% (w / v) of a chelating agent. For example, the chelating agent may be ethylenediaminetetraacetic acid (EDTA), a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof. In certain embodiments, the chelating agent is EDTA. In certain embodiments, the chelating agent is a pharmaceutically acceptable salt of EDTA. In certain embodiments, the chelating agent is a mixture of EDTA and a pharmaceutically acceptable salt of EDTA.

[0090] In certain embodiments, the formulation contains 6.9% isotonic agent. In certain embodiments, the isotonic agent is a disaccharide. In certain embodiments, the isotonic agent is sucrose.

[0091] In certain embodiments, the formulation contains at least 91% water.

[0092] Part C - Third Aqueous Formulation Another aspect of the present invention is an aqueous formulation, (a) The following formula I for approximately 0.5% (w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) Approximately 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A buffering agent of approximately 20 mM containing citric acid and pharmaceutically acceptable salts of citric acid; (d) Approximately 6.9% (w / v) sucrose; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH of approximately 8.

[0093] The third aqueous formulation can be further described according to additional characteristics such as the amount and type of components in the formulation. A more detailed description of these functions is given below. The present invention encompasses all permutations and combinations of these characteristics.

[0094] For example, in certain embodiments, the formulation contains 0.02% (w / v) of a chelating agent. For example, the chelating agent may be ethylenediaminetetraacetic acid (EDTA), a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof. In certain embodiments, the chelating agent is EDTA. In certain embodiments, the chelating agent is a pharmaceutically acceptable salt of EDTA. In certain embodiments, the chelating agent is a mixture of EDTA and a pharmaceutically acceptable salt of EDTA.

[0095] In certain embodiments, the formulation contains at least 91% (w / v) water.

[0096] In certain embodiments, the formulation has a pH in the range of 7.8 to 8.2. In certain embodiments, the formulation has a pH of 8.0.

[0097] In a more specific embodiment, the formulation is (a) Formula I for 0.5% (w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A 20 mM buffer containing citric acid and pharmaceutically acceptable salts of citric acid; (d) 6.9% (w / v) sucrose; and (e) containing at least 90% (w / v) water, The pH is 8.

[0098] Part D - Aqueous formulations of type 4 Another aspect of the present invention is an aqueous formulation, (a) Formula I below for 0.25%(w / v) to 0.75%(w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) Chelating agents; and (c) Provide an aqueous formulation containing at least 85% (w / v) water.

[0099] The fourth aqueous formulation can be further described according to additional characteristics such as the amount and type of components in the formulation. A more detailed description of these functions is given below. The present invention encompasses all permutations and combinations of these characteristics.

[0100] In a more specific embodiment, the present invention is an aqueous formulation, (a) Formula I below for 0.25%(w / v) to 0.75%(w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.06% (w / v) chelating agent; (c) buffering agent; and (d) containing at least 85% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.0 to 8.5.

[0101] In a more specific embodiment, the present invention is an aqueous formulation, (a) Formula I below for 0.25%(w / v) to 0.75%(w / v): [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.06% (w / v) chelating agent; (c) 0.25% (w / v) to 2% (w / v) of buffering agent; and (d) containing at least 85% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.0 to 8.5.

[0102] For example, in a particular embodiment, the compound of formula I is [ka] It is a pharmaceutically acceptable salt of . In certain embodiments, the compound of formula I is [ka] It is a pharmaceutically acceptable salt of an alkali metal or alkaline earth metal. In certain embodiments, the compound of formula I is [ka] It is the sodium salt of [the substance].

[0103] As generally explained above, the formulation contains 0.25% (w / v) to 0.75% (w / v) of the compound of formula I. In certain embodiments, the compound of formula I is present in an amount of 0.4% (w / v) to 0.6% (w / v). In certain embodiments, the compound of formula I is present in an amount of about 0.5% (w / v). In certain embodiments, the compound of formula I is present in an amount of 0.5% (w / v).

[0104] In certain embodiments, the formulation contains the compound of formula I in concentrations of 0.25%~0.75% (w / v), 0.25%~0.70% (w / v), 0.25%~0.65% (w / v), 0.25%~0.60% (w / v), 0.25%~0.55% (w / v), 0.25%~0.50% (w / v), 0.25%~0.45% (w / v), 0.25%~0.40% (w / v), 0.25%~0.35% (w / v), 0.25%~0.30% (w / v), 0.30%~0.75% (w / v), 0.30%~0.70% (w / v), and 0.30%~0.65% (w / v). , 0.30%~0.60%(w / v), 0.30%~0.55%(w / v), 0.30%~0.50%(w / v), 0.30%~0. 45%(w / v), 0.30%~0.40%(w / v), 0.30%~0.35%(w / v), 0.35%~0.75%(w / v), 0 .35%~0.70%(w / v), 0.35%~0.65%(w / v), 0.35%~0.60%(w / v), 0.35%~0.55 %(w / v), 0.35%~0.50%(w / v), 0.35%~0.45%(w / v), 0.35%~0.40%(w / v), 0.4 0%~0.75%(w / v), 0.40%~0.70%(w / v), 0.40%~0.65%(w / v), 0.40%~0.60%( w / v), 0.40%~0.55%(w / v), 0.40%~0.50%(w / v), 0.40%~0.45%(w / v), 0.45% ~0.75%(w / v), 0.45%~0.70%(w / v), 0.45%~0.65%(w / v), 0.45%~0.60%(w / v), 0.45%~0.55%(w / v), 0.45%~0.50%(w / v), 0.50%~0.75%(w / v), 0.50%~0 It contains 0.70% (w / v), 0.50%~0.65% (w / v), 0.50%~0.60% (w / v), 0.50%~0.55% (w / v), 0.55%~0.75% (w / v), 0.55%~0.70% (w / v), 0.55%~0.65% (w / v), 0.55%~0.60% (w / v), 0.60%~0.75% (w / v), 0.60%~0.70% (w / v), 0.60%~0.65% (w / v), 0.65%~0.75% (w / v), 0.65%~0.70% (w / v), or 0.70%~0.75% (w / v).

[0105] In certain embodiments, the formulation contains the compound of formula I in amounts of about 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, or 0.75% (w / v). In certain embodiments of the formulation, the compound of formula I is present in amounts of 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, or 0.75% (w / v).

[0106] In certain embodiments, the chelating agent is a carboxylic acid or carboxylate compound. For example, in certain embodiments, the chelating agent is ethylene glycol tetraacetic acid, ethylenediamine tetraacetic acid, C 4-10 The chelating agent is a hydroxyalkyltricarboxylic acid, or a pharmaceutically acceptable salt of any of the foregoing, or a mixture of any of the foregoing. In certain embodiments, the chelating agent is selected from EDTA, a pharmaceutically acceptable salt of EDTA, or a mixture of EDTA and a pharmaceutically acceptable salt of EDTA. In certain embodiments, the chelating agent is selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof.

[0107] In certain embodiments, the formulation contains 0.01% (w / v) to 0.03% (w / v) of a chelating agent. In certain embodiments, the formulation contains about 0.02% (w / v) of a chelating agent. In certain embodiments, the formulation contains 0.02% (w / v) of a chelating agent.

[0108] The formulation may be further characterized based on the buffer. For example, in certain embodiments, the formulation contains 10 mM to 30 mM of buffer. In certain embodiments, the formulation contains 15 mM to 25 mM of buffer. In certain embodiments, the formulation contains about 20 mM of buffer. In certain embodiments, the formulation contains 20 mM of buffer. In certain embodiments, the formulation contains about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mM of buffer. In certain embodiments, the formulation contains 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mM of buffer.

[0109] In certain embodiments, the formulation contains 0.25% (w / v) to 2% (w / v) of buffering agent. In certain embodiments, the formulation contains 0.25% to 2% (w / v), 0.25% to 1.75%, 0.25% to 1.5% (w / v), 0.25% to 1.25%, 0.25% to 1% (w / v), 0.25% to 0.75%, 0.25% to 0.5%, 0.5% to 2% (w / v), 0.5% to 1.75%, 0.5% to 1.5% (w / v), 0.5% to 1.25%, 0.5% to 1% (w / v), 0.5% to 0.75%, 0.75% to 2% (w / v). The formulation contains a buffer in the following amounts: w / v), 0.75%~1.75%, 0.75%~1.5%(w / v), 0.75%~1.25%, 0.75%~1%(w / v), 1%~2%(w / v), 1%~1.75%, 1%~1.5%(w / v), 1%~1.25%, 1.25%~2%(w / v), 1.25%~1.75%, 1.25%~1.5%(w / v), 1.5%~2%(w / v), 1.5%~1.75%, or 1.75%~2%(w / v). In certain embodiments, the formulation contains a buffer in the following amounts: w / v, 0.4%~0.6%, 0.4%~0.5%, or 0.5%~0.6%(w / v).

[0110] In certain embodiments, the formulation contains about 0.25%, 0.4%, 0.50%, 0.6%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, or 2% (w / v) of buffering agent. In certain embodiments of the formulation, the buffering agent is present in amounts of 0.25%, 0.4%, 0.50%, 0.6%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, or 2% (w / v).

[0111] The buffering agent may include, for example, carboxylic acid compounds and carboxylate compounds. In certain embodiments, the buffering agent is C 4-10 Hydroxyalkyldicarboxylic acid, C 4-10 Hydroxyalkyltricarboxylic acid, C 1-6 The buffer comprises an alkanoic acid, glutamic acid, phosphoric acid, or any pharmaceutically acceptable salt thereof. In certain embodiments, the buffer is C 4-10 It comprises a hydroxyalkyltricarboxylic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the buffer comprises citric acid and a pharmaceutically acceptable salt of citric acid.

[0112] In certain embodiments, the formulation further comprises an isotonic agent. For example, in certain embodiments, the formulation comprises 1% to 15% (w / v) of an isotonic agent. In certain embodiments, the isotonic agent is present in the formulation in an amount of 1% (w / v) to 15%. In certain embodiments, the isotonic agent is present in the formulation in an amount of 5% (w / v) to 9%. In certain embodiments, the isotonic agent is present in the formulation in an amount of about 6.9% (w / v). In certain embodiments, the isotonic agent is present in the formulation in an amount of 6.9% (w / v).

[0113] In a specific embodiment, the formulations are 1%~15%, 1%~14%, 1%~13%, 1%~12%, 1%~11%, 1%~10%, 1%~9%, 1%~8%, 1%~7%, 1%~6%, 1%~5%, 1%~4%, 1%~3%, 1%~2%, 2%~15%, 2%~14%, 2%~13%, 2%~12%, 2%~12%, 2%~10%, 2%~9%, 2%~8%, 2%~7%, 2%~6%, 2%~5%, 2%~4%, 2%~3% %, 3%~15%, 3%~14%, 3%~13%, 3%~12%, 3%~12%, 3%~10%, 3%~9%, 3%~8%, 3%~7%, 3%~6%, 3%~5%, 3%~4%, 4%~15%, 4%~14%, 4%~13%, 4%~12%, 4%~12%, 4%~10%, 4%~9%, 4%~8%, 4%~7%, 4%~6%, 4%~5%, 5%~15%, 5%~14%, 5%~13%, 5%~12%, 5%~12% 5%~10%, 5%~9%, 5%~8%, 5%~7%, 5%~6%, 6%~15%, 6%~14%, 6%~13%, 6%~12%, 6%~12%, 6%~10%, 6%~9%, 6%~8%, 6%~7%, 7%~15%, 7%~14%, 7%~13%, 7%~12%, 7%~12%, 7%~10%, 7%~9%, 7%~8%, 8%~15%, 8%~14%, 8%~13%, 8%~12%, 8%~12%, 8%~10 Contains an isotonic agent in the following proportions: %, 8%~9%, 9%~15%, 9%~14%, 9%~13%, 9%~12%, 9%~12%, 9%~10%, 10%~15%, 10%~14%, 10%~13%, 10%~12%, 10%~11%, 11%~15%, 11%~14%, 11%~13%, 11%~12%, 12%~15%, 12%~14%, 12%~13%, 13%~15%, 13%~14%, or 14%~15% (w / v).

[0114] In certain embodiments, the formulation contains about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% (w / v) of an isotonic agent. In certain embodiments of the formulation, the isotonic agent is present in amounts of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% (w / v). In certain embodiments, the formulation contains 6.9% or about 6.9% of an isotonic agent.

[0115] In certain embodiments, the isotonic agent is a disaccharide, a monosaccharide, sodium chloride, or potassium chloride. In certain embodiments, the isotonic agent is a disaccharide. In certain embodiments, the isotonic agent is sucrose.

[0116] The formulation may be further characterized based on its pH. In certain embodiments, the pH of the formulation is in the range of 7.8 to 8.2. In certain embodiments, the formulation has a pH of about 8.0. In certain embodiments, the formulation has a pH of 8.0. In certain embodiments, the pH range is 7.5~8.5, 7.5~8.4, 7.5~8.3, 7.5~8.2, 7.5~8.1, 7.5~8, 7.5~7.9, 7.5~7.8, 7.5~7.7, 7.5~7.6, 7.6~8.5, 7.6~8.4, 7.6~8.3, 7.6~8.2, 7.6~8.1, 7.6~8, 7.6~7.9, 7.6~7.8, 7.6~7.7, 7.7~8.5, 7.7~8.4, 7.7~8.3, 7.7~8.2, 7.7~8.1, 7.7~8, 7.7~7.9, 7.7~7. The ranges are 0.8, 7.8~8.5, 7.8~8.4, 7.8~8.3, 7.8~8.2, 7.8~8.1, 7.8~8, 7.8~7.9, 7.9~8.5, 7.9~8.4, 7.9~8.3, 7.9~8.2, 7.9~8.1, 7.9~8, 8~8.5, 8~8.4, 8~8.3, 8~8.2, 8~8.1, 8.1~8.5, 8.1~8.4, 8.1~8.3, 8.1~8.2, 8.2~8.5, 8.2~8.4, 8.2~8.3, 8.3~8.5, 8.3~8.4, or 8.4~8.5. In certain embodiments, the formulation has a pH of 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5.

[0117] Adjusting the pH of aqueous formulations is beneficial. Therefore, in certain embodiments, the formulation includes one or more pH adjusting agents. In certain embodiments, the formulation includes a pH adjusting agent. In certain embodiments, the pH adjusting agent is one or more alkali metal hydroxides or hydrochloric acid. In certain embodiments, the pH adjusting agent is one or more sodium hydroxide or hydrochloric acid. In certain embodiments, the pH adjusting agent is sodium hydroxide. In certain embodiments, the pH adjusting agent is hydrochloric acid.

[0118] In certain embodiments, the formulation contains at least 85% (w / v) water. In certain embodiments, the formulation contains at least 90% (w / v) water. In certain embodiments, the formulation contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% (w / v) water. In certain embodiments, the formulation contains 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% (w / v) water.

[0119] Part E - 5 Aqueous Formulations Another aspect of the present invention is an aqueous formulation, (a) Formula I below: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) Chelating agents; and (c) Provide an aqueous formulation containing water.

[0120] The fifth aqueous formulation can be further described according to additional characteristics such as the amount and type of components in the formulation. A more detailed description of these functions is given below. The present invention encompasses all permutations and combinations of these characteristics.

[0121] In certain embodiments, the formulation contains about 6 mM to about 19 mM of the compound of formula I. In certain embodiments, the formulation contains about 10 mM to about 16 mM of the compound of formula I. In certain embodiments, the formulation contains about 11 mM to about 14 mM of the compound of formula I. In certain embodiments, the formulation contains about 12 mM to about 13 mM of the compound of formula I. In certain embodiments, the formulation contains 6 mM to 19 mM of the compound of formula I. In certain embodiments, the formulation contains 10 mM to 16 mM of the compound of formula I. In certain embodiments, the formulation contains 11 mM to 14 mM of the compound of formula I. In certain embodiments, the formulation contains 12 mM to 13 mM of the compound of formula I.

[0122] In certain embodiments, the formulation contains approximately 13 mM of the compound of formula I. In certain embodiments, the formulation contains 13 mM of the compound of formula I. In certain embodiments, the formulation contains 12.8 mM of the compound of formula I.

[0123] In certain embodiments, the formulation contains at least 85% (w / v) water.

[0124] In a more specific embodiment, the present invention is an aqueous formulation, (a) Formula I below for 6mM to 19mM: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) Chelating agents; and (c) Provide an aqueous formulation containing at least 85% (w / v) water.

[0125] In a more specific embodiment, the present invention is an aqueous formulation, (a) Formula I below for 6mM to 19mM: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.06% (w / v) chelating agent; (c) 0.25% (w / v) to 2% (w / v) of buffering agent; and (d) containing at least 85% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.0 to 8.5.

[0126] In a more specific embodiment, the present invention is an aqueous formulation, (a) For 11mM to 16mM, the following equation I: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.06% (w / v) chelating agent; (c) 0.25% (w / v) to 2% (w / v) of buffering agent; and (d) containing at least 85% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.0 to 8.5.

[0127] In a more specific embodiment, the present invention is an aqueous formulation, (a) For 12mM to 14mM, the following equation I: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.06% (w / v) chelating agent; (c) 0.25% (w / v) to 2% (w / v) of buffering agent; and (d) containing at least 85% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.0 to 8.5.

[0128] In a more specific embodiment, the present invention is an aqueous formulation, (a) For 12mM to 13mM, the following equation I: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.06% (w / v) chelating agent; (c) 0.25% (w / v) to 2% (w / v) of buffering agent; and (d) containing at least 85% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.0 to 8.5.

[0129] For example, in a particular embodiment, the compound of formula I is [ka] It is a pharmaceutically acceptable salt of . In certain embodiments, the compound of formula I is [ka] It is a pharmaceutically acceptable salt of an alkali metal or alkaline earth metal. In certain embodiments, the compound of formula I is [ka] It is the sodium salt of [the substance].

[0130] In certain embodiments, the chelating agent is a carboxylic acid or carboxylate compound. For example, in certain embodiments, the chelating agent is ethylene glycol tetraacetic acid, ethylenediamine tetraacetic acid, C 4-10 The chelating agent is a hydroxyalkyltricarboxylic acid, or a pharmaceutically acceptable salt of any of the foregoing, or a mixture of any of the foregoing. In certain embodiments, the chelating agent is selected from EDTA, a pharmaceutically acceptable salt of EDTA, or a mixture of EDTA and a pharmaceutically acceptable salt of EDTA.

[0131] In certain embodiments, the formulation contains 0.01% (w / v) to 0.03% (w / v) of a chelating agent. In certain embodiments, the formulation contains about 0.02% (w / v) of a chelating agent. In certain embodiments, the formulation contains 0.02% (w / v) of a chelating agent.

[0132] The formulation may be further characterized based on the buffer. For example, in certain embodiments, the formulation contains 10 mM to 30 mM of buffer. In certain embodiments, the formulation contains 15 mM to 25 mM of buffer. In certain embodiments, the formulation contains about 20 mM of buffer. In certain embodiments, the formulation contains 20 mM of buffer. In certain embodiments, the formulation contains about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mM of buffer. In certain embodiments, the formulation contains 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mM of buffer.

[0133] In certain embodiments, the formulation contains 0.25% (w / v) to 2% (w / v) of buffering agent. In certain embodiments, the formulation contains 0.25% to 2% (w / v), 0.25% to 1.75%, 0.25% to 1.5% (w / v), 0.25% to 1.25%, 0.25% to 1% (w / v), 0.25% to 0.75%, 0.25% to 0.5%, 0.5% to 2% (w / v), 0.5% to 1.75%, 0.5% to 1.5% (w / v), 0.5% to 1.25%, 0.5% to 1% (w / v), 0.5% to 0.75%, 0.75% to 2% (w / v). The formulation contains a buffer in the following amounts: w / v), 0.75%~1.75%, 0.75%~1.5%(w / v), 0.75%~1.25%, 0.75%~1%(w / v), 1%~2%(w / v), 1%~1.75%, 1%~1.5%(w / v), 1%~1.25%, 1.25%~2%(w / v), 1.25%~1.75%, 1.25%~1.5%(w / v), 1.5%~2%(w / v), 1.5%~1.75%, or 1.75%~2%(w / v). In certain embodiments, the formulation contains a buffer in the following amounts: w / v, 0.4%~0.6%, 0.4%~0.5%, or 0.5%~0.6%(w / v).

[0134] In certain embodiments, the formulation contains about 0.25%, 0.4%, 0.50%, 0.6%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, or 2% (w / v) of buffering agent. In certain embodiments of the formulation, the buffering agent is present in amounts of 0.25%, 0.4%, 0.50%, 0.6%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, or 2% (w / v).

[0135] The buffering agent may include, for example, carboxylic acid compounds and carboxylate compounds. In certain embodiments, the buffering agent is C 4-10 Hydroxyalkyldicarboxylic acid, C 4-10 Hydroxyalkyltricarboxylic acid, C 1-6 The buffer comprises an alkanoic acid, glutamic acid, phosphoric acid, or any pharmaceutically acceptable salt thereof. In certain embodiments, the buffer is C 4-10 It comprises a hydroxyalkyltricarboxylic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the buffer comprises citric acid and a pharmaceutically acceptable salt of citric acid.

[0136] In certain embodiments, the formulation further comprises an isotonic agent. For example, in certain embodiments, the formulation comprises 1% to 15% (w / v) of an isotonic agent. In certain embodiments, the isotonic agent is present in the formulation in an amount of 1% (w / v) to 15%. In certain embodiments, the isotonic agent is present in the formulation in an amount of 5% (w / v) to 9%. In certain embodiments, the isotonic agent is present in the formulation in an amount of about 6.9% (w / v). In certain embodiments, the isotonic agent is present in the formulation in an amount of 6.9% (w / v).

[0137] In a specific embodiment, the formulations are 1%~15%, 1%~14%, 1%~13%, 1%~12%, 1%~11%, 1%~10%, 1%~9%, 1%~8%, 1%~7%, 1%~6%, 1%~5%, 1%~4%, 1%~3%, 1%~2%, 2%~15%, 2%~14%, 2%~13%, 2%~12%, 2%~12%, 2%~10%, 2%~9%, 2%~8%, 2%~7%, 2%~6%, 2%~5%, 2%~4%, 2%~3% %, 3%~15%, 3%~14%, 3%~13%, 3%~12%, 3%~12%, 3%~10%, 3%~9%, 3%~8%, 3%~7%, 3%~6%, 3%~5%, 3%~4%, 4%~15%, 4%~14%, 4%~13%, 4%~12%, 4%~12%, 4%~10%, 4%~9%, 4%~8%, 4%~7%, 4%~6%, 4%~5%, 5%~15%, 5%~14%, 5%~13%, 5%~12%, 5%~12% 5%~10%, 5%~9%, 5%~8%, 5%~7%, 5%~6%, 6%~15%, 6%~14%, 6%~13%, 6%~12%, 6%~12%, 6%~10%, 6%~9%, 6%~8%, 6%~7%, 7%~15%, 7%~14%, 7%~13%, 7%~12%, 7%~12%, 7%~10%, 7%~9%, 7%~8%, 8%~15%, 8%~14%, 8%~13%, 8%~12%, 8%~12%, 8%~10 Contains an isotonic agent in the following proportions: %, 8%~9%, 9%~15%, 9%~14%, 9%~13%, 9%~12%, 9%~12%, 9%~10%, 10%~15%, 10%~14%, 10%~13%, 10%~12%, 10%~11%, 11%~15%, 11%~14%, 11%~13%, 11%~12%, 12%~15%, 12%~14%, 12%~13%, 13%~15%, 13%~14%, or 14%~15% (w / v).

[0138] In certain embodiments, the formulation contains about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% (w / v) of an isotonic agent. In certain embodiments, the isotonic agent is present in amounts of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% (w / v). In certain embodiments, the formulation contains 6.9% or about 6.9% of an isotonic agent.

[0139] In certain embodiments, the isotonic agent is a disaccharide, a monosaccharide, sodium chloride, or potassium chloride. In certain embodiments, the isotonic agent is a disaccharide. In certain embodiments, the isotonic agent is sucrose.

[0140] The formulation may be further characterized based on its pH. In certain embodiments, the pH of the formulation is in the range of 7.8 to 8.2. In certain embodiments, the formulation has a pH of about 8.0. In certain embodiments, the formulation has a pH of 8.0. In certain embodiments, the pH range is 7.5~8.5, 7.5~8.4, 7.5~8.3, 7.5~8.2, 7.5~8.1, 7.5~8, 7.5~7.9, 7.5~7.8, 7.5~7.7, 7.5~7.6, 7.6~8.5, 7.6~8.4, 7.6~8.3, 7.6~8.2, 7.6~8.1, 7.6~8, 7.6~7.9, 7.6~7.8, 7.6~7.7, 7.7~8.5, 7.7~8.4, 7.7~8.3, 7.7~8.2, 7.7~8.1, 7.7~8, 7.7~7.9, 7.7~7. The ranges are 0.8, 7.8~8.5, 7.8~8.4, 7.8~8.3, 7.8~8.2, 7.8~8.1, 7.8~8, 7.8~7.9, 7.9~8.5, 7.9~8.4, 7.9~8.3, 7.9~8.2, 7.9~8.1, 7.9~8, 8~8.5, 8~8.4, 8~8.3, 8~8.2, 8~8.1, 8.1~8.5, 8.1~8.4, 8.1~8.3, 8.1~8.2, 8.2~8.5, 8.2~8.4, 8.2~8.3, 8.3~8.5, 8.3~8.4, or 8.4~8.5. In certain embodiments, the formulation has a pH of 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5.

[0141] Adjusting the pH of aqueous formulations is beneficial. Therefore, in certain embodiments, the formulation includes one or more pH adjusting agents. In certain embodiments, the formulation includes a pH adjusting agent. In certain embodiments, the pH adjusting agent is one or more alkali metal hydroxides or hydrochloric acid. In certain embodiments, the pH adjusting agent is one or more sodium hydroxide or hydrochloric acid. In certain embodiments, the pH adjusting agent is sodium hydroxide. In certain embodiments, the pH adjusting agent is hydrochloric acid.

[0142] In certain embodiments, the formulation contains at least 85% (w / v) water. In certain embodiments, the formulation contains at least 90% (w / v) water. In certain embodiments, the formulation contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% (w / v) water. In certain embodiments, the formulation contains 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% (w / v) water.

[0143] In a more specific embodiment, the present invention is an aqueous formulation, (a) Formula I below for 6mM to 19mM: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.03% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, pharmaceutically acceptable salts of ethylenediaminetetraacetic acid, or mixtures thereof; (c) A buffering agent containing citric acid and pharmaceutically acceptable salts of citric acid, in a concentration of 10 mM to 30 mM; (d) 3.5% (w / v) to 11% (w / v) isotonic agent; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH in the range of 7.5 to 8.5.

[0144] In a more specific embodiment, the present invention is an aqueous formulation, (a) Equation I below for approximately 12.8 mM: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) Approximately 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A buffering agent of approximately 20 mM containing citric acid and pharmaceutically acceptable salts of citric acid; (d) Approximately 6.9% (w / v) of isotonic agent; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH of approximately 8.

[0145] In a more specific embodiment, the present invention is an aqueous formulation, (a) Equation I below for approximately 12.8 mM: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) Approximately 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A buffering agent of approximately 20 mM containing citric acid and pharmaceutically acceptable salts of citric acid; (d) Approximately 6.9% (w / v) sucrose; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH of approximately 8.

[0146] In a more specific embodiment, the present invention is an aqueous formulation, (a) Equation I for 12.8 mM: [ka] Compounds of or pharmaceutically acceptable salts thereof; (b) 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A 20 mM buffer containing citric acid and pharmaceutically acceptable salts of citric acid; (d) 6.9% (w / v) sucrose; and (e) containing at least 90% (w / v) water, The present invention provides an aqueous formulation with a pH of 8.

[0147] Part F - Additional Features of Aqueous Formulations 1, 2, 3, 4, and 5 The first, second, third, fourth, and fifth aqueous formulations may be further characterized according to additional features such as osmotic pressure concentration and purity during storage. A more detailed description of these features is given below. The present invention encompasses all permutations and combinations of these features.

[0148] For example, in certain embodiments, the osmotic concentration of the formulation is in the range of approximately 240 to approximately 340 mOsm / kg. In certain embodiments, the osmotic concentration of the formulation is in the range of approximately 270 mOsm / kg to approximately 330 mOsm / kg. In certain embodiments, the osmotic concentration of the formulation is approximately 240 to approximately 340, approximately 240 to approximately 330, approximately 240 to approximately 320, approximately 240 to approximately 310, approximately 240 to approximately 300, approximately 240 to approximately 290, approximately 240 to approximately 280, approximately 240 to approximately 270, approximately 240 to approximately 260, approximately 240 to approximately 250, approximately 250 to approximately 340, approximately 250 to approximately 330, approximately 250 to Approximately 320, approximately 250-310, approximately 250-300, approximately 250-290, approximately 250-280, approximately 250-270, approximately 250-260, approximately 260-340, approximately 260-330, approximately 260-320, approximately 260-310, approximately 260-300, approximately 260-290, approximately 260-280, approximately 260-270, approximately 270~approx. 340, approx. 270~approx. 330, approx. 270~approx. 320, approx. 270~approx. 310, approx. 270~approx. 300, approx. 270~approx. 290, approx. 270~approx. 280, approx. 280~approx. 340, approx. 280~approx. 330, approx. 280~approx. 320, approx. 280~approx. 310, approx. 280~approx. 300, approx. 280~approx. 290, approx. 290~approx. 340, approx. 290~approx. 3 The values ​​are approximately 30, 290-320, 290-310, 290-300, 300-340, 300-330, 300-320, 300-310, 310-340, 310-330, 310-320, 320-340, 320-330, or 330-340 mOsm / kg.

[0149] In certain embodiments, the osmotic concentration of the formulation is approximately 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, or 340 mOsm / kg.

[0150] In certain embodiments of the formulations described herein, if the formulation is stored for more than 4 weeks, less than 0.5% by weight, 1% by weight, 1.5% by weight, or 2% by weight of the compound of formula I will decompose. In certain embodiments, if the formulation is stored for more than 24 weeks, less than 0.5% by weight, 1% by weight, 1.5% by weight, or 2% by weight of the compound of formula I will decompose.

[0151] In certain embodiments, less than 2% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 4 weeks. In certain embodiments, less than 1% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 4 weeks. In certain embodiments, less than 0.5% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 4 weeks. In certain embodiments of the formulations described herein, less than 0.5% by weight, 1% by weight, 1.5% by weight, or 2% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 4 weeks or longer.

[0152] In certain embodiments, when the formulation is stored at 25°C for 24 weeks, less than 2% by weight of the compound of formula I decomposes. In certain embodiments, when the formulation is stored at 25°C for 24 weeks, less than 1% by weight of the compound of formula I decomposes. In certain embodiments, when the formulation is stored at 25°C for 24 weeks, less than 0.5% by weight of the compound of formula I decomposes. In certain embodiments, when the formulation is stored at 25°C for 24 weeks or longer, less than 0.5% by weight, 1% by weight, 1.5% by weight, or 2% by weight of the compound of formula I decomposes.

[0153] In certain embodiments, less than 2% by weight of the compound of formula I decomposes when the formulation is stored at 40°C for 4 weeks. In certain embodiments, less than 1% by weight of the compound of formula I decomposes when the formulation is stored at 40°C for 4 weeks. In certain embodiments, less than 0.5% by weight of the compound of formula I decomposes when the formulation is stored at 40°C for 4 weeks. In certain embodiments of the formulations described herein, less than 0.5% by weight, 1% by weight, 1.5% by weight, or 2% by weight of the compound of formula I decomposes when the formulation is stored at 40°C for 4 weeks or longer.

[0154] In certain embodiments, when the formulation is stored at 40 °C for 24 weeks, less than 2% by weight of the compound of Formula I decomposes. In certain embodiments, when the formulation is stored at 40 °C for 24 weeks, less than 1% by weight of the compound of Formula I decomposes. In certain embodiments, when the formulation is stored at 40 °C for 24 weeks, less than 0.5% by weight of the compound of Formula I decomposes. In certain embodiments, when the formulation is stored at 40 °C for 24 weeks or more, less than 0.5%, 1%, 1.5%, or 2% by weight of the compound of Formula I decomposes.

[0155] In certain embodiments, the formulation contains less than 0.02% (w / v) of the following compound or a pharmaceutically acceptable salt thereof.

Chemical formula

[0156] In certain embodiments, the formulation contains less than 0.01% (w / v) of the following compound or a pharmaceutically acceptable salt thereof. ​​​​​​​​​​​​​​​​​​​​​​​​​​​In certain embodiments, the formulation does not contain polyethoxysorbitan fatty acid esters. In certain embodiments, the formulation does not contain polysorbate. In certain embodiments, the formulation contains less than 0.01% (w / v) of polyethoxysorbitan fatty acid esters. In certain embodiments, the formulation contains less than 0.01% (w / v) of polysorbate.

[0160] In certain embodiments, a pharmaceutically acceptable salt of citrate is an alkali metal salt or an alkaline earth metal salt of citrate. In certain embodiments, a pharmaceutically acceptable salt of citrate is an alkali metal salt of citrate. In certain embodiments, a pharmaceutically acceptable salt of citrate is a sodium salt of citrate. In certain embodiments, a pharmaceutically acceptable salt of citrate is an ammonium salt of citrate.

[0161] II. Aqueous Injectable Preparations Another aspect of the present invention provides an aqueous injectable formulation comprising an aqueous formulation described herein (e.g., the aqueous formulation described in Section I) and a diluent for intravenous administration. In certain embodiments, the diluent for intravenous administration is physiological saline. In certain embodiments, the diluent for intravenous administration is Ringer's lactate solution. In certain embodiments, the aqueous injectable formulation contains about 0.3% (w / v) to about 0.5% (w / v) of the compound of formula I. In certain embodiments, the aqueous injectable formulation contains about 0.4% (w / v) of the compound of formula I. In certain embodiments, the aqueous injectable formulation contains 0.4% (w / v) of the compound of formula I. In certain embodiments, the aqueous injectable formulation contains about 0.01% (w / v) to about 0.1% (w / v) of the compound of formula I. In certain embodiments, the aqueous injectable formulation contains about 0.03% (w / v) to about 0.05% (w / v) of the compound of formula I. In certain embodiments, the aqueous injection formulation contains about 0.04% (w / v) of the compound of formula I.

[0162] Another aspect of the present invention provides an aqueous injectable formulation prepared by mixing an aqueous formulation described herein (e.g., the aqueous formulation described in Section I) with a diluent for intravenous administration. In certain embodiments, the diluent for intravenous administration is physiological saline. In certain embodiments, the diluent for intravenous administration is Ringer's lactate solution. In certain embodiments, the aqueous injectable formulation contains about 0.3% (w / v) to about 0.5% (w / v) of the compound of formula I. In certain embodiments, the aqueous injectable formulation contains about 0.4% (w / v) of the compound of formula I. In certain embodiments, the aqueous injectable formulation contains 0.4% (w / v) of the compound of formula I. In certain embodiments, the aqueous injectable formulation contains about 0.01% (w / v) to about 0.1% (w / v) of the compound of formula I. In certain embodiments, the aqueous injectable formulation contains about 0.03% (w / v) to about 0.05% (w / v) of the compound of formula I. In certain embodiments, the aqueous injection formulation contains about 0.04% (w / v) of the compound of formula I.

[0163] Another aspect of the present invention provides a method for preparing an aqueous injection formulation, comprising mixing an aqueous formulation described herein (e.g., the aqueous formulation described in Section I) with a diluent for intravenous administration. In certain embodiments, the diluent for intravenous administration is physiological saline. In certain embodiments, the diluent for intravenous administration is Ringer's lactate solution. In certain embodiments, the aqueous injection formulation contains about 0.3% (w / v) to about 0.5% (w / v) of the compound of formula I. In certain embodiments, the aqueous injection formulation contains about 0.4% (w / v) of the compound of formula I. In certain embodiments, the aqueous injection formulation contains 0.4% (w / v) of the compound of formula I. In certain embodiments, the aqueous injection formulation contains about 0.01% (w / v) to about 0.1% (w / v) of the compound of formula I. In certain embodiments, the aqueous injection formulation contains about 0.03% (w / v) to about 0.05% (w / v) of the compound of formula I. In certain embodiments, the aqueous injection formulation contains about 0.04% (w / v) of the compound of formula I.

[0164] III. Therapeutic Applications The aqueous formulations described herein provide therapeutic effects to subjects suffering from diseases, including heart disease. Accordingly, this specification provides a method for treating heart disease, which includes administering a therapeutically effective dose of the aqueous injectable formulation described herein (for example, the aqueous injectable formulation described in Section II) to a subject in need of treatment to treat the heart disease.

[0165] Another aspect of the present invention provides a method for improving myocardial contractility in a subject, the method comprising administering an effective amount of the aqueous injectable formulation described herein to a subject in need of improvement to improve myocardial contractility.

[0166] Another aspect of the present invention provides a method for improving cardiac function in a subject, the method comprising administering an effective amount of the aqueous injectable formulation described herein to a subject in need of improvement to improve cardiac function.

[0167] In certain embodiments, the improvement in cardiac function is characterized by one or more of the following: improved cardiac relaxation ability, favorable remodeling in subjects with heart failure, reduced fibrosis, reduced cardiomyocyte hypertrophy, or improved calcium processing in cardiomyocytes in subjects with heart failure.

[0168] Another aspect of the present invention provides a method for stimulating the activity of cardiac P2X receptors in a subject, the method comprising stimulating the activity of cardiac P2X receptors by administering an effective amount of the aqueous injectable formulation described herein to a subject requiring stimulation.

[0169] In certain embodiments, the subject has a heart disease. In certain embodiments, the heart disease is heart failure, cardiac hypertrophy, ischemic cardiomyopathy, non-ischemic cardiomyopathy, or harmful remodeling and injury after ischemia / reperfusion injury. In certain embodiments, the heart disease is heart failure. In certain embodiments, the heart disease is cardiac hypertrophy. In certain embodiments, the heart disease is ischemic cardiomyopathy. In certain embodiments, the heart disease is non-ischemic cardiomyopathy. In certain embodiments, the heart disease is harmful remodeling and injury after ischemia / reperfusion injury. In certain embodiments, the subject has more than one of the aforementioned heart diseases.

[0170] In certain embodiments, the heart disease is heart failure. In certain embodiments, the heart failure is one or more of systolic heart failure or diastolic heart failure. In certain embodiments, the heart failure is systolic heart failure. In certain embodiments, the heart failure is diastolic heart failure.

[0171] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In embodiments, the subject is a pediatric human. In certain embodiments, the subject is an elderly human.

[0172] Another aspect of the present invention provides for using the aqueous formulation described herein in the manufacture of a pharmaceutical. In certain embodiments, the pharmaceutical is for treating a disease or condition described herein, such as heart failure.

[0173] Another aspect of the present invention provides for using the aqueous formulation described herein to treat a disease or condition described herein, such as a disease or condition such as heart failure.

[0174] Another aspect of the present invention is a kit comprising the aqueous formulation described herein. In certain embodiments, the kit further comprises instructions, such as instructions for treating a disease or condition described herein.

[0175] IV. Administration Modes The aqueous injectable formulations of the present invention described herein are preferably administered intravenously. The actual dosage of the aqueous injectable formulations of the present invention can be appropriately adjusted to provide the amount of active ingredient necessary to obtain the desired therapeutic effect while avoiding toxicity to the patient, given the specific patient, composition, and route of administration.

[0176] The selected dosage level depends on a variety of factors, including the activity of the particular aqueous injectable formulation of this disclosure used, the route of administration, the time of administration, the rate of elimination or metabolism of the particular compound used, the rate and range of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular aqueous formulation used, the age, sex, weight, medical condition, general health status, and medical history of the patient being treated, and similar factors that are well known in the medical field.

[0177] A physician or veterinarian with ordinary skill in the field can easily determine and prescribe the required effective amount of the aqueous injectable formulation. For example, a physician or veterinarian can start administering the aqueous injectable formulation of the present invention at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0178] Generally, the appropriate daily dose of the aqueous injectable formulation of the present invention is the minimum amount of the aqueous injectable formulation necessary to produce a therapeutic effect. Such an effective dose generally depends on the factors described above.

[0179] If desired, the effective daily dose of the aqueous injection formulation may be administered separately in 2, 3, 4, 5, 6, or more doses at appropriate intervals throughout the day, or optionally in unit dose form. [Examples]

[0180] The present invention, as generally described herein, will be more readily understood by referring to the following examples. The following examples are merely for illustrative purposes of specific aspects and embodiments of the present invention and are not intended to limit the invention. The starting materials described herein can be obtained from commercially available sources or can be readily prepared from commercially available materials using conversions known to those skilled in the art. Example 1 - Stability analysis of aqueous formulations containing compound 1 and optionally histidine or polyethylene glycol

[0181] Compound 1 was prepared into the aqueous formulations listed in Table 1 below, and the stability of these formulations was evaluated after storage at temperatures of 4°C, 25°C, or 40°C for one week. Compound 1 has the following formula: [ka] [Table 1-1] [Table 1-2]

[0182] Each of the above formulations 1-7 was evaluated by physically observing the presence of particles in the formulation immediately after preparation. Visual observation immediately after preparation revealed that each formulation was a transparent solution free of visible particles or fibers.

[0183] Multiple samples of each formulation 1-7 were placed in vials and stored at 4°C, 25°C, or 40°C for one week. After one week of storage, each vial was visually inspected for the presence of particles or fibers. The results are shown in Tables 2-4 below. These results indicate that a significant number of vials contained particles or fibers after one week of storage under the specified temperature conditions (i.e., 4°C, 25°C, or 40°C). Therefore, formulations 1-7 did not exhibit sufficient stability for storage. [Table 2] [Table 3] [Table 4] Example 2 - Stability analysis of aqueous formulations containing compound 1 with polysorbate, cremofol EL, or cyclodextrin.

[0184] Compound 1 was prepared as an aqueous formulation, and the stability of the aqueous formulation was evaluated. To evaluate the stability of the formulation, the formulation was stored at 25°C for 1 or 7 days, after which the appearance, the concentration of Compound 1 in the formulation, and the purity of the formulation were evaluated by liquid chromatography. The formulations contained Tween 20, Tween 80, Cremofor EL, or hydroxypropyl-β-cyclodextrin (HPβCD). The concentration of Compound 1 in the formulation is expressed in mg / mL, regardless of whether Compound 1 exists as a free acid or in the form of a salt (e.g., sodium salt of Compound 1).

[0185] Compound 1 has the following formula: [ka]

[0186] Tables 5-8 below show the results of the stability tests. These results indicate that precipitate formation was observed under the storage conditions applied in the experiments, and that many of the formulations are unstable during storage. [Table 5] [Table 6] [Table 7] [Table 8] Example 3- Stability analysis of aqueous formulations containing compound 1 and polysorbate

[0187] Compound 1 was prepared as an aqueous formulation containing polysorbate 20, and the stability of the resulting aqueous formulation was evaluated. To evaluate the stability of the formulation, the formulation was stored for 4 weeks, after which particles in the formulation were visually identified by physical examination. In this stability test, the formulation samples were stored at -20°C, 2°C–8°C, 25°C at 60% relative humidity (RH), or 40°C at 75% relative humidity. The concentration of Compound 1 in the formulation is expressed in mg / mL, regardless of whether Compound 1 exists as a free acid or in the form of a salt (e.g., sodium salt of Compound 1).

[0188] Compound 1 has the following formula: [ka]

[0189] Tables 9 and 10 below show the results of the stability tests. These results indicate that particle formation was observed in formulations stored for at least two weeks at 25°C and 60% relative humidity, and at 40°C and 75% relative humidity. The formation of particles during storage indicates that the formulation did not have good storage stability. [Table 9] [Table 10] Example 4 - Stability analysis of additional formulations containing compound 1 based on pH value

[0190] Compound 1 was prepared as an aqueous formulation containing EDTA, citrate buffer, and sucrose, and the stability of the resulting aqueous formulation was evaluated. To evaluate the stability of the formulation, the formulation was stored for two weeks, and then evaluated for degradation, including physical testing to check for the presence of visible particles in the formulation. In the stability test, the formulation samples were stored at 40°C. The concentration of Compound 1 in the formulation is expressed in mg / mL, regardless of whether Compound 1 exists as a free acid or in the form of a salt (e.g., sodium salt of Compound 1). Each formulation contained 0.02% (w / v) EDTA, 20 mM citrate buffer, 7% (w / v) sucrose, and a specific amount of Compound 1. The purity of the formulation was evaluated by liquid chromatography and expressed as percentage purity.

[0191] Compound 1 has the following formula: [ka]

[0192] The results are shown in Tables 11-13 below. [Table 11] [Table 12] [Table 13] Example 5 - Preparation of additional formulations containing compound 1

[0193] Compound 1 was prepared as an aqueous formulation containing EDTA sodium salt, a citrate buffer, and sucrose, and the stability of the resulting aqueous formulation was evaluated. The stability of the formulation was evaluated by a 4-week stability test. The results are shown below. Compound 1 has the following formula: [ka] Part I - Preparation of aqueous formulations

[0194] The formulations listed in Table 14 were prepared according to the following procedure. The concentration of compound 1 in the formulation is expressed in mg / mL, regardless of whether compound 1 exists as a free acid or as a salt (e.g., sodium salt of compound 1).

[0195] To obtain 100 mL of the formulation, 80 mL of water was added to a bottle equipped with a rotor. Then, 514.06 mg of sodium citrate dihydrate was added to the water in the bottle. 53 mg of citric acid monohydrate was added to the resulting mixture. 2.7 mL of 1 M NaOH was added to the resulting mixture.

[0196] Next, 20 mg of EDTA was added to the mixture, followed by 6.9 g of sucrose, and the resulting solution was thoroughly mixed. 50 mg of compound 1 was added to the resulting solution. The pH of the resulting solution was adjusted to 8.0 ± 0.2 by adding 0.1 M NaOH or 0.1 M HCl to the solution as needed. Purified water was added to the solution to a total volume of 100 mL. After confirming the final pH, the resulting solution was filtered through a 0.22 μm filter to obtain the final aqueous formulation. [Table 14] Part II - Analysis of the storage stability of the formulation

[0197] The stability of the aqueous formulations shown in Table 14 above was analyzed for storage over a period of four weeks. The aqueous formulation samples were stored at one of the following temperatures: -20°C, 2°C to 8°C, 25°C, or 40°C.

[0198] The following table shows the results of the stability test. The formulation showed good stability when stored under the conditions under which the test was conducted. [Table 15] [Table 16] Example 6- Stability analysis of exemplary formulations in combination with intravenous diluents

[0199] The formulations listed in Table 17 below were diluted with physiological saline or Ringer's lactate solution to prepare test solutions containing compound 1 at a concentration of 0.4 mg / mL. The concentration of compound 1 in the formulation is expressed in mg / mL, regardless of whether compound 1 exists as a free acid or as a salt (e.g., sodium salt of compound 1). The test solutions were stored for 128 hours to evaluate their stability. Compound 1 has the following formula: [ka] [Table 17]

[0200] These results indicate that both test solutions exhibit good stability, and that the formulations listed in Table 17 above are compatible with physiological saline and Ringer's lactate solution under the test conditions.

[0201] Reference The entirety of the disclosures of each patent document and scientific paper referred to herein is incorporated by reference for all purposes.

[0202] Equal portions The present invention may be embodied in other specific forms without departing from the spirit or essential features of the invention. Accordingly, the embodiments described herein should be considered illustrative in all respects and not limiting the invention as described herein. Accordingly, the scope of the invention is indicated not by the foregoing description but by the appended claims, and all modifications that fall within the meaning and scope of the claims are intended to be included therein.

Claims

1. A aqueous formulation, (a) Formula I below for 0.25% (w / v) to 0.75% (w / v): 【Chemistry 1】 Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.03% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, pharmaceutically acceptable salts of ethylenediaminetetraacetic acid, or mixtures thereof; (c) A buffering agent in a concentration of 10 mM to 30 mM containing citric acid and pharmaceutically acceptable salts of citric acid; (d) 3.5% (w / v) to 11% (w / v) isotonic agent; and (e) containing at least 90% (w / v) water, The aqueous formulation having a pH in the range of 7.5 to 8.

5.

2. The formulation according to claim 1, wherein the compound of formula I is present in an amount of 0.4% (w / v) to 0.6% (w / v).

3. The formulation according to claim 1, wherein the compound of formula I is present in an amount of about 0.5% (w / v).

4. The formulation according to claim 1, wherein the compound of formula I is present in an amount of 0.5% (w / v).

5. A pharmaceutical preparation according to any one of claims 1 to 4, wherein the compound of formula I is 【Chemistry 2】 The preparation is a pharmaceutically acceptable salt of the preparation.

6. A pharmaceutical preparation according to any one of claims 1 to 4, wherein the compound of formula I is 【Transformation 3】 The preparation is a pharmaceutically acceptable salt of an alkali metal or alkaline earth metal.

7. A pharmaceutical preparation according to any one of claims 1 to 4, wherein the compound of formula I is 【Chemistry 4】 The preparation is a sodium salt of the above.

8. A formulation according to any one of claims 1 to 7, wherein the formulation comprises 0.015% (w / v) to 0.025% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof.

9. A formulation according to any one of claims 1 to 7, wherein the formulation comprises about 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof.

10. A formulation according to any one of claims 1 to 7, wherein the formulation comprises 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof.

11. A formulation according to any one of claims 1 to 10, wherein the formulation comprises a buffer in a concentration of 15 mM to 25 mM containing citric acid and a pharmaceutically acceptable salt of citric acid.

12. A formulation according to any one of claims 1 to 10, wherein the formulation comprises about 20 mM of a buffer containing citric acid and a pharmaceutically acceptable salt of citric acid.

13. A formulation according to any one of claims 1 to 10, wherein the formulation comprises a 20 mM buffer containing citric acid and a pharmaceutically acceptable salt of citric acid.

14. A formulation according to any one of claims 1 to 13, wherein the formulation contains 6% (w / v) to 8% (w / v) of an isotonic agent.

15. A formulation according to any one of claims 1 to 13, wherein the formulation contains about 6.9% (w / v) of an isotonic agent.

16. A formulation according to any one of claims 1 to 13, wherein the formulation contains 6.9% (w / v) of an isotonic agent.

17. A formulation according to any one of claims 1 to 16, wherein the isotonic agent is a disaccharide.

18. A formulation according to any one of claims 1 to 16, wherein the isotonic agent is sucrose.

19. A formulation according to any one of claims 1 to 18, wherein the pH of the formulation is in the range of 7.8 to 8.

2.

20. A formulation according to any one of claims 1 to 18, wherein the pH of the formulation is 8.

0.

21. A formulation according to any one of claims 1 to 20, wherein the formulation further comprises a pH adjusting agent.

22. The formulation according to claim 21, wherein the pH adjusting agent is one or more alkali metal hydroxides or hydrochloric acid.

23. The formulation according to claim 21, wherein the pH adjusting agent is one or more of sodium hydroxide or hydrochloric acid.

24. A formulation according to any one of claims 1 to 23, wherein the formulation comprises at least 91% water.

25. A aqueous formulation, (a) Formula I below at approximately 0.5% (w / v): 【Transformation 5】 Compounds of or pharmaceutically acceptable salts thereof; (b) About 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A buffer of about 20 mM containing citric acid and pharmaceutically acceptable salts of citric acid; (d) about 6.9% (w / v) isotonic agent; and (e) containing at least 90% (w / v) water, The aqueous formulation having a pH of approximately 8.

26. A aqueous formulation, (a) Formula I below at approximately 0.5% (w / v): 【Transformation 6】 Compounds of or pharmaceutically acceptable salts thereof; (b) About 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A buffer of about 20 mM containing citric acid and pharmaceutically acceptable salts of citric acid; (d) Approximately 6.9% (w / v) sucrose; and (e) containing at least 90% (w / v) water, The aqueous formulation having a pH of approximately 8.

27. The formulation according to claim 26, wherein the formulation is (a) Formula I of 0.5% (w / v): 【Transformation 7】 Compounds of or pharmaceutically acceptable salts thereof; (b) 0.02% (w / v) of a chelating agent selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof; (c) A 20 mM buffer containing citric acid and pharmaceutically acceptable salts of citric acid; (d) 6.9% (w / v) sucrose; and (e) containing at least 90% (w / v) water, The aqueous formulation having a pH of 8.

28. A aqueous formulation, (a) Formula I below for 0.25% (w / v) to 0.75% (w / v): 【Transformation 8】 Compounds of or pharmaceutically acceptable salts thereof; (b) 0.01% (w / v) to 0.06% (w / v) chelating agent; (c) buffering agent; and (d) containing at least 85% (w / v) water, The aqueous formulation having a pH in the range of 7.0 to 8.

5.

29. The formulation according to claim 28, wherein the compound of formula I is present in an amount of 0.4% (w / v) to 0.6% (w / v).

30. The formulation according to claim 28, wherein the compound of formula I is present in an amount of about 0.5% (w / v).

31. The formulation according to claim 28, wherein the compound of formula I is present in an amount of 0.5% (w / v).

32. A formulation according to any one of claims 28 to 31, wherein the compound of formula I is 【Chemistry 9】 The preparation is a pharmaceutically acceptable salt of the preparation.

33. A formulation according to any one of claims 28 to 31, wherein the compound of formula I is 【Chemistry 10】 The preparation is a pharmaceutically acceptable salt of an alkali metal or alkaline earth metal.

34. A formulation according to any one of claims 28 to 31, wherein the compound of formula I is 【Chemistry 11】 The preparation is a sodium salt of the above.

35. A formulation according to any one of claims 28 to 34, wherein the chelating agent is a carboxylic acid or a carboxylate compound.

36. A formulation according to any one of claims 28 to 34, wherein the chelating agent is ethylene glycol tetraacetic acid, ethylenediamine tetraacetic acid, C ４－１０ The formulation is a hydroxyalkyltricarboxylic acid, or a pharmaceutically acceptable salt thereof, or a mixture thereof.

37. A formulation according to any one of claims 28 to 34, wherein the chelating agent is selected from ethylenediaminetetraacetic acid, a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid, or a mixture thereof.

38. A formulation according to any one of claims 28 to 37, wherein the formulation comprises 0.01% (w / v) to 0.03% (w / v) of the chelating agent.

39. A formulation according to any one of claims 28 to 37, wherein the formulation contains about 0.02% (w / v) of the chelating agent.

40. A formulation according to any one of claims 28 to 39, wherein the buffering agent comprises a carboxylic acid compound and a carboxylic acid salt compound.

41. A formulation according to any one of claims 28 to 39, wherein the buffering agent is C ４－１０ Hydroxyalkyldicarboxylic acid, C ４－１０ Hydroxyalkyltricarboxylic acid, C １－６ The preparation comprising an alkanoic acid, glutamic acid, phosphoric acid, or a pharmaceutically acceptable salt thereof.

42. A formulation according to any one of claims 28 to 39, wherein the buffer comprises citric acid and a pharmaceutically acceptable salt of citric acid.

43. A formulation according to any one of claims 28 to 42, wherein the formulation comprises 10 mM to 30 mM of the buffering agent.

44. A formulation according to any one of claims 28 to 42, wherein the formulation comprises 15 mM to 25 mM of the buffering agent.

45. A formulation according to any one of claims 28 to 44, wherein the formulation further comprises an isotonic agent.

46. The formulation according to claim 45, wherein the isotonic agent is present in the formulation in an amount of 1% (w / v) to 15% (w / v).

47. The formulation according to claim 45, wherein the isotonic agent is present in the formulation in an amount of 5% (w / v) to 9% (w / v).

48. The formulation according to claim 45, wherein the isotonic agent is present in the formulation in an amount of about 6.9% (w / v).

49. A formulation according to any one of claims 45 to 48, wherein the isotonic agent is a disaccharide, a monosaccharide, sodium chloride, or potassium chloride.

50. A formulation according to any one of claims 45 to 48, wherein the isotonic agent is sucrose.

51. A formulation according to any one of claims 28 to 50, wherein the pH of the formulation is in the range of 7.8 to 8.

2.

52. A formulation according to any one of claims 28 to 50, wherein the pH of the formulation is 8.

0.

53. A formulation according to any one of claims 28 to 52, wherein the formulation further comprises a pH adjusting agent.

54. The formulation according to claim 53, wherein the pH adjusting agent is one or more alkali metal hydroxides or hydrochloric acid.

55. The formulation according to claim 53, wherein the pH adjusting agent is one or more of sodium hydroxide or hydrochloric acid.

56. A formulation according to any one of claims 28 to 55, wherein the formulation contains at least 90% (w / v) water.

57. A formulation according to any one of claims 1 to 56, wherein the osmotic pressure concentration of the formulation is in the range of about 240 mOsm / kg to about 340 mOsm / kg.

58. A formulation according to any one of claims 1 to 56, wherein the osmotic pressure concentration of the formulation is in the range of about 270 mOsm / kg to about 330 mOsm / kg.

59. A formulation according to any one of claims 1 to 58, wherein less than 2% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 4 weeks.

60. A formulation according to any one of claims 1 to 58, wherein less than 1% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 4 weeks.

61. A formulation according to any one of claims 1 to 58, wherein less than 2% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 24 weeks.

62. A formulation according to any one of claims 1 to 58, wherein less than 1% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 24 weeks.

63. A formulation according to any one of claims 1 to 58, wherein less than 0.5% by weight of the compound of formula I decomposes when the formulation is stored at 25°C for 24 weeks.

64. A formulation according to any one of claims 1 to 63, wherein less than 1% by weight of the compound of formula I decomposes when the formulation is stored at 40°C for 4 weeks.

65. A formulation according to any one of claims 1 to 63, wherein less than 0.5% by weight of the compound of formula I decomposes when the formulation is stored at 40°C for 4 weeks.

66. A formulation according to any one of claims 1 to 65, wherein the formulation contains less than 0.02% (w / v) of the following compounds: 【Chemistry 12】 The preparation comprising a pharmaceutically acceptable salt thereof.

67. A formulation according to any one of claims 1 to 65, wherein the formulation contains less than 0.01% (w / v) of the following compounds: 【Chemistry 13】 The preparation comprising a pharmaceutically acceptable salt thereof.

68. A formulation according to any one of claims 1 to 65, wherein when the formulation is stored at 25°C for 4 weeks, the formulation contains less than 0.02% (w / v) of the following compounds: 【Chemistry 14】 The preparation comprising a pharmaceutically acceptable salt thereof.

69. A formulation according to any one of claims 1 to 65, wherein when the formulation is stored at 25°C for 24 weeks, the formulation contains less than 0.02% (w / v) of the following compounds: 【Chemistry 15】 The preparation comprising a pharmaceutically acceptable salt thereof.

70. A formulation according to any one of claims 1 to 69, wherein the formulation does not contain a fatty acid ester of polyethoxysorbitan.

71. A formulation according to any one of claims 1 to 69, wherein the formulation does not contain polysorbate.

72. An aqueous injection preparation comprising the preparation according to any one of claims 1 to 71 and a diluent for intravenous administration.

73. An aqueous injection preparation, which is manufactured by mixing the preparation described in any one of claims 1 to 71 with a diluent for intravenous administration.

74. A method for preparing an aqueous injection preparation, comprising mixing the preparation according to any one of claims 1 to 71 with a diluent for intravenous administration.

75. A method for treating heart disease, comprising administering a therapeutically effective amount of the aqueous injectable preparation described in claim 72 or 73 to a subject requiring the treatment, thereby treating the heart disease.

76. A method for improving myocardial contractility in a subject, comprising administering an effective amount of the aqueous injectable preparation described in claim 72 or 73 to a subject requiring improvement, thereby improving myocardial contractility.

77. A method for improving cardiac function in a subject, comprising administering an effective amount of the aqueous injectable preparation described in claim 72 or 73 to a subject requiring improvement, thereby improving cardiac function.

78. The method according to claim 77, wherein the improvement in cardiac function is characterized by one or more of the following: improved cardiac relaxation ability, favorable remodeling in subjects with heart failure, reduced fibrosis, reduced hypertrophy of cardiomyocytes, or improved calcium processing in cardiomyocytes in subjects with heart failure.

79. A method for stimulating the activity of cardiac P2X receptors in a subject, comprising administering an effective amount of the aqueous injectable formulation according to claim 72 or 73 to the subject requiring stimulation, thereby stimulating the activity of cardiac P2X receptors.

80. The method according to any one of claims 76 to 79, wherein the subject has a heart disease.

81. The method according to claim 75 or 80, wherein the heart disease is heart failure, cardiac hypertrophy, ischemic cardiomyopathy, non-ischemic cardiomyopathy, or adverse remodeling and injury following ischemia / reperfusion injury.

82. The method according to claim 75 or 80, wherein the heart disease is heart failure.

83. The method according to claim 82, wherein the heart failure is systolic heart failure or diastolic heart failure.

84. The method according to any one of claims 75 to 83, wherein the subject is a human.

Images