On-demand nitric oxide generation and delivery device

Abstract

An apparatus and method for generating nitric oxide gas that can be implemented as needed are provided. The method may include a step of electrolyzing an iron(III)-ligand complex in a medium containing nitrite ions. The medium preferably has a pH of 5 to 9, and the iron(III)-ligand complex can maintain a stable dissolved state even at temperatures of 40 to 95°C. According to one embodiment of the present disclosure, there is provided an apparatus for generating nitric oxide, the apparatus including a working electrode, a reference electrode or a counter electrode, a medium containing nitrite ions in contact with the working electrode and the reference electrode or the counter electrode, an iron(III)-ligand complex in contact with the working electrode, and an outlet for releasing nitric oxide generated from the medium.

Description

[Background technology]

[0001] Nitric oxide (NO) is a gaseous signaling molecule and an important biological messenger in vertebrates. It is endogenously synthesized in vivo from L-arginine, oxygen, and NADPH by multiple nitric oxide synthases (NOS). Nitric oxide can also be produced by the reduction of inorganic nitrate. In the presence of iron, nitric oxide binds to the heme domain of the enzyme, activating it.

[0002] Nitric oxide plays an important role in many physiological and pathological processes. Because nitric oxide diffuses across cell membranes without an intermediate transport mechanism, it can effectively and rapidly transmit signals to neighboring cells and tissues. For example, nitric oxide produced by vascular endothelial cells can transmit signals to surrounding vascular smooth muscle, causing it to relax, thereby dilating blood vessels and increasing blood flow. Furthermore, nitric oxide can also participate in electron transport and redox reactions in cellular biochemical events in the body. NO can induce various physiological effects, such as endothelium-dependent vasodilation, by activating guanylyl cyclase.

[0003] Inhaled nitric oxide can improve the body's oxidative capacity and reduce the reliance on high-risk extracorporeal cardiopulmonary support in critically ill patients. Appropriately administered doses of inhaled nitric oxide can reduce pulmonary arterial hypertension and improve oxygen synthesis. Inhaled nitric oxide is approved by the U.S. Food and Drug Administration for the treatment of persistent pulmonary hypertension of the newborn. Inhaled nitric oxide therapy is also used in a variety of diseases and clinical areas, including neonatal respiratory disorders, intensive care medicine, cardiothoracic surgery, acute respiratory distress syndrome, and anesthesiology. Summary of the Invention [Means for solving the problem]

[0004] The present disclosure provides an apparatus and method for generating nitric oxide gas, which can be implemented as needed. The method can include electrolyzing an iron(III)-ligand complex in a medium containing nitrite ions. The medium preferably has a pH of 5 to 9, and the iron(III)-ligand complex remains in a stable dissolved state even at temperatures of 40 to 95°C.

[0005] According to one embodiment of the present disclosure, there is provided an apparatus for generating nitric oxide, the apparatus including a working electrode, a reference electrode or a counter electrode, a medium containing nitrite ions in contact with the working electrode and the reference electrode or the counter electrode, an iron(III)-ligand complex in contact with the working electrode, and an outlet for releasing nitric oxide generated from the medium.

[0006] In some embodiments, the ligand is an oxygen- or nitrogen-containing iron complexing agent, and in some embodiments, the iron(III)-ligand complex is stable at 40-95° C. for at least 1 hour.

[0007] In some embodiments, the ligand is selected from Table A.

[0008] In some embodiments, the ligand is selected from the group consisting of nitrilotriacetic acid (NTA) or a salt thereof, 8-hydroxyquinoline-5-sulfonic acid (HQSA) or a salt thereof, citric acid (CA) or a salt thereof, and N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) or a salt thereof.

[0009] In some embodiments, the iron(III)-ligand complex is [ka] [ka] is selected from the group consisting of:

[0010] In some embodiments, the iron(III)-ligand complex is present at a concentration of 1.0 to 70.0 mM.

[0011] In some embodiments, the pH of the medium is 5 to 9, preferably 5.5 to 8.5, 6.5 to 8.2, or 6.8 to 8.0.

[0012] In some embodiments, the medium comprises a buffer.

[0013] In some embodiments, the buffer solution is selected from the group consisting of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) or a salt thereof, 3-(N-morpholino)propanesulfonic acid (MOPS) or a salt thereof, tris(hydroxymethyl)aminomethane (Tris) or a salt thereof, barbital or a salt thereof, phosphoric acid or a salt thereof, boric acid or a salt thereof, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-tris(hydroxymethyl)methylglycine (Tricine) or a salt thereof, N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis ...bis(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-bis(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-bis(hydroxymethyl)methylglycine (Tricine) or a salt thereof, N-bis(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-bis(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-bis(hydroxymethyl)methyl The reagent contains a reagent selected from the group consisting of bis(2-hydroxyethyl)glycine (Bicine) or a salt thereof, piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES) or a salt thereof, cacodylic acid or a salt thereof, citric acid or a salt thereof, 2-(N-morpholino)ethanesulfonic acid (MES) or a salt thereof, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) or a salt thereof, 2,2-bis(hydroxyethyl)-(aminotris)-(hydroxymethyl)-methane (Bis-Tris) or a salt thereof, glycine hydrochloride, tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), and combinations thereof.

[0014] In some embodiments, the concentration of the buffer solution is 0.05 to 1.5M.

[0015] In some embodiments, the nitrite ions are provided using inorganic or organic nitrites.

[0016] In some embodiments, the nitrite ions are provided using NaNO2.

[0017] In some embodiments, the nitrite ions are present at a concentration of 0.05 to 7.0 mM.

[0018] In some embodiments, the medium further comprises an inlet for supplying a carrier gas to the medium.

[0019] In another embodiment, there is further provided a method for producing nitric oxide, the method comprising the step of electrolyzing an iron(III)-ligand complex in a medium containing nitrite ions to produce nitric oxide, wherein the medium has a pH of 5 to 9, and the iron(III)-ligand complex is soluble in the medium at a temperature of 40 to 95°C and is stable for at least 1 hour.

[0020] In another embodiment, when the pH of the medium is 5.5 to 8.5, 6.5 to 8.2, or 6.8 to 8.0, the iron(III)-ligand complex can be stably dissolved in the medium.

[0021] According to some embodiments, the ligand is an oxygen- or nitrogen-containing iron complexing agent.

[0022] In some embodiments, the ligand is selected from Table A.

[0023] In some embodiments, the ligand is selected from the group consisting of nitrilotriacetic acid (NTA) or a salt thereof, 8-hydroxyquinoline-5-sulfonic acid (HQSA) or a salt thereof, citric acid (CA) or a salt thereof, and N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) or a salt thereof.

[0024] In some embodiments, the iron(III)-ligand complex is [ka] [ka] is selected from the group consisting of:

[0025] In some embodiments, the iron(III)-ligand complex is present at a concentration of 1.0 to 70.0 mM.

[0026] In some embodiments, the medium comprises a buffer.

[0027] In some embodiments, the buffer solution is selected from the group consisting of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) or a salt thereof, 3-(N-morpholino)propanesulfonic acid (MOPS) or a salt thereof, tris(hydroxymethyl)aminomethane (Tris) or a salt thereof, barbital or a salt thereof, phosphoric acid or a salt thereof, boric acid or a salt thereof, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-tris(hydroxymethyl)methylglycine (Tricine) or a salt thereof, N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis ...bis(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-bis(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-bis(hydroxymethyl)methylglycine (Tricine) or a salt thereof, N-bis(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-bis(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-bis(hydroxymethyl)methyl The reagent contains a reagent selected from the group consisting of bis(2-hydroxyethyl)glycine (Bicine) or a salt thereof, piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES) or a salt thereof, cacodylic acid or a salt thereof, citric acid or a salt thereof, 2-(N-morpholino)ethanesulfonic acid (MES) or a salt thereof, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) or a salt thereof, 2,2-bis(hydroxyethyl)-(aminotris)-(hydroxymethyl)-methane (Bis-Tris) or a salt thereof, glycine hydrochloride, tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), and combinations thereof.

[0028] In some embodiments, the concentration of the buffer solution is 0.05 to 1.5M.

[0029] In some embodiments, the nitrite ions are provided using inorganic or organic nitrites.

[0030] In some embodiments, the nitrite ions are provided using NaNO2.

[0031] In some embodiments, the nitrite ions are present at a concentration of 0.05 to 7.0 mM.

[0032] In some embodiments, the method further includes supplying a carrier gas to the medium to evacuate the generated nitric oxide from the medium.

[0033] In some embodiments, the method further comprises adjusting the production of nitric oxide by adjusting the potential and current applied during the electrolysis.

[0034] In some embodiments, the method further comprises adjusting the flow rate of the carrier gas to adjust the production of nitric oxide.

[0035] In some embodiments, the method further comprises adjusting the contact area between the iron(III)-ligand complex and a working electrode for electrolysis to adjust the production of nitric oxide. [Brief explanation of the drawings]

[0036] [Figure 1A] Nitric oxide (NO) concentrations measured using Fe-trisodium nitrilotriacetate (NTA) complex under different current levels (40 mA, 20 mA, and 10 mA) are shown.

[0037] [Figure 1B] 1 shows a correlation diagram between current and NO concentration.

[0038] [Figure 2] Nitric oxide (NO) concentrations measured under different current levels (40 mA and 20 mA) using Fe-8-hydroxyquinoline-5-sulfonic acid (HQSA) complex are shown.

[0039] [Figure 3A] Nitric oxide (NO) concentrations measured using Fe-citrate (CA) complex under different current levels (40 mA, 20 mA, and 10 mA) are shown.

[0040] [Figure 3B] 1 shows a correlation diagram between current and NO concentration.

[0041] [Figure 4] Nitric oxide (NO) concentrations measured using Fe-N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) complex under different current levels (40 mA, 20 mA, and 10 mA) are shown.

[0042] [Figure 5] Nitric oxide (NO) concentrations measured under different current levels (10 mA and 20 mA) using an Fe-porphyrin complex are shown.

[0043] [Figure 6] Nitric oxide (NO) concentration measured using Cu-citrate (CA) complex under a current of 40 mA is shown.

[0044] [Figure 7] 1 illustrates a nitric oxide generating device according to several embodiments.

[0045] [Figure 8] The correlation between the rate of nitric oxide (NO) production and NaNO2 concentration is shown.

[0046] [Figure 9]This shows that when the nitrite ion concentration is less than 5M, the melting point (or freezing point) of the electrolyte decreases as the nitrite ion concentration increases, whereas when the nitrite ion concentration is greater than 5M, the melting point of the electrolyte increases as the nitrite ion concentration increases.

[0047] [Figure 10] We show that the rate of nitric oxide (NO) production in this reaction system is almost the same when using 5 M NaNO2 at different operating temperatures.

[0048] [Figure 11] This shows the correlation between the rate of nitric oxide (NO) production and NaNO2 concentration when HEDTA is used as a ligand.

[0049] Some or all of the figures are shown diagrammatically for illustrative purposes. DETAILED DESCRIPTION OF THE INVENTION

[0050] definition The following description illustrates exemplary embodiments of the present technology, but is not intended to limit the scope of the disclosure, but rather to describe exemplary embodiments.

[0051] As used herein, the following words, phrases and symbols are generally intended to have the following meanings, unless the context indicates otherwise.

[0052] A dash ("-") that is not between two letters or symbols is intended to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes at the beginning or end of a chemical group are for convenience; a chemical group may be designated with one, multiple dashes, or no dashes at all without loss of normal meaning. A drawn wavy line in a structure indicates the point of attachment of a group. No directionality is shown or implied by the order in which chemical groups are written or named unless chemically or structurally necessary.

[0053] As used herein, the term "about" of a value or parameter includes embodiments of the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Also, the term "about X" includes the reference to "X". Unless the context requires otherwise, nouns not qualified by quantifiers include singular and / or plural. Thus, for example, a reference to "a compound" includes a plurality of such compounds, and a reference to "a measurement" includes a reference to one or more measurements and equivalents thereof known to those of skill in the art.

[0054] As used herein, reference to "about" a value or parameter includes (describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, the term "about X" includes a description of "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "compound" includes a plurality of such compounds, and reference to an "assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0055] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), 1 to 4 carbon atoms (i.e., C 1~4alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular carbon atom is named by a chemical name or specified by a molecular formula, all positional isomers having that carbon atom are intended. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-butyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0056] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0057] "Haloalkoxy" refers to an alkoxy as defined above in which one or more hydrogen atoms have been replaced with halogen.

[0058] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0059] "Amino" refers to the group NRyRz, where Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, and heteroaryl, each of which can be optionally substituted.

[0060] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 ring carbon atoms (i.e., C 6~12 aryl), 6 to 10 ring carbon atoms (i.e., C 6~10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

[0061] "Carboxyl" refers to -C(O)OH.

[0062] "Carboxylic ester" refers to both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each group being optionally substituted as defined herein.

[0063] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to a group having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0064] "Imine" refers to the group -C(NR)R, where each R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, and each group can be optionally substituted as defined herein.

[0065] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with a halogen. For example, if a residue is substituted with two or more halogens, it can be referred to using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups. These halogen groups may or may not be the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0066] "Heteroalkyl" refers to an alkyl in which one or more carbon atoms (and associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)-, and the like. R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which can be optionally substituted. Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH, where R is hydrogen, alkyl, aryl, aralkyl, heteroalkyl, or heteroaryl, each of which can be optionally substituted. As used herein, heteroalkyl contains 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0067] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1~20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), 3 to 8 ring carbon atoms (i.e., C 3~8Heteroaryl) and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl. Heteroaryl can be bonded through any ring of the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered heteroaryl, regardless of how it is attached to other parts of the molecule (i.e., through any fused ring). Heteroaryl does not encompass or overlap with aryl, as defined above.

[0068] "Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyls having at least one double bond), bridged heterocyclyls, fused heterocyclyls, and spiroheterocyclyls. Heterocyclyls may be monocyclic or polycyclic, and polycyclic rings may be fused, bridged, or spiro. Any non-aromatic ring having at least one heteroatom is considered to be a heterocyclyl, regardless of its mode of attachment (i.e., it may be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring having at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of its mode of attachment to other moieties in the molecule. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2~20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2~12heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2~10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2~8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3~12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3~8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 Heterocyclyls have 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4- to 10-membered cyclic moiety in which two non-adjacent atoms are bonded to one or more (e.g., one or two) 4- to 10-membered cyclic moieties having at least one heteroatom. Each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged heterocyclyls include bicyclic and tricyclic ring systems. As used herein, the term "spiroheterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, which are 3- to 10-membered cycloalkyls or 3- to 10-membered heterocyclyls, and one atom of the additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyls include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl. The heterocyclyl can be attached via any ring of the fused ring system.

[0069] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0070] "Oxo" refers to the (=O) or (O) group.

[0071] "Nitro" refers to the -NO2 group.

[0072] "Sulfonyl" refers to the group -S(O)R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0073] Alternative commonly used chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may be referred to as "alkylene" groups, "alkylenyl" groups, "arylene" groups, or "arylenyl" groups, respectively. Unless otherwise specified, when a combination of groups is referred to herein as a single group (e.g., arylalkyl), the last group listed includes the atoms that are attached to other moieties in the molecule.

[0074] The term "optionally" or "optionally" refers to the fact that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence and non-occurrence of said event or circumstance. Additionally, the term "optionally substituted" refers to the fact that one or more hydrogen atoms on a particular atom or group may or may not be replaced with a non-hydrogen moiety.

[0075] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds may be in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood that these compounds include both amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0076] The formulas or structures shown herein are intended to represent isotopically labeled compounds as well as unlabeled forms. Isotopically labeled compounds have the structure shown by the formulas shown herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into compounds according to the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I. Various isotopically labeled compounds according to the present disclosure include, for example, radioisotopes (e.g., 3 H, 13 C. 14 C). Such isotopically labeled compounds are useful for detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including metabolism studies, reaction kinetic studies, and drug or substrate tissue distribution analysis, or for radiation treatment of patients.

[0077] The present disclosure further includes "deuterated analogs" of compounds of Formula I, in which one to n hydrogens attached to a carbon atom have been replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds have improved resistance to metabolism and can therefore be useful for extending the half-life of compounds of Formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be synthesized by methods well known in the art, for example, using starting materials in which one or more hydrogens have been replaced with deuterium.

[0078] Deuterium-labeled or substituted therapeutic compounds according to the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes (e.g., deuterium) can provide several therapeutic advantages due to increased metabolic stability (e.g., increased in vivo half-life), reduced dose requirements, and / or improved therapeutic index. 18 F-labeled compounds may be suitable for PET or SPECT studies. Isotopically labeled compounds and prodrugs thereof according to the present disclosure can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents according to the procedures disclosed in the art or in the Examples and Preparation Methods below. In this context, deuterium is considered to be a substituent in compounds of Formula I.

[0079] The concentration of such heavy isotopes (particularly deuterium) can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, an atom not expressly designated as a particular isotope represents any stable isotope of that atom. Unless otherwise specified, when a position is expressly designated as "H" or "hydrogen," the position is understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, an atom expressly designated as deuterium (D) represents deuterium.

[0080] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0081] The term "substituted" means that any one or more hydrogen atoms on the designated atom or group are replaced with one or more non-hydrogen substituents, provided that the replacement does not exceed the normal valence of the designated atom. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinium, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imine, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar undefined structures defined by an infinite number of substituents (e.g., substituted aryls have substituted alkyls, which are themselves substituted with substituted aryls, which are further substituted with substituted heteroalkyls, etc.) are not intended to be encompassed herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the sequential substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are known to those of ordinary skill in the art. When used to modify a chemical group, the term "substituted" can refer to other chemical groups as defined herein. Unless otherwise specified, when a group is described as being optionally substituted, the substituents on that group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxy, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In other embodiments, one or more substituents can be further substituted with substituted halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.In other embodiments, the substituent may be further substituted with an unsubstituted halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Nitric oxide (NO) production

[0082] Methods for generating nitric oxide from electrochemical reactions have already been developed. For example, in PCT application WO2022127902A1, the applicant disclosed a method and apparatus for realizing a copper (Cu)(II)-based nitric oxide generation mechanism. Complexed copper(II) ions (i.e., copper ions in a Cu(II)-ligand complex) are reduced to copper(I) by electrolysis. Cu 2+ +e - →Cu +

[0083] This can then react with nitrite ions in the medium to produce nitric oxide gas. Cu + +NO2 - +2H + →NO+Cu 2+ +H2O

[0084] An example of a Cu(II)-ligand complex is Cu(II)-1,4,7-trimethyl-1,4,7-triazacyclononane (Me3TACN). A major drawback of Cu(II)-based systems is that all of the ligands commonly used to prepare Cu(II)-ligand complexes are stable only at low temperatures (e.g., 2-8°C). At temperatures above 35°C, these Cu(II)-ligand complexes tend to decompose. Additionally, these ligands are very expensive.

[0085] It is believed that the development of nitric oxide-producing chemical reactions based on other metals (e.g., iron and cobalt) may encounter significant obstacles. It is known that the hydrated pK1 of copper(II) ion is 8.0, that of iron(II) ion is 6.74, and that of iron(III) ion is 2.83 and 4.59. However, at pH 5.5 or below, aqueous nitrite solutions are H+ Iron(III) is highly reactive with ions, which adversely affects the electrolysis process. Furthermore, iron(III) precipitates at such low pH. Therefore, the development of a stable iron(III) ion-based electrolyte is a major challenge.

[0086] Through trial and error, we have surprisingly found that certain oxygen- or nitrogen-containing ligands can successfully complex with iron(III) ions, and that the resulting complexes remain soluble and stable even at near-neutral pH (e.g., 5-9) and high temperatures (e.g., 40-95°C). Equally important, many of these ligands are much less expensive than Me3TACN.

[0087] An even more surprising finding was that the tested iron(III)-ligand reaction systems exhibited much higher (30-90%) faradaic efficiencies than the copper(II)-ligand reaction systems (see Comparative Example 3, 9.34%). Therefore, these findings enable those skilled in the art to generate nitric oxide under more favorable conditions (e.g., weakly acidic, basic, or neutral pH compared to strongly acidic pH, room temperature or higher compared to low temperatures) with significantly improved efficiency and at much lower cost.

[0088] Therefore, according to one embodiment of the present disclosure, there is provided a method for producing nitric oxide (NO), comprising the step of electrolyzing an iron(III)-ligand complex in a medium containing nitrite ions. NO can be produced and supplied at a predetermined concentration and / or flow rate. For example, NO can be produced at a clinically appropriate concentration and / or flow rate for use in NO inhalation therapy. The concentration and / or flow rate of NO in the product gas can be adjusted. The concentration of NO in the product gas can range, for example, from about 0 to about 20,000 ppm. A. Ligands and Iron(III)-Ligand Complexes

[0089] In some embodiments, the ligand forming the iron(III)-ligand complex is an iron complexing agent. The term "iron complexing agent" refers to a chemical substance that can bind to an iron ion through one or more binding sites. These binding sites have a lone pair of electrons that can be donated to a d orbital of a metal ion to form a coordinate bond, thereby creating a coordination compound. The iron complexing agent can surround an iron ion or act as a bridge between two iron ions. The iron complexing agent may have one, two, or more binding sites for the iron ion. In some embodiments, the iron complexing agent is an iron(III) complexing agent.

[0090] In some embodiments, the iron-complexing agent contains one or more nitrogen atoms. In some embodiments, the iron-complexing agent contains one or more oxygen atoms. In some embodiments, the iron-complexing agent contains both nitrogen and oxygen atoms.

[0091] In some embodiments, the iron(III)-ligand complexes of the present disclosure are soluble in a medium having a pH between 5 and 9. In some embodiments, the solubility in the medium is at least 0.1 mM. In some embodiments, the solubility in the medium is at least 0.2 mM, 0.5 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 30 mM, 40 mM, or 50 mM. In some embodiments, the solubility in the medium is at least 0.1 mM, 0.2 mM, 0.5 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 30 mM, 40 mM, or 50 mM when the pH is 5.5 to 9, 5.5 to 8.5, 6.5 to 8.2, or 6.8 to 8.0, including but not limited to these.

[0092] In some embodiments, the iron(III)-ligand complexes of the present disclosure are stable at temperatures above 30° C. and / or below 95° C., 90° C., 85° C., or 80° C. In some embodiments, the iron(III)-ligand complexes of the present disclosure are stable at temperatures above 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., or higher.

[0093] In some embodiments, stability of an iron(III)-ligand complex in a medium under specified conditions means that the complex does not decompose and / or form a precipitate in the medium for at least 1 hour, 2 hours, 4 hours, 8 hours, 16 hours, 1 day, 2 days, 1 week, 2 weeks, 1 month, 2 months, or 6 months. In some embodiments, the conditions include a pH level and / or temperature, as described above. For example, the pH can be, but is not limited to, 5-9, 5.5-8.5, 6.5-8.2, or 6.8-8.0. In some embodiments, the temperature is 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or higher.

[0094] Also, in the present technology, iron(II)-ligand complexes can be similarly prepared and used, and then oxidized to iron(III)-ligand complexes. In some embodiments, no additional reactants are required for oxidation, since oxygen in the air or medium can oxidize the iron(II)-ligand complexes.

[0095] Table A below lists non-limiting examples of iron complexing agents (ligands) and the corresponding iron-ligand complexes. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6]

[0096] In certain embodiments, the iron complexing agent (ligand) is nitrilotriacetic acid (NTA) or a salt thereof. In other embodiments, the iron complexing agent (ligand) is 8-hydroxyquinoline-5-sulfonic acid (HQSA) or a salt thereof. In other embodiments, the iron complexing agent (ligand) is citric acid (CA) or a salt thereof. In other embodiments, the iron complexing agent (ligand) is N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) or a salt thereof. Examples of these corresponding iron(III)-ligand complexes are shown in the table above.

[0097] In some embodiments, an iron(III)-ligand complex is provided in the medium in which electrolysis is carried out. In some embodiments, the iron(III)-ligand complex is present in the medium at a concentration of 0.1 to 100.0 mM. In some embodiments, the iron(III)-ligand complex is present in the medium at a concentration of 0.1 to 50.0 mM. In some embodiments, the iron(III)-ligand complex is present in the medium at a concentration of 0.1 to 100.0 mM, 0.5 to 100.0 mM, 0.5 to 90.0 mM, 0.5 to 80.0 mM, 0.5 to 75.0 mM, 0.5 to 70.0 mM, 0.5 to 65.0 mM, 0.5 to 60.0 mM, 0.5 to 55.0 mM, 0.5 to 50.0 mM, 1.0 to 100.0 mM, 1.0 to 90.0 mM, 1.0 to 80.0 mM. In some embodiments, the iron(III)-ligand complex is present at a concentration of at least 0.1 mM, 0.2 mM, 0.5 mM, 1 mM, 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, or 40 mM. In some embodiments, the iron(III)-ligand complex is present at a concentration of less than or equal to 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, or 10 mM.

[0098] In some embodiments, the iron(III)-ligand complex is bonded or otherwise immobilized to the working electrode while in contact with the medium. For example, immobilization can include covalently binding the iron(III)-ligand complex to the surface of the working electrode. In another example, the iron(III)-ligand complex can be physically adsorbed to the working electrode or doped or covalently bound to a polymer, film, or hydrogel deposited on the surface of the working electrode. B. Electrolytes

[0099] The medium containing nitrite ions is used as an electrolyte in the electrochemical process. In some embodiments, the medium includes at least an appropriate buffer (or buffering agent) to provide and / or maintain a desired pH.

[0100] In some embodiments, the buffer may be any commonly used buffer as long as it does not impair the stability or solubility of the iron(III)-ligand complex. Many such useful buffers are known, and non-limiting examples include 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) or a salt thereof, 3-(N-morpholino)propanesulfonic acid (MOPS) or a salt thereof, tris(hydroxymethyl)aminomethane (Tris) or a salt thereof, barbital or a salt thereof, phosphoric acid or a salt thereof, boric acid or a salt thereof, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-tris(hydroxymethyl)methylglycine (Tricine) or a salt thereof, N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid ( TAPS) or a salt thereof, N,N-bis(2-hydroxyethyl)glycine (Bicine) or a salt thereof, piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES) or a salt thereof, cacodylic acid or a salt thereof, citric acid or a salt thereof, 2-(N-morpholino)ethanesulfonic acid (MES) or a salt thereof, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) or a salt thereof, 2,2-bis(hydroxyethyl)-(aminotris)-(hydroxymethyl)-methane (Bis-Tris) or a salt thereof, glycine hydrochloride, and tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl).

[0101] The buffer may have a concentration appropriate for the desired pH. In one embodiment, the concentration is 0.01 to 5.0 M. In one embodiment, the concentration is 0.01 to 4.0 M, 0.02 to 3.0 M, 0.02 to 2.5 M, 0.02 to 2.0 M, 0.05 to 2.0 M, 0.05 to 1.0 M, 0.05 to 1.5 M, 0.05 to 1.2 M, 0.1 to 0.9 M, 0.2 to 0.8 M, or 0.3 to 0.7 M, but is not limited to these.

[0102] In some embodiments, the medium includes a nitrite source, such as an inorganic nitrate or an organic nitrite. - Examples include, but are not limited to, nitrites of Li, Na, K, Rb, Ca, Mg, Al, and Fe. In one embodiment, the nitrite is sodium nitrite (NaNO). Examples of organic nitrites include R4N + NO2 - , RNH3 + NO2 - , niclosamide, nifedipine, flutamine, isobutyl nitrite, isoamyl nitrite, 1,3-propane nitrite, 1,5-pentane nitrite, 1,7-heptane nitrite, cyclohexylmethyl nitrite.

[0103] Nitrite ions can be present in the medium at a concentration of at least 0.01 M. In some embodiments, the concentration is 0.01 to 20.0 M. In some embodiments, the concentration is 0.02 to 10.0 M. In some embodiments, the concentration is 0.05 to 7.0 M. In some embodiments, the concentration is 0.05 to 5.0 M. In some embodiments, the concentration is, but is not limited to, 0.1 to 4.0 M, 0.2 to 2 M, 0.5 to 1.0 M, 0.5 to 7.0 M, 0.5 to 6.0 M, 0.5 to 5.0 M, 0.5 to 4.0 M, 0.5 to 3 M, 0.5 to 2.0 M, or 0.5 to 1.5 M.

[0104] In some embodiments, the generated nitric oxide can be evacuated in a carrier gas. The carrier gas can include any suitable gas, such as air, nitrogen gas, helium gas, argon gas, or oxygen gas. In some embodiments, the carrier gas includes nitrogen gas. In some embodiments, the concentration of nitrogen gas in the carrier gas is about 99.0% by volume or greater. For example, the concentration of nitrogen gas in the carrier gas can be about 99.10% by volume, 99.20% by volume, 99.30% by volume, 99.40% by volume, 99.50% by volume, 99.60% by volume, 99.70% by volume, 99.80% by volume, 99.90% by volume, 99.95% by volume, 99.98% by volume, or 99.99% by volume or greater. In some embodiments, the carrier gas includes oxygen gas. For example, the concentration of oxygen gas in the carrier gas can be less than about 1%, 0.5%, or 0.1%.

[0105] In some embodiments, a carrier gas may be used to sweep the surface of the working electrode, which can improve the faradaic efficiency and / or kinetics of the electrochemical reaction at and / or near the electrode and / or increase the concentration of nitric oxide in the product gas. C. Nitric Oxide Generation and Exemplary Devices

[0106] As disclosed herein, nitric oxide (NO) can be generated and supplied at a predetermined concentration and / or flow rate by the present technology. For example, NO can be generated at a clinically appropriate concentration and / or flow rate for use in NO inhalation therapy. Furthermore, the concentration and / or flow rate of NO in the generated gas can be adjusted. The concentration of NO in the generated gas can range, for example, from about 0 to about 20,000 ppm.

[0107] In this disclosure, the dimensionless unit "ppm" for expressing gas concentration refers to parts per million by volume, which can be converted to other concentration units, such as parts per million by mole or milligrams per liter (mg / L). In this disclosure, the dimensionless unit "%" or "vol %" for expressing gas concentration refers to volume percentage, which can be converted to other concentration units, such as weight percentage or molar concentration.

[0108] In some embodiments, the present technology can allow for the production of NO in a session that can include at least one operating period. During the operating period, the concentration and / or flow rate of NO in the product gas can reach and / or be maintained at a steady state. The operating period can last, for example, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 60 hours, or more.

[0109] Further provided are exemplary devices and instruments capable of implementing the NO generation techniques of the present invention. As shown in FIG. 7, the device may include a carrier gas generation chamber 710, a reaction chamber 720, a purge chamber 730, and / or an output chamber 740. The carrier gas generation chamber 710 generates or generates a carrier gas (e.g., nitrogen gas (N)) and removes the generated nitric oxide from the reaction chamber 720. The reaction chamber 720 includes an electrolysis cell (e.g., a first electrode 722 and a second electrode 724 connected to and activated by a power source 726), reactants, and trace release-control reactants. The reaction chamber 720 can store an iron-based ligand complex. As described above, an electrochemical reaction occurs when a current or voltage is applied to the first electrode 722, which can be used as a working electrode. The second electrode 724 can be a reference electrode, a counter electrode, or a combination thereof.

[0110] The purge chamber 730 can filter and absorb contaminants from the removed and generated nitric oxide. The removed contaminants can include salt mist and / or water vapor. The output chamber 740 can include a pressure tank that stores nitric oxide and other nitrogen gases. At the output of the pressure tank, an NO2 conversion filter can remove NO2 oxidized from the nitric oxide. In some examples, oxygen gas can be added to mix with the NO before the generated gas is delivered to the patient.

[0111] In some embodiments, the apparatus may include one or more NO sensors (not shown) for detecting the NO concentration in the product gas. The NO sensors may be located in any suitable location. For example, the NO sensors may be positioned so as to contact the product gas in the output chamber 740. In some embodiments, the NO sensors are located in or near the purge chamber 730.

[0112] In some embodiments, the catalyst can be immobilized on the surface of an electrode (e.g., working electrode 722). In some embodiments, the catalyst includes one or more compounds selected from the group consisting of cystine, cysteine, methionine, thiophene, and derivatives thereof. For example, the one or more catalysts can be covalently bound, adsorbed, or doped into a material (e.g., a polymer, film, or hydrogel) deposited on the electrode.

[0113] In some embodiments, the working electrode 722 and / or the reference / counter electrode 724 can have any suitable shape including one or more surfaces. For example, the working electrode 722 can include a plate, a sheet, or a mesh. In some embodiments, when a cathodic voltage or a cathodic current is applied to the working electrode 722, NO is electrochemically produced by one or more electrochemical reactions occurring at and / or near one or more surface locations of the working electrode 722.

[0114] The power source 726 may include one or more suitable power sources or circuits that allow a voltage or current to be applied to the electrodes, such as, for example, an electrical outlet, a power circuit, a DC power source, an AC power source, a generator, or an energy storage device. The energy storage device may include, for example, one or more batteries or fuel cells. In some embodiments, the power source 726 includes one or more circuits for controlling or regulating the voltage or current applied to the electrodes. In some embodiments, the one or more circuits may include a potentiostat for controlling or regulating the voltage applied to the electrodes. In some embodiments, the one or more circuits may include a galvanostat for controlling or regulating the current through the electrodes.

[0115] The electrode can be made of one or more materials, such as conductive materials. The conductive material can be a metallic material or a non-metallic material. Non-limiting examples of conductive materials include platinum, palladium, gold, copper, brass, silver, carbon, glassy carbon, boron-doped diamond (BDD), graphite, stainless steel, titanium, iridium, ruthenium, and one or more alloys thereof, such as ruthenium-iridium alloy.

[0116] In some embodiments, the electrode can include a substrate. In some embodiments, the conductive material is applied to the substrate. Application can be by any suitable plating method, such as electroplating, physical vapor deposition (PVD), chemical vapor deposition (CVD), plasma-enhanced chemical vapor deposition (PECVD), etc.

[0117] By controlling the magnitude of the voltage or current applied to the working electrode, the ratio of the reduced to the oxidized form of the iron(III)-ligand complex at and / or near the electrode can be controlled, thereby controlling the amount and / or rate at which NO is produced by a given concentration of nitrite ions and iron(III)-ligand complex in the medium.

[0118] In some embodiments, the voltage applied to the electrodes is a DC voltage, and in some embodiments, the voltage ranges from about 0.1 V to about 5.0 V, such as, but not limited to, about 0.1 V to about 4.0 V, about 0.2 V to about 3.0 V, about 0.4 V to about 2.0 V, or about 0.5 V to about 1.5 V.

[0119] In some embodiments, the current applied to the electrodes is a DC current, which may range from about 0 mA to about 600 mA, such as from about 0 mA to about 10 mA, from about 10 mA to about 50 mA, from about 50 mA to about 100 mA, from about 100 mA to about 200 mA, from about 200 mA to about 300 mA, from about 300 mA to about 400 mA, from about 400 mA to about 500 mA, or from about 500 mA to about 600 mA.

[0120] In some embodiments, the medium is maintained at or near the reaction temperature, or within a temperature range. The electrochemical reaction in the reaction chamber 720 may have the highest, desired, or optimized reaction rate and / or faradaic efficiency at or near the reaction temperature, or within a temperature range. The reaction temperature or temperature range may be determined based on one or more conditions, such as, for example, the buffer and / or catalyst components and concentrations in the reaction medium. In some embodiments, the reaction temperature or temperature range may be about 5°C to about 80°C, about 10°C to about 80°C, about 15°C to about 80°C, about 20°C to about 80°C, about 30°C to about 80°C, about 40°C to about 80°C, about 50°C to about 80°C, about 55°C to about 80°C, about 60°C to about 80°C, or a combination thereof.

[0121] Thus, according to one embodiment of the present disclosure, there is provided an apparatus for generating nitric oxide, comprising a working electrode and a reference or counter electrode, a medium containing nitrite ions in contact with the working electrode and the reference or counter electrode, an iron(III)-ligand complex in contact with the working electrode, and an outlet for releasing nitric oxide generated from the medium.

[0122] In some embodiments, the ligand forming the iron(III)-ligand complex is an iron complexing agent. The iron complexing agent may have one, two, or more binding sites for iron ions. In some embodiments, the iron complexing agent is an iron(III) complexing agent. In some embodiments, the iron complexing agent contains one or more nitrogen atoms. In some embodiments, the iron complexing agent contains one or more oxygen atoms. In some embodiments, the iron complexing agent contains both nitrogen and oxygen atoms.

[0123] In some embodiments, the iron(III)-ligand complexes of the present disclosure are soluble in a medium having a pH between 5 and 9. In some embodiments, the solubility in the medium is at least 0.1 mM. In some embodiments, the solubility in the medium is at least 0.2 mM, 0.5 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 30 mM, 40 mM, or 50 mM. In some embodiments, the solubility in the medium is at least 0.1 mM, 0.2 mM, 0.5 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 30 mM, 40 mM, or 50 mM when the pH is between 5.5 and 9, between 5.5 and 8.5, between 6.5 and 8.2, or between 6.8 and 8.0, including but not limited to these.

[0124] In some embodiments, the iron(III)-ligand complexes of the present disclosure are stable at temperatures above 30° C. and / or below 95° C., 90° C., 85° C., or 80° C. In some embodiments, the iron(III)-ligand complexes of the present disclosure are stable at temperatures above 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., or higher.

[0125] In some embodiments, stability of an iron(III)-ligand complex in a medium under specified conditions means that the complex does not decompose and / or form a precipitate in the medium for at least 1 hour, 2 hours, 4 hours, 8 hours, 16 hours, 1 day, 2 days, 1 week, 2 weeks, 1 month, 2 months, or 6 months. In some embodiments, the conditions include a pH level and / or temperature as described above. For example, the pH can be, but is not limited to, 5-9, 5.5-8.5, 6.5-8.2, or 6.8-8.0. In some embodiments, the temperature is 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or higher.

[0126] Table A provides non-limiting examples of iron complexing agents (ligands) and corresponding iron-ligand complexes. In certain embodiments, the iron complexing agent (ligand) is nitrilotriacetic acid (NTA) or a salt thereof. In other embodiments, the iron complexing agent (ligand) is 8-hydroxyquinoline-5-sulfonic acid (HQSA) or a salt thereof. In other embodiments, the iron complexing agent (ligand) is citric acid (CA) or a salt thereof. In other embodiments, the iron complexing agent (ligand) is N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) or a salt thereof.

[0127] In one embodiment, the iron(III)-ligand complex is [ka] is.

[0128] In one embodiment, the iron(III)-ligand complex is [ka] is.

[0129] In one embodiment, the iron(III)-ligand complex is [ka] is.

[0130] In one embodiment, the iron(III)-ligand complex is [ka] is.

[0131] In some embodiments, an iron(III)-ligand complex is provided in the medium in which electrolysis is carried out. In some embodiments, the iron(III)-ligand complex is present in the medium at a concentration of 0.1 to 50.0 mM. In some embodiments, the iron(III)-ligand complex is present at a concentration of 0.5 to 50.0 mM, 1.0 to 50.0 mM, 2.0 to 40.0 mM, 5.0 to 50.0 mM, 5.0 to 40.0 mM, 5.0 to 35.0 mM, 5.0 to 30.0 mM, 10.0 to 50.0 mM, 10.0 to 40.0 mM, 10.0 to 30.0 mM, or 10.0 to 25.0 mM. In some embodiments, the iron(III)-ligand complex is present at a concentration of at least 0.1 mM, 0.2 mM, 0.5 mM, 1 mM, 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, or 40 mM. In some embodiments, the iron(III)-ligand complex is present at a concentration of no more than 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, or 10 mM.

[0132] In some embodiments, the iron(III)-ligand complex is bonded or otherwise immobilized to the working electrode while in contact with the medium. For example, immobilization can include covalently binding the iron(III)-ligand complex to the surface of the working electrode. In another example, the iron(III)-ligand complex can be physically adsorbed to the working electrode or doped or covalently bound to a polymer, film, or hydrogel deposited on the surface of the working electrode.

[0133] The medium containing nitrite ions is used as an electrolyte in the electrochemical process. In some embodiments, the medium includes at least an appropriate buffer (or buffering agent) to provide and / or maintain a desired pH.

[0134] In some embodiments, the buffer may be any commonly used buffer as long as it does not impair the stability or solubility of the iron(III)-ligand complex. Many such useful buffers are known, and non-limiting examples include 4-hydroxyethylpiperazineethanesulfonic acid, 3-morpholinopropanesulfonic acid, tris, diethylbarbituric acid, glycine-hydrochloric acid, phosphate-borax, phosphate, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, tris(hydroxymethyl)aminomethane, N-tris(hydroxymethyl)methylglycine, boric acid-borax, and combinations thereof.

[0135] The buffer may have a concentration appropriate for the desired pH. In one embodiment, the concentration is 0.01 to 5.0 M. In another embodiment, the concentration is 0.02 to 2.0 M, 0.05 to 1.0 M, 0.1 to 0.9 M, 0.2 to 0.8 M, or 0.3 to 0.7 M, but is not limited to these.

[0136] In some embodiments, the medium includes a nitrite source, such as an inorganic nitrate or an organic nitrite. - Examples include, but are not limited to, nitrites of Li, Na, K, Rb, Ca, Mg, Al, and Fe. In one embodiment, the nitrite is sodium nitrite (NaNO). Examples of organic nitrites include R4N + NO2 - , RNH3 + NO2 - , niclosamide, nifedipine, flutamine, isobutyl nitrite, isoamyl nitrite, 1,3-propane nitrite, 1,5-pentane nitrite, 1,7-heptane nitrite, cyclohexylmethyl nitrite.

[0137] Nitrite ions can be present in the medium at a concentration of at least 0.01 M. In some embodiments, the concentration is 0.01 to 20.0 M. In some embodiments, the concentration is 0.02 to 10.0 M. In some embodiments, the concentration is 0.05 to 7.0 M. In some embodiments, the concentration is 0.05 to 5.0 M. In some embodiments, the concentration is, but is not limited to, 0.1 to 4.0 M, 0.2 to 2 M, 0.5 to 1.0 M, 0.5 to 7.0 M, 0.5 to 6.0 M, 0.5 to 5.0 M, 0.5 to 4.0 M, 0.5 to 3 M, 0.5 to 2.0 M, or 0.5 to 1.5 M.

[0138] In some embodiments, the medium further includes an inlet for supplying a carrier gas to the medium. The carrier gas may include any suitable gas, such as air, nitrogen gas, helium gas, argon gas, or oxygen gas. In some embodiments, the carrier gas includes nitrogen gas. In some embodiments, the concentration of nitrogen gas in the carrier gas is about 99.0% by volume or greater. For example, the concentration of nitrogen gas in the carrier gas may be about 99.10% by volume, 99.20% by volume, 99.30% by volume, 99.40% by volume, 99.50% by volume, 99.60% by volume, 99.70% by volume, 99.80% by volume, 99.90% by volume, 99.95% by volume, 99.98% by volume, or 99.99% by volume or greater. In some embodiments, the carrier gas includes oxygen gas. For example, the concentration of oxygen gas in the carrier gas may be less than about 1%, 0.5%, or 0.1%.

[0139] In some embodiments, the inlet is positioned so that the carrier gas sweeps over the surface of the working electrode, which can improve the faradaic efficiency and / or kinetics of the electrochemical reaction at and / or near the electrode and / or increase the concentration of nitric oxide in the product gas. [Example]

[0140] Example The following examples are included to illustrate specific embodiments of the present disclosure. Those skilled in the art should understand that the techniques disclosed in the following examples are techniques that function well in the practice of the present disclosure and therefore can be considered to constitute specific embodiments thereof. However, as will be apparent from the present disclosure, those skilled in the art will recognize that many modifications can be made to the specific embodiments disclosed and still achieve the same or similar results without departing from the spirit and scope of the present disclosure.

[0141] material and method The electrolyte was prepared as follows.

[0142] Step 1. Prepare NaNO2 solution in HEPES buffer and adjust to the desired pH using NaOH solution.

[0143] Step 2. The desired amount of ligand was slowly dissolved in the Fe2(SO4)3 solution and stirred until completely dissolved.

[0144] Step 3. The Fe2(SO4)3 solution prepared in step 2 was added to the NaNO2 solution prepared in step 1, and the resulting mixture was stirred to obtain an electrolyte.

[0145] Nitric oxide production tests were performed using a device manufactured according to the description in PCT application WO2022127902A1. The concentration of nitric oxide at different current values ​​was shown.

[0146] Example 1. Trisodium nitrilotriacetate (NTA) as a ligand In this example, the performance of Fe-trisodium nitrilotriacetate (NTA) complex was tested. The structure of NTA is as follows: [ka] Trisodium Nitrilotriacetate

[0147] The structure of the Fe-ligand complex is as follows: [ka]

[0148] The electrolyte used contained 5 mM Fe2(SO4)3, 20 mM NTA, 1.0 M NaNO2, 0.5 M Hepes, pH 7.01. Nitric oxide concentrations were measured at a flow rate of 2 L / min with currents of 40 mA, 20 mA, and 10 mA, respectively.

[0149] The measured NO concentration is shown in Figure 1A. As shown in Figure 1B, a good correlation was observed between the current and NO concentration (R2 = 0.9953). The faradaic efficiency (FE%) of the reaction system was calculated as follows:

number

[0150] where C NO is the concentration of nitric oxide (unit: ppm), Q is the flow rate (unit: L / min), n is the number of electrons transferred (1 in this case), F is the Faraday constant (96485 C / mol), I is the operating current (unit: A), t is time (unit: seconds), and Vm is the molar volume of the gas calculated from the temperature and pressure (pV=nRT). The calculated Faraday efficiency is shown in Table 1. [Table 1]

[0151] Example 2. 8-Hydroxyquinoline-5-sulfonic acid (HQSA) as a ligand In this example, the performance of the Fe-8-hydroxyquinoline-5-sulfonic acid (HQSA) complex was tested. The structure of HQSA is as follows: [ka] 8-Hydroxyquinoline-5-sulfonic acid

[0152] The structure of the Fe-ligand complex is as follows: [ka]

[0153] The electrolyte used contained 5 mM Fe2(SO4)3, 30 mM HQSA, 1.0 M NaNO2, 0.5 M Hepes, pH 6.82. Nitric oxide concentrations were measured at a flow rate of 2 L / min with currents of 40 mA and 20 mA, respectively.

[0154] The measured NO concentrations are shown in Figure 2. The calculated faradaic efficiencies are shown in Table 2. [Table 2]

[0155] Example 3. Citric acid (CA) as a ligand In this example, the performance of an Fe-citric acid (CA) complex was tested. The structure of CA is as follows: [ka] citric acid

[0156] The structure of the Fe-ligand complex is as follows: [ka]

[0157] The electrolyte used contained 10 mM Fe2(SO4)3, 20 mM citric acid, 1.0 M NaNO2, 0.5 M Hepes, pH 7.4. Nitric oxide concentrations were measured at a flow rate of 2 L / min with currents of 40 mA, 20 mA, and 10 mA, respectively.

[0158] The measured NO concentrations are shown in Figure 3A. As shown in Figure 3B, there was a good correlation between the current and NO concentrations (R2 = 0.9924).

[0159] The calculated faradaic efficiencies are shown in Table 3. [Table 3]

[0160] Example 4. N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) as a ligand In this example, the performance of the Fe-N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) complex was tested. HEDTA has the following structure: [ka]

[0161] The structure of the Fe-ligand complex is as follows: [ka]

[0162] The electrolyte used contained 5 mM Fe2(SO4)3, 10 mM HEDTA, 1.0 M NaNO2, 0.5 M Hepes, pH 7.3. Nitric oxide concentrations were measured at a flow rate of 2 L / min with currents of 40 mA, 20 mA, and 30 mA, respectively.

[0163] The measured NO concentrations are shown in Figure 4. The calculated faradaic efficiencies are shown in Table 4. [Table 4]

[0164] Comparative Example 1 In this comparative example, porphyrin is used as the ligand. The structure of the Fe-ligand complex is as follows: [ka]

[0165] The electrolyte used contained 5 mM Fe-porphyrin, 1.0 M NaNO2, 0.5 M Hepes, pH 7.05. Nitric oxide concentrations were measured at a flow rate of 2 L / min with currents of 10 mA and 20 mA, respectively.

[0166] The measured NO concentrations are shown in Figure 5. The actual performance was not only inferior to those tested in Examples 1-4, but also inferior to the copper(II) ligand complexes.

[0167] Comparative Example 2 In this comparative example, N,N',N''-trimethyl-1,4,7-triazacyclononane (Me3TACN) is used as the ligand. [ka] N,N',N''-trimethyl-1,4,7-triazacyclononane

[0168] Unfortunately, preparation of the electrolyte (7 mM Fe-Me3TACN, 1.0 M NaNO2, 0.5 M Hepes, pH = 6.99) resulted in a large amount of orange precipitate, and the experiment was not pursued.

[0169] Comparative Example 3 In this comparative example, Cu-citric acid was used instead of the Fe-ligand complex, whose structure is as follows: [ka]

[0170] The electrolyte used contained 10 mM Cu-CA, 1.0 M NaNO2, 0.5 M Hepes, pH 7.01. Nitric oxide concentration was measured at a flow rate of 2 L / min and a current of 40 mA.

[0171] The measured NO concentration is shown in Figure 6. The faradaic efficiency at a current of 40 mA was 9.34%, which was much lower than that of its Fe-ligand counterpart.

[0172] Example 5. Effects of different nitrite ion concentrations In this example, the effect of the concentration of nitrite ions on the efficiency of NO production was examined.

[0173] The electrolytes tested were 15 mM Fe2(SO4)3, 60 mM citric acid (CA), 0.5 M Hepes (pH 7.0), and NaNO2 concentrations of 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, or 7.0 M. Nitric oxide concentrations were measured at a flow rate of 0.24 L / min with a current of 5 mA.

[0174] The results are shown in Figure 8. Surprisingly, the efficiency of NO production was highest at about 5.0 M NaNO2, and higher concentrations (e.g., 6.0 M or 7.0 M) did not further improve the efficiency.

[0175] In this example, the operating qualities of these electrolytes were also tested. It was observed that higher nitrite ion concentrations decreased the melting (or freezing) point of the electrolyte (Figure 9), broadening the range of operating conditions for such electrolytes. Surprisingly, at nitrite ion concentrations above 5M, this high nitrite ion concentration (<5M) increased the melting (or freezing) point of the electrolyte.

[0176] In subsequent experiments, the behavior of the electrolyte containing 5.0 M NaNO2 (all other components were the same) was tested at two temperatures: 25 °C and -12 °C. Unexpectedly, the electrolyte performed nearly identically at these two very different temperatures (Figure 10).

[0177] Example 6. Effect of nitrite ion concentration using other ligands In Example 5, the influence of nitrite ion concentration was tested using an electrolyte with citric acid (CA) as a ligand, but in this example, HEDTA was used instead of CA.

[0178] The electrolyte used contained 5 mM Fe2(SO4)3, 10 mM N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), 0.5-7 M NaNO2, and 0.5 M HEPES, with a pH of 7.0. The nitric oxide concentration was measured at a flow rate of 300 L / min and a current of 5 mA. As a result (Figure 11), similar to the case of CA, when HEDTA was used as a ligand, good NO generation efficiency was observed at NaNO2 concentrations in the range of 0.5-7 M. * * *

[0179] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0180] The inventions illustratively described herein can be suitably implemented in the absence of any one or more elements or one or more limitations not specifically disclosed herein. Therefore, terms such as "have," "include," and "contain" should be understood broadly and not limiting. The terms and expressions used in this specification are used for descriptive purposes, not limiting terms. The use of these terms and expressions does not intentionally exclude any equivalents of the indicated features or portions thereof, but various modifications can be made within the scope of the invention to be protected.

[0181] Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, those skilled in the art may alter, improve, and vary the invention disclosed herein. These alterations, improvements, and variations are included within the scope of the present invention. The materials, methods, and examples provided herein are exemplary of preferred embodiments and are not intended to limit the scope of the present invention.

[0182] The invention has been described broadly and generically herein. Each of the narrower species and subgroups encompassed by this generic disclosure also form part of the invention. This includes the generic description of the invention excluding, with qualification or negative limitation, any subject matter from its generic concept, regardless of whether the omitted material is specifically described herein.

[0183] Furthermore, when features or aspects of the invention are described in terms of a Markush group, one skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of that Markush group.

[0184] All publications, patent applications, patents, and other documents cited herein are expressly incorporated by reference in their entirety to the same extent as if they were individually incorporated by reference. In the case of conflict, the present specification, including definitions, will control.

[0185] While the present disclosure has been described with reference to the above embodiments, the above description and examples are intended to be illustrative, not limiting, of the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will readily occur to those of ordinary skill in the art to which the present disclosure pertains.

Claims

1. a working electrode and a reference or counter electrode; a medium containing nitrite ions in contact with the working electrode and the reference or counter electrode; an iron(III)-ligand complex in contact with the working electrode; an outlet for releasing the generated nitric oxide from the medium. A device for generating nitric oxide.

2. The ligand is an oxygen- or nitrogen-containing iron complexing agent.

2. The device of claim 1 .

3. The iron(III)-ligand complex is stable at 40-95°C for at least 1 hour.

2. The device of claim 1 .

4. The ligand is selected from Table A 2. The device of claim 1 .

5. The ligand is selected from the group consisting of nitrilotriacetic acid (NTA) or a salt thereof, 8-hydroxyquinoline-5-sulfonic acid (HQSA) or a salt thereof, citric acid (CA) or a salt thereof, and N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) or a salt thereof.

5. The device according to claim 4.

6. The iron(III)-ligand complex is 【Chemistry 18-1】 【Chemistry 18-2】 selected from the group consisting of 6. The device according to claim 5.

7. The iron(III)-ligand complex is present at a concentration of 1.0 to 70.0 mM.

7. The device according to any one of claims 1 to 6.

8. The pH of the medium is 5 to 9, preferably 5.5 to 8.5, 6.5 to 8.2, or 6.8 to 8.

0.

8. Apparatus according to any one of claims 1 to 7.

9. The medium comprises a buffer solution.

9. The device according to claim 8.

10. The buffer solution may be 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) or a salt thereof, 3-(N-morpholino)propanesulfonic acid (MOPS) or a salt thereof, tris(hydroxymethyl)aminomethane (Tris) or a salt thereof, barbital or a salt thereof, phosphoric acid or a salt thereof, boric acid or a salt thereof, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-tris(hydroxymethyl)methylglycine (Tricine) or a salt thereof, N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis(2-hydroxymethyl)methyl and a salt thereof, N,N'-bis(2-hydroxyethyl)glycine (Bicine) or a salt thereof, piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES) or a salt thereof, cacodylic acid or a salt thereof, citric acid or a salt thereof, 2-(N-morpholino)ethanesulfonic acid (MES) or a salt thereof, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) or a salt thereof, 2,2-bis(hydroxyethyl)-(aminotris)-(hydroxymethyl)-methane (Bis-Tris) or a salt thereof, glycine-hydrochloric acid, tris(hydroxymethyl)aminomethane-hydrochloric acid (Tris-HCl), and combinations thereof.

10. The device of claim 9.

11. The concentration of the buffer solution is 0.05 to 1.5M.

11. Apparatus according to claim 9 or 10.

12. The nitrite ions are provided using inorganic or organic nitrite radicals.

12. Apparatus according to any one of claims 1 to 11.

13. The nitrite ion is NaNO ２ Provided using 13. The device of claim 12.

14. The concentration of the nitrite ions is 0.05 to 7.0M.

14. Apparatus according to claim 12 or 13.

15. and an inlet for supplying a carrier gas to said medium.

15. Apparatus according to any one of claims 1 to 14.

16. Electrolyzing an iron(III)-ligand complex in a medium containing nitrite ions to produce nitric oxide; the pH of the medium is between 5 and 9; The iron(III)-ligand complex can dissolve in the medium at a temperature of 40 to 95° C. and remain stable for at least 1 hour. A method for producing nitric oxide, comprising:

17. When the pH of the medium is 5.5 to 8.5, 6.5 to 8.2, or 6.8 to 8.0, the iron(III)-ligand complex can be stably dissolved in the medium.

17. The method of claim 16.

18. The ligand is an oxygen- or nitrogen-containing iron complexing agent.

18. A method according to claim 16 or 17.

19. The ligand is selected from Table A 19. The method according to any one of claims 16 to 18.

20. The ligand is selected from the group consisting of nitrilotriacetic acid (NTA) or a salt thereof, 8-hydroxyquinoline-5-sulfonic acid (HQSA) or a salt thereof, citric acid (CA) or a salt thereof, and N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) or a salt thereof.

20. The method of claim 19.

21. The iron(III)-ligand complex is 【Chemistry 19-1】 【Chemistry 19-2】 selected from the group consisting of 21. The method of claim 20.

22. The iron(III)-ligand complex is present at a concentration of 1.0 to 50.0 mM.

22. The method according to any one of claims 16 to 21.

23. The medium comprises a buffer solution.

23. The method according to any one of claims 16 to 22.

24. The buffer solution may be 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) or a salt thereof, 3-(N-morpholino)propanesulfonic acid (MOPS) or a salt thereof, tris(hydroxymethyl)aminomethane (Tris) or a salt thereof, barbital or a salt thereof, phosphoric acid or a salt thereof, boric acid or a salt thereof, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES) or a salt thereof, N-tris(hydroxymethyl)methylglycine (Tricine) or a salt thereof, N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS) or a salt thereof, N,N-bis(2-hydroxymethyl)methyl and a salt thereof, N,N'-bis(2-hydroxyethyl)glycine (Bicine) or a salt thereof, piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES) or a salt thereof, cacodylic acid or a salt thereof, citric acid or a salt thereof, 2-(N-morpholino)ethanesulfonic acid (MES) or a salt thereof, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) or a salt thereof, 2,2-bis(hydroxyethyl)-(aminotris)-(hydroxymethyl)-methane (Bis-Tris) or a salt thereof, glycine-hydrochloric acid, tris(hydroxymethyl)aminomethane-hydrochloric acid (Tris-HCl), and combinations thereof.

24. The method of claim 23.

25. The concentration of the buffer solution is 0.05 to 1.0 M.

25. A method according to claim 23 or 24.

26. The nitrite ions are provided using inorganic or organic nitrite radicals.

26. The method according to any one of claims 16 to 25.

27. The nitrite ion is NaNO ２ Provided using 27. The method of claim 26.

28. The concentration of the nitrite ions is 0.05 to 7.0M.

28. A method according to claim 26 or 27.

29. The method further includes the step of supplying a carrier gas to the medium so as to exhaust the nitric oxide produced from the medium.

29. The method according to any one of claims 16 to 28.

30. The step of adjusting the potential and current applied during the electrolysis to adjust the production of nitric oxide is further included.

30. The method according to any one of claims 16 to 29.

31. The method further includes adjusting the flow rate of the carrier gas to adjust the production of nitric oxide.

31. A method according to claim 29 or 30.

32. The method further includes a step of adjusting the contact area between the iron(III)-ligand complex and a working electrode for electrolysis to adjust the production of nitric oxide.

32. The method according to any one of claims 16 to 31.

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