Thiolactone derivative compounds for producing nitric oxide and methods of forming same

Abstract

A nitric oxide precursor for providing nitric oxide is provided. The nitric oxide precursor comprises a reaction product of a thiolactone, a primary amine, and a nitrosated compound. The nitric oxide precursor is capable of decomposing to form nitric oxide.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 427,051, filed November 21, 2022, and incorporated herein by reference.

[0002] The present invention relates generally to nitric oxide precursors comprising the reaction product of a thiolactone, a primary amine, and a nitrosating compound. [Background technology]

[0003] The Background Description includes information that may be useful in understanding the present invention. No admission is made that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly mentioned is prior art.

[0004] All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In the event that a definition or use of a term in an incorporated reference contradicts or is contrary to a definition of the term provided herein, the definition of the term provided herein shall apply and the definition of the term in the reference shall not apply.

[0005] Various products and articles, including, for example, medical instruments, devices, and equipment, must be sterilized before use to prevent biological contamination of wound sites, specimens, organisms, or the like. Several sterilization processes are used that involve contacting the product or article with a sterilant. Examples of such sterilants include dinitrogen tetroxide, nitric oxide, water vapor, ethylene oxide, hydrogen peroxide, dry heat, and the like. Traditional methods of forming nitric oxide use catalytic and enzymatic generation of nitric oxide from NO-donor compounds, such as nitrite compounds or diazeniumdiolates.

[0006] For example, in one approach, as described in WO 2023 / 205125, selected polymers were chemically modified to provide amounts of nitrosothiol groups useful in NO-based sterilization processes. Here, certain polymeric materials were chemically modified to introduce pendant nitrosothiol groups, which act as reactive groups to anchor thiols that can be converted into nitrosothiol groups capable of releasing nitric oxide. More specifically, polycarbonate-polydimethylsiloxane (PCPDMS) block copolymers, polyurethane-polydimethylsiloxane (PUPDMS) block copolymers, polyurethane (PU), poly(ethylene-co-vinyl acetate) copolymers (EVA), or polydimethylsiloxanes were first reacted with 3-aminopropyltrimethoxysiloxane to introduce pendant amine groups, then with acetylpenicillamine thiolactone to generate pendant thiol groups, which were then converted to the corresponding S-nitrosothiols by reaction with t-butyl nitrite. Unfortunately, such approaches have been limited to modified polymers having relatively high molecular weights and have been further limited by the specific chemistry required to produce the modified polymers. Furthermore, such modifications have required relatively complex multi-step processes.

[0007] Thus, such and other methods for forming nitric oxide from precursors typically require expensive reactants and must be utilized in controlled systems to enable nitric oxide production. Furthermore, such nitric oxide precursors have large molecular weights, thereby limiting their use in various applications where smaller precursors are required. Unfortunately, most small molecule nitrosothiols that decompose to form nitric oxide are known to be highly unstable, especially in solution. These limitations have prevented mainstream commercialization of sterilization or sanitation compositions capable of generating nitric oxide by consumers and professionals. Thus, there remains a need for improved compositions capable of generating nitric oxide for a variety of medical and consumer purposes. Summary of the Invention [Means for solving the problem]

[0008] Nitric oxide precursors for providing nitric oxide are provided herein. The nitric oxide precursors comprise, consist essentially of, consist of, or are the reaction product of a thiolactone, a primary amine, and a nitrosated compound. In various embodiments, the thiolactone and the primary amine can react to form an intermediate, and the intermediate and the nitrosated compound can react to form the nitric oxide precursor. In these and other embodiments, the thiolactone and the primary amine can react to form the intermediate in the presence of a solvent. It is contemplated herein that the thiolactone and the primary amine can react at a temperature of about 1° C. to about 25° C.

[0009] The nitric oxide precursor is capable of decomposing to form nitric oxide. In various embodiments, the nitric oxide precursor comprises a nitrosothiol capable of decomposing to form nitric oxide. It is contemplated herein that the nitric oxide precursor may decompose to form nitric oxide at a predetermined rate and / or for a predetermined period of time based on the rate of formation of the nitric oxide precursor resulting from the reaction of the intermediate with the nitrosated compound. Furthermore, the nitric oxide precursor may exhibit minimal decomposition to nitric oxide for at least 5 minutes after formation of the nitric oxide precursor, depending on the particular amine compound used and the manner in which the precursor is stored. Alternatively, the nitric oxide precursor may exhibit minimal decomposition to nitric oxide for 5 minutes to 365 days after formation of the nitric oxide precursor, depending on the particular amine compound used and the manner in which the precursor is stored. As described in further detail below, adjusting the rate of formation of the nitric oxide precursor is suitable for various applications requiring such control over nitric oxide formation.

[0010] Nitric oxide precursors may be used in a wide variety of medical and consumer applications. The properties of the nitric oxide precursor can be tailored based on the selection of the primary amine and nitrosated compound to suit a particular application. Non-limiting examples of suitable tailoring include nitric oxide generating capacity and nitric oxide release rate. As described in further detail below, the nitric oxide precursor can be incorporated into various substrates such that nitric oxide is released from the substrate due to decomposition of the nitric oxide precursor. In addition to tailoring the decomposition of the nitric oxide precursor, the release of nitric oxide can also be tailored based on the composition and properties of the substrate to further control the release of nitric oxide from the substrate. This controlled release of nitric oxide is useful for sterilizing and sanitizing medical and consumer devices.

[0011] In particular, the physicochemical properties of the nitric oxide precursor, such as reactivity, hydrophobicity, number of nitric oxide donors, stability of the oxide donors, etc., can be tailored based on the selection of the primary amine. For example, in embodiments in which a thiolactone is reacted with a primary amine that also contains a thiol group, the resulting intermediate can be reacted with a nitrosating compound to form a nitric oxide precursor containing two nitrosothiols per molecule. These nitric oxide precursors can be used in formulations and applications related to disinfection, sanitization, and sterile cleaning of a wide variety of objects and devices and in some applications, as additives to polymer films / matrices, powder materials, such as desiccants (e.g., silica gel or sodium polyacrylate), or as additives in solution phase.

[0012] Thiolactones are represented by the following formula (I):

[0013] [ka] (In the formula, R 1 is a bond or a divalent organic group, and R 2 is a bond or a divalent organic group, and R 3 is a hydrogen atom or a monovalent organic group, and R 4 is an oxygen atom or a sulfur atom) The thiolactone may have a structure according to the formula: Non-limiting examples of suitable thiolactone groups include α-acetothiolactone, β-propiothiolactone, γ-butyrothiolactone, δ-valerothiolactone, ε-caprothiolactone, ζ-enanthothiolactone, η-caprylothiolactone, and θ-pelargothiolactone. In some embodiments, the thiolactone is an amine-containing thiolactone, such as thietanone (e.g., N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide).

[0014] In various embodiments, the primary amine comprises cysteine ​​or a derivative thereof, lysine or a derivative thereof, butylamine or a derivative thereof, or a combination thereof. In these and other embodiments, the primary amine contains a thiol functional group. In exemplary embodiments, the cysteine ​​or a derivative thereof comprises cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bucillamine, or a combination thereof.

[0015] In certain embodiments, the nitrosating compound comprises a nitrite compound, which may include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, pentyl nitrite, nitrite salts, ion-pair nitrite compounds, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, or combinations thereof.

[0016] Therefore, it should be understood that the nitric oxide precursors prepared in accordance with the present inventive subject matter have a relatively low molecular weight. From a different perspective, the nitric oxide precursor does not include a polymer (e.g., having 4, 10, 20, 100, or 1,000 repeating units). For example, contemplated nitric oxide precursors may have a molecular weight between 100 and 500 Da, or between 250 and 750 Da, or between 400 and 1,000 Da, typically less than 5,000 Da, or less than 2,500 Da, or less than 1,500 Da. Unexpectedly, despite their relatively low molecular weight, the nitric oxide precursors contemplated herein also have relatively high stability and, therefore, can be incorporated into various materials to form composite articles. In some embodiments, the nitric oxide precursor may be in a crystalline form and combined with a carrier or a suitable liquid.

[0017] The inventors contemplate that the nitric oxide precursor may exhibit decomposition to nitric oxide within a predetermined time, e.g., within one hour, after forming the reaction product. Of course, this decomposition of the nitric oxide precursor within this predetermined time may, as described above, undergo minimal decomposition to nitric oxide for at least five minutes after forming the nitric oxide precursor. In various embodiments, the decomposition to nitric oxide may be sustained for a predetermined time, e.g., from about one minute to about one year. Without wishing to be bound by theory, it is believed that the properties of the nitric oxide precursor can be tailored based on the selection of the primary amine and nitrosated compound to tailor the decomposition to nitric oxide for a particular application.

[0018] Viewed from a different perspective, the nitric oxide precursor can be incorporated into or with composite articles, such as polymer films and matrices, and powder materials. Non-limiting examples of suitable powder materials include desiccants, such as silica gel or sodium polyacrylate desiccants.

[0019] Also provided herein are methods of sterilizing or sanitizing an article (e.g., a device or object), the methods comprising applying to the article a nitric oxide precursor as described above.

[0020] In one aspect of the inventive subject matter, the inventors contemplate a method for producing a nitric oxide precursor, comprising reacting a thiolactone with a primary amine in a solvent in a ring-opening reaction to form an intermediate having a thiol group, and reacting the thiol group of the intermediate with a nitrosating compound in a solvent to form a nitric oxide precursor having a nitrosothiol. In another step, the solvent is at least partially removed. As can be readily appreciated, the nitric oxide precursor can decompose to form nitric oxide.

[0021] In some embodiments, the thiolactone has a molecular weight of less than 500 Da. For example, a suitable thiolactone will have a structure according to formula (III):

[0022] [ka] wherein each occurrence of R6 is independently hydrogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 heteroalkenyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C1-C6 heteroalkoxy; and when R6 is substituted, the substituents are selected from the group consisting of OH, SH, NH3, NO2, acyl groups, amide groups, and halogens.

[0023] Where necessary, the thiolactone contains an amine group. Thus, suitable thiolactones include N-(2,2-dimethyl-4-oxo-3-thietanyl)-acetamide, N-acetylcysteine ​​thiolactone, N-acetyl-homocysteine ​​thiolactone, homocysteine ​​thiolactone, or butyryl-homocysteine ​​thiolactone.

[0024] In further embodiments, the primary amine has a molecular weight of less than 500 Da. Among other options, suitable primary amines include amino acids. For example, contemplated primary amines include butylamine, cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, and bucillamine.

[0025] With respect to the nitrosating compound, it is contemplated that a variety of organic nitrites or nitrite salts can be used, with particularly contemplated nitrosating compounds including sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, and pentyl nitrite.

[0026] Most typically, but not necessarily, the solvent is aqueous and / or may include a polar alcohol solvent. For example, suitable solvents include water and methanol and / or ethanol. As described in more detail below, the reaction may be carried out in the presence of an acid (e.g., an organic acid), and the reaction is advantageously carried out at ambient temperature and pressure. In further contemplated embodiments, the solvent may be at least partially removed (e.g., at least 50%) and / or the nitric oxide precursor may be crystallized, if necessary. In some embodiments, the nitric oxide precursor exhibits minimal degradation at 23°C for a period of at least one month. Furthermore, it is generally preferred that the nitric oxide precursor does not include a polymer having four or more repeating units.

[0027] Viewed from a different perspective, therefore, the inventors also contemplate a nitric oxide precursor for providing nitric oxide comprising the reaction product of a thiolactone, a primary amine, and a nitrosated compound, the nitric oxide precursor being capable of decomposing to form nitric oxide.

[0028] In most embodiments, the thiolactone and the primary amine can react to form an intermediate, and the intermediate and the nitrosated compound can react to form the nitric oxide precursor. Thus, the thiolactone and the primary amine can react to form the intermediate in the presence of a solvent, for example, at a temperature of about 1° C. to about 25° C. Most typically, the nitric oxide precursor comprises a nitrosothiol that can decompose to form nitric oxide. In some embodiments, the nitric oxide precursor exhibits minimal decomposition to nitrogen oxide for at least 24 hours after forming the nitrogen oxide precursor.

[0029] It is further contemplated that the thiolactone is an amine-containing thiolactone (e.g., including thietanone). Contemplated primary amines may be cysteine ​​or a derivative thereof, lysine or a derivative thereof, butylamine or a derivative thereof, or a combination thereof. If necessary, the primary amine contains a thiol functional group (e.g., cysteine ​​or a derivative thereof, where cysteine ​​or a derivative thereof includes cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bucillamine, or a combination thereof).

[0030] Suitable nitrosating compounds would include organic nitrite compounds or nitrite salts such as sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, or pentyl nitrite.

[0031] In further contemplated embodiments, the nitric oxide precursor is in a crystalline form, which typically exhibits improved storage stability compared to the corresponding non-crystallized nitric oxide precursor.

[0032] In yet further contemplated aspects of the present subject matter, the inventors contemplate composite articles comprising a carrier and the nitric oxide precursors provided herein. In some embodiments, the composite articles exhibit minimal release of nitric oxide for at least 24 hours after formation of the nitric oxide precursor. Additionally, the inventors contemplate methods of sterilizing or sanitizing an article, in which the nitric oxide precursors provided herein are applied to the article.

[0033] Various objects, features, aspects and advantages of the present subject matter will become more apparent from the following detailed description of preferred embodiments, taken in conjunction with the accompanying drawing figures in which like numerals represent like elements. [Brief explanation of the drawings]

[0034] [Figure 1] 1A-1D are images showing non-limiting embodiments of nitric oxide precursors. [Figure 2] 2A-2D are images showing non-limiting embodiments of nitric oxide precursors. [Figure 3] Figure 3A is an image showing a non-limiting embodiment of a nitric oxide precursor, and Figures 3B and 3C are graphs showing the release of nitric oxide from non-limiting embodiments of a composite article including a nitric oxide precursor. [Figure 4] 4A-4D are images illustrating non-limiting embodiments of composite articles including nitric oxide precursors. DETAILED DESCRIPTION OF THE INVENTION

[0035] The following detailed description is merely exemplary in nature and is not intended to limit the subject embodiments or the application and uses of such embodiments. Furthermore, there is no intention to be bound by any theory presented, explained, or implied in the preceding technical field, background, brief summary, or the following detailed description.

[0036] Nitric oxide precursors for providing nitric oxide are provided herein. The nitric oxide precursor comprises, consists essentially of, consists of, or is the reaction product of a thiolactone, a primary amine, and a nitrosated compound. In various embodiments, the thiolactone and the primary amine react to form an intermediate, and the intermediate and the nitrosated compound react to form the nitric oxide precursor. In these and other embodiments, the thiolactone and the primary amine react to form the intermediate in the presence of a solvent. Preferably, but not necessarily, the thiolactone and the primary amine can react at a temperature of about 1° C. to about 25° C. Therefore, it should be understood that high temperatures are not necessarily required to form the intermediate. An exemplary reaction scheme is shown below.

[0037] [ka]

[0038] In various embodiments, the nitric oxide precursor comprises a nitrosothiol that can decompose to form nitric oxide. Nitric oxide is lipid-soluble and has the ability to disrupt the lipid membranes of microorganisms, modulating cellular and tissue responses, controlling aggregation and biological integration, and providing antibacterial properties. Furthermore, nitric oxide can inactivate thioproteins, thereby destroying functional proteins in microorganisms. As can be readily understood, nitric oxide can react with ambient air to form various nitrogen oxides, such as nitrogen dioxide and nitrous oxide. Nitric oxide is more water-soluble than nitric oxide. Furthermore, nitric oxide and nitrogen dioxide are potent DNA breakers, causing strand breaks and other damage, resulting in the inability of cells to function.

[0039] As used herein, the term "nitric oxide" or "NO" refers to the NO free radical. Nitric oxide can react with ambient air to form various nitrogen oxides, including nitrogen dioxide (NO), nitrogen trioxide (NO), dinitrogen trioxide (NO), dinitrogen tetroxide (NO), dinitrogen pentoxide (NO), and nitrous oxide (NO). As used herein, the phrase "nitric oxide precursor" refers to a compound or composition capable of generating or releasing nitric oxide.

[0040] The nitric oxide precursors contemplated herein can be used in a wide variety of medical and consumer applications. The properties of the nitric oxide precursor can be tailored based on the selection of the primary amine and nitrosated compound to suit a particular application. Non-limiting examples of suitable tailoring include nitric oxide generating capacity and nitric oxide release rate. As described in further detail below, the nitric oxide precursor can be incorporated into various substrates such that nitric oxide is released from the substrate due to decomposition of the nitric oxide precursor. In addition to tailoring the decomposition rate of the nitric oxide precursor to form nitric oxide, the release of nitric oxide can also be tailored based on the composition and properties of the substrate to further control the release of nitric oxide from the substrate. This controlled release of nitric oxide is useful for sterilizing and sanitizing medical and consumer devices.

[0041] From a different perspective, the inventors contemplate utilizing nitric oxide precursors to form nitric oxide for a variety of medical and consumer applications. In various embodiments, articles (e.g., devices or objects) may be treated with nitric oxide precursors in the form of liquids, powders, films, coatings, etc. Non-limiting examples of suitable uses of nitric oxide precursors (e.g., as liquids, powders, films, or coatings) include: detergents or cleaning solutions for sanitizing or sterilizing solution-treated objects (e.g., sports equipment, e.g., hockey gloves and cycling gloves, cleaning surgical instruments, the inner lumens of endoscopes, surfaces of medical devices, and the like); detergents or cleaning powders for sanitizing or sterilizing powder-treated objects; sanitary containers (e.g., desiccants and the like) for sanitizing devices; medical device containers for sanitizing medical devices (e.g., stethoscopes, otoscopes, and the like), medical devices (e.g., portable ultrasound devices, communication devices, and the like); devices exposed to moisture to resist mold or mildew growth. sporting equipment (e.g., yoga mats, accessible surfaces of strength training equipment, accessible surfaces of cardio equipment, and the like); liners for sports equipment bags for sanitizing sports equipment (e.g., shoes, hockey equipment, ski equipment, face masks, goggles, helmets, and the like); food packaging for preserving food ingredients (e.g., meat, fruit, vegetables, cheese, their ingredients, and the like); vehicle components for sanitizing vehicles (e.g., headliners, seat cushion liners, carpet liners, and the like); and within drawers of cabinets, desks, boxes, etc., for eliminating musty odors.

[0042] The inventors contemplate that the nitric oxide precursor may exhibit relatively rapid decomposition to release nitric oxide within a predetermined time after formation of the nitric oxide precursor, for example, within 1 hour, or within 30 minutes, or within 5 minutes, or within 1 minute, or within 10 seconds, or within 1 second, or within 0.1 seconds. Alternatively, the nitric oxide precursor can be formulated to exhibit relatively minimal decomposition to form nitric oxide for a period of at least 5 minutes, alternatively at least 10 minutes, alternatively at least 15 minutes, alternatively at least 30 minutes, alternatively at least 45 minutes, alternatively at least 1 hour, alternatively at least 2 hours, alternatively at least 3 hours, alternatively at least 4 hours, alternatively at least 5 hours, alternatively at least 6 hours, alternatively at least 7 hours, alternatively at least 8 hours, alternatively at least 9 hours, alternatively at least 10 hours, alternatively at least 11 hours, alternatively at least 12 hours, alternatively at least 13 hours, alternatively at least 14 hours, alternatively at least 15 hours, alternatively at least 16 hours, alternatively at least 17 hours, alternatively at least 18 hours, alternatively at least 19 hours, alternatively at least 20 hours, alternatively at least 21 hours, alternatively at least 22 hours, alternatively at least 23 hours, alternatively at least 24 hours, alternatively at least 48 hours, or alternatively at least 365 days, after formation of the nitric oxide precursor, depending on the particular amine compound used and the manner in which the precursor is stored.

[0043] Thus, the nitric oxide precursors contemplated herein may exhibit minimal decomposition to nitric oxide for a period of from 5 minutes to 365 days, or from 5 minutes to 48 hours, or from 5 minutes to 24 hours, or from 1 hour to 24 hours, or from 4 hours to 24 hours, or from 8 hours to 24 hours, or from 16 hours to 24 hours, or from 20 hours to 24 hours, depending on the particular amine compound used and the manner in which the precursor is stored. In various embodiments, the decomposition of the nitric oxide precursor to form nitric oxide may be sustained for a predetermined period of time, e.g., from about 1 minute to about 1 year, or from about 1 hour to about 6 months, or from about 24 hours to about 3 months, or from about 1 week to about 8 weeks. Thus, viewed from different perspectives, the decomposition to form nitric oxide may be sustained for a period of at least 1 minute, or at least 1 hour, or at least 24 hours, or at least 1 week, or at least 4 weeks, or at least 12 weeks, or at least 26 weeks. Without wishing to be bound by theory, it is believed that the properties of the nitric oxide precursor can be tailored based on the selection of the primary amine and nitrosating compound to tailor the decomposition into nitric oxide suitable for a particular application.

[0044] In particularly contemplated aspects, the nitric oxide precursor will exhibit desirable storage stability. For example, in various embodiments, the nitric oxide precursor exhibits minimal degradation at 4° C. for a period of at least 1 month, alternatively at least 2 months, alternatively at least 3 months, alternatively at least 6 months, or alternatively at least 12 months. In other embodiments, the nitric oxide precursor exhibits minimal degradation at 23° C. for a period of at least 1 month, alternatively at least 2 months, alternatively at least 3 months, alternatively at least 6 months, or alternatively at least 12 months. The phrase “minimal degradation” means that the nitric oxide precursor exhibits a minimal color difference of 10% ΔE*ab, alternatively at least 5% ΔE*ab, alternatively at least 4% ΔE*ab, alternatively at least 3% ΔE*ab, alternatively at least 2% ΔE*ab, alternatively at least 1% ΔE*ab, or alternatively at least 0.1% ΔE*ab over the desired period of time, according to ASTM D2244-21.

[0045] The inventors further contemplate that suitable nitric oxide precursors may be blended into polymers, solution phases, or powders and used to generate nitric oxide to create a wide range of NO donors / producers by blending them into carriers (polymers or powders, or embedded within and / or on solid carriers), or to create solutions that generate NO in a controlled and predictable manner from the carrier / solution phase. Described herein are methods for synthesizing novel small molecule NO donors that can be used for this purpose, as well as formulations and applications of these NO-generating moieties that can be used as disinfectants, sanitizers, and aseptic cleaners for a wide variety of objects and in a variety of settings.

[0046] It should further be appreciated that the nitric oxide precursors described herein, and their use in polymers, powders, on solid supports, or as solutions, allow for the simple synthesis, controlled formation, and release of NO, with or without acid (in polar or non-polar phases). Indeed, the nitric oxide precursors can be formed at ambient conditions and remain stable over time. Furthermore, the nitric oxide precursors can be crystallized, can withstand polymer casting processes, can be blended into or otherwise combined with a variety of different supports, and can be formed in organic, aqueous, or a combination of organic and aqueous phases.

[0047] In an exemplary embodiment, it is contemplated herein that a self-protected thiolactone (e.g., formed from N-acetylpenicillamine, etc.) can be reacted with individual amine compounds (e.g., cysteine, leucine, isoleucine, lysine, penicillamine, glutathione, etc.) to form intermediates in the form of monomers, dimers, trimers, tetramers, etc. These small molecule intermediates have the ability to carry more NO compounds, creating tunable nitric oxide precursors. For example, when a thiolactone is reacted with a primary amine containing a thiol group, the resulting nitric oxide precursor can have two nitrosothiol groups per molecule. Combining various primary amines containing thiol groups can yield a variety of nitric oxide precursors that exhibit tunable release profiles. These nitric oxide precursors can be used as additives to polymer films / matrices, powder materials, such as desiccants (silica gel or sodium polyacrylate), or in solution phase.

[0048] Nitric oxide precursors, such as small molecule nitrosothiols formed from thiolactones, primary amines, and nitrosated compounds, may be formed in both organic and aqueous phases. Solutions containing cleaning agents (e.g., enzymes, surfactants, etc.) may be combined with the nitric oxide precursors. The nitric oxide precursors can then rapidly decompose to produce nitric oxide. These nitric oxide precursors may be combined with various carriers, desiccants, and cleaning agents, such as powder or solution components (e.g., silica gel, sodium polyacrylate, Alconox soap, proteases, etc.), and used to reprocess articles, such as endoscopes and probes, and to sterilize other objects.

[0049] With respect to suitable thiolactones, it should be understood that there is a wide variety of thiolactones that are suitable for use herein, depending on the design constraints of the desired application of the nitric oxide precursor. In some embodiments, the thiolactone has the following formula (I):

[0050] [ka] (In the formula, R 1 is a bond or a divalent organic group, and R 2 is a bond or a divalent organic group, and R 0 and R 3 are independently a hydrogen atom or a monovalent organic group, and R 4 is an oxygen atom or a sulfur atom) Non-limiting examples of suitable thiolactone groups of thiolactones include α-acetothiolactone, β-propiothiolactone, γ-butyrothiolactone, δ-valerothiolactone, ε-caprothiolactone, ζ-enanthothiolactone, η-caprylothiolactone, and θ-pelargothiolactone groups.

[0051] For example, contemplated thiolactones are represented by the following formula (II):

[0052] [ka] (In the formula, R 5 is substituted or unsubstituted C1-C 12 alkyl) It may have a structure according to:

[0053] In another example, contemplated thiolactones have the following formula (III):

[0054] [ka] (In the formula, R 6 each occurrence is independently hydrogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 heteroalkenyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C1-C6 heteroalkoxy). It may have a structure according to:

[0055] In yet another example, contemplated thiolactones have the following formula (III):

[0056] [ka] (In the formula, R 7 is a group containing an ethylenically unsaturated polymerizable double bond, and R 8 is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 acyl Alternatively, in formula (IV), R 7 and R 8 together form a group containing an ethylenically unsaturated polymerizable double bond.

[0057] It is further contemplated that the thiolactone may be an amine-containing thiolactone. Non-limiting examples of suitable amine-containing thiolactones include thietanone (e.g., N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide), N-acetylcysteine ​​thiolactone, N-acetyl-homocysteine ​​thiolactone, homocysteine ​​thiolactone, butyryl-homocysteine ​​thiolactone, or combinations thereof. In one exemplary embodiment, the amine-containing thiolactone comprises N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide. In most embodiments, contemplated thiolactones will have a molecular weight of less than 1,000 Da, or less than 900 Da, or less than 800 Da, or less than 700 Da, or less than 600 Da, or less than 500 Da, or less than 400 Da, or less than 300 Da, and even lower. For example, suitable thiolactones may have a molecular weight between 150 and 300 Da, or between 250 and 400 Da, or between 350 and 600 Da, or between 500 and 750 Da, or between 700 and 1,000 Da.

[0058] Returning to the primary amine utilized to form the intermediate, there is a wide variety of possible primary amines that can be used depending on the design constraints of the desired application of the nitric oxide precursor. Primary amines can include cysteine ​​or a derivative thereof, lysine or a derivative thereof, butylamine or a derivative thereof, or a combination thereof. In embodiments where cysteine ​​or a derivative thereof is utilized, the cysteine ​​or a derivative thereof can include cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bucillamine, or a combination thereof. Non-limiting examples of suitable cysteine ​​or derivatives thereof are described in the journal article entitled "S-Nitrosothiol Detection via Amperometric Nitric Oxide Sensor with Surface Modified Hydrogel Layer Containing Immobilized Organoselenium Catalyst," cited as Langmuir 2006, 22, 25, 10830-10836, which is incorporated by reference in its entirety. In most embodiments, contemplated primary amines will have a molecular weight of less than 1,200 Da, or less than 1,000 Da, or less than 750 Da, or less than 500 Da, or less than 400 Da, or less than 300 Da, or less than 200 Da, or less than 150 Da. For example, suitable primary amines may have a molecular weight between 120 and 300 Da, or between 250 and 400 Da, or between 350 and 600 Da, or between 500 and 750 Da, or between 700 and 1,000 Da.

[0059] Returning to the nitrosating compound utilized to form the nitric oxide precursor, the nitrosating compound can be any compound that serves as a source of a nitroso group, generally a compound of the formula NOX, where X is an organic or inorganic anion or an OR group, where R is an organic group. Thus, X can be an organic anion derived from a carboxylic acid, such as an alkanecarboxylic acid containing 2 to 7 carbon atoms; nitrosating agents of this type include acetyl nitrite and propionyl nitrite. When X is an inorganic anion, it can be derived, for example, from a mineral acid, such as a halide, e.g., chloride, bromide, or sulfate, or from a Lewis acid, such as fluoroborate. Other inorganic anions include hydroxides and sulfonates. Thus, nitrosating compounds of this type include nitrosyl chloride, nitrosyl sulfate, nitrosyl fluoroborate, nitrous acid, and Fremy's salt (potassium nitrosyl disulfonate). When X is a group of formula OR2, the organic group R2 may be, for example, a lower alkyl group, such as one containing 1 to 9 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or isopentyl.

[0060] In certain embodiments, the nitrosating compound comprises a nitrite compound. The nitrite compound may include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, pentyl nitrite, nitrite salts, ion-pair nitrite compounds, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, or combinations thereof. Nitric oxide gas may also be used as a nitrosating agent.

[0061] In various embodiments, the nitrosated compound has a weight average molecular weight of 10,000 g / mol or less, alternatively 1,000 g / mol or less, alternatively 500 g / mol or less, or alternatively 250 g / mol or less. From a different perspective, the nitrosated compound may have a weight average molecular weight of about 10 g / mol to about 10,000 g / mol, alternatively 10 g / mol to about 1,000 g / mol, alternatively 10 g / mol to about 500 g / mol, or alternatively 10 g / mol to about 250 g / mol. For example, NaNO2 has a weight average molecular weight of 69 g / mol, and butyl nitrite has a weight average molecular weight of 103 g / mol. Without being bound by theory, it is believed that the reaction kinetics for forming the reaction product are improved by utilizing a nitrosated compound with a lower weight average molecular weight.

[0062] It should be understood that the resulting nitric oxide precursor will therefore have a relatively low molecular weight and, therefore, will preferably be free of polymers having four or more repeating units. Thus, in some embodiments, the nitric oxide precursor will not have hetero- or homopolymeric components. On the other hand, when the primary amine comprises a polypeptide, it is generally preferred that the polypeptide have fewer than 10, or fewer than 8, or fewer than 6, or fewer than 4 amino acids.

[0063] As mentioned above, it is generally preferred that the thiolactone and the primary amine react in the presence of a solvent to form an intermediate, and then the intermediate and the nitrosated compound react to form the nitric oxide precursor. When utilized, the solvent may be present in various amounts. The solvent may be aqueous, organic, non-organic, or a combination thereof. In certain embodiments, the solvent is an aqueous solvent, such as water, or a mixture of water and methanol. In other embodiments, the solvent may include an organic solvent, such as tetrahydrofuran. Thus, most typically, the solvent may be characterized as a polar solvent or a polar alcohol solvent. Other non-limiting examples of suitable solvents include aromatic, aliphatic, ketones, such as methyl ethyl ketone, isobutyl ketone, ethyl amyl ketone, acetone, alcohols, such as methanol, ethanol n-butanol isopropanol esters, such as ethyl acetate, glycols, such as ethylene glycol propylene glycol ether, such as tetrahydrofuran, ethylene glycol monobutyl ether, or combinations thereof. In further contemplated embodiments, when the solvent is a mixture of organic solvent and water, the solvent will have a relatively low water content, for example, 25 vol.% or less, or 20 vol.% or less, or 15 vol.% or less, or 10 vol.% or less, or 5 vol.% or less, or 2.5 vol.% or less.

[0064] The components utilized to form the nitric oxide precursor may be combined in a reaction mixture. It should be understood that the components of the reaction mixture have not yet reacted with each other. The reaction mixture to form the reaction product may include a thiolactone in an amount of about 1 to about 80 wt%, alternatively about 1 to about 7 wt%, alternatively about 50 to about 80 wt%, based on the total weight of the reaction mixture. The reaction mixture to form the reaction product may include a primary amine in an amount of about 1 to about 80 wt%, alternatively about 1 to about 7 wt%, alternatively about 50 to about 80 wt%, based on the total weight of the reaction mixture. The reaction mixture to form the reaction product may include a nitrosating compound in an amount of about 1 to about 75 wt%, alternatively about 1 to about 10 wt%, alternatively about 10 to about 75 wt%, based on the total weight of the reaction mixture. If utilized, the reaction mixture to form the reaction product may include a solvent in an amount of about 1 to about 99 wt%, based on the total weight of the reaction mixture.

[0065] In various embodiments, the thiolactone and primary amine are reacted in the presence of an acid. The acid can be used to improve the formation and / or stability of the reaction product, such as when using primary amine containing amino acids, such as cysteine. In certain embodiments, the acid can include hydrochloric acid. Other non-limiting examples of suitable acids include citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, acetic acid, hydroxyacetic acid, propionic acid, hydroxypropionic acid, α-ketopropionic acid, butyric acid, mandelic acid, valeric acid, succinic acid, tartaric acid, malic acid, oxalic acid, fumaric acid, adipic acid, maleic acid, sorbic acid, benzoic acid, succinic acid, glutaric acid, adipic acid, α-hydroxy acid, ethylenediaminetetraacetic acid (EDTA), phosphonic acid, octylphosphoric acid, acrylic acid, polyacrylic acid, aspartic acid, polyaspartic acid, p-hydroxybenzoic acid, iminoacetic acid, or combinations thereof. It should be understood that the acid can be included as part of any component of the composition (e.g., carrier, solvent, etc.) or reactant of the reaction product.

[0066] In other embodiments, the reaction product is formed in the substantial absence of acid. The inventors contemplate that the reaction product is substantially free of acid. As used herein, the term "substantially free" refers to either the complete absence of acid or a minimal amount thereof merely as an impurity, an unintended by-product of another component, or an amount having a negligible impact on the composition or nitric oxide precursor. In certain embodiments, "substantially free" means that acid is present in the reaction product in an amount of less than 0.5 wt.%, less than 0.25 wt.%, less than 0.1 wt.%, less than 0.05 wt.%, or less than 0.01 wt.%, or even 0 wt.%, based on the total weight of the reaction product.

[0067] In some embodiments, the reaction mixture for forming the nitric oxide precursor may include a thiol-containing compound in addition to the thiolactone and the primary amine containing a thiol group. If utilized, there is a wide variety of potential thiol-containing compounds that can be used depending on the design constraints of the desired application of the nitric oxide precursor. Thiol-containing compounds can include, but are not limited to, one or more of 1,2-ethanedithiol, 2,3-dimercaptopropanol, pyrithione, dithioerythritol, 3,4-dimercaptotoluene, 2,3-butanedithiol, 1,3-propanedithiol, 2-hydroxypropanethiol, 1-mercapto-2-propanol, dithioerythritol, and dithiothreitol. Other exemplary thiol-containing compounds include alpha-lipoic acid, methanethiol (CHSH [m-mercaptan]), ethanethiol (CHSH [e-mercaptan]), 1-propanethiol (CHSH [nP-mercaptan]), 2-propanethiol (CHCH(SH)CH [C3-mercaptan]), butanethiol (CHSH ([n-butyl mercaptan]), tert-butyl mercaptan (C(CH)SH [t-butyl mercaptan]), pentanethiol (CHSH [Pentyl mercaptan]), coenzyme A, lipoamide, glutathione, cysteine, cystine, 2-mercaptoethanol, dithiothreitol, dithioerythritol, 2-mercaptoindole, transglutaminase, (11-mercaptoundecyl)hexa(ethylene glycol), (11-mercaptoundecyl)tetra(ethylene glycol), (11-mercaptoundecyl)tetra (Ethylene glycol) functionalized gold nanoparticles, 1,1',4',1"-terphenyl-4-thiol, 1,11-undecanedithiol, 1,16-hexadecanedithiol, 1,2-ethanedithiol, 1,3-propanedithiol, 1,4-benzenedimethanethiol, 1,4-butanedithiol, 1,4-butanedithiol diacetate, 1,5-pentanedithiol, 1,6-hexanedithiol, 1,8-octanedithiol, 1,9-Nonanedithiol, Adamantanethiol, 1-Butanethiol, 1-Decanethiol, 1-Dodecanethiol, 1-Heptanethiol, 1-Heptanethiol Purum, 1-Hexadecanethiol, 1-Hexanethiol, 1-Mercapto-(triethylene glycol), 1-Mercapto-(triethylene glycol) methyl ether functionalized gold nanoparticles, 1-Mercapto-2-propanol, 1-Nonanthiol, 1-Octadecanethiol, 1-Octanethiol, 1-Octanethiol, 1-Phenyl Undecanethiol, 1-pentanethiol, 1-propanethiol, 1-tetradecanethiol, 1-tetradecanethiol purum, 1-undecanethiol, 11-(1H-pyrrol-1-yl)undecane-1-thiol, 11-amino-1-undecanethiol hydrochloride, 11-bromo-1-undecanethiol, 11-mercapto-1-undecanol, 11-mercapto-1-undecanol, 11-mercaptoundecanoic acid, 11-mercaptoundecanoic acid, 11-mercaptoundecyl Trifluoroacetate, 11-mercaptoundecyl phosphate, 12-mercaptododecanoic acid, 12-mercaptododecanoic acid, 15-mercaptopentadecanoic acid, 16-mercaptohexadecanoic acid, 16-mercaptohexadecanoic acid, 1H,1H,2H,2H-perfluorodecanethiol, 2,2'-(ethylenedioxy)diethanethiol, 2,3-butanedithiol, 2-butanethiol, 2-ethylhexanethiol, 2-methyl-1-propanethiol, 2-methyl-2-propanethiol, 2- Phenylethanethiol, 3,3,4,4,5,5,6,6,6-nonafluoro-1-hexanethiol, purum, 3-(dimethoxymethylsilyl)-1-propanethiol, 3-chloro-1-propanethiol, 3-mercapto-1-propanol, 3-mercapto-2-butanol, 3-mercapto-N-nonylpropionamine, 3-mercaptopropionic acid, 3-mercaptopropyl-functionalized silica gel, 3-methyl-1-butanethiol, 4,4'-bis(mercaptomethyl)biphenyl, 4,4'-Dimercaptostilbene, 4-(6-mercaptohexyloxy)benzyl alcohol, 4-cyano-1-butanethiol, 4-mercapto-1-butanol, 6-(ferrocenyl)hexanethiol, 6-mercapto-1-hexanol, 6-mercaptohexanoic acid, 8-mercapto-1-octanol, 8-mercaptooctanoic acid, 9-mercapto-1-nonanol, biphenyl-4,4'-dithiol, butyl 3-mercaptopropionate, copper(I) 1-butanethiolate, cyclohexanethiol, cyclopentanethiol, decanethiol-functionalized silver nanoparticles, dodecanethiol-functionalized gold nanoparticles, dodecanethiol-functionalized silver nanoparticles, hexa(ethylene glycol) [11-(methylcarbonylthio)undecyl]tetra-(ethylene glycol), m-carborane-9-thiol, p-terphenyl-4,4"-dithiol, tert-dodecyl mercaptan, or tert-nonyl mercaptan.

[0068] In certain embodiments, when utilized, the thiol-containing compound comprises a thiol-derivatized polymer or bulking agent. It is understood that the thiol-containing compound can be included as part of a peptide or other macromolecule, so long as the thiol-containing compound is compatible with the components of the reaction mixture of the reaction product.

[0069] In various embodiments, when utilized, the thiol-containing compound has a weight average molecular weight of 500,000 g / mol or less, alternatively 100,000 g / mol or less, alternatively 10,000 g / mol or less, alternatively 1,000 g / mol or less, alternatively 500 g / mol or less. From a different perspective, the thiol-containing compound may have a weight average molecular weight of about 10 g / mol to about 500,000 g / mol, alternatively about 10 g / mol to about 100,000 g / mol, alternatively about 10 g / mol to about 1,000 g / mol, alternatively about 10 g / mol to about 500 g / mol.

[0070] In certain embodiments, the nitric oxide precursor is in crystalline form. Therefore, from a different perspective, the inventors contemplate that crystallization can pull the compound out of solution, thereby eliminating ions that may cause decomposition. In contrast to crystallization, granular nitric oxide precursors may exhibit a greater amount of impurities compared to crystallized nitric oxide precursors due to the incorporation of foreign substances. In various embodiments, crystallization includes at least partially (e.g., at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%) removing the solvent after the formation of the nitric oxide precursor. Crystallization may proceed via nucleation, supersaturation, and / or cooling. Crystallization methods are well known to those skilled in the art and are described in textbooks such as A. Mersmann, Crystallization Technology Handbook (2001) CRC; 2nd Edition, ISBN 0-8247-0528-9, which is incorporated by reference in its entirety.

[0071] In this context, it should be understood that the crystallized nitric oxide precursor may exhibit improved storage stability compared to a non-crystallized nitric oxide precursor. In various embodiments, the crystallized nitric oxide precursor exhibits minimal degradation at 4° C. for a period of at least 1 month, alternatively at least 2 months, alternatively at least 3 months, alternatively at least 6 months, or alternatively at least 12 months. In other embodiments, the crystallized nitric oxide precursor exhibits minimal degradation at 23° C. for a period of at least 1 month, alternatively at least 2 months, alternatively at least 3 months, alternatively at least 6 months, or alternatively at least 12 months. The phrase “minimal degradation” means that the crystallized nitric oxide precursor exhibits a loss of total weight of no more than 10% by weight, alternatively at least 5% by weight, alternatively at least 4% by weight, alternatively at least 3% by weight, alternatively at least 2% by weight, alternatively at least 1% by weight, or alternatively at least 0.1% by weight over the desired period of time.

[0072] As introduced above, composite articles are also contemplated herein. The composite article includes a carrier and a nitric oxide precursor. In some embodiments, the composite article exhibits minimal release of nitric oxide for at least 5 minutes after forming the nitric oxide precursor. In various embodiments, the composite article exhibits minimal release of nitric oxide for a period of at least at least 10 minutes, alternatively at least 15 minutes, alternatively at least 30 minutes, alternatively at least 45 minutes, alternatively at least 1 hour, alternatively at least 2 hours, alternatively at least 3 hours, alternatively at least 4 hours, alternatively at least 5 hours, alternatively at least 6 hours, alternatively at least 7 hours, alternatively at least 8 hours, alternatively at least 9 hours, alternatively at least 10 hours, alternatively at least 11 hours, alternatively at least 12 hours, alternatively at least 13 hours, alternatively at least 14 hours, alternatively at least 15 hours, alternatively at least 16 hours, alternatively at least 17 hours, alternatively at least 18 hours, alternatively at least 19 hours, alternatively at least 20 hours, alternatively at least 21 hours, alternatively at least 22 hours, alternatively at least 23 hours, alternatively at least 24 hours, alternatively at least 48 hours, alternatively at least 7 days, alternatively at least 4 weeks, alternatively at least 26 weeks, or alternatively at least 365 days after formation of the nitric oxide precursor, depending on the particular amine compound used and the manner in which the precursor is stored. The carrier may comprise silica gel, sodium polyacrylate, or a combination thereof. However, it should be understood that any other carrier can be used.Non-limiting examples of other suitable carriers include filter paper, polyacrylate, polyvinyl chloride, polydimethylsiloxane, polyurethane, and combinations thereof.Such carriers are well known to those skilled in the art and are described in textbooks such as Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, which is incorporated by reference in its entirety.

[0073] The composite article may comprise the nitric oxide precursor in an amount of about 0.5 to about 10 wt%, about 10 to about 25 wt%, about 25 to about 50 wt%, about 50 to about 70 wt%, or about 70 to about 90 wt%, such as about 5 to about 25 wt%, based on the total weight of the composite article. The composite article may comprise the carrier in an amount of about 5 to about 95 wt%, alternatively about 10 to about 80 wt%, or alternatively about 80 to about 95 wt%, based on the total weight of the composite article.

[0074] In exemplary embodiments, the nitric oxide precursor is included in a detergent or cleaning composition. As used herein, the terms "detergent composition" or "cleaning composition" include compositions and formulations designed to clean soiled materials. Such compositions include, but are not limited to, object cleaning compositions, medical device cleaning compositions, hard surface cleaning compositions, dishware cleaning compositions, laundry cleaning compositions and detergents, spray products, dry cleaning agents or compositions, unit dose formulations, delayed delivery formulations, detergents contained on or in porous substrates or nonwoven sheets, detergents contained on or in water-soluble films, and other suitable forms that may be apparent to those skilled in the art in light of the teachings herein. The multi-component composition may have a form selected from a liquid, powder, single-phase or multi-phase unit dose, a two-layer paper carrier, a pouch, a tablet, a gel, a paste, a bar, or a thin strip.

[0075] In these and other embodiments, the cleaning or sanitizing composition further comprises a detergent. The detergent may comprise a detergent, an enzyme, or a combination thereof. Non-limiting examples of suitable detergents include Alconox powder. In embodiments where the cleaning composition comprises a detergent, the detergent may also comprise a surfactant, such as an amine oxide, alkyl benzene sulfonate, alkyl ether sulfate, fatty alcohol ethoxylate, alkyl glycoside, alkoxylated fatty acid alkyl ester, amine oxide, fatty acid alkanolamide, hydroxy mixed ether, sorbitan fatty acid ester, polyhydroxy fatty acid amide, and alkoxylated alcohol.

[0076] In embodiments where the cleaning agent includes an enzyme, the enzyme may include one or more enzymes capable of exhibiting catalytic activity in the cleaning agent, such as proteases, amylases, lipases, cellulases, hemicellulases, mannanases, pectin-cleaving enzymes, tannases, xylanases, xanthanases, β-glucosidases, carrageenases, perhydrolases, oxidases, oxidoreductases, and mixtures thereof. In certain embodiments, the enzyme includes proteases, amylases (e.g., α-amylases), cellulases, lipases, hemicellulases, pectinases, mannanases, β-glucanases, or combinations thereof. The properties of the enzymes should be compatible with the multi-component composition (i.e., pH-optimal, compatibility with other enzyme and non-enzyme components, etc.). When utilized, the enzymes should be present in effective amounts.

[0077] When utilized, the protease may be of animal, plant, or microbial origin, including chemically or genetically engineered variants. Microbial origin is preferred. It may be an alkaline protease, such as a serine protease or a metalloprotease. The serine protease may be, for example, from the Si family, such as trypsin, or from the S8 family, such as subtilisin. The metalloprotease protease may be, for example, from the M4, M5, M7, or M8 family, such as thermolysin.

[0078] Where utilized, suitable lipases and cutinases include those of bacterial or fungal origin, including chemically modified or protein engineered variants. Examples include lipases from Thermomyces, such as T. lanuginosus (previously called Humicola lanuginosa), as described in EP 258 068 and EP 305 216, cutinases from Humicola, such as H. insolens, as described in WO 96 / 13580, Pseudomonas lipases, such as P. alcaligenes or P. pseudoalcaligenes (EP 218 272), P. cepacia (EP 331 376), P. stutzeri (GB 2004). 1,372,034), P. fluorescens, Pseudomonas sp., strain SD 705 (WO 95 / 06720 and WO 96 / 27002), P. wisconsinensis (WO 96 / 12012), Bacillus lipase, for example, from B. subtilis (Dartois et al., 1993, Biochemica et Biophysica Acta, 1131: 253-360), B. stearothermophilus (JP 64 / 744992), or B. pumilus (WO 91 / 16422).

[0079] Other examples are lipase variants such as those described in WO 92 / 05249, WO 94 / 01541, EP 407 225, EP 260 105, WO 95 / 35381, WO 96 / 00292, WO 95 / 30744, WO 94 / 25578, WO 95 / 14783, WO 95 / 22615, WO 97 / 04079, WO 97 / 07202, WO 00 / 060063, WO2007 / 087508, and WO 2009 / 109500, which are incorporated by reference in their entireties.

[0080] Suitable amylases, if utilized, include those of bacterial or fungal origin, including chemically modified or protein-engineered variants. Examples of amylases include α-amylases obtained from specialized strains of Bacillus, such as Bacillus licheniformis, as described in further detail in GB 1,296,839. Examples of useful amylases are the variants described in WO 94 / 02597, WO 94 / 18314, WO 96 / 23873, and WO 97 / 43424, the entire contents of which are incorporated by reference.

[0081] Suitable cellulases, when utilized, include those of bacterial or fungal origin, including chemically modified or protein-engineered variants. Suitable cellulases include cellulases from the genera Bacillus, Pseudomonas, Humicola, Fusarium, Thielavia, and Acremonium, such as fungal cellulases produced from Humicola insolens, Myceliophthora thermophila, and Fusarium oxysporum, as disclosed in U.S. Pat. Nos. 4,435,307, 5,648,263, 5,691,178, 5,776,757, and WO 89 / 09259, the entire contents of which are incorporated by reference.

[0082] Where utilized, suitable peroxidases / oxidases include those of plant, bacterial, or fungal origin, including variants that have been chemically modified or engineered by protein engineering. Examples of useful peroxidases include peroxidases from Coprinus, e.g., C. cinereus, and variants thereof, as described in WO 93 / 24618, WO 95 / 10602, and WO 98 / 15257, the entire contents of which are incorporated by reference.

[0083] The detergent or cleaning composition may further comprise additives such as builders, bleaches, electrolytes, non-aqueous solvents, pH adjusters, fragrances, perfume carriers, fluorescent agents, dyes, hydrotropes, foam inhibitors, silicone oils, anti-redeposition agents, anti-graying agents, anti-shrinkage agents, anti-wrinkle agents, dye transfer inhibitors, antimicrobial substances, bactericides, fungicides, antioxidants, preservatives, corrosion inhibitors, antistatic agents, bittering agents, ironing aids, hydrophobizing and impregnating agents, swelling and anti-slip agents, softening components, and UV absorbers.

[0084] The cleaning or cleaning composition may comprise the nitric oxide precursor in an amount of about 0.01 to about 40% by weight, alternatively about 0.01 to about 5% by weight, alternatively about 5 to about 10% by weight, alternatively about 10 to about 40% by weight, based on the total weight of the composition. The cleaning or cleaning composition may comprise the cleaning agent in an amount of about 1 to about 99% by weight, based on the total weight of the composition. The cleaning or cleaning composition may comprise the solvent in an amount of about 1 to about 99% by weight, based on the total weight of the composition.

[0085] In various embodiments, the cleaning or sanitizing compositions described herein can be filled into a water-soluble envelope and thus become part of a water-soluble package. The water-soluble envelope can be formed from a water-soluble film material. Such water-soluble packages can be manufactured by a vertical fill-seal (VFFS) method or a thermoforming method.

[0086] The envelope can be made of one or more layers of water-soluble film material. The water-soluble film material of the first layer and, if present, of the other layers can be the same or different. The water-soluble envelope is made, for example, from a water-soluble film material selected from a group including a polymer or a polymer mixture. The water-soluble envelope may contain polyvinyl alcohol or a polyvinyl alcohol copolymer. A polymer selected from a group including acrylic acid-containing polymers, polyacrylamides, oxazoline polymers, polystyrene sulfonates, polyurethanes, polyesters, polyether polyacetic acids, and / or mixtures of the above polymers can be added to a film material suitable for producing the water-soluble envelope.

[0087] The thermoforming method generally includes the steps of forming a first layer from a water-soluble film material to create a convex portion for receiving the composition therein, filling the convex portion with the composition, covering the composition-filled convex portion with a second layer of water-soluble film material, and sealing the first and second layers together at least around the convex portion. The water-soluble package containing the liquid detergent and the water-soluble envelope can have one or more chambers. The water-soluble package can have substantially dimensionally stable spherical and pillow-shaped shapes, with a circular, oval, square, or rectangular basic shape. The chambers can be separated from each other.

[0088] Also provided herein is a method for sterilizing or sanitizing an article, the method comprising applying to the article a nitric oxide precursor as described above.

[0089] Methods for forming a nitric oxide precursor are provided herein. The methods include combining a thiolactone and a primary amine, optionally in the presence of a solvent and optionally in the presence of an acid, to form an intermediate. In various embodiments, the methods may include allowing the intermediate to stand for 1 minute to 24 hours, alternatively, 1 minute to 6 hours, alternatively, 10 minutes to 4 hours, or alternatively, 30 minutes to 150 minutes. The methods further include combining the intermediate and a nitrosated compound to form a nitric oxide precursor. In various embodiments, the combining and standing steps are performed at a temperature of about 1° C. to about 25° C.

[0090] In an exemplary embodiment, thiolactones react with primary amines, such as cysteine, penicillamine, glutathione, leucine, isoleucine, and lysine, to form intermediates in a ring-opening reaction, generating (typically secondary or tertiary) thiol groups. Physicochemical properties, such as reactivity, hydrophobicity, number of NO donors, and stability of the NO donors, can be tailored to create a wide range of properties. This allows for precise control of the NO loading, NO release, and partition coefficient of the donors when incorporated into polymer matrices, powders, and solutions. To carry out this reaction, thiolactones and primary amine compounds are dissolved in a solvent and reacted. This reaction cleaves the thiolactone ring, forming an amide bond with the primary amine and exposing the thiol group in the thiolactone. The thiol group of the intermediate is then converted to a nitrosothiol by reacting the intermediate with a nitrosating agent, such as sodium nitrite or tert-butyl nitrite, to form a nitric oxide precursor.

[0091] The nitric oxide precursors formed can exhibit green or red color depending on the molecular structure of the primary amine and the substituents around the thiol used. Advantageously, these nitric oxide precursors can be crystallized from solution or used in solution with different matrices and / or supports (e.g., filter paper, polyacrylate, PVC, PDMS, PU, ​​silica gel powder, sodium polyacrylate, etc.). It should be further appreciated that the above-described reaction conditions for forming nitric oxide precursors are mild compared to conventional reaction products and methods for forming nitric oxide precursors. Notably, by using a ring-opening reaction followed by nitrosation, the reaction can be carried out at ambient temperature (e.g., between 15 and 25 °C), atmospheric pressure (e.g., between 950 and 1,060 mbar), and ambient humidity (e.g., between 15 and 90% relative humidity), and can be carried out without protection from ambient light. [Example]

[0092] The following examples are included to demonstrate various embodiments as contemplated herein. Those of skill in the art should understand that the techniques disclosed in the examples that follow represent techniques discovered by the inventor(s) to function well in the practice of the invention, and therefore can be considered to constitute desired modes for its implementation. However, those of skill in the art should understand in light of the present invention that many changes can be made in the specific embodiments disclosed and still obtain like or similar results without departing from the spirit and scope of the invention. All percentages are by weight and all measurements are performed at 23° C. unless otherwise indicated.

[0093] Example 1A SNAP-cysteine 29.8 mg of cysteine ​​(a primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in 1 mL of water, 4 mL of methanol, and 100 μL of 1 M HCl to form an intermediate in solution. After standing for 1 hour, 50 mg of NaNO (a nitrosated compound) was added to the intermediate solution to form the nitric oxide precursor.

[0094] Example 1B SNAP-Leucine 31.4 mg of leucine (a primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in an aqueous solvent solution of 1 mL of water, 4 mL of methanol, and 100 μL of 1 M HCl to form an intermediate solution. After standing for 1 hour, 50 mg of NaNO (a nitrosated compound) was added to the intermediate solution to form the nitric oxide precursor.

[0095] Example 1C SNAP-Penicillamine 36 mg of penicillamine (a primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in an aqueous solvent solution of 1 mL of water, 4 mL of methanol, and 100 μL of 1 M HCl to form an intermediate solution. After standing for 1 hour, 50 mg of NaNO (a nitrosated compound) was added to the intermediate solution to form a nitric oxide precursor.

[0096] Example 1D SNAP-lysine 23 mg of lysine (a primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in 200 μL of water, 1.8 mL of methanol, and 100 μL of 1 M HCl to form an intermediate solution. After standing for 1 hour, 50 mg of NaNO (a nitrosated compound) was added to the intermediate solution to form the nitric oxide precursor.

[0097] Example 1E SNAP-acetyllysine 29 mg of acetyllysine (a primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in an aqueous solvent solution of 200 μL of water, 1.8 mL of methanol, and 100 μL of 1 M HCl to form an intermediate solution. After standing for 1 hour, 50 mg of NaNO (a nitrosated compound) was added to the intermediate solution to form the nitric oxide precursor.

[0098] [Examples 1A-E] observation After 1 hour, the solution changed color from deep red / green to green to darker green to deep red / green to deep red / green, which is expected due to the formation of SNAP and NOCys (green and red RSNOs), SNAP alone (one green RSNO), SNAP and nitrosopenicillamine (two green RSNOs), SNAP alone (one green RSNO), and SNAP alone (one green RSNO).

[0099] The inventors obtained a concentrated solution of the same color after evaporation of the methanol, indicating high stability. After 24 hours, the color persisted, indicating high stability. Exemplary samples of the reaction products are shown in Figures 1A-1D.

[0100] Example 2A SNAP-cysteine 28 mg of cysteine ​​(a primary amine) and 40.8 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in 5 mL of methanol to form an intermediate solution. After standing for 2 hours, 200 mg of tert-butyl nitrite (a nitrosated compound) was added to the intermediate solution to form the nitric oxide precursor.

[0101] Example 2B SNAP-Leucine 33 mg of leucine (a primary amine) and 40.8 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in 5 mL of methanol to form an intermediate solution. After standing for 2 hours, 200 mg of tert-butyl nitrite (a nitrosated compound) was added to the intermediate solution to form the nitric oxide precursor.

[0102] [Example 2C] SNAP-Penicillamine 34.5 mg of penicillamine (a primary amine) and 40.8 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in 5 mL of methanol to form an intermediate solution. After standing for 2 hours, 200 mg of tert-butyl nitrite (a nitrosated compound) was added to the intermediate solution to form a nitric oxide precursor.

[0103] Example 2D SNAP-Glutathione 76.6 mg of glutathione (a primary amine) and 40.8 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in 5 mL of methanol to form an intermediate solution. After standing for 2 hours, 200 mg of tert-butyl nitrite (a nitrosated compound) was added to the intermediate solution to form the nitric oxide precursor.

[0104] [Examples 2A-D] observation After 1 hour, the solution changed color from deep red / green to green to darker green to red / green, which is expected due to the formation of SNAP and NOCys (one green and one red RSNO), SNAP alone (one green RSNO), SNAP and nitrosopenicillamine (two green RSNOs), and SNAP-GSNO (one green and one red RSNO).

[0105] We obtained concentrated solutions of the same color after evaporation of the methanol, indicating high stability. After 24 hours, the color persisted, indicating high stability. See Figure 2, which shows examples of SNAP-Pen, SNAP-Leu, and SNAP-GSNO (Figures 2A, 2B, and 2C, respectively). Figure 2D is an image of SNAP-Pen synthesized in dichloromethane and crystallized with all solvent removed. The green-red color indicates a concentrated tertiary RSNO, which is a green-red biaxial crystal.

[0106] Example 3A SNAP-n-butylamine (acid-free) 22 μL of n-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene solvent solution to form an intermediate solution. 200 mg of tert-butyl nitrite (nitrosated compound) was then added to the intermediate solution to form the nitric oxide precursor. A dark green solution was obtained.

[0107] Example 3B SNAP-n-butylamine(acid) 22 μL of n-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene and 20 μL of dodecybenzenesulfonic acid to form an intermediate solution. 200 mg of tert-butyl nitrite (nitrosated compound) was then added to the intermediate solution to form the nitric oxide precursor. The addition of acid accelerated the rate of RSNO production. A dark green solution was obtained.

[0108] Example 3C SNAP-sec-butylamine (acid-free) 22 μL of sec-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene solvent solution to form an intermediate solution. 200 mg of tert-butyl nitrite (nitrosated compound) was then added to the intermediate solution to form the nitric oxide precursor. A dark green solution was obtained.

[0109] Example 3D SNAP-sec-butylamine(acid) 22 μL of sec-butylamine (a primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (a thiolactone) were mixed in 2 mL of a solvent solution of THF / toluene and 20 μL of dodecybenzenesulfonic acid to form an intermediate solution. 200 mg of tert-butyl nitrite (a nitrosated compound) was then added to the intermediate solution to form the nitric oxide precursor. The addition of acid accelerated the rate of RSNO production. A dark green solution was obtained.

[0110] Example 3E SNAP-tert-butylamine (acid-free) 22 μL of tert-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene solvent solution to form an intermediate solution. 200 mg of tert-butyl nitrite (nitrosated compound) was then added to the intermediate solution to form the nitric oxide precursor. A dark green solution was obtained.

[0111] Example 3F SNAP-tert-butylamine(acid) 22 μL of tert-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene and 20 μL of dodecybenzenesulfonic acid to form an intermediate solution. 200 mg of tert-butyl nitrite (nitrosated compound) was then added to the intermediate solution to form the nitric oxide precursor. The addition of acid accelerated the rate of RSNO production. A dark green solution was obtained.

[0112] [Examples 3A-F] composite article Next, 1 mL of each nitric oxide precursor solution was combined with 1 mL of PVC polymer solution (0.1 g / mL PVC in THF) and cast into a film. A green PVC polymer was obtained that released NO. The same experiment was completed using toluene as the solvent and RTV-3140 PDMS as the polymer. See Figure 3A, which shows the reaction mixture immediately after the addition of tert-butyl nitrite when toluene was used as the solvent. See Figures 3B and 3C, which show NO release from three-layer PVC films containing SNAP-n-butylamine and SNAP-sec-butylamine, respectively, detected by chemiluminescence.

[0113] [Example 4] SNAP-Lys Silica Gel and SNAP-Lys Sodium Polyacrylate Composite Article SNAP-Lys was synthesized by adding 23 mg of lysine, 40 mg of N-(2,2-dimethyl-4-oxo-3-thietanyl)acetamide, and 100 μL of 1 M HCl in 200 μL of water and 1.8 mL of methanol. After 1 h, 50 mg of NaNO was added. The solution was stored overnight at 4 °C, and the methanol was removed with a stream of nitrogen.

[0114] 300 μL of the concentrated SNAP-Lys aqueous / methanol solution was pipetted onto 500 mg of silica gel, and 300 μL of the concentrated SNAP-Lys aqueous / methanol solution was pipetted onto 500 mg of sodium polyacrylate. Both particle sets were allowed to air dry. A deep green-red desiccant capable of releasing NO was obtained. The same desiccant was also prepared using GSNO as the NO source by combining 50 mg of GSH and 100 mg of NaNO in 3 mL of HO. 1.5 mL of this red solution was then pipetted onto 500 mg of silica gel and 500 mg of sodium polyacrylate. A pink NO-releasing desiccant was obtained. See Figure 4 for images of these NO-releasing desiccant solutions from SNAP-Lys (green; Figures 4A and 4B) and GSNO (red; Figures 4C and 4D), respectively.

[0115] It is understood that the appended claims are not limited to representing the specific compounds, compositions, or methods described in the detailed description, which may vary among specific embodiments encompassed within the scope of the appended claims. With respect to any Markush group relied upon herein to describe particular features or aspects of various embodiments, different, extraordinary, and / or unexpected results may be obtained from each element of the respective Markush group, independent of all other Markush groups. Each element of a Markush group may be relied upon individually and / or in combination, with each such element providing adequate support for specific embodiments within the scope of the appended claims.

[0116] It should also be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to an element in the singular is intended to include plural elements.

[0117] Furthermore, any ranges and subranges relied upon in describing various embodiments of the present invention are understood to be individually and jointly encompassed within the scope of the appended claims, and to describe and contemplate all ranges, including entire and / or partial values ​​therein, even if such values ​​are not expressly written herein. Those skilled in the art will readily understand that the recited ranges and subranges fully describe and enable various embodiments of the present invention, and that such ranges and subranges may be further delineated by relevant half, third, quarter, fifth, etc. By way of example only, the range "0.1 to 0.9" may be further delineated into a lower third, i.e., 0.1 to 0.3, a middle third, i.e., 0.4 to 0.6, and an upper third, i.e., 0.7 to 0.9, which are individually and jointly within the scope of the appended claims and may be relied upon individually and / or jointly to provide adequate support for particular embodiments within the scope of the appended claims. Furthermore, with regard to language defining or modifying ranges, such as "at least," "greater than," "less than," "less than or equal to," and the like, it is to be understood that such language includes subranges and / or upper or lower limits. As another example, the range "at least 10" inherently includes subranges of at least 10 to 35, at least 10 to 25, 25 to 35, etc., each of which may be relied upon individually and / or jointly to provide proper support for particular embodiments within the scope of the appended claims. Finally, individual numbers within disclosed ranges may be relied upon to provide proper support for particular embodiments within the scope of the appended claims. For example, the range "1 to 9" includes various individual integers, such as 3, as well as individual numbers containing decimal points (or fractions), such as 4.1, which may be relied upon to provide proper support for particular embodiments within the scope of the appended claims.

[0118] Except in the examples or where otherwise expressly stated, all numerical values ​​in this description indicating amounts of materials or reaction conditions and / or uses are understood to be modified by the word "about" when describing the broadest scope of the invention. In various embodiments, the terms "about" and "approximately," when referring to a specified measurable value (such as a parameter, amount, temporal duration, and the like), are meant to encompass the specified value and variations therefrom, to the extent that such variations are appropriate for the disclosed embodiments, e.g., ±10% or less, or ±5% or less, or ±1% or less, or ±0.1% or less. Thus, values ​​referred to by the modifiers "about" or "approximately" are themselves specifically disclosed.

[0119] Practice within the stated numerical limits is generally preferred, and unless expressly stated to the contrary, percents, "parts," and ratio values ​​are by weight; the description of a group or class of materials as suitable or preferred for a given purpose in connection with this invention does not imply that mixtures of any two or more members of the group or class are equally suitable or preferred; the description of components in chemical terms refers to the components when added in any combination specified in the description and does not necessarily exclude chemical interactions between the components of the mixture once mixed; the first definition of an acronym or other abbreviation applies to all subsequent uses herein of the same abbreviation, mutatis mutandis, of normal grammatical variations of the initially defined abbreviation; and unless expressly stated to the contrary, measurements of properties are determined by the same techniques as previously or subsequently referenced for the same property.

[0120] The present invention has been described herein in an illustrative manner, and it should be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. The present invention may be practiced other than as specifically described within the scope of the appended claims. The subject matter of all combinations of independent and dependent claims, both singular and multiple dependent, is expressly contemplated herein.

Claims

1. 1. A method for producing a nitric oxide precursor, comprising: reacting a thiolactone with a primary amine in a solvent in a ring-opening reaction to form an intermediate having a thiol group; reacting the thiol group of the intermediate with a nitrosating compound in a solvent to form a nitrosothiol-bearing nitric oxide precursor; and At least partially removing the solvent Including, The nitric oxide precursor is capable of decomposing to form nitric oxide; method.

2. 10. The method of claim 1, wherein the thiolactone has a molecular weight of less than 500 Da.

3. The thiolactone is represented by the following formula (III): 【Chemistry 1】 (In the formula, R 6 Each occurrence of is independently hydrogen, hydroxyl, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 2 ~C 6 Alkenyl, substituted or unsubstituted C 2 ~C 6 Heteroalkenyl, substituted or unsubstituted C 1 ~C 6 Alkoxy, or substituted or unsubstituted C 1 ~C 6 When R6 is substituted, the substituents are OH, SH, NH 3 , NO 2 and halogens) 10. The method of claim 1, having a structure according to

4. 10. The method of claim 1, wherein the thiolactone comprises an amine group.

5. 5. The method of claim 4, wherein the thiolactone is N-(2,2-dimethyl-4-oxo-3-thietanyl)-acetamide, N-acetylcysteine ​​thiolactone, N-acetyl-homocysteine ​​thiolactone, homocysteine ​​thiolactone, or butyryl-homocysteine ​​thiolactone.

6. 10. The method of claim 1, wherein the primary amine has a molecular weight of less than 500 Da.

7. 10. The method of claim 1, wherein the primary amine is an amino acid.

8. 2. The method of claim 1, wherein the primary amine is butylamine, cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, or bucillamine.

9. 2. The method of claim 1, wherein the nitrosating compound is an organic nitrite compound or a nitrite salt.

10. 2. The method of claim 1, wherein the nitrosating compound is sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, or pentyl nitrite.

11. The method of claim 1 , wherein the solvent is an aqueous solvent.

12. The method of claim 1 , wherein the solvent comprises a polar alcohol solvent.

13. 10. The method of claim 1, wherein the solvent comprises water and further comprises methanol and / or ethanol.

14. 10. The method of claim 1, wherein the reacting step is carried out in the presence of an acid.

15. The method of claim 1, wherein the reacting step is carried out at ambient temperature and pressure.

16. The method of claim 1 , wherein the step of at least partially removing the solvent removes at least 50% of the solvent.

17. 10. The method of claim 1, wherein the nitric oxide precursor exhibits minimal degradation at 23°C for a period of at least one month.

18. 10. The method of claim 1, further comprising the step of crystallizing the nitric oxide precursor.

19. 10. The method of claim 1, wherein the nitric oxide precursor does not include a polymer having four or more repeating units.

21. 1. A nitric oxide precursor for providing nitric oxide, comprising: thiolactone, primary amines, and Nitrosated compounds and The nitric oxide precursor is capable of decomposing to form nitric oxide; Nitric oxide precursor.

22. 22. The nitric oxide precursor of claim 21, wherein the thiolactone and the primary amine are capable of reacting to form an intermediate, and the intermediate and the nitrosated compound are capable of reacting to form the nitric oxide precursor.

23. 23. The nitric oxide precursor of claim 22, wherein the thiolactone and the primary amine are capable of reacting in the presence of a solvent to form the intermediate.

24. 23. The nitric oxide precursor of claim 22, wherein the thiolactone and the primary amine are capable of reacting at a temperature of from about 1°C to about 25°C.

25. 22. The nitric oxide precursor of claim 21, wherein the nitric oxide precursor comprises a nitrosothiol, the nitrosothiol being capable of decomposing to form nitric oxide.

26. 22. The nitric oxide precursor of claim 21, wherein the nitric oxide precursor exhibits minimal decomposition to nitric oxides for at least 24 hours after forming the nitric oxide precursor.

27. 22. The nitric oxide precursor of claim 21, wherein the thiolactone is an amine-containing thiolactone.

28. 28. The nitric oxide precursor of claim 27, wherein the amine-containing thiolactone comprises thietanone.

29. 22. The nitric oxide precursor of claim 21, wherein the primary amine comprises cysteine ​​or a derivative thereof, lysine or a derivative thereof, butylamine or a derivative thereof, or a combination thereof.

30. 22. The nitric oxide precursor of claim 21, wherein the primary amine contains a thiol functional group.

31. 31. The nitric oxide precursor of claim 30, wherein the primary amine comprises cysteine ​​or a derivative thereof, and the cysteine ​​or a derivative thereof comprises cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bucillamine, or a combination thereof.

32. 22. The nitric oxide precursor of claim 21, wherein the nitrosated compound comprises an organic nitrite compound or a nitrite salt.

33. 33. The nitric oxide precursor of claim 32, wherein the nitrite compound comprises sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, or pentyl nitrite.

34. 22. The nitric oxide precursor of claim 21, wherein the nitric oxide precursor is in a crystalline form, and wherein the crystallized nitric oxide precursor exhibits improved storage stability compared to a corresponding non-crystallized nitric oxide precursor.

35. a carrier, and Nitric oxide precursor according to any one of claims 21 to 34 A composite article comprising: exhibit minimal release of nitric oxide for at least 24 hours after forming the nitric oxide precursor; Composite goods.

36. 35. A method of sterilizing or sanitizing an article, comprising applying to the article a nitric oxide precursor according to any one of claims 21 to 34.

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