Sultone-derived compounds for the generation of nitric oxide and methods of forming the same

Abstract

Nitric oxide precursors for providing nitric oxide are provided. The nitric oxide precursors comprise a reaction product of a thiolactone, a primary amine, and a nitrosating compound. The nitric oxide precursors are capable of decomposing to form nitric oxide.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 427,051, filed November 21, 2022, which is incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to nitric oxide precursors comprising reaction products of thiolactones, primary amines, and nitrosamines. Background Technology

[0004] The background description includes information that can be used to understand the invention. It is not an admission that any information provided herein is prior art or related to the claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0005] All publications and patent applications herein are incorporated by reference to the extent that each individual publication or patent application is specifically and individually indicated to be incorporated herein by reference. If a definition or usage of a term in an incorporated reference is inconsistent with or contrary to the definition of a term provided herein, the definition of that term provided herein shall apply, and the definition of that term in the reference shall not apply.

[0006] Various products and articles, including, for example, medical devices, medical apparatus, and medical equipment, must be sterilized before use to prevent biological contamination from wound sites, samples, organisms, etc. Many sterilization methods are used that involve contacting the product or article with a sterilizing agent. Examples of these sterilizing agents include dinitrogen tetroxide, nitric oxide, steam, ethylene oxide, hydrogen peroxide, dry heat, etc. A common method for forming nitric oxide is through catalytic and enzymatic generation using nitrite / ester or NO donor compounds such as diazenium diolate.

[0007] For example, in one method, as described in WO2023 / 205125, a selected polymer is chemically modified to provide an amount of nitrosothiol groups that can be used in NO-based sterilization processes. In this document, a specific polymer material is modified in a chemical reaction to introduce nitrosothiol side groups into the polymer, which subsequently anchor thiols as reactive groups, the thiols being converted to nitrosothiol groups from which nitric oxide can be released. More specifically, a polycarbonate-polydimethylsiloxane (PCPDMS) block copolymer, polyurethane-polydimethylsiloxane (PUPDMS) block copolymer, polyurethane (PU), poly(ethylene-co-vinyl acetate) copolymer (EVA), or polydimethylsiloxane is first reacted with 3-aminopropyltrimethoxysiloxane to introduce amino side groups. These amino side groups are then reacted with acetylpenicillin aminothiolactone to generate thiol side groups, which are subsequently reacted with tert-butyl nitrite to convert the thiol side groups into the corresponding S-nitrosothiols. Unfortunately, this method is limited to modified polymers with relatively high molecular weights and is also restricted by the specific chemical properties required to generate the modified polymers. Furthermore, this modification requires a relatively complex multi-step process.

[0008] Therefore, this method and other approaches to the formation of nitric oxide from precursors typically require expensive reactants and must be used in a controlled system to allow for the generation of nitric oxide. Furthermore, these nitric oxide precursors have large molecular weights, thus limiting their use in a variety of applications requiring smaller precursors. Unfortunately, most small-molecule nitrosothiols that decompose to form nitric oxide are known to be unstable, especially in solution. These limitations hinder the mainstream commercialization of sterilization or disinfection compositions capable of generating nitric oxide by consumers and professionals. Therefore, there remains a need for improved compositions capable of generating nitric oxide for various medical and consumer purposes. Summary of the Invention

[0009] This document provides nitric oxide precursors for providing nitric oxide. The nitric oxide precursor comprises, is substantially composed of, or is composed of the reaction product of a thiolactone, a primary amine, and a nitrosamine. In various embodiments, the thiolactone reacts with the primary amine to form an intermediate, and the intermediate reacts with the nitrosamine to form the nitric oxide precursor. In these and other embodiments, the thiolactone reacts with the primary amine in the presence of a solvent to form the intermediate. This document envisions the thiolactone reacting with the primary amine at a temperature of about 1°C to about 25°C.

[0010] Nitric oxide precursors are capable of decomposing to form nitric oxide. In various embodiments, the nitric oxide precursor comprises a nitrosothiol capable of decomposing to form nitric oxide. This document envisions that the nitric oxide precursor can decompose to form nitric oxide at a predetermined rate and / or decompose to form nitric oxide for a predetermined duration, based on the formation rate of the nitric oxide precursor produced by the reaction of an intermediate with a nitrososide compound. Furthermore, depending on the specific amine compound used and the storage method of the precursor, the nitric oxide precursor may exhibit minimal decomposition to nitric oxide for at least 5 minutes after its formation. Alternatively, depending on the specific amine compound used and the storage method of the precursor, the nitric oxide precursor may exhibit minimal decomposition to nitric oxide for from 5 minutes to 365 days after its formation. The formation rate of the nitric oxide precursor is tuned to suit various applications requiring such control over the formation of nitric oxide, as described in more detail below.

[0011] Nitric oxide precursors have broad applicability in various medical and consumer applications. The properties of nitric oxide precursors can be tuned based on the selection of primary amines and nitrosamines to suit specific applications. Non-limiting examples of suitable tuning include nitric oxide generation capacity and nitric oxide release rate. As described in more detail below, nitric oxide precursors can be incorporated into various substrates such that nitric oxide is released from the substrate by decomposition of the precursor. In addition to tuning the decomposition of the nitric oxide precursor, nitric oxide release can be tuned based on substrate composition and properties to further control the release of nitric oxide from the substrate. This controlled nitric oxide release is useful for sterilization and disinfection of medical and consumer devices.

[0012] In particular, the physicochemical properties of the nitric oxide precursor can be tuned based on the selection of the primary amine, such as reactivity, hydrophobicity, the number of nitric oxide donors, and the stability of the oxide donors. For example, in embodiments where the thiolactone reacts with a primary amine also containing a thiol group, the resulting intermediate can react with a nitrosyl compound to form a nitric oxide precursor containing two nitrosothiols on a single molecule. These nitric oxide precursors can be used as polymer films / polymer matrices, powder materials such as desiccants (e.g., silica gel or sodium polyacrylate), or in formulations and applications involving solution phases related to sterilizing, disinfecting, and disinfecting washing in a variety of objects and devices.

[0013] Thiolactones can have a structure according to the following formula (I):

[0014]

[0015] Where R 1 R is a bond or a divalent organic group. 2 R is a bond or a divalent organic group. 3It is a hydrogen atom or a monovalent organic group, and R 4 It may be an oxygen atom or a sulfur atom. 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 thiohexacyclic butylamine (e.g., N-(2,2-dimethyl-4-oxo-3-thiohexacyclic butyl)acetamide).

[0016] In various embodiments, the primary amine includes 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, cysteine ​​or a derivative thereof includes cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bexiramamine, or a combination thereof.

[0017] In some embodiments, the nitrosating compound includes nitrites / esters. Nitrites / esters may include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, tert-butyl nitrite, isoamyl nitrite, amyl nitrite, nitrites, ion-pair nitrites, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, or combinations thereof.

[0018] Therefore, it should be understood that the nitric oxide precursor prepared according to the subject matter of the present invention has a relatively small molecular weight. From different perspectives, the nitric oxide precursor will not contain polymers (e.g., having 4, 10, 20, 100, or 1000 repeating units). For example, the molecular weight of the contemplated nitric oxide precursor can be from 100 Da to 500 Da, or 250 Da to 750 Da, or 400 Da to 1000 Da, and is generally less than 5000 Da, less than 2500 Da, or less than 1500 Da. Surprisingly, despite its relatively small molecular weight, the nitric oxide precursor contemplated herein will also have relatively high stability and can therefore be incorporated into a variety of materials to form composite articles. In some embodiments, the nitric oxide precursor will exist in crystalline form, which can be combined with a carrier or a suitable liquid.

[0019] The inventors envision that the nitric oxide precursor can decompose into nitric oxide within a predetermined time period, such as one hour, after the formation of the reaction product. Of course, as mentioned above, after the formation of the nitric oxide precursor, this decomposition into nitric oxide can occur with minimal degradation over a predetermined time period of at least five minutes. In various embodiments, the decomposition of nitric oxide can continue for a predetermined time period, for example, from about one minute to about one year. Without being bound by theory, it is believed that the properties of the nitric oxide precursor can be tuned based on the selection of primary amines and nitrosamines to regulate the decomposition into nitric oxide suitable for a particular application.

[0020] From different perspectives, nitric oxide precursors can be incorporated into or combined with composite articles, such as polymer films and polymer matrices, as well as powder materials. Non-limiting examples of suitable powder materials include desiccants, such as silica gel desiccants or sodium polyacrylate desiccants.

[0021] This document also provides methods for sterilizing or disinfecting articles (e.g., devices or objects). The methods include applying the aforementioned nitric oxide precursor to the article.

[0022] In one aspect of the subject matter of this invention, the inventors have conceived of a method for preparing a nitric oxide precursor, comprising the steps of: conducting a ring-opening reaction of a thiolactone with a primary amine in a solvent to form an intermediate having a thiol group, and reacting the thiol group of the intermediate with a nitrosamine compound in a solvent to thereby form a nitric oxide precursor having a nitrosothiol. In another step, the solvent is at least partially removed. It should be readily understood that the nitric oxide precursor is capable of decomposition to form nitric oxide.

[0023] 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):

[0024]

[0025] Wherein, each occurrence of R6 is independently hydrogen, hydroxyl, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 heteroalkyl, substituted or unsubstituted C2 to C6 alkenyl, substituted or unsubstituted C2 to C6 heteroalkenyl, substituted or unsubstituted C1 to C6 alkoxy or substituted or unsubstituted C1 to C6 heteroalkoxy; and wherein, when R6 is substituted, the substituent is selected from OH, SH, NH3, NO2, acyl, amino and halogen.

[0026] As is expected, thiolactones contain an amino group. Therefore, suitable thiolactones include N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide, N-acetylcysteine ​​thiolactone, N-acetylhomocysteine ​​thiolactone, homocysteine ​​thiolactone, or butyrylhomocysteine ​​thiolactone.

[0027] In other embodiments, the primary amine has a molecular weight of less than 500 Da. Among other alternatives, suitable primary amines include amino acids. For example, envisioned primary amines include butylamine, cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, and buxicamin.

[0028] Regarding nitrosating compounds, it is envisioned that various organic nitrites or nitrites can be used, and in particular, the envisioned nitrosating compounds include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, tert-butyl nitrite, isoamyl nitrite, and amyl nitrite.

[0029] Most typically, but not necessarily, the solvent is an aqueous solvent and / or may contain a polar alcohol solvent. Suitable solvents include, for example, water and methanol and / or ethanol. As shown in more detail below, the reaction can be carried out in the presence of an acid (such as an organic acid), and advantageously, the reaction will be carried out at ambient temperature and ambient pressure. In other envisioned aspects, the solvent can be removed at least partially (e.g., at least 50%), and / or, if desired, the nitric oxide precursor can be crystallized. In some embodiments, the nitric oxide precursor exhibits minimal degradation over a period of at least one month at 23°C. Furthermore, it is generally preferred that the nitric oxide precursor does not contain polymers having four or more repeating units.

[0030] Therefore, from a different perspective, the inventors have also conceived of a nitric oxide precursor for providing nitric oxide, comprising the reaction products of a thiolactone, a primary amine, and a nitrosamine, wherein the nitric oxide precursor is capable of decomposing to form nitric oxide.

[0031] In most embodiments, thiolactones react with primary amines to form an intermediate, which in turn reacts with a nitrosamine to form a nitric oxide precursor. Therefore, thiolactones and primary amines can react in the presence of a solvent to form an intermediate, for example, at a temperature of about 1°C to about 25°C. Most typically, the nitric oxide precursor comprises a nitrosothiol capable of decomposing to form nitric oxide. In some embodiments, after the formation of the nitric oxide precursor, the nitric oxide precursor exhibits minimal decomposition to nitric oxides for at least 24 hours.

[0032] It is also envisioned that the thiolactone is an amine-containing thiolactone (e.g., containing thiohexacyclic methyl ethyl ketone). The envisioned primary amine may be cysteine ​​or a derivative thereof, lysine or a derivative thereof, butylamine or a derivative thereof, or a combination thereof. If desired, the primary amine contains a thiol functional group (e.g., cysteine ​​or a derivative thereof, wherein cysteine ​​or a derivative thereof includes cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, buxicamin or a combination thereof).

[0033] Suitable nitrosating compounds will include organic nitrites or nitrites, such as sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, tert-butyl nitrite, isoamyl nitrite, or amyl nitrite.

[0034] In another envisioned aspect, the nitric oxide precursor is in crystalline form, which typically exhibits improved storage stability compared to the corresponding amorphous nitric oxide precursor.

[0035] In a further aspect of the subject matter of the invention, the inventors have contemplated composite articles comprising a carrier and a nitric oxide precursor as described herein. In some embodiments, the composite article exhibits minimal nitric oxide release for at least 24 hours after the formation of the nitric oxide precursor. Furthermore, the inventors have contemplated methods for sterilizing or disinfecting the article, wherein the nitric oxide precursor described herein is applied to the article.

[0036] Various objects, features, aspects and advantages of the subject matter of the invention will become more apparent from the following detailed description of preferred embodiments and the accompanying drawings, wherein the same numbers denote the same components. Attached Figure Description

[0037] Figure 1 A to Figure 1 D is an image illustrating a non-limiting embodiment of a nitric oxide precursor.

[0038] Figure 2 A to Figure 2 D is an image illustrating a non-limiting embodiment of a nitric oxide precursor.

[0039] Figure 3 A is an image illustrating a non-limiting embodiment of a nitric oxide precursor.

[0040] Figure 3 B and Figure 3 C is a graph showing the release of nitric oxide from a non-limiting embodiment of a composite article containing a nitric oxide precursor.

[0041] Figure 4 A to Figure 4 D is an image illustrating a non-limiting embodiment of a composite article containing a nitric oxide precursor. Detailed Implementation

[0042] The following detailed description is merely illustrative in nature and is not intended to limit the implementation of the subject matter or the application and use of said implementation. Furthermore, it is not intended to be bound by any express or implied theory presented in the prior art, background art, summary of the invention, or the detailed description below.

[0043] This document provides a nitric oxide precursor for providing nitric oxide. The nitric oxide precursor comprises, substantially constitutes, or is composed of, the reaction product of a thiolactone, a primary amine, and a nitrosamine. In various embodiments, the thiolactone reacts with the primary amine to form an intermediate, and the intermediate reacts with the nitrosamine to form the nitric oxide precursor. In these and other embodiments, the thiolactone reacts with the primary amine in the presence of a solvent to form the intermediate. 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 the formation of the intermediate does not require an increased temperature. An exemplary reaction diagram is shown below:

[0044]

[0045] In various implementations, the nitric oxide precursor comprises a nitrosothiol capable of decomposing to form nitric oxide. Nitric oxide is lipid-soluble and possesses the ability to disrupt microbial lipid membranes, regulate cellular and tissue responses, control coagulation and biointegration, and impart antimicrobial properties. Furthermore, nitric oxide can inactivate sulfur proteins, thereby disrupting the functional proteins of microorganisms. It is readily understood that nitric oxide can react with ambient air to form various nitrogen oxides, such as nitrogen dioxide and nitrous oxide. Nitrogen dioxide is more soluble in water than nitric oxide. Moreover, both nitric oxide and nitrogen dioxide are potent DNA disruptors, causing strand breaks and other damage that renders cells unable to function.

[0046] As used herein, the terms “nitric oxide” or “NO” refer to the NO radical. Nitric oxide can react with ambient air to form a variety of nitrogen oxides, including nitrogen dioxide (NO2), nitrogen trioxide (NO3), dinitrogen trioxide (N2O3), dinitrogen tetroxide (N2O4), dinitrogen pentoxide (N2O5), and nitrous oxide (N2O). As used herein, the phrase “nitric oxide precursor” means a compound or composition capable of generating or releasing nitric oxide.

[0047] This paper envisions the widespread use of nitric oxide precursors in various medical and consumer applications. The properties of the nitric oxide precursor can be tuned based on the selection of primary amines and nitrosamines to suit specific applications. Non-limiting examples of appropriate tuning include the ability to generate and release nitric oxide. As described in more detail below, the nitric oxide precursor can be introduced into various substrates such that nitric oxide is released from the substrate by the decomposition of the precursor. In addition to tuning the rate of decomposition of the nitric oxide precursor to form nitric oxide, the release of nitric oxide can be tuned based on substrate composition and properties to further control the release of nitric oxide from the substrate. This controlled nitric oxide release can be used for sterilization and disinfection in medical and consumer devices.

[0048] From different perspectives, the inventors envision utilizing nitric oxide precursors to form nitric oxide for various medical and consumer applications. In several embodiments, articles (e.g., devices or articles) can be treated with nitric oxide precursors, which may be 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 disinfecting or sterilizing objects treated with solutions (e.g., sports equipment such as hockey gloves and cycling gloves, cleaning surgical equipment, the interior of endoscopes, the surface of medical devices, etc.); detergents or cleaning powders for disinfecting or sterilizing objects treated with powders; sanitary containers for disinfecting sanitary devices (e.g., desiccants); and medical devices for disinfecting medical instruments (e.g., stethoscopes, otoscopes, etc.) and medical devices (e.g., portable ultrasound devices, communication devices, etc.). Containers; equipment components (such as washing machines, ship cabins, etc.) used to resist mold growth or mildew in humid environments; sports equipment (such as yoga mats, touch surfaces of strength training equipment, touch surfaces of aerobic exercise equipment, etc.); sports equipment bag liners used for disinfecting sports equipment (such as shoes, hockey equipment, ski equipment, masks, diving goggles, helmets, etc.); food packaging used for preserving food (such as meat, fruits, vegetables, cheese and their ingredients, etc.); vehicle parts used for disinfecting vehicles (such as headliners, seat cushions, carpet linings, etc.); and items used in cabinets, desks, boxes, and drawers to eliminate musty odors.

[0049] The inventors envision that after the formation of the nitric oxide precursor, the nitric oxide precursor can decompose relatively rapidly within a predetermined time period to release nitric oxide, such as 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 prepared to exhibit relatively minimal degradation of nitric oxide for at least 5 minutes, or at least 10 minutes, or at least 15 minutes, or at least 30 minutes, or at least 45 minutes, or at least 1 hour, or at least 2 hours, or at least 3 hours, or at least 4 hours, or at least 5 hours, or at least 6 hours, or at least 7 hours, or at least 8 hours, or at least 9 hours, or at least 10 hours, or at least 11 hours, or at least 12 hours, or at least 13 hours, or at least 14 hours, or at least 15 hours, or at least 16 hours, or at least 17 hours, or at least 18 hours, or at least 19 hours, or at least 20 hours, or at least 21 hours, or at least 22 hours, or at least 23 hours, or at least 24 hours, or at least 48 hours, or at least 365 days after its formation, depending on the specific amine compound used and the precursor storage method.

[0050] Therefore, the nitric oxide precursors envisioned herein can exhibit minimal decomposition into nitric oxide for a period of 5 minutes to 365 days, or 5 minutes to 48 hours, or 5 minutes to 24 hours, or 1 hour to 24 hours, or 4 hours to 24 hours, or 8 hours to 24 hours, or 16 hours to 24 hours, or 20 hours to 24 hours after their formation, depending on the specific amine compound used and the storage method of the precursor. In several embodiments, the decomposition of the nitric oxide precursor to form nitric oxide can sustain for a predetermined amount of time, such as about 1 minute to about 1 year, or about 1 hour to about 6 months, or about 24 hours to about 3 months, or about 1 week to about 8 weeks. Thus, from different perspectives, the decomposition to form nitric oxide can sustain for 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. Unbound by theory, it is believed that the properties of nitric oxide precursors can be tuned based on the selection of primary amines and nitrosamines to regulate their decomposition into nitric oxide for specific applications.

[0051] In a particularly envisioned aspect, the nitric oxide precursor will exhibit the desired 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, or at least 2 months, or at least 3 months, or at least 6 months, or 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, or at least 2 months, or at least 3 months, or at least 6 months, or at least 12 months. The phrase "minimal degradation" refers to the nitric oxide precursor exhibiting a very small color difference within the desired time period, conforming to ASTM D2244-21, of 10%, 5%, 4%, 3%, 2%, 1%, or 0.1% of ΔE*ab.

[0052] The inventors also envision suitable nitric oxide precursors being mixed into polymers, solution phases, or powders and used to generate nitric oxide, to generate a wide variety of NO donors / generating entities by incorporating the nitric oxide precursor into a support (polymer or powder or embedded in and / or on a solid support), or to generate solutions from a support / solution phase in a controlled and predictable manner. This document describes methods for synthesizing novel small-molecule NO donors that can be used for this purpose and for formulations and applications of these NO-generating moieties, which can be used for sterilizing, disinfecting, and disinfecting a wide variety of objects and in many different situations.

[0053] Furthermore, it should be understood that the nitric oxide precursors described herein and their use in polymers, powders, on solid supports, or as solutions allow for simple synthesis, controlled formation and release of NO, with or without acid (in polar or nonpolar phases). In fact, the nitric oxide precursors can form under ambient conditions and remain stable over time. Moreover, the nitric oxide precursors can crystallize, undergo polymer casting processes, be mixed into or combined with a variety of different supports, and can be formed in organic, aqueous, or a combination of organic and aqueous phases.

[0054] In exemplary embodiments, this document envisions reacting self-protected thiolactones (e.g., formed from N-acetylopine, etc.) with discrete 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 potential for higher NO compound loading to produce tunable nitric oxide precursors. For example, if a thiolactone reacts with a primary amine containing a thiol group, the resulting nitric oxide precursor can have two nitrosothiol groups on a single molecule. Combinations of various primary amines containing thiol groups provide a variety of nitric oxide precursors exhibiting tunable release properties. These nitric oxide precursors can be used as additives to polymer films / polymer matrices, powder materials such as desiccants (silica gel or sodium polyacrylate), or in solution phases.

[0055] Nitric oxide precursors, such as small-molecule nitrosothiols, formed from thiolactones, primary amines, and nitroso compounds, can be formed in both organic and aqueous phases. Solutions containing detergents (such as enzymes, surfactants, etc.) can be combined with nitric oxide precursors. These precursors can then rapidly decompose to generate nitric oxide. Combinations of these nitric oxide precursors with several carriers, desiccants, and detergents (such as silica gel, sodium polyacrylate, Alconox soap, proteases, etc.) such as powder or solution components can be used for the reprocessing of products such as endoscopes and probes, as well as for the sterilization of other objects.

[0056] Regarding suitable thiolactones, it should be understood that a variety of suitable thiolactones may be used herein, depending on the design constraints of the desired application of the nitric oxide precursor. In some embodiments, the thiolactone may have a structure according to the following formula (I):

[0057]

[0058] Where R 1 R is a bond or a divalent organic group. 2 It is a bond or a divalent organic group, and R 0 and R 3 R is either a hydrogen atom or a monovalent organic group. 4 It can be an oxygen atom or a sulfur atom. Non-limiting examples of suitable thiolactone groups include α-acetylthiolactone, β-propionylthiolactone, γ-butyrylthiolactone, δ-valerylthiolactone, ε-hexanoylthiolactone, ζ-heptanoylthiolactone, η-octanoylthiolactone, and θ-nonanoylthiolactone.

[0059] For example, a hypolactone could be conceived to have a structure according to formula (II):

[0060]

[0061] Where R 5 C1 to C2, whether substituted or unsubstituted 12 alkyl.

[0062] In another example, the envisioned thiolactone could have a structure according to the following formula (III):

[0063]

[0064] Among them, R 6 Each time it appears independently of hydrogen, hydroxyl, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 heteroalkyl, substituted or unsubstituted C2 to C6 alkenyl, substituted or unsubstituted C2 to C6 heteroalkenyl, substituted or unsubstituted C1 to C6 alkoxy, or substituted or unsubstituted C1 to C6 heteroalkoxy.

[0065] In another example, the contemplated thiolactone could have a structure according to the following formula (III):

[0066]

[0067] Among them, R 7 It is a group containing an ethylene unsaturated bond, a polymerizable double bond, and R 8 Selected from H, C1 to C6 alkyl, and C1 to C6 acyl. Alternatively, in formula (IV), R 7 and R 8 Together they form a group containing ethylene unsaturated bonds and polymerizable double bonds.

[0068] It is also envisioned that the thiolactone can be an amine-containing thiolactone. Non-limiting examples of suitable amine-containing thiolactones include thiohexacyclobutanes (e.g., N-(2,2-dimethyl-4-oxo-3-thiohexacyclobutyl)acetamide), N-acetylcysteine ​​thiolactone, N-acetylhomocysteine ​​thiolactone, homocysteine ​​thiolactone butyrylhomocysteine ​​thiolactone, or combinations thereof. In one exemplary embodiment, the amine-containing thiolactone comprises N-(2,2-dimethyl-4-oxo-3-thiohexacyclobutyl)acetamide. In most embodiments, the envisioned thiolactone will have a molecular weight of less than 1000 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 less than 300 Da. For example, suitable thiolactones can have a molecular weight of 150 Da to 300 Da, or 250 Da to 400 Da, or 350 Da to 600 Da, or 500 Da to 750 Da, or 700 Da to 1000 Da.

[0069] Returning to the primary amines used to form intermediates, a variety of possible primary amines can be used depending on the design constraints of the desired application of the nitric oxide precursor. Primary amines may include cysteine ​​or derivatives thereof, lysine or derivatives thereof, butylamine or derivatives thereof, or combinations thereof. In embodiments using cysteine ​​or derivatives thereof, cysteine ​​or derivatives thereof may include cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bexilamine, or combinations thereof. Suitable, non-limiting examples of 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 in Langmuir 2006, 22, 25, 10830-10836, which is incorporated herein by reference in its entirety. In most embodiments, the envisioned primary amine will have a molecular weight of less than 1200 Da, or less than 1000 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 of 120 Da to 300 Da, or 250 Da to 400 Da, or 350 Da to 600 Da, or 500 Da to 750 Da, or 700 Da to 1000 Da.

[0070] Returning to the mention of nitrosating compounds used to form nitric oxide precursors, these compounds can be any compound serving as the source of the nitrosyl group, and are typically compounds of the formula NOX, where X is an organic or inorganic anion or the group OR2, where R2 is an organic group. X can be an organic anion derived from a carboxylic acid, such as an alkane carboxylic acid containing 2 to 7 carbon atoms; this type of nitrosating agent includes acetyl nitrite / salts and propionyl nitrite / salts. When X is an inorganic anion, it can be derived from, for example, a halide ion or sulfate ion from an inorganic acid such as chloride or bromide, or from a Lewis acid such as fluoroborate. Other inorganic anions include hydroxides and sulfonates. Therefore, such nitrosating compounds include nitrosyl chlorides, nitrosyl sulfates, nitrosyl fluoroborates, nitrites, and fluorosulfonates (potassium nitrosyl disulfonate). When X is a group of the formula OR2, the organic group R2 can be, for example, a lower alkyl group, such as a lower alkyl group containing 1 to 9 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or isopentyl.

[0071] In some embodiments, the nitrosating compound includes nitrites / esters. Nitrites / esters may include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, tert-butyl nitrite, isoamyl nitrite, amyl nitrite, nitrites, ion-pair nitrites, silver nitrite, zinc nitrite, ferric nitrite, copper nitrite, transition metal-nitrite compounds, or combinations thereof. Furthermore, nitric oxide gas may be used as a nitrosating agent.

[0072] In various embodiments, the weight-average molecular weight of the nitrosating compound is no greater than 10,000 g / mol, or no greater than 1,000 g / mol, or no greater than 500 g / mol, or no greater than 250 g / mol. From different perspectives, the weight-average molecular weight of the nitrosating compound can be about 10 g / mol to about 10,000 g / mol, or about 10 g / mol to about 1,000 g / mol, or about 10 g / mol to about 500 g / mol, or about 10 g / mol to about 250 g / mol. For example, the weight-average molecular weight of NaNO2 is 69 g / mol, and the weight-average molecular weight of butyl nitrite is 103 g / mol. Without being bound by theory, it can be considered that using nitrosating compounds with lower weight-average molecular weights can improve the reaction kinetics for forming the reaction products.

[0073] Therefore, it should be understood that the resulting nitric oxide precursor will have a relatively small molecular weight and is therefore preferably free of polymers having four or more repeating units. Thus, in some embodiments, the nitric oxide precursor will not have heteropolymers or homopolymers as components. On the other hand, where the primary amine contains a polypeptide, it is generally preferred that the polypeptide has fewer than ten amino acids, or fewer than eight amino acids, or fewer than six amino acids, or fewer than four amino acids.

[0074] As described above, it is generally preferred that the thiolactone reacts with the primary amine in the presence of a solvent to form an intermediate, and the intermediate reacts with the nitrosamine compound to form a nitric oxide precursor. If a solvent is used, the solvent may contain varying amounts of solvent. The solvent may be aqueous, organic, inorganic, or a combination thereof. In some embodiments, the solvent is an aqueous solvent, such as water or a mixture of water and methanol. In other embodiments, the solvent may contain 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 compounds, aliphatic compounds, ketones such as methyl ethyl ketone, isobutyl ketone, ethylpentyl ketone, acetone, alcohols such as methanol, ethanol, n-butanol, isopropanol, esters such as ethyl acetate, glycols such as ethylene glycol, propylene glycol, ethers such as tetrahydrofuran, diethylene glycol monobutyl ether, or combinations thereof. In another envisioned aspect, where the solvent is a mixture of an organic solvent and water, the solvent will have a relatively low water content, for example, equal to or less than 25% by volume, or equal to or less than 20% by volume, or equal to or less than 15% by volume, or equal to or less than 10% by volume, or equal to or less than 5% by volume, or equal to or less than 2.5% by volume.

[0075] The components used to form the nitric oxide precursor may be combined in the reaction mixture. It should be understood that the components of the reaction mixture have not yet reacted with each other. Based on the total weight of the reaction mixture, the reaction mixture used to form the reaction product may contain about 1% to about 80% by weight, or about 1% to about 7% by weight, or about 50% to about 80% by weight of a thiolactone. Based on the total weight of the reaction mixture, the reaction mixture used to form the reaction product may contain about 1% to about 80% by weight, or about 1% to about 7% by weight, or about 50% to about 80% by weight of a primary amine. Based on the total weight of the reaction mixture, the reaction mixture used to form the reaction product may contain about 1% to about 75% by weight, or about 1% to about 10% by weight, or about 10% to about 75% by weight of a nitrosating compound. When used, based on the total weight of the reaction mixture, the reaction mixture used to form the reaction product may contain about 1% by weight to about 99% by weight of a solvent.

[0076] In various embodiments, the thiolactone and the primary amine react in the presence of an acid. The acid can be used to improve the formation and / or stability of the reaction product, for example, when using a primary amine containing an amino acid such as cysteine. In some embodiments, the acid may comprise hydrochloric acid. Other non-limiting examples of suitable acids include citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, acetic acid, glycolic 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, octyl phosphate, acrylic acid, polyacrylic acid, aspartic acid, polyaspartic acid, p-hydroxybenzoic acid, iminoacetic acid, or combinations thereof. It should be understood that the acid may be included as part of any component of the composition (such as a carrier, solvent, etc.) or as part of the reactants of the reaction products.

[0077] In other embodiments, the reaction products are formed under substantially acid-free conditions. The inventors envision that the reaction products are substantially acid-free. As used herein, the phrase "substantially acid-free" means completely free of acid, or in extremely small amounts, existing only as an impurity, a non-intended byproduct of another component, or in an amount whose effect on the composition or nitric oxide precursor is negligible. In some embodiments, "substantially acid-free" means that, based on the total weight of the reaction products, the amount of acid present in the reaction products is less than 0.5% by weight, less than 0.25% by weight, less than 0.1% by weight, less than 0.05% by weight, or less than 0.01% by weight, or even 0% by weight.

[0078] In some embodiments, the reaction mixture for forming the nitric oxide precursor may include, in addition to thiolactone and a primary amine containing a thiol group, a thiol-containing compound. When used, a variety of thiol-containing compounds may be used depending on the design constraints of the desired application of the nitric oxide precursor. Thiol-containing compounds may include, but are not limited to, one or more of 1,2-ethanedithiol, 2,3-dimercaptopropanol, pyridinethione, 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 α-lipoic acid, methanethiol (CH3SH [m-thiol]), ethanethiol (C2H5SH [e-thiol]), 1-propanethiol (C3H7SH [n-propylthiol]), 2-propanethiol (CH3CH(SH)CH3 [2C3 thiol]), butylthiol (C4H9SH [n-butylthiol]), tert-butylthiol (C(CH3)3SH [tert-butylthiol]), pentylenetetrazol (C5H11SH [pentylthiol]), coenzyme A, lipoamide, glutathione, cysteine, cystine, 2-mercaptoethanol, and diethylcarboxylic acid. Thiostretol, 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-ethylenedithiol, 1,3-propanedithiol, 1,4-phenylenediol, 1,4-butanedithiol, 1,4-butanedithiol diacetate, 1,5-pentanedithiol, 1,6-hexanediol Dithiols, 1,8-octadithiol, 1,9-nonanedithiol, adamantanethiol, 1-butanethiol, 1-decanethiol, 1-dodecanethiol, 1-heptanethiol, 1-heptanethiol pumum, 1-hexadecanethiol, 1-hexanethiol, 1-mercapto-(triethylene glycol), 1-mercapto-(triethylene glycol) methyl ether functionalized gold nanoparticles, 1-mercapto-2-propanol, 1-nonanethiol, 1-octadecanethiol, 1-octanethiol, 1-pentadecanthiol, 1-pentanethiol, 1-propanethiol, 1-tetradecanethiol pumum, 1-undecanethiol Alcohols, 11-(1H-pyrrolo-1-yl)undecane-1-thiol, 11-amino-1-undecanethiol hydrochloride, 11-bromo-1-undecanethiol, 11-mercapto-1-undecaneol, 11-mercapto-1-undecaneol, 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-perfluorodecylthiol, 2,2′-(ethylenedioxy)diethylthiol, 2,3-butanedithiol, 2-butanethiol, 2-ethylhexylthiol, 2-methyl-1-propanethiol, 2-methyl-2-propanethiol, 2-phenylethanethiol, 3,3,4,4,5,5,6,6,6-nonafluoro-1-hexanethiol purulent, 3-(dimethoxymethylsilyl)-1-propanethiol, 3-chloro-1-propanethiol, 3-mercapto-1-propanol, 3-mercapto-2-butanol 3-Mercapto-N-nonylpropionamide, 3-mercaptopropionic acid, 3-mercaptopropyl-functionalized silica gel, 3-methyl-1-butanethiol, 4,4′-bis(mercapto-methyl)biphenyl, 4,4′-dimercaptostilbene, 4-(6-mercaptohexoxy)benzyl alcohol, 4-cyano-1-butanethiol, 4-mercapto-1-butanol, 6-(ferrocene)hexamethylenethiol, 6-mercapto-1-hexanol, 6-mercaptohexanoic acid, 8-mercapto-1-octanoic acid Alcohols, 8-mercaptooctanoic acid, 9-mercapto-1-nonanol, biphenyl-4,4′-dithiol, butyl 3-mercaptopropionate, copper 1-butanethiol (I), cyclohexanethiol, cyclopentanethiol, decanethiol-functionalized silver nanoparticles, dodecanethiol-functionalized gold nanoparticles, dodecanethiol-functionalized silver nanoparticles, hexa(ethylene glycol)mono-11-(acetylthio)undecyl ether, mercaptosuccinic acid, methyl 3-mercaptopropionate, octylthiol-functionalized The composition includes gold nanoparticles, PEG dithiol, S-(11-bromoundecyl)thioacetate, S-(4-cyanobutyl)thioacetate, thiophenol, triethylene glycol mono-11-mercaptoundecyl ether, trimethylolpropane tris(3-mercaptopropionate), [11-(methylcarbonylthio)undecyl]tetra(ethylene glycol), m-carborane-9-thiol, p-terphenyl-4,4″-dithiol, tert-dodecylthiol, or tert-nonylthiol.

[0079] In some embodiments, when used, the thiol-containing compound includes a thiol-derived polymer or filler. It should be understood that the thiol-containing compound can be included as part of a peptide or other macromolecule, provided that the thiol-containing compound is compatible with the components of the reaction mixture of the reaction products.

[0080] In various embodiments, when used, the weight-average molecular weight of the thiol-containing compound is not greater than 500,000 g / mol, or not greater than 100,000 g / mol, or not greater than 10,000 g / mol, or not greater than 1,000 g / mol, or not greater than 500 g / mol. From different perspectives, the weight-average molecular weight of the thiol-containing compound can be from about 10 g / mol to about 500,000 g / mol, or from about 10 g / mol to about 100,000 g / mol, or from about 10 g / mol to about 1,000 g / mol, or from about 10 g / mol to about 500 g / mol.

[0081] In some embodiments, the nitric oxide precursor is in crystalline form. Therefore, and from different perspectives, the inventors envision that crystallization can pull the compound out of solution and thus eliminate ions that could lead to decomposition. In contrast to crystallization, particulate nitric oxide precursors can exhibit more impurities than crystalline nitric oxide precursors due to contaminant trapping. In various embodiments, crystallization includes a step of removing the solvent 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%) after the formation of the nitric oxide precursor. Crystallization can be carried out by nucleation, supersaturation, and / or cooling. Methods of crystallization are well known to those skilled in the art and are described in textbooks such as A. Mersmann, Crystallization Technology Handbook (2001) CRC; 2nd ed. ISBN 0-8247-0528-9, which is incorporated herein by reference in its entirety.

[0082] In this context, it should be understood that crystalline nitric oxide precursors can exhibit improved storage stability compared to amorphous nitric oxide precursors. In various embodiments, the crystalline nitric oxide precursor exhibits minimal degradation at 4°C for at least 1 month, or at least 2 months, or at least 3 months, or at least 6 months, or at least 12 months. In other embodiments, the crystalline nitric oxide precursor exhibits minimal degradation at 23°C for at least 1 month, or at least 2 months, or at least 3 months, or at least 6 months, or at least 12 months. The phrase "minimal degradation" means that the total weight reduction of the crystalline nitric oxide precursor over the desired period is not greater than 10% by weight, or not greater than 5% by weight, or not greater than 4% by weight, or not greater than 3% by weight, or not greater than 2% by weight, or not greater than 1% by weight, or not greater than 0.1% by weight.

[0083] As described above, this document also envisions composite articles. The composite article comprises a carrier and a nitric oxide precursor. In some embodiments, after the formation of the nitric oxide precursor, the composite article exhibits minimal nitric oxide release over a period of at least 24 minutes. In various embodiments, after the formation of the nitric oxide precursor, the composite article exhibits minimal nitric oxide release for at least 10 minutes, or at least 15 minutes, or at least 30 minutes, or at least 45 minutes, or at least 1 hour, or at least 2 hours, or at least 3 hours, or at least 4 hours, or at least 5 hours, or at least 6 hours, or at least 7 hours, or at least 8 hours, or at least 9 hours, or at least 10 hours, or at least 11 hours, or at least 12 hours, or at least 13 hours, or at least 14 hours, or at least 15 hours, or at least 16 hours, or at least 17 hours, or at least 18 hours, or at least 19 hours, or at least 20 hours, or at least 21 hours, or at least 22 hours, or at least 23 hours, or at least 24 hours, or at least 48 hours, at least seven days, at least four weeks, at least 26 weeks, or at least 365 days, depending on the specific amine compound used and the precursor storage method. The carrier may comprise silica gel, sodium polyacrylate, or a combination thereof. However, it should be understood that any other carrier may be used. Other suitable carriers, in their entirety, include filter paper, polyacrylates, polyvinyl chloride, polydimethylsiloxane, polyurethane, and combinations thereof. These 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 are incorporated herein by reference.

[0084] Based on the total weight of the composite article, the composite article may contain amounts of about 0.5 wt% to about 10 wt%, about 10 wt% to about 25 wt%, about 25 wt% to about 50 wt%, about 50 wt% to about 70 wt%, or about 70 wt% to about 90 wt%, for example, about 5 wt% to about 25 wt% of a nitric oxide precursor. Based on the total weight of the composite article, the composite article may contain amounts of about 5 wt% to about 95 wt%, or about 10 wt% to about 80 wt%, or about 80 wt% to about 95 wt% of a carrier.

[0085] In exemplary embodiments, the nitric oxide precursor is included in the detergent composition or cleaning composition. As used herein, the phrase "detergent composition" or "cleaning composition" encompasses compositions and formulations designed for cleaning soiled materials. These compositions include, but are not limited to, object cleaning compositions, medical device cleaning compositions, hard surface cleaning compositions, dishwashing compositions, laundry cleaning compositions and detergents, spray products, dry cleaning agents or compositions, unit-dose formulations, delayed-release formulations, detergents contained on or in porous substrates or nonwoven fabrics, detergents contained on or in water-soluble membranes, and other suitable forms, which will be apparent to those skilled in the art in light of the guidance herein. Multicomponent compositions may be in the form of liquids, powders, single-phase unit doses or multi-phase unit doses, two-layer paper carriers, bags, tablets, gels, pastes, strips, or sheets.

[0086] In these and other embodiments, the detergent composition or cleaning composition further comprises a cleaning agent. The cleaning agent includes detergents, enzymes, or combinations thereof. Non-limiting examples of suitable cleaning agents include Alconox powder. In embodiments where the cleaning agent includes detergents, the detergent may include surfactants such as amine oxides, alkylbenzene sulfonates, alkyl ether sulfates, fatty alcohol ethoxylates, alkyl glycosides, alkoxylated fatty acid alkyl esters, amine oxides, fatty acid alkanolamides, mixed hydroxy ethers, sorbitan fatty acid esters, polyhydroxy fatty acid amides, and alkoxylated alcohols.

[0087] In embodiments where the detergent includes an enzyme, the enzyme may include one or more enzymes that can exhibit catalytic activity in the detergent, such as proteases, amylases, lipases, cellulases, hemicellulases, mannanases, pectin lyases, tanninases, xylanases, xanthan gumases, β-glucosidases, carrageenases, hydrolases, oxidases, oxidoreductases, and mixtures thereof. In some embodiments, the enzyme includes proteases, amylases (e.g., α-amylases), cellulases, lipases, hemicellulases, pectinases, mannanases, β-glucanases, or combinations thereof. The properties of the enzyme should be compatible with the multi-component composition (i.e., optimal pH, compatibility with other enzymatic and non-enzymatic components, etc.). If an enzyme is used, it should be present in an effective amount.

[0088] When proteases are used, they can be of animal, plant, or microbial origin, including chemically modified or genetically modified mutants. Microbial origin is preferred. Proteases can be alkaline proteases, such as serine proteases or metalloproteinases. For example, serine proteases can be from the Si family, such as trypsin, or the S8 family, such as subtilisin. For example, metalloproteinases can be thermophilic bacterial proteases from, for example, the M4, M5, M7, or M8 families.

[0089] When using suitable lipases and keratins, the lipases and keratins include those of bacterial or fungal origin. The lipases and keratins include chemically modified or protein-engineered mutants. Examples include lipases from thermomyces, such as *T. lanuginosus* (formerly known as *Humicola lanuginosa*) described in EP 258068 and EP 305216; keratinases from *Humicola*, such as *H. insolens* described in WO 96 / 13580; and lipases from *Pseudomonas*, such as those from *P. alcaligenes* or *P. pseudoalcaligenes* (EP 218272), *P. cepacia* (EP 331376), *P. stutzeri* (GB 1372034), *P. fluorescens*, and *P. SD* species. Strain 705 (WO 95 / 06720 and WO 96 / 27002), *Pseudomonas wisconsinensis* (WO 96 / 12012), Bacillus lipases, such as those from *Bacillus subtilis* (Dartois et al., 1993, Biochemica et Biophysica Acta, 1131:253-360), *Bacillus stearothermophilus* (JP 64 / 744992), or *Bacillus pumilus* (WO 91 / 16422).

[0090] Other examples are lipase variants, as described in WO 92 / 05249, WO 94 / 01541, EP 407225, EP 260105, 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, WO 2007 / 087508 and WO 2009 / 109500, which are incorporated herein by reference in their entirety.

[0091] When using a suitable amylase, the amylase includes amylases of bacterial or fungal origin. The amylase includes chemically modified or protein-engineered mutants. Amylases include, for example, α-amylases obtained from Bacillus species, such as specific strains of *Bacillus licheniformis*, which are described in more 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, which are incorporated herein by reference in their entirety.

[0092] When a suitable cellulase is used, the cellulase includes cellulases of bacterial or fungal origin. The amylase includes chemically modified or protein-engineered mutants. Suitable cellulases include those derived from the genera *Bacillus*, *Pseudomonas*, *Pyrophyllus*, *Fusarium*, *Thielavia*, and *Acremonium*, such as fungal cellulases from *Pyrophyllus spp.*, *Myceliophthorathermophila*, and *Fusarium oxysporum*, disclosed in U.S. Patent Nos. 4,435,307, 5,648,263, 5,691,178, 5,776,757, and WO 89 / 09259, all of which are incorporated herein by reference in their entirety.

[0093] When a suitable peroxidase / oxidase is used, it includes peroxidases / oxidases of plant, bacterial, or fungal origin. The amylase includes chemically modified or protein-engineered mutants. Examples of useful peroxidases include peroxidases and variants from the genus *Coprinus*, such as those from *C. cinereus*, as described in WO 93 / 24618, WO 95 / 10602, and WO 98 / 15257, which are incorporated herein by reference in their entirety.

[0094] Detergent compositions or cleaning compositions may also contain additives such as builders, bleaching agents, electrolytes, non-aqueous solvents, pH adjusters, fragrances, fragrance carriers, fluorescent agents, dyes, water-soluble auxiliaries, foam inhibitors, silicone oils, anti-redeposition agents, ashing inhibitors, anti-shrinkage agents, anti-wrinkle agents, dye transfer inhibitors, antimicrobial substances, bactericides, fungicides, antioxidants, preservatives, corrosion inhibitors, antistatic agents, bittering agents, ironing auxiliaries, hydrophobic agents and impregnating agents, swelling agents and antislip agents, softening components and ultraviolet absorbers.

[0095] Based on the total weight of the composition, the detergent composition or cleaning composition may contain about 0.01 wt% to about 40 wt%, or about 0.01 wt% to about 5 wt%, or about 5 wt% to about 10 wt%, or about 10 wt% to about 40 wt% of a nitric oxide precursor. Based on the total weight of the composition, the detergent composition or cleaning composition may contain about 1 wt% to about 99 wt% of a cleaning agent. Based on the total weight of the composition, the detergent composition or cleaning composition may contain about 1 wt% to about 99 wt% of a solvent.

[0096] In various embodiments, the detergent or cleaning compositions described herein may be incorporated into a water-soluble envelope, thereby becoming part of a water-soluble package. The water-soluble envelope may be formed from a water-soluble film material. Such a water-soluble package may be prepared by a vertically molded fill-seal (VFFS) method or by a thermoforming method.

[0097] The coating may be made of one, two, or more layers of water-soluble membrane material. If other layers are present, the water-soluble membrane material of the first layer may be the same as or different from the water-soluble membrane materials of the other layers. For example, the water-soluble coating material may be made of a water-soluble membrane material selected from polymers or mixtures of polymers. The water-soluble coating may contain polyvinyl alcohol or polyvinyl alcohol copolymers. The polymer is selected from acrylic acid-containing polymers, polyacrylamide, oxazoline polymers, polystyrene sulfonates, polyurethanes, polyesters, polyethers, polylactic acid, and / or mixtures of the above polymers, which may be added to the membrane material suitable for preparing the water-soluble coating.

[0098] Thermoforming methods typically include the following steps: forming a first layer from a water-soluble film material to form a protrusion for receiving a composition therein; filling the protrusion with the composition; covering the protrusion filled with the composition with a second layer of water-soluble film material; and sealing the first and second layers together at least around the protrusion. Water-soluble packages containing liquid washes and water-soluble films may have one or more chambers. Water-soluble packages may have substantially dimensionally stable spherical and pillow-shaped configurations, having a basic shape of circular, elliptical, square, or rectangular. The chambers may be isolated from each other.

[0099] This article also provides a method for sterilizing or disinfecting articles. The method includes applying the above-mentioned nitric oxide precursor to the articles.

[0100] This document provides a method for forming a nitric oxide precursor. The method includes combining a thiolactone with 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 method may include allowing the intermediate to stand for a period of 1 minute to 24 hours, or 1 minute to 6 hours, or 10 minutes to 4 hours, or 30 minutes to 150 minutes. The method also includes combining the intermediate with a nitrosamine compound to form the nitric oxide precursor. In various embodiments, the combination and standing steps are carried out at a temperature of about 1°C to about 25°C.

[0101] In an exemplary embodiment, a thiolactone is reacted with a primary amine such as cysteine, penicillamine, glutathione, leucine, isoleucine, or lysine to form an intermediate in a ring-opening reaction, thereby generating a (typically secondary or tertiary) thiol group. A range of properties can be produced by adjusting physicochemical properties such as reactivity, hydrophobicity, the amount of NO donor, and the stability of the NO donor. This allows for precise tuning of the NO loading, NO release, partition coefficient, etc., of the donor when incorporated into polymer matrices, powders, and solutions. To carry out this reaction, the thiolactone is dissolved in a solvent with a primary amine compound and allowed to react. This reaction opens the thiolactone ring, forms an amide bond with the primary amine, and exposes one or more thiol groups in the thiolactone. One or more thiol groups in the intermediate are subsequently converted to nitrosothiols by reacting the intermediate with a nitrosating agent such as sodium nitrite or tert-butyl nitrite to form a nitric oxide precursor.

[0102] The resulting nitric oxide precursors can appear green or red, depending on the molecular structure of the primary amine and the substituents surrounding the thiol used. Advantageously, these nitric oxide precursors can crystallize out of solution or be used in solutions with different matrices and / or supports (e.g., filter paper, polyacrylate, PVC, PDMS, PU, ​​silica powder, sodium polyacrylate, etc.). It should also be understood that the reaction conditions described above for forming nitric oxide precursors are mild compared to conventional reaction products and methods for forming nitric oxide precursors. Notably, the use of ring-opening reaction and subsequent nitrosation allows the reaction to proceed at ambient temperature (e.g., 15°C to 25°C), ambient pressure (e.g., 950 mbar to 1060 mbar), and ambient humidity (e.g., 15% to 90% relative humidity), and can be carried out without the protection of ambient light.

[0103] Example

[0104] The following examples are included to illustrate several embodiments contemplated herein. Those skilled in the art will understand that the techniques disclosed in the following examples represent techniques discovered by one or more inventors that work well in carrying out the invention, and are therefore considered to constitute an ideal mode for carrying out the invention. However, based on this disclosure, those skilled in the art will understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention, and still obtain the same or similar results. Unless otherwise stated, all percentages are in weight percent, and all measurements were performed at 23°C.

[0105] Example 1A: SNAP-cysteine

[0106] 29.8 mg of cysteine ​​(primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in an aqueous solvent solution of 1 mL water, 4 mL methanol, and 100 μL 1 M HCl to form an intermediate in solution. After standing for 1 hour, 50 mg of NaNO2 (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0107] Example 1B: SNAP-Leucine

[0108] 31.4 mg of leucine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thienobutyl)acetamide (thiolactone) were mixed in an aqueous solvent solution of 1 mL water, 4 mL methanol, and 100 μL 1 M HCl to form an intermediate solution. After standing for 1 hour, 50 mg of NaNO2 (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0109] Example 1C: SNAP-Penicillamine

[0110] 36 mg of penicillamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in an aqueous solvent solution of 1 mL water, 4 mL methanol, and 100 μL 1 M HCl to form an intermediate solution. After standing for 1 hour, 50 mg of NaNO2 (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0111] Example 1D: SNAP-Lysine

[0112] 23 mg of lysine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in an aqueous solvent solution of 200 μL water, 1.8 mL methanol, and 100 μL 1 M HCl to form an intermediate solution. After standing for 1 hour, 50 mg of NaNO2 (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0113] Example 1E: SNAP-acetyllysine

[0114] 29 mg of acetyllysine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in an aqueous solvent solution of 200 μL water, 1.8 mL methanol, and 100 μL 1 M HCl to form an intermediate solution. After standing for 1 hour, 50 mg of NaNO2 (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0115] Examples 1A to 1E: Observations

[0116] One hour later, the solution turned into dark red / dark green, green, darker green, dark red / dark green, and dark red / dark green – just as envisioned for the formation of SNAP and NOCys (green RSNO and red RSNO), SNAP only (1 green RSNO), SNAP and nitrosopyridine (2 green RSNO), SNAP only (1 green RSNO), and SNAP only (1 green RSNO).

[0117] The inventors obtained a highly concentrated solution of the same color after evaporating methanol, indicating high stability. The color remained after 24 hours, further demonstrating high stability. An exemplary sample of the reaction product is shown below. Figure 1 A to Figure 1 As shown in D.

[0118] Example 2A: SNAP-cysteine

[0119] 28 mg of cysteine ​​(primary amine) and 40.8 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 5 mL of methanol to form an intermediate solution. After standing for 2 hours, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0120] Example 2B: SNAP-Leucine

[0121] 33 mg of leucine (primary amine) and 40.8 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 5 mL of methanol to form an intermediate solution. After standing for 2 hours, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0122] Example 2C: SNAP-Penicillamine

[0123] 34.5 mg of penicillamine (primary amine) and 40.8 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 5 mL of methanol to form an intermediate solution. After standing for 2 hours, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0124] Example 2D: SNAP-Glutathione

[0125] 76.6 mg of glutathione (primary amine) and 40.8 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 5 mL of methanol to form an intermediate solution. After standing for 2 hours, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor.

[0126] Examples 2A to 2D: Observation Results

[0127] One hour later, the solution turned into deep red / deep green, green, darker green, red / green – just as envisioned for the formation of SNAP and NOCys (1 green RSNO and 1 red, SNAP only (1 green RSNO), SNAP and nitrosopyridine (2 green RSNO), SNAP-GSNO (1 green RSNO and 1 red RSNO).

[0128] The inventors obtained a highly concentrated solution of the same color after evaporating methanol, indicating high stability. The color remained after 24 hours, further demonstrating high stability. Figure 2 Examples of SNAP-Pen, SNAP-Leu, and SNAP-GSNO are shown below (respectively). Figure 2 A, Figure 2 B and Figure 2 C). Figure 2 D is a SNAP-Pen diagram showing the synthesis in dichloromethane and crystallization after removal of all solvents. Green-red indicates a high concentration of tertiary RSNOs, which are green-red biaxial crystals.

[0129] Example 3A: SNAP-n-Butylamine (acid-free)

[0130] 22 μL of n-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene to form an intermediate solution. Subsequently, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor. A dark green solution was obtained.

[0131] Example 3B: SNAP-n-Butylamine (containing acid)

[0132] 22 μL of n-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene and 20 μL of dodecylbenzenesulfonic acid to form an intermediate solution. Subsequently, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor. The addition of acid accelerated the formation rate of RSNO. A dark green solution was obtained.

[0133] Example 3C: SNAP-sec-butylamine (acid-free)

[0134] 22 μL of sec-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene to form an intermediate solution. Subsequently, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor. A dark green solution was obtained.

[0135] Example 3D: SNAP-sec-butylamine (containing acid)

[0136] 22 μL of sec-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene and 20 μL of dodecylbenzenesulfonic acid to form an intermediate solution. Subsequently, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor. The addition of acid accelerated the formation rate of RSNO. A dark green solution was obtained.

[0137] Example 3E: SNAP-tert-butylamine (acid-free)

[0138] 22 μL of tert-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene to form an intermediate solution. Subsequently, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor. A dark green solution was obtained.

[0139] Example 3F: SNAP-tert-butylamine (containing acid)

[0140] 22 μL of tert-butylamine (primary amine) and 40 mg of N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide (thiolactone) were mixed in 2 mL of THF / toluene and 20 μL of dodecylbenzenesulfonic acid to form an intermediate solution. Subsequently, 200 mg of tert-butyl nitrite (nitrosamine) was added to the intermediate solution to form a nitric oxide precursor. The addition of acid accelerated the formation rate of RSNO. A dark green solution was obtained.

[0141] Examples 3A to 3F: Composite Articles

[0142] Then, 1 mL of each nitric oxide precursor solution was mixed with 1 mL of PVC polymer solution (0.1 g PVC / mL THF) and cast into a film. The resulting green PVC polymer released NO. The same experiment was performed using toluene as a solvent and RTV-3140PDMS as the polymer. See [link to relevant documentation] Figure 3 A shows the reaction mixture obtained immediately after the addition of nitrosotert-butyl ester when toluene is used as a solvent. See also Figure 3 B and Figure 3 C, which shows the release of NO from a 3-layer PVC film containing SNAP-n-butylamine and SNAP-sec-butylamine, respectively, by chemiluminescence detection.

[0143] Example 4: Composite product of SNAP-Lys silica gel and SNAP-Lys sodium polyacrylate

[0144] SNAP-Lys was synthesized from 23 mg lysine and 40 mg N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide in 200 μL water and 1.8 mL methanol in 100 μL 1M HCl. After 1 hour, 50 mg NaNO2 was added. The solution was stored overnight at 4 °C, and methanol was removed with a nitrogen stream.

[0145] Then, 300 μL of a concentrated SNAP-Lys aqueous / methanol solution was transferred onto 500 mg of silica gel, and another 300 μL of the concentrated SNAP-Lys aqueous / methanol solution was transferred onto 500 mg of sodium polyacrylate. Both groups of particles were air-dried. A dark green-red desiccant capable of releasing NO was obtained. A desiccant using GSNO as the NO source was also prepared by combining 50 mg of GSH and 100 mg of NaNO2 in 3 mL of H2O. Then, 1.5 mL of this red solution was transferred onto 500 mg of silica gel and 500 mg of sodium polyacrylate. A pink NO-releasing desiccant was obtained. Figure 4 For those from SNAP-Lys (green); Figure 4 A and Figure 4 B) and GSNO (red); Figure 4 C and Figure 4 The diagram shows the NO release of the desiccant in D).

[0146] It should be understood that the appended claims are not limited to the specific compounds, compositions, or methods described in the detailed embodiments, and may vary among specific embodiments falling within the scope of the appended claims. Regarding any Markush group upon which a particular feature or aspect of several embodiments described herein depends, different, specific, and / or unexpected results can be obtained from each member of the corresponding Markush group, independent of all other Markush members. Each member of the Markush group may be relied upon individually and / or in combination, and provides sufficient support for the specific embodiments within the scope of the appended claims.

[0147] It must also be noted that, as used in the specification and appended claims, the singular form of an element without a quantifier includes a plural indicator unless the context clearly indicates otherwise. For example, a component referred to in the singular form is intended to include multiple components.

[0148] Furthermore, any scopes and subscopes relied upon in describing several embodiments of the invention fall independently and collectively within the scope of the appended claims, and are to be understood as describing and contemplating all ranges of integer and / or fractional values ​​included therein, even if such values ​​are not explicitly stated herein. It will be readily recognized by one skilled in the art that the enumerated scopes and subscopes adequately describe and implement several embodiments of the invention, and that these scopes and subscopes may be further described as related halves, thirds, quarters, fifths, etc. By way of example only, the range “0.1 to 0.9” may also be described as the lower third, i.e., 0.1 to 0.3, the middle third, i.e., 0.4 to 0.6, and the upper third, i.e., 0.7 to 0.9, which are individually and collectively within the scope of the appended claims and may be individually and / or collectively relied upon, providing sufficient support for specific embodiments within the scope of the appended claims. Furthermore, language defining or modifying scopes, such as “at least,” “greater than,” “less than,” “no more than,” etc., should be understood to include subscopes and / or upper or lower limits. As another example, the scope of "at least 10" inherently includes sub-scopes of at least 10 to 35, at least 10 to 25, 25 to 35, etc., and each sub-scope can be relied upon individually and / or collectively, providing sufficient support for a particular embodiment within the scope of the appended claims. Finally, individual numbers within the disclosed scope are reliable and provide sufficient support for a particular embodiment within the scope of the appended claims. For example, the scope of "1 to 9" includes various single integers, such as 3, and single numbers including decimal points (or fractions), such as 4.1, which are reliable and provide sufficient support for a particular embodiment within the scope of the appended claims.

[0149] Except where explicitly stated in the embodiments or elsewhere, all numerical values ​​representing the amount of material or the conditions of reaction and / or use in this specification should be understood to be modified by the word “about” when describing the widest scope of this disclosure. In various embodiments, when referring to a specific, measurable value (e.g., parameter, quantity, duration, etc.), the terms “about” and “approximately” indicate a variation including the specific value and variations thereof, such as +10% / -10% or less than +10% / -10%, or +5% / -5% or less than +5% / -5%, or +1% / -1% or less than +1% / -1%, or +0.1% / -0.1% or less than +0.1% / -0.1%, provided that such variations are suitable for implementation in the disclosed embodiments. Therefore, the values ​​referred to by the modifiers “about” or “approximately” are themselves specifically disclosed.

[0150] Practice within the specified numerical range is generally preferred. Furthermore, unless explicitly stated to the contrary: percentages, “parts”, and ratios are by weight; a description of a group or class of materials is suitable or preferred for the given purpose related to the invention, meaning that a mixture of any two or more materials in that group or class is equally suitable or preferred; a description of components in chemical terms refers to the components when added to 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 acronyms or other abbreviations applies to all subsequent uses of the same abbreviation herein, and is consistent with the normal grammatical variations applicable to the initially defined abbreviations; and, unless explicitly stated to the contrary, the measurement of properties is determined by the same technique as the same properties mentioned above or below.

[0151] The invention has been described in an illustrative manner herein, and it should be understood that the terminology used is intended to be descriptive rather than limiting. Many modifications and variations of the invention are possible based on the foregoing teachings. The invention may be practiced in ways other than those specifically described within the scope of the appended claims. All combinations of the subject matter of the independent and dependent claims, including single and multiple dependent claims, are explicitly contemplated herein.

Claims

1. A method for preparing a consumer product containing a small molecule nitric oxide precursor, comprising: The thiolactone is reacted with a primary amine in a solvent to undergo a ring-opening reaction to form an intermediate with a thiol group; The thiol group of the intermediate is reacted with the nitrosyl compound in a solvent to form a nitric oxide precursor having a nitrosyl thiol; and The consumer product is treated with a nitric oxide precursor containing nitrosothiol, and optionally at least partially the solvent is removed. The consumer products include desiccants, detergent solutions or cleaning solutions, detergent powders or cleaning powders, or pads used for disinfection, wherein the nitric oxide precursor can decompose to form nitric oxide within 1 hour. The nitric oxide precursor showed very little degradation over a period of at least one month; Thiolactones have the structure shown according to formula (III): (III), Among them, R 6 Each occurrence is independently hydrogen, hydroxyl, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 heteroalkyl, substituted or unsubstituted C2 to C6 alkenyl, substituted or unsubstituted C2 to C6 heteroalkenyl, substituted or unsubstituted C1 to C6 alkoxy, or substituted or unsubstituted C1 to C6 heteroalkoxy; and wherein, when R 6 When substituted, the substituents are selected from OH, SH, NH3, NO2, and halogens; The primary amine has a molecular weight of less than 500 Da; and The nitrosating compounds include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, tert-butyl nitrite, isoamyl nitrite, or amyl nitrite.

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

3. The method of claim 1, wherein the thiolactone comprises an amino group.

4. The method according to claim 3, wherein the thiolactone is N-(2,2-dimethyl-4-oxo-3-thionecyclobutyl)acetamide, N-acetylcysteine ​​thiolactone, N-acetylhomocysteine ​​thiolactone, homocysteine ​​thiolactone, or butyrylhomocysteine ​​thiolactone.

5. The method according to claim 1, wherein the primary amine is an amino acid.

6. The method according to claim 1, wherein the solvent is an aqueous solvent.

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

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

9. The method of claim 1, wherein the reaction step is carried out in the presence of an acid.

10. The method of claim 1, wherein the reaction steps are carried out at ambient temperature and ambient pressure.

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

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

13. The method of claim 1, wherein the processing step comprises coating the consumer article with a nitric oxide precursor or blending the nitric oxide precursor with the consumer article in solid form.

14. A consumer article comprising a small molecule nitric oxide precursor for providing nitric oxide, prepared according to the method of claim 1, comprising: The reaction products of the following substances: Thiolactone, Primary amines, and Nitrosamines; The nitric oxide precursor can decompose to form nitric oxide within 1 hour; The nitric oxide precursor showed very little degradation over a period of at least one month; and The consumer products are treated with nitric oxide precursors containing nitrosothiols, and the consumer products are desiccants, detergent solutions or cleaning solutions, detergent powders or cleaning powders, or pads for disinfection.

15. The consumer article of claim 14, wherein the thiolactone can react with the primary amine to form an intermediate, and wherein the intermediate can react with the nitrosamine compound to form a nitric oxide precursor.

16. The consumer article of claim 15, wherein the thiolactone and the primary amine can react in the presence of a solvent to form an intermediate.

17. The consumer article of claim 15, wherein the thiolactone and the primary amine are capable of reacting at a temperature of about 1°C to about 25°C.

18. The consumer article of claim 14, wherein the nitric oxide precursor comprises nitrosothiol, and wherein the nitrosothiol is capable of decomposing to form nitric oxide.

19. The consumer article of claim 14, wherein after the formation of the nitrogen oxide precursor, the nitric oxide precursor exhibits minimal decomposition into nitrogen oxides for at least 24 hours.

20. The consumer article of claim 14, wherein the thiolactone is an amine-containing thiolactone.

21. The consumer article according to claim 14, wherein the primary amine is selected from cysteine, glutathione, acetylcysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bexilamine, lysine, acetyllysine, n-butylamine, sec-butylamine, tert-butylamine, or combinations thereof.

22. The consumer article of claim 14, wherein the primary amine contains a thiol functional group.

23. The consumer article of claim 14, wherein the nitric oxide precursor is in crystalline form, and wherein the crystalline nitric oxide precursor exhibits improved storage stability compared to the corresponding amorphous nitric oxide precursor.

24. A composite article comprising: carrier; and The small molecule nitric oxide precursor prepared by the method according to claim 1 is a reaction product of thiolactone, primary amine and nitrosamine compound; The nitric oxide precursor is coated onto the support or blended with the support in solid form; and After the formation of the nitric oxide precursor, the composite product exhibited minimal nitric oxide release for at least one month; and During the release of nitric oxide, the nitric oxide precursor decomposes into nitric oxide within 1 hour.

25. A method for sterilizing or disinfecting an article, the method comprising applying a small molecule nitric oxide precursor prepared according to the method of claim 1 to the article, wherein the nitric oxide precursor is a reaction product of a thiolactone, a primary amine and a nitrosamine, wherein the nitric oxide precursor exhibits minimal degradation over a period of at least one month, and wherein the nitric oxide precursor is capable of decomposing to form nitric oxide within one hour.

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