No-release coatings

Abstract

Embodiments of the present disclosure relate to chemical entities formed from the reaction of components B and C wherein component C is a moiety comprising one or more amine groups, and component B is a compound of formula (I): # imgabs0 # wherein A is the core moiety; l is an optional linking group; r1 and R2 are independently selected from H and C1-5 alkyl; or R1 and R2 combine together with the C atom to which they are attached to form a C4-7 cycloalkyl ring or a 4-7 membered heterocyclic ring, both optionally substituted on the available atoms by one or more groups selected from C1-2 alkyl and oxo; n is 0 or 1; and m is an integer of at least 1. In one embodiment, at least a portion of the thiol (-SH) groups in the chemical entity have been converted to S-nitrosothiol (-SNO) groups.

Description

Technical Field

[0001] Embodiments of the present disclosure relate to chemical entities capable of releasing nitric oxide. These chemical entities can be used for surface coatings, particularly the surfaces of medical devices. Methods for making the chemical entities and coatings are also described. Background Art

[0002] It is increasingly common to treat a variety of medical conditions by introducing medical devices into organs or tissues within the human body. Such medical devices can be temporarily or permanently implanted in tissues or organs such as bone, nerve, brain, smooth muscle, heart muscle, kidney, lung, liver, stomach, intestine, uterus, vagina, prostate, testicles, etc. Many implants are prosthetics, designed to replace missing body parts, while others perform important functions such as delivering medications, monitoring body functions, or providing support for organs and tissues.

[0003] For example, medical devices for treating vascular disease include stents, stent grafts, grafts, catheters, balloon catheters, guidewires, cannulas, and the like. Such devices may be implantable, such as implantable in a blood vessel, typically providing medical benefits through mechanical action (e.g., by dilating and / or supporting the vessel wall), but may also provide additional medical benefits through drug elution (e.g., eluting antiproliferative compounds such as paclitaxel to prevent restenosis). Several implantable devices for local drug delivery are known, including stents coated with elutable drugs, also known as drug eluting stents (DES). Medical devices introduced into the vascular system for a short period of time may also be drug-coated, such as drug-coated balloon catheters (also known as drug-coated balloons (DCBs)), or drug-coated catheters (also known as drug-coated catheters (DCCs)).

[0004] However, the use of such medical devices may present problems well known in the art, including early and late thrombosis associated with vascular inflammation, formation of mural emboli, anastomotic hyperplasia, endoleaks, vascular constriction, etc. It is well known that when medical devices come into contact with blood, plasma proteins adsorb to the device surface. These adsorbed plasma proteins promote the attachment of platelets, which directly interact with the plasma proteins after attachment to expose platelet glycoprotein GPIIb / IIIa integrin receptors, which promote binding to fibrinogen (Calvete et al., 1995). A positive feedback loop of platelet activation and aggregation ensues, ultimately leading to the formation of a blood clot. There is a secondary risk that the clot will break off and cause embolism elsewhere in the vascular system.

[0005] Additionally, certain implantable medical devices can be a major source of infection, especially those that are implanted for a longer period of time. Such infections may be associated with early device failure, requiring repeat surgical procedures. Percutaneous devices such as percutaneous catheters, pacing leads, colostomies, cranial shunts, etc. have an increased risk of infection, which can lead to increased patient discomfort when these devices are routinely removed and replaced to avoid infection.

[0006] Nitric oxide (NO) is a signaling molecule produced by the nitric oxide synthase processing of L-arginine. Endothelial cells (ECs) are NO producers and are the main source of NO production in the vascular system. In this context, NO is important in maintaining cardiovascular homeostasis and regulating vasodilation. In addition, NO has other effects, such as effectively inhibiting platelet adhesion and aggregation; preventing thrombosis; inhibiting inflammatory cell proliferation, inhibiting smooth muscle cell proliferation, promoting endothelial cell growth and adhesion; and inhibiting leukocyte activation. Therefore, NO has been shown to improve the biocompatibility of medical devices (Frost et al., 2005). Similarly, NO has been associated with the treatment of atherosclerosis (Matthys and Bult, 1997). In addition, NO is an inhibitor of bacterial adhesion and proliferation (Schairer et al., 2012), and inducible nitric oxide synthase is expressed by T cells, macrophages, and mature dendritic cells, and regulates the differentiation and function of immune cells by nitration of key molecules involved in transcriptional or signaling pathways (Xue et al., 2018). NO plays an important role in the mobilization, differentiation, and function of endothelial progenitor cells. Thus, NO has been implicated in the regulation of endothelialization and angiogenesis (Cooke and Losordo, 2002).

[0007] US 2015 / 0247005 discloses stable photosensitive polymers that release NO in response to light intensity and wavelength.

[0008] US2017 / 0246353 discloses a method for producing a nitric oxide generating coating, the method comprising: preparing a buffer solution containing a polyphenol compound, an organic selenium compound or an organic sulfur compound and a soluble copper salt; then contacting a base material with the solution, and washing and drying to obtain a product. The organic selenium compound and the organic sulfur compound are said to have glutathione peroxidase-like activity, that is, they can catalyze nitrosothiol to release NO.

[0009] US2019 / 0358368 discloses a tubing impregnated with silicone oil and an NO-releasing agent, which has anti-fouling properties, that is, the tubing has a reduced tendency to adhere to platelets, induce thrombosis or promote infection. Also disclosed are methods for preparing such tubing and methods for delivering pharmaceutically acceptable fluids through the tubing.

[0010] WO2020 / 018488 discloses NO-releasing materials, methods for preparing the materials, and devices comprising the materials. The NO-releasing materials include a polymer matrix comprising a plurality of polysiloxanes, an amine-containing crosslinker, and an NO-donating moiety, such as an S-nitrosothiol moiety derived from a thiol (such as a tertiary thiol), wherein the NO-donating moiety reacts with the amine-containing crosslinker. The methods and materials described are said to prevent thrombosis and biofilm formation.

[0011] WO2021 / 126084A1 discloses a composite material comprising a substrate coated with a block copolymer brush, wherein the block copolymer brush comprises a hydrophobic polymer first block conjugated to a nitric oxide source and a hydrophilic polymer second block, wherein the hydrophobic polymer first block is covalently bonded to the surface of the substrate, or the cationic polymer first block is covalently bonded to the surface of the substrate; the hydrophilic polymer second block extends from the first block to form the outer surface of the block copolymer brush.

[0012] It is known in the art that peptide sequences can contain thiols in the form of side chain tertiary thiols along the peptide chain backbone. For example, a first peptide can be linked to penicillamine thiolactone at the C-terminus to produce a peptide containing an electrophilic thioester, and a second peptide can be modified with an N-terminal cysteine ​​to produce a peptide containing a nucleophilic tertiary thiol (Chen et al., 2018). In another example, a first peptide can be modified to produce a peptide containing an electrophilic thioester, and a second peptide can be linked to penicillamine to produce a peptide containing a nucleophilic tertiary thiol (Altenbruun et al., 2009). Therefore, in both teachings, a first peptide can be condensed by thioester exchange with a second peptide to produce an intermediate dipeptide conjugate, which undergoes a chemoselective S to N acyl transfer (i.e., a well-known native chemical ligation reaction) to produce a final dipeptide conjugate containing side chain tertiary thiols along its backbone. However, such dipeptide conjugates are not suitable for derivatization as side chain NO donor moieties, such as S-nitrosothiol moieties, for surface coatings, particularly for the surface of medical devices for treating human or animal tissues. It is well known that peptide coatings are enzymatically unstable when implanted in humans or animals. Therefore, peptide coatings containing side chain tertiary thiols along the peptide backbone will be subject to enzymatic degradation, which may lead to desorption, flaking, leaching or other damage to the coating and are therefore unsuitable as nitric oxide-releasing coatings.

[0013] There is a need for further development of NO-releasing coatings, particularly for devices that are introduced into the human body, such as for topical treatment of vascular disease. In particular, there is a need to develop coatings for NO-containing medical devices that can deliver therapeutically relevant levels of NO to target tissues (e.g., vascular tissue) in a localized manner and on an appropriate time scale. When a medical device has a coating containing other therapeutic agents (i.e., in addition to NO), the NO-containing coating should be compatible with the other therapeutic agents.

[0014] This coating can also be used in ex vivo or extracorporeal medical devices, such as blood oxygenators, dialysis machines, etc. Summary of the invention

[0015] Embodiments of the present disclosure relate to novel chemical entities capable of releasing nitric oxide. When applied to a surface, particularly a medical device surface, the coating can be used to treat diseases that benefit from the release of nitric oxide.

[0016] Thus, in one embodiment there is provided a chemical entity formed by reacting components B and C, wherein component B is a compound of formula (I):

[0017]

[0018] in,

[0019] A is the core part;

[0020] L is an optional linker;

[0021] R 1 and R 2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radical substitution;

[0022] n is 0 or 1; and

[0023] m is an integer at least 1;

[0024] and,

[0025] Component C is a moiety comprising one or more amine groups.

[0026] In another embodiment, a surface having a coating comprising a chemical entity formed by the reaction of components B and C is provided.

[0027] The reaction of components B and C results in the opening of the thiolactone ring and the formation of a chemical entity comprising one or more SH groups. In another embodiment, a chemical entity and a surface having a coating comprising the chemical entity are provided, wherein at least a portion of the -SH groups in the chemical entity have been converted to -SNO (S-nitrosothiol) groups. The surface forms at least a portion of the surface of a medical device that can be used to treat or prevent conditions that benefit from nitric oxide delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1A Shown are: embodiment 1, wherein, for component B, m is 1, and component C contains one amine group; embodiment 2, wherein, for component B, m is 1, and component C contains two amine groups; and embodiment 3, wherein, for component B, m is 2, and component C contains one amine group.

[0029] Figure 1B Embodiment 4 is shown wherein, for component B, m is 2, and component C comprises two amine groups.

[0030] Figure 1C Embodiment 5 is shown, wherein, for component B, m is 2, and component C is a dendrimer (PAMAM-GO).

[0031] Figure 1D Embodiment 6 is shown wherein, for component B, m is 4, and component C comprises two amine groups.

[0032] Figure 1E Embodiment 7 is shown wherein, for component B, m is 2, and component C is a polyamine (branched PEI).

[0033] Figure 2 The copolymer (19) (Example 17) 1 H NMR (DMSO-d6) spectrum.

[0034] Figure 3 Overlaid FTIR spectra of copolymers (19) and (20) (Example 23) are shown.

[0035] Figure 4 The NO release profile of the ePTFE membrane coated with compound (16) (Example 25) is shown.

[0036] Figure 5 The NO release profile of the ePTFE membrane coated with compound (17) (Example 25) is shown.

[0037] Figure 6 The NO release profile of an ePTFE film coated with VDF-HFP fluoropolymer and compound (16) (Example 26) is shown.

[0038] Figure 7 The NO release profile of an ePTFE film coated with VDF-HFP fluoropolymer and compound (18) (Example 26) is shown.

[0039] Figure 8 The NO release profile of a stainless steel foil coated with VDF-HFP fluoropolymer and compound (18) (Example 27) is shown.

[0040] Fig. 9 The coating of VDF-HFP fluoropolymer and compound (18) is shown. NO release profile of nylon (Example 28).

[0041] Fig.10 The NO release profile of ePE (Example 29) coated with VDF-HFP fluoropolymer and compound (18) is shown.

[0042] Fig.11 The NO release profile of ePTFE membranes coated with VDF-HFP fluoropolymers and copolymers (20) (Example 26) is shown.

[0043] Fig.12 The NO release profile of an ePTFE membrane coated with polymer (22) (Example 30) is shown.

[0044] Fig.13 is a gel permeation chromatography (GPC)-light scattering (LS) graph of the polymer (32) of Example A2 (designated herein as DDPP) obtained using a refractive index and light scattering detector and showing the average M n 、M w 、M z and M w / M n value.

[0045] Fig.14 The FT-IR spectra of the non-nitrosylated PPO-400 dimethylmalonyl penicillamine polymer (33) of Example A3 and the nitrosylated PPO-400 dimethylmalonyl penicillamine polymer (37) of Example A5 are shown. The dotted line is the spectrum of the non-nitrosylated polymer (33), and the solid line is the spectrum of the nitrosylated polymer (37).

[0046] Fig.15 The TGA curves of the non-nitrosylated PPO-400 dimethylmalonyl penicillamine polymer (33) of Example A3 and the nitrosylated PPO-400 dimethylmalonyl penicillamine polymer (37) of Example A5 are shown in Figure 1. The upper (solid) line represents the non-nitrosylated polymer (33), and the lower (dashed) line represents the nitrosylated polymer (37).

[0047] Fig.16 is a graph showing the NO release profile of nitrosylated PPO-400 dimethylmalonylpenicillamine polymer (37) over 648 hours (27 days) as measured using the Griess reagent NO elution test method.

[0048] Fig.17is a series of SEM images showing the surface of a vascular graft that is uncoated or coated with the nitrosylated PPO-400 dimethylmalonyl penicillamine polymer (37) of Example A5. 17a: uncoated, 50 times magnification; 17b: coated, 50 times magnification; 17c: uncoated, 2000 times magnification; 17d: coated, 2000 times magnification.

[0049] Fig.18 is a series of SEM images showing the surface of a vascular graft coated with the nitrosylated PPO-400 dimethylmalonylpenicillamine polymer (37) of Example A5 after passing around a stainless steel cone with an outer diameter of 15 mm according to ISO 7198.

[0050] Fig.19 is the ESI mass spectrum of compound 14, showing M+H + and M+Na + peak.

[0051] Fig. 20 is the ESI mass spectrum of compound 14 after fragmentation into the thiolactone and amine starting materials, and shows the M+H corresponding to the compound, the fragments losing one or two amine fragments, and the amine fragment. + peak.

[0052] Fig.21 is the ESI mass spectrum of compound 38, showing M+H + and M+Na + peak.

[0053] Fig. 22 This is the ESI mass spectrum of compound 38 after the fragmentation and loss of a thiolactone fragment.

[0054] Fig.23 is the ESI mass spectrum of compound (38) after fragmentation, showing M+H corresponding to the following fragments: + Peaks: fragment with loss of thiolactone fragment, thiolactone fragment, and amine fragment remaining after loss of two thiolactone fragments.

[0055] Details

[0056] The present disclosure relates to novel thiol-containing and / or S-nitrosothiol-containing chemical entities, and surfaces having coatings comprising such chemical entities.

[0057] The chemical entities of the present disclosure may be in a "thiol form / -SH form" (containing at least a portion of thiol groups) or an "S-nitrosothiol / -SNO form" (containing at least a portion of S-nitrosothiol groups).

[0058] As is known in the art, chemical entities containing an S-nitrosothiol group are capable of releasing nitric oxide. When the chemical entity is applied as a coating on a surface, particularly a surface of a medical device, the resulting coating is capable of releasing nitric oxide.

[0059] The thiol form of the chemical entity of the present disclosure is prepared by the reaction of components B and C. In this case and in the context of the claims, the term "chemical entity" is intended to encompass all possible moieties resulting from the reaction of component B with component C, such as compounds, copolymers or polymers.

[0060] Component B comprises a core part A bonded to at least one cyclic thioester part. Component C is a part comprising one or more amine groups. When components B and C are reacted together, the amine groups of component C react with one or more cyclic thioester parts of component B through an aminolysis reaction to form one or more secondary amide linking groups and one or more free thiol groups (-SH). Depending on the group R 1 and R 2 Depending on the nature of components B and C, the thiol will be a primary thiol, a secondary thiol or a tertiary thiol. Depending on the nature of components B and C, the chemical entity may be further defined as a compound, a copolymer or a polymer.

[0061] The chemical entities of the present disclosure include chiral moieties and may include D-stereoisomers, L-stereoisomers, or mixtures of the two (e.g., racemic mixtures). In embodiments where the chemical entity includes at least two chiral centers, the chemical entity may be chiral or achiral (meso). In one embodiment, the chemical entity may be incorporated into a medical device and may include one or more D-stereoisomers, one or more L-stereoisomers, or a racemic mixture of stereoisomers. In another embodiment, the chemical entity may be eluted from a medical device and may include a specific stereoisomer or a specific racemic mixture selected to maximize the therapeutic effect.

[0062] Component B

[0063] Component B is a compound of formula (I):

[0064]

[0065] in,

[0066] A is the core part;

[0067] L is an optional linker;

[0068] R 1 and R 2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radical substitution;

[0069] n is 0 or 1; and

[0070] m is an integer of at least 1. In one embodiment, the core moiety A comprises one or more moieties independently selected from the group consisting of alkyl, spiroalkyl, aryl, heteroaryl, alkylaryl, porphyrin, polymer, and macrocycle, wherein the alkyl, spiroalkyl, aryl, heteroaryl, and alkylaryl are optionally substituted (e.g., substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, fluoroalkyl, and fluoroalkoxy).

[0071] When the core part A comprises an alkyl group or the core part A is an alkyl group (e.g., C 1-20 Alkyl, C 1-10 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl or C 1-3 alkyl (e.g. methyl or ethyl)), which is optionally substituted by one or more substituents (e.g. selected from the group consisting of alkyl, alkoxy, fluoroalkyl and fluoroalkoxy, e.g., C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkyl and C 1-6 Fluoroalkoxy, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl and C 1-4 In one embodiment, the core part A is an alkyl group.

[0072] In some cases, when the core part A comprises an alkyl group or the core part A is an alkyl group, and m is 1 or 2, especially 2. In some suitable compounds, m is 2, and the core part comprises or consists of the following parts: C 1-10 Alkylene moieties, such as C 1-6 Alkylene moieties, especially C 1-4 Alkylene moieties such as -(CH2)4-, -(CH2)3-, -C(CH3)2-, -CH(CH3)-, -CH2-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2CH2-, more particularly C 2-4Alkylene such as -(CH2)4-, -(CH2)3-, -C(CH3)2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2CH2-. In one embodiment, A is -C(CH3)2-, and m is 2. In one embodiment, A is -(CH2)4-, and m is 2. In suitable embodiments, the linking group L is absent.

[0073] When the core part A comprises a spiroalkyl group (e.g. C 1-20 Spiroalkyl, C 1-10 Spiroalkyl or C 1-6 When the core moiety A is a spiroalkyl group, it is optionally substituted by one or more substituents (e.g. selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy). In one embodiment, the core moiety A is a spiroalkyl group.

[0074] When core part A comprises aryl (for example 5-20 yuan aryl, 5-12 yuan aryl, 5-10 yuan aryl or 5-7 yuan aryl), it is optionally substituted by one or more substituents (for example selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy). "Aryl" used herein is a cyclic group with aromatic characteristics, such as phenyl or naphthyl. Aryl also includes diaryl and polyaryl. In a suitable embodiment, aryl is phenyl, which is optionally substituted by one or more substituents selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy. In one embodiment, core part A is aryl.

[0075] In one embodiment, m is 2, and the core portion A is:

[0076] or

[0077] m is 3, and the core part A is:

[0078]

[0079] For example, m is 2, and the core part A is:

[0080] or

[0081] m is 3, and the core part A is:

[0082]

[0083] When core part A comprises heteroaryl, it is optionally substituted by one or more substituents (selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy). In one embodiment, heteroaryl is 5-10 yuan heteroaryl, for example pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl or pyrazinyl. In one embodiment, core part A is heteroaryl.

[0084] When the core part A comprises an alkylaryl group (e.g., 1-10 alkyl) or substituted by an alkyl group (e.g., C 1-5 In one embodiment, the core part A is an alkylaryl group.

[0085] In one embodiment, core moiety A comprises a porphyrin, such as tetra-4-aryl-meso. In one embodiment, core moiety A is a porphyrin.

[0086] In one embodiment, core part A comprises polymer (for example, polyamine compound, dendrimer or hyperbranched polymer). In one embodiment, polyamine compound is selected from the group consisting of polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane. In one embodiment, core part A comprises polyethyleneimine (PEI), in particular branched polyethyleneimine. Suitably, the molecular weight of polyethyleneimine (in particular branched polyethyleneimine) is 10-1,000kDa, for example 10-50kDa or 50-100kDa. In one embodiment, core part A comprises dendrimer, for example, polyamine dendrimer, for example PAMAM dendrimer or PPI dendrimer. In one embodiment, core part A is a polymer.

[0087] In one embodiment, core moiety A comprises a macrocycle, such as cyclodextrin. In one embodiment, core moiety A is a macrocycle.

[0088] In one embodiment, the linker L comprises C 1-10 In another embodiment, the linker L is absent.

[0089] In one embodiment, n is 0. In another embodiment, n is 1. Suitably, n is 0.

[0090] In one embodiment, R 1 and R 2 Independently selected from H and C1 -5 In another embodiment, R1 and R 2 are independently selected from CH2CH3 and CH3; in particular both are CH3. In another embodiment, R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl or 4-7 membered heterocyclic ring (these two groups are optionally substituted on available atoms by one or more groups selected from the following: C 1-2 alkyl and oxo); for example, R 1 and R 2 Together with the C atoms to which they are attached, they form a cycloheptyl or cyclohexyl ring (which is optionally substituted on available atoms by one or more groups selected from the following: C 1-2 alkyl and oxo).

[0091] As used herein, the term "oxo" refers to an a=O substituent wherein the oxygen atom is double bonded to carbon (eg, C=O) or another element (eg, S=O, S(=O)2).

[0092] Terminology C 4-7 Cycloalkyl ring (such as C 4-5 Cycloalkyl, C 4-6 Cycloalkyl or C 5-6 Cycloalkyl) refers to a fully saturated cyclic hydrocarbon group having 4 to 7 carbon atoms. The term includes cyclobutyl, cyclopentyl and cyclohexyl.

[0093] The term "4-7 membered heterocycle" refers to a non-aromatic cyclic group having 4 to 7 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, S and B, in particular a heteroatom selected from the following: N, O and S, for example, selected from N and O. The term "heterocycle" is interchangeable with "heterocyclyl". The term includes pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Other heterocyclyls (e.g., 5-7 membered heterocyclyl, 5-6 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl and 7 membered heterocyclyl) are as described above, but contain different numbers of ring atoms.

[0094] When n is 0, suitably, R 1 and R 2 Both are CH3 or CH2CH3, in particular, both are CH3. When n is 1, suitably, R 1 and R 2 Both are H.

[0095] The variable m is an integer of at least 1. In one embodiment, particularly when component B is a gel, m is from 1 to infinity, or more suitably from 2 to infinity. In one embodiment, m is 1-5,000,000, 2-5,000,000, 1-1,000,000, 2-1,000,000, 1-500,000, 2-500,000, 1-400,000, 2-400,000, 1-200,000, 2-200,000, 1-100,000, 2-100,000, 1-50,000, 2-5 or 0,000, 1-20,000, 2-20,000, 1-10,000, 2-10,000, 1-5,000, 2-5,000, 1-2,000, 2-2,000, 1-1,000, 2-1,000, 1-500, 2-500, 1-100, 2-100, 1-50, 2-50, 1-20, 2-20, 1-10, 2-10, 1-5, or 2-5.

[0096] In one embodiment, m is 2-500,000, 50-500,000, 100-500,000, 500-500,000, 1,000-500,000, or 5,000-500,000. In one embodiment, m is 1-200,000, 2-200,000, 50-200,000, 100-200,000, 500-200,000, 1,000-200,000, or 5,000-200,000. In one embodiment, m is 1-100,000, 2-100,000, 50-100,000, 100-100,000, 500-100,000, 1,000-100,000, or 5,000-100,000. In one embodiment, m is 1-50,000, 2-50,000, 50-50,000, 100-50,000, 500-50,000, 1,000-50,000, or 5,000-50,000. In one embodiment, m is 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, or 5,000-20,000. In one embodiment, m is 1-5,000, 2-5,000, 50-5,000, 100-5,000, 500-5,000, or 1,000-5,000. In one embodiment, m is 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, or 5,000-20,000. In one embodiment, m is 1-1,000, 2-1,000, 50-1,000, 100-1,000, or 500-1,000. In one embodiment, m is 1,000, 5,000, 20,000, 100,000, 200,000, or 500,000. In one embodiment, m is 11-44, 44-110, or 110-4200. In one embodiment, m is 1-10, 10-100, 100-6,200, or 1-infinity. In one embodiment, m is 1-1,000, for example, 1-500, 1-100, 1-50, 1-25, 1-20, or 1-10. In one embodiment, m is 2-100, for example, 2-50, 2-25, 2-20, or 2-10. In one embodiment, m is 1, 2, 3 or 4; for example, m is 2, 3 or 4, especially 2 or 3. In another embodiment, m is 5-10, for example, m is 5-8. In another embodiment, m is 5,000-100,000, 5,000-50,000 or 5,000-20,000.

[0097] Compounds of the formula (I) in which m is at least 2 are particularly suitable since they can react with components C having two or more amine groups to form polymers which are particularly suitable for use as coating materials.

[0098] In one embodiment, the weight average molecular weight of Component B is from 5,000 Da to 1,000,000 Da, such as from 5,000 Da to 20,000 Da, or from 50,000 Da to 1,000,000 Da.

[0099] In one embodiment, component B has formula (Ia):

[0100]

[0101] in,

[0102] R 1 and R 2 Independently selected from H and C 1-5 Alkyl, for example selected from CH3 and CH2CH3 (especially both are CH3); or R 1 and R 2 Together with the C atoms to which they are attached, they form a cycloheptyl or cyclohexyl ring (which is optionally replaced on available atoms by one or more selected from C 1-2 alkyl and oxo groups).

[0103] In one embodiment, component B is:

[0104]

[0105] Where n is 0 or 1, and R 1 and R 2 Independently selected from H and C 1-5 alkyl;

[0106] When n is 0, R 1 and R 2 Suitable for both C 1-5 alkyl, especially methyl or ethyl, for example, both are methyl; and when n is 1, R 1 and R 2 Suitably both are H.

[0107] In one embodiment, component B is:

[0108]

[0109] Where n is 0 or 1, and R 1 and R 2 Independently selected from H and C 1-5 alkyl;

[0110] When n is 0, R 1 and R 2 Suitable for both C 1-5 alkyl, especially methyl or ethyl, for example, both are methyl; and when n is 1, R 1 and R 2 Suitably both are H.

[0111] In one embodiment, component B is:

[0112]

[0113] Wherein, when n is 0 or 1, x is 1-10, such as 1-6, and R 1 and R 2 Independently selected from H and C 1-5 alkyl;

[0114] When n is 0, R 1 and R 2 Suitable for both C 1-5 alkyl, especially methyl or ethyl, for example, both are methyl; and when n is 1, R 1 and R 2 Suitably both are H.

[0115] In one embodiment, component B has formula (Iaa):

[0116]

[0117] Where L, n, R 1 and R 2 As defined above.

[0118] More suitably, L is absent and component B has formula (Iab):

[0119]

[0120] In a suitable embodiment, L is absent, n is 0, and component B has formula (lac):

[0121]

[0122] In the compounds of formula (Iaa), (Iab) and (Iac), R 1 and R 2 Suitably independently selected from H and C 1-5 Alkyl is suitably H, methyl or ethyl, more suitably H or methyl. In suitable embodiments of the compounds of formula (lac), and in compounds of formula (laa) and (lab) where n is 0, R 1and R 2 In some compounds of formula (Iaa) and (Iab) where n is 1, R 1 and R 2 Suitably both are H.

[0123] In one embodiment, a method for preparing a compound of formula (I) is provided:

[0124]

[0125] in,

[0126] A is the core part;

[0127] L is an optional linker;

[0128] R 1 and R 2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radical substitution;

[0129] n is 0 or 1;

[0130] m is an integer at least 1;

[0131] The method comprises: reacting a compound of formula (IV) with a compound of formula (V) under suitable conditions to form a compound of formula (I):

[0132]

[0133] in,

[0134] For formula (IV):

[0135] LG is a leaving group or an electrophilic group, or the moiety C=O-LG is an electrophilic group;

[0136] A is the core part;

[0137] L is an optional linker; and

[0138] m is an integer at least 1;

[0139] And for formula (V):

[0140] n is 0 or 1;

[0141] R 1 and R 2 Independently selected from H and C1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radicals are substituted; and

[0142] X is NH2 or NH3 + Y - , where Y - is a suitable anion, such as Cl - .

[0143] LG can be a leaving group such as a halogen (e.g., chlorine or bromine), OM or OT. Alternatively, LG can be an electrophilic group, such as one that can react with a group X (NH2 or NH3 + Y - ) react to form a covalent bond, such as an azide, an epoxide, or an isocycloalkanoate. Alternatively, the portion C=O-LG is an electrophilic group, for example, the portion C=O-LG includes an ester (such as a succinimide ester), a carbonate (such as a succinimide carbonate), or an anhydride. In one embodiment, the reaction is carried out in the presence of an aqueous base and / or a buffer. In another embodiment, the reaction is carried out in an organic solvent.

[0144] The general procedure for the synthesis of compounds of formula (I) is provided in the experimental section below, and specific synthesis examples can be found in Examples 2-7. In the above method, compounds of formula (I) include compounds of formula (Ia), (Iaa), (Iab) and (Iac) and other embodiments of component B described above.

[0145] The starting materials of formula (IV) and (V) are commercially available or can be prepared by known methods, for example, wherein m is 1 and R 1 and R 2 Compounds of formula (V) in which all of the methyl groups are present may be prepared as described by Martens et al. (1991).

[0146] It should be noted that component B contains at least one chiral center. For example, in an embodiment containing a single chiral center (m is 1), the chiral center is marked with an * as shown below:

[0147]

[0148] When m is greater than 1, component B will include at least two chiral centers. In these embodiments, component B can be chiral or achiral (meso). In one embodiment, component B is a D-stereoisomer. In another embodiment, component B is an L-stereoisomer. In another embodiment, component B is a compound (e.g., a racemic mixture) of a D-stereoisomer and an L-stereoisomer. Suitably, component B is a D-stereoisomer. It should be noted that for structures described herein that are not limited by the stereochemistry of the chiral center, the structure is intended to encompass D-stereoisomers, L-stereoisomers, and all mixtures thereof (including racemic mixtures).

[0149] Component C

[0150] Component C is a moiety containing one or more amine groups. This moiety can be a single compound or a mixture of compounds.

[0151] In the context of the present invention, the term "amine" refers to a primary, secondary or tertiary amine, more typically a primary or secondary amine. The terms "amine" and "amino" can be used interchangeably.

[0152] In some embodiments, component C can be a single monomeric compound (ie, a single compound having a well-defined composition).

[0153] In another embodiment, component C may be a polymer. As is known in the art, a polymer is generally a mixture of compounds formed as a product of a polymerization reaction, which may occur to different extents in different members of the mixture, and may be defined by its average molecular weight, for example, its number average molecular weight M. n and / or weight average molecular weight M w and / or z-average molecular weight M z and / or polydispersity index M w / M n .

[0154] In a further embodiment, component C may be a mixture of two or more compounds, in particular two compounds, wherein the two or more compounds are selected from single monomeric compounds and polymers.

[0155] For example, component C is a mixture of two or more monomeric compounds. Suitably, at least one or all of the two or more compounds can include two or more amine groups, for example two amine groups. This monomeric compound can be polymerized with component B having n of 2 or higher (for example 2).

[0156] Alternatively, component C may be a mixture of two or more compounds, wherein the two or more compounds are two or more polymers.

[0157] In the case of component C, the term "polymer" refers to a macromolecule comprising 2 or more monomer units, which may be up to, for example, 5,000,000, such as 11 or more monomer units, such as 11 to 5,000,000, 11-1,000,000, 11-500,000, 11-400,000, 11-200,000, 11-100,000, 11-50,000, 11-20,000, 11-10,000, 11-5000, 11-2000, 11-10,000, 11-5000, 11-2000, 11-1000, 11-5000, 11-2000, 11-1000, 11-500, 11-100, 11-500, 11-100, 11-50 or 11-20 monomer units. Those skilled in the art will appreciate that the length of the polymer chain will vary due to molecular differences in the polymer and, therefore, the above numbers of monomer units represent average numbers.

[0158] Polymer can be formed by polymerization of selected number of monomers, and the monomer can be one or more types. In some cases, polymer is formed by single monomer, and examples of such polymer include polyethyleneimine, polylysine, polypropylene oxide and polyethylene oxide. Alternatively, polymer can be a copolymer formed by two or more monomers (e.g., two monomers). Example is a polymer formed by propylene oxide and ethylene oxide units. The copolymer can be a block copolymer or a random copolymer, for example, a block copolymer.

[0159] In some cases, the monomeric unit forming the polymer is an oxyalkylene unit or a mixture of oxyalkylene units. As an alternative or additional technical solution, the monomeric unit has a pendant amine group, for example, the monomeric unit can be an alkylene imine, allylamine, lysine, arginine or aminosilane.

[0160] In some cases, the polymer can be a linear polymer. Alternatively, the polymer can be a branched or hyperbranched polymer or a dendrimer.

[0161] The amine groups of component C are independently primary or secondary. In component C, the secondary amine groups may be present in cyclic amines such as morpholine, piperidine or piperazine. Alternatively, the secondary amine groups may be present as NH(C 1-6 alkyl) group is present.

[0162] In one embodiment, component C includes a single amine group, wherein the single amine group is a primary amine or a secondary amine (wherein "single" in this context means that component C contains only one amine group). In this case, component C is usually a single monomer compound or a mixture of two or more monomer compounds. In one embodiment, component C is selected from the group consisting of aniline, benzylamine, morpholine, diethylamine, dibutylamine, 1-ethylpropylamine, 2-aminopentane, piperidine, 4-methylpiperidine, pyrrolidine, tert-butylamine, tert-amylamine, propylamine, butylamine, amylamine, isopentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, dodecylamine, hexadecylamine, octadecylamine, 4-methylaniline, 2-fluorobenzylamine, 3-fluorobenzylamine, 4-fluorobenzylamine, 3-(trifluoromethyl)benzylamine, 4-(trifluoromethyl)benzylamine, and 3,5-bis(trifluoromethyl)benzylamine. In a suitable embodiment in which C includes a single amine group, component C is selected from aniline, benzylamine, and morpholine.

[0163] In another embodiment, component C comprises two or more amine groups, wherein the amine groups are independently primary or secondary amine groups. In another embodiment, component C comprises two or more primary amine groups. In another embodiment, component C comprises a mixture of primary and secondary amine groups.

[0164] In one embodiment, component C includes polyamine compounds, for example, polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane. Therefore, in one embodiment, component C includes one or more parts independently selected from the group consisting of polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane. In a suitable embodiment, component C includes polyethyleneimine (PEI), particularly branched polyethyleneimine. Suitably, the molecular weight of polyethyleneimine (particularly branched polyethyleneimine) is 10-1,000kDa, for example 10-50kDa or 50-100kDa. In one embodiment, component C is PEI.

[0165] In one embodiment, component C comprises a polyamine compound comprising a dendrimer or a hyperbranched polymer.

[0166] When component C is a linear polymer, it contains two amine groups, one at each end of the polymer chain. Suitably, the amine groups are primary or secondary. For example, both amine groups may be primary or both amine groups may be secondary, or there may be a primary amine group at one end and a secondary amine group at the other end.

[0167] In one embodiment, component C comprises or consists of one or more, for example one or two, polyoxyalkylene polymers, wherein each polymer has one or more terminal amino groups. Suitably, component C comprises one or more linear polyoxyalkylene monomer units having an amine group at each end.

[0168] In one embodiment, component C comprises a single linear polyoxyalkylene polymer having an amino group (suitably a primary or secondary amino group) at each end.

[0169] In another embodiment, component C comprises two or more (suitably two) linear polyoxyalkylene polymers, wherein each polymer has an amine group at each end, suitably a primary or secondary amino group.

[0170] In these embodiments, the secondary amine group can be the group NH(C 1-6 Alkyl), suitably NH(C 1-3 alkyl), such as NH(CH2CH3) or NH(CH3).

[0171] In one embodiment, component C is a compound of formula (X) or a mixture of two or more compounds of formula (X).

[0172]

[0173] wherein D is a core moiety, wherein in one embodiment, it comprises one or more moieties independently selected from the group consisting of alkyl, spiroalkyl, aryl, heteroaryl, alkylaryl, porphyrin, polymer, and macrocycle, wherein the alkyl, spiroalkyl, aryl, heteroaryl, and alkylaryl are optionally substituted (e.g., substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, fluoroalkyl, and fluoroalkoxy).

[0174] Suitably, D is a compound comprising one or more C 2-4 Polymers of oxyalkylene units (e.g., ethylene oxide units and / or propylene oxide units) (i.e., D is polyoxy C 2-4 olefins). The core portion D may contain a single C 2-4 Oxyalkylene units, but more preferably contain 2 to 100 C 2-4 A polymer of oxyalkylene units. In this case, the core portion is suitably a linear polymer.

[0175] When the core D is composed of two or more C 2-4 Since the length of the polymer chain varies from one polymer molecule to another, the number of oxyalkylene units is expressed as an average value.

[0176] In some cases, component C is a single compound of formula (X), wherein the average number of oxyalkylene units in the core portion D can be from about 2 to about 20, such as from about 2 to 10, 3 to 7, or 3.5 to 6.

[0177] Alternatively, component C can be a mixture of a first compound of formula (X) and a second compound of formula (X). For example, the first compound of formula (X) is a polymer wherein D is an average number of oxyalkylene units from about 2 to about 20, such as from about 2 to 10, 3 to 7, or 3.5 to 6, and the second compound of formula (X) is a polymer wherein D is an average number of oxyalkylene units from about 11 to about 100, such as from about 20 to about 60, or from 30 to 50.

[0178] In some compounds of formula (X), the oxyalkylene units will all be identical, for example, all oxyalkylene units will be ethylene oxide units, or all oxyalkylene units will be propylene oxide units.

[0179] The compound of other formula (X) comprises two or more different types of oxyalkylene units. For example, in the compound of formula (X), core part D can be a polymer comprising ethylene oxide units and propylene oxide units. It can exist in a fixed ratio on average, although the ratio may be different between the single molecules of oligomer or polymer. The assembly order of ethylene oxide units and propylene oxide units in the polymer structure is random and can vary between molecules.

[0180] In the compounds of formula (X), wherein D is a moiety, for example, comprising one or more C 2-4 A polymer of oxyalkylene units, suitably no linking group G is present and / or p is suitably 2.

[0181] As another alternative, D may be a polyalkylsiloxane moiety substituted with one or more primary and / or secondary amine groups, particularly one or more primary amine groups.

[0182] Likewise, in the polyalkylsiloxane compound of formula (X), the linking group G is suitably absent and / or p is suitably 2.

[0183] When the core portion D comprises an alkyl group (e.g., C 1-20 Alkyl, C 1-10 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl or C 1-6 The core portion D is an alkyl group (e.g., methyl or ethyl), which is optionally substituted with one or more substituents selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy. The alkyl group may be branched or unbranched. In one embodiment, the core portion D is an alkyl group.

[0184] When the core portion D comprises a spiroalkyl group (e.g. C 1-20 Spiroalkyl, C 1-10 Spiroalkyl or C 1-6When the core part D is a spiroalkyl group, it is optionally substituted by one or more substituents (e.g. selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy). In one embodiment, the core part D is a spiroalkyl group.

[0185] When core part D comprises aryl (for example 5-20 yuan aryl, 5-12 yuan aryl, 5-10 yuan aryl or 5-7 yuan aryl), it is optionally substituted by one or more substituents (for example selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy). "Aryl" used herein is a cyclic group with aromatic characteristics, such as phenyl or naphthyl. Aryl also includes diaryl and polyaryl. In a suitable embodiment, aryl is phenyl, which is optionally substituted by one or more substituents selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy. In one embodiment, core part D is aryl.

[0186] When core part D comprises heteroaryl, it is optionally substituted by one or more substituents (selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy). In one embodiment, heteroaryl is 5-10 yuan heteroaryl, for example pyrrole radical, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl or pyrazinyl. In one embodiment, core part D is heteroaryl.

[0187] When the core portion D comprises an alkylaryl group (eg, 1-10 alkyl) or substituted by an alkyl group (e.g., C 1-5 In one embodiment, the core portion D is an alkylaryl group.

[0188] In one embodiment, the core moiety D comprises a porphyrin, such as a tetra-4-aryl-meso. In one embodiment, the core moiety D is a porphyrin.

[0189] In one embodiment, the core part D comprises a polymer (e.g., a polyamine compound, a dendrimer or a hyperbranched polymer). In one embodiment, the polyamine compound is selected from the group consisting of polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane. In one embodiment, the core part D comprises polyethyleneimine (PEI), particularly branched polyethyleneimine. Suitably, the molecular weight of polyethyleneimine (particularly branched polyethyleneimine) is 10-1,000 kDa, such as about 10-50 kDa or 50-100 kDa. In one embodiment, the core part D comprises a dendrimer, such as a polyamine dendrimer, such as a PAMAM dendrimer or a PPI dendrimer. In one embodiment, the core part D is a polymer.

[0190] In one embodiment, the core moiety D is a macrocycle, such as a cyclodextrin. In one embodiment, the core moiety D is a macrocycle.

[0191] In one embodiment, the core portion D is a secondary amine group. In one embodiment, the core portion D comprises C 1-10 Alkylene, aryl, aryl-(CH2) 1-10 -aryl or –[CH2CH2NH] 1-20,000 – 。

[0192] G is an optional linker. In one embodiment, G includes the moiety -(CH2CH2NH) 1-5 -CH2CH2- In another embodiment, G is absent.

[0193] E is N (R z )H, where each R z Is H or C 1-6 More suitably, each R z independently H or C 1-3 In one embodiment, each E is NH2. In another embodiment, each E is NH(C 1-6 In another embodiment, p>1 and one or more E is NH2 and one or more E is NH(C 1-6 For example, when p is 2, the two E groups may be NH2 groups, or the two E groups may be NH(C 1-6 alkyl), such as NH(CH3), or one E group may be an NH2 group and the other E group may be NH(C 1-6 alkyl), such as NH(CH3).

[0194] The variable p is an integer of at least 1. In one embodiment, particularly when component C is a gel, p is from 1 to infinity, or more suitably from 2 to infinity. In one embodiment, p is 1-5,000,000, 2-5,000,000, 1-1,000,000, 2-1,000,000, 1-500,000, 2-500,000, 1-400,000, 2-400,000, 1-200,000, 2-200,000, 1-100,000, 2-100,000, 1-50,000, 2-5 or 0,000, 1-20,000, 2-20,000, 1-10,000, 2-10,000, 1-5,000, 2-5,000, 1-2,000, 2-2,000, 1-1,000, 2-1,000, 1-500, 2-500, 1-100, 2-100, 1-50, 2-50, 1-20, 2-20, 1-10, 2-10, 1-5, or 2-5.

[0195] In one embodiment, p is 2-500,000, 50-500,000, 100-500,000, 500-500,000, 1,000-500,000, or 5,000-500,000. In one embodiment, p is 1-200,000, 2-200,000, 50-200,000, 100-200,000, 500-200,000, 1,000-200,000, or 5,000-200,000. In one embodiment, p is 1-100,000, 2-100,000, 50-100,000, 100-100,000, 500-100,000, 1,000-100,000, or 5,000-100,000. In one embodiment, p is 1-50,000, 2-50,000, 50-50,000, 100-50,000, 500-50,000, 1,000-50,000, or 5,000-50,000. In one embodiment, p is 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, or 5,000-20,000. In one embodiment, p is 1-5,000, 2-5,000, 50-5,000, 100-5,000, 500-5,000, or 1,000-5,000. In one embodiment, p is 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, or 5,000-20,000. In one embodiment, p is 1-1,000, 2-1,000, 50-1,000, 100-1,000, or 500-1,000. In one embodiment, p is 1,000, 5,000, 20,000, 100,000, 200,000, or 500,000. In one embodiment, p is 11-44, 44-110, or 110-4200. In one embodiment, p is 1-10, 10-100, 100-6,200, or 1-infinity. In one embodiment, p is 1-1,000, for example, 1-500, 1-100, 1-50, 1-25, 1-20, or 1-10. In one embodiment, p is 2-100, for example, 2-50, 2-25, 2-20, or 2-10. In one embodiment, p is 1, 2, 3 or 4, for example, p is 2, 3 or 4, especially 2 or 3. In another embodiment, p is 5-10, for example, p is 5-8. In another embodiment, p is 5,000-100,000, 5,000-50,000 or 5,000-20,000.In another embodiment, p is 1-100,000, 2-100,000, 2-50,000, 2-20, 2-12, 2-5, 2-4, or 2-3.

[0196] In more suitable compounds of formula (X), p is at least 2, as this enables the formation of a polymer when the compound of formula (X) is reacted with a compound of formula (I) wherein m is at least 2. Most suitably, p is 2.

[0197] In some cases, component C is a single compound of formula (X). In other cases, component C is a mixture of two or more compounds of formula (X), for example, a mixture of two compounds of formula (X).

[0198] In one embodiment, component C is p-phenylenediamine.

[0199] In one embodiment, component C has the formula (Xx):

[0200]

[0201] wherein each x is independently 0-10.

[0202] In one embodiment, component C has the formula (Xxx):

[0203]

[0204] Where x is 0-10.

[0205] In one embodiment, component C has the formula (Xxy):

[0206] H2N-(CH2) x -NH2

[0207] Formula (Xxy)

[0208] Here, x is 1-10, for example, 3-8.

[0209] In one embodiment, component C is H2N-(CH2)6-NH2.

[0210] In one embodiment, component C is H2N-(CH2)4-NH2.

[0211] In one embodiment, component C has the formula (Xxz):

[0212]

[0213] Here, x is 0-10, for example, 1.

[0214] In other embodiments, component C comprises a compound of formula (Xu):

[0215]

[0216] Where X 1 Is a straight chain or branched C 2-4 Alkylene, r is a number representing the average number of oxyalkylene units per molecule, R x and R y Each is H or C 1-6 Alkyl, such as H or C 1-3 Alkyl, such as H, methyl or ethyl, especially H or methyl. In some suitable embodiments, Rx and Ry are both H. In other suitable embodiments, R x and R y In other suitable embodiments, R x and R y One is H, and R x and R y The other one is methyl.

[0217] The weight average molecular weight of the compound of formula (Xu) is generally about 100 to 10000 g / mol, for example 100 to 5000 g / mol, 100 to 1000 g / mol, 200 to 800 g / mol or 400 to 500 g / mol.

[0218] Examples of compounds of formula (Xu) include compounds of formula (Xva):

[0219]

[0220] It is based on a core D comprising propylene oxide units; and

[0221] Compounds of formula (Xvb):

[0222]

[0223]

[0224] It is based on a core D comprising ethylene oxide units.

[0225] In formulas (Xva) and (Xvb), R x and R y As defined above in formula (Xu).

[0226] In some cases, in the compound of Formula (Xu), r is 2-10.

[0227] Suitably, the compound of formula (Xu) is a compound of formula (Xva) or (Xvb), wherein the value of r is typically from about 2 to about 10, for example from about 3 to 7 or 3.5 to 6.

[0228] Alternatively, in the compound of formula (Xu), not all X 1 The groups are the same, for example, some X 1 The group may be an ethylene oxide unit, while other X 1 The group may be a propylene oxide unit. In this case, r is suitably from about 11 to about 100, for example, from about 20 to about 60 or from 30 to 50.

[0229] In some cases, when the compound of formula (Xu) is a polymer comprising ethylene oxide units and propylene oxide units, it may be a polymer of formula (Xw):

[0230]

[0231] wherein e, f and g are each independently a number representing the average number of oxyalkylene units per polymer molecule, and wherein

[0232] e and g are each independently 0 to 10, and the sum of e and g is 2 to 15; and

[0233] f is from about 2 to about 100;

[0234] The premise is that e and f are not 0 at the same time.

[0235] Suitably, e and g are each independently 1 to 8, more suitably 2 to 5, the sum of e and g is 2 to 10, more suitably about 4 to 8, and f is about 10 to 70, more suitably 20 to 60, most suitably 30 to 50.

[0236] The weight average molecular weight of the compound of formula (Xw) and similar polymers is typically about 100 to 10,000 g / mol, such as 100 to 5,000 g / mol, 100 to 1,000 g / mol, or 200 to 800 g / mol, such as about 600 g / mol.

[0237] In a further embodiment, component C comprises a mixture of two or more compounds of formula (Xu), for example, a mixture of two compounds of formula (Xu).

[0238] Suitably, component C comprises a mixture of a first compound of formula (Xu) and a second compound of formula (Xu).

[0239] The first compound of formula (Xu) may be a compound of formula (Xva) or formula (Xvb) as shown above, wherein the value of r is from about 2 to about 10, for example from about 3 to 7 or 3.5 to 6. More suitably, the first compound of formula (Xu) is a compound of formula (Xva).

[0240] In the second compound of formula (Xu), r is suitably from about 11 to about 100, for example, from about 20 to about 60 or from 30 to 50. In this compound, not all X 1 The groups are the same, for example, some X 1 The group may be an ethylene oxide unit, while other X 1 The groups may be propylene oxide units.

[0241] In a further embodiment, component C is an amine-functionalized polyalkylsiloxane of formula (Xt):

[0242]

[0243] Where R 20 , R 21 , R 22 and R 23 Each independently is C 1-6 Alkyl, more preferably C 1-4 Alkyl, R 24 H or C 1-4 Alkyl, especially H, X 2 Straight or branched chain C 1-6 Alkylene, more preferably a straight chain or branched C 1-4 Alkylene, especially (CH2) 2-4 , s and t are each independently an integer of about 10 to 400, more suitably about 50 to 250. Typically, the molecular weight of the amine-functionalized polyalkylsiloxane of formula (Xt) is from about 5000 g / mol to about 100000 g / mol, for example from about 20000 g / mol to 80000 g / mol or from about 30000 to 70000 g / mol, typically about 50000 g / mol.

[0244] An exemplary compound of formula (Xt) is an amine-functionalized polydimethylsiloxane (PDMS) wherein R 20 , R 21 , R 22 and R 23 Each of the R 24 It is H, X 2 Yes (CH2) 2-4 , especially (CH2)3.

[0245] In one embodiment, the exemplary compound has a weight average molecular weight of about 50,000 g / mol.

[0246] Formulas (Xw) and (Xt) are provided to illustrate the composition of the polymers, and it is understood that although e, f and g in formula (Xw) and s and t in formula (Xt) each independently represent the average number of monomer units in each polymer molecule, individual monomer units may appear in such a polymer without restriction in order.

[0247] Reaction of components B and C

[0248] When reacted together, components B and C form a chemical entity which, depending on the nature of components B and C, may be a compound, a copolymer or a polymer.

[0249] Figure 1A (Embodiment 1) shows the reaction between component B having a single thioester moiety and component C having a single amine moiety. The resulting chemical entity (compound) has one thiol group (thiol form / -SH form). When exposed to appropriate conditions (as described herein), the thiol can be converted to an S-nitrosothiol group (S-nitrosothiol / -SNO form).

[0250] Figure 1A (Embodiment 2) shows the reaction between component B having a single thioester moiety and component C having two amine moieties. The resulting chemical entity (compound) has two thiol groups (thiol form / -SH form). Similarly, the thiol group can be converted into an S-nitrosothiol group (S-nitrosothiol / -SNO form).

[0251] Figure 1A (Embodiment 3) shows the reaction between component B having two thioester moieties and component C having one amine moiety. The resulting chemical entity (compound) has two thiol groups (thiol form / -SH form). Similarly, the thiol group can be converted into an S-nitrosothiol group (S-nitrosothiol / -SNO form).

[0252] Figure 1B(Embodiment 4) shows the reaction between component B having two thioester parts and component C having two amine parts. In this embodiment, the reaction of components B and C results in a linear polymer. The resulting chemical entity (copolymer) has multiple thiol groups (thiol form / -SH form). Similarly, some / all thiol groups can be converted into S-nitrosothiol groups (S-nitrosothiol / -SNO form). It should be noted that although the figure shows that all-SH groups are converted into-SNO groups, this embodiment also covers copolymers in which only a portion of-SH groups are converted into-SNO groups. In a sub-embodiment of embodiment 4, component C is a mixture, and there is more than one D part. For example, there are two types of D, such as D1 and D2, and the product of the reaction of components B and C produces a linear polymer, wherein parts D1 and D2 are randomly distributed in the polymer chain.

[0253] Figure 1C (Embodiment 5) shows the reaction between component B having two thioester moieties and component C (which is a dendrimer, particularly PAMAM-GO). The resulting chemical entity (copolymer) has multiple thiol groups (thiol form / -SH form). Similarly, some / all thiol groups can be converted to S-nitrosothiol groups (S-nitrosothiol / -SNO form). It should be noted that although the figure shows that all -SH groups are converted to -SNO groups, this embodiment also covers copolymers in which only a portion of the -SH groups are converted to -SNO groups.

[0254] Figure 1D (Embodiment 6) shows the reaction between component B having four thioester moieties and component C having two amine moieties. The resulting chemical entity (copolymer) has multiple thiol groups (thiol form / -SH form). Similarly, some / all thiol groups can be converted to S-nitrosothiol groups (S-nitrosothiol / -SNO form). It should be noted that although the figure shows that all -SH groups are converted to -SNO groups, this embodiment also covers copolymers in which only a portion of the -SH groups are converted to -SNO groups.

[0255] Figure 1E(Embodiment 7) shows the reaction between component B having two thioester moieties and component C (which is PEI (polyethyleneimine)). The resulting chemical entity (cross-linked polymer) has multiple sulfhydryl groups (thiol form / -SH form). Similarly, some / all sulfhydryl groups can be converted into S-nitrosothiol groups (S-nitrosothiol / -SNO form). It should be noted that although the figure shows that all -SH groups are converted into -SNO groups, this embodiment also covers cross-linked polymers in which only a portion of -SH groups are converted into -SNO groups. As shown in the figure, cross-linking occurs between primary amines and secondary amines and between primary amines and secondary amines. It should be noted that the accompanying drawings are only representative, because depending on the amount of component B reacted with component C, more or less cross-linking can be formed.

[0256] Figure 1B Embodiments of , IC, 1D and 1E are advantageous because the reaction between component B and component C results in a polymeric chemical entity that is particularly suitable for use as a coating material.

[0257] Thus, when m in the compound of formula (I) (ie component B) is 2 or greater, for example 2, the chemical entity produced by the reaction with component C is a polymer.

[0258] In the case where component B has m of 2 and component C comprises a single compound (single monomeric compound or polymer), such as a compound of formula (X), the chemical entity resulting from the reaction between components B and C will be a copolymer having alternating units derived from components B and C. The synthesis of such chemical entities is shown below in Examples 17, 18, A2 and A3.

[0259] In other cases, the m of component B is 2, and component C comprises the mixture of the first component C compound and the second component C mixture.The first component C compound and the second component C compound can be single monomer compound or polymer, and for example can be the compound of different formula (X).In these cases, the chemical entity produced by reaction between component B and C will be multipolymer, and it comprises the unit derived from component B alternately with the unit derived from the first component C compound or the second component C compound.The order that the first component C compound and the second component C compound mix any given molecule of multipolymer will be random.The synthesis of this type of chemical entity is shown in the embodiment A4 below.

[0260] Figure 1B , 1CThe weight average molecular weight of the polymer of embodiments 1A, 1D and 1E is suitably from about 500 g / mol to 2,000,000 g / mol, for example from about 10,000 g / mol to 1,000,000 g / mol, 20,000 g / mol to 700,000 g / mol, 30,000 g / mol to 500,000 g / mol or 35,000 g / mol to 200,000 g / mol.

[0261] In one embodiment, the chemical entity comprises:

[0262]

[0263] and / or

[0264]

[0265] and / or

[0266]

[0267] and / or

[0268]

[0269] in,

[0270] A, L, n, R 1 , R 2 and D is as defined herein;

[0271] R s is H or N=O; and

[0272] q is 10-1000, for example, 15-500, 20-250 or 25-180.

[0273] In one embodiment, the chemical entity comprises:

[0274]

[0275] and / or

[0276]

[0277] and / or

[0278]

[0279] and / or

[0280]

[0281] Wherein, n is as defined herein;

[0282] x is 1-10, for example 2-6;

[0283] R s is H or N=O; and

[0284] q is 10-1000, for example, 15-500, 20-250 or 25-180.

[0285] Typically, such polymers have a weight average molecular weight (Mw) of about 10,000 to 100,000 g / mol, such as 20,000 to 80,000 g / mol or 30,000 to 60,000 g / mol.

[0286] In a further embodiment, the chemical entity comprises:

[0287]

[0288] and / or

[0289]

[0290] and / or

[0291]

[0292] and / or

[0293]

[0294] x is 1-10, for example 2-6;

[0295] R s is H or N=O; and

[0296] q is 10-1000, for example, 15-500, 20-250 or 25-180.

[0297] Typically, such polymers have a weight average molecular weight (Mw) of about 10,000 to 100,000 g / mol, such as 20,000 to 80,000 g / mol or 30,000 to 60,000 g / mol.

[0298] The synthesis of such polymers is described in Example A2 below.

[0299] In another embodiment, the chemical entity comprises:

[0300]

[0301] and / or

[0302]

[0303] and / or

[0304]

[0305] and / or

[0306]

[0307] Among them, n, X 1 and r is as defined herein;

[0308] R s is H or N=O;

[0309] R x and R y As defined above in formula (Xu), and

[0310] q is 10-1000, for example, 15-500, 20-250 or 25-180.

[0311] The unit-X of the chemical entity 1 -O-(X 1 -O) r -X 1 Derived from component C, which is a compound of formula (Xu) or a mixture of compounds of formula (Xu).

[0312] In some cases, component C comprises or consists of a single compound of formula (Xu). The compound of formula (Xu) may be a compound of formula (Xva) or formula (Xvb) as defined above, wherein the value of r is 2 to 10, for example 3 to 7 or 3.5 to 6. The synthesis of such polymers is described in Example A3 below.

[0313] The weight average molecular weight (Mw) of such polymers may be about 15,000 g / mol to 100,000 g / mol, for example, 20,000 g / mol to 80,000 g / mol or 30,000 g / mol to 60,000 g / mol.

[0314] In other cases, component C can be a mixture, for example, component C can contain two or more compounds of formula (Xu) or consist of two or more compounds of formula (Xu). Suitably, in this case, component C consists of a first compound of formula (Xu) and a second compound of formula (Xu).

[0315] The first compound of formula (Xu) may be a compound of formula (Xva) or (Xvb) as defined above, wherein the value of r is 2 to 10, such as 3 to 7 or 3.5 to 6.

[0316] The second compound of formula (Xu) may be a compound in which not all X 1The groups are the same, for example, some X 1 The group may be an ethylene oxide unit, and other X 1 The group may be a propylene oxide unit. In this case, r is suitably from about 11 to about 100, for example, from about 20 to about 60 or from 30 to 50.

[0317] The synthesis of a polymer formed by reacting Component B with Component C, which includes a first and a second compound of Formula (Xu), is shown in Example A4.

[0318] Typically, such polymers have a weight average molecular weight (Mw) of about 10,000 to 200,000 g / mol, such as 30,000 to 150,000 g / mol or 45,000 to 100,000 g / mol.

[0319] In a further embodiment, the chemical entity comprises:

[0320]

[0321] Among them, R 1 , R 2 , R 20 , R 21 , R 22 , R 23 , n, X 2 , s and t are as defined herein;

[0322] R s is H or N=O; and

[0323] x is 1-10, suitably 1-6, and more suitably 1-4.

[0324] Some such polymers have a weight average molecular weight of about 50,000 to 200,000 g / mol, such as about 100,000 g / mol. In other cases, the polymer is cross-linked and has an infinite weight average molecular weight.

[0325] The synthesis of such polymers is described in Example 18 below.

[0326] The chemical entity formed by the reaction of component B with component C may be unstable, as described below. The unstable nature of the entity is usually caused by one (or both) of components B and / or C containing a labile group.

[0327] Thus, in one embodiment, the chemical entity (e.g., core portion A (component B) and / or core portion D (component C)) comprises a labile moiety, e.g., a moiety that is labile by hydrolysis or nucleophilic substitution, e.g., a moiety containing one or more functional groups independently selected from the group consisting of esters, anhydrides, imines, imines, acetals, carbonates, phosphazenes, phosphates, carbamates, lactides, and lipolactones. In one embodiment, the chemical entity comprises a biocompatible, semi-crystalline, hydrolytically degradable polymer, such as polydioxanone (PDO), polyglycolide (PGA), polylactide (PLA), poly(s-caprolactone), polyanhydrides such as polysebacic acid, polyhydroxyalkanoates such as poly(3-hydroxybutyrate) (P30HB), or copolymers of these polymers, such as polyglycolide / trimethylene carbonate (PGA / TMC, e.g., 2:1 PGA / CMC), polylactide / trimethylene carbonate (PLA / TMC), or polyhydroxybutyrate / hydroxyvalerate (PHB / PHV).

[0328] Moieties may also be unstable by reduction-oxidation, such as moieties containing one or more functional groups independently selected from the group consisting of oxides, superoxides, ozone, oxyacids, halites, hypohalites, and hypohalous acids.

[0329] The moiety may also be labile by photolysis (eg, by ultraviolet or visible light), such as a moiety containing one or more functional groups independently selected from benzoylcarbonyl and azide.

[0330] When a chemical entity is incorporated into a coating on a surface, the chemical entity / substrate / coating may degrade over time, or be resorbed over time, depending on the degree of instability of the chemical entity and the distribution of the chemical entity within the bulk substrate or within the surface coating.

[0331] In one embodiment, the chemical entity / substrate / coating is bioresorbable, meaning that the chemical entity / substrate / coating is substantially broken down by the in vivo environment within a period of 1 to 48 months (e.g., 1 to 36 months, 1 to 24 months, 2 to 18 months, or 1 to 12 months).

[0332] The thiol (-SH) form is converted to the S-nitrosothiol (-SNO) group

[0333] Chemical entities in the form of thiol (-SH) can be modified so that at least a portion of the sulfhydryl groups are converted to S-nitrosothiol (-SNO) groups. Such reagents and techniques are well known to those of ordinary skill in the art and include, but are not limited to, reaction with aqueous nitric acid (e.g., formed in situ using sodium nitrite) or, when the reaction is carried out in an organic medium, reaction with an alkyl nitrite such as tert-butyl nitrite.

[0334] In one embodiment, relative to the mole % of component B, the chemical entity has 20-100% thiol (-SH) groups, such as 30-100%, 40-100%, 50-100%, or 60-100% free SH groups.

[0335] In one embodiment, relative to the mole % of component B, the chemical entity has 20-100% S-nitrosothiol (-SNO) groups, such as 30-100%, 40-100%, 50-100%, or 60-100% free SH groups.

[0336] Medical devices and materials

[0337] The thiol-containing and S-nitrosothiol-containing chemical entities disclosed herein are particularly suitable for coating surfaces of medical devices. In at least some embodiments, the coating is uniform and uninterrupted (ie, defect-free) and / or is expected to have good adhesion to the surface and / or low brittleness.

[0338] The medical devices of the present disclosure are suitable for a wide range of applications, including, for example, a range of medical applications in vivo. Exemplary applications include: use as a catheter balloon, for transferring drugs to an implanted stent, stent graft, or vascular graft, placing an implanted stent, stent graft, or vascular graft, or "modifying" an implanted stent, stent graft, or vascular graft, use as a stent, stent graft, catheter, permanent or temporary prosthesis, or other type of medical implant, treat target tissue in vivo and treat any body cavity, space, or hollow organ passage (such as blood vessels, urinary tract, intestinal tract, nasal or sinus cavity, nerve sheath, intervertebral area, bone cavity, esophagus, uterine cavity space, pancreas and bile duct, rectum and body spaces that have been previously intervened with implantable vascular grafts, stents, prostheses or other types of medical implants).

[0339] Other examples of medical devices include indwelling monitoring devices, artificial heart valves (leaflets, stents and / or cuffs), pacemaker or defibrillator electrodes, guidewires, cardiac catheters, sutures, thrombus filters, vascular filters, cardiopulmonary bypass circuits, cannulas, plugs, drug delivery devices, tissue patch devices, blood pumps, patches, bone prostheses, long-term infusion lines, arterial lines, continuous subarachnoid infusion devices, feeding tubes, CNS shunts (e.g., ventriculothoracic shunts, ventriculo-atrial (VA) shunts, or ventriculoperitoneal (VP) shunts), ventriculoperitoneal shunts, ventriculoatrial shunts, portosystemic shunts, and ascites shunts, devices for filtering or removing obstructions such as emboli and thrombi from blood vessels, dilation devices for restoring patency of blocked body passages, occlusion devices for selectively delivering devices to occlude or fill passages or spaces, and centering mechanisms for use as transluminal devices such as catheters. In one embodiment, the medical device can be used to treat stent restenosis or to treat a tissue site where a previously placed drug eluting structure has failed. In another embodiment, the medical device herein can be used to establish, connect or maintain arteriovenous access sites, such as those used during renal dialysis.

[0340] Other examples of medical devices that may be permanent or temporary are catheters. Examples of catheters include, but are not limited to, central venous catheters, peripheral venous catheters, hemodialysis catheters, catheters such as coated catheters including implantable intravenous catheters, tunneled venous catheters, arterial catheters that can be used for angiography, angioplasty, or ultrasound procedures in the heart or peripheral veins or arteries, hepatic artery infusion catheters, CVCs (central venous catheters), peripheral venous catheters, peripherally inserted central venous catheters (PIC lines), flow-directed balloon pulmonary artery catheters, total parenteral nutrition catheters, long-term residence catheters (e.g., long-term residence gastrointestinal catheters and long-term residence urogenital catheters), peritoneal dialysis catheters, CPB catheters (cardiopulmonary bypass), urinary catheters, and microcatheters (e.g., for intracranial applications). The catheter may be indwelling.

[0341] In one embodiment, the medical device is an expandable element. In another embodiment, the medical device is a balloon, a stent, a stent graft, or a graft.

[0342] Thus, in one embodiment, the medical device is an expandable element, which can be a balloon, an expandable catheter, a stent, a stent graft, a self-expanding structure, a balloon expandable structure, a combination of self-expanding and balloon self-expanding structures, a graft or a mechanical, radially expandable device that can be expanded, for example, by using torque or longitudinal force. Expandable elements may also include those that expand due to pneumatic pressure or hydraulic pressure, those that expand due to magnetic force, those that expand due to the use of energy (e.g., heat, electricity, or ultrasonic (piezoelectric) energy). The expandable element can be temporarily placed in any lumen (e.g., a blood vessel) by expanding the device and then the device is collapsed by torque or longitudinal force to be removed. The chemical entities described herein can be used to coat the surface of the device used in early cannulation. Thus, in one embodiment, the surface having a coating comprising the chemical entity described herein is an early cannulation graft. In another embodiment, an early cannulation graft comprising a surface having a coating is provided, the coating comprising the chemical entity described herein.

[0343] In one embodiment, the medical device is a stent, such as a bifurcated stent, a balloon expandable stent or a self-expanding stent. The stent is constructed as a braid, a winding form, a laser cutting form, a deposited material, a 3D printing construct or a combination thereof, or other structural forms are adopted, including those structural forms with length adjustability, which provide support to the cavity wall or region. The stent is composed of a biocompatible material including metals, metal alloys such as stainless steel and nickel-titanium alloys (NiTi), polymers, ceramics, biodegradable materials (such as biodegradable polymers, ceramics, metals and metal alloys) or a combination thereof. The stent can be a basic single form, or include separated components, for example, a ring. Whether it is single or composed of components, the stent structure can be joined together by struts, hinges, connectors, or materials arranged or covering the stent in whole or in part. In one embodiment, the stent structure is joined with a "net" formed by a fluoropolymer described in US2009 / 0182413 (Gore Enterprise Holdings, Inc., incorporated herein by reference).

[0344] In one embodiment, the medical device is a stent, such as a bifurcated stent, a balloon expandable stent, or a self-expanding stent. In one embodiment, the medical device is a stent formed of a metal, a metal alloy, a polymer, a ceramic, a biodegradable material, or a combination thereof.

[0345] In one embodiment, the medical device is a stent graft. The stent graft combines at least one stent element with a graft assembly. The graft is generally constructed as a tubular element with a closed wall and a wall with an opening. The graft material includes a biocompatible material, such as a fluoropolymer, including polytetrafluoroethylene (PTFE) and expanded polytetrafluoroethylene (ePTFE). Other suitable graft materials include polymers, such as polyethylene terephthalate and ultra-high molecular weight polyethylene (UHMWPE). The graft material can have different strengths, densities, sizes, porosities and other functional properties, and can be a film, an extrudate, an electrostatic spinning material, a coating, a deposit or a molded article. The graft can be used alone, or the graft material can be arranged along the stent structure or cover the stent structure in whole or in part. In one embodiment, the stent graft can adopt the form described in US5,876,432 (Gore Enterprises Holdings, incorporated herein by reference).

[0346] In one embodiment, the medical device is a stent graft, wherein the graft is formed from a polymer, suitably a biocompatible polymer. Suitably, the graft is formed from a fluoropolymer such as expanded polytetrafluoroethylene (ePTFE). In one embodiment, the medical device is a graft.

[0347] Stents, stent grafts and grafts can be covered with various materials such as polymers and primer layers. In one embodiment, the stent or graft structure is modified to enhance the ability of the device to accommodate or release the therapeutic agent applied to the device. For example, a pit or blind hole can be formed in the stent strut loaded with the therapeutic agent. When coated on a stent, stent graft or graft, the composition will release the therapeutic agent in a local manner, so the stent, stent graft or graft coated with the disclosed composition is referred to as a drug eluting stent (DES) in this article.

[0348] In one embodiment, the medical device is a medical airbag. The airbags available in the embodiments of the present disclosure can be formed by using any conventional method, such as extrusion, blow molding and other molding techniques. The airbags can be compliant, semi-compliant, or non-compliant, and can have different lengths, diameters, sizes and shapes. The airbags can also be referred to as "conformable" or "conforming", "adjustable in length" or "steerable" airbags. In another embodiment, the medical device may include: an airbag constructed of a wrapping film, an airbag wound by a fiber, an airbag with a variable length, a segmented airbag and / or an airbag with a controlled or variable expansion profile. In other embodiments, the airbag can be covered with a material, or can include more than one layer, or can have a composite structure. In one embodiment, the airbag surface or structure is modified to enhance the ability of the airbag to accommodate or release a therapeutic agent applied thereto. For example, the airbag can be folded in a way to keep the therapeutic agent in the fold. When coated onto a balloon, the composition will release the therapeutic agent in a localized manner, and thus, a balloon coated with the composition of the present disclosure is referred to herein as a drug eluting balloon (DEB).

[0349] In one embodiment, the medical device is selected from the following group: stents, including bifurcated stents, balloon-expandable stents and self-expanding stents; stent grafts, including bifurcated stent grafts; grafts, including vascular grafts, bifurcated grafts and early catheter grafts; dialators; vascular occluders; thrombus filters; vascular filters; embolectomy devices; catheters, including microcatheters, central venous catheters, peripheral venous catheters, indwelling catheters and hemodialysis catheters; artificial blood vessels; sheaths, including retractable sheaths; blood indwelling monitoring devices; artificial heart valves; pacemaker electrodes; guidewires; cardiac pacemaker electrodes (cardiac leads); cardiopulmonary bypass circuits; cannulas; plugs; drug delivery devices; balloons; tissue patch devices; blood pumps; artificial pancreas devices; cell encapsulation devices; implantable sensor devices; embolic particles; drug-releasing particles and liquid embolic agents.

[0350] In one embodiment, the medical device, in particular the surface of the medical device, is composed of synthetic or natural organic or inorganic polymers or materials, including but not limited to the following materials, such as: polyolefins, polyesters, polyurethanes, polyamides, polyether block amides, polyimides, polycarbonates, polyphenylene sulfides, polyphenylene oxides, polyethers, silicones, polycarbonates, polyhydroxyethyl methacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, rubber, silicone rubber, polyhydroxy acids, polyallylamines, polyallyl alcohols, polyacrylamides, and polyacrylic acids, styrene polymers, polytetrafluoroethylene and copolymers thereof, expanded polytetrafluoroethylene and copolymers thereof, derivatives thereof and mixtures thereof, fluoropolymers such as VDF-HDF polymers, TFE-vinyl acetate copolymers or TFE-vinyl alcohol copolymers (see, for example, US10688188 and WO2021 / 097210 and WO2021 / 150962, both of which are incorporated herein by reference). Some of these categories are both thermosetting and thermoplastic polymers. As used herein, the term "copolymer" shall be used to refer to any polymer formed from two or more monomers (e.g., 2, 3, 4, 5, etc.). Bioresorbable materials such as poly(D,L-lactide) and polyglycolide and copolymers thereof may also be used. Nonwoven, bioresorbable mesh materials comprising triblock copolymers such as poly(glycolide-co-trimethylene carbonate) triblock copolymer (PGA:TMC) may also be used (described in US 7,659,219; Biran et al., which are incorporated herein by reference). Useful polyamides include, but are not limited to, nylon 12, nylon 11, nylon 9, nylon 6 / 9, and nylon 6 / 6. Examples of some copolymers of these materials include those based on Polyether-block-amides are available from Elf Atochem North America in Philadelphia, Pennsylvania under the trade name of HYTREL. Another suitable copolymer is a polyetheresteramide. Suitable polyester copolymers include, for example, polyethylene terephthalate and polybutylene terephthalate, polyester ether and polyester elastomer copolymers, such as those available from DuPont in Wilmington, Delaware under the trade name HYTREL.RTM. Block copolymer elastomers may also be used herein, such as those copolymers having styrene end blocks, and midblocks formed from butadiene, isoprene, ethylene / butylene, ethylene / propylene, etc. Other styrenic block copolymers include: acrylonitrile-styrene and acrylonitrile-butadiene-styrene block copolymers. In addition, specific thermoplastic elastomer block copolymers may also be used herein, wherein the block copolymer is made of a hard segment of a polyester or polyimide and a soft segment of a polyether. Other useful materials are polystyrene, poly(methyl)methacrylate, polyacrylonitrile, poly(vinyl acetate), poly(vinyl alcohol), chlorine-containing polymers such as poly(vinyl chloride), polyoxymethylene, polycarbonate, polyamide, polyimide, polyurethane, phenols, amino-epoxy resins, polyesters, silicones, cellulose-based plastics, and rubber-like plastics. Combinations of these materials can be used with and without crosslinking. The polymeric material can optionally be blended with fillers and / or colorants, such as gold, barium or tantalum fillers, to render the polymeric material radiopaque. The polymeric material can optionally be modified on its surface using methods known in the art while retaining the overall properties, such as acid or base etching, hydrolysis, aminolysis, plasma modification, plasma implantation, corona discharge modification, chemical vapor deposition, ion implantation, ion sputtering, ozonation, photomodification, electron beam modification, gamma-beam modification, and the like.

[0351] In one embodiment, the surface of the medical device comprises nylon.

[0352] In one embodiment, the medical device, in particular the surface of the medical device, is biocompatible and comprises a polyether-block-amide (e.g. ).

[0353] The medical device, in particular the surface of the medical device, may comprise one or more fluorinated polymers, such as fluoropolymers, such as expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene (FEP), perfluorocarbon copolymers, such as tetrafluoroethylene perfluoroalkyl vinyl ether (TFE / PAVE) copolymers, polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene (FEP), perfluorocarbon copolymers, such as tetrafluoroethylene perfluoroalkyl vinyl ether (TFE / PAVE) copolymers, copolymers of tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE), copolymers of TFE and functional monomers containing acetic acid, alcohol, amine, amide, sulfonic acid functional groups, etc., such as U.S. Pat. No. 8,658,707 (WL Gore Associates, Inc. (WL Gore and Associates, Inc.), which are incorporated herein by reference), and the like, and combinations thereof (see also US 10,688,188 and WO 2021 / 097210 and WO 2021 / 150962, all of which are incorporated herein by reference). Combinations of the above with and without crosslinking between polymer chains, expanded polyethylene, polyvinyl chloride, polyurethane, silicone, polyethylene, polypropylene, polyurethane, polyglycolic acid, polyester, polyamide, elastomers, and mixtures, blends, and copolymers or derivatives thereof are also contemplated. ePTFE has a porous microstructure that is particularly compatible with the coatings disclosed herein. Suitably, the surface of the medical device comprises ePTFE.

[0354] As used herein, the term "porous" refers to a material having openings (e.g., spaces (or pores) between ePTFE nodes and fibrils). Typically, in the case of ePTFE, the pores of a porous material contain air when the material is not "wetted," i.e., when the material is not in contact with a liquid that fills the pores and displaces the air. The porosity of a device comprising ePTFE can be assessed using various methods and parameters described in US2013 / 0231733 (WL Gore & Associates, Inc., which is incorporated herein by reference).

[0355] Medical devices, in particular the surfaces of medical devices, may also contain one or more metals, including but not limited to: biocompatible metals, titanium, stainless steel, high nitrogen stainless steel, gold, silver, rhodium, zinc, platinum, rubidium, copper and magnesium, and combinations thereof. Suitable alloys include: cobalt alloys, including cobalt-chromium alloys such as L-605, MP35N, Elgiloy; titanium alloys, including nickel-titanium alloys (such as Nitinol; tantalum; and niobium alloys such as Nb-1% Zr; and others. In one embodiment, the medical device is a stent and comprises a biocompatible metal selected from stainless steel, tantalum, titanium alloys and cobalt alloys. Medical devices, in particular the surfaces of medical devices, may also contain ceramic substrates, including but not limited to silicon oxides, aluminum oxides, aluminum oxides, silicon dioxide, hydroxyapatite, glass, calcium oxide, polysilanol and phosphorus oxides.

[0356] In one embodiment, the medical device is covered with a porous material to which a coating layer of the present disclosure is applied. In one embodiment, at least a portion of the surface of the device to be coated is porous. In one embodiment, the medical device covering material is a fluoropolymer, such as polytetrafluoroethylene (PTFE) or expanded PTFE (ePTFE). The structure of expanded PTFE is characterized by nodes interconnected by fibrils, as described in U.S. Patents Nos. 3,953,566 and 4,187,390 (WL Gore Associates, Inc., both patents are incorporated herein by reference). In one embodiment, the fluoropolymer medical device covering includes ePTFE having a material structure with fibrils, or fibrils and nodes. In another embodiment, the fibrils or fibrils and nodes vary in size, dimension or orientation as the size of the expandable element covering changes. In one embodiment, the medical device is an airbag, on which a covering is at least partially provided, the covering is at least partially made of ePTFE, and the covering provided on at least a portion of the ePTFE airbag is a coating of the present disclosure.

[0357] In one embodiment, a medical device comprises a covering disposed around at least a portion of a coating layer of the present disclosure. The covering may also be described as a sleeve. In one embodiment, the covering is removable from above the coating layer. In one embodiment, the covering is disposed above a coating layer of the present disclosure applied to an expandable element. The covering may comprise any biocompatible material, including any material having porosity or permeability. In one embodiment, the porosity or permeability changes as the material deforms or otherwise changes in size.

[0358] Materials that may exhibit porosity or permeability that varies with the size of the covering include, but are not limited to: fibrillated structures, such as expanded fluoropolymers (e.g., expanded polytetrafluoroethylene (ePTFE) or expanded polyethylene (as described in U.S. Pat. No. 6,743,388 (Sridharan et al.), which is incorporated herein by reference); fibrous structures (e.g., woven or knitted fabrics; nonwoven mats of fibers, microfibers, or nanofibers; materials prepared by processes such as electrospinning or flash spinning; polymeric materials such as fluoropolymers, polyamides, polyurethanes, polyolefins, polyesters, polyglycolic acid (PGA), polylactic acid (PLA), and trimethylene carbonate (TMC), etc., comprising or consisting of melt- or solution-processable materials; membranes having openings created during processing (e.g., laser- or mechanical-drilling); open-cell foams; microporous membranes made from materials such as fluoropolymers, polyamides, polyurethanes, polyolefins, polyesters, PGA, PLA, etc. and TMC, etc.; porous polyglycolide-co-trimethylene carbonate (PGA:TMC) materials (as described in U.S. Patent No. 8,048,503 (Gore Enterprise Holdings Company), which is incorporated herein by reference); or combinations thereof. Processing of the above materials can be used to adjust, increase or control porosity or permeability between a first closed state and a second more porous or permeable state. The processing can help make the material structure closed (thereby reducing porosity or permeability) in the first state, help make the material structure open in the second state, or a combination of both. The processing that can help make the material structure closed can include, but is not limited to: calendaring, coating (intermittent or continuous), compression, densification, coagulation, thermal cycling, or shrinkage, etc. The processing that can help make the structural material open includes, but is not limited to: expansion, perforation, cutting, pattern densification and / or coating, etc. In another embodiment, the material contains pores between fibrils, or between nodes interconnected by fibrils, such as pores in ePTFE.

[0359] Those skilled in the art will appreciate a variety of methods for characterizing changes in porosity or permeability by comparing a test conducted at a first state with a test conducted at a second state. These methods include, but are not limited to, characterization of gas or liquid flow across a material structure at a certain pressure differential, criteria for determining the pressure differential of different flows impacting through a material structure, such as water entry pressure or bubble point, and visual criteria as measured from images (e.g., images from a scanning electron microscope or optical microscope).

[0360] In one embodiment, the covering material is a fluoropolymer such as expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), a perfluorocarbon copolymer, such as a tetrafluoroethylene perfluoroalkyl vinyl ether (TFE / PAVE) copolymer, a copolymer of tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE), or a copolymer of TFE and a functional monomer including acetic acid, alcohol, amine, amide, sulfonic acid / sulfonate / sulfonate functional groups, etc., as described in U.S. Pat. No. 8,658,707 (WL Gore and Associates, incorporated herein by reference), and combinations thereof. In another embodiment, the fluoropolymer covering has a material structure that changes as the size of the covering changes. In one embodiment, the fluoropolymer covering includes ePTFE having a material structure with fibrils, or fibrils and nodes. In another embodiment, the fibrils, or fibrils and nodes change in size, dimension, or orientation as the size of the covering changes. In one embodiment, the medical device is a balloon having a covering at least partially disposed thereon, the covering being at least partially made of ePTFE, and the material structure of the ePTFE changes when the balloon is inflated.

[0361] In another embodiment, the medical device is a balloon having at least partially disposed thereon a coating layer of the present disclosure, which is then at least partially covered with a covering (e.g., a sleeve) at least partially made of ePTFE, and the material structure of the ePTFE changes when the balloon is inflated.

[0362] In one embodiment, the covering is substantially hydrophobic and is treated to render it hydrophilic by the method described in US 2013 / 0253426 (WL Gore & Associates, incorporated herein by reference). In another embodiment, the covering comprises a film or film tube of ePTFE.

[0363] In another embodiment, the surface or outward configuration of the covering material can be modified with textures, protrusions, lines, blades, spikes, notches, depressions, grooves, coatings, particles, etc. In another embodiment, the surface or outward configuration of the covering material can be modified with needles, catheters, etc. These modifications can be used for a variety of purposes, for example, to modify the tissue to which the therapeutic agent will be (or has been) delivered, to control the placement of the disclosed system, and to direct fluid transfer. The texture can help increase the transfer of the therapeutic agent to deeper tissues, or deeper and / or into deeper tissues. The texture can consist of the covering material, or can consist of an additional material.

[0364] In another embodiment, the location of the permeable microstructure can be varied. For example, the covering can be constructed so that only a portion of its microstructure is variably permeable. This configuration may be desirable where transfer is undesirable, for example, at one or both ends of the expandable medical device of the present disclosure. This may be desirable when multiple drug eluting devices are used for specific anatomy, but it is not desirable for overlapping treatment locations (i.e., when delivering too much drug to a specific location).

[0365] In another embodiment, the covering may contain or be marked with a radiopaque marker, or be constructed entirely to be radiopaque. Clinicians use such radiopaque indicators to properly track and place the expandable medical devices of the present disclosure.

[0366] The coating of the present disclosure can be applied to the entire surface of the medical device, or only to a portion of the medical device surface. Certain devices may have an outer surface and an inner surface, one or both of which may be coated. For example, a tubular substrate including but not limited to an artificial blood vessel, a vascular graft, a stent, and a stent graft has an inner surface or cavity that can be coated independently of the outer surface. A device comprising an inner surface and an outer surface may require coating only on the outer surface. Conversely, only the inner surface may require coating. In one embodiment, the amount or thickness of the coating may vary on the surface of the medical device. The coating layer may be continuous or discontinuous over the entire surface of the device and cover only a portion or a separate portion of the device. The coating layer may also be "carved" or modified to produce a desired surface topography or modified with a texture, as described above.

[0367] In one embodiment, the coating may also be applied to the medical device in liquid form (US10688188, WO2021 / 097210, both of which are incorporated herein by reference) or as nanoparticles (WO2021 / 150962, which is incorporated herein by reference).

[0368] In one embodiment, up to 99% (e.g., up to 95%, 90%, 75%, 50%, or 25%) of the surface area of ​​the medical device is coated with a chemical entity of the present disclosure. In one embodiment, both the outer and inner surfaces of the medical device are coated. In another embodiment, only the outer surface of the medical device is coated.

[0369] The surface having a coating comprising a chemical entity described herein may include one or more additional coatings. In one embodiment, the additional coating is selected from the group consisting of synthetic or naturally occurring organic or inorganic polymers or materials such as polyolefins, polyesters, polyurethanes, polyamides, polyether block amides, polyimides, polycarbonates, polyphenylene sulfides, polyphenylene oxides, polyethers, silicones, polycarbonates, polyhydroxyethyl methacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, rubber, silicone rubber, polyhydroxy acids, polyallylamines, polyallyl alcohols, polyacrylamides, polyacrylic acids, styrene polymers, fluoropolymers (e.g., expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluorocarbon copolymers, polystyrene ... Polymers (e.g., tetrafluoroethylene-perfluoroalkyl vinyl ether (TFE / PAVE) copolymers, copolymers of tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE)), copolymers of TFE and functional monomers (the functional monomers include acetates, alcohols, amines, amides, sulfonates, functional groups, etc., such as U.S. Pat. No. 8,658,707 (WL Gore & Associates, incorporated herein by reference, and combinations thereof (see also US10688188 and WO2021 / 097210 and WO2021 / 150962, all of which are incorporated herein by reference) and VDF-HFP), biocompatible Absorbent materials such as poly(D,L-lactide), polyglycolide and copolymers thereof, nonwoven, bioabsorbable mesh materials comprising triblock copolymers such as poly(glycolide-co-trimethylene carbonate) triblock copolymer (PGA:TMC), nylon 12, nylon 11, nylon 9, nylon 6 / 9 and nylon 6 / 6, polyetheresteramides, polyethylene terephthalate and polybutylene terephthalate, polyester ethers, polyester elastomeric copolymers, block copolymer elastomers such as those having styrene end blocks and a midblock formed from butadiene, isoprene, ethylene / butylene, ethylene / propylene, etc., styrene block copolymers, polystyrene ... Block copolymers, including: acrylonitrile-styrene and acrylonitrile-butadiene-styrene block copolymers, polystyrene, poly(methyl)methacrylate, polyacrylonitrile, poly(vinyl acetate), poly(vinyl alcohol), chlorine-containing polymers such as poly(vinyl chloride), polyoxymethylene, polycarbonate, polyamide, polyimide, polyurethane, phenolic / phenolic materials, amino-epoxy resins, polyesters, silicones, cellulose-based plastics, rubber-like plastics, expanded polyethylene, polyvinyl chloride, polyurethanes, silicones, polyethylene, polypropylene, polyurethanes, polyglycolic acid, polyesters, polyamides, elastomers and mixtures, blends and copolymers or derivatives thereof.

[0370] At least one of the one or more additional coatings can include a therapeutic agent, such as a therapeutic agent selected from the group consisting of antithrombotic agents, anticalcific agents, hemostatic agents, antiangiogenic agents, angiogenic agents, antimicrobial agents, antiproliferative agents, proliferative agents, and anti-inflammatory agents, or combinations thereof.

[0371] In one embodiment, at least one of the one or more additional coatings comprises a therapeutic agent selected from the group consisting of cilostazol, mTOR inhibitors (e.g., sirolimus, zotarolimus, tacrolimus, or everolimus), dicoumarol, dicoumarol complexed with an appropriate cyclodextrin, carvedilol; antithrombotic agents (e.g., heparin, heparin derivatives, urokinase, dextrorotatory phenylalanine) proline, polyproline, arginine, polyarginine, lysine, polylysine, chloromethyl ketone; anti-inflammatory agents (e.g., dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, or mesalazine); anti-tumor / anti-proliferative / anti-miotic agents (e.g., taxane domain-bound drugs, such as paclitaxel and its analogs, macrolides, picrotoxin, docetaxel, paclitaxel protein-bound particles such as (ABRAXANE is a registered trademark of ABRAXISBIOSCIENCE, LLC), paclitaxel complexed with a suitable cyclodextrin (or cyclodextrin-like molecule), rapamycin, rapamycin analogs, rapamycin complexed with a suitable cyclodextrin (or cyclodextrin-like molecule), 17β-estradiol, 17β-estradiol complexed with a suitable cyclodextrin, β-lapachone or its analogs, 5-fluorouracil, cisplatin, vinblastine, cladribine, vincristine, epothilone, endostatin, angiostatin, angiopeptin, monoclonal antibodies capable of blocking smooth muscle cell proliferation, thymidine inhibitors; lytic agents; anesthetics (such as lidocaine, bupivacaine or ropivacaine); anticoagulants (such as D-Phe-Pro-Arg chloroquine, peptide compounds containing RGD, AZX100 cell peptides that mimic HSP20 (Capstone Therapeutics, Inc. Corp., USA), heparin, hirudin, antithrombin compounds, platelet receptor antagonists, antithrombin antibodies, antiplatelet receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors, or tick antiplatelet peptides); vascular cell growth promoting factors such as growth factors, transcription activators, translation promoters, vascular cell growth inhibitors, growth factor inhibitors, growth factor antibody antagonists, transcription repressors, translation repressors, replication inhibitors, inhibitory antibodies, antibodies against growth factors, functional molecules composed of growth factors and cytotoxins, bifunctional molecules composed of antibodies and cytotoxins; protein kinases and Tyrosine kinase inhibitors (e.g., tyrosine phosphorylation inhibitors, genistein, quinoxaline); prostacyclin analogs; cholesterol-lowering agents; angiogenin; antimicrobial agents (such as triclosan, cephalosporins, aminoglucosides or nitrofurantoin), cytotoxic agents, cell growth inhibitors, cell proliferation-affecting factors, vasodilators; agents that interfere with the mechanism of endogenous vascular action; leukocyte recruitment inhibitors (monoclonal antibodies or cytokines), hormones, radiopaque agents (e.g., iodinated contrast agents), gold or barium; or combinations thereof. Suitably, the additional coating comprises an antithrombotic agent, such as heparin or a heparin derivative. In one embodiment, the additional coating is Bioactive Surface

[0372] In one embodiment, the additional coating is selected from a fluoropolymer and an antithrombotic agent. In one embodiment, the additional coating is selected from the group consisting of expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene (FEP), perfluorocarbon copolymers, such as tetrafluoroethylene perfluoroalkyl vinyl ether (TFE / PAVE) copolymers, polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene (FEP), perfluorocarbon copolymers, such as tetrafluoroethylene perfluoroalkyl vinyl ether (TFE / PAVE) copolymers, copolymers of tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE), copolymers of TFE and functional monomers containing acetic acid, alcohol, amine, amide, sulfonic acid functional groups, etc., such as U.S. Pat. No. 8,658,707 (WL Gore Associates, Inc.) and Associates, Inc.), which are incorporated herein by reference), and the like, and combinations thereof (see also US 10,688,188 and WO 2021 / 097210 and WO 2021 / 150962, all of which are incorporated herein by reference), VDF-HFP, heparin, and heparin derivatives.

[0373] In one embodiment, the additional coating is applied to the surface as a first coating, wherein the chemical entity is applied to the surface as a second coating, e.g., at least a portion or all of the chemical entity is coated on top of the first coating. In an alternative embodiment, the chemical entity is applied to the surface as a first coating, wherein the additional coating is applied to the surface as a second coating, e.g., at least a portion or all of the additional coating is applied on top of the first coating of the chemical entity. Alternatively, the additional coating can be mixed with the chemical entity prior to application to the surface, e.g., as described in Examples 26-29, a fluoropolymer (VDF-HFP fluoropolymer) is mixed with the chemical entity and the mixture is then applied to the surface (e.g., ePTFE film, stainless steel foil, Nylon film or ePE film).

[0374] When an additional coating is applied as a second coating on top of the coating comprising the chemical entity, nitric oxide release is still expected to occur because the NO molecule is expected to diffuse, permeate or otherwise pass through the additional coating due to its low molecular weight and small molecular size.

[0375] In this regard, adding an additional coating (e.g., a fluoropolymer such as VDF-HFP) on top of a chemical entity coating, or applied as a mixture with the chemical entity, can effectively delay the onset of NO release from the surface, for example as shown in Examples 26-29.

[0376] The surface with the coating containing the chemical entity can be sterilized, especially when the surface is the surface of a medical device. Suitable sterilization processes include, but are not limited to, the use of ethylene oxide, steam hydrogen peroxide, plasma hydrogen peroxide, dry heat sterilization, high pressure steam sterilization, chlorine dioxide sterilization, gamma-ray sterilization, or electron beam sterilization. The use of ethylene oxide sterilization is the most commonly used, proven, and easy-to-use sterilization technique for implantable medical devices such as stents, stent grafts, balloons, indwelling catheters, and balloon catheters. Therefore, in one embodiment, the coating containing the chemical entity is stable to sterilization, especially ethylene oxide sterilization. Therefore, in one aspect, a coated medical device described herein that has been sterilized (e.g., ethylene oxide sterilization) is provided. In another embodiment, a chemical entity described herein that has been sterilized (e.g., ethylene oxide sterilization) is provided. Representative evaluation method B includes: ethylene oxide sterilization method and post-sterilization stability evaluation method.

[0377] In one embodiment, after sterilization using Assessment Method B, at least 85%, 90% or 95% of the NO releasing activity is retained.

[0378] In one embodiment, the chemical entity is free of polysiloxane.

[0379] Treatment

[0380] The chemical entities and devices comprising S-nitrosothiol groups disclosed herein, in particular medical devices coated with chemical entities comprising S-nitrosothiol groups, can be used for medical treatments, wherein the coating comprising the chemical entity / chemical entity releases nitric oxide.

[0381] In one embodiment, a medical device having a coating on its surface is provided, the coating comprising a chemical entity comprising an S-nitrosothiol group as described above, which is used in a method for treating tissue in a human or animal body, wherein the coating / chemical entity comprising the chemical entity releases nitric oxide. The tissue to be treated includes any body cavity, space, or hollow organ passage, such as blood vessels, arteriovenous fistulas (AVFs), lymphatic vessels, etc., fistulas, urinary tracts, intestines, nasal cavities, nerve sheaths, intervertebral areas, bone cavities, esophagus, uterine cavity spaces, pancreas and bile ducts, glomeruli, liver sinuses, rectum, and body spaces that have been previously intervened with implantable vascular grafts, stents, prostheses, or other types of medical grafts.

[0382] Medical devices having a coating layer as described herein on their surfaces can be used to remove obstacles such as thrombi and emboli from within blood vessels, as expansion devices to restore patency to blocked body passages, as blocking devices to selectively deliver devices to block or fill passages or spaces, and as centering mechanisms for transluminal instruments such as catheters.

[0383] In one embodiment, the chemical entities described above are provided for use in preventing or treating a disease that benefits from nitric oxide delivery.

[0384] In one embodiment, a chemical entity as described above is provided for use in opening blood vessels and / or improving oxygen levels.

[0385] In another embodiment, a chemical entity as described above is provided for use in preventing or treating atherosclerotic lesions.

[0386] In another embodiment, the chemical entity described above is provided for use in preventing or treating hypervascular lesions, such as hemangiomas and hypervascular tumors.

[0387] In another embodiment, there is provided a chemical entity as described above for use in preventing or treating angiogenesis (including vasculogenesis).

[0388] In another embodiment, a chemical entity as described above is provided for use in promoting endothelialization, in particular endothelialization of a graft / stent graft / stent.

[0389] In another embodiment, there is provided a chemical entity as described above for use in preventing or treating an infection, particularly a bacterial infection.

[0390] In another embodiment, a chemical entity as described above is provided for use in maturing an arteriovenous fistula.

[0391] In another embodiment, there is provided a chemical entity as described above for use in preventing or treating a skin ulcer, such as a foot ulcer.

[0392] In another embodiment, a chemical entity as described herein is provided for use in accelerating healing of an inflammatory cycle.

[0393] In all of the above embodiments utilizing chemical entities described herein, the chemical entity may be administered as a pharmaceutical composition. Thus, in one embodiment, a pharmaceutical composition is provided comprising a chemical entity as described herein and one or more pharmaceutically acceptable diluents or carriers (including but not limited to tonicity agents, buffers, surfactants, stabilizing polymers, preservatives, cosolvents and / or viscosity building agents).

[0394] The chemical entity may be administered by any convenient method, for example, orally, parenterally, buccally, sublingually, nasally, rectally, intrathecally or transdermally, and the pharmaceutical composition adjusted accordingly.

[0395] The chemical entity may be administered topically to a target organ, for example, the chemical entity may be formulated as a solution, suspension, emulsion, ointment, gel, or patch.

[0396] Suspensions or solutions of chemical entities as described herein will include suitable liquid carriers. Typical parenteral compositions consist of solutions or suspensions of chemical entities in sterile aqueous carriers or parenterally acceptable oils (e.g., polyethylene glycol, polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil). Alternatively, the solution can be lyophilized and then redissolved with a suitable solvent before administration.

[0397] The chemical entity may also be administered by injection, for example, by subcutaneous or intramuscular injection, or by intravenous injection or infusion. Suitable diluents for injection include isotonic saline, isotonic glucose and water (eg, sterile water for injection or bacteriostatic water for injection).

[0398] In another embodiment, a method of preventing or treating a condition that benefits from nitric oxide delivery is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0399] In another embodiment, a method for opening blood vessels and / or improving oxygen levels is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0400] In another embodiment, a method of preventing or treating atherosclerotic lesions is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0401] In another embodiment, a method for preventing or treating a hypervascular lesion (eg, a hemangioma, a hypervascular tumor) is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0402] In another embodiment, a method of preventing or treating angiogenesis (including vasculogenesis) is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0403] In another embodiment, a method of promoting endothelialization, particularly graft / scaffold graft / scaffold endothelialization, is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0404] In another embodiment, a method of preventing or treating infection, particularly bacterial infection, is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0405] In another embodiment, a method of maturing an arteriovenous fistula is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0406] In another embodiment, a method of preventing or treating skin ulcers (eg, foot ulcers) is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0407] In another embodiment, a method of accelerating healing of an inflammatory cycle is provided, the method comprising administering a chemical entity described herein to a subject in need thereof.

[0408] In one embodiment, a method for preventing or treating a condition that benefits from nitric oxide delivery is provided, wherein a coated medical device as described herein is used. Suitably, the coated medical device is implanted in or in contact with an area to be treated, i.e., an area that benefits from nitric oxide delivery.

[0409] In another embodiment, a method for opening a blood vessel and / or improving oxygen levels is provided, wherein a coated medical device as described herein is used.

[0410] In another embodiment, a method for preventing or treating atherosclerotic lesions is provided, wherein a coated medical device as described herein is used.

[0411] In another embodiment, a method for preventing or treating a hypervascular lesion (eg, a hemangioma, a hypervascular tumor) is provided, wherein a coated medical device as described herein is used.

[0412] In another embodiment, a method for preventing or treating angiogenesis is provided, wherein a coated medical device as described herein is used. In these embodiments, the treatment of angiogenesis may include inducing angiogenesis around or within a coated medical device (e.g., an implantable cell encapsulation device, an implantable sensor device, an implantable drug delivery device, etc.).

[0413] In another embodiment, a method for promoting endothelialization, in particular graft / stent graft / stent endothelialization, is provided, wherein a coated medical device as described herein is used.

[0414] In another embodiment, a method for preventing or treating infection, particularly bacterial infection, is provided, wherein a coated medical device as described herein is used.

[0415] In another embodiment, a method for maturing an arteriovenous fistula is provided, wherein a coated medical device as described herein is used. Suitably, the medical device coated with a chemical entity as described herein is a sandwich structure, such as Vascular grafts.

[0416] In another embodiment, a method for preventing or treating skin ulcers (e.g., foot ulcers) is provided, wherein a medical device coated as described herein is used. Suitably, the medical device is a dressing or filling material coated with a chemical entity as described herein. Suitable dressings include hydrogel dressings and hydrocolloid dressings. Suitable fillers include, but are not limited to, synthetic biodegradable polymers such as polydioxanone (PDO), polyglycolide (PGA), polylactide (PLA), poly (s-caprolactone), polyanhydrides such as polysebacic acid, polyhydroxyalkanoates such as poly (3-hydroxybutyrate) (P30HB), or copolymers of these polymers, such as polyglycolide / trimethylene carbonate (PGA / TMC, e.g., 2:1PGA / CMC), polylactide / trimethylene carbonate (PLA / TMC), or polyhydroxybutyrate / hydroxyvalerate (PHB / PHV).

[0417] In another embodiment, a method for accelerating the healing of an inflammatory cycle is provided, wherein a coated medical device as described herein is used.

[0418] In one embodiment, the coating is an antimicrobial coating.

[0419] In all of the above treatment aspects and embodiments, the coating / chemical entity comprising the chemical entity releases nitric oxide.

[0420] Methods for preparing the disclosed chemical entities and coatings

[0421] As discussed above, the thiol-form chemical entity of the present disclosure is formed by the reaction of components B and C. Thus, in one embodiment, a method comprising reacting components B and C as described herein is provided.

[0422] Suitably, the process is carried out by dissolving components B and C in an organic anhydrous solvent such as chloroform, THF, ethanol or DMSO, or a mixture thereof. Suitable procedures for forming the chemical entities of the present disclosure are described in Examples 9-18.

[0423] As described above, the thiol form of a chemical entity can be converted to the S-nitrosothiol form using reagents and techniques well known to those of ordinary skill in the art.

[0424] As described above, the chemical entity of the present disclosure (thiol form or S-nitrosothiol form) can be applied to a surface to form a coating. Therefore, in one embodiment, a method of forming a coating on a surface is provided, wherein the method comprises the following steps:

[0425] (a) contacting a surface with a chemical entity described herein.

[0426] Step (a) is suitably carried out by the following steps: step (a-1) dissolving the chemical entity in a solvent to form a solution, and then step (a-2) coating the surface with the solution. The solution can be applied to the surface by a variety of methods, such as pipetting, dipping, spraying, casting, rolling or brushing. Spraying is a particularly suitable method. Solvents that can be used include: water, aqueous buffer (such as PBS), acetone, alcohol (such as methanol, ethanol, propanol, isopropanol), THF, DMF, DMSO, EtOAc, dioxane, acetonitrile, chloroform or mixtures thereof. In at least some embodiments, the chemical entity is soluble in a mild and / or solvent suitable for batch manufacturing of set components, such as water, alcohol and acetone.

[0427] After step (a-2), a drying step (a-3) may be required to remove the solvent. Drying can be, for example, by local heating, or air drying, or drying under a gas flow (such as argon). When a solvent such as acetone, alcohol and water can be used in step (a-1), the drying step can become quite easy.

[0428] An example of this method is described in Example 25.

[0429] If step (a) (steps (a-1) and (a-2) and optionally (a-3)) is performed using a thiol-form chemical entity, the method may further comprise step (b): converting at least a portion of the thiol (-SH) groups in the chemical entity coating into S-nitrosothiol (-SNO) groups. Thus, step (b) comprises reacting the surface of step (a), (a-2) or (a-3) under conditions such that at least a portion of the thiol groups are converted into S-nitrosothiol groups, such conditions being well known to those of ordinary skill in the art.

[0430] In some cases, in addition to the coating that forms the chemical entity defined herein, it may be beneficial to include one or more additional coatings, as described above.

[0431] The additional coating may be mixed with the chemical entity before being applied to the surface. Thus, in one embodiment, a method of forming a coating on a surface is provided, wherein the method comprises the steps of:

[0432] (a) forming a mixture of a chemical entity as defined herein and an additional coating component;

[0433] (b) contacting a surface with the mixture of step (a).

[0434] Step (a) is suitably carried out by dissolving the chemical entity and the additional coating components in a solvent to form a solution, which is then applied to the surface in step (b). The solution can be applied directly to the surface as described above. Useful solvents are as described in the above method. Suitable procedures for coating a surface with a mixture of the chemical entity of the present disclosure and the additional coating are described in Examples 26-29.

[0435] After step (b), a drying step (b-1) may be necessary to remove the solvent. Drying may be, for example, by local heating, or air drying, or drying under a gas flow (such as argon).

[0436] If steps (a) and (b) (or step (b-1)) are performed using a thiol-form chemical entity, the method may further comprise step (c): converting at least a portion of the thiol (-SH) groups in the chemical entity coating into S-nitrosothiol (-SNO) groups. Thus, step (c) comprises reacting the surface of step (b) or (b-1) under conditions such that at least a portion of the thiol groups are converted into S-nitrosothiol groups, such conditions being well known to those of ordinary skill in the art.

[0437] Alternatively, an additional coating may be applied to the surface prior to applying the chemical entity to the surface. Thus, in one embodiment, a method of forming a coating on a surface is provided, wherein the method comprises the steps of:

[0438] (a) contacting the surface with an additional coating component;

[0439] (b) contacting the surface of step (a) with a chemical entity described herein.

[0440] Step (a) can be carried out using any known coating method suitable for the particular additional coating. Step (b) is suitably carried out by the following steps: step (b-1) dissolving the chemical entity in a solvent to form a solution, and then step (b-2) coating the surface of step (a) with the solution. The solution can be applied directly to the surface according to the above method. The solvent that can be used is as described in the above method.

[0441] After step (a) and / or (b), a drying step may be necessary to remove the solvent. Drying may be, for example, by local heating, or air drying, or drying under a stream of gas (such as argon).

[0442] If step (b) is performed using a thiol-form chemical entity, the method may further comprise step (c): converting at least a portion of the thiol (-SH) groups in the chemical entity coating into S-nitrosothiol (-SNO) groups. Thus, step (c) comprises reacting the surface of step (b) under conditions such that at least a portion of the thiol groups are converted into S-nitrosothiol groups, such conditions being well known to those of ordinary skill in the art.

[0443] Alternatively, after applying the chemical entity to the surface, an additional coating may be applied to the surface. Thus, in one embodiment, a method of forming a coating on a surface is provided, wherein the method comprises the steps of:

[0444] (a) contacting a surface with a chemical entity described herein;

[0445] (b) contacting the surface of step (a) with an additional coating component.

[0446] Step (a) is suitably carried out by the following steps: step (a-1) dissolving the chemical entity in a solvent to form a solution, and then step (a-2) coating the surface of step (a) with the solution. The solution can be applied directly to the surface according to the above method. The solvents that can be used are as described in the above method. Step (b) can be carried out using any known coating method suitable for the specific additional coating.

[0447] After step (a) and / or (b), a drying step may be necessary to remove the solvent. Drying may be, for example, by local heating, or air drying, or drying under a stream of gas (such as argon).

[0448] If step (a) is performed using a thiol-form chemical entity, the method may further comprise step (c): converting at least a portion of the thiol (-SH) groups in the chemical entity coating into S-nitrosothiol (-SNO) groups. Thus, step (c) comprises reacting the surface of step (a) or step (b) under conditions such that at least a portion of the thiol groups are converted into S-nitrosothiol groups, such conditions being well known to those of ordinary skill in the art.

[0449] In another embodiment, the chemical entity (thiol form or S-nitrosothiol form) is formed in situ when the coating is formed on the surface. In other words, one of components B and C is first coated on the surface, and then the remaining component B or C is reacted with the coated surface to form the chemical entity coating. An example of this method is given in Example 31, where an ePTFE membrane is first coated with PEI (component C), and then the coated membrane is reacted with adipoyl-1,6-dipenicillamine dithiolactone (component B), resulting in the formation of a cross-linked PEI polymer (chemical entity).

[0450] Therefore, in one embodiment, a method of forming a coating on a surface is provided, wherein the method comprises the steps of:

[0451] (a) contacting a surface with component B; and

[0452] (b) reacting the coated surface of step (a) with component C so that component B reacts with component C to form a chemical entity coating.

[0453] In another embodiment, a method of forming a coating on a surface is provided, wherein the method comprises the steps of:

[0454] (a) contacting a surface with component C; and

[0455] (b) reacting the coated surface of step (a) with component B, such that component C reacts with component B to form a chemical entity coating.

[0456] The embodiments described above with respect to the chemical entity embodiments are equally applicable to the process / method embodiments.

[0457] It should also be noted that medical devices manufactured according to the present invention and processes used herein are also considered to form part of the present disclosure.

[0458] Other terms / technical solutions

[0459] 1. A chemical entity formed by the reaction of components B and C, wherein:

[0460] Component B is a compound of formula (I):

[0461]

[0462] in,

[0463] A is the core part;

[0464] L is an optional linker;

[0465] R 1 and R 2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radical substitution;

[0466] n is 0 or 1; and

[0467] m is an integer at least 1;

[0468] and,

[0469] Component C is a moiety comprising one or more amine groups.

[0470] 2. A surface having a coating, wherein the coating comprises a chemical entity as described in clause / technical solution 1.

[0471] 3. A chemical entity as described in clause / technical solution 1 or a surface with a coating as described in clause / technical solution 2, wherein at least a portion of the thiol (-SH) groups in the chemical entity have been converted into S-nitrosothiol (-SNO) groups.

[0472] 4. A method for forming a coating on a surface, wherein the method comprises the steps of:

[0473] (a) contacting a surface with a chemical entity as described in clause / technical solution 1.

[0474] 5. The method as described in clause / technical solution 4 further includes step (b): converting at least a portion of the thiol (-SH) groups in the chemical entity into S-nitrosothiol (-SNO) groups.

[0475] 6. A chemical entity as described in clause / technical solution 1, a surface with a coating as described in clause / technical solution 2 or clause / technical solution 3, or a method as described in clause / technical solution 4 or clause / technical solution 5, wherein the core part A includes one or more parts independently selected from the following groups: alkyl, spiroalkyl, aryl, heteroaryl, alkylaryl, porphyrin, polymer and macrocycle, wherein the alkyl, spiroalkyl, aryl, heteroaryl and alkylaryl are optionally substituted by one or more substituents (for example, selected from the following group: alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0476] 7. A chemical entity, a surface having a coating, or a method as described in clause 6, wherein the core portion A comprises an alkyl group (e.g., C 1-20 alkyl), which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, fluoroalkyl and fluoroalkoxy.

[0477] 8. A chemical entity, a coated surface or a method as described in clause / technical solution 7, wherein the core part A includes an alkyl group or the core part A is an alkyl group, and m is 1 or 2, in particular 2.

[0478] 9. The chemical entity, coated surface or method of clause 8, wherein m is 2 and the core portion A comprises C 1-10 The alkylene part or C 1-10 The alkylene moiety is composed of, for example, C 1-6 Alkylene moieties, especially C1-4 An alkylene moiety, such as -(CH2)4-, -(CH2)3-, -C(CH3)2-, -CH(CH3)-, -CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2-.

[0479] 10. A chemical entity, a coated surface or a method as described in clause / technical solution 9, wherein A is -C(CH3)2- and m is 2.

[0480] 11. A chemical entity, a coated surface or a method as described in clause / technical solution 9, wherein A is -(CH2)4- and m is 2.

[0481] 12. A chemical entity, a surface having a coating, or a method as described in clause 6, wherein the core portion A comprises a spiroalkyl group (e.g., C 1-20 spiroalkyl), which is optionally substituted with one or more substituents selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy.

[0482] 13. A chemical entity, a coated surface or a method as described in clause / technical solution 6, wherein the core portion A comprises an aromatic group (e.g., a 5-20 membered aromatic group) which is optionally substituted by one or more substituents (selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0483] 14. A chemical entity, a coated surface or a method as described in clause / technical solution 13, wherein the aromatic group is a phenyl group, which is optionally substituted by one or more substituents selected from the group consisting of an alkyl group, an alkoxy group, a fluoroalkyl group and a fluoroalkoxy group.

[0484] 15. The chemical entity of clause 1, the surface having a coating of clause 2 or clause 3, or the method of clause 4 or clause 5, wherein:

[0485] m is 2, and the core part A is:

[0486] or

[0487] m is 3, and the core part A is:

[0488]

[0489] 16. The chemical entity, coated surface or method of clause 15, wherein:

[0490] m is 2, and the core part A is:

[0491] or

[0492] m is 3, and the core part A is:

[0493]

[0494] 17. A chemical entity, a coated surface or a method as described in clause / technical solution 6, wherein the core portion A comprises a heteroaryl group (e.g., a 5-10 membered heteroaryl group), which is optionally substituted by one or more substituents (selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0495] 18. A chemical entity, a surface having a coating, or a method as described in clause 6, wherein the core portion A comprises an alkylaryl group (e.g., an alkyl group (e.g., C 1-10 alkyl) or substituted by an alkyl group (e.g., C 1-5 The polyaryl group is a polyaryl group linked to an alkyl group) which is optionally substituted with one or more substituents selected from the group consisting of an alkyl group, an alkoxy group, a fluoroalkyl group and a fluoroalkoxy group.

[0496] 19. A chemical entity, a surface having a coating or a method as described in clause / technical solution 6, wherein the core portion A comprises a porphyrin, such as tetra-4-aryl-meso.

[0497] 20. A chemical entity, a coated surface or a method as described in clause / technical solution 6, wherein the core portion A comprises a polymer, for example, a polyamine compound (for example, selected from the group consisting of polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane), a dendrimer (for example, a PAMAM dendrimer or a PPI dendrimer) or a hyperbranched polymer.

[0498] 21. A chemical entity, a coated surface or a method as described in clause / technical solution 6, wherein the core portion A comprises a macrocycle, such as a cyclodextrin.

[0499] 22. A chemical entity, a surface with a coating or a method as described in any of clauses / technical solutions 1 to 21, wherein the core portion A includes an unstable portion.

[0500] 23. A chemical entity, a coated surface or a method as described in clause / technical solution 22, wherein the core portion A comprises a portion that is unstable by hydrolysis or nucleophilic substitution, such as a portion containing one or more functional groups independently selected from the following group: esters, anhydrides, imines, imines, acetals, carbonates, phosphazenes, phosphates, carbamates, lactides and lactones.

[0501] 24. A chemical entity, a coated surface or a method as described in clause / technical solution 22, wherein the core portion A includes a portion that is unstable by reduction and oxidation, such as a portion containing one or more functional groups, the functional groups being independently selected from: oxides, superoxides, ozone, oxygen-containing acids, halites, hypohalites and hypohalous acids.

[0502] 25. A chemical entity, a coated surface or a method as described in clause / technical solution 22, wherein the core portion A includes a portion that is unstable by photolysis (e.g., by UV or visible light), such as a portion containing one or more functional groups independently selected from benzoyl carbonyl and azide.

[0503] 26. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 22 to 25, wherein the chemical entity is bioabsorbable.

[0504] 27. A chemical entity, a surface having a coating, or a method as described in any one of clauses 1 to 26, wherein the linker L comprises C 1-10 Alkylene, secondary amine or amide.

[0505] 28. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 26, wherein the linker L is not present.

[0506] 29. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 1 to 28, wherein n is 0.

[0507] 30. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 1 to 28, wherein n is 1.

[0508] 31. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 30, wherein R 1 and R 2 Independently selected from the group consisting of H and C 1-5 alkyl.

[0509] 32. A chemical entity, a surface having a coating, or a method as described in clause 31, wherein R 1 and R 2 Independently selected from the group consisting of CH2CH3 and CH3; in particular both are CH3.

[0510] 33. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 30, wherein R 1 and R 2Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo groups are substituted.

[0511] 34. A chemical entity, a surface having a coating, or a method as described in clause 33, wherein R 1 and R 2 Together with the C atoms to which they are attached, they form a cycloheptyl or cyclohexyl ring (which is optionally replaced on available atoms by one or more selected from C 1-2 alkyl and oxo groups).

[0512] 35. The chemical entity, coated surface or method of any one of clauses 1 to 14 or 17 to 34, wherein m is 1-5,000,000, 2-5,000,000, 1-1,000,000, 2-1,000,000, 1-500,000, 2-500,000, 1-400,000, 2-400,000, 1-200,000, 2-200,000, 1-100,000, 2-1 00,000, 1-50,000, 2-50,000, 1-20,000, 2-20,000, 1-10,000, 2-10,000, 1-5,000, 2-5,000, 1-2,000, 2-2,000, 1-1,000, 2-1,000, 1-500, 2-500, 1-100, 2-100, 1-50, 2-50, 1-20, 2-20, 1-10, 2-10, 1-5 or 2-5.

[0513] 36. The chemical entity, coated surface or method of clause 35, wherein m is 2-500,000, 50-500,000, 100-500,000, 500-500,000, 1,000-500,000, 5,000-500,000, 1-200,000, 2-200,000, 50-200,000, 100-200,000 0, 500-200,000, 1,000-200,000, 5,000-200,000, 1-100,000, 2-100,000, 50-100,000, 100-100,000, 500-100,000, 1,000-100,000, 5,000-100,000, 1-50,000, 2-50,000, 50-50,000 , 100-50,000, 500-50,000, 1,000-50,000, 5,000-50,000, 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, 5,000-20,000, 1-5,000, 2-5,000, 50-5,000, 10 0-5,000, 500-5,000, 1,000-5,000, 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, 5,000-20,000, 1-1,000, 2-1,000, 50-1,000, 100-1,000, or 500-1,000.

[0514] 37. A chemical entity, a coated surface or a method as described in clause / technical solution 36, wherein m is 1-1,000, 2-1,000, 50-1,000, 100-1,000, or 500-1,000.

[0515] 38. A chemical entity, a coated surface or a method as described in clause / technical solution 37, wherein m is 2, 3 or 4; in particular 2 or 3.

[0516] 39. A compound, a surface having a coating or a method as described in clause / technical solution 37, wherein m is 5-10, for example m is 5-8.

[0517] 40. A chemical entity, a coated surface or a method as described in clause / technical solution 35 or 36, wherein m is 5,000-100,000, for example, m is 5,000-50,000 or 5,000-20,000.

[0518] 41. The chemical entity of clause 1, the surface having a coating of clause 2 or clause 3, or the method of clause 4 or clause 5, wherein:

[0519] Component B has formula (Ia):

[0520]

[0521] in,

[0522] R 1 and R 2 Independently selected from H and C 1-5 Alkyl, for example selected from CH3 and CH2CH3 (especially both are CH3); or R 1 and R 2 Together with the C atoms to which they are attached, they form a cycloheptyl or cyclohexyl ring (which is optionally replaced on available atoms by one or more selected from C 1-2 alkyl and oxo groups).

[0523] 42. The chemical entity, coated surface or method of clause 41, wherein:

[0524] Component B is

[0525]

[0526] Where n is 0 or 1, and R 1 and R 2 Independently selected from H and C 1-5 alkyl;

[0527] When n is 0, R 1 and R 2 Suitable for both C 1-5 alkyl, especially methyl or ethyl, for example, both are methyl; and when n is 1, R 1 and R 2 Suitably both are H.

[0528] 43. The chemical entity, coated surface or method of clause 41, wherein:

[0529] Component B is

[0530]

[0531] Where n is 0 or 1, and R 1 and R 2 Independently selected from H and C 1-5 alkyl;

[0532] When n is 0, R 1 and R 2 Suitable for both C 1-5 alkyl, especially methyl or ethyl, for example, both are methyl; and when n is 1, R 1 and R 2 Suitably both are H.

[0533] 44. The chemical entity, coated surface or method of clause 1, the coated surface of clause 2 or clause 3 or the method of clause 4 or clause 5, wherein component B is:

[0534]

[0535] Wherein, when n is 0 or 1, x is 1-10, such as 1-6, and R 1 and R 2 Independently selected from H and C 1-5 alkyl;

[0536] When n is 0, R 1 and R 2 Suitable for both C 1-5 alkyl, especially methyl or ethyl, for example, both are methyl; and when n is 1, R 1 and R 2 Suitably both are H.

[0537] 45. The chemical entity, coated surface or method of clause 1, the coated surface of clause 2 or clause 3, or the method of clause 4 or clause 5, wherein component B has formula (Iaa):

[0538]

[0539] Among them, L, n, R 1 and R 2 As defined in Clause / Technical Solution 1.

[0540] 46. ​​The chemical entity, coated surface or method of clause 45, wherein L is absent and component B has formula (Iab):

[0541]

[0542] Among them, n, R 1 and R 2 As defined in Clause / Technical Solution 1.

[0543] 47. The chemical entity, coated surface or method of clause 46, wherein L is absent, n is 0, and component B has formula (lac):

[0544]

[0545] Among them, R 1 and R 2 As defined in Clause / Technical Solution 1.

[0546] 48. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 45 to 47, wherein R 1 and R 2 Suitably selected from H and C 1-5 Alkyl is suitably H, methyl or ethyl, more suitably H or methyl.

[0547] 49. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 48, wherein component B is a D-stereoisomer.

[0548] 50. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 48, wherein component B is an L-stereoisomer.

[0549] 51. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 1 to 48, wherein component B is a mixture of D-stereoisomers and L-stereoisomers (e.g., a racemic mixture).

[0550] 52. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 1 to 51, wherein component C is a single compound or a mixture of compounds.

[0551] 53. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 52, wherein component C is a single monomer compound (i.e., a single compound with a well-defined composition).

[0552] 54. A chemical entity, a coated surface or a method as described in clause / technical solution 52, wherein component C is a polymer.

[0553] 55. A chemical entity, a coated surface or a method as described in clause / technical solution 52, wherein component C is a mixture of two or more compounds (especially two compounds) selected from monomeric compounds and polymers.

[0554] 56. A chemical entity, a coated surface or a method as described in clause / technical solution 55, wherein component C is a mixture of two or more monomeric compounds, wherein at least one or all of the two or more monomeric compounds may include two or more amine groups, for example, two amine groups.

[0555] 57. A chemical entity, a coated surface or a method as described in clause / technical solution 55, wherein component C is a mixture of two or more polymers.

[0556] 58. A chemical entity, a surface having a coating or a method as described in any of clauses / technical solutions 54 to 57, wherein the polymer is formed from a single monomer; and is, for example, polyethyleneimine, polylysine, polypropylene oxide and polyethylene oxide.

[0557] 59. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 54 to 57, wherein the polymer is a copolymer formed by two or more monomers (e.g., two monomers), and is, for example, a polymer formed by propylene oxide and ethylene oxide units.

[0558] 60. A chemical entity, a surface having a coating or a method as described in any of clauses / technical solutions 1 to 59, wherein the amine groups of component C are independently primary amine groups or secondary amine groups, wherein the secondary amine groups can be present in cyclic amines such as morpholine, piperidine or piperazine.

[0559] 61. A chemical entity, a surface having a coating or a method as described in any of clauses / technical solutions 1 to 60, wherein component C comprises a single amine group.

[0560] 62. A chemical entity, a coated surface or a method as described in clause / technical solution 61, wherein component C is selected from the following group: aniline, benzylamine, morpholine, diethylamine, dibutylamine, 1-ethylpropylamine, 2-aminopentane, piperidine, 4-methylpiperidine, pyrrolidine, tert-butylamine, tert-amylamine, propylamine, butylamine, pentylamine, isopentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, dodecylamine, hexadecylamine, octadecylamine, 4-methylaniline, 2-fluorobenzylamine, 3-fluorobenzylamine, 4-fluorobenzylamine, 3-(trifluoromethyl)benzylamine, 4-(trifluoromethyl)benzylamine and 3,5-bis(trifluoromethyl)benzylamine, in particular aniline, benzylamine and morpholine.

[0561] 63. A chemical entity, a surface having a coating or a method as described in any of clauses / technical solutions 1 to 60, wherein component C comprises two or more amine groups, wherein the amine groups are independently primary amine groups or secondary amine groups.

[0562] 64. A chemical entity, a coated surface or a method as described in clause / technical solution 63, wherein component C comprises a polyamine compound, for example, component C comprises one or more parts independently selected from the following: polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane.

[0563] 65. A chemical entity, a coated surface or a method as described in clause / technical solution 64, wherein component C comprises polyethyleneimine, such as a branched polyethyleneimine having a molecular weight of 10-1000 kDa (such as 10-50 kDa or 50-100 kDa).

[0564] 66. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 65, wherein component C is a polyamine compound comprising a dendrimer or a hyperbranched polymer.

[0565] 67. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 1 to 63, wherein component C is a linear polymer comprising two amine groups (suitably primary or secondary amine groups), one at each end of the polymer chain.

[0566] 68. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 67, wherein component C is a compound of formula (X):

[0567]

[0568] in,

[0569] D is the core part;

[0570] G is an optional linker;

[0571] E is NH2; and

[0572] p is an integer of at least 1.

[0573] 69. A chemical entity, a coated surface or a method as described in clause / technical solution 68, wherein the core portion D comprises one or more portions independently selected from the following groups: alkyl, spiroalkyl, aryl, heteroaryl, alkylaryl, porphyrin, polymer and macrocycle, wherein the alkyl, spiroalkyl, aryl, heteroaryl and alkylaryl are optionally substituted by one or more substituents (for example, selected from the following group: alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0574] 70. The chemical entity, coated surface or method of clause 69, wherein the core portion D is a compound comprising one or more C 2-4Polymers of oxyalkylene units such as ethylene oxide units or propylene oxide units (i.e., D is polyoxy C 2-4 Olefins).

[0575] 71. A chemical entity, a coated surface or a method as described in clause / technical solution 70, wherein component C is a single compound of formula (X), wherein the average number of oxyalkylene units in the core portion D is from about 2 to about 20, for example, from about 2 to 10, 3 to 7 or 3.5 to 6.

[0576] 72. A chemical entity, a coated surface or a method as described in clause / technical solution 70, wherein component C is a mixture of a first compound of formula (X) and a second compound of formula (X).

[0577] 73. A chemical entity, a coated surface or a method as described in clause / technical solution 72, wherein component C is a mixture of a first compound of formula (X) and a second compound of formula (X), wherein in the first compound of formula (X), D is a polymer comprising an average number of oxyalkylene units of about 2 to about 20, for example, about 2 to 10, 3 to 7 or 3.5 to 6, and in the second compound of formula (X), D is a polymer comprising an average number of oxyalkylene units of about 11 to about 100, for example, about 20 to about 60 or 30 to 50.

[0578] 74. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 68 to 73, wherein the linker G is not present and p is 2.

[0579] 75. A chemical entity, a coated surface or a method as described in clause / technical solution 68, wherein the core portion D is a polyalkylsiloxane portion substituted with one or more primary amine and / or secondary amine groups, in particular one or more primary amine groups.

[0580] 76. A chemical entity, a surface having a coating, or a method as described in clause 69, wherein the core portion D comprises an alkyl group (e.g., C 1-10 alkyl), which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, fluoroalkyl and fluoroalkoxy.

[0581] 77. A chemical entity, a coated surface or a method as described in clause / technical solution 69, wherein the core portion D comprises an aromatic group (e.g., a 5-20 membered aromatic group) which is optionally substituted by one or more substituents (selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0582] 78. A chemical entity, a coated surface or a method as described in clause / technical solution 77, wherein the aromatic group is a phenyl group, which is optionally substituted by one or more substituents selected from the group consisting of an alkyl group, an alkoxy group, a fluoroalkyl group and a fluoroalkoxy group.

[0583] 79. A chemical entity, a surface having a coating, or a method as described in clause 69, wherein the core portion D comprises a spiroalkyl group (e.g., C 1-20 spiroalkyl), which is optionally substituted with one or more substituents selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy; or

[0584] wherein the core portion D comprises a heteroaryl group (e.g., a 5-10 membered heteroaryl group) which is optionally substituted by one or more substituents (e.g., selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy); or

[0585] Wherein the core portion D comprises an alkylaryl group (eg, 1-10 alkyl) or substituted by an alkyl group (e.g., C 1-5 alkyl) linked to a polyaryl group), which is optionally substituted with one or more substituents (e.g., selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy); or

[0586] wherein the core portion D comprises a porphyrin, such as tetra-4-aryl-meso; or

[0587] The core moiety D comprises a macrocycle, such as cyclodextrin.

[0588] 80. A chemical entity, a coated surface or a method as described in clause / technical solution 69, wherein the core portion D comprises a polymer, such as a polyamine compound (for example, selected from the group consisting of polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane), a dendrimer (such as a PAMAM dendrimer or a PPI dendrimer) or a hyperbranched polymer.

[0589] 81. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 68 to 80, wherein the core portion D includes an unstable portion.

[0590] 82. A chemical entity, a coated surface or a method as described in clause / technical solution 81, wherein the core portion D comprises a portion that is unstable by hydrolysis or nucleophilic substitution, such as a portion containing one or more functional groups independently selected from the following group: esters, anhydrides, imines, imines, acetals, carbonates, phosphazenes, phosphates, carbamates, lactides and lactones; or

[0591] a moiety that is oxidatively labile by reduction, such as a moiety containing one or more functional groups independently selected from the group consisting of oxides, superoxides, ozone, oxyacids, halites, hypohalites, and hypohalous acids; or

[0592] Moieties that are labile by photolysis (eg, by ultraviolet or visible light), for example, moieties containing one or more functional groups independently selected from benzoylcarbonyl and azide.

[0593] 83. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 68 to 82, wherein the core portion D comprises a secondary amine group.

[0594] 84. A chemical entity, a surface having a coating, or a method as described in any one of clauses 68 to 83, wherein the core portion D comprises C 1-10 Alkylene, aryl, aryl-(CH2) 1-10 -aryl or –[CH2CH2NH] 1-20,000 .

[0595] 85. The chemical entity, coated surface or method of any one of clauses 68 to 84, wherein G comprises the moiety -(CH2CH2NH) 1-5 -CH2CH2-.

[0596] 86. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 68 to 84, wherein G is not present.

[0597] 87. A chemical entity, a surface having a coating, or a method as described in any one of clauses 68 to 86, wherein E is N(R z )H, where each R z Is H or C 1-6 Alkyl groups, for example, each R z independently H or C 1-3 Alkyl, for example, H, methyl or ethyl.

[0598] 88. The chemical entity, coated surface or method of clause 87, wherein:

[0599] each E is NH2; or

[0600] Each E is NH(C 1-6 alkyl), such as NH(CH3); or

[0601] p>1 and one or more E is NH2 and one or more E is NH(C 1-6 alkyl); or

[0602] p is 2, both E groups are NH2 groups, or both E groups are NH(C 1-6 alkyl), such as NH(CH3), or one E group is an NH2 group and the other E group is NH(C 1-6alkyl), such as NH(CH3).

[0603] 89. The chemical entity, coated surface or method of any one of clauses 68 to 88, wherein p is 1-5,000,000, 2-5,000,000, 1-1,000,000, 2-1,000,000, 1-500,000, 2-500,000, 1-400,000, 2-400,000, 1-200,000, 2-200,000, 1-100,000, 2-100, or 2-5.

[0604] 90. A chemical entity, a coated surface or a method as described in clause / technical solution 89, wherein p is 1-100,000, 2-100,000, 2-50,000, 2-20, 2-12, 2-5, 2-4 or 2-3.

[0605] 91. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 90, wherein component C has formula (Xx):

[0606]

[0607] wherein each x is independently 0-10.

[0608] 92. The chemical entity, coated surface or method of clause 91, wherein component C has formula (Xxx):

[0609]

[0610]

[0611] where x is 0-10; or

[0612] Wherein, component C has the formula (Xxy):

[0613] H2N-(CH2) x -NH2

[0614] Formula (Xxy)

[0615] Here, x is 1-10, for example, 3-8.

[0616] 93. The chemical entity, coated surface or method of clause 92, wherein:

[0617] Component C is H2N-(CH2)6-NH2 or H2N-(CH2)4-NH2; or

[0618] Component C has the formula (Xxz):

[0619]

[0620] Here, x is 0-10, for example, 1.

[0621] 94. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 90, wherein component C has formula (Xu):

[0622]

[0623] Among them, X 1 Is a straight chain or branched C 2-4 Alkylene, r is a number representing the average number of oxyalkylene units per molecule, R x and R y Each is H or C 1-6 Alkyl, such as H or C 1-3 Alkyl, for example H, methyl or ethyl, in particular H or methyl.

[0624] 95. The chemical entity, coated surface or method of clause 94, wherein the compound of formula (Xu) is a compound of formula (Xva):

[0625]

[0626] which are based on a core D comprising propylene oxide units; or

[0627] Compounds of formula (Xvb):

[0628]

[0629] It is based on a core D comprising ethylene oxide units, wherein r, R x and R y As defined in clause / technical solution 94, for example, r is 2 to 10.

[0630] 96. The chemical entity, coated surface or method of clause 94, wherein in the compound of formula (Xu), not all X 1 The groups are all the same, for example, some X 1The group is an ethylene oxide unit, and another X 1 The group is a propylene oxide unit, and r is from about 11 to about 100, such as 20-60 or 30-50.

[0631] 97. A chemical entity, a surface having a coating or a method as described in any one of clauses / technical solutions 1 to 90, wherein component C is an amine-functionalized polyalkylsiloxane of formula (Xt):

[0632]

[0633] Where R 20 , R 21 , R 22 and R 23 Each independently is C 1-6 Alkyl, more preferably C 1-4 Alkyl, R 24 H or C 1-4 Alkyl, especially H, X 2 Straight or branched chain C 1-6 Alkylene, more preferably a straight chain or branched C 1-4 Alkylene, especially (CH2) 2-4 , s and t are each independently an integer of about 10 to 400, more preferably about 50 to 250.

[0634] 98. A chemical entity, a surface having a coating, or a method as described in any one of clauses 1 or 3 to 97, wherein the chemical entity comprises:

[0635]

[0636] and / or

[0637]

[0638] and / or

[0639]

[0640] and / or

[0641]

[0642] in,

[0643] A, L, n, R 1 and R 2 As defined in any one of clauses / technical solutions 1 to 97;

[0644] R s is H or N=O; and

[0645] q is 10-1000, for example, 15-500, 20-250 or 25-180.

[0646] 99. The chemical entity, coated surface or method of clause 98, wherein the chemical entity comprises:

[0647]

[0648] and / or

[0649]

[0650] and / or

[0651]

[0652] and / or

[0653]

[0654] Wherein, n is as defined in any one of clauses / technical solutions 1 to 98;

[0655] x is 1-10;

[0656] R s is H or N=O; and

[0657] q is 10-1000, for example, 15-500, 20-250 or 25-180.

[0658] 100. The chemical entity, coated surface or method of clause 98, wherein the chemical entity comprises:

[0659]

[0660] Among them, R 1 , R 2 , R 20 , R 21 , R 22 , R 23 , n, X 2 , s and t are as defined herein;

[0661] R s is H or N=O; and

[0662] x is 1-10, suitably 1-6, and more suitably 1-4.

[0663] The weight average molecular weight of the polymer is generally from about 50,000 to 200,000, such as about 100,000.

[0664] 101. The chemical entity, coated surface or method of clause 98, wherein the chemical entity comprises:

[0665]

[0666] and / or

[0667]

[0668] and / or

[0669]

[0670] and / or

[0671]

[0672] Among them, n, X 1 and r as defined in any one of clauses / technical solutions 1 to 99;

[0673] R s is H or N=O;

[0674] R x and R y Each is H or C 1-6 Alkyl; and

[0675] q is 10-1000, for example, 15-500, 20-250 or 25-180.

[0676] 102. The chemical entity, coated surface, or method of clause 98, wherein the chemical entity comprises:

[0677]

[0678] and / or

[0679]

[0680] and / or

[0681]

[0682] and / or

[0683]

[0684] x is 1-10, for example 2-6;

[0685] R s is H or N=O; and

[0686] q is 10-1000, for example, 15-500, 20-250 or 25-180.

[0687] 103. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 1 to 102, wherein, relative to the mole % of component B, the chemical entity has 20-100% of thiol (-SH) groups, for example, 30-100%, 40-100%, 50-100% or 60-100% of free SH groups.

[0688] 104. A chemical entity, a coated surface or a method as described in any of clauses / technical solutions 3 to 103, wherein, relative to the mole % of component B, the chemical entity has 20-100% S-nitrosothiol (-SNO) groups, for example, 30-100%, 40-100%, 50-100% or 60-100% free SH groups.

[0689] 105. A surface having a coating obtainable by the method according to any one of clauses / technical solutions 3 to 104.

[0690] 106. A coated surface as described in any of clauses / technical solutions 3 to 105, wherein the surface comprises expanded polytetrafluoroethylene (ePTFE) or expanded polyethylene (ePE), in particular ePTFE.

[0691] 107. A surface with a coating as described in any of clauses / technical solutions 4 to 106, wherein the surface has one or more additional coatings, for example, one or more additional coatings are selected from the following group: synthetic or naturally occurring organic or inorganic polymers or materials, such as polyolefins, polyesters, polyurethanes, polyamides, polyether block amides, polyimides, polycarbonates, polyphenylene sulfides, polyphenylene ethers, polyethers, silicones, polycarbonates, polyhydroxyethyl methacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, rubber, silicone rubber, polyhydroxy acids, polyallylamines, polyallyl alcohols, polyacrylamides, polyacrylic acids, Styrene polymers, fluorinated polymers (e.g., expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluorocarbon copolymers (e.g., tetrafluoroethylene-perfluoroalkyl vinyl ether (TFE / PAVE) copolymers, copolymers of tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE)), copolymers of TFE and functional monomers (the functional monomers include acetate, alcohol, amine, amide and / or sulfonate, VDF-HFP), bioresorbable materials such as poly (D, L-lactide), polyglycolide and copolymers thereof Polymers, nonwoven, bioresorbable mesh materials comprising triblock copolymers such as poly(glycolide-co-trimethylene carbonate) triblock copolymer (PGA:TMC), nylon 12, nylon 11, nylon 9, nylon 6 / 9 and nylon 6 / 6, polyetheresteramides, polyethylene terephthalate and polybutylene terephthalate, polyester ethers, polyester elastomeric copolymers, block copolymer elastomers such as those having styrene end blocks and a midblock formed from butadiene, isoprene, ethylene / butylene, ethylene / propylene, etc., styrenic block copolymers including: acrylonitrile -Styrene and acrylonitrile-butadiene-styrene block copolymers, polystyrene, poly(methyl)methacrylate, polyacrylonitrile, poly(vinyl acetate), poly(vinyl alcohol), chlorine-containing polymers such as poly(vinyl chloride), polyoxymethylene, polycarbonate, polyamide, polyimide, polyurethane, phenolic / phenolic materials, amino-epoxy resins, polyesters, silicones, cellulose-based plastics, rubber-like plastics, expanded polyethylene, polyvinyl chloride, polyurethanes, silicones, polyethylene, polypropylene, polyurethanes, polyglycolic acid, polyesters, polyamides, elastomers and mixtures, blends and copolymers or derivatives thereof.

[0692] 108. A coated surface or method as described in clause / technical solution 107, wherein at least one of the one or more additional coatings contains a therapeutic agent.

[0693] 109. A coated surface or method as described in clause / technical solution 108, wherein the therapeutic agent is selected from the following group: antithrombotic agents, anticalcific agents, hemostatic agents, antiangiogenic agents, angiogenic agents, antimicrobial agents, antiproliferative agents, proliferative agents and anti-inflammatory agents, or a combination thereof.

[0694] 110. A coated surface or method as described in claim 109, wherein the therapeutic agent is an antithrombotic agent, such as heparin, and the additional coating is Bioactive Surface

[0695] 111. A coated surface or method as described in any of clauses / technical solutions 106-110, wherein at least one of the one or more additional coatings is a subsequent coating.

[0696] 112. A coated surface or method as described in any of clauses / technical solutions 3 to 110, wherein the surface is a surface of a medical device.

[0697] 113. A coated surface or method as described in clause / technical solution 112, wherein the medical device comprises expanded polytetrafluoroethylene (ePTFE) or expanded polyethylene (ePE), in particular ePTFE.

[0698] 114. A coated surface or method as described in clause / technical solution 112 or clause / technical solution 113, wherein the medical device is selected from the following group: stents, including bifurcated stents, balloon-expandable stents and self-expanding stents; stent grafts, including bifurcated stent grafts; grafts, including vascular grafts, bifurcated grafts and early catheter grafts; dialators; vascular occluders; thrombus filters; vascular filters; embolectomy devices; catheters, including microcatheters, central venous catheters, peripheral venous catheters, indwelling catheters and hemodialysis catheters; artificial blood vessels; sheaths, including retractable sheaths; blood indwelling monitoring devices; artificial heart valves; pacemaker electrodes; guidewires; cardiac pacemaker leads; cardiopulmonary bypass circuits; cannulas; plugs; drug delivery devices; balloons; tissue patch devices; blood pumps; artificial pancreas devices; cell encapsulation devices; implantable sensor devices; embolic particles; drug releasing particles and liquid embolic agents.

[0699] 115. A medical device comprising a coated surface as described in any one of clauses / technical solutions 3 to 114.

[0700] 116. Use of a chemical entity as described in any of clauses / technical solutions 3 to 104 for preventing or treating conditions that benefit from nitric oxide delivery.

[0701] 117. Use of the chemical entity as described in clause / technical solution 116 for opening blood vessels and / or improving oxygen levels.

[0702] 118. Use of the chemical entity as described in clause / technical solution 116 for preventing or treating atherosclerotic lesions or hypervascular lesions.

[0703] 119. Use of the chemical entity described in clause / technical solution 116 for preventing or treating angiogenesis (including vasculogenesis).

[0704] 120. Use of the chemical entity as described in clause / technical solution 116 to promote endothelialization, in particular transplantation / stent transplantation / stent endothelialization.

[0705] 121. Use of the chemical entity as described in clause / technical solution 116 for preventing or treating infections, especially bacterial infections.

[0706] 122. Use of the chemical entity as described in clause / technical solution 116 for maturing an arteriovenous fistula.

[0707] 123. Use of the chemical entity as described in clause / technical solution 116 for preventing or treating skin ulcers (e.g. foot ulcers).

[0708] 124. Use of the chemical entity as described in clause / technical solution 116 to accelerate the healing of the inflammatory cycle.

[0709] 125. A method for preventing or treating a condition that benefits from nitric oxide delivery, comprising using a medical device as described in clause / technical solution 115.

[0710] 126. A method for opening blood vessels and / or improving oxygen levels, wherein a medical device as described in clause / technical solution 115 is used.

[0711] 127. A method for preventing or treating atherosclerotic lesions or hypervascular lesions, wherein a medical device as described in clause / technical solution 115 is used.

[0712] 128. A method for preventing or treating angiogenesis (including vasculogenesis), wherein a medical device as described in clause / technical solution 115 is used.

[0713] 129. A method for promoting endothelialization, in particular endothelialization of a transplant / stent graft / stent, wherein a medical device as described in clause / technical solution 115 is used.

[0714] 130. A method for preventing or treating infection, especially bacterial infection, wherein a medical device as described in clause / technical solution 115 is used.

[0715] 131. A method for maturing an arteriovenous fistula, wherein a medical device as described in clause / technical solution 115 is used.

[0716] 132. A method for preventing or treating skin ulcers (e.g. foot ulcers), wherein a medical device as described in clause / technical solution 115 is used.

[0717] 133. A method for accelerating the healing of an inflammatory cycle, wherein a medical device as described in clause / technical solution 115 is used.

[0718] 134. A coated surface or method as described in any of clauses / technical solutions 4 to 114, wherein the coating is an antimicrobial coating.

[0719] 135. A coated surface or method as described in any of clauses / technical solutions 4 to 114, wherein the coating is stable to sterilization, in particular to ethylene oxide sterilization.

[0720] 136. A compound of formula (I):

[0721]

[0722] in,

[0723] A is the core part;

[0724] L is an optional linker;

[0725] R 1 and R 2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radical substitution;

[0726] n is 0 or 1; and

[0727] m is an integer of at least 1.

[0728] 137. A compound of formula (I) as described in clause / technical solution 136, wherein the core part A includes one or more parts independently selected from the following groups: alkyl, spiroalkyl, aryl, heteroaryl, alkylaryl, porphyrin, polymer and macrocycle, wherein the alkyl, spiroalkyl, aryl, heteroaryl and alkylaryl are optionally substituted by one or more substituents (for example, selected from the following group: alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0729] 138. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A comprises an alkyl group (e.g., C 1-20 alkyl), which is optionally substituted with one or more substituents (e.g. selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0730] 139. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A includes an alkyl group or is an alkyl group, and m is 1 or 2, especially 2.

[0731] 140. A compound of formula (I) as described in clause / technical solution 139, wherein the core part A comprises C 1-10 The alkylene part or C 1-10 The alkylene moiety is composed of, for example, C 1-6 Alkylene moieties, especially C 1-3 An alkylene moiety, such as -C(CH3)2-, -CH(CH3)-, -CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2-.

[0732] 141. A compound of formula (I) as described in clause / technical solution 140, wherein the core part A is -C(CH3)2- and m is 2.

[0733] 142. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A comprises a spiroalkyl group (e.g., C 1-20 spiroalkyl), which is optionally substituted with one or more substituents selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy.

[0734] 143. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A includes an aromatic group (e.g., a 5-10 membered aromatic group), which is optionally substituted by one or more substituents (selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0735] 144. A compound of formula (I) as described in clause / technical solution 143, wherein the aryl group is phenyl, which is optionally substituted by one or more substituents selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy.

[0736] 145. A compound of formula (I) as described in clause / technical solution 137, wherein

[0737] m is 2, and the core part A is:

[0738] or

[0739] m is 3, and the core part A is:

[0740]

[0741] 146. A compound of formula (I) as described in clause / technical solution 145, wherein

[0742] m is 2, and the core part A is:

[0743] or

[0744] m is 3, and the core part A is:

[0745]

[0746] 147. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A includes a heteroaryl group (e.g., a 5-10 membered heteroaryl group), which is optionally substituted by one or more substituents (selected from alkyl, alkoxy, fluoroalkyl and fluoroalkoxy).

[0747] 148. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A comprises an alkylaryl group (e.g., an alkyl group (e.g., C 1-10 alkyl) or substituted by an alkyl group (e.g., C 1-5 The polyaryl group is a polyaryl group linked to an alkyl group) which is optionally substituted with one or more substituents selected from the group consisting of an alkyl group, an alkoxy group, a fluoroalkyl group and a fluoroalkoxy group.

[0748] 149. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A comprises a porphyrin, such as tetra-4-aryl-meso.

[0749] 150. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A comprises a polymer, for example, a polyamine compound (for example, selected from the group consisting of polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane), a dendrimer (for example, a PAMAM dendrimer or a PPI dendrimer) or a hyperbranched polymer.

[0750] 151. A compound of formula (I) as described in clause / technical solution 137, wherein the core part A comprises a macrocycle, such as cyclodextrin.

[0751] 152. A compound of formula (I) as described in any one of clauses / technical solutions 136 to 151, wherein the core part A includes an unstable part.

[0752] 153. A compound of formula (I) as described in clause / technical solution 152, wherein the core part A contains a part that is unstable by hydrolysis or nucleophilic substitution, such as a part containing one or more functional groups independently selected from the following group: ester, anhydride, imine, imine, acetal, carbonate, phosphazene, phosphate, carbamate, lactide and lactone.

[0753] 154. A compound of formula (I) as described in clause / technical solution 152, wherein the core part A includes a part that is unstable by reduction and oxidation, such as a part containing one or more functional groups, and the functional groups are independently selected from: oxides, superoxides, ozone, oxygen-containing acids, halites, hypohalites and hypohalous acids.

[0754] 155. A compound of formula (I) as described in clause / technical solution 152, wherein the core part A includes a part that is unstable by photolysis (for example, by UV or visible light), such as a part containing one or more functional groups independently selected from benzoylcarbonyl and azide.

[0755] 156. A compound of formula (I) as described in any one of clauses / technical solutions 136 to 155, wherein the linker L comprises C 1-10 Alkylene, secondary amine or amide.

[0756] 157. A compound of formula (I) as described in any one of clauses / technical solutions 136 to 155, wherein the linker L is not present.

[0757] 158. A compound of formula (I) as described in any one of clauses / technical solutions 136 to 157, wherein n is 0.

[0758] 159. A compound of formula (I) as described in any one of clauses / technical solutions 136 to 157, wherein n is 1.

[0759] 160. A compound of formula (I) as described in any one of clauses / technical solutions 136 to 159, wherein R 1 and R 2 Independently selected from H and C 1-5 alkyl.

[0760] 161. A compound of formula (I) as described in any one of clauses / technical solutions 1 to 160, wherein R 1 and R 2 Independently selected from the group consisting of CH2CH3 and CH3; in particular both are CH3.

[0761] 162. A compound of formula (I) as described in any one of clauses / technical solutions 136 to 159, wherein R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo groups are substituted.

[0762] 163. A compound of formula (I) as described in clause / technical solution 162, wherein R 1 and R 2 Together with the C atoms to which they are attached, they form a cycloheptyl or cyclohexyl ring (which is optionally replaced on available atoms by one or more selected from C 1-2 alkyl and oxo groups).

[0763] 164. The chemical entity, coated surface or method of any one of clauses 136 to 144 or 147 to 163, wherein m is 1-5,000,000, 2-5,000,000, 1-1,000,000, 2-1,000,000, 1-500,000, 2-500,000, 1-400,000, 2-400,000, 1-200,000, 2-200,000, 1-100,000, or 2-100,000, 1-50,000, 2-50,000, 1-20,000, 2-20,000, 1-10,000, 2-10,000, 1-5,000, 2-5,000, 1-2,000, 2-2,000, 1-1,000, 2-1,000, 1-500, 2-500, 1-100, 2-100, 1-50, 2-50, 1-20, 2-20, 1-10, 2-10, 1-5, or 2-5.

[0764] 165. The chemical entity, coated surface or method of clause 164, wherein m is 2-500,000, 50-500,000, 100-500,000, 500-500,000, 1,000-500,000, 5,000-500,000, 1-200,000, 2-200,000, 50-200,000, 100-200,0 00, 500-200,000, 1,000-200,000, 5,000-200,000, 1-100,000, 2-100,000, 50-100,000, 100-100,000, 500-100,000, 1,000-100,000, 5,000-100,000, 1-50,000, 2-50,000, 50-50,000 0, 100-50,000, 500-50,000, 1,000-50,000, 5,000-50,000, 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, 5,000-20,000, 1-5,000, 2-5,000, 50-5,000, 1 -20,000, 500-5,000, 1,000-5,000, 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, 5,000-20,000, 1-1,000, 2-1,000, 50-1,000, 100-1,000, or 500-1,000.

[0765] 166. A chemical entity, a coated surface or a method as described in clause / technical solution 165, wherein m is 1-1,000, 2-1,000, 50-1,000, 100-1,000, or 500-1,000.

[0766] 167. A compound of formula (I) as described in clause / technical solution 166, wherein m is 2, 3 or 4; in particular 2 or 3.

[0767] 168. A compound of formula (I) as described in clause / technical solution 164 or clause / technical solution 165, wherein m is 5,000-100,000, for example, m is 5,000-50,000 or 5,000-20,000.

[0768] 169. A compound of formula (I) as described in clause / technical solution 136, which has formula (Ia):

[0769]

[0770] in,

[0771] R 1 and R 2 Independently selected from H and C 1-5 Alkyl, for example selected from CH3 and CH2CH3 (especially both are CH3); or R 1 and R 2 Together with the C atoms to which they are attached, they form a cycloheptyl or cyclohexyl ring (which is optionally replaced on available atoms by one or more selected from C 1-2 alkyl and oxo groups).

[0772] 170. A compound of formula (I) as described in clause / technical solution 136, which has formula (Iaa):

[0773]

[0774] Among them, L, n, R 1 and R 2 As defined in Clause / Technical Solution 1.

[0775] 171. A compound of formula (I) as described in clause / technical solution 170, which has formula (Iab):

[0776]

[0777] Among them, n, R 1 and R 2 As defined in Clause / Technical Solution 1.

[0778] 172. A compound of formula (I) as described in clause / technical solution 171, which has formula (lac):

[0779]

[0780] Among them, R 1 and R 2 As defined in Clause / Technical Solution 1.

[0781] 173. A method for preparing a compound of formula (I)

[0782]

[0783] in,

[0784] A is the core part;

[0785] L is an optional linker;

[0786] R 1 and R2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radical substitution;

[0787] n is 0 or 1;

[0788] m is an integer at least 1;

[0789] The method comprises: reacting a compound of formula (IV) with a compound of formula (V) under suitable conditions to form a compound of formula (I):

[0790]

[0791] in,

[0792] For formula (IV):

[0793] LG is a leaving group or an electrophilic group, or the moiety C=O-LG is an electrophilic group;

[0794] A is the core part;

[0795] L is an optional linker; and

[0796] m is an integer at least 1;

[0797] And for formula (V):

[0798] n is 0 or 1;

[0799] R 1 and R 2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radicals are substituted; and

[0800] X is NH2 or NH3 + Y - , where Y - is a suitable anion, such as Cl - .

[0801] 174. A method as described in clause / technical solution 173, wherein LG is a leaving group (for example, selected from halogen (such as chlorine or bromine), OM or OT) or an electrophilic group (for example, selected from azide, epoxide and isocyclopentane ester); or the part C=O-LG is an electrophilic group (for example, the part C=O-LG includes an ester (such as succinimidyl ester), a carbonate (such as succinimidyl carbonate) or anhydride).

[0802] 175. A method as described in clause / technical solution 173 or clause / technical solution 174, wherein the reaction is carried out in the presence of an aqueous base solution and / or a buffer solution.

[0803] As described herein, in at least some embodiments, chemical entities and coatings / paints comprising such chemical entities are expected to have one or more of the following advantages or benefits:

[0804] Suitable nitric oxide release characteristics, for example as measured using Assessment Methods Ai and Aii;

[0805] Good adhesion to substrate surfaces (e.g., medical device surfaces), such as measured using Assessment Method C;

[0806] When applied to a substrate surface (e.g., a medical device), the coating is uniform and uninterrupted (i.e., defect-free);

[0807] Low brittleness when coated on substrate surfaces (such as medical device surfaces);

[0808] Compatibility with other therapeutic agents such as heparin;

[0809] Soluble in solvents that are mild and / or suitable for mass production of the intended product; and

[0810] • Compatibility with different substrate materials commonly used in medical device manufacturing.

[0811] Definitions and Abbreviations

[0812] Boc tert-Butyloxycarbonyl

[0813] DCM Dichloromethane

[0814] DIPEA Diisopropylethylamine

[0815] Da Dalton (Dalton) (=g / mol)

[0816] EDTA Ethylenediaminetetraacetic acid

[0817] ePE Expanded Polyethylene

[0818] ePTFE Expanded Polytetrafluoroethylene

[0819] ESI Electrospray ionization

[0820] GPC Gel Permeation Chromatography

[0821] h hour

[0822] HFP Hexafluoropropylene

[0823] HMDA Hexamethylenediamine

[0824] HPLC High Performance Liquid Chromatography

[0825] IPA Isopropyl Alcohol

[0826] LS Light Scattering

[0827] M n Number average molecular weight

[0828] M w Weight average molecular weight

[0829] M z z-average molecular weight

[0830] MALDI matrix-assisted laser desorption ionization

[0831] Ms Methanesulfonyl

[0832] MS

[0833] NMP N-Methyl-2-pyrrolidone

[0834] PBS Phosphate buffered saline

[0835] PDMS Polydimethylsiloxane

[0836] PEI Polyethyleneimine

[0837] PPD p-phenylenediamine

[0838] PPI Polypropyleneimine

[0839] Q-ToF Quadrupole - Time of Flight

[0840] RT Room temperature

[0841] ToF-SIMS Time-of-Flight Secondary Ion Mass Spectrometry

[0842] Ts Tosyl

[0843] VDF Vinylidene Fluoride Example

[0844] General process

[0845] Chemicals

[0846] D / L-homocysteine ​​thiolactone hydrochloride (Compound (5)) was purchased from Sigma-Aldrich (PN 53530). Benzene-1,3-dicarbonyloxysuccinimide was purchased from Sigma-Aldrich (PN BOG00213). PEI was purchased from Sigma-Aldrich, catalog number 408727 (average Mw measured by LS was about 25,000, average Mn measured by GPC was about 10,000, branched). D-penicillamine (Compound (1)) was purchased from Sigma-Aldrich (PN P4875). Isophthaloyl chloride was purchased from Sigma-Aldrich (PNI19403). Benzene-1,3-dicarbonyloxysuccinimide was purchased from Sigma-Aldrich (PN BOG00213). 1,3,5-Benzenetricarbonyl trichloride was purchased from Sigma-Aldrich (PN 147532). VDF-HFP fluoropolymer was purchased from Sigma-Aldrich (PN 427150).

[0847] Material

[0848] Expanded polytetrafluoroethylene (ePTFE) membrane (C401939418 / 10932368) was obtained from WL Gore & Associates, Inc. Stainless steel foil was purchased from Trinity Brand Industries, Inc. (PN 24S-3165). Nylon film was purchased from WL Gore & Associates, Inc. (02219-03TMVR). Expanded polyethylene (ePE) film was prepared as described in US9926416 or US10577468. Berkeley Life Nitric Oxide Saliva Test Strip was purchased from Berkeley Life Professional, Chicago Illinois.

[0849] Analytical methods

[0850] NMR analysis

[0851] Prepare by dissolving approximately 15 mg of sample in 1 mL of deuterated solvent. 1 H solution NMR samples were collected using a Bruker BioSpin Neo 300 MHz system to collect the 300.13 MHz 1H NMR data. A Bruker BioSpin 5 mm BBFO probe was installed into a standard bore 7.05 T Bruker BioSpin supershielded superconducting magnet. The temperature during NMR acquisition was 300 K (26.9° C.). The software used for data acquisition and data processing was Topspin 1.3 or higher (Bruker). The spectra were referenced to the residual proton peaks of the deuterated solvent.

[0852] FTIR spectroscopy

[0853] FTIR spectra were performed on an Agilent 670 spectrometer (Agilent Technologies, Santa Clara, CA USA) or a Thermo Scientific Nicolet iS50 spectrometer (Thermo Fisher Scientific, Waltham, MA USA) equipped with an attenuated total reflectance (ATR) diamond cell. At least 32 scans were recorded for each spectrum with a resolution of 4 cm -1 .

[0854] Liquid chromatography-mass spectrometry

[0855] Waters Xevo TQ-S LC Conditions:

[0856] Column: 2.1mm x 50mm, 1.7μm, ACQUITY UPLC BEH C8

[0857] Column oven: 30°C

[0858] Injection: 5L

[0859] Solvent A: water + 0.1% formic acid

[0860] Solvent B: acetonitrile + 0.1% formic acid

[0861] Gradient: Time (min) B Flow (mL / min) 0.00 50.0 0.400 10.00 50.0

[0864] Run time 10 minutes

[0865] Waters PDA detector conditions:

[0866] PDA detector type: UPLC LG 500nm

[0867] Run time: 10.0 minutes

[0868] Scanning range: 192-400nm

[0869] Sampling rate: 10 points / second

[0870] Resolution: 2.4nm

[0871] Waters Xevo TQ-S LC-MS / MS conditions:

[0872] ESI positive or negative mode

[0873]

[0874] Nebulizer gas flow (bar): 7.00.

[0875] Molecular weight determination by end group analysis

[0876] The estimated number average molecular weight was determined by titration of carboxylic acid end groups in n-methylpyrrolidone at room temperature by a colorimetric method based on ASTM D7409. Prior to the carboxylate end group analysis, a ninhydrin test was performed to demonstrate the absence of amine end groups.

[0877] Molecular weight determined by gel permeation chromatography

[0878] The polymer samples were diluted in dimethyl sulfoxide. The diluted solutions were then measured on a Malvern PanAnalytic OmniSec gel permeation chromatography light scattering instrument using a dual angle light scattering detector and a refractive index detector. The gel permeation chromatography column was run on an Agilent 1260 Infinity II liquid chromatography system.

[0879] Evaluation Methodology

[0880] Ai. Nitric oxide (NO) release

[0881] The ability of chemical entities described herein or surfaces with coatings containing chemical entities described herein to release nitric oxide (NO) is assessed using commercially available Berkeley nitric oxide test strips ("Berkeley Life Nitric Oxide Saliva Test Papers"). The instructions for use of such test strips are provided in the packaging of the Berkeley nitric oxide test strips, and are also described in WO2013 / 023217A1 and WO2014 / 039794A2 (which are incorporated herein by reference). The test strips provide semi-quantitative measurements of NO-derived analytes (mainly aqueous nitrite anion solutions) rather than NO itself, because as known in the art (Ignarro et al., 1993), the half-life of NO aqueous solutions is very short, only a few seconds, while nitrite anion solutions (derived from NO aqueous solutions) have a half-life of several hours. Therefore, nitrite anions are suitable substitutes for measuring the NO concentration of aqueous solutions. The test strips include a nitrite detection pad, which includes a dry chemical reagent that reacts to different nitric oxide analytes, thereby indicating the concentration of nitric oxide. The test strip is capable of detecting a nitric oxide analyte concentration range of 0 to 400 μmol / L nitrite, and the intensity of the colorimetric range is significantly different, manifested as an increased intensity of red (i.e., approximately 700 nm wavelength), qualitatively corresponding to micromolar, specifically including but not limited to: 0 μM, 1 μM to 25 μM, 25 μM to 100 μM, 100 μM to 200 μM, 200 μM to 350 μM and greater than 400 μM nitrite.

[0882] The surface with the coating to be evaluated is immersed in a PBS test solution of 10.0mM pH 7.4 containing 100μM EDTA. By immersing the test strip in the solution, the NO concentration is evaluated at a given time point. After 5 seconds, the test strip is taken out, the test strip is folded up, and the sample pad is gently pressed on the test pad and kept for 10 seconds. The ends are separated and compared with the Berkeley test nitric oxide scale, wherein the significantly different colorimetric range includes 6 subjective levels of red wavelength intensity (i.e., about 700nm wavelength), corresponding to 0μM, 25μM, 100μM, 200μM, 350μM and 400μM nitric oxide derivative analytes, depending on the red qualitative intensity subjectively observed by the user. Therefore, once the strip allows development, the color intensity of the strip is determined subjectively, and the concentration of nitrate anions (thereby determining the release of NO) is determined. As shown in the examples below, because each bar is assigned to one of six subjective intensity levels (the sixth being no response), the resulting NO release graph has discrete jumps rather than a continuous curve, although in practice continuous release is expected to occur.

[0883] Aii Measurement of NO by thermogravimetric analysis (TGA)

[0884] The amount of nitric oxide bound to the thiol functional group was determined by the thermal desorption mass loss measured on the TGA. Prior to the experiment, the characteristics of the initial thermal desorption (depending on the monomer unit, the starting temperature was between 75°C and 102°C) were measured by thermal desorption FT-IR. By thermal desorption FT-IR, the initial mass loss was characterized as mainly nitric oxide, where the thiol decomposition product portion was not obvious in the parent non-nitrosylated polymer. The amount of nitric oxide was determined by TGA using a Q500 TGA from TA Instruments. The sample was heated from room temperature to 400°C using a high resolution scan at 5°C / min until mass loss was detected. The NO mass loss was calculated from the derivative curve of the mass loss curve from the first mass loss to the inflection point between the first and second mass loss peaks.

[0885] Aiii NO elution measurement

[0886] Determination of NO absorbance using Griess reagent

[0887] The sample weighed before is added to the scintillation bottle.15mL of 10mM PBS and 100μM EDTA (pH 7.2) are added to the vial.Then, the sample is incubated at 37°C in dark for a specified time point.At the time point, 50μL elution medium is taken out and added to a 96-well plate.Then six sodium nitrite standard solutions (140, 70, 30, 10, 2 and 0μM sodium nitrite) in the 10mM PBS containing 100μM EDTA (pH7.2) are added to the 96-well plate.50μL PBS and 50μL Griess reagent A and B (VWR product number 102965-266) are added to each sample and standard.Then the 96-well plate is incubated at room temperature (22-25°C) for 10 minutes, and then the absorption spectrum at 540nm is taken on the Molecular Devices SpectraMax 190 plate reader. A calibration curve was calculated based on sodium nitrite standards and the elution time points were calculated using the calibration standard curve fit parameters.

[0888] NO measurement by NO analyzer

[0889] Nitric oxide elution was measured using a Thermo Scientific 42i NOX Analyzer. Nitrosated polymer samples were added to PBS and the solution was heated to 37°C. Measurements were taken on days 1, 2, 3, 7, and weekly thereafter.

[0890] A 5 mM sodium nitrite standard solution was prepared. Five different volumes (10-50 uL) of each standard were injected into the sample chamber containing a vanadium trichloride and HCl solution, which converts nitrite to nitric oxide and delivers NO under an argon flow. XThe analyzer then detects the chemiluminescent signal from the reaction of nitric oxide with ozone.

[0891] The samples were added to fresh PBS at 37°C in the sample chamber. Headspace analysis was performed, in which the PBS solution containing the sample was sealed in a container for a period of time, and then the system was opened and an argon flow was introduced into the system to drive the released nitric oxide through NO X The released nitric oxide was analyzed using the chemiluminescent signal and its amount was determined using a prepared calibration curve.

[0892] B. Stability to ethylene oxide (EO)

[0893] A sample of a chemical entity described herein or a surface having a coating comprising a chemical entity described herein is placed in a breathable polyethylene pouch (e.g., a Tyvek pouch) and preconditioned at 43°C and 65% relative humidity for at least 12 hours, followed by exposure to 600 mg / L ethylene oxide at 52°F and 25% relative humidity for 12 hours. The chamber is then aerated at 32°F for at least 12 hours until the ethylene oxide concentration is less than 0.25 ppm. After sterilization, the sample or surface is evaluated for NO release using Evaluation Method Ai.

[0894] C. Adhesion to medical devices

[0895] Adhesion test of NO release coating on the surface includes nano scratch test, scratch area imaging and nano indentation test, to record quasi-static reduced modulus value, which is then converted into adhesive critical failure load value (conventional test procedure well known in the art). Test is performed using Hysitron950Tribointender (Bruker Co., Ltd., Eden Prairie, Minn.). Five samples of each nitric oxide release coating formulation are tested at random positions. This technology is used to study the amount or thickness or distribution of coating on the surface, and to determine the position where the amount, thickness or distribution of coating changes on the surface. This technology is also used to examine the coating containing one or more additional coatings by measuring the relationship between the modulus and / or adhesion strength of the coating and the nano indentation depth. In addition, this technology is also used to examine the incorporation of therapeutic agents in coatings / coatings. In addition to nanomechanical testing, ASTM D3359 "Test method for measuring adhesive tape adhesion" can be used to observe the adhesion of NO release coatings to underlying substrates.

[0896] General process

[0897] A. Synthesis of compounds of formula (I) from acyl chlorides

[0898]

[0899] To a stirred CHCl3 or DCM solution / suspension of a polyfunctional acid chloride (compound of formula (IVa), for example obtained from a source described in the examples below) and a thiolactone-HCl salt (compound of formula (Va), compound (4) prepared as described in Example 1, or commercially available compound (5)) is added dropwise 2 equivalents of DIPEA / equivalent of compound of formula (Va) in an appropriate stoichiometric ratio (mx) via a syringe. After a few minutes, the solution becomes clear and is stirred for an additional 30 minutes. The solution is then washed with 1M HCl (3x) and then with water (1x). The organic layer is then dried over anhydrous Na2SO4, filtered, and the solvent is rotary evaporated under reduced pressure to give a compound of formula (I), which is typically a white microcrystalline powder.

[0900] B. Synthesis of Compounds of Formula (I) from Succinimide Esters

[0901]

[0902] To a vigorously stirred MeCN solution / suspension of a multifunctional succinimide ester (compound of formula (IVb), obtained from a source described in the following examples) and a thiolactone-HCl salt (compound of formula (Va), compound (4) prepared as described in Example 1, or commercially available compound (5)) is added an equal volume of brine (250 g / L NaCl) via syringe in an appropriate stoichiometric ratio (mx). 1 M sodium carbonate is added to the resulting emulsion in one portion, the mixture is stirred vigorously at room temperature for 15 minutes, and then the layers are separated. The aqueous layer is discarded, and the organic layer is washed twice more with brine and dried over anhydrous Na2SO4. The solution is then filtered and the solvent is rotary evaporated under reduced pressure to yield the compound of formula (I), which is typically a white microcrystalline powder.

[0903] Synthesis of intermediates

[0904] For all examples shown below, where the structure contains one or more chiral centers, the absolute stereochemistry is not shown, but is indicated in the intermediate or chemical entity name, or can be derived from the indicated stereochemistry of the starting materials. It should be noted that when the examples refer to the D-stereoisomer, the methods described are also applicable to the synthesis of the L-stereoisomer and mixtures of the D-stereoisomer and the L-stereoisomer (including racemic mixtures), and when the examples refer to mixtures of the D-stereoisomer and the L-stereoisomer, the methods described are also applicable to the synthesis of the L-stereoisomer and the D-stereoisomer alone. When the structure contains more than one chiral center, in some cases, depending on the number of chiral centers, a number of different diastereomers can be formed. Such structures can be chiral or achiral (meso).

[0905] Example 1: Synthesis of D-penicillamine thiolactone HCl salt (4)

[0906]

[0907] D-penicillamine (1) is N-protected with a Boc group as described in EP1165532A1 (incorporated herein by reference) for L-penicillamine. Specifically, D-penicillamine ((1), 15 g, 0.1 mol) is suspended in methanol (250 ml) and cooled to 0°C. Triethylamine (14 ml, 0.1 mol) is added, followed by a single addition of solid di-tert-butyl dicarbonate (24 g, 0.11 mol). The reaction mixture is stirred overnight at 25°C, and the solvent is then removed by rotary evaporation to give a residue. The residue is dissolved in EtOAc (100 ml), washed with 1 M HCl (100 ml), water (50 ml) and brine (50 ml), dried over anhydrous MgSO4, filtered, and rotary evaporated under reduced pressure to give a clear, viscous residue. About 20 mL of hexanes were added to the viscous residue to form an azeotrope with the residual EtOAc, and the solvent was rotary evaporated under reduced pressure to give Boc-protected penicillamine (2) as a fluffy white solid.

[0908] Compound (2) was cyclized to the corresponding thiolactone (3) according to the process for the synthesis of N-acetylpenicillamine described in Hopkins et al. (2018). Specifically, compound (2) was dissolved in 40 mL of pyridine and cooled to 0°C on an ice bath. At the same time, 40 mL of pyridine and 40 mL of acetic anhydride were mixed in a separate container and placed in a refrigerator (-5°C). The two solutions were cooled for 0.5 hours, then combined and stirred overnight at room temperature. The combined solution was then rotary evaporated under reduced pressure at 40°C until a crude solid remained. The crude solid was then dissolved in 80 mL of CHCl3, washed with 1M HCl (3x 50 ml), and the organic layer and the aqueous layer were separated. The organic layer was separated, dried over anhydrous MgSO4 and filtered. CHCl3 was removed under rotary evaporation to obtain a white solid compound (3), which was dried under vacuum overnight.

[0909] The deprotection step to produce the ammonium salt (4) was carried out by the following steps: Compound (3) was dissolved in 200 mL MeCN at 25°C. Then 37.5 mL of 4.0 M HCl in dioxane (1.5 equivalents) was added dropwise to the solution under stirring via a syringe. The solution initially became clear, and then after approximately 5-10 minutes, the reaction product began to precipitate to give a white, turbid suspension. The suspension was stirred for 45 minutes, 100 mL Et2O was added, and the suspension was stirred for an additional 5-10 minutes. The white microcrystalline product was collected on a glass frit, washed with additional Et2O, and dried overnight under vacuum to give D-penicillamine thiolactone HCl salt (4).

[0910] Synthesis of compounds of formula (I)

[0911] Example 2: N 1 ,N 6 -Synthesis of bis(2,2-dimethyl-4-oxothiophene-3-yl)adipamide (6)

[0912]

[0913] Adipoyl chloride (2.4 g, 0.013 mol) was reacted with two equivalents of D-penicillamine thiolactone HCl salt (Example 1, compound (4), 4.4 g, 0.026 mol) according to the general procedure A. The title compound (6) was isolated as a white solid. 1 H NMR (400 MHz, DMF-d7)d 8.92 (d, 2H, J = 8.67 Hz), 5.76 (d, 2H, J = 8.79 Hz), 2.29 (m, 4H), 1.79 (s, 6H), 1.67 (s, 6H), 1.62 (m, 4H). FTIR-ATR(cm -1 ) 最大 =1754.

[0914] Example 3: N 1 ,N 8 -Synthesis of bis(2-oxotetrahydrothiophene-3-yl)octanediamide (7)

[0915]

[0916] Disuccinimidyl suberate (1.0 g, 2.7 mmol) was reacted with two equivalents of D / L-homocysteine ​​thiolactone hydrochloride (compound (5), 0.83 g, 5.4 mmol) following general procedure B. The title compound (7) was isolated as a white solid. 1 H NMR (400 MHz, DMSO-d6)d 8.12 (d, 2H, J = 8.41 Hz), 4.59 (m, 2H), 3.44-3.22 (m, 4H), 2.40 (m, 2H), 2.14-1.97 (m, 6H), 1.48 (m, 4H), 1.25 (m, 4H). FTIR-ATR(cm -1 ) 最大 =1648.

[0917] D / L-Homocysteine ​​thiolactone hydrochloride (compound (5)) can be obtained by the method of Martens et al. (1991).

[0918] Example 4: N 1 ,N 3-Synthesis of bis(2,2-dimethyl-4-oxothiophene-3-yl)isophthalimide (8)

[0919]

[0920] Isophthaloyl chloride (500 mg, 2.46 mmol) was reacted with two equivalents of D-penicillamine thiolactone HCl salt (Example 1, compound (4), 826 mg, 4.92 mmol) according to the general procedure A. The title compound (8) was isolated as a white solid. 1 HNMR(400MHz,CDCl3)d 8.09(d,2H,J=8.82Hz),7.92(t,1H,J=1.47Hz),7.84(dd,2H,J=7.79,1.67Hz ), 7.41 (t, 1H, J = 7.77Hz), 5.96 (d, 2H, J = 8.86Hz), 1.93 (s, 6H), 1.79 (s, 6H). FTIR-ATR(cm -1 ) 最大 =1748.

[0921] Example 5: N 1 ,N 3 -Synthesis of bis(2-oxotetrahydrothiophene-3-yl)isophthalimide (9)

[0922]

[0923] Benzene-1,3-dicarbonyloxysuccinimide (2.0 g, 5.6 mmol) was reacted with two equivalents of D / L-homocysteine ​​thiolactone hydrochloride (compound (5), 1.7 g, 11 mmol) as described in General Procedure B. The title compound (9) was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)d 8.79(d,2H,J=8.2Hz),8.37(t,1H,J=1.67Hz),8.01(dd,2H,J=5.97,1.80Hz),7.59 (t,1H,J=7.75Hz),4.84(m,2H),3.53-3.31(m,4H),2.58-2.47(m,1H),2.35(m,3H). FTIR-ATR(cm -1 ) 最大 =1694.

[0924] Example 6: N 1 ,N 3 ,N 5 -Synthesis of tris(2,2-dimethyl-4-oxothiophen-3-yl)benzene-1,3,5-tricarboxamide (10)

[0925]

[0926] 1,3,5-Benzenetricarbonyl trichloride (500 mg, 1.9 mmol) was reacted with three equivalents of D-penicillamine thiolactone HCl salt (Example 1, compound (4), 950 mg, 5.7 mmol) according to General Procedure A, except that in this case, compound (10) precipitated from the reaction solution. After stirring for 2 hours, the product was collected on a frit, washed with 1M HCl, then with water, and then dried. The title compound (10) was isolated as a white solid. 1 H NMR (400MHz, DMF-d7)d 9.94 (d, 3H, J = 8.38Hz), 8.77 (s, 3H), 6.02 (d, 3H, J = 8.46Hz), 1.92 (s, 9H), 1.79 (s, 9H). FTIR-ATR(cm -1 ) 最大 =1655.

[0927] Example 7: N 1 ,N 3 ,N 5 -Synthesis of tris(2-oxotetrahydrothiophen-3-yl)benzene-1,3,5-tricarboxamide (11)

[0928]

[0929] 1,3,5-Benzenetricarbonyl trichloride (3.4 g, 12.8 mmol) was reacted with three equivalents of D / L-homocysteine ​​thiolactone hydrochloride (compound (5), 5.9 g, 38 mmol) following general procedure B. The title compound (11) was isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)d 9.16(d,3H,J=8.32Hz),8.50(s,3H),4.90(m,3H),3.55-3.42(m,3H),3.40-3.28(m,3H),2.57-2.46(m,3H),2.42-2.25(m,3H). FTIR-ATR(cm -1 ) 最大 =1638.

[0930] Embodiment A1: N 1 ,N 3 -Synthesis of Bis(2,2-dimethyl-4-oxothiophen-3-yl)-2,2-dimethylpropanediamide (31)

[0931]

[0932] 10 g of 2,2'-dimethylmalonyl chloride, 20.8 g of D-penicillamine thiolactone hydrochloride (Example 1, compound (4)) and 200 mL of chloroform were added to a 500 mL round-bottom flask. 42 mL of diisopropylethylamine (DIPEA) was added to the addition funnel. The reactor was purged with argon and cooled to 4 °C with an ice bath. DIPEA was added dropwise to the thiolactone suspension. After the addition of DIPEA, the reaction solution was slowly cooled to room temperature and stirred for 1 hour. The reaction medium was then added to a separatory funnel and extracted with 1.2 L of 1 N hydrochloric acid. The chloroform solution was dried over magnesium sulfate and filtered. Chloroform was evaporated on a rotary evaporator until 50 mL of chloroform remained. 25 mL of ether was added to the solution to crystallize the product. The title compound (31) was collected on a glass frit and then dried under vacuum. 1 H NMRδ1.61(s)δ1.70(s)δ1.95(s)δ5.65(d)δ7.54(d).

[0933] Hydrolysis of the compound of formula (I) and S-nitrosothiol derivatization

[0934] Test Example 8: Compound 6 is hydrolyzed and derivatized with S-nitrosothiol to form 2,2'-(adipoylbis(azadiyl))bis(3-methyl-3-(nitrosothiol)butanoic acid) (13)

[0935]

[0936] 200 mg N 1 ,N 6 -bis(2,2-dimethyl-4-oxothiophene-3-yl)adipamide (Example 2, compound (6)) was suspended in 5 mL of water and a few drops of concentrated HCl were added. The suspension was heated under reflux for 2 hours to obtain a clear solution of the hydrolyzed product compound (12) (2,2'-(adipylbis(azadiyl))bis(3-mercapto-3-methylbutanoic acid)) with an ESI-MS m / z of C 16 H 28 N2O6S2 408.1(M–H) - Calculated; measured value, 407.0.

[0937] After cooling to room temperature, water and HCl were added to the clear solution to a final volume of 10 mL with 1 M HCl, and then cooled to 0°C. 1 mL of concentrated H2SO4 was added to form a suspension, and the suspension was cooled to 0°C in an ice bath. Sodium nitrite (3 equivalents relative to the thiol residue of compound (6)) was dissolved in a few milliliters of water (nitrous acid (HONO) was formed in situ) and added to the suspension at one time. The ice bath was removed and the suspension was stirred in the dark for 1 hour. 30 mL of DCM was added to the resulting green suspension, and the green suspension was vigorously stirred for 15-20 minutes to form an emulsion. The emulsion was then poured into a separatory funnel, and the bright green DCM layer was poured onto Na2SO4 and placed in a refrigerator (5°C) for 30 minutes. After filtering the DCM layer, the DCM solvent was rotary evaporated under reduced pressure to obtain a green solid S-nitrosothiol derivative compound (13). Compound (13): 1 H NMR (400MHz, DMSO-d6) d13.13 (s, 2H), 8.40 (d, 2H, J = 9.51Hz), 5.18 (d, 2H, J = 9.51Hz), 2.15 (m, 4H), 1.96 (s, 6H), 1.93 (s, 6H), 1.40 (m, 4H).

[0938] Components B and C react to form a "thiol / -SH" chemical entity

[0939] Example 9: Compound 6 reacts with benzylamine to form N1,N6-bis(1-(benzylamino)-3-mercapto-3-methyl-1-oxobutan-2-yl)hexanediamide (14)

[0940]

[0941] To N in CHCl3 1 ,N 6 To a stirred suspension of bis(2,2-dimethyl-4-oxothiophene-3-yl)adipamide (6) (Example 2, compound (6)), 10% excess benzylamine (based on the mole % of compound (6)) was added. The suspension was stirred at room temperature overnight and the resulting clear solution was washed twice with 1M HCl. The organic layer was dried over Na2SO4, filtered, and the solvent was rotary evaporated under reduced pressure to give compound (14) as a white solid. 1HNMR(400MHz,CDCl3)d 7.86 (t, 2H, J = 5.55Hz), 7.37 (d, 2H, J = 9.61Hz), 7.19 (m, 6H), 7.11 (m, 4H), 4.88 (d, 2H, J = 9.70Hz), 4.29 (dd, 2H, J = 15. 02, 8.85Hz), 3.99 (dd, 2H, J = 15.02.9.94Hz), 2.47 (s, 2H), 2.33 (m, 4H), 1.79-1.52 (m, 4H), 1.49 (s, 6H), 1.36 (s, 6H). ESI-MS m / z in C 30 H 42 N4O4S2 calculated value 586.3 (M–H) - ; Found, 586.2. FTIR-ATR (cm -1 ) 最大 =1640.

[0942] Example 10: Compound 6 reacts with aniline to form N1,N6-bis(3-mercapto-3-methyl-1-oxo-1-(phenylamino)butan-2-yl)adipamide (15)

[0943]

[0944] To N in CHCl3 1 ,N 6 To a stirred suspension of bis(2,2-dimethyl-4-oxothiophene-3-yl)adipamide (Example 2, compound (6)), a 3-fold excess of aniline (based on the mole % of compound (6)) was added. The suspension was stirred at 25°C in the dark for 3 days, and the resulting clear solution was washed twice with 1M HCl. The organic layer was dried over Na2SO4, filtered, and the solvent was rotary evaporated under reduced pressure to give compound (15) as a white solid. 1 H NMR (400MHz, CDCl3)d 9.17(s,2H),7.40-7.30(m,6H),7.13,(m,4H),7.01(t,2H,J=7.35Hz),4.98(d,2H, J=9.42Hz),2.57(s,2H),2.31(m,4H),1.78-1.50(m,4H),1.60(s,6H),1.43(s,6H). ESI-MS m / z in C 28 H 38 N4O4S2 calculated value 558.2 (M–H) - ; Measured value, 557.6. FTIR-ATR (cm -1 ) 最大 =1641.

[0945] Example 11: Compound 6 reacts with morpholine to form N1,N6-bis(3-mercapto-3-methyl-1-morpholine-1-oxobutan-2-yl)hexamethylenediamide (6a)

[0946]

[0947] To a stirred suspension of adipoyl-1,6-dipenicillamine dithiolactone (Example 2, compound (6)) in chloroform, a 3-fold excess of morpholine (based on the mole % of compound (6)) was added. The suspension was stirred at room temperature overnight and the resulting clear solution was washed twice with 1M HCl. The organic layer was dried over Na2SO4, filtered, and the solvent was rotary evaporated under reduced pressure to give compound (6a) as a white solid. 1 H NMR(400MHz,DMSO-d6)d 8.08(d,2H,J=9.42Hz),4.96(d,2H,J=9.43Hz),3.68-3.40(m,16H),2.94(s,2H),2.19(m,4H),1.46(m,4H),1.36(s,6H),1.32(s,6H). ESI-MS m / z in C 24 H 42 N4O6S2 Calcd. 546.3 (M–H) - ; Found, 545.1. FTIR-ATR (cm -1 ) 最大 =1618.

[0948] Example 12: Compound 8 reacts with benzylamine to form N1,N3-bis(1-(benzylamino)-3-mercapto-3-methyl-1-oxobutan-2-yl)isophthalimide (8a)

[0949]

[0950] To N in CHCl3 1 ,N 3 To a stirred suspension of 1-bis(2,2-dimethyl-4-oxothiophen-3-yl)isophthalimide (Example 4, compound (8)) was added 10% excess benzylamine (based on the mole % of compound (8)). The solution / suspension was stirred at room temperature overnight and the resulting clear solution was washed twice with 1M HCl. The organic layer was dried over Na2SO4, filtered, and the solvent was rotary evaporated under reduced pressure to give compound (8a) as a white solid. 1H NMR(400MHz, DMSO-d6)d8.74,(t,2H,J=5.83Hz),8.33-8.25(m,3H),8.03(dd,2H,J=7.76,1.63Hz),7.59(t,1H,J=7 .76Hz), 7.37-7.17 (m, 10H), 4.79 (d, 2H, J = 9.35Hz), 4.33 (d, 4H, J = 5.80Hz), 2.97 (s, 2H), 1.46 (s, 6H), 1.43 (s, 6H). ESI-MS m / z in C 32 H 38 N4O4S2 calculated value 606.2 (M–H) - ; Found, 604.9. FTIR-ATR (cm -1 ) 最大 =1636.

[0951] Example 13: Compound 8 reacts with aniline to form N1,N3-bis(3-mercapto-3-methyl-1-oxo-1-(phenylamino)butan-2-yl)isophthalimide (8b)

[0952]

[0953] To N in chloroform 1 ,N 3 To a stirred suspension of 1-bis(2,2-dimethyl-4-oxothiophen-3-yl)isophthalimide (Example 4, compound (8)) was added a 3-fold excess of aniline (based on the mole % of compound (6)). The suspension was stirred at room temperature overnight and the resulting clear solution was washed twice with 1M HCl. The organic layer was dried over Na2SO4, filtered, and the solvent was rotary evaporated under reduced pressure to give compound (8b) as a white solid. 1 H NMR(400MHz,DMSO-d6)d 10.31(s,2H),8.45,(d,2H,J=9.12Hz),8.29(t,1H,J=1.54Hz),8.04(dd,2H,J=7.75,1.72Hz),7.66-7.56( m, 5H), 7.32 (m, 4H), 7.07 (t, 2H, J = 7.38Hz), 4.96 (d, 2H, J = 9.13Hz), 3.00 (s, 2H), 1.53 (s, 6H), 1.49 (s, 6H). ESI-MS m / z in C 30 H 34 N4O4S2 calculated value 578.2 (M–H) - ; Found, 577.0. FTIR-ATR (cm -1 ) 最大=1497.

[0954] Example 14: Compound 8 reacts with morpholine to form N1,N3-bis(3-mercapto-3-methyl-1-morpholine-1-oxobutan-2-yl)isophthalimide (8c)

[0955]

[0956] To N in chloroform 1 ,N 3 To a stirred suspension of 1-bis(2,2-dimethyl-4-oxothiophen-3-yl)isophthalimide (Example 4, compound (8)) was added a 3-fold excess of morpholine (based on the mole % of compound (8)). The suspension was stirred at room temperature overnight and the resulting clear solution was washed twice with 1M HCl. The organic layer was dried over Na2SO4, filtered, and the solvent was rotary evaporated under reduced pressure to give compound (8c) as a white solid. 1 H NMR(400MHz,DMSO-d6)d 8.59(d,2H,J=9.04Hz),8.25(t,1H,J=1.51Hz),8.02(dd,2H,J=7.76,1.72Hz),7.56(t,1H,J=7.76Hz ),5.18(d,2H,J=9.03Hz),3.79-3.44(m,16H),3.13(s,2H),1.47(s,6H),1.44(s,6H).ESI-MSm / z, with C 26 H 38 Calculated for N4O6S2: 566.2 (M–H) - ; Found, 566.2. FTIR-ATR (cm -1 ) 最大 =1625.

[0957] Example 15: Compound 10 reacts with benzylamine to form N1,N3,N5-tris(1-(benzylamino)-3-mercapto-3-methyl-1-oxobutan-2-yl)benzene-1,3,5-tricarboxamide (10a)

[0958]

[0959] To N in chloroform 1 ,N 3 ,N 5To a stirred suspension of 1,3,5-tris(2,2-dimethyl-4-oxothiophen-3-yl)benzene-1,3,5-tricarboxamide (Example 6, compound (10)) was added 10% excess benzylamine (based on the mole % of compound (10)). The suspension was stirred at room temperature overnight and the resulting clear solution was washed twice with 1M HCl. The organic layer was dried over Na2SO4, filtered, and the solvent was rotary evaporated under reduced pressure to give compound (10a) as a white solid. 1 H NMR (400MHz, CDCl3)d 8.21(s,3H),7.92(d,3H,J=8.75Hz),7.46,(m,3H),7.31-7.19(m,15H),4.80(d,3H,J=8.80Hz),4.6 0(dd,3H,J=14.70,6.20Hz),4.28(dd,3H,J=14.69,4.56Hz),2.50(s,3H),1.6(s,9H),1.41(s,9H). ESI-MS m / z in C 45 H 54 N6O6S3 calculated value 870.3 (M–H) - ; Found, 869.2. FTIR-ATR (cm -1 ) 最大 =1643.

[0960] Example 16: Compound 10 reacts with morpholine to form N1,N3,N5-tris(3-mercapto-3-methyl-1-morpholin-1-oxobutan-2-yl)benzene-1,3,5-tricarboxamide (10b)

[0961]

[0962] To N in chloroform 1 ,N 3 ,N 5 To a stirred suspension of tris(2,2-dimethyl-4-oxothiophen-3-yl)benzene-1,3,5-tricarboxamide (Example 6, compound (10)) was added a 3-fold excess of morpholine (based on the mole % of compound (8)). The suspension was stirred at room temperature overnight to obtain a white solid compound (10b). 1 H NMR (400 MHz, DMSO-d6) d 8.81 (d, 3H, J = 9.01 Hz), 8.36 (s, 3H), 5.20 (d, 3H, J = 9.03 Hz), 3.80-3.44 (m, 24H), 3.13 (s, 3H), 1.48 (s, 9H), 1.45 (s, 9H). ESI-MS m / z, C 36 H 54 N6O9S3 calculated value 810.3 (M–H)- ; Found, 809.0. FTIR-ATR (cm -1 ) 最大 =1627.

[0963] Polymer preparation

[0964] The following examples relate to polymers. The structures provided for polymers in the following schemes show polymer chains without terminal groups, where n represents the number of repeating units. If a number is provided for the number of monomeric units, it represents the average number of monomeric units in the polymer, and these units may be present in the polymer in any order.

[0965] Example 17: Copolymerization of Compound 6 with Hexamethylenediamine (HMDA) to Form Copolymer (19)

[0966]

[0967] To the stirring N 1 ,N 6 An equimolar amount of HMDA solution in THF was added dropwise to a THF solution of -bis(2,2-dimethyl-4-oxothiophene-3-yl)adipamide (Example 2, compound (6)). The solution was stirred at 25°C for 3 days to obtain copolymer (19) as a turbid white suspension. 1 H NMR (DMSO-d6) spectrum Figure 2 shown. 1 H NMR(400MHz, DMSO-d6)d 8.15-7.73(m,2H),4.56-4.37(m,1H),3.19-2.88(m,2H),2.77-2.63(m,1H),2.36-2.04(m,2H),1.56-1.08(m,12H). FTIR-ATR(cm -1 ) 最大 =1637.

[0968] Example 18: Reaction of Compound 6 with amine-functionalized polydimethylsiloxane to form N1,N6-bis(3-mercapto-3-methyl-1-((3-(1,1,1,3,5,5,7,7,7-nonamethyltetrasiloxane-3-yl)propyl)amino)-1-oxobutan-2-yl)hexanediamide (21)

[0969]

[0970] To a stirred solution of 500 mg of amine-functionalized PDMS (Gelest AMS-163, described as (6-7% aminopropylmethylsiloxane)-dimethylsiloxane copolymer, 1800-2200 cSt, Mw 50000 g / mol) in 15 mL of CHCl3 was added 70 mg of N 1 ,N 6 -bis(2,2-dimethyl-4-oxothiophene-3-yl)adipamide (Example 2, compound (6)), and the turbid solution was stirred at room temperature overnight. The next day, the turbid solution turned into a clear gel. The reactants formed a cross-linked product, which became silicone polymer (21), as evidenced by the formation of a clear gel.

[0971] Example A2 - Compound (6) reacts with 1,3-diamino-2,2-dimethylpropane to form poly(N 1 -(1-((2,2-dimethyl-3-(methylamino)propyl)amino)-3-mercapto-3-methyl-1-oxobutan-2-yl)-N 6 -(3-mercapto-3-methyl-1-(methylamino)-1-oxobutan-2-yl)hexanediamide)(32)

[0972]

[0973] 40 mL of dimethyl sulfoxide was added to a 100 mL round bottom flask. 1,6-bis(thiolactone)adipamide (5 g) and 1,3-diamino-2,2-dimethylpropane (1.373 g Sigma-Aldrich 22690). The solution was stirred at 60 °C for 3 days, and then the viscous solution was added dropwise to 800 mL of water / methanol (4:1). The precipitated polymer was flocculated with 30 g of sodium chloride, filtered, and washed with 500 g of deionized water. The polymer precipitate was dried under vacuum. 1 H NMR: δ0.75 (s) δ1.02 (d) δ1.28 (s-wide) δ2.16 (s-wide) δ2.49 (s) δ2.71 (s) δ2.91 (s-wide) δ3.27 (s) δ4.52 (d) δ8.04 (d) GPC-LS M n :16,849 Dalton,M w :43,456 Daltons DSC:T g (Midpoint) 84.6℃

[0974] The gel permeation chromatography / light scattering diagram of the polymer is shown in Fig.13 Refractive index and light scattering detectors were used and the following polymer averages were obtained: Average M n =16,849, average M w =43,456, average M z=80,399, and the average M w / M n =2.597.

[0975] Example A3 - Compound (31) reacts with bis(diaminopolypropylene oxide) to form poly(N 1 -(2-Mercapto-2-methyl-4-oxopentan-3-yl)-N 3 -(3-Mercapto-3-methyl-1-((1-(2-(methylamino)propoxy)propan-2-yl)amino)-1-oxobutan-2-yl)-2,2-dimethylmalonamide)(33)

[0976]

[0977] 2,2'-dimethylmalonylthiolactone (Example A1, compound (31), 5.0 g) was added to a round bottom flask. The monomer was dissolved in 40 mL of dimethyl sulfoxide. Bis(diaminopolypropylene oxide) (Mw: 430 g / mol; Sigma-Aldrich 406651) was added to the solution, and the mixture was stirred at 60°C for 72 hours. The viscous solution was then added dropwise to deionized water to form a light yellow polymer. The polymer was then redissolved in acetone and reprecipitated in deionized water, and the light yellow polymer (33) was dried under vacuum. <M n >:40,890 DSC(midpoint)T g : 22℃ 1 H NMR (broad): δ0.97 (s) δ1.04 (s) δ1.22 (s) δ1.32 (s) δ2.49 (s) δ2.73 (s) δ3.48 (s) δ3.56 (s) δ4.50 (s) δ7.28 (d) δ8.08 (d) δ8.75 (s).

[0978] Polymer (33) is referred to as dimethylmalonylpenicillamine PPO-400 polymer in the following examples and figures.

[0979] Example A4 - Compound (31) and bis(diaminopolypropylene oxide) react with bis(diaminopropylene oxide-block polyethylene oxide-block propylene oxide) to form a block copolymer P(N 1 -(33-Mercapto-16,22-bis(2-mercaptopropane-2-yl)-3,6,13,19,25,25,29,33-octamethyl-15,18,20,23,31-pentaoxo-5,8,11,27-tetraoxa-2,14,17,21,24,30-hexaazatetratriacontane-32-yl)-N 3-(3-mercapto-3-methyl-1-(methylamino)-1-oxobutan-2-yl)-2,2-dimethylmalonamide) (35)

[0980] The reaction scheme for forming this polymer is shown in Scheme 1 below.

[0981] Solution 1

[0982]

[0983] To a round-bottom flask was added 2,2'-dimethylmalonylthiolactone (Example A1, compound (31), 5.000 g) dissolved in 40 mL of dimethyl sulfoxide. Then, bis(diaminopolypropylene oxide), Mw: 430 g / mol; Sigma-Aldrich 406678 (2.790 g) and bis(diaminopropylene oxide-block polyethylene oxide-block propylene oxide) Mw: 600, Sigma-Alderch 14526 (4.184 g) were added to the solution. The solution was stirred at 60°C for 72 hours to form a viscous solution. The solution was then added dropwise to 800 mL of deionized water. The precipitated polymer was flocculated with 25 g of sodium chloride, collected by vacuum filtration, and washed with excess deionized water. The polymer (35) was then dried under vacuum. DSC: Tg (midpoint): 3.6°C 1 H NMR: δ1.08δ1.16 (d-broad)δ1.46 (d-broad)δ2.56 (s)δ2.84 (s)δ3.46 (t-broad)δ4.48 (t-broad)δ4.61 (s)δ7.5 (d-broad)δ8.19 (d-broad).

[0984] The polymer is cross-linked and therefore has infinite molecular weight.

[0985] Converts "thiol / -SH" chemical entities to "S-nitrosothiol / -SNO" chemical entities

[0986] Example 19: Derivatization of Compound 14 with S-nitrosothiol to Form N 1 ,N 6 -Bis(1-(benzylamino)-3-mercapto-3-methyl-1-oxobutan-2-yl)hexanediamide (16)

[0987]

[0988] About 200mg of compound (14) (embodiment 9) is dissolved in 10mL MeOH, then dissolved with 10mL1M HCl, and the resulting suspension is cooled to 0 ℃ in an ice bath.Then, 2mL concentrated H is added SO , the suspension is cooled to 0 ℃ in an ice bath again. Sodium nitrite (3 equivalents, relative to the thiol of compound (14)) is dissolved in several milliliters of water (original position forms nitrous acid (HONO)), and added once. 10mL DCM is added, the ice bath is removed, and the suspension is stirred vigorously in the dark for 1.5 hours. The resulting emulsion is then poured into a separating funnel, and the bright green DCM layer is poured into Na SO On, put into a refrigerator (5 ℃) for 30 minutes. Filter the DCM layer, and rotary evaporate the DCM solvent under reduced pressure to obtain a green solid compound (16). 1 HNMR(400MHz,CDCl3)d 8.25(s,2H),7.87(d,2H,J=9.53Hz),7.19-7.08(m,6H),6.97-6.90(m,4H),5.68(d,2H,J=10.04Hz),4.07(dd,2 H, J=14.92, 5.94Hz), 3.70 (dd, 2H, J=14.63, 3.62Hz), 2.35 (m, 4H), 2.05 (s, 6H), 2.02 (s, 6H), 1.76-1.35 (m, 4H). FTIR-ATR(cm -1 ) 最大 =1639.

[0989] Example 20: Derivatization of Compound 15 S-nitrosothiol to Form S,S'-((adipoylbis(azadiyl))bis(2-methyl-4-oxo-4-(anilino)butane-3,2-diyl)dinitrothiosulfate (17)

[0990]

[0991] About 200mg of compound (15) (embodiment 10) is dissolved in 10mL MeOH, then dissolved with 10mL1M HCl, and the resulting suspension is cooled to 0 ℃ in an ice bath.Then, 2mL concentrated H is added SO , the suspension is cooled to 0 ℃ in an ice bath again.Sodium nitrite (3 equivalents, relative to the thiol of compound (15)) is dissolved in several milliliters of water (original position forms nitrous acid (HONO)), and added once.10mL DCM is added, the ice bath is removed, and the suspension is stirred vigorously in the dark for 1.5 hours.Then the resulting emulsion is poured into a separating funnel, and the bright green DCM layer is poured into Na SO On, put into a refrigerator (5 ℃) for 30 minutes.Filter the DCM layer, and rotary evaporate the DCM solvent under reduced pressure to obtain a green solid compound (17). 1HNMR(400MHz,DMSO-d6)d 10.47(s,2H),8.43(d,2H,J=9.59Hz),7.59(m,4H),7.31(m,4H),7.08(m,2H), 7.43(d,2H,J=9.59Hz,),2.18(m,4H),2.03(m,6H),1.98(m,6H),1.39(m,4H). FTIR-ATR(cm -1 ) 最大 =1496.

[0992] Example 21: Derivatization of compound (8c) with S-nitrosothiol to form S,S'-((isophthaloylbis(azadiyl))bis(2-methyl-4-morpholino-4-oxobutane-3,2-diyl)dinitrothiosulfate (nitrothioite) (8d)

[0993]

[0994] The compound (8c) (embodiment 14) of about 200mg is dissolved in 10mL MeOH, then dissolves with 10mL1M HCl, and the gained suspension is cooled to 0 ℃ in an ice bath.Then, add 2mL concentrated H2SO4, the suspension is cooled to 0 ℃ in an ice bath again.Sodium nitrite (3 equivalents, relative to the mercaptan of compound (8c)) is dissolved in several milliliters of water (original position forms nitrous acid (HONO)), and disposable addition.Add 10mL DCM, remove ice bath, the suspension is stirred vigorously in the dark for 1.5 hours.Then the gained emulsion is poured in a separating funnel, bright green DCM layer is poured into Na2SO4, put into a refrigerator (5 ℃) for 30 minutes.Filter the DCM layer, and rotary evaporation of the DCM solvent under reduced pressure, obtain green solid compound (8d). 1 HNMR(400MHz,DMSO-d6)d 9.10(d,2H,J=9.19Hz),8.16(t.1H,J=1.54Hz),7.94(dd,2H,J=7.76,1.71Hz),7.51(t, 1H, J=7.76Hz), 5.86, (d, 2H, J=9.21Hz), 3.63-3.42, (m, 16H), 2.12 (s, 6H), 2.04 (s, 6H). FTIR-ATR(cm -1 ) 最大 =1631.

[0995] Example 22: Derivatization of Compound 10a with S-nitrosothiol to form S,S',S"-((benzene-1,3,5-tricarbonyl)tris(azadiyl))tris(4-(benzylamino)-2-methyl-4-oxobutane-3,2-diyl)trinitrothiosulfate (18)

[0996]

[0997] The compound (10a) (embodiment 15) of about 200mg is dissolved in 10mL MeOH, then dissolves with 10mL1M HCl, and the obtained suspension is cooled to 0 ℃ in an ice bath.Then, 2mL concentrated H is added SO , the suspension is cooled to 0 ℃ in an ice bath again.Sodium nitrite (3 equivalents, relative to the thiol of compound (10a)) is dissolved in several milliliters of water (original position forms nitrous acid (HONO)), and is added once.10mL DCM is added, ice bath is removed, and the suspension is stirred vigorously in the dark for 1.5 hours.Then the obtained emulsion is poured in a separating funnel, and the bright green DCM layer is poured into Na SO On, put into a refrigerator (5 ℃) for 30 minutes.Filter the DCM layer, and rotary evaporation of the DCM solvent under reduced pressure obtains green solid compound (18). 1 HNMR(400MHz,CDCl3)d 8.21(s,3H),7.92(d,3H,J=8.76Hz),7.46(t,3H,J=4.88Hz),7.30-7.19(m,12H),4.80(d,3H,J=8.81Hz) ,4.60(dd,3H,J=14.64,6.13Hz),4.28(dd,3H,J=14.64,4.63Hz),2.50(s,3H),1.60(s,9H),1.41(s,9H). FTIR-ATR(cm -1 ) 最大 =1496.

[0998] Example 23: Derivatization of S-nitrosothiol from Copolymer 19 to Form S-(2-methyl-3-(6-(2-methyl-2-(nitrosothiol)-4-oxopentan-3-yl)amino)-6-oxohexanamido)-4-((6-(methylamino)hexyl)amino)-4-oxobutan-2-yl)nitrothiosulfate (20)

[0999]

[1000] In about 200mg copolymer (19) (embodiment 17) suspended in 10mL THF, add 10mL1M HCl, and the suspension is cooled to 0 ℃ in an ice bath.Then, add 2mL concentrated H SO , the suspension is cooled to 0 ℃ in an ice bath again.Sodium nitrite (3 equivalents, with respect to the mercaptan of compound (19)) is dissolved in several milliliters of water (original position forms nitrous acid (HONO)), and added once.Remove ice bath, the suspension is stirred 3 hours in the dark.Then the green suspension of gained is collected on glass frit, washed with water and dried overnight under vacuum to obtain copolymer (20). 1 H NMR(400MHz, DMSO-d6)d 8.46-8.14(m,2H),5.24-5.09(m,1H),3.23-2.86(m,2H),2.37-2.02(m,2H),2.02-1.80(m,6H),1.22-1.07(m,6H). FTIR-ATR(cm -1 ) 最大 = 1641. The FTIR spectra of copolymers (19) and (20) overlap at Figure 3 middle.

[1001] Example 24: Derivatization of S-nitrosothiol of silicone compound (21) to form S,S'-((adipoylbis(azadiyl))bis(2-methyl-4-((3-(1,1,1,3,5,5,7,7,7-nonamethyltetrasiloxane-3-yl)propyl)amino)-4-oxobutane-3,2-diyl)dinitrothiosulfate (22)

[1002]

[1003] The silicone polymer (21) prepared according to Example 18 was converted to S-nitrosothiol silicone polymer (22) by adding 5 mL of glacial acetic acid and then tert-butyl nitrite (2 equivalents per equivalent of silicone (21)), and the gel immediately began to turn green. The green gel was placed in the dark for one hour with periodic vigorous shaking to give S-nitrosothiol silicone polymer (22), which was observed to release nitric oxide using Evaluation Method Ai.

[1004] Example A5: Poly(N 1 -(2-Mercapto-2-methyl-4-oxopentan-3-yl)-N 3 -(3-mercapto-3-methyl-1-(1-(2-(methylamino)propoxy)propan-2-yl)amino)-1-oxobutan-2-yl)-2,2-dimethylmalonamide) was subjected to S-nitrosothiol derivatization to form a nitrosated polymer (37)

[1005]

[1006] The dimethylmalonyl penicillamine PPO (400) polymer (33) (2 g) of Example A3 was dissolved in acetone (40 mL) to form a pale yellow solution. Tert-butyl nitrite (Sigma-Aldrich 235385299 μL) and acetic acid (500 μL) were added to the solution. The solution was stirred overnight in a round-bottom flask wrapped in aluminum foil to protect from light, and the solution changed from yellow to dark green, which is characteristic of the formation of S-nitrosothiol as described by Hopkins and Frost (2020). The solution was then stirred at room temperature for 12 hours, and the acetone was then removed under vacuum, leaving the nitrosated polymer (37). T g :(midpoint) 21.2℃, FT-IR: –SH stretching loss 2551cm -1 , S-NO telescopic extension: 1553cm -1 .

[1007] FT-IR spectrum ( Fig.14 ) shows 2551cm -1 Loss of -SH stretching and development of S-NO stretching: 1553 cm -1 .exist Fig.14 In the figure, the dashed line is the spectrum of the non-nitrosylated form and the solid line is the spectrum of the nitrosylated form.

[1008] As shown in the above evaluation method Aii, TGA ( Fig.15 ) to determine the degree of nitrosation. Fig.15 In the figure, the solid line represents the non-nitrosylated form and the dashed line represents the nitrosylated form. The weight fraction of nitrosylation is 4.868 wt % or a conversion fraction of 68%.

[1009] A sample of the nitrosylated polymer of PPO-400 dimethylmalonyl penicillamine (33) dissolved in 5 wt% acetone was then diluted to 2.5 wt% with acetone. The polymer was then coated on a glass substrate by drop coating and tested for NO elution using the Griess reagent NO elution test method (Evaluation Method Aiii above). Fig.16 The elution of NO from the polymer is shown over 27 days (648 hours). As can be seen, the graph has an essentially constant gradient, indicating a first order release of NO from the polymer.

[1010] Preparation of surface coatings of S-nitrosothiol chemical entities

[1011] Example 25: Preparation of NO-releasing coating on ePTFE membrane

[1012] In separate experiments, chloroform solutions of S-nitrosothiol-containing compound 16 (Example 19) and compound 17 (Example 20) were dropwise deposited onto an ePTFE membrane fixed to an embroidery hoop, allowing the solvent to evaporate as the solution was deposited. Once the solvent evaporated and the resulting coating dried, 10 mL of PBS buffer solution (containing 10 mM phosphate-buffered saline and 100 μM EDTA) was poured onto a single coated membrane in a round polyethylene container with a screw cap and placed in a 37°C water bath. The PBS buffer solution was periodically tested for NO release according to Evaluation Method Ai. The NO release profile of the membrane coated with compound 16 is shown in Figure 2. Figure 4 As shown, the NO release curve of the film coated with compound 17 is as follows Figure 5 shown.

[1013] Figure 4 The results shown indicate that NO was immediately released from the coating comprising Compound 16, with a steady state of NO release being reached within 5 days. Figure 5 The results shown indicate that NO was immediately released from the coating comprising compound 17, reaching a steady-state concentration of nitrite anions at 7 days. Figure 4 and Figure 5 The results presented indicate that coatings comprising compounds of the present disclosure are effective in immediately releasing NO from the coating deposited on the ePTFE membrane over a period of several days.

[1014] Example 26: Preparation of NO-releasing coating on ePTFE membrane with additional fluoropolymer coating

[1015] In a separate experiment, 50 mg of an acetone solution of S-nitrosothiol-containing compound 16 (Example 19), compound 18 (Example 22), and copolymer 20 (Example 23) was added to a separate mixture of 200 mg of VDF-HFP fluoropolymer in 10 mL of acetone. The green mixture was then poured onto a 3-inch ePTFE membrane disk fixed on an embroidery hoop, and the solvent was evaporated under an argon stream. Once the resulting coating was dry, 10 mL of PBS buffer solution was poured onto the coated film in a round polyethylene container with a screw cap and placed in a water bath at 37°C. The PBS buffer solution was periodically tested for NO release according to Evaluation Method Ai. The NO release curves of the films coated with VDF-HFP fluoropolymer and compound 16 are shown in Figure 2. Figure 6 As shown in Figure 2, the NO release curve of the membrane coated with VDF-HFP fluorine-containing resin and compound 18 is shown in Figure 2. Figure 7 As shown, the NO release curve of the membrane coated with VDF-HFP fluoropolymer and copolymer 20 is as follows Fig.11 shown.

[1016] Figure 7The results shown show that the coating containing VDF-HFP fluoropolymer and compound 16 has a delayed release of NO for 2 days, reaching a steady-state concentration of nitrite anions at 8 days. When applied to an ePTFE membrane, the release curve is similar to that of the coating containing compound 16 ( Figure 4 ), but the initial release was delayed by 2 days, indicating that the addition of VDF-HFP fluoropolymer effectively delayed the onset of release.

[1017] Figure 7 The results shown indicate that the release of NO from the coating containing VDF-HFP fluoropolymer and compound 18 was delayed for 2 days, with a steady-state concentration of nitrite anions being reached at day 12. The results indicate that the addition of VDF-HFP fluoropolymer effectively delayed the onset of release.

[1018] Fig.11 The results shown indicate that the release of NO from the coating containing VDF-HFP fluoropolymer and Compound 20 was delayed for 6 days, with a steady-state concentration of nitrite anions being reached at day 9. The results indicate that the addition of VDF-HFP fluoropolymer effectively delayed the onset of release.

[1019] Compared to the release profile of Example 25, which showed immediate release of NO from its respective coating compound, the release profile of Example 26 exhibited delayed release, indicating that the addition of fluoropolymers to the coating was effective in delaying the onset of release.

[1020] Example 27: Preparation of NO-releasing coating on stainless steel with additional fluoropolymer

[1021] In a separate experiment, an acetone solution containing 50 mg of S-nitrosothiol-containing compound 18 (Example 22) was added to a solution of 200 mg of VDF-HFP fluoropolymer in 10 mL of acetone. The green solution was then poured onto a stainless steel foil. Once the solvent evaporated and the coating was dry, 10 mL of PBS buffer solution was poured onto the coated foil in a polyethylene container with a screw cap and placed in a 37°C water bath. The PBS buffer solution was regularly tested for NO release according to Evaluation Method Ai. The NO release curves of the foils coated with VDF-HFP fluoropolymer and compound 18 are shown in Figure 2. Figure 8 shown.

[1022] Figure 8 The results shown indicate that the NO release from the coating containing VDF-HFP fluoropolymer and compound 18 was delayed for 9 days, with a steady-state concentration of nitrite anions being reached at day 14. The results indicate that the addition of VDF-HFP fluoropolymer effectively delayed the onset of NO release from stainless steel foil.

[1023] Example 28: In the presence of additional fluorinated polymer Preparation of NO-releasing coating on nylon membrane

[1024] In a separate experiment, 50 mg of an acetone solution of S-nitrosothiol compound 18 (Example 22) was added to a solution of 200 mg of VDF-HFP fluoropolymer in 10 mL of acetone. The green solution was then poured over The acetone was evaporated to form a coating; once the coating was dry, 10 mL of PBS buffer solution was poured onto the coated membrane in a polyethylene container with a screw cap and placed in a 37°C water bath. The PBS buffer solution was tested regularly for NO release according to Evaluation Method Ai. The NO release curves of nylon coated with VDF-HFP fluoropolymer and compound 18 are shown in Fig. 9 shown.

[1025] Fig. 9 The results shown in the figure show that the coating containing VDF-HFP fluoropolymer and compound 18 has a delayed release of NO for 4 days and reaches a steady-state concentration of nitrite anions at 13 days. The results show that the addition of VDF-HFP fluoropolymer can effectively delay the release of NO. The release of NO from the nylon membrane was similar to that from the ePTFE membrane ( Figure 7 ) and applied to stainless steel foil ( Figure 8 ) showed similar results for coatings containing VDF-HFP fluoropolymer and compound 18.

[1026] Example 29: Preparation of NO-releasing coating on ePE film with additional fluoropolymer

[1027] In a separate experiment, an acetone solution of 50 mg of S-nitrosothiol-containing compound 18 (Example 22) was added to a solution of 200 mg of VDF-HFP fluoropolymer in 10 mL of acetone. The green solution was then poured onto the ePE membrane. The acetone evaporated to form a coating; once the coating was dry, 10 mL of PBS buffer solution was poured onto the coated membrane in a polyethylene container with a screw cap and placed in a 37°C water bath. The PBS buffer solution was periodically tested for NO release according to Evaluation Method Ai. The NO release curves of ePE coated with VDF-HFP fluoropolymer and compound 18 are shown in Figure 2. Fig.10 shown.

[1028] Fig.10 The results shown in Figure 1 show that the release of NO in the coating containing VDF-HFP fluoropolymer and compound 18 was delayed by 2 days, and the steady-state concentration of nitrite anions was reached at 15 days. The results show that the addition of VDF-HFP fluoropolymer can effectively delay the release of NO in the ePE film, which is consistent with the application on the ePTFE membrane ( Figure 7 ) when applied to stainless steel foil ( Figure 8 ) and applied to Nylon membrane ( Fig. 9 ) showed similar results for coatings containing VDF-HFP fluoropolymer and compound 18.

[1029] Example 30: Preparation of NO-releasing silicone coating on ePTFE membrane

[1030] The S-nitrosothiol silicone polymer (22) prepared according to Example 24 was poured onto a 3-inch ePTFE membrane disk fixed on an embroidery hoop, and the solvent was evaporated under an argon stream. Once the solvent evaporated and the resulting coating was dry, 10 mL of PBS buffer solution was poured onto the coated membrane in a round polyethylene container with a screw cap and placed in a 37°C water bath. The PBS buffer solution was periodically tested for NO release according to Evaluation Method Ai. The NO release profile of the membrane coated with polymer 22 is shown in Figure 2. Fig.12 shown.

[1031] Fig.12 The results presented indicate that there is an immediate first release of NO from the coating comprising VDF-HFP fluoropolymer and compound 18, with a steady-state concentration of nitrite anions being reached at 7 days.

[1032] Example A6 - Coating of Vascular Grafts and Stent Grafts with the Nitrosylated Polymer (37) of Example A5

[1033] An 8mm x 50mm vascular graft or stent graft was added to a stainless steel 8mm mandrel. A Sonotek DES4000 sprayer was equipped with an IVEK 3500001-46 nozzle. Nitrosated 2,2' dimethylmalonyl penicillamine bis(diaminopolypropylene oxide) (37) was dissolved in acetone (0.5 wt%) and a 20 mL syringe was filled with the nitrosated polymer solution. While the stent or graft was rotating at 100 rpm, the stent and vascular graft were sprayed with 2.0 mL of the nitrosated polymer solution at a rate of 0.25 mL / min using 3.5 psi of nitrogen carrier gas over the last 1 cm. The coating was then dried at 23°C for 8 minutes, and the end of the stent or graft was then coated a second time with an additional 2 mL of the nitrosated polymer solution. The coating was then dried at room temperature for another 8 minutes to obtain a green polymer coating.

[1034] Fig.17 is a series of scanning electron microscopy (SEM) images of coated and uncoated vascular graft surfaces. Fig.17 a and 17b are 50 times magnified images of uncoated and coated grafts, respectively. Fig.17 c and 17d are images of coated and uncoated grafts at 2000× magnification, respectively.

[1035] The images show that the polymer coating forms a uniform coating without defects on the graft or stent graft.

[1036] Example A7 - Adhesion and fragility test of the nitrosylated polymer (37) coating of Example A5 to a vascular graft try

[1037] The samples were tested for adhesion using the Gardco Cross Hatch / WFT Temper 2 ASTM test kit using ASTM F1842-15.

[1038] The vascular grafts were coated with a 0.5 wt% solution of the nitrosylated polymer (37) in acetone. Using the procedure described above, 10 mL of the solution was applied to the vascular grafts along a 125 mm length at a translation rate of 1 mm / sec. Coating adhesion was tested according to ASTM F1842-15 using a Gardco Cross Hatch / WFT Temper 2 ASTM test kit. The crack resistance of the coatings was tested according to ISO 7198 by passing the coated stent grafts around a stainless steel cone with an outer diameter of 15 mm. The coatings were then evaluated by SEM. The thinner coatings had a coating structure similar to the underlying node and fibril structure of the substrate.

[1039] Fig.18 A and 18B are SEM images of the vascular graft coated with the nitrosylated polymer (37) at 30x and 200x magnification, respectively, after bypassing the 15 mm cone. It can be seen that the coating remains intact and the surface is Fig.17 The uncoated grafts shown in A and C are more uniform.

[1040] In-situ formation of chemically solid coatings

[1041] Example 31: In situ formation of thiol-containing polymers on coated surfaces

[1042] A 3-inch ePTFE membrane disk was mounted on an embroidery hoop and immersed in a 4% PEI aqueous solution for 15 minutes. The membrane was rinsed with deionized water and then placed in 800 mL of fresh deionized water with stirring for 15 minutes. The membrane was then divided into two samples. The first sample was placed in 50 mL of a methanol solution containing 20 mg of adipoyl-1,6-dipenicillamine dithiolactone (Example 2, compound (6)) to form a cross-linked PEI polymer on the surface of the ePTFE membrane. The second sample was used as is (i.e., the ePTFE membrane surface had uncross-linked PEI polymer).

[1043] The two samples were then dyed red using Ponceau S (a dye that dyes the PEI coating red) and rinsed in deionized water. Both samples were dyed red, indicating PEI deposition. Each dyed sample was then placed in boiling isopropyl alcohol (IPA) for 15 minutes and then rinsed with additional IPA. Boiling IPA effectively removes uncrosslinked PEI coatings from the surface because these coatings are only physically adsorbed on the surface, while boiling IPA does not remove crosslinked PEI coatings from the surface because these coatings are chemically crosslinked on the surface. The second uncrosslinked PEI sample no longer dyes red, indicating that boiling IPA effectively removes uncrosslinked (i.e., only physically adsorbed) PEI from the ePTFE membrane, while the first crosslinked PEI sample still dyes red, indicating that PEI cannot be removed from the ePTFE surface by boiling IPA, proving that the PEI coating is chemically crosslinked on the surface by the reaction of PEI with adipoyl-1,6-dipenicillamine dithiolactone (Example 2, compound (6)) to form a crosslinked PEI coating.

[1044] Chemical Entity and Coating Analysis

[1045] Example A8: Mass spectrometry analysis of chemical entities and coatings of the invention

[1046] Mass spectrometry may be used to determine whether a chemical entity (eg, a chemical entity that forms a coating) is formed by the reaction of components B and C as defined herein.

[1047] When the chemical entity or coating formed by the chemical entity is soluble in a convenient solvent, HPLC mass spectrometry can be used. If the chemical entity or coating is not soluble in a convenient solvent, MALDI and / or ToF-SIMS are more suitable.

[1048] HPLC and MS analyses were performed using the following instruments and conditions.

[1049] Agilent 1260HPLC conditions:

[1050] Column: 2.1mm x 100mm, 3.5μm, Zorbax Eclipse XDB-C8

[1051] Column oven: 50°C

[1052] Injection: 3 μL

[1053] Solvent A: 10 mM ammonium acetate aqueous solution

[1054] Solvent B: Acetonitrile

[1055] Flow rate (mL / min) 0.4

[1056] gradient:

[1057] Agilent 6540 Q-TOF-MS conditions

[1058] Agilent JetStream Spray Ionization Positive Mode

[1059] Forward Calibration 2 GHz Extended Dynamic Range

[1060] Data acquisition: curve; MS absolute threshold: 200; MS correlation threshold 0.01%

[1061] Gas temperature: 320°C, flow rate: 11.0 L / min, nebulizer: 45 psi

[1062] Sheath gas flow rate: 12 L / min; sheath gas temperature: 350℃

[1063] Fragmentation voltage: 150 V Skimmer 60 V Octapole RFV: 750 V

[1064] Capillary: 3000 V; Scan rate: 1.5 scans / s; Scan range: m / z 80-1000 Nozzle voltage = 0 V

[1065] Reference calibration: Enabled, Reference mass: m / z 121.00509,922.0098

[1066] Add 0.1% acetic acid (aqueous solution) after the column at 0.1 mL / min

[1067] Sample preparation

[1068] Samples were prepared on a mass basis and diluted in acetonitrile to a concentration of 1 μg / mL.

[1069] The ESI spectra of compound (14) and compound (38) were measured. Using a method similar to compound (14), compound (38) was formed by reacting hexamethylenediamine and two equivalents of N-acetylpenicillamine thiolactone, as shown below:

[1070]

[1071] Compound (14) is Figure 1A The example of the compound of Example 3, and compound (38) is Figure 1A Examples of compounds of Example 2.

[1072] MS analysis of both samples under the above conditions resulted in fragmentation into thiolactone and amine starting materials (reverse polymerization). Thus, molecular fragments indicating the presence of structural units derived from component B given by formula (I) can be identified.

[1073] Fig.19 is the ESI mass spectrum of compound (14), and shows M+H + and M+Na + Ion peak. Fig. 20 is the mass spectrum of compound (14), which was performed under the Q-ToF-MS / MS conditions described above, so that the compound was fragmented. The spectrum has a peak at 587.2713, representing the M+H of the uncleaved compound (14). + There are peaks at 480.1984 and 373.1242, representing the fragmented compound (13) from which one or two amine fragments with a mass of 107.07 have been extracted. There is also a peak at 108.0799, indicating the M+H + .

[1074] Fig.21 is the ESI mass spectrum of compound 38, showing M+H + and M+Na + The peaks at 463.2420 and 485.2337.

[1075] Fig. 22 This is the Q-ToF mass spectrum of compound 38 after fragmentation. Its peak is located at 463.2403, representing the M+H of the unfragmented compound. + The peak is located at 290.1900, representing the loss of a thiolactone fragment with a mass of 173.05 M+H + .

[1076] Fig.23 is the ESI mass spectrum of compound (38) after fragmentation under more stringent conditions, showing M+H corresponding to the following fragments + Peaks: fragment with loss of thiolactone fragment, thiolactone fragment, and amine fragment remaining after loss of two thiolactone fragments.

[1077] Therefore, Fig. 20 , 22 Comparison with 23 shows that it can be shown that, like compound (14), the material or coating contains a penicillamine-type moiety bound to the central core moiety A via the N-terminus. Fig. 20 , 22 As shown in Figures 2 and 23, this analysis distinguishes structures of the type of compound (14) from structures similar to compound (38), which consists only of a C-bonded penicillamine moiety (eg, N-acetylpenicillamine).

[1078] Chemical entities and coatings detectable by MS methods may be present in the form of nitrosothiols. Nitrosothiols may be converted to thiols by exposing the chemical entity or coating to a solution containing an excess of low molecular weight thiols prior to analysis.

[1079] As shown in Scheme 2, the NO group will transfer to the thiol in solution, leaving the thiol in the chemical entity or coating / paint being studied.

[1080] Solution 2

[1081]

[1082] MS analysis of the resulting thiol-containing material will reveal components of the structure described above.

[1083] If the material or coating / painting cannot be brought into solution for analysis, analytical mass spectrometry techniques such as MALDI and / or ToF-SIMS can be used to analyze solid materials or surfaces and obtain similar relevant structural information.

[1084] References

[1085] Altenbruun et al., Pure Appl. Chem. 2009, 81(2), pp. 273-284

[1086] Calvete, Proceedings of the Society for Experimental Biology and Medicine1995,208(4):346-360

[1087] Chen et al., Chem. Sci. 2018, 9, 1982–1988

[1088] Cooke and Losordo, Circulation 2002,105(18):2133-2135

[1089] Frost et al., Biomaterials 2005, 26(14): 1685-1693

[1090] Hopkins et al., Bioengineering 2018, 5(3), 72

[1091] Hopkins and Frost, Bioengineering 2020, 7(1), 9 Ignarro et al., Proc. Nat. Acad. Sci. USA 1993, 90, 8103-8107

[1092] Martens et al., Synthesis, 1991, 497-498

[1093] Matthys and Bult, Mediators Inflamm.1997,6(1):3-21

[1094] Schairer et al., Virulence 2012, 3(3): 271-279

[1095] Xue et al., Int. J. Mol. Sci. 2018, 19, p. 3805

[1096] other

[1097] The present disclosure includes all combinations of the indicated groups and embodiments of the groups described above.

[1098] All patents and patent applications cited herein are incorporated by reference in their entirety.

[1099] Unless otherwise stated, percentage values ​​provided in the specification are based on weight.

[1100] Unless the context requires otherwise, in this specification and the appended claims, the word "comprise" and variations such as "comprising" and "containing" should be understood to mean the inclusion of the stated integer, step, group of integers or group of steps, but not the exclusion of any other integer, step, group of integers or group of steps.

Claims

1. A chemical entity formed by reacting components B and C, wherein: Component B is a compound of formula (I): in, A is the core part; L is an optional linker; R 1 and R 2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radical substitution; n is 0 or 1; and m is an integer at least 1; and, Component C is a moiety comprising one or more amine groups.

2. A surface having a coating, the coating comprising the chemical entity of claim 1.

3. The chemical entity of claim 1 or the surface having a coating of claim 2, wherein At least a portion of the thiol (-SH) groups in the chemical entity have been converted to S-nitrosothiol (-SNO) groups.

4. A method of forming a coating on a surface, wherein: The method comprises the following steps: (a) contacting a surface with a chemical entity as claimed in claim 1.

5. The method of claim 4, further comprising step (b) of converting at least a portion of the thiol (-SH) groups in the chemical entity into S-nitrosothiol (-SNO) groups.

6. The chemical entity of claim 1, the surface having a coating of claim 2 or claim 3, or the method of claim 4 or claim 5, wherein: The core portion A comprises one or more moieties independently selected from the group consisting of alkyl, spiroalkyl, aryl, heteroaryl, alkylaryl, porphyrin, polymer and macrocycle, wherein the alkyl, spiroalkyl, aryl, heteroaryl and alkylaryl are optionally substituted.

7. The chemical entity, coated surface or method of claim 6, wherein: m is 1 or 2 and the core part A comprises an alkyl group or is an alkyl group, for example m is 2 and the core part A comprises or consists of a C1-10 alkylene moiety, for example a C1-6 alkylene moiety, in particular a C1-4 alkylene moiety, such as -(CH2)4-, -(CH2)3-, -C(CH3)2-, -CH(CH3)-, -CH2-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2CH2-; or m is 2, and the core part A is: or m is 3, and the core part A is: For example, m is 2, and the core part A is: or m is 3, and the core part A is:

8. The chemical entity, coated surface or method of any one of claims 1 to 7, wherein: The linker L is absent.

9. The chemical entity, coated surface or method of any one of claims 1 to 8, wherein: n is 0.

10. The chemical entity, coated surface or method of any one of claims 1 to 8, wherein n is 1.

11. The chemical entity, coated surface or method of any one of claims 1 to 10, wherein: R 1 and R 2 Independently selected from the group consisting of H and C 1-5 alkyl.

12. The chemical entity, coated surface or method of claim 11, wherein: R 1 and R 2 Independently selected from the group consisting of CH2CH3 and CH3.

13. The chemical entity, coated surface or method of claim 11, wherein: n is 0, and R 1 and R 2 are all methyl groups; or n is 1, and R 1 and R 2 All are H.

14. The chemical entity, coated surface or method of any one of claims 1 to 6 or 8 to 13, wherein m is 1-5,000,000, 2-5,000,000, 1-1,000,000, 2-1,000,000, 1-500,000, 2-500,000, 1-400,000, 2-400,000, 1-200,000, 2-200,000, 1-100,000, 2-100,000, 1-50,000, 2-50,000 , 1-20,000, 2-20,000, 1-10,000, 2-10,000, 1-5,000, 2-5,000, 1-2,000, 2-2,000, 1-1,000, 2-1,000, 1-500, 2-500, 1-100, 2-100, 1-50, 2-50, 1-20, 2-20, 1-10, 2-10, 1-5 or 2-5.

15. The chemical entity, coated surface or method of claim 14, wherein: m is 2-500,000, 50-500,000, 100-500,000, 500-500,000, 1,000-500,000, 5,000-500,000, 1-200,000, 2-200,000, 50-200,000, 100-200,000, 500-200,000, 1,000-200,000 , 5,000-200,000, 1-100,000, 2-100,000, 50-100,000, 100-100,000, 500-100,000, 1,000-100,000, 5,000-100,000, 1-50,000, 2-50,000, 50-50,000, 100-50,000, 500-50 ,000, 1,000-50,000, 5,000-50,000, 1-20,000, 2-20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, 5,000-20,000, 1-5,000, 2-5,000, 50-5,000, 100-5,000, 5 -20,000, 50-20,000, 100-20,000, 500-20,000, 1,000-20,000, 5,000-20,000, 1-1,000, 2-1,000, 50-1,000, 100-1,000, or 500-1,000.

16. The chemical entity, coated surface or method of claim 15, wherein: m is 1-1,000, 2-1,000, 50-1,000, 100-1,000, or 500-1,000.

17. The chemical entity, coated surface or method of claim 16, wherein: m is 2, 3 or 4.

18. The chemical entity, coated surface or method of claim 17, wherein: m is 5-10.

19. The chemical entity, coated surface or method of claim 14 or claim 15, wherein: m is 5,000-100,000.

20. The chemical entity, coated surface or method of any one of claims 1 to 19, wherein: Component B has formula (Ia): Or component B has formula (Iaa): Among them, L, n, R 1 and R 2 As defined in any one of claims 1 to 19; for example, L is absent and component B has formula (Iab): Or L is absent, n is 0, and component B has formula (lac):

21. The chemical entity, coated surface or method of any one of claims 1 to 20, wherein: Component C is a single monomer compound.

22. The chemical entity, coated surface or method of any one of claims 1 to 20, wherein: Component C is a polymer.

23. The chemical entity, coated surface or method of any one of claims 1 to 22, wherein: Component C is a mixture of two or more compounds.

24. The chemical entity, coated surface or method of claim 23, wherein: The two or more compounds are two or more polymers.

25. The chemical entity, coated surface or method of any one of claims 22 to 24, wherein: The polymer is formed from a single monomer; or wherein the polymer is formed from two or more monomers.

26. The chemical entity, coated surface or method of claim 25, wherein: The monomer units forming the polymer are oxyalkylene units or a mixture of oxyalkylene units; and / or the monomer units forming the polymer have pendant amine groups.

27. The chemical entity, coated surface or method of any one of claims 22 to 26, wherein: The polymer is a linear polymer.

28. The chemical entity, coated surface or method of any one of claims 22 to 26, wherein: The polymer is a branched or hyperbranched polymer or a dendrimer.

29. The chemical entity, coated surface or method of claim 21, wherein: Component C is selected from the group consisting of aniline, benzylamine, morpholine, diethylamine, dibutylamine, 1-ethylpropylamine, 2-aminopentane, piperidine, 4-methylpiperidine, pyrrolidine, tert-butylamine, tert-amylamine, propylamine, butylamine, amylamine, isoamylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, dodecylamine, hexadecylamine, octadecylamine, 4-methylaniline, 2-fluorobenzylamine, 3-fluorobenzylamine, 4-fluorobenzylamine, 3-(trifluoromethyl)benzylamine, 4-(trifluoromethyl)benzylamine and 3,5-bis(trifluoromethyl)benzylamine.

30. The chemical entity, coated surface or method of any one of claims 1 to 28, wherein: Component C comprises two or more amine groups, wherein the amine groups are independently primary amine groups or secondary amine groups.

31. The chemical entity, coated surface or method of claim 30, wherein: Component C comprises a mixture of primary and secondary amine groups.

32. The chemical entity, coated surface or method of claim 30 or claim 31, wherein: Component C includes a polyamine compound.

33. The chemical entity, coated surface or method of claim 32, wherein: Component C comprises one or more moieties independently selected from the group consisting of polyethyleneimine, polyallylamine, polylysine, polyarginine and polyaminosilane.

34. The chemical entity, coated surface or method of claim 33, wherein: Component C is a branched polyethyleneimine.

35. The chemical entity, coated surface or method of any one of claims 30 to 34, wherein: Component C is a polyamine compound including a dendrimer or a hyperbranched polymer.

36. The chemical entity, coated surface or method of claim 27, wherein: Component C is a linear polymer comprising two amine groups, one at each end of the polymer chain.

37. The chemical entity, coated surface or method of claim 36, wherein: Component C includes or consists of one or two polyoxyalkylene polymers, wherein each polymer has an amino group at each terminal.

38. The chemical entity, coated surface or method of claim 37, wherein: Component C comprises a single linear polyoxyalkylene polymer having an amino group at each end; or Component C comprises a mixture of two linear polyoxyalkylene polymers, wherein each polymer has an amino group at each terminal.

39. The chemical entity, coated surface or method of any one of claims 1 to 38, wherein: Component C is a compound of formula (X) or a mixture of two or more compounds of formula (X): in, D is the core part; G is an optional linker; E is NH2; and p is an integer of at least 1.

40. The chemical entity, coated surface or method of claim 39, wherein: The core portion D comprises one or more moieties independently selected from the group consisting of alkyl, spiroalkyl, aryl, heteroaryl, alkylaryl, porphyrin, polymer and macrocycle, wherein the alkyl, spiroalkyl, aryl, heteroaryl and alkylaryl are optionally substituted.

41. The chemical entity, coated surface or method of claim 40, wherein: D is a combination of one or more C 2-4 Polymers of alkylene oxide units, for example, ethylene oxide units and / or propylene oxide units.

42. The chemical entity, coated surface or method of claim 41, wherein: Component C is a single compound of formula (X) wherein the average number of oxyalkylene units in the core portion D is from about 2 to about 20, for example, from about 2 to 10, 3 to 7, or 3.5 to 6.

43. The chemical entity, coated surface or method of claim 41, wherein: Component C is a mixture of a first compound of formula (X) and a second compound of formula (X), wherein, in the first compound of formula (X), D is a polymer comprising an average number of oxyalkylene units of about 2 to about 20, for example, about 2 to 10, 3 to 7 or 3.5 to 6, and in the second compound of formula (X), D is a polymer comprising an average number of oxyalkylene units of about 11 to about 100, for example, about 20 to about 60 or 30 to 50.

44. The chemical entity, coated surface or method of any one of claims 41 to 43, wherein: In the compounds of formula (X), the oxyalkylene units are all identical.

45. The chemical entity, coated surface or method of any one of claims 41 to 43, wherein: The compound of formula (X) contains two or more types of oxyalkylene units.

46. ​​The chemical entity, coated surface or method of any one of claims 41 to 45, wherein The linker G is absent and / or p is 2.

47. The chemical entity, coated surface or method of claim 39 or claim 40, wherein: D is a polyalkylsiloxane moiety substituted with primary and / or secondary amine groups.

48. The chemical entity, coated surface or method of any one of claims 39 to 47, wherein p is 1-5,000,000, 2-5,000,000, 1-1,000,000, 2-1,000,000, 1-500,000, 2-500,000, 1-400,000, 2-400,000, 1-200,000, 2-200,000, 1-100,000, 2-100,000, 1-50,000, 2-50,000 , 1-20,000, 2-20,000, 1-10,000, 2-10,000, 1-5,000, 2-5,000, 1-2,000, 2-2,000, 1-1,000, 2-1,000, 1-500, 2-500, 1-100, 2-100, 1-50, 2-50, 1-20, 2-20, 1-10, 2-10, 1-5 or 2-5.

49. The chemical entity, coated surface or method of claim 48, wherein: p is 1-100,000, 2-100,000, 2-50,000, 2-20, 2-12, 2-5, 2-4 or 2-3.

50. The chemical entity, coated surface or method of any one of claims 1 to 49, wherein The chemical entities include: and / or and / or and / or in, A, L, n, R 1 and R 2 As defined in any one of claims 1 to 33; R s is H or N=O; and q is 10 to 1000, for example 15 to 500, 20 to 250 or 25 to 180; or Chemical entities include: and / or and / or and / or wherein n is as defined in any one of claims 1 to 49; x is 1-10; R s is H or N=O; and q is 10 to 1000, such as 15 to 500, 20 to 250 or 25 to 180; or the chemical entity comprises: and / or and / or and / or x is 1-10, for example 2-6; R s is H or N=O; and q is 100-20,000, such as 2,000-20,000 or 5,000-15,000; or the chemical entity comprises: and / or and / or and / or Among them, n, X 1 and r as defined in any one of claims 1 to 49; R s is H or N=O; R x and R y Each is H or C 1-6 Alkyl; and q is 10 to 1000, for example 15 to 500, 20 to 250 or 25 to 180; or Chemical entities include: Among them, R 1 , R 2 , R 20 , R 21 , R 22 , R 23 , n, X 2 , s and t are as defined herein; R s is H or N=O; and x is 1-10, suitably 1-6, and more suitably 1-4.

51. A coated surface or method as claimed in any one of claims 2 to 50, wherein: The surface is the surface of a medical device.

52. A coated surface or method as claimed in any one of claims 2 to 51, wherein: The surface comprises expanded polytetrafluoroethylene (ePTFE) or expanded polyethylene (ePE), in particular ePTFE.

53. A medical device comprising a coated surface as claimed in any one of claims 2 to 52.

54. Use of a chemical entity as claimed in claim 3 or any one of claims 6 to 53 for preventing or treating a condition that benefits from nitric oxide delivery.

55. Use of a chemical entity as claimed in claim 54, To open blood vessels and / or improve oxygen levels; or For the prevention or treatment of atherosclerotic lesions; or For the prevention or treatment of hypervascular disease; or For use in preventing or treating angiogenesis (including vasculogenesis); or Used to promote endothelialization, especially endothelialization of grafts / stents; For the prevention or treatment of infections, especially bacterial infections; Used to mature arteriovenous fistulas; for the prevention or treatment of skin ulcers, such as foot ulcers; or Used to accelerate the healing of inflammatory cycles.

56. A method of preventing or treating a condition that benefits from nitric oxide delivery, wherein: Use of the medical device as claimed in claim 53.

57. A compound of formula (I): in, A is the core part; L is an optional linker; R 1 and R 2 Independently selected from H and C 1-5 Alkyl; or R 1 and R 2 Combined with the C atom to which it is attached to form C 4-7 Cycloalkyl ring or 4-7 membered heterocyclic ring, both of which are optionally substituted on available atoms with one or more selected from C 1-2 Alkyl and oxo radical substitution; n is 0 or 1; and m is an integer of at least 1.

Images