Anti-inflammatory benzoxazine polymer coating

Abstract

The present invention relates to monomer(s) based on 3,4-dihydro-2H-1,3-benzoxazine derivatives. The present invention also relates to a composition comprising a mixture of the monomer(s) with a second benzoxazine derivative selected from the group consisting of monofunctional amines bridged with diphenolic compounds, monophenolic compounds bridged with diamines, and diamines bridged with diphenolic compounds, or a mixture thereof. These compounds are suitable for preparing heterogeneous polymers of benzoxazine derivatives, for example, in the form of coatings or films, which exhibit enhanced anti-inflammatory and / or antioxidant properties. Materials having a substrate coated with the heterogeneous polymer can be part of implantable materials, such as biologically compatible implantable metal devices, such as catheters, metal implants, or metal prostheses. These implantable materials can be used safely because the coated substrate prevents inflammatory and / or oxidative reactions from the host into which it is implanted or grafted.

Description

[Technical field]

[0001] The present invention relates to benzoxazine derivative compounds useful in the preparation of anti-inflammatory benzoxazine derivative polymeric coatings. [Background technology]

[0002] Synthetic polymer coatings are widely used in modern medical devices and implants due to their material versatility and processability. However, implanting these materials in the body induces a strong inflammatory host response, severely limiting the integration and biological performance of the device (J.Diab.Sci.Tech.,2008,2(6),984-994). There are various approaches used to modify material surfaces to modulate the inflammatory response, such as non-fouling surface treatments (passive strategies) and delivery of anti-inflammatory agents (active strategies).

[0003] The prior art patent document published in WO 2005 / 039443 A2 relates to the implantation of a stent in the damaged area in combination with the delivery of tocopherol or tocotrienol. Among other advantages, these molecules exhibit anti-inflammatory properties. The delivery of anti-inflammatory agents has the drawback that they can only provide the desired properties for a limited period of time.Furthermore, the use of tocopherol or tocotrienol derivatives is not easily straightforward, as the compounds themselves are hardly polymerizable and their deposition on the substrate needs to be optimized. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2005 / 039443(A2) Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention has the technical problem to provide new benzoxazine derivative compounds which are advantageously used as precursors for the preparation of anti-inflammatory and / or anti-oxidative benzoxazine polymer coatings in a method for rendering the surface of an implantable object, including the coating, less susceptible in the long term to inflammatory and / or anti-oxidative responses from the host into which the object is implanted or grafted. [Means for solving the problem]

[0006] The present invention relates to anti-inflammatory and / or antioxidant monomers based on 3,4-dihydro-2H-1,3-benzoxazine derivatives having formula (I):

[0007] [ka] During the ceremony, R 4 =CH 3 and R 2 and R 3 Both,

[0008] [ka] represents

[0009] [ka] and R 1 =H or CH 3 or or in the formula: R 4 and R 3 Together,

[0010] [ka] represents

[0011] [ka] and R 2 =R 1 =CH 3 or or a mixture thereof.

[0012] Applicants have surprisingly shown that these monomers, which exhibit, but are not limited to, anti-inflammatory and / or antioxidant effects, are highly useful for the preparation of benzoxazine derivative heterogeneous polymers, for example in the form of coatings or films, which exhibit enhanced anti-inflammatory and / or antioxidant properties.

[0013] The anti-inflammatory and / or antioxidant properties of both monomers as starting materials and of the heterogeneous polymer obtained by the polymerization process described below are maintained. This is one of the main objectives of the present invention. Moreover, the coating with the heterogeneous polymer is also compatible with the cells of the body, i.e. non-toxic. This allows the development of implantable materials such as implantable metal devices, such as catheters, metal implants or metal prostheses, that may not cause inflammatory effects or effects that are essentially avoided when used in the human or animal body. Furthermore, the coating with the heterogeneous polymer may advantageously exhibit radical scavenging activity and certainly antioxidant properties. The use of benzoxazine chemistry also allows the self-condensation of the monomer(s), which avoids the use of catalysts or hardeners (in the case of epoxy resins) that are generally devastating to human health.

[0014] Furthermore, the derivation of tocopherol, tocotrienol, cardanol and / or eugenol derivatives into polymers that can be deposited on the surface of a substrate is investigated. This is another aspect of the present invention. Among the various isomers of benzoxazine, the 3,4-dihydro-2H-1,3-benzoxazine derivative monomers of the present invention are interesting for the development of polymeric materials because they crosslink via polymerization, particularly ring-opening polymerization. In other words, the polymerization results in three-dimensional crosslinked polymers. It is known that benzoxazines are synthesized by heating a mixture of appropriate amines, phenols, and formaldehyde. In particular, the applicant has implemented a solvent-free synthesis procedure to prevent the formation of oligomers (see US Pat. No. 5,543,516), which is one of the advantages of the present invention.

[0015] Another aspect of the present invention is a composition comprising a mixture of a first monomer of the anti-inflammatory and / or antioxidant 3,4-dihydro-2H-1,3-benzoxazine derivative monomer of the present invention or a mixture thereof and a second benzoxazine derivative selected from the group consisting of monofunctional amines crosslinked with diphenol compounds, monophenol compounds crosslinked with diamines and diamines crosslinked with diphenol compounds, or a mixture thereof.

[0016] The second benzoxazine derivative is very useful for carrying out the self-polymerization of the first monomer. This can be explained by the fact that the first monomer possesses one oxazine ring (monofunctional benzoxazine), and the self-polymerization leads to a heterogeneous polymer that is less favorable for the realization of coating. Therefore, due to the second benzoxazine derivative possessing at least two oxazine rings, this composition is particularly suitable for preparing materials coated with heterogeneous polymers with improved properties, such as adhesion to various substrates, such as steel or glass-based materials.

[0017] Moreover, it is not necessary for the second benzoxazine derivative to exhibit any significant antioxidant and / or anti-inflammatory effects. It is advantageously used to enable or even enhance polymerization, and is specifically selected so as not to impair the anti-inflammatory and / or antioxidant activity of the tocopherol, tocotrienol, cardanol and / or eugenol derivative or the first benzoxazine derivative monomer.

[0018] Preferentially, in the composition, the second benzoxazine derivative has a concentration of 50% by weight or more compared to the concentration of the first monomer. Such a concentration of the second benzoxazine derivative improves the coating properties on various substrates, for example in terms of adhesion, hardness and abrasion resistance. More preferably, the concentration of the second benzoxazine derivative is in the range of 55% to 90% by weight, and the most preferred concentration is in the range of 60% to 80% by weight. These last two concentration ranges provide even better performance in terms of hardness, adhesion and / or abrasion resistance.

[0019] More preferably, the second benzoxazine derivative is a compound of formula A:

[0020] [ka] In the formula, R is -CH 2 -, -C(CH 3 ) 2 -, SO 2 , -C(CF 3 ) 2 -, -C(CH 3 )(C 6 H 5 )-, -C(CH 3 )(C 2 H 5 )-, -C(C 6 H 5 ) 2 -, -CHCH 3 -, -C 6 H 10 - or -C(CH 3 )CH 2 CH 2COOH-group; R 1 -CH 2 CH 2 OH, vinyl, methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclohexyl, fluorene, phenylacetylene, phenylpropargyl ether, benzonitrile, furfuryl, phenylene or -(CH 2 ) 17 CH 3 It is based on

[0021] According to another preferred embodiment, the second benzoxazine derivative is a compound of formula B:

[0022] [ka] During the ceremony, R is -(CH) 2 -, -(CH) 4 -, -(CH) 6 -, -(CH) 8 -, -(CH) 10 -, -(CH) 12 -, -(CH) 14 -, -(CH) 18 - group or or

[0023] [ka] and Here, R 1 , R 2 , R 3 , R 4 is selected from the group consisting of: R 1 =R 2 =R 3 =R 4 =H, R 1 =OCH 3 , R 2 =R 4 =H, R 3 =CH 2 CH=CH 2 , R1 =OCH 3 , R 2 =R 4 =H, R 3 =CH=CHCH 3 , R 1 =OCH 3 , R 2 =R 4 =H, R 3 =CHO, R 1 =OCH 3 , R 2 =R 3 =R 4 =H, R 1 =OCH 3 , R 2 =R 4 =H, R 3 =CHO, R 1 =OCH 3 , R 2 =R 4 =H, R 3 =CH 2 CH 2 COOH, R 1 =R 2 =R 4 =H, R 3 =CH 2 CH 2 COOH, R 1 =R 2 =R 4 =H, R 3 =CH=CHCOOH, and R 1 =OCH 3 , R 2 =R 4 =H, R 3 =CH=CHCOOH, or in the formula: R 3 =R 4 =H,

[0024] [ka] and R 1 =COOH or or in the formula: R 1 =H, R 2 =OH, R 3 =H,

[0025] [ka] or or in the formula: R 1 =H,

[0026] [ka] R 3 =H, R 4 =OH or or in the formula: R 1 =CH 3 , R 2 =OH, R 3 =H,

[0027] [ka] or or in the formula: R 1 =R 3 =R 4 =H,

[0028] [ka] or or in the formula: R 1 =R 3 =H, R 2 =-CH 2 HC=CH 2 and R 4 =OCH 3 Is it; or R 1 =R 3 =H, R 2=-CH=HCCH 3 and R 4 =OCH 3 Is it; or R 1 =R 2 =R 4 =H and

[0029] [ka] or or R 1 =R 2 =R 3 =H and R 4 =CH 2 CH=CH 2 or or R 1 =R 2 =R 4 =H and R 3 =CH 2 CH=CH 2 or R 1 =R 3 =R 4 =H and R 2 =CH 2 CH=CH 2 It is.

[0030] According to an alternative embodiment, the second benzoxazine derivative is a compound of formula C:

[0031] [ka] In the formula, R is -CH 2 -, -C(CH 3 ) 2 -, SO 2 , -C(CF 3 ) 2 -, -C(CH 3 )(C 6 H 5 )-, -C(CH 3 )(C 2 H 5 )-, -C(C 6 H 5 )2 -, -CHCH 3 -, -C 6 H 10 - or -C(CH 3 )CH 2 CH 2 COOH-group; n is an integer from 1 to 10; R 1 But -(CH) 2 -, -(CH) 4 -, -(CH) 6 -, -(CH) 8 -, -(CH) 10 -, -(CH) 12 -, -(CH) 14 -, -(CH) 18 - group or or

[0032] [ka] It is.

[0033] Most preferably, the second benzoxazine derivative has the formula

[0034] [ka] It is a compound of Pe.

[0035] According to the present invention, the second benzoxazine derivative is either a monomeric or a polymeric derivative.

[0036] Another aspect of the invention relates to a process for producing an anti-inflammatory and / or antioxidant material comprising a substrate coated with a 3,4-dihydro-2H-1,3-benzoxazine based anti-inflammatory and / or antioxidant heterogeneous polymer, the process comprising the steps of: (a) depositing on a substrate an anti-inflammatory and / or anti-oxidant monomer selected from the group consisting of at least one optional monomer of the above formula and additional formulas:

[0037] [ka] During the ceremony, R 3 =R 4 =H,

[0038] [ka] and R 1 =COOH or or in the formula: R 1 =H, R 2 =OH, R 3 =H,

[0039] [ka] or or in the formula: R 1 =H,

[0040] [ka] and R 3 =H, R 4 =OH or or in the formula: R 1 =CH 3 , R 2 =OH, R 3 =H,

[0041] [ka] or or in the formula: R 1 =R 3 =R 4 =H,

[0042] [ka] or or in the formula: R 2 =R 4 =H, R 3 =-CH 2 HC=CH 2 and R 1 =OCH 3 Is it; or R 2 =R 4 =H, R 3 =-CH=HCCH 3 , R 1 =OCH 3 or or a mixture thereof, (b) heating the deposit obtained in step (a) at a predetermined temperature for a predetermined time to polymerize the monomers to obtain the material.

[0043] The applicant believes that this process, in which the polymerization is carried out in particular via ring-opening polymerization, is advantageously useful, on the one hand, for preparing heterogeneous polymeric compounds (three-dimensional crosslinked polymers) for their non-limiting use, for example, as coatings on various substrate(s), and, on the other hand, for maintaining or not compromising the anti-inflammatory and / or antioxidant properties of the starting materials (monomers based on 3,4-dihydro-2H-1,3-benzoxazine derivatives) during the polymerization of the heterogeneous polymers based on 3,4-dihydro-2H-1,3-benzoxazine derivatives. Both of these aspects are the object of the present invention. In the context of the present invention, a "heterogeneous polymer based on 3,4-dihydro-2H-1,3-benzoxazine derivatives" should be understood to result from monomers carrying 1,3 benzoxazine moieties, but the polymers do not contain such benzoxazine moieties either.

[0044] Also in the context of the present invention, the expressions "heterogeneous polymers based on 3,4-dihydro-2H-1,3-benzoxazine derivatives", "heterogeneous polymers", "benzoxazine derivative heterogeneous polymers" and "heterogeneous polymers with anti-inflammatory and / or antioxidant properties" have the same meaning.

[0045] According to the present process, heating to a predetermined temperature for a predetermined period of time is advantageously carried out to convert at least 80% of the starting monomers, more preferably at least 90%, and most preferably 99.9% of the starting monomers to the anti-inflammatory and / or antioxidant heterogeneous polymer.

[0046] The implementation of this process allows the production of coatings or films comprising heterogeneous polymeric compounds that exhibit enhanced anti-inflammatory and / or antioxidant properties. The coatings or films can be obtained very preferably by directly implementing the process, which avoids any need for further reformation of the heterogeneous polymer on the surface of the substrate. These coatings can also be very particularly compatible with the cells of the body, i.e., non-toxic. This allows the development of implantable materials such as biologically compatible implantable metal devices such as catheters, metal implants, or metal prostheses that may not cause inflammatory effects or these effects are essentially avoided when used in the human or animal body. The use of benzoxazine chemistry also allows the self-condensation of the monomer(s), which avoids the use of catalysts or hardeners (in the case of epoxy resins) that are generally harmful to human health.

[0047] According to a preferred embodiment, the heating step (b) may be carried out at a temperature in the range of 100° C. to 250° C. Preferably, the heating temperature is in the range of 120° C. to 200° C., in particular in the range of 150° C. to 180° C.

[0048] The duration of the polymerization may depend mainly on the polymerization temperature, and the polymerization duration may advantageously be between 30 minutes and 4 hours.

[0049] The depositing step (step (a)) may cover at least a portion of the substrate or may completely cover the substrate.

[0050] The deposition step (a) is preferably carried out to form a layer exhibiting a thickness between 100 μm and 2 mm, more preferentially between 100 μm and 1 mm. A coating or film thickness between 100 μm and 500 μm provides the maximum anti-inflammatory and / or anti-oxidant effect.

[0051] According to a very advantageous embodiment, an anti-inflammatory and / or antioxidant monomer based on a 3,4-dihydro-2H-1,3-benzoxazine derivative is the first monomer and the process comprises a step of depositing a second benzoxazine derivative selected from the group consisting of monofunctional amines crosslinked with diphenolic compounds, monophenolic compounds crosslinked with diamines and diamines crosslinked with diphenolic compounds, or mixtures thereof, on the substrate on which the first monomer has been deposited during step (a) for producing a mixture, prior to the heating step (b).

[0052] The resulting mixture is preferentially a two-layer system on the substrate, i.e. a first layer of a first monomer is deposited on the substrate, followed by a deposition step of a second benzoxazine derivative, which results in a mixture that is at least partially homogeneous at least at the interface of the layers.

[0053] In the context of the present invention, the first monomer may be pure or just sufficiently diluted with a suitable solvent to obtain a composition of the first monomer.

[0054] The second benzoxazine derivative is very useful for enhancing or even enhancing the self-polymerization (step (b)) of the first monomer. This can be explained by the fact that the first monomer possesses one oxazine ring (monofunctional benzoxazine) which, by self-polymerization, i.e. ring-opening polymerization, leads to a three-dimensional crosslinked polymer, which is the heterogeneous polymer of the invention, which is less favorable for realizing coatings. Thus, the second benzoxazine derivative possessing at least two oxazine rings allows the process according to the invention to prepare coatings based on heterogeneous polymers with improved properties, such as adhesion to various substrates, such as steel or glass-based materials. Advantageously, the second benzoxazine derivative is a compound of formula A or B as defined above, or a mixture thereof.

[0055] Preferably, the process comprises the steps of adding a second benzoxazine derivative selected from the group consisting of monofunctional amines crosslinked with diphenolic compounds, monophenolic compounds crosslinked with diamines and diamines crosslinked with diphenolic compounds, or mixtures thereof, to a first monomeric 3,4-dihydro-2H-1,3-benzoxazine derivative-based anti-inflammatory and / or antioxidant monomer, and mixing to form a resulting composition of the first monomer and the second benzoxazine derivative, which is deposited on a substrate in step (a).

[0056] Preferentially, the second benzoxazine derivative preferably has a concentration of 50% by weight or more in the above obtained composition compared to the concentration of the first monomer. Such a concentration of the second benzoxazine derivative improves the coating properties on various substrates, for example in terms of adhesion. More preferably, the concentration of the second benzoxazine derivative is in the range of 55% by weight to 90% by weight, and the most preferred concentration is in the range of 60% by weight to 80% by weight. These concentration ranges are effective in improving the adhesion, hardness, and abrasion resistance of the coating on various substrates.

[0057] According to a preferred embodiment, the deposition step (a) may be carried out by melting or dissolving the first monomer or the second benzoxazine derivative, or the resulting composition of the first monomer and the second benzoxazine derivative, thereby obtaining a homogeneous mixture. However, the melting process of the monomer(s) known in the art is most preferred, which avoids the use of organic solvents, which may be toxic. Furthermore, the absence of solvents results in better coating properties, such as recovery ability at the substrate, uniformity, reduced or no minor destruction observed on the coating. When using the melting process, the typical melting temperature is between 100°C and 120°C, preferably between 100°C and 110°C.

[0058] Alternatively, the deposition step (a) can be carried out in an aprotic solvent, provided that it results in a homogeneous mixture and the process can be carried out without limitation. For example, aromatic hydrocarbons, such as toluene, and halogenated hydrocarbons, such as chloroform, carbon tetrachloride, and dichloromethane, can be used. Ketone solvents such as acetone can also be used.

[0059] The substrate used to carry out the process may be, for example, steel, glass, or a polymer-based material, provided that the heating step (b) does not adversely affect the substrate.

[0060] Advantageously, the heating step (b) is carried out in the presence of a Lewis acid type catalyst, which is preferably PCl 5 , PCl 3 , POCl 3 , TiCl 4 , AlCl 3 and C.H. 3OTf, or mixtures thereof. The use of such Lewis acid catalysts allows for the performance of step (c) at temperatures below 180° C., most preferably at temperatures between 150° C. and 180° C. Reducing the temperature of step (c) is highly desirable to avoid any thermal degradation of the monomer and / or substrate.

[0061] The process may further comprise a step (c) of sterilizing the heterogeneous polymer on the substrate, which step (c) is preferentially carried out by immersing the heterogeneous polymer on the substrate in a solution of a primary alcohol, such as methanol or ethanol. The solution may consist of a pure primary alcohol or a dilute aqueous solution thereof, typically comprising at least 60% alcohol by volume.

[0062] The process may also include the step of adding an adhesion promoter onto the substrate, preferably as a coating or film, prior to step (a). Examples of suitable adhesion promoters include amino-silane coupling agents such as (3-aminopropyl)-triethoxysilane, (3-aminopropyl)-diethoxy-methylsilane, (3-aminopropyl)-dimethyl-ethoxysilane or (3-aminopropyl)-trimethoxysilane, or mixtures thereof.

[0063] The present invention further relates to an anti-inflammatory and / or antioxidant material comprising a substrate having an anti-inflammatory and / or antioxidant heterogeneous polymer based 3,4-dihydro-2H-1,3-benzoxazine coating or film obtainable by the process of the present invention.

[0064] In the material, the heterogeneous polymer based on 3,4-dihydro-2H-1,3-benzoxazine derivatives obtained by the process of the invention preferably exhibits a mechanical relaxation temperature corresponding to a maximum of the loss factor from 100°C to 300°C, preferentially from 100°C to 250°C and in particular from 100°C to 150°C.

[0065] The coating or film has a thickness of 100 μm to 2 mm, more preferentially 100 μm to 1 mm. A coating or film thickness of 100 μm to 500 μm provides the maximum anti-inflammatory and / or antioxidant effect.

[0066] The hardness of the coating or film is measured using a Pencil Hardness Tester Elcometer 501 according to the following standard ASTM D 3363. Scratching of the coating is typically not observed using a pencil of hardness less than 5H. The coating also preferentially exhibits a mechanical relaxation temperature corresponding to a maximum of the loss factor between 100 ° C and 300 ° C, preferentially between 100 ° C and 250 ° C, in particular between 100 ° C and 150 ° C.

[0067] Yet another aspect of the present invention relates to the use of a monomer based on a 3,4-dihydro-2H-1,3-benzoxazine derivative of any one of the formulae defined above, or a mixture thereof, or of the abovementioned composition, as a precursor, to obtain a heterogeneous polymer having anti-inflammatory and / or antioxidant properties.

[0068] The present invention also relates to a coated substrate of the material defined above, comprising a film or coating of a heterogeneous polymer prepared from any one of the 3,4-dihydro-2H-1,3-benzoxazine derivative-based monomers of any one of the formulas or compositions defined above. The raw substrate before coating can be a steel or glass-based material, etc.

[0069] The coated substrate of material may also preferably contain an adhesion promoter between the substrate and the film or coating prepared from the monomer based on 3,4-dihydro-2H-1,3-benzoxazine derivatives as a coating or film. Examples of suitable adhesion promoters include amino-silane coupling agents such as (3-aminopropyl)-triethoxysilane, (3-aminopropyl)-diethoxy-methylsilane, (3-aminopropyl)-dimethyl-ethoxysilane or (3-aminopropyl)-trimethoxysilane, or mixtures thereof.

[0070] The material is advantageously part of an implantable material, such as a biologically compatible implantable metallic device, such as a catheter, metallic implant, or metallic prosthesis, which may be used safely since the coated substrate prevents inflammatory and / or oxidative reaction(s) from the host into which it is implanted or grafted.

[0071] The present invention also relates to an anti-inflammatory and / or antioxidant material according to the invention for use for the treatment or prevention of inflammatory and / or oxidative disease(s).

[0072] The present invention also relates to the use of anti-inflammatory and / or antioxidant monomers based on 3,4-dihydro-2H-1,3-benzoxazine derivatives as precursors for obtaining the anti-inflammatory and / or antioxidant heterogeneous polymers of the present invention. [Brief description of the drawings]

[0073] [Figure 1] FIG. 1 shows the chemical structures of Monomers 1 to 13 (Comparative Examples) used in the present invention. [Diagram 2] FIG. 1 shows the chemical structures of monomers 7b, 8b, 9b, 10b, 11b, 12b, and 13b (Comparative Examples). [Diagram 3] FIG. 1 shows the chemical structures of monomers 7c, 8c, 9c, 10c, 11c, 13c and (Comparative Example). [Figure 4] FIG. 1 shows the chemical structures of monomers 7d, 8d, 9d, 10d, 11d, and 13d (Comparative Examples). [Diagram 5] FIG. 2 shows the chemical structure of Pe (a second benzoxazine derivative). [Figure 6] FIG. 1 shows the 1H NMR (600 MHz, CDCl3) spectrum of Monomer 1. [Figure 7] FIG. 1 shows the 13C NMR (150 MHz, CDCl3) spectrum of Monomer 1. [Figure 8] FIG. 1 shows the mass spectrum (MALDI-Tof / MS) of Monomer 1. [Figure 9] FIG. 1 shows the IR spectrum of Monomer 1. [Figure 10] FIG. 1 shows the DSC curve of Monomer 1. [Figure 11] FIG. 1 shows a DSC curve of a composition containing Monomer 1 and Pe. [Figure 12] FIG. 1 shows the coating of Pe onto NaOH-treated steel coverslips. [Figure 13] FIG. 1 shows the coating of the composition (monomer 1+Pe) onto a steel coverslip treated with NaOH. [Figure 14] FIG. 1 shows the coating of the composition (Monomer 1+Pe) onto a steel coverslip that was not treated with NaOH. [Figure 15] FIG. 2 shows a rheogram characterizing the polymerization of a composition (Monomer 1+Pe). [Figure 16] FIG. 2 shows a rheogram characterized by the mechanical relaxation temperature of a crosslinked composition (Monomer 1+Pe). [Figure 17] FIG. 1 shows the effect of substrates on metabolic activity in RAW264.7 (left) and THP-1 (right) macrophages. [Figure 18] FIG. 1 shows the effect of substrates on TNF-α production in RAW264.7 (left) and THP-1 (right) macrophages. [Figure 19]FIG. 1 shows the measurement results of the inflammation inhibitory activity of five samples. [Figure 20] FIG. 1 shows the results of measuring the pro-inflammatory activity of five samples. [Figure 21] FIG. 1 shows the toxicity measurements of five samples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] Preparation of monomers Figures 1-3 show the monomers 1-12 used in the present invention based on benzoxazine. Monomer 13 is used here as a comparative example, not of the present invention. Looking more closely at compounds 1-13 in Figure 1, it is highlighted that monomers 7, 8, 9, 10, 11, and 13 have side chains that may differ in their degree of unsaturation. The corresponding monomers 7b, 8b, 9b, 10b, 11b, and 13b have only two olefinic groups, as shown in Figure 2, while the corresponding monomers 7c, 8c, 9c, 10c, 11c, and 13c have only one olefinic group, as described in Figure 3. Finally, for the corresponding monomers 7d, 8d, 9d, 10d, 11d, and 13d, the side chains can be fully saturated, as shown in Figure 4. It is precisely shown that among these similar monomers, the monomers carrying three unsaturations are the major compounds, and the monomers with only one unsaturation are the minor compounds. Furthermore, it should be noted that when one of these particular monomers is used, it is relatively difficult to know which one is used. For the purposes of the present invention, for example, when compound 8 is used, compounds 8b, 8c and 8d are also considered to be included. It is ultimately accurate to say that all unsaturations shown in connection with these particular compounds have the configuration Z (or cis). Starting from δ-tocopherol as the phenol derivative starting material, the following reaction scheme was established (Scheme I). δ-Tocopherol

[0075] [ka]

[0076] Scheme I: Synthesis of mono-tocopherol-furfurylamine 1 The solventless reaction is carried out at 80° C. for 24 hours. The product is then separated by distillation with CHCl. 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times) containing MgSO 4 The mixture was dried at 40° C., filtered and dried under reduced pressure at 50° C. No further purification was necessary. The overall yield of the reaction was determined to be equal to 96%. The state of monomer 1 at room temperature is a viscous liquid.

[0077] Figures 6 to 9 show the analytical data for compound 1 ( 1 H and 13 C NMR, mass and IR spectra are shown.

[0078] Polymerization behavior study FIG. 10 shows the DSC (differential scanning calorimetry) analysis results of Monomer 1. The DSC analysis was carried out in the following temperature range: 25° C. to 280° C. The DSC traces were recorded under nitrogen at a heating rate of 5° C. / min. Thus, the polymerization temperature (T p ) was determined to be equivalent to 254° C. (ring opening of the oxazine moiety of monomer 1).

[0079] Because monomers 1-13 are monofunctional, their polymerization is not sufficient for the materials to be efficiently crosslinked and form effective free-standing coatings. To study the behavior of these monomers for coating experiments, we performed a DSC analysis of a composition containing monomer 1 and Pe (3,3'-ethane-1,2-diylbis(3,4-dihydro-2H-1,3-benzoxazine). Pe is a bifunctional compound (see chemical structure in Figure 5), exhibiting two oxazine rings.

[0080] Pe has been synthesized according to known protocols (Ganfoud R. et al., Composites Sci. Technol., 2015, 110, 1-7; Puchot L. et al, Polymer Chemistry, 2018, 9, 472).

[0081] The composition contains 33% Monomer 1 (17 mg) and 67% Pe (34 mg), and mixing is accomplished at 100°C. An orange pasty solid is obtained. Figure 11 shows the DSC curve obtained for the composition. The temperature range is 25°C to 280°C, and the heating rate is 5°C / min under nitrogen.

[0082] The DSC curve of Pe alone shows a melting point at 107° C. and two exothermic peaks (186° C. and 238° C., not shown as such in FIG. 11), identifying the sequential opening of the two benzoxazine rings. The aspect of the DSC curve of the composition indicates that polymerization of Pe appears to occur first, followed by polymerization with monomer 1.

[0083] Coating experiment Pe Coating Steel coverslips are then coated with NaOH to promote adhesion of the polymer film. (aq) A drop of Pe (obtained by melting Pe at 107 °C) is deposited and spread on the coverslip. The coverslip is then placed in a sterilizer at 180 °C for 2 h to promote polymerization and the formation of a coating. Finally, the disk is sterilized by immersing it in 70% ethanol / water for 30 min.

[0084] Figure 12 shows a photograph of a coating of Pe on a steel coverslip treated with NaOH, the thickness being approximately 120 μm. The coating is smooth and uniform.

[0085] Coating composition (monomer 1+Pe) Steel coverslips are then coated with NaOH to promote adhesion of the polymer film.(aq) A drop of the composition (obtained by melting the composition at 110° C.) is deposited and spread on the cover slip. The cover slip is then placed in a sterilizer at 180° C. for 2 hours to promote polymerization and the formation of a coating. Finally, the substrate is sterilized by immersion in 70% ethanol / water for 30 minutes.

[0086] FIG. 13 shows a photograph of the coating of the composition on a steel coverslip treated with NaOH.

[0087] The coating shown in the photograph of FIG. 13 is uneven and rough compared to the coating shown in the photograph of FIG. 12, so the results are less satisfactory than those obtained with Pe alone.

[0088] Coating of the composition (monomer 1+Pe) without pretreatment of the coverslip Here, the coating is performed on an untreated steel coverslip. A drop of the composition (obtained by melting the composition at 110°C) is deposited and spread on the coverslip. The coverslip is then placed in a sterilizer at 180°C for 2 hours to promote polymerization and the formation of the coating. Finally, the substrate is sterilized by immersion in 70% ethanol / water for 30 minutes. The thickness of the coating is approximately 110 μm.

[0089] FIG. 14 shows a photograph of the coating of the composition on a steel cover slip that was not treated with NaOH. These coating experiments show that the substrates can be used without any pretreatment.

[0090] The hardness of the coating was measured using a Pencil Hardness Tester Elcometer 501 according to the following standard ASTM D 3363. No scratching of the coating was observed using a pencil with a hardness of less than 5H.

[0091] To carry out the polymerization at temperatures below 180° C., Lewis acids can be used as catalysts. Such Lewis acid catalysts are preferentially PCl 5 , PCl 3 , POCl 3 , TiCl 4 , AlCl 3 or CH 3 OTf. These catalysts can be added in different concentrations, from 0.5% to 10% by weight. These compounds are added in a composition that is deposited on the surface of the substrate and washed off during immersion in ethanol. The temperature used can then be reduced to 150°C. Thus, the temperature range in the presence of these catalysts varies from 150°C to 180°C.

[0092] To reduce the polymerization temperature, primary amines, quaternary ammonium, thiols and elemental sulfur can be used. These compounds are added into the composition that is deposited on the surface of the substrate and washed off during immersion in ethanol. The thickness of the film is about 120 μm.

[0093] Figure 15 shows the rheograms. Rheokinetic measurements were performed using an Anton Paar Physica MCR302 rheometer equipped with a CDT450 temperature control device in the form of a disposable aluminum plate (diameter 25 mm, measurement gap 0.35 mm). Polymerization measurements were recorded in oscillatory mode with imposed strain amplitude (γ) of 1% and frequency (f) of 1 Hz. To reach a temperature of 150 °C, a heating ramp of 20 °C / min was used. The gel point was measured at 150 °C, but the deformation of the sample remained within the limits of the instrument, ramping linearly from 1% to 0.2%, maintaining a linear viscoelastic behavior even if the modulus increased over several orders of magnitude upon curing. The gel point corresponds to the time required to reach the crossover between the storage and loss moduli at this temperature. The measurements show that a solid material is formed after 200 s at 150 °C.

[0094] Figure 16 shows the rheogram of the final crosslinked polymer consisting of monomer 1 and Pe. Rheokinetic measurements were carried out on the pre-crosslinked sample between the plates of the rheometer, as described above, using an Anton Paar Physica MCR302 rheometer equipped with a CDT450 temperature control device in the form of a disposable aluminum plate (diameter 25 mm, measurement gap 0.35 mm). The measurements were recorded in oscillatory mode imposing a strain amplitude (γ) of 0.05% and a frequency (f) of 1 Hz. A heating ramp of 20 °C / min was used to reach a temperature of 150 °C. The mechanical relaxation temperature corresponds to the maximum of the loss factor at 122 °C.

[0095] Pharmaceutical aspects Preparation of films Tocopheryl benzoxazine 1 and Pe were provided according to the above protocol. Poly(L-lysine) (catalog number P2636) was purchased from Sigma-Aldrich (UK).

[0096] The monomers were dissolved in chloroform at a weight ratio of 1:2 (monomer 1:Pe) at a total final concentration of 20% w / v. Alternatively, other aprotic solvents such as acetone or dichloromethane can be used. Further alternatively, the monomers at a weight ratio of 1:2 (monomer 1:Pe) are melted together at a temperature ranging from 105 °C to 110 °C. This second method of mixing both monomer 1 and Pe can avoid the use of chloroform. Approximately 100 mg of the solution or molten mixture was deposited on a circular glass coverslip with Φ = 13 mm placed on a stir plate and then maintained at 100 °C for 15 min. Heat treatment was performed at 150 °C for 1 h, followed by post-curing at 170 °C for 2 h. Finally, the discs were sterilized by immersion in 70% ethanol / water for 30 min. The thickness of the film is approximately 110 μm.

[0097] In addition to the clear glass coverslips, glass coverslips coated with poly-L-lysine were also used as controls. In particular, 50 μL of a 0.01% w / v sterile solution of poly-L-lysine in MilliQ water was deposited on the coverslips, and after 10 min the solution was removed and the glass surface was rinsed with MilliQ water. The coverslips were allowed to dry for at least 2 h before introducing cell culture medium.

[0098] cell research General cell culture. The murine leukemia monocyte macrophage cell line RAW264.7 and the human monocyte cell line THP-1 (TIB-202™) were purchased from ATCC (Manassas, VA, USA) and maintained in cell culture medium (Dulbecco's Modified Eagle Medium (DMEM) High Glucose (#D5671) for RAW264.7 and RPMI 1640 medium (#R0883 for THP-1) supplemented with 10% (v / v) fetal bovine serum (FBS, #F7524), 2 mM L-glutamine (#G7513), and 1% (v / v) penicillin-streptomycin (#P4333). All cell culture reagents were purchased from Sigma-Aldrich (UK) unless otherwise specified. Cells were cultured in humidified 5% (v / v) CO 2 The cells were routinely cultured at 37°C in an air atmosphere and used up to a maximum of 15 passages.

[0099] THP-1 differentiation (M0 macrophages). THP-1 promonocytes (1.25x105 cells / cm) of less than 20 passages 2 ) were differentiated into THP-1 macrophages for 24 h by incubation in complete medium containing 50 ng mL-1 phorbol 12-myristate 13-acetate (PMA; #P1585, Sigma-Aldrich, UK) (see de la Rosa JMR et al., Adv. Healthcare Mater, 2017, 1601012 for the protocol). After differentiation, the PMA medium was removed. Cells were washed once with serum-free RPMI 1640 and left to rest or further activated in complete medium without PMA for 24 h.

[0100] Metabolic activity. RAW264.7 macrophages were cultured on tissue culture polystyrene (TCPS), glass, or polymer films (poly-L-lysine or tocopherol) at 2.5x104 cells / cm2. 2 Cells were seeded into wells of a 24-well plate at a density of 1000 x 1000 and grown for 48 h. To obtain THP-1 macrophages, THP-1 promonocytes were differentiated and plated on the substrate as described above. Cells were then washed with PBS and incubated for 1 h at 37° C. in serum-free and phenol red-free medium containing CellTiter96® AQueous One Solution Cell Proliferation Assay (MTS) 5% (v / v). Metabolic activity was measured by reading absorbance values ​​at 490 nm (using a Synergy2 Biotek plate reader, Gen5 software) and normalized by the total protein content of each well using a BCA kit (Sigma-Aldrich, UK).

[0101] Effect of substrate on the production of inflammatory mediators. RAW264.7 macrophages were cultured at 2.5x104 cells / cm on tissue culture polystyrene (TCPS), glass, or polymer films (polylysine or tocopherol). 2Cells were seeded into wells of a 24-well plate at a density of 100 μg / mL and grown for 24 h. RAW 264.7 macrophages were treated with fresh medium containing 1 μg / mL lipopolysaccharide (LPS) from Escherichia coli O26:B6 alone (L5543, Sigma-Aldrich, UK) for 24 h. Newly differentiated THP-1 macrophages were treated with fresh medium containing 100 ng / mL LPS and 20 ng / mL IFN-γ (#300-02, Prepotech, Inc.) for 24 h. RAW264.7 and THP-1 cells cultured in fresh medium without any effector were used as negative controls. After activation, the supernatants were collected and centrifuged at 13,000 rpm for 5 min. For RAW264.7 macrophages, the amount of TNF-α in the culture medium was determined by BD OptEIATM Mouse TNF (Mono / Mono) ELISA set up according to the manufacturer's instructions. For THP-1 macrophages, the amount of TNF-α was determined by TNF-α ELISA MAX™ Deluxe (#43020, BioLegend, UK) according to the manufacturer's instructions. TNF-α levels were normalized by the total protein content of each well using a BCA kit.

[0102] Figure 17 shows the effect of substrates on metabolic activity in RAW264.7 (left) and THP-1 (right) macrophages. Concentration values ​​are normalized to the total amount of protein in the sample, which is assumed to be roughly proportional to cell number.

[0103] No significant differences in metabolic activity have been observed between macrophages exposed to tissue culture polystyrene (TCPS), glass disks (uncoated or coated with poly-L-lysine), or polymer films (specifically containing monomer 1) deposited on glass substrates. Thus, macrophage viability is maintained.

[0104] Figure 18 shows the effect of substrates on TNF-α production in RAW264.7 (left) and THP-1 (right) macrophages. Concentration values ​​are normalized to the total amount of protein in the sample, which is assumed to be roughly proportional to cell number.

[0105] TNF-α production of macrophages seeded on either tissue culture polystyrene (TCPS) or polymer films (specifically containing monomer 1) was measured by ELISA after 24 h incubation with LPS (1 μg / mL) for RAW264.7 and LPS (100 ng / mL) and IFN-γ (20 ng / mL) for THP-1.

[0106] Anti-inflammatory effects Compounds 1, 8, 12, and 13 in combination with Pe (Comparative Example) and Pe alone were tested for their anti-inflammatory properties.

[0107] In humans, inflammation can occur through the activation of nuclear factor-κB (NF-κB), a central transcription factor in chronic inflammatory diseases, which induces the expression of many inflammation-related genes, such as tumor necrosis factor α (TNFα) and cytokines such as IL-1β, IL-10, IL-6 or IL-8 (Medzhitov R., Nature, 2008, 454, 428-435). In the present invention, an inflammation-related human cell line, namely monocytic THP-1 cells, is used to evaluate the potential of coatings to reduce inflammation. Their cytotoxicity is first evaluated using the resazurin reduction test (O'Brien J. et al., Eur. J. Biochem., 2000, 267, 5421-5426). Next, the general anti-inflammatory properties are determined using THP-1 cells transfected with a reporter plasmid expressing the secreted alkaline phosphatase (SEAP) gene under the control of an NF-κB inducible promoter. TNFα was used as an inflammatory inducer and data are expressed as percentage inhibition of NF-κB activation. Furthermore, the effect of the most promising monomers was further evaluated on inflammation-related genes by real-time qPCR using macrophage-differentiated THP-1 cells (Andre CM et al., J. Agric. Food. Chem, 2013, 61, 2773-2779) and IL-1β, IL-10, IL-6, and COX-2 as markers (Kaulmann A. et al., Mol. Nutr. Food Res., 2016, 60, 992-1005).

[0108] Figure 19 shows that samples coated with polymers formed from monomers 1, 8, and 12 (film thickness approximately 120 μm) have a strong anti-inflammatory effect compared to samples coated with compounds Pe or 13 (not of the invention). The inhibition of inflammation is approximately 20%. The high variability of the coating produced by compositions containing monomers 1 and Pe may be explained by differences in the amount of coating or biological variability.

[0109] Figure 20 shows the proinflammatory properties of five compounds 1, Pe, 8, 12, and 13. Indeed, only the film-coated sample derived from compound 13 shows a tendency to induce an inflammatory response in the host.

[0110] Furthermore, as shown in FIG. 21, none of the five compounds 1, Pe, 8, 12, and 13 are toxic to living cells. Antioxidant Effects

[0111] When polymerized upon heating, polybenzoxazines exhibit phenolic structures which are highly suspected to exhibit radical scavenging activity and certainly exhibit antioxidant properties.

[0112] A wide range of methods, both in vivo and in vitro, are currently used to evaluate the antioxidant activity of compounds or polymers, all of which have certain advantages and limitations. Here, both the oxygen radical absorbance capacity (ORAC) method and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity assay are used to obtain a more complete picture of their antioxidant potential. In the ORAC assay, the peroxyl radical reaction involves a hydrogen atom transfer mechanism, whereas the DPPH assay is based on electron transfer. Briefly, in the ORAC analysis, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), a water-soluble azo compound, is used as the peroxyl radical generator, Trolox, a water-soluble tocopherol analog, is used as the standard, and fluorescein is used as the fluorescent probe. Fluorescence is measured every minute for 50 minutes. All samples are analyzed in triplicate and final ORAC values ​​are calculated using the net area under the decay curve as described (Andre CM, et al., J. Agric. Food Chem., 2007, 55, 366-378). In the DPPH assay, the ability of various building blocks to reduce an oxidant (an organic nitrogen radical that changes color when reduced) is monitored spectrophotometrically at 515 nm.

[0113] Studies carried out using only the polymer Pe (Comparative Example) and especially polybenzoxazines formed from monomers 1, 8 and 12 with or without Pe, show that when using the polybenzoxazines of the invention, the antioxidant properties are improved by 5% to 25% without any limitations compared to Pe.

[0114] Carrying out the Coating of the Invention These interesting properties (anti-inflammatory, anti-oxidant, low pro-inflammatory tendency and lack of toxicity) make them ideal for all implementations related to implantable metallic devices, preferentially catheters, metallic implants or metallic prostheses.

[0115] [Table 1]

[0116] The reaction is carried out without the use of a solvent. Furfurylamine, tocopherol, and paraformaldehyde are all weighed into the flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C. The yield of the reaction is 96%.

[0117] [Table 2]

[0118] The reaction is carried out without the use of a solvent. Furfurylamine, delta tocotrienol, and paraformaldehyde are all weighed into the flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C.

[0119] [Table 3]

[0120] The reaction is carried out without the use of a solvent. Furfurylamine, beta-tocopherol, and paraformaldehyde are all weighed into a flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C.

[0121] [Table 4]

[0122] The reaction is carried out without the use of a solvent. Furfurylamine, beta-tocotrienol, and paraformaldehyde are all weighed into the flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C.

[0123] [Table 5]

[0124] The reaction is carried out without the use of a solvent. Furfurylamine, gamma tocopherol, and paraformaldehyde are all weighed into the flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C.

[0125] [Table 6]

[0126] The reaction is carried out without the use of a solvent. Furfurylamine, gamma tocopherol, and paraformaldehyde are all weighed into the flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C.

[0127] [Table 7]

[0128] The reaction is carried out without the use of a solvent. Furfurylamine, anacardic acid, and paraformaldehyde are all weighed into a flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C.

[0129] [Table 8]

[0130] The reaction is carried out without the use of a solvent. Furfurylamine, cardanol, and paraformaldehyde are all weighed into a flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C. The yield of the reaction is 96%.

[0131] [Table 9]

[0132] The reaction is carried out without the use of a solvent. Furfurylamine, cardol, and paraformaldehyde are all weighed into the flask. The mixture is stirred and heated at 80°C without reflux for 2 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C.

[0133] [Table 10]

[0134] The reaction is carried out without the use of a solvent. Furfurylamine, methyl cardol, and paraformaldehyde are all weighed into the flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C.

[0135] [Table 11]

[0136] The reaction is carried out without the use of a solvent. Furfurylamine, isoeugenol, and paraformaldehyde are all weighed into the flask. The mixture is stirred and heated at 80°C without reflux for 24 hours. The product is CHCl 3 The mixture is then purified by liquid-liquid extraction from 1M NaOH (3 times) and water (3 times), containing MgSO 4 The mixture is dried at 40° C., filtered and vacuum dried at 50° C. The yield of the reaction is 92%.

Claims

1. 1. Anti-inflammatory and / or antioxidant monomers based on 3,4-dihydro-2H-1,3-benzoxazine derivatives having the structural formula: 【Chemistry 1】 During the ceremony, R ４ =CH ３ and R ２ and R ３ Together, 【Chemistry 2】 represents 【Chemistry 3】 and R １ = H or CH ３ or or in the formula: R ４ and R ３ Together, 【Chemistry 4】 represents 【Chemistry 5】 and R ２ = R １ =CH ３ or or a mixture thereof.

2. 10. A composition comprising a mixture of a first monomer consisting of an anti-inflammatory and / or antioxidant 3,4-dihydro-2H-1,3-benzoxazine derivative monomer derivative of any one of the formulas according to claim 1 or a mixture thereof and a second benzoxazine derivative selected from the group consisting of monofunctional amines crosslinked with diphenolic compounds, monophenolic compounds crosslinked with diamines and diamines crosslinked with diphenolic compounds, or a mixture thereof.

3. The second benzoxazine derivative is a compound of formula A, 【Chemistry 6】 In the formula, R is -CH ２ -, -C(CH ３ ) ２ -, SO ２ , -C(CF ３ ) ２ -, -C(CH ３ ) (C ６ H ５ ) -, -C(CH ３ ) (C ２ H ５ ) -, -C(C ６ H ５ ) ２ --, --CHCH ３ -, -C ６ H １０ - or -C(CH ３ ) CH ２ CH ２ is a COOH- group; R １ But -CH ２ CH ２ OH, vinyl, methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclohexyl, fluorene, phenylacetylene, phenylpropargyl ether, benzonitrile, furfuryl, phenylene or -(CH ２ ) １７ CH ３ The composition of claim 2 , wherein the R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -

4. The second benzoxazine derivative is a compound of formula B: 【Chemistry 7】 During the ceremony, R is -(CH) ２ -, -(CH) ４ -, -(CH) ６ -, -(CH) ８ -, -(CH) １０ -, -(CH) １２ -, -(CH) １４ -, -(CH) １８ - group, or 【Chemistry 8】 and In the formula, R １ , R ２ , R ３ , R ４ is selected from the group consisting of: R １ =R ２ =R ３ =R ４ =H、 R １ =OCH ３ ,R ２ =R ４ =H、R ３ =CH ２ CH=CH ２ 、 R １ =OCH ３ ,R ２ =R ４ =H、R ３ =CH�H ３ 、 R １ =OCH ３ ,R ２ =R ４ =H、R ３ =HO、 R １ =OCH ３ ,R ２ =R ３ =R ４ =H、 R １ =OCH ３ ,R ２ =R ４ =H、R ３ =HO、 R １ =OCH ３ ,R ２ =R ４ =H、R ３ =CH ２ CH ２ COOOH、 R １ =R ２ =R ４ =H、R ３ =CH ２ CH ２ COOH、 R １ = R ２ = R ４ = H, R ３ = CH = CHCOOH, and R １ = OCH ３ , R ２ = R ４ = H, R ３ =CH=CHCOOH, or in the formula: R ３ =R ４ =H、 【Chemistry 9】 and R １ =COOH or or in the formula: R １ =H、R ２ =OH、R ３ =H、 【Chemistry 10】 or or in the formula: R １ =H、 【Chemistry 11】 R ３ = H, R ４ =OH, or in the formula: R １ =CH ３ , R ２ =OH, R ３ = H, 【Chemistry 12】 or or in the formula: R １ = R ３ = R ４ = H, 【Chemistry 13】 or or in the formula: R １ =R ３ =H、 R ２ =-CH ２ HC=CH ２ and R ４ = OCH ３ Is it; or R １ =R ３ =H、 R ２ =-CH=HCCH ３ and R ４ = OCH ３ Is it; Or R １ = R ２ = R ４ = H and 【Chemistry 14】 or Or R １ = R ２ = R ３ = H and R ４ =CH ２ CH=CH ２ or Or R １ = R ２ = R4 = H and R ３ =CH ２ CH=CH ２ or Or R １ = R ３ = R ４ = H and R ２ =CH ２ CH=CH ２ The composition of claim 2 ,

5. The composition according to any one of claims 2 to 4, wherein the second benzoxazine derivative has a concentration of 50% by weight or more compared to the concentration of the first monomer according to claim 1.

6. 1. A process for producing a material having anti-inflammatory and / or anti-oxidant properties, comprising a substrate coated with a 3,4-dihydro-2H-1,3-benzoxazine-based anti-inflammatory and / or anti-oxidant heterogeneous polymer, comprising the steps of: (a) depositing on said substrate an anti-inflammatory and / or anti-oxidant monomer selected from the group consisting of at least one any monomer of the formula according to claim 1; (b) heating the deposit obtained in step (a) at a predetermined temperature for a predetermined time to polymerize said monomers to obtain said material.

7. 7. The process of claim 6, wherein the anti-inflammatory and / or antioxidant monomer based on a 3,4-dihydro-2H-1,3-benzoxazine derivative is a first monomer, the process comprising the step of depositing a second benzoxazine derivative selected from the group consisting of monofunctional amines crosslinked with diphenolic compounds, monophenolic compounds crosslinked with diamines and diamines crosslinked with diphenolic compounds, or mixtures thereof, on the substrate having the first monomer deposited thereon during step (a) to produce a mixture, prior to the heating step (b).

8. 7. The process of claim 6, comprising adding a second benzoxazine derivative selected from the group consisting of monofunctional amines crosslinked with diphenol compounds, monophenol compounds crosslinked with diamines and diamines crosslinked with diphenol compounds, or mixtures thereof, to a first monomer, an anti-inflammatory and / or antioxidant monomer based on a 3,4-dihydro-2H-1,3-benzoxazine derivative, and mixing to form a resulting composition of the first monomer and the second benzoxazine derivative, the resulting composition being deposited on the substrate in step (a).

9. 9. The process according to claim 7 or 8, wherein the second benzoxazine derivative is a compound of formula A or B according to claim 3 or 4, or a mixture thereof.

10. 10. The process of claim 8 or 9, wherein in the resulting composition, the second benzoxazine derivative has a concentration of 50% or more by weight compared to the concentration of the first monomer.

11. The process of any one of claims 6 to 10, wherein the heating step (b) is carried out at a temperature in the range of from 100°C to 250°C.

12. The heating step (b) is carried out in the presence of a Lewis acid type catalyst, the catalyst being PCl ５ , PCl ３ , POCl ３ , TiCl ４ , AlCl ３ and C.H. ３ The process of any one of claims 6 to 11, wherein the SiO2 is selected from the group consisting of SiO2, SiO2+ ...

13. 13. The process of any one of claims 6 to 12, further comprising a step (c) of sterilizing the heterogeneous polymer on the substrate, wherein the step (c) is carried out by immersing the heterogeneous polymer on the substrate in a solution of a primary alcohol.

14. An anti-inflammatory and / or anti-oxidant material comprising a substrate having an anti-inflammatory and / or anti-oxidant heterogeneous polymer based 3,4-dihydro-2H-1,3-benzoxazine coating or film obtainable by the process according to any one of claims 6 to 13.

15. 15. The anti-inflammatory and / or anti-oxidant material according to claim 14, wherein said heterogeneous polymer exhibits a mechanical relaxation temperature corresponding to a maximum of the loss factor between 100°C and 300°C.

16. The anti-inflammatory and / or anti-oxidant material according to claim 14 or 15, wherein said coating or film exhibits a thickness comprised between 100 μm and 2 mm.

17. The anti-inflammatory and / or anti-oxidant material according to any one of claims 14 to 16, wherein said coating or film exhibits a hardness of more than 5H measured according to the ASTM D 3363 standard.

18. 18. The anti-inflammatory and / or anti-oxidant material according to any one of claims 14 to 17, which is part of an implantable material, such as an implantable metallic device, such as a biologically compatible catheter, metallic implant or metallic prosthesis.

19. 19. The anti-inflammatory and / or anti-oxidant material according to any one of claims 14 to 18 for use in the treatment or prevention of anti-inflammatory and / or anti-oxidant disease(s).

20. Use of anti-inflammatory and / or antioxidant monomers based on 3,4-dihydro-2H-1,3-benzoxazine derivatives according to one of the formulae according to claim 6, or mixtures thereof, or on mixtures or compositions according to claims 7 or 8, respectively, as precursors for obtaining heterogeneous polymers having anti-inflammatory and / or antioxidant properties.

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