Compounds for coating nanostructures

Abstract

The present disclosure relates to compounds according to formula (I) and methods for making the compounds, as well as the use of the compounds as intermediates in the manufacture of coated nanostructures. The disclosure also relates to such nanostructures and the use of such nanostructures as carriers of radionuclides, as well as pharmaceutical compositions comprising such nanostructures.

Description

[Technical field]

[0001] The present disclosure relates to compounds suitable for coating polymeric nanostructures that have use as intermediates in the manufacture of nanostructures that have use in total body radiation therapy and imaging. [Background technology]

[0002] Polymer coatings, such as PEG-containing polymer coatings, can be used to prevent aggregation of nanostructures and improve biocompatibility. While PEG remains the polymer of choice, other polymers have been reported that are suitable for coating nanostructures for biomedical applications, such as polyvinylpyrrolidone and polyamides.

[0003] WO2018130713 describes dipodal structures with one or more short chain PEGs, which have a cyclic core, such as an aromatic core, and have been found to produce some impurities during large scale production.

[0004] WO2021122859 describes this problem in detail and presents a method to remove the impurities, but this method involves several purification steps that increase the production cost and may affect the quality of the final pharmaceutical product containing the coated nanostructures. Summary of the Invention

[0005] The aim of the present disclosure is to overcome these problems.

[0006] According to a first aspect, the above and other objects are achieved in whole or at least in part by the compounds defined in claim 1. According to this claim, the above objects are achieved by compounds according to formula (I), TIFF2025509109000002.tif68170, Poly 1 and Poly2 is independently selected from the group consisting of hydrogen and a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da; 1 or Poly 2 At least one of Y is a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da. 1 and Y 2 are independently -A(CH2) n B-, where A is bonded to X and Y 1 The B stands for Poly 1 is bonded to Y 2 The B stands for Poly 2 wherein n is an integer from 0 to 5; A is selected from the group consisting of -O-, -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, -NH(C=O)-, and a covalent bond; and B is selected from the group consisting of -O-, -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, -NH(C=O)-, and a covalent bond, with the proviso that Poly 1 or Poly 2 Y in 1 Or Y 2 If the atom bonded to Y is not a carbon atom, then B is a covalent bond. 3 and Y 4 are independently -E(CH2) m where E is bonded to X, m is an integer from 2 to 5, and E is independently selected from the group consisting of -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, -NH(C=O)-, and a covalent bond. X is of the structure X 1 , X 2 , X 3 , X 4 , and X 5 is selected from the group consisting of In the formula, the bold bonds represent Y 1 Or Y 2 The non-bold bonds represent bonds to Y 3 Or Y 4 and p is an integer of 1 to 5. 1 and Z2 is independently -SiR 1 R 2 R 3 where R 1 , R 2 , and R 3 is independently selected from the group consisting of chloride, bromide, iodide, lower alkoxy, aryloxy, carboxy, amino, and -NH-acyl.

[0007] These compounds (also referred to as coating precursors) can be applied as a layer to the surface of nanostructures to extend the blood circulation time (plasma half-life) of the nanostructures, allowing sufficient time for them to bind to cells in the target tissue, and furthermore, such coated nanostructures have extended stability.

[0008] Such compounds have the advantage that no extra purification steps are required after synthesis of the compounds, which is beneficial for the cost and quality of pharmaceutical products that include nanostructures coated with the coating precursor.

[0009] Poly 1 and Poly 2 may contain ethylene glycol units. 1 and Poly 2 may include other hydrophilic polymers such as polyvinylpyrrolidone and polyamides, which, although more chemically sensitive than polyethylene glycol, e.g., to hydrolysis, may be used in certain cases because these groups are generally less immunogenic than polyethylene glycol.

[0010] Poly 1 and Poly 2 Poly may contain 10 to 200 ethylene glycol units. Multiple ethylene glycol units linked together are also called polyethylene glycol chains or PEG chains. 1 and Poly 2may contain 12 to 170, such as 15 to 120, such as 20 to 90, such as 30 to 75, such as 35 to 60, such as 40 to 50, such as 42 to 48, such as 45, ethylene glycol units. 1 and Poly 2 Poly may contain 12 to 30 ethylene glycol units. 1 and Poly 2 may contain 15 to 60, such as 20 to 50, such as 30 to 60, ethylene glycol units. 1 and Poly 2 may contain 40 to 100, such as 50 to 90, such as 60 to 120, such as 75 to 170, ethylene glycol units.

[0011] Preferably, Poly 1 and Poly 2 contains 30 to 60 ethylene glycol units, and even more preferably 40 to 50 ethylene glycol units.

[0012] If desired, Poly 1 and Poly 2 may be end-capped with a capping group such as a lower alkyl group, particularly when it contains ethylene glycol units. Thus, in one embodiment, Poly 1 and Poly 2 comprises 30-60 ethylene glycol units, such as 40-50 ethylene glycol units, and is end-capped with a capping group that is a methyl or ethyl group.

[0013] According to one embodiment, Poly 1 and Poly 2 is a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da.

[0014] According to another embodiment, n is an integer from 1 to 3, preferably n is 1 or 2, and even more preferably n is 1. Such compounds are stable and synthetically accessible in a convenient manner.

[0015] According to a further embodiment, Y 1 and Y 2 In both of these, n is 1. Such compounds are stable and conveniently accessible synthetically.

[0016] According to another embodiment, X is X 1 It is.

[0017] According to one embodiment, Y 1 and Y 2 In both of the above, A is a covalent bond, B is -O-, and n is an integer from 1 to 3. Such compounds are stable and synthetically accessible in a convenient manner.

[0018] According to another embodiment, Y 3 and Y 4 In both of the above, E is a covalent bond. Such compounds are stable and synthetically accessible in a convenient manner.

[0019] According to a further embodiment, the hydrophilic polymeric group comprises a PEG chain. Optionally, the PEG chain is end-capped with a lower alkyl.

[0020] According to yet another embodiment, each hydrophilic polymer group comprises 20 to 150 ethylene glycol residues, preferably 30 to 60 ethylene glycol groups, such as 40 to 50. Such compounds are resistant to interaction with plasma proteins, have a long plasma half-life and are synthetically accessible in a convenient manner.

[0021] According to a further embodiment, Poly 1 and Poly 2 is ω-methyl-(ethyleneoxy) w In the formula, w is 20 to 150; Y 1 and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 3 and Y 4 are both -CH2-CH2-CH2- and X is X1 and Z 1 and Z 2 is independently selected from the group consisting of triethoxysilyl and trimethoxysilyl. Such compounds are conveniently synthetically accessible and have convenient reactivity when used as coatings to yield coated nanostructures with advantageous in vivo properties. Preferably, w is between 30 and 60, and even more preferably, w is between 40 and 50.

[0022] A second aspect of the present disclosure relates to a compound according to formula (II): TIFF2025509109000004.tif77170, R 7 and R 8 is independently selected from the group consisting of lower alkyl, p is an integer of 20 to 150, q is an integer of 20 to 150, r is an integer of 1 to 3, s is an integer of 1 to 3, t is an integer of 0 to 3, and u is an integer of 0 to 3. In formula (II), X is 1 , X 2 , X 3 , X 4 , and X 5 is selected from the group consisting of TIFF2025509109000005.tif43170In the formula, the thick bond is [CH2] r and [CH2] s The non-bold bonds represent bonds to [CH2]. t and [CH2] u and p is an integer of 1 to 5.

[0023] Preferably, p is an integer from 30 to 60, such as 40 to 50.

[0024] Preferably, q is an integer from 30 to 60, such as 40 to 50.

[0025] Preferably, the lower alkyl is methyl and / or ethyl.

[0026] In a third aspect, the present disclosure relates to the use of a compound according to formula (II) as defined above in the manufacture of a compound according to formula (I) as defined above, wherein the hydrophilic polymeric group in formula (I) comprises a PEG chain.

[0027] In a fourth aspect, the present disclosure relates to a method for purifying a compound according to formula (II) as defined above, comprising: a) providing an aqueous solution of a non-pure compound according to formula (II) as defined above, the aqueous solution comprising: Water in an amount between 7.5 and 16.5 times the total mass of the impure compound according to formula (II) defined above, and NaCl in an amount between 6% and 9% (weight / volume) of the amount of water, and b) subjecting the aqueous solution of step a) to 2 to 5 intermediate extractions carried out at temperatures between 40° C. and 70° C., each intermediate extraction comprising the following steps: b1) optionally adding further portions of NaCl, so that the total amount of NaCl added corresponds to an amount of NaCl that is less than 9% (w / v) of the amount of water in the aqueous solution of step a); b2) extracting the aqueous solution with a carboxylic acid ester solvent; and b3) obtaining an aqueous phase by removing the organic phase; and c) adding NaCl to the aqueous phase from step b3) in an amount of at least 1% of the amount of water in step a) so that the total amount of NaCl corresponds to an NaCl amount of 8% to 12% and subjecting the aqueous phase to 2 to 5 product extractions carried out at a temperature of 40° C. to 70° C., each product extraction comprising the following steps: c1) extracting the aqueous phase with a carboxylic acid ester solvent; and c2) removing the organic phase; and d) pooling the organic phases from each step c2); e) concentrating the pooled organic phase from step d) to obtain a residue; f) dissolving the residue from step e) in an aqueous buffer solution having a pH of 6-9 to obtain an aqueous phase; g) subjecting the aqueous phase from step f) to 2 to 4 polishing extractions, each polishing extraction comprising the steps of: g1) extracting the aqueous phase from step f) with a chlorinated solvent; and g2) removing the organic phase; and h) pooling the organic phases from each step g2); i) concentrating the pooled organic phase from step h) to obtain a residue comprising a di-PEGylated diene according to formula (II) as defined above, with less than 10% (w / w) impurities; Includes.

[0028] The compound according to formula (II) defined above and purified according to the method described herein can be used to produce a compound according to formula (I) with high purity. Therefore, no extra purification steps are required, which is also beneficial for the cost and quality of the produced coating precursor and nanostructures coated with the coating precursor.

[0029] The amounts of the above mentioned impurities can be measured by HPLC ELSD.

[0030] The temperature in step b) may be between 50° C. and 70° C., preferably between 55° C. and 65° C., such as 60° C. It has been shown that these temperatures break down the emulsion formed at lower temperatures, allowing the phases to be separated cleanly.

[0031] In step c1), the carboxylic acid ester may be ethyl acetate or isopropyl acetate. Such carboxylic acid esters are good solvents for the species to be extracted and have boiling points that allow operation at the desired temperature while also making removal by evaporation practical.

[0032] After step d), the organic phase may be subjected to a drying step before concentration (step e). This can be achieved by many methods known to those skilled in the art, such as drying over a drying agent such as magnesium sulfate or using molecular sieves. A drying step is desirable since subsequent steps in the synthesis generally require water-free conditions.

[0033] The aqueous buffer of step f) is preferably aqueous sodium bicarbonate, as it achieves the desired pH in a convenient and economical manner.

[0034] In step g1), the chlorinated solvent may be dichloromethane, chloroform or tetrachloroethane. Such chlorinated solvents are preferred due to their high affinity for the PEGylated species.

[0035] Preferably, the chlorinated solvent is dichloromethane.

[0036] In a fourth aspect, the present disclosure provides a method for producing a polysaccharide comprising: 1 and Poly 2 and wherein both of said PEG chains are end-capped with a lower alkyl, the process comprising the steps of: i) providing a diene according to formula (II) as defined above, optionally purified as described above; ii) reacting a diene with a compound of the structure HSiR 1 R 2 R 3 wherein R 1 , R 2 , and R 3 with at least 30 equivalents of a hydrosilylation reagent, independently selected from the group consisting of lower alkoxy groups, in the presence of a platinum catalyst and an aromatic hydrocarbon solvent at a temperature between 10 and 35° C.; iii) removing excess hydrosilylation reagent; and iv) removing platinum from the product; Includes.

[0037] Therefore, this method can be used for the synthesis of silylated dipodal structures containing one or more poly(ethylene glycol) methyl ether chains.

[0038] Importantly, no extra purification steps are required, which also benefits the cost and quality of the produced coating precursor and nanostructures coated with the coating precursor.

[0039] In step ii), the alkoxy groups are preferably methoxy and / or ethoxy groups. Such compounds have suitable reactivity when used to coat nanostructures, while also being stable enough to allow easy handling.

[0040] Preferably, the alkoxy groups in step ii) are methoxy and / or ethoxy.

[0041] Preferably, step iii) is carried out after step ii) at a time when the reaction has proceeded essentially to completion, such as after 24 hours.

[0042] In a fifth aspect, the present disclosure relates to the use of a compound according to formula (I) as defined above, or a compound according to formula (II) as defined above, or a product of any one of the methods described above, as an intermediate in the manufacture of coated nanostructures. Preferably, the compound used contains from 30 to 60, such as 50-50, ethylene glycol groups.

[0043] In a sixth aspect, the present disclosure relates to spherical nanostructures having a hydrodynamic diameter of 10-100 nm, the nanostructures having a coating derived from a compound according to formula (I) as defined above, or a compound according to formula (II) as defined above, or the product of any one of the methods described above, the hydrodynamic diameter being measured as the average of the volume-weighted peaks of the sample measured by DLS at 25° C. in an aqueous solution of ionic strength equivalent to 150 mM NaCl, also referred to as saline, or in 8% ethylene glycol (volume / volume) in saline (also described below).

[0044] Such nanostructures can be used in cancer treatment and imaging.

[0045] The hydrodynamic diameter may be from 10 nm to 100 nm, such as from 12 nm to 80 nm, such as from 14 nm to 60 nm, such as from 16 nm to 50 nm, such as from 18 nm to 45 nm, such as from 20 nm to 40 nm, such as from 25 nm to 35 nm.

[0046] The nanostructures may include a chelating group, which may be a bisphosphonate, preferably a geminal bisphosphonate.

[0047] According to one embodiment, the spherical nanostructures further comprise a radionuclide, which may be suitable for medical imaging, such as a radionuclide suitable for PET or a radionuclide suitable for SPECT and / or a radionuclide suitable for radionuclide therapy.

[0048] Radionuclides are 177 Lu, 153 Sm, and / or 90 It can be Y.

[0049] In a seventh aspect, the present disclosure relates to a pharmaceutical composition comprising a plurality of spherical nanostructures as described above. The nanostructures may comprise radionuclides. Thus, both "empty" nanostructures, i.e., nanostructures that do not comprise radionuclides, and / or "loaded" nanostructures, i.e., nanostructures that comprise radionuclides, may be included in the pharmaceutical composition.

[0050] In an eighth aspect, the present disclosure relates to a pharmaceutical composition for use in the treatment or imaging of cancer, the pharmaceutical composition comprising a plurality of spherical nanostructures comprising a radionuclide, which may be suitable for medical imaging, such as a radionuclide suitable for PET, or a radionuclide suitable for SPECT, and / or a radionuclide suitable for radionuclide therapy.

[0051] In a ninth aspect, the present disclosure relates to the use of spherical nanostructures according to the present disclosure as carriers of radionuclides. The radionuclides may be suitable for medical imaging, such as radionuclides suitable for PET or radionuclides suitable for SPECT and / or radionuclides suitable for radionuclide therapy. In particular, the radionuclides may be: 177 Lu, 153 Sm, and / or 90 It can be Y.

[0052] Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description, from the experimental data, and from the appended claims. It is noted that the present disclosure relates to all possible combinations of features.

[0053] In general, all terms used in the claims should be interpreted according to their ordinary meaning in the art, unless expressly stated otherwise herein. Any reference to "a / an / the [component, means, step, etc.]" should be interpreted in an open-ended manner as referring to at least one example of said component, means, step, etc., unless expressly stated otherwise. The steps of any method disclosed herein do not have to be performed in the exact order disclosed, unless expressly stated otherwise.

[0054] As used herein, the term "comprising" and variations of this term are not intended to exclude other additives, components, integers, or steps.

[0055] Definition of Terms As used herein, a chemical bond terminated with a wavy line perpendicular to the bond indicates that the bond connects the depicted structure to some portion of the structure of a chemical entity that is not shown in the structure. TIFF2025509109000006.tif13170 indicates that R is attached to a portion of the structure of a chemical entity that is not shown in the structure.

[0056] As used herein, the term "nanostructure" relates to an entity whose overall size is in the nano range, i.e. below 100 nm.

[0057] As used herein, the term "spherical" is intended to describe a shape whose minor axis is equal to or greater than half of its major axis, i.e., the length of the longest axis passing through the center (centre of gravity) of the structure is equal to or less than twice the length of the shortest axis passing through the same point. For a non-limiting illustration of this definition, see Figure 1.

[0058] As used herein, the term "spherical nanostructures" refers to nanostructures as discussed above that have an essentially spherical morphology or shape, which is meant to exclude shapes such as flakes, rods, tubes, toroids, chains, and ribbons.

[0059] As used herein, the term "monomer" refers to a molecule that can be covalently linked to other molecules of the same type (and, optionally, other types of molecules) to form a polymer, which is a macromolecule composed of multiple monomer residues.

[0060] As used herein, the term "monomer residue" refers to the atoms from one monomer unit that has been incorporated into a larger polymer. Depending on how the monomers are bonded, all of the atoms may be retained or some may be lost when the bonds are formed.

[0061] As used herein, the term "polymeric group" refers to a polymeric portion of a chemical structure, i.e., the group comprises multiple monomeric residues. The monomeric residues may be the same or different. The polymeric group may be linear or branched. The ends of the polymeric group may comprise a structure different from the remainder of the polymeric group. In many cases, it will be clear to one skilled in the art how a polymeric group is attached to the remainder of the chemical structure of which it forms a part. For some polymeric groups that have the ability to form bonds in multiple ways to the remainder of the chemical structure of which it forms a part, it may be necessary to indicate how the polymeric group is attached to the remainder of the chemical structure.

[0062] As used herein, the term "hydrophilic polymer" refers to a polymer or polymer group having repeating monomer units with a ratio of (oxygen+nitrogen / total number of non-hydrogen atoms) of 0.25 or greater.

[0063] As used herein, the term "PEG" refers to the polymer polyethylene glycol, which is represented by the following structure: TIFF2025509109000007.tif17170 or any polymer or polymer group that contains a polyethylene glycol residue represented by the structure: TIFF2025509109000008.tif17170

[0064] As used herein, the term "mPEG" refers to a polymer of polyethylene glycol methyl ether, represented by the structure: TIFF2025509109000009.tif17170 or a polymer group of the following structure: TIFF2025509109000010.tif17170

[0065] As used herein, the terms "covalently attached," "covalently linked," and "covalently bound" are synonymous and have the meaning known to those of skill in the art.

[0066] As used herein, the term "independently selected" means that each of the different components mentioned preceding the term is selected from the group that follows the term independently or separately from the selection of the other mentioned components.

[0067] The term "geminal bisphosphonate group" refers to two phosphonate groups separated by one carbon atom, i.e., the phosphonate groups are attached to the same carbon atom. Compounds containing such geminal bisphosphonate groups are often referred to as 1,1-bisphosphonates (or 1,1-diphosphonates). The phosphonate group in the geminal bisphosphonate group may be substituted.

[0068] As used herein, the term "alkyl" refers to a substituted or unsubstituted, fully saturated (no double or triple bonds), straight or branched chain hydrocarbon group. As used herein, an alkyl group can have 1 to 10 carbon atoms. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like.

[0069] As used herein, the term "lower alkyl" means an alkyl having 1 to 8 carbon atoms.

[0070] As used herein, the term "alkoxy" refers to the formula -OR, where R is lower alkyl, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amyloxy, iso-amyloxy, etc. Alkoxy groups in accordance with the present disclosure may be optionally substituted.

[0071] As used herein, the term "aryl" refers to a carbocyclic (i.e., all carbon) ring or two or more fused rings (i.e., rings sharing two adjacent carbon atoms) having a completely delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups according to the present disclosure may be optionally substituted, such as, for example, phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio, and the like. Aryloxy may be optionally substituted.

[0072] As used herein, the term "acyl" refers to the functional group RC(=O)--, where R is an organic residue.

[0073] As used herein, the terms "siloxane bond," "siloxane linkage," and "siloxane network" refer to moieties that contain Si-O-Si.

[0074] As used herein, the term "coating" refers to a layer of material applied to a surface to impart one or more properties to the surface. Often, the coating is covalently attached to the surface. Often, the surface is a nanostructured surface. Often, the properties imparted to the surface include inertness, such as bioinertness. The term "coating" can also refer to the process of applying a coating to a surface, and the term "coat" can be used as a verb meaning "to apply a coating to." It will generally be clear to one of ordinary skill in the art which form of the term "coating" is to be used in a particular case.

[0075] The term "coated nanostructures" (or nanostructures having a coating) is used to describe materials that can be produced from the nanostructures of the present disclosure by the addition of one or more layers of additional materials. Often, such coated nanostructures are intended for use in radioisotope therapy.

[0076] The term "chelating group" refers to a chemical group that can compete well with water for electrostatic binding of a positively charged ion. A single chelating group does not bind very strongly, but when multiple chelating groups surround a positively charged ion, a synergistic binding enhancement occurs. This is called chelation.

[0077] As used herein, the term "organosilane" means an organic compound that contains one or more carbon-silicon bonds.

[0078] As used herein, the term "alkoxysilane" means an organic group bonded to silicon through an oxygen atom having the formula Si-OR, where R is lower alkyl, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amyloxy, iso-amyloxy, and the like.

[0079] As used herein, the term "hydrodynamic diameter" refers to the diameter of a hypothetical hard sphere diffusing at the same rate as the nanostructure in solution, i.e., the diameter of an equivalent hard sphere calculated from the diffusion coefficient according to the Stokes-Einstein equation. This term is also known as the "Stokes diameter" or "Stokes-Einstein diameter". Hydration and shape are included in the behavior of the sphere. The diffusion coefficient is then calculated from time-dependent light scattering data obtained, for example, by dynamic light scattering (DLS). Other technical methods for measuring the diffusion coefficient of nanostructures are known to those skilled in the art and may be used instead. In such cases, the measurements should be referenced against DLS measurements. As a comparison, bovine serum albumin has been measured to have a hydrodynamic diameter of 6.9 nm by DLS in saline (150 mM NaCl) at room temperature at pH 7. Depending on whether number average, volume average, or scattering intensity average is used, the calculated values ​​may vary slightly. The volume average is generally the most useful since it indicates what the nanostructure size is throughout the material. The mean diameters referred to herein refer to the volume average, i.e. the volume average hydrodynamic diameter, measured in saline or 8% ethylene glycol in saline (vol / vol) at 25°C.

[0080] As used herein, the term "DLS" is an acronym for Dynamic Light Scattering, a particle size measurement technique, which may also be referred to as Photon Correlation Spectroscopy or Quasi-Elastic Light Scattering. DLS diameters given herein and in the claims, unless otherwise specified, refer to the average of the volume-weighted peaks of a sample measured at 25°C in an aqueous solution of ionic strength equivalent to 150 mM NaCl, also referred to as saline, or in 8% ethylene glycol (volume / volume) in saline. In other words, the hydrodynamic diameters specified herein refer to the average of the volume-weighted peaks of a sample measured by DLS at 25°C in an aqueous solution of ionic strength equivalent to 150 mM NaCl, also referred to as saline, or in 8% ethylene glycol (volume / volume) in saline.

[0081] Impurities in the products of any process described herein are given as the impurities as measured by HPLC ELSD unless otherwise noted.

[0082] As used herein, the term "HPLC ELSD" is an acronym for High Pressure Liquid Chromatography Evaporative Light Scattering Detector.

[0083] As used herein, SEC-ELSD is an acronym for Size Exclusion Chromatography with Evaporative Light Scattering Detection.

[0084] As used herein, the term "ICP-OES" is an acronym for Inductively Coupled Plasma - Optical Emission Spectrometry. ICP-OES is a technique used to determine the elemental composition in a sample.

[0085] As used herein, the term "molecular weight" refers to the molecular weight of a compound having a specific molecular structure, or the weight-average molecular weight, also called mass-average molar mass or weight-average molar mass, of a compound that contains a polymeric portion, and the number of monomers of the polymeric portion varies between different individual molecules.Thus, the molecular weight of a compound having a specific molecular structure is the molecular weight calculated based on the number and nature of atoms of the compound, or the molecular weight measured, for example, by mass spectrometry.The molecular weight of a compound that contains a polymeric portion refers to the weight-average molecular weight, also called mass-average molar mass or weight-average molar mass, which can be determined, for example, by gel filtration chromatography or size exclusion chromatography (SEC). More specifically, the weight average molecular weight may be determined according to ISO 16014-1:2019 and ISO 16014-5:2019 ("Determination of average molecular weight and molecular weight distribution of polymers using size-exclusion chromatography"), or according to ISO 16014-1:2019 in combination with any of ISO 16014-2:2019 through ISO 16014-4:2019. Alternatively, the weight average molecular weight may be determined by SEC and confirmed using liquid chromatography-mass spectrometry (LC-MS) or high performance liquid chromatography (HPLC).

[0086] As used herein, the term "bioinert" refers to a material that is biocompatible, i.e., non-harmful to mammals and mammalian cells, and at the same time, stable to degradation in the human body for a period of one week or more (less than 10% degradation).

[0087] The term "radionuclide" means an unstable form of a chemical element that undergoes radioactive decay resulting in the emission of alpha, beta, and / or gamma rays.

[0088] As used herein, the expression "radionuclide for imaging and / or radiotherapy" refers to actinium-225 ( 225 Ac), copper-62( 62 Cu), Copper-64( 64 Cu), Copper-67( 67 Cu), Gallium-67( 67 Ga), Gallium-68( 68 Ga), Holmium-166( 166 Ho), Indium-111 ( 111 In), Pb-212( 212 Pb), Lutetium-177( 177 Lu), Radium-223 ( 223 Ra), Rhenium-186( 186 Re), rhenium-188( 188 Re), Rubidium-82 ( 82 Rb), Samarium-153( 153 Sm), Strontium-89 ( 89 Sr), Technetium-99m ( 99m Tc 3+ ), Thallium-201( 201 Tl), thorium-227( 227 Th), Yttrium-86( 86 Y), Yttrium-90 ( 90 Y), and zirconium-89 ( 89 The expression "radionuclide for imaging and / or radiotherapy" also encompasses combinations of two or more of the abovementioned radionuclides.

[0089] As used herein, the expression "radionuclide for imaging" refers to copper-62 ( 62 Cu), Copper-67( 67 Cu), Gallium-67( 67 Ga), Gallium-68( 68 Ga), Indium-111 ( 111 In), Lutetium-177( 177 Lu), Rhenium-186( 186 Re), Rubidium-82 ( 82 Rb), Technetium-99m ( 99m Tc 3+), Thallium-201( 201 Tl), Yttrium-86( 86 Y), and zirconium-89 ( 89 The expression "radionuclide for imaging" also encompasses combinations of two or more of the abovementioned radionuclides.

[0090] As used herein, the expression "radionuclide for PET imaging" refers to copper-62 ( 62 Cu), Gallium-68( 68 Ga), Rubidium-82( 82 Rb), Yttrium-86( 86 Y), and zirconium-89 ( 89 The expression "radionuclide for PET imaging" also encompasses combinations of two or more of the abovementioned radionuclides.

[0091] As used herein, the expression "radionuclide for SPECT imaging" refers to gallium-67 ( 67 Ga), Indium-111 ( 111 In), Technetium-99m ( 99m Tc 3+ ), Lutetium-177( 177 Lu), and Thallium-201 ( 201 Tl). The expression "radionuclide for SPECT imaging" also encompasses combinations of two or more of the abovementioned radionuclides.

[0092] As used herein, the expression "radionuclide for radiotherapy" refers to actinium-225 ( 225 Ac), copper-64( 64 Cu), Copper-67( 67 Cu), Holmium-166( 166 Ho), lead-212( 212 Pb), Lutetium-177( 177 Lu), Radium-223 ( 223 Ra), Rhenium-186( 186 Re), rhenium-188( 188 Re), Samarium-153(153 Sm), Strontium-89 ( 89 Sr), Thorium-227( 227 Th), and Yttrium-90 ( 90 The expression "radionuclide for radiotherapy" also encompasses combinations of two or more of the abovementioned radionuclides.

[0093] As used herein, the expression "radionuclide for PET imaging and radiotherapy" refers to actinium-225 ( 225 Ac), copper-62( 62 Cu), Copper-64( 64 Cu), Copper-67( 67 Cu), Gallium-68( 68 Ga), Holmium-166( 166 Ho), lead-212( 212 Pb), Lutetium-177( 177 Lu), Radium-223 ( 223 Ra), Rhenium-186( 186 Re), rhenium-188( 188 Re), Rubidium-82 ( 82 Rb), Samarium-153( 153 Sm), Strontium-89 ( 89 Sr), Thorium-227( 227 Th), Yttrium-90( 90 Y), and zirconium-89 ( 89 The expression "radionuclide for PET imaging and radiotherapy" also encompasses combinations of two or more of the abovementioned radionuclides.

[0094] As used herein, the expression "radionuclide for SPECT imaging and radiotherapy" refers to actinium-225 ( 225 Ac), copper-64( 64 Cu), Copper-67( 67 Cu), Gallium-67( 67 Ga), Holmium-166( 166 Ho), Indium-111 ( 111 In), Pb-212( 212Pb), Lutetium-177( 177 Lu), Radium-223 ( 223 Ra), Rhenium-186( 186 Re), rhenium-188( 188 Re), Samarium-153( 153 Sm), Strontium-89 ( 89 Sr), Technetium-99m ( 99m Tc 3+ ), Thallium-201( 201 Tl), thorium-227( 227 Th), and Yttrium-90 ( 90 The expression "radionuclide for SPECT imaging and radiotherapy" also encompasses a combination of two or more of the abovementioned radionuclides.

[0095] Numeric ranges: whenever used herein, unless otherwise specified, a numerical range such as "1 to 8" or "1-8" refers to each integer within the given range, for example, "1 to 8 carbon atoms" and "1-8 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 8 carbon atoms. However, there are some exceptions that will be apparent to those skilled in the art. In particular, whenever a range is given herein for a molar ratio, such as the Si / P molar ratio, diameter or size, pH, duration, concentration, osmolality, or temperature of a nanostructure, the range includes all decimals within the range, including the upper and lower limits.

[0096] As used herein, the term "resin" is defined as an insoluble organic material.

[0097] As used herein, the term (w / w) stands for weight / weight.

[0098] As used herein, the term (w / v) stands for weight / volume.

[0099] As used herein, the term (v / v) stands for volume / volume.

[0100] As used herein, 90.0% (vol / vol) aqueous ethylene glycol means a mixture of 90.0% (vol / vol) ethylene glycol and 10.0% (vol / vol) water.

[0101] By way of example, embodiments of the present teachings will now be described with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0102] [Figure 1] FIG. 1 is a diagram of a spherical object, showing its minor and major axes. [Diagram 2] FIG. 2 is a diagram of the structure of a coated nanostructure including a center portion, an intermediate layer, and a coating layer. [Diagram 3] FIG. 3 shows a process scheme of the extraction and purification process. [Figure 4] FIG. 4 shows a process scheme for pre-extraction. [Diagram 5] FIG. 5 shows a process scheme for intermediate extraction. [Figure 6] FIG. 6 shows a process scheme for product extraction. [Figure 7] FIG. 7 shows a process scheme for product finishing. [Figure 8] FIG. 8 is a diagram of the extractive purification, showing the transfer of the di-PEGylated diene through the extraction. [Figure 9] FIG. 9 shows an example composition of the quenched reaction mixture from the synthesis of di-PEGylated diene 9b. [Figure 10] FIG. 10 shows HPLC-ELSD chromatograms of the reaction mixture from the synthesis of diPEGylated diene 9 before (A) and after (B) extraction and purification. [Figure 11] FIG. 11 is a diagram of the coating precursor reacted with the surface of the nanostructure. [Figure 12] FIG. 12 is a graph of tumor growth for the treatment (diamonds) and control (squares) groups from Example 17. [Figure 13] FIG. 13 shows a compound according to formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0103] The present disclosure relates to chemical compounds (hereinafter referred to as "coating precursors") capable of forming dense coating layers on nanostructures. In particular, they are suitable for forming dense coatings on nanostructures that have available silanol groups on their surfaces.

[0104] The compounds according to the present disclosure offer a significant improvement over the prior art in that they can be synthesized in high purity and on a large scale, as shown in Example 3.

[0105] These compounds further provide significant improvements over the prior art in forming coatings on nanostructures. As shown in Example 16, nanostructures coated with coating precursors according to the present disclosure have higher storage stability and more favorable in vivo properties compared to nanostructures coated with coating precursors outside the scope of the present disclosure.

[0106] Additionally, nanostructures coated with coating precursors according to the present disclosure have been shown to be effective in treating tumors (see Example 17).

[0107] The coating precursor and the resulting coating comprise a polymeric group. As known to those skilled in the art, polymers synthesized by most methods are not identical chemical entities, but rather comprise multiple polymer molecules with different degrees of polymerization, crosslinking, and branching. The degree of polymerization can be measured by mass spectrometry, gel filtration, or dynamic light scattering. The degree of polymerization can be expressed as the number of monomer residues in the polymer, or alternatively, as the chain length or by the molecular weight of the polymer. The polymeric groups of the present disclosure are present as a mixture of polymeric groups with different degrees of polymerization, unless otherwise specified.

[0108] The coating precursors according to the present disclosure contain reactive silane functional groups that allow them to form bonds to surfaces that contain functional groups capable of forming bonds of the structure GO-Si, where G represents an atom at the surface, such as a silicon atom, and Si represents a silicon atom from the coating precursor molecule.

[0109] When the degree of polymerization is given as a range, it is understood by those skilled in the art to mean that the majority of the polymer molecules have a degree of polymerization that falls within the given range, such as the majority of the polymer molecules, such as more than 80%, such as more than 90%, or such as more than 95%. It is also understood that a small percentage of the polymer groups present may have a degree of polymerization that is outside the given range, and that this may include both degrees of polymerization higher and lower than the given range. When the degree of polymerization is given as a single value, it is understood that the value means the average or typical degree of polymerization, unless otherwise specified.

[0110] Coating Precursors (Compounds According to the Present Disclosure) The present disclosure relates to compounds according to formula (I): TIFF2025509109000011.tif64170In formula, Poly 1 and Poly 2 is independently selected from the group consisting of hydrogen and a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da; 1 or Poly 2 At least one of the groups is a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da; Y 1 and Y 2 are independently -A(CH2) n B-, wherein A is bonded to X, Y 1 The B stands for Poly 1 is bound to Y 2 The B stands for Poly 2 is bound to n is an integer from 0 to 5, A is selected from the group consisting of -O-, -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, -NH(C=O)-, and a covalent bond; and B is selected from the group consisting of -O-, -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, -NH(C=O)-, and a covalent bond, with the proviso that Poly 1 or Poly 2 Y in 1 Or Y 2 If the atom bonded to is not a carbon atom, then B is a covalent bond, Y 3 and Y 4 are independently -E(CH2) m - in which E is bonded to X, m is an integer from 2 to 5; and E is independently selected from the group consisting of: -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, -NH(C=O)-, and a covalent bond; X is structure X 1 , X 2 , X 3 , X 4 , and X 5 is selected from the group consisting of TIFF2025509109000012.tif43170In formula, The thick bond is Y 1 Or Y 2 represents a bond to Bonds that are not bold are Y 3 Or Y 4 represents a bond to p is an integer from 1 to 5; and Z 1 and Z 2 is independently -SiR 1 R 2 R 3 where: R 1 , R 2 , and R 3is independently selected from the group consisting of chloride, bromide, iodide, lower alkoxy, aryloxy, carboxy, amino, and -NH-acyl.

[0111] In considering the above structures, when two or more covalent bonds are joined in tandem, they should be construed together as one bond.

[0112] Poly 1 and Poly 2 Poly 1 and / or Poly 2 may contain capping groups suitable for further derivatization, such groups include carboxylic acids, amines, activated esters, azides, thiols, N-succinimides, epoxides, double bonds, and alkynes.

[0113] Poly 1 and Poly 2 may each be a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da.

[0114] Poly 1 and / or Poly 2 may comprise a polyether.

[0115] Preferably, Poly 1 and / or Poly 2 Poly includes polyethylene glycol. 1 and Poly 2 may contain, on average, 10 to 200, such as 12 to 170, such as 15 to 120, such as 20 to 90, such as 30 to 75, such as 35 to 60, such as 40 to 50, such as 12 to 170, such as 75 to 170, such as 60 to 120, such as 50 to 90, such as 30 to 60, such as 20 to 50, or such as 12 to 30, ethylene glycol units.

[0116] The polyethylene glycol chain may be end-capped with a hydroxyl group or a lower alkyl group such as methyl or ethyl.

[0117] Alternatively, the polyethylene glycol chain may be end-capped with a carboxylic acid ester group, such as a -CH2-C(O)-O-tBu group, or an amide group.

[0118] In a preferred embodiment, each polyethylene glycol chain comprises 20 to 150 ethylene glycol residues, and each polyethylene glycol chain is end-capped with a methyl group.

[0119] In certain embodiments, Poly 1 and Poly 2 comprises polyethylene glycol, each polyethylene glycol chain is end-capped with a methyl group and the number of ethylene glycol residues in each polymer group is from 10 to 200, such as from 12 to 170, such as from 15 to 120, such as from 20 to 90, such as from 30 to 75, such as from 35 to 60, such as from 40 to 50, such as from 12 to 170, such as from 75 to 170, such as from 60 to 120, such as from 50 to 90, such as from 30 to 60, such as from 20 to 50, or such as from 12 to 30, ethylene glycol units.

[0120] Specifically, Poly 1 and Poly 2 may comprise polyethylene glycol, each polyethylene glycol chain being end-capped with a methyl group, and the average number of ethylene glycol residues in each polymer group being 42-48.

[0121] Poly 1 and / or Poly 2 It may also include polyethylene glycol in combination with one or more other polymers as a block copolymer. 1 and / or Poly 2 may include polymeric groups derived from the copolymerization of ethylene oxide with other monomers.

[0122] In some embodiments, Poly 1 and / or Poly 2includes polyoxazolines such as polymethyloxazoline or polyethyloxazoline.

[0123] In some embodiments, Poly 1 and Poly 2 comprises polymethyloxazoline, each polymer group being end-capped with a lower alkyl group, and each polymer group comprising 12 to 120 monomer residues.

[0124] In some embodiments, Poly 1 and Poly 2 comprises polyethyloxazoline, each polymer group being end-capped with a lower alkyl group, and each polymer group comprising 10 to 100 monomer residues.

[0125] In some embodiments, Poly 1 and / or Poly 2 contains polyglycerol.

[0126] In some embodiments, Poly 1 and Poly 2 comprises polyglycerol, which is linear or essentially linear.

[0127] In some embodiments, Poly 1 and Poly 2 comprises polyglycerol, the polyglycerol being branched, such as highly branched.

[0128] In some embodiments, Poly 1 and / or Poly 2 contains polyvinylpyrrolidone.

[0129] In some embodiments, Poly 1 and / or Poly 2 includes polyamides.

[0130] In some embodiments, Poly 1 and Poly 2contains polyglycine.

[0131] In some embodiments, Poly 1 and Poly 2 comprises a polymeric group of the structure -[NH-CH(O-{mPEG})-C(O)]-, where mPEG is methyl-terminated polyethylene glycol.

[0132] In some embodiments, Poly 1 and Poly 2 includes peptoids.

[0133] Y 1 and Y 2 Y 1 and Y 2 may be the same or different.

[0134] In one embodiment, n is an integer from 1 to 3. Preferably, n is 1 or 2, and even more preferably, n is 1.

[0135] In specific embodiments, Y 1 and Y 2 In both cases, n is 1.

[0136] In specific embodiments, A is Y 1 and Y 2 are covalent bonds, B is a covalent bond or -O-, and n is 2.

[0137] Preferably, A is Y 1 and Y 2 are covalent bonds, B is -O-, and n is 1.

[0138] In another embodiment, Y 1 In the formula (I), A is a covalent bond, B is a covalent bond or -O-, n is 1, and Y 2 In the formula, A is a covalent bond, B is a covalent bond or -O-, and n is 2.

[0139] In yet another embodiment, Y 1 In the formula (I), A is a covalent bond, B is a covalent bond or -O-, n is 1 to 3, and Y 2 In the formula (I), A and B are covalent bonds, n is 0, and Poly 2 is H.

[0140] In yet a further embodiment, Y 1 and Y 2 In one or both of the above, A is a covalent bond and B is -O-, -S-, -N-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, or -NH(C=O)-.

[0141] In yet another embodiment, Y 1 Or Y 2 In one of the groups, A is a covalent bond and Y 1 Or Y 2 In the other of the above, A is -O-, -S-, -N-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, or -NH(C=O)-.

[0142] In yet another embodiment, Y 1 and Y 2 In both of the above, A is -O-, -S-, -N-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, or -NH(C=O)-, and X is X 3 Or X 5 It is.

[0143] Also, Y 1 and / or Y 2 However, it is also possible that the structure may be other than that shown above. For example, Y 1 and / or Y 2 The alkyl portion of Y may be further substituted. 1 and / or Y 2 The alkyl portion of the formula (I) may be a branched alkyl, or may be substituted with a group such as F or methoxy.

[0144] Y 3and Y 4 Y 3 and Y 4 may be the same or different. Specifically, m is Y 3 and Y 4 may be the same or different.

[0145] In one embodiment, E is a covalent bond and m is Y 3 and Y 4 In both cases, the range is 2 to 5.

[0146] In specific embodiments, E is a covalent bond and m is Y 3 and Y 4 In both cases, the answer is 3.

[0147] In another specific embodiment, E is a covalent bond and m is Y 3 and Y 4 In both cases, the value is 4.

[0148] In yet another specific embodiment, E is a covalent bond and m is Y 3 and Y 4 In both cases, the value is 5.

[0149] Thus, preferably, E is Y 3 and Y 4 m is a covalent bond in both Y 3 and Y 4 For example, in specific embodiments, E may be the same or different in Y 3 and Y 4 m is a covalent bond in both Y 3 m is 2 to 5, and Y 4 In the range of 2 to 5, Y 3 is not identical to the value of m in

[0150] In some embodiments, Y 3 and Y 4In one of the above, E is -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, or -NH(C=O)-; 3 and Y 4 In the other of these, E is a covalent bond.

[0151] In another embodiment, Y 3 and Y 4 In both of the above, E is -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, or -NH(C=O)-, and X is X 3 Or X 5 It is.

[0152] Also, Y 3 and / or Y 4 The alkyl portion of Y may be further substituted. 3 and / or Y 4 The alkyl portion of is a branched alkyl or is substituted with a group such as F or methoxy.

[0153] Also, Y 3 and / or Y 4 It is also possible that the alkyl portion of the formula contains heteroatoms such as O or S.

[0154] Z 1 and Z 2 In one embodiment, R 1 , R 2 , and R 3 is Z 1 and Z 2 In both cases, it is a halogen. The halogen can be Cl and / or Br.

[0155] Thus, in specific embodiments, R 1 , R 2 , and R 3 is Z 1 and Z 2 In both cases, it is Cl.

[0156] In another specific embodiment, R1 , R 2 , and R 3 is Z 1 and Z 2 In both cases, Br.

[0157] In one embodiment, R 1 , R 2 , and R 3 is Z 1 and Z 2 In both cases, the lower alkoxy group is preferably methoxy, ethoxy, and / or iso-propyloxy.

[0158] Thus, in specific embodiments, R 1 , R 2 , and R 3 is Z 1 and Z 2 In both cases, it is methoxy.

[0159] In another specific embodiment, R 1 , R 2 , and R 3 is Z 1 and Z 2 In both cases, it is ethoxy.

[0160] In further specific embodiments, R 1 , R 2 , and R 3 is Z 1 and Z 2 In both cases, it is isopropyloxy.

[0161] Alternatively, Z 1 and Z 2 The R groups above are a mixture of Cl and lower alkoxy.

[0162] Specific Coating Precursors Some non-limiting examples of specific coating precursors are given below.

[0163] Y 1 and Y 2, and Poly 1 and Poly 2 Specific combinations of In some embodiments, Y 1 and Y 2 In both of the above, A is a covalent bond, B is a covalent bond or -O-, n is 1 or 2, and Poly 1 and Poly 2 comprises a polyether. The polyether is as described above. Preferably, the polyether is polyethylene glycol.

[0164] In some embodiments, Y 1 and Y 2 In both of the above, A is a covalent bond, B is -O-, n is 1 or 2, and Poly 1 and Poly 2 comprises polyethylene glycol, each polyethylene glycol chain containing 20-150 ethylene glycol residues, and each PEG chain is end-capped with a methyl group.

[0165] In a preferred embodiment, Y 1 and Y 2 In both of the above, A is a covalent bond, B is -O-, and n is 1; and 1 and Poly 2 comprises polyethylene glycol, each polyethylene glycol chain is end-capped with a methyl group, and the number of ethylene glycol residues in each polymer group is 12-170, such as 20-120, such as 30-90, such as 40-75, such as 50-60.

[0166] In a preferred embodiment, Y 1 and Y 2 In both of the above, A is a covalent bond, B is -O-, and n is 1; and 1 and Poly 2comprises polyethylene glycol, each polyethylene glycol chain is end-capped with a methyl group, and the number of ethylene glycol residues in each polymer group is 12-30, or 20-50, or 30-60, or 50-90, or 60-120, or 75-170.

[0167] In one embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1 to 3, and Y 2 In the formula (I), A and B are covalent bonds, n is 0, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group. 2 is H.

[0168] Also, Y 1 and Y 2 Either or both of the above and Poly 1 or Poly 2 It is also possible that the bond between may have structures other than those shown above. Such alternative structures may include a triazole bond.

[0169] Y 1 and Y 2 and Y 3 and Y 4 Specific combinations of In one embodiment, Y 1 and Y 2 In both of the above, A is a covalent bond, B is -O-, n is 1 or 2, and Y 3 and Y 4 In both of the above, E is a covalent bond and m is 2 to 4.

[0170] In a preferred embodiment, Y 1 and Y 2 In both of the above, A is a covalent bond, B is -O-, n is 1, and Y 3 and Y 4 In both of the above, E is a covalent bond and m is 3.

[0171] Y 1 and Y 2 , X, Poly 1 and Poly 2 Specific combinations of In one embodiment, Y 1 and Y 2 In both of the above, A is a covalent bond, B is -O-, n is 1 or 2, and X is X 1 Or X 2 And Poly 1 and Poly 2 comprises polyethylene glycol, each polyethylene glycol chain is end-capped with a methyl group, and the number of ethylene glycol residues in each polymer group is 12-170, such as 20-120, such as 30-90, such as 40-75, such as 50-60.

[0172] In one embodiment, Y 1 and Y 2 In both of the above, A is a covalent bond, B is -O-, n is 1 or 2, and X is X 1 Or X 2 And Poly 1 and Poly 2 comprises polyethylene glycol, each polyethylene glycol chain is end-capped with a methyl group, and the number of ethylene glycol residues in each polymer group is 12-30, or 20-50, or 30-60, or 50-90, or 60-120, or 75-170.

[0173] In another embodiment, Y 1 and Y 2 In the formula (I), A is -O-, -S-, -C(=O)O-, or -O(C=O)-, n is 0 or 2 to 5, and X is X 3 Or X 5 And Poly 1 and Poly 2 comprises polyethylene glycol, with each PEG chain end-capped with a methyl group.

[0174] In a further embodiment, Y 1 and Y2 In the formula (I), A is -C(=O)O- or -O(C=O)-, n is 0, and X is X 1 , X 2 , or X 4 And Poly 1 and Poly 2 comprises polyethylene glycol, with each PEG chain end-capped with a methyl group.

[0175] Y 3 and Y 4 and specific combinations of X In one embodiment, Y 3 and Y 4 In the formula, E is -S-, -N-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, or -NH(C=O)-, and X is X 3 Or X 5 It is.

[0176] In another embodiment, Y 3 and Y 4 In both of these, E is a covalent bond, m is 3, and X is X 1 , X 2 , or X 4 It is.

[0177] Y 1 and Y 2 , X, and Y 3 and Y 4 Specific combinations of In one embodiment, Y 1 In the formula (I), A is a covalent bond, B is a covalent bond or -O-, n is 1, and Y 2 In the formula, A and B are covalent bonds, n is 0, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula, E is a covalent bond and m is 3.

[0178] In another embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 4 where p is 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula, E is a covalent bond and m is 3.

[0179] In a further embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 5, and Y 4 In the formula, E is a covalent bond and m is 5.

[0180] In yet another embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 5, and Y 4 In the formula, E is a covalent bond and m is 4.

[0181] In a further embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 2, and Y 4 In the formula, E is a covalent bond and m is 2.

[0182] In yet another embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 0, and Y 2In the formula (I), A is a covalent bond, B is -O-, n is 0, and X is X 3 and Y 3 In the formula (I), E is a covalent bond, m is 2, and Y 4 In the formula, E is a covalent bond and m is 2.

[0183] In one embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 4 where p is 1 and Y 3 In the formula (I), E is a covalent bond, m is 4, and Y 4 In the formula, E is a covalent bond and m is 4.

[0184] In a further embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 4 where p is 1 and Y 3 In the formula (I), E is a covalent bond, m is 2, and Y 4 In the formula, E is a covalent bond and m is 2.

[0185] In a preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula, E is a covalent bond and m is 3.

[0186] Y 1 and Y 2 , X, Y 3 and Y 4 , and Poly1 and Poly 2 Specific combinations of In one embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula, A and B are covalent bonds, n is 0, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 is H.

[0187] In another embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1 to 3, and Y 2 In the formula, A is a covalent bond, B is -O-, n is 1 to 3, and X is X 4 p is 1 to 3; Y 3 In the formula (I), E is a covalent bond, m is 3 or 4, and Y 4 In the formula (I), E is a covalent bond, m is 3 or 4, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 comprises polyethylene glycol containing 20 to 150 ethylene glycol residues and end-capped with methyl groups.

[0188] In a further embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula, E is a covalent bond, m is 2 to 5, and Y 4In the formula, E is a covalent bond, m is 2 to 5, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 comprises polyethylene glycol containing 20 to 150 ethylene glycol residues and end-capped with methyl groups.

[0189] In yet another embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 0, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 0, and X is X 3 and Y 3 In the formula, E is a covalent bond, m is 2 to 4, and Y 4 In the formula (I), E is a covalent bond, m is 2 to 4, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 comprises polyethylene glycol containing 20 to 150 ethylene glycol residues and end-capped with methyl groups.

[0190] In a further embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 4 p is 1 to 3; Y 3 In the formula, E is a covalent bond, m is 2 to 4, and Y 4 In the formula (I), E is a covalent bond, m is 2 to 4, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 comprises polyethylene glycol containing 20 to 150 ethylene glycol residues and end-capped with methyl groups.

[0191] In a preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 comprises polyethylene glycol containing 20 to 150 ethylene glycol residues and end-capped with methyl groups.

[0192] In another preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 comprises polyethylene glycol, each PEG chain is end-capped with a methyl group, and the number of ethylene glycol residues in each polymer group is 12-170, such as 20-120, such as 30-90, such as 40-75, such as 50-60.

[0193] In another preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 comprises polyethylene glycol, each PEG chain is end-capped with a methyl group, and the number of ethylene glycol residues in each polymer group is 12-30, or 20-50, or 30-60, or 50-90, or 60-120, or 75-170.

[0194] In a further preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 comprises polyethylene glycol, each PEG chain is end-capped with a methyl group, and the average number of ethylene glycol residues in each polymer group is 42-48.

[0195] Y 1 and Y 2 , X, Y 3 and Y 4 , Poly 1 and Poly 2 , Z 1 and Z 2 Specific combinations of In one embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula, A and B are covalent bonds, n is 0, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group;2 is H, and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0196] In another embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1 to 3, and Y 2 In the formula, A is a covalent bond, B is -O-, n is 1 to 3, and X is X 4 p is 1 to 3; Y 3 In the formula (I), E is a covalent bond, m is 3 or 4, and Y 4 In the formula (I), E is a covalent bond, m is 3 or 4, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0197] In a further embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y3 In the formula, E is a covalent bond, m is 2 to 5, and Y 4 In the formula, E is a covalent bond, m is 2 to 5, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0198] In yet another embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 0, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 0, and X is X 3 and Y 3 In the formula, E is a covalent bond, m is 2 to 4, and Y 4 In the formula (I), E is a covalent bond, m is 2 to 4, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3is chloride or lower alkoxy such as methoxy or ethoxy.

[0199] In a further embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 4 p is 1 to 3; Y 3 In the formula, E is a covalent bond, m is 2 to 4, and Y 4 In the formula (I), E is a covalent bond, m is 2 to 4, and Poly 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2 contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0200] In a preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 Polyethylene glycol contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; 2contains 20 to 150 ethylene glycol residues and is end-capped with a methyl group; and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0201] In another preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 comprises polyethylene glycol, each polyethylene glycol chain is end-capped with a methyl group, and the number of ethylene glycol residues in each polymer group is 12-170, such as 20-120, such as 30-90, such as 40-75, such as 50-60; and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0202] In another preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 comprises polyethylene glycol, each polyethylene glycol chain being end-capped with a methyl group, and the number of ethylene glycol residues in each polymer group is 12 to 30, or 20 to 50, or 30 to 60, or 50 to 90, or 60 to 120, or 75 to 170; and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0203] In a further preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 comprises polyethylene glycol, each PEG chain is end-capped with a methyl group, the average number of ethylene glycol residues in each polymer group is approximately 45, such as 42-48, and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0204] In one embodiment, Y 1 In the formula, A and B are covalent bonds, n is 1, and Y 2 In the formula, A and B are covalent bonds, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 comprises a polyoxazoline, such as polymethyloxazoline or polyethyloxazoline, in which each polymer chain is end-capped with a lower alkyl group, such as a methyl group or an ethyl group, and Z 1 In R 1 , R 2 , and R 3 is chloride or lower alkoxy, such as methoxy or ethoxy; Z 2 In R 1 , R 2 , and R 3 is chloride or lower alkoxy such as methoxy or ethoxy.

[0205] In one preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 is polyethylene glycol, each polyethylene glycol chain is end-capped with a methyl group, the average number of ethylene glycol residues in each polymer group is approximately 45, such as 42 to 48, and Z1 and Z 2 In R 1 , R 2 , and R 3 is ethoxy.

[0206] In another preferred embodiment, Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and X is X 1 and Y 3 In the formula (I), E is a covalent bond, m is 3, and Y 4 In the formula (I), E is a covalent bond, m is 3, and 1 and Poly 2 is polyethylene glycol, each polyethylene glycol chain is end-capped with a methyl group, the average number of ethylene glycol residues in each polymer group is 65 to 72, and Z 1 and Z 2 In R 1 , R 2 , and R 3 is ethoxy.

[0207] Method for producing the precursor The present disclosure also relates to a method for making the coating precursor.

[0208] The method is useful across a range of scales, from small laboratory scale to kilogram production scale and beyond, providing clear advantages over alternative methods that are only suitable at certain scales.

[0209] When the coating precursors of the present disclosure are used to coat nanostructures (described in more detail below), coated nanostructures having, for example, longer plasma half-lives and better storage stability are produced when the coating precursor has a higher purity, such as at least 90%, than when the coating precursor has a lower purity.

[0210] Advantageously, the method produces coating precursors of such purity that when the coating precursors are used to coat nanostructures, the resulting coated nanostructures are of high quality having desirable in vivo properties and desirable storage stability.

[0211] Due to the nature of the coating precursors, it is difficult to purify the finished coating precursors, and many methods commonly employed for the purification of chemical compounds are not suitable for the coating precursors of the present disclosure.

[0212] The compounds contain polymeric groups, which generally exist as multiple chain lengths, making purification by crystallization difficult, and furthermore, because the compounds contain polymeric groups, the compounds are non-volatile or essentially non-volatile, making purification by distillation and / or sublimation impossible or essentially impossible.

[0213] The compounds also contain reactive silyl groups, which make the most commonly used chromatographic purification techniques unsuitable. The reactive silyl groups bind to surfaces containing silanol functional groups and form strong bonds. Chromatography using silica and similar materials as stationary phase, commonly referred to as normal phase chromatography, is therefore difficult because a significant portion of the material to be purified is irreversibly bound to the stationary phase and cannot be eluted.

[0214] Reactive silyl groups are also prone to hydrolysis and self-condensation reactions in the presence of water. Chromatography using hydrophobic materials as stationary phases and aqueous mobile phases, commonly referred to as reversed-phase chromatography, is therefore difficult because a significant portion of the material to be purified hydrolyzes and / or oligomerizes during the course of the chromatographic procedure.

[0215] The disclosed methods have the advantage of producing coating precursors of sufficient purity for use in the fabrication of high quality coated nanostructures without the need for purification of the coating precursor other than removal of catalyst residues and evaporation of volatile solvents and reagents.

[0216] This method allows the introduction of silyl groups into the coating precursor molecules, with the structure H-SiR 1 R 2 R 3 This is efficiently achieved by hydrosilylation of the alkene moiety with a reagent of the formula: 1 , R 2 , and R 3 is as defined for formula (I) above, i.e., R 1 , R 2 , and R 3 is independently selected from the group consisting of chloride, bromide, iodide, lower alkoxy, aryloxy, carboxy, amino, and -NH-acyl. It will be apparent to one skilled in the art that to obtain a product of the structure of formula (I), the hydrosilylation reaction must be carried out on a substrate containing two alkene moieties, i.e., a diene.

[0217] Furthermore, it has been found that the introduction of the polymeric group is most efficiently accomplished prior to the introduction of the silyl group. Thus, the introduction of the silyl group by hydrosilylation is accomplished by hydrosilylation of the diene which is the polymeric dialkene conjugate.

[0218] Hydrosilylation is generally achieved by using a catalyst. The catalyst may be a platinum catalyst, such as a platinum(0) compound, such as Karstedt's catalyst. It is known in the art that when such a catalyst is used in hydrosilylation, some side reactions are possible. Such side reactions include reduction of the alkene double bond and migration of the alkene double bond. It is known that the hydrosilylation reaction of an internal double bond is much slower than the hydrosilylation of a terminal double bond.

[0219] Specifically, the synthesis of a coating precursor according to formula (I), 1 and Poly 2 is polyethylene glycol, each polyethylene glycol chain being end-capped with a lower alkyl group; and Y 1 In the formula (I), A is a covalent bond, B is -O-, n is 1 to 3, and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1 to 3, and Y 3 In the formula, E is a covalent bond, m is 2 to 5, and Y 4 In the formula (I), E is a covalent bond, m is 2 to 5, and Z 1 In R 1 , R 2 , and R 3 is lower alkoxy; Z 1 In R 1 , R 2 , and R 3 is a lower alkoxy, in the synthesis of a coating precursor according to formula (I), it is suitable to use the hydrosilylation of a diene according to formula (II), TIFF2025509109000013.tif64170, R 7 and R 8 is independently selected to be a lower alkyl; p is an integer from 20 to 150; q is an integer from 20 to 150, preferably from 30 to 60 or 40 to 50; r is an integer from 1 to 3; s is an integer from 1 to 3; t is an integer from 0 to 3; u is an integer from 0 to 3; X is X 1 , X 2 , X 3 , X 4 , and X 5 is selected from the group consisting of TIFF2025509109000014.tif39170In the formula, the thick bond is [CH2] r and [CH2] s The non-bold bonds represent bonds to [CH2]. t and [CH2] u and p is an integer of 1 to 5.

[0220] Accordingly, the present disclosure also relates to such dienes, which are described in more detail below.

[0221] Preferably, p is an integer of 30-60, and even more preferably an integer of 40-50.

[0222] Preferably, q is an integer of 30-60, and even more preferably an integer of 40-50.

[0223] In considering the above structures, when two or more covalent bonds are joined in tandem, they should be construed together as one bond.

[0224] It is worth noting that the diene according to formula (II) is 1 , R 2 , and R 3 is lower alkoxy; 1 R 2 R 3 When hydrosilylated under standard hydrosilylation conditions, significant amounts of impurities are produced by the hydrosilylation reagent of Example 16, which shows the results of a poor synthesis using standard hydrosilylation conditions.

[0225] Examples of such impurities include hydrogenation products of one or both of the double bonds in the structure according to formula (II) and products of double bond migration reactions. An attempted synthesis of compound 10 using standard hydrosilylation conditions is shown in Example 19, and a chromatogram showing the product composition of Example 19 is shown in Figure 10.

[0226] It has been found that when coating precursors containing large amounts of diene-based by-products containing only one silyl group are used to coat nanostructures, the resulting coated nanostructures have poorer properties, including shorter circulation times in vivo and reduced stability, i.e., loss of coating. Furthermore, chromatographic separation of the coating precursor from the by-product containing only one silyl group can only be performed under chromatographic conditions that are not suitable for large-scale production of the coating precursor due to the relatively high costs involved.

[0227] However, it is surprising that dienes according to formula (II) can be prepared by reacting R 1 , R 2 , and R 3 is lower alkoxy; 1 R 2 R 3 When the hydrosilation reagent is present in excess of greater than 30 equivalents relative to the diene, the formation of impurities containing less than two silyl groups is significantly reduced.

[0228] Thus, the present disclosure also relates to methods of making compounds according to the present disclosure, wherein the compounds are 1 and Poly 2 both of which comprise a PEG chain, each PEG chain being end-capped with a lower alkyl; the hydrophilic polymer group comprises a PEG chain, optionally end-capped with a lower alkyl; and optionally each hydrophilic polymer group comprises 20 to 150 ethylene glycol residues; or 1 and Poly 2 is ω-methyl-(ethyleneoxy) w where w is 20 to 150, preferably 30 to 60; Y 1 and Y 2 In the formula (I), A is a covalent bond, B is -O-, n is 1, and Y 3 and Y 4 are both -CH2-CH2-CH2- and X is X 1 and Z 1 and Z2 is independently selected from the group consisting of triethoxysilyl and trimethoxysilyl.

[0229] Specifically, the method comprises: i) providing a diene according to formula (II) as above, optionally purified as described below; ii) reacting a diene with a compound of the structure HSiR 1 R 2 R 3 wherein R 1 , R 2 , and R 3 with at least 30 equivalents of a hydrosilylation reagent, independently selected from the group consisting of lower alkoxy groups, in the presence of a platinum catalyst and an aromatic hydrocarbon solvent at a temperature between 10 and 35° C.; iii) removing excess hydrosilylation reagent; and iv) removing platinum from the product; Includes.

[0230] When nanostructures are coated with the coating precursor thus prepared, the resulting coated nanostructures are of high quality.

[0231] The diene provided in step i) may have a purity of at least 95%.

[0232] Typically, when the purity of the diene provided in step i) of the process is at least 95%, the purity of the resulting coating precursor is at least 90%.

[0233] Preferably, the alkoxy groups in step ii) are methoxy and / or ethoxy.

[0234] In particular, when the diene used for hydrosilylation is of high purity, such as greater than 90%, such as greater than 95%, or such as greater than 97%, and the hydrosilylation reagent is present in more than 30 equivalents, such as 40 equivalents, the resulting coating precursor is of high purity, such as greater than 90%, such as greater than 95%. Coating precursors prepared under such conditions contain only limited amounts of by-products containing less than two silyl groups, such as less than 10%, or less than 5%, or less than 3%, or less than 1% of the amount of coating precursor. When nanostructures are coated with the coating precursors prepared in this way, the resulting coated nanostructures are of particularly high quality.

[0235] Examples 2, 3, 4, 5, 7, 8, and 9 demonstrate the application of this method to produce high purity coating precursors.

[0236] Alternatively, the diene used for hydrosilylation may be of lower purity if the impurities present in the diene are of such a nature that they do not interfere with the use of the coating precursor to coat nanostructures and do not interfere with hydrosilylation. Impurities known to not interfere with either the use of the coating precursor to coat nanostructures or with hydrosilylation include polymers of the structures mPEG2O and mPEG.

[0237] In the diene according to formula (II), R 7 and R 8 may be methyl, ethyl, iso-propyl, n-propyl, or t-butyl. 7 and R 8 is methyl.

[0238] In the dienes according to formula (II), r and s may be 1.

[0239] In the dienes according to formula (II), t and u may be 1.

[0240] The solvent used in step ii) may be toluene or xylene or a mixture containing toluene or xylene.

[0241] Preferably, the solvent in step ii) is toluene or xylene.

[0242] Additionally, it is often advantageous to dry the diene prior to contacting it with the hydrosilylation reagent. This is conveniently accomplished by azeotropic distillation of a solution of the diene in the reaction solvent. The azeotropic distillation can be accomplished in a vessel which can subsequently be used as the reaction vessel for hydrosilylation.

[0243] The catalyst in step ii) may be a platinum(0) compound, such as Karstedt's catalyst. Alternatively, other platinum catalysts, such as K2PtCl6, may be used.

[0244] Advantageously, the concentration of diene in step ii) is high, such as more than 10% (w / v).

[0245] A catalyst loading of 0.5-3 mol %, such as 1-2 mol % relative to the diene, is suitable in step ii).

[0246] It is often convenient to first contact the diene with the hydrosilation reagent in the presence of a reaction solvent before introducing the catalyst, which is conveniently accomplished by mixing a solution of the azeotropically dried diene with the hydrosilation reagent.

[0247] In many cases, an exotherm is observed upon introduction of the catalyst, and in such cases it is advantageous to introduce the catalyst slowly, such as by adding it in small portions to the solution of diene and hydrosilylation reagent, or by slowly injecting the catalyst solution.

[0248] The hydrosilylation reagent used in step ii) may be trimethoxysilane, triethoxysilane, or triisopropoxysilane.

[0249] In a specific embodiment, the hydrosilylation reagent used in step ii) is trimethoxysilane.

[0250] In another specific embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane.

[0251] In a further specific embodiment, the hydrosilylation reagent used in step ii) is triisopropoxysilane.

[0252] The hydrosilylation reagent used in step ii) may be present in more than 30 equivalents, such as present in 40 equivalents, or present in more than 40 equivalents.

[0253] The catalyst used in step ii) may be a platinum(0) compound. Preferably, the catalyst used in step ii) is a chloride-free or essentially chloride-free platinum(0) compound.

[0254] In one embodiment, the catalyst used in step ii) is Karstedt's catalyst.

[0255] When step ii) is carried out at a temperature of 20-25° C., the reaction is often complete or substantially complete within 1 hour after addition of the catalyst.

[0256] The presence of unreacted hydrosilation reagent is detrimental to the capture of platinum by the thiol-derivatized polystyrene resin, therefore excess hydrosilation reagent is removed in step iii).

[0257] Complete or essentially complete removal of the unreacted silane reagent from the coating precursor can be achieved by repeated distillation of the hydrosilylation reagent from the reaction mixture, in particular by repeated co-distillation with a solvent. Preferably, the reaction mixture is first concentrated, such as by using a rotary evaporator or by vacuum distillation from the reaction vessel, resulting in a residue containing a significant amount of unreacted silane reagent. The residue is then repeatedly redissolved in an aromatic hydrocarbon solvent, such as toluene or xylene, and the concentration procedure is repeated, with each repeated dissolution-concentration cycle resulting in a residue with a decreasing concentration of unreacted hydrosilylation reagent. In many cases, 3 to 8 cycles of dissolution-concentration are sufficient to obtain a residue free or essentially free of unreacted hydrosilylation reagent. Advantageously, the repeated dissolution-concentration procedure is carried out under dry conditions.

[0258] Because the coating precursor is non-volatile or essentially non-volatile, it is not feasible to separate it from the catalyst and catalyst-derived residues by distillation of the silylation product, as is standard procedure for many silylated materials. However, there are several ways to carry out step iv), some of which are presented below.

[0259] Trapping platinum from the coating precursor with a material that has an affinity for platinum and separating the coating precursor and the scavenging material by physical methods such as filtration is a sufficient method for removing platinum from the coating precursor. In particular, thiol-derivatized polystyrene resins have been found to be useful for scavenging platinum from the coating precursor. Activated carbon has also been found to be useful. Examples of other scavenging materials are materials such as those containing thiourea groups or those containing phosphine groups. Other possible scavenging materials are known to those skilled in the art.

[0260] Thus, when a toluene solution of the coating precursor is contacted with thiol-derivatized polystyrene resin at 45-75°C, the platinum concentration often drops within a few days to very low levels, such as less than 10 ppm, as measured by ICP-OES. If sufficient platinum removal cannot be obtained within a few days, separating the solution from the thiol-derivatized polystyrene resin and treating with either fresh thiol-derivatized polystyrene resin or activated charcoal often results in sufficiently low levels of platinum. Multiple treatments with thiol-derivatized polystyrene resin and / or charcoal may be used if necessary.

[0261] In one embodiment, the platinum present after completion of the hydrosilylation reaction is removed by scavenging with a thiolated polystyrene resin.

[0262] In another embodiment, platinum present after completion of the hydrosilylation reaction is removed by scavenging with a charcoal-containing scavenging material, such as activated carbon.

[0263] In a further embodiment, platinum present after completion of the hydrosilylation reaction is removed by a combination of scavenging with a thiolated polystyrene resin and scavenging with a scavenging material comprising charcoal.

[0264] Examples 2c, 3b, 4b, 5b, 6b, 7d, and 9d illustrate some applications of the inventive synthesis method for coating precursors.

[0265] Specific embodiments of the method for producing the coating precursor Some embodiments of the method include 7 and R 8 A diene according to formula (II) is used, in which p is methyl and p and q are 30 to 60.

[0266] Some embodiments of the method include 7 and R 8 A diene according to formula (II) is used, in which p is methyl and p and q are 50 to 70.

[0267] Some embodiments of the method include 7 and R 8 A diene according to formula (II) is used, in which p is methyl, p and q are 30 to 60, and r and s are 1.

[0268] Some embodiments of the method include 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, and t and u are 1.

[0269] Some embodiments of the method include 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, t and u are 1, and X is X 1 In one embodiment, a diene according to formula (II) is used:

[0270] In one embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane and is present in 40 equivalents.

[0271] In another embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane and in the diene, t and u are 1.

[0272] In a further embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane and in the diene R 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, and t and u are 1.

[0273] In yet another embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane, and in the diene, R 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, t and u are 1, and X is X 1 It is.

[0274] In one embodiment, the catalyst used in step ii) is a platinum compound comprising 1,1,3,3-tetramethyl-1,3-divinyldisiloxane and further comprising other ligands coordinated to platinum.

[0275] In a specific embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane, which is present in an amount of 35-45 equivalents, and which is a silyl group having a moiety R 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, t and u are 1, and X is X 1 and the solvent is toluene.

[0276] In another specific embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane, which is present in an amount of 35-45 equivalents, and in the diene, R 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, t and u are 1, and X is X 1 the solvent is toluene, the diene concentration is 10% (wt / vol) to 20% (wt / vol), the catalyst is a Karstedt catalyst, the catalyst loading is 1 mol% to 2 mol%, and the reaction temperature is 18°C ​​to 28°C.

[0277] In a further specific embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane, which is present in 35-45 equivalents, the solvent is toluene, and excess triethoxysilane is removed by repeated co-distillation with toluene.

[0278] In yet another specific embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane, which is present in 35-45 equivalents, the solvent is toluene, and excess triethoxysilane is removed by repeated co-distillation with xylene.

[0279] In another specific embodiment, the hydrosilylation reagent used in step ii) is triethoxysilane, which is present in an amount of 35-45 equivalents, and in the diene, R 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, t and u are 1, and X is X 1 the solvent is toluene, the diene concentration is 10% (wt / vol)-20% (wt / vol), the catalyst is Karstedt catalyst, the catalyst loading is 1 mol%-2 mol%, the reaction temperature is 18°C-28°C, the excess triethoxysilane is removed by repeated co-distillation with toluene or xylene, and the platinum is removed by scavenging with a thiolated polystyrene resin.

[0280] DiPEGylated Dienes As mentioned above, the present disclosure also relates to compounds according to formula (II): TIFF2025509109000015.tif60170, R 7 and R 8 is independently selected to be lower alkyl; p is an integer from 20 to 150; q is an integer from 20 to 150; r is an integer from 1 to 3; s is an integer from 1 to 3; t is an integer from 0 to 3; u is an integer from 0 to 3; and X is 1 , X 2 , X 3 , X 4 , and X 5 is selected from the group consisting of TIFF2025509109000016.tif36170In the formula, the thick bond is [CH2] r and [CH2] s The non-bold bonds represent bonds to [CH2]. t and [CH2] u and p is an integer of 1 to 5.

[0281] In considering the above structures, when two or more covalent bonds are joined in tandem, they should be construed together as one bond.

[0282] R 7 and R 8 may be methyl, ethyl, iso-propyl, n-propyl, and / or t-butyl.

[0283] Preferably, R 7 and R 8 is methyl.

[0284] In one embodiment, R 7 and R 8 is methyl, and p and q are 30 to 60.

[0285] In another embodiment, R 7 and R 8 is methyl, and p and q are 50 to 70.

[0286] In yet another embodiment, r and s are 1.

[0287] In a further embodiment, t and u are 1.

[0288] In specific embodiments, R 7 and R 8 is methyl, p and q are 30 to 60, and r and s are 1.

[0289] In another specific embodiment, R 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, and t and u are 1.

[0290] In a further embodiment, R 7 and R 8 is methyl, p and q are 30 to 60, r and s are 1, t and u are 1, and X is X 1 It is.

[0291] Synthesis of diPEGylated dienes Alkylation of dialkenediols with electrophilic PEGylation reagents has been found to be a suitable method for the production of diPEGylated dienes. An excess of PEGylation reagent is required to ensure complete conversion of the dialkenediols to diPEGylated dienes and minimize the formation of intermediate monoPEGylated dialkenediols. This produces a reaction mixture containing multiple components that require purification prior to hydrosilylation in order for the diPEGylated dienes to be useful in the production of coating precursors.

[0292] Specifically, dienes according to formula (III) In the formula, r is an integer of 1 to 3, s is an integer of 1 to 3, t is an integer of 0 to 3, u is an integer of 0 to 3, and X is X 1 , X 2 , X 3 , X 4 , and X 5 is selected from the group consisting of TIFF2025509109000018.tif39170In the formula, the thick bond is [CH2] r and [CH2] s The non-bold bonds represent bonds to [CH2]. t and [CH2] u and p is an integer from 1 to 5; TIFF2025509109000019.tif26170, R 7 / 8 , i.e. R 7 and R 8 is independently selected from the group consisting of lower alkyl; p / q, i.e., p and q, are independently integers from 20 to 150; and L is a leaving group selected from the group consisting of chloride, bromide, iodide, mesylate, tosylate, and triflate; It has been found that upon reaction, a di-PEGylated diene according to formula (II) above is synthesized. The reaction mixture is suitable for purification by the methods disclosed below.

[0293] In specific dienes according to formula (III), r and s are 1, t and u are 0, and X is X 1 It is.

[0294] In specific dienes according to formula (III), r and s are 1, t and u are 1, and X is X 1 It is.

[0295] In specific dienes according to formula (III), r and s are 1, t and u are 2, and X is X 1 It is.

[0296] In specific dienes according to formula (III), r and s are 1, t and u are 3, and X is X 1 It is.

[0297] In specific dienes according to formula (III), r and s are 1, t and u are 1, and X is X 4 and p is 1.

[0298] In specific dienes according to formula (III), r and s are 1, t and u are 2, and X is X 4 and p is 1.

[0299] In specific dienes according to formula (III), r and s are 1, t and u are 0, and X is X 4 and p is 1.

[0300] In the PEGylation reagent according to formula (IV), R 7 / 8 may independently be methyl or ethyl.

[0301] In the PEGylation reagent according to formula (IV), L may be a tosylate or a mesylate.

[0302] In the PEGylation reagent according to formula (IV), p and q may independently be integers from 30 to 60.

[0303] In the PEGylation reagent according to formula (IV), p and q are independently integers from 30 to 60, L is tosylate, and R 7 / 8 is methyl.

[0304] The reaction mixture in which a dialkenediols according to formula (III) are alkylated with more than two equivalents of a PEGylating reagent according to formula (IV) typically contains a di-PEGylated diene according to formula (II) as a mixture containing impurities. Examples of such impurities include mono-PEGylated dialkenediols reaction intermediates; unreacted PEGylating reagent, R 7 / 8 -PEG-L; the dimerization product of the PEGylation reagent, (R 7 / 8 -PEG)O; hydrolysis product of PEGylation reagent, R 7 / 8 -PEG-OH; and also HL and / or L - is a metal salt of

[0305] The reaction mixture may also contain hydrophobic impurities such as solvent stabilizers and mineral oils used to protect reagents such as hydride bases used in the synthesis.

[0306] An example of the components of the reaction mixture from the alkylation of 2,2-diallyl-propane-1,3-diol with mPEG-OTs from the synthesis of compound 9 (Example 3a), the diPEGylated diene used in the synthesis of compound 10 (Example 3b), is shown in Figure 9. The n-decane in Figure 9 represents the mineral oil from the sodium hydride suspension used in the synthesis.

[0307] When analyzed by reversed-phase HPLC, the PEGylated species TIFF2025509109000020.tif9170. Figure 10A shows a reversed-phase HPLC-ELSD chromatogram of the reaction mixture from the synthesis of compound 9 (Example 3a), showing mPEG (Tr (retention time) = 0.86 min), mPEG2O (Tr = 1.38 min), mPEG-OTs (Tr = 2.38 min), mono-PEGylated intermediate (Tr = 2.63 min), and di-PEGylated diene (Tr = 3.68 min). The purity of the reaction mixture in Figure 10A, as measured by HPLC-ELSD, is approximately 67% area / area (a / a).

[0308] Purification of diPEGylated dienes The present disclosure also relates to a method for purifying di-PEGylated dienes suitable for use in the preparation of coating precursors by hydrosilylation as described above. This method has the advantage of producing high purity di-PEGylated dienes without the use of costly chromatography. This method also has the advantage that it is useful across a range of scales, from small laboratory scale to kilogram production scale and beyond, giving it clear advantages over alternative methods that are only suitable for certain scales.

[0309] The method involves stepwise extraction of an aqueous solution of impure di-PEGylated diene with hot organic solvents, during which the polarity of the aqueous phase is controlled by the addition of salt.

[0310] Surprisingly, an impurity eluting in the middle of a reversed-phase HPLC chromatogram can be selectively extracted from the aqueous phase before the di-PEGylated diene, allowing separation of the di-PEGylated diene from the impurity.

[0311] This method produces di-PEGylated dienes of high purity, such as greater than 90%, or greater than 95%, or greater than 97%. When such high purity di-PEGylated dienes are used in the synthesis of a coating precursor, the resulting coating precursor can be of high purity.

[0312] Surprisingly, it has been found that under certain extraction conditions, the stepwise extraction purification process disclosed herein can selectively extract the desired di-PEGylated diene from the reaction mixture. Specifically, under such certain extraction conditions, impurities that elute close to but earlier than the di-PEGylated diene in the reversed-phase chromatogram can be selectively extracted from the aqueous solution containing the reaction product into an organic phase, while the di-PEGylated diene remains in the aqueous phase. Notably, this behavior is opposite to what would be expected from the elution order. The di-PEGylated diene can then be extracted from the aqueous phase, while the earlier eluting impurities remain in the aqueous phase.

[0313] In summary, the stepwise extraction comprises two main parts: an intermediate extraction step (steps a) and b)) and a product extraction step (step c)).

[0314] In the intermediate extraction step, an aqueous solution of the impure di-PEGylated diene is treated with salt to adjust the polarity of the solution (step a)), and the aqueous solution is repeatedly extracted with the hot primary organic extraction solvent (step b)). 7 / 8 -PEG-L and any monoPEGylated dialkenediol reaction intermediates present are extracted into the organic phase leaving the aqueous phase highly depleted in these impurities.

[0315] In the subsequent product extraction step (step c)), the amount of salt in the aqueous solution is increased and the solution is again repeatedly extracted at elevated temperature with the primary extraction solvent. In the product extraction, the di-PEGylated diene is extracted into the organic phase along with only trace amounts of impurities.

[0316] The organic phase from the product extraction is concentrated (step d)), thereby obtaining a residue (step e)). The residue obtained in step e) is dissolved in an aqueous buffer (step f)) and subjected to a finishing extraction (step g)), followed by concentration of the organic phase from the finishing extraction (steps h) and i)), which is then used for the synthesis of the coating precursor.

[0317] Specifically, the method comprises: a) providing an aqueous solution of an impure compound according to formula (II) above, the aqueous solution comprising: Water in an amount between 7.5 and 16.5 times the total mass of the impure compound according to formula (II) above, and NaCl in an amount between 6% and 9% (weight / volume) of the amount of water, and b) subjecting the aqueous solution of step a) to 2 to 5 intermediate extractions carried out at temperatures between 40° C. and 70° C., each intermediate extraction comprising the following steps: b1) optionally adding further portions of NaCl, so that the total amount of NaCl added corresponds to an amount of NaCl that is less than 9% (w / v) of the amount of water in the aqueous solution of step a); b2) extracting the aqueous solution with a carboxylic acid ester solvent; and b3) obtaining an aqueous phase by removing the organic phase; and c) adding NaCl to the aqueous phase from step b3) in an amount of at least 1% of the amount of water in step a) so that the total amount of NaCl corresponds to an NaCl amount of 8% to 12% and subjecting the aqueous phase to 2 to 5 product extractions carried out at a temperature of 40° C. to 70° C., each product extraction comprising the following steps: c1) extracting the aqueous phase with a carboxylic acid ester solvent; and c2) removing the organic phase; and d) pooling the organic phases from each step c2); e) concentrating the pooled organic phase from step d) to obtain a residue; f) dissolving the residue from step e) in an aqueous buffer solution having a pH of 6-9 to obtain an aqueous phase; g) subjecting the aqueous phase from step f) to 2 to 4 finishing extractions, each finishing extraction comprising the steps of: g1) extracting the aqueous phase from step f) with a chlorinated solvent; and g2) removing the organic phase; and h) pooling the organic phases from each step g2); i) concentrating the pooled organic phase from step h) to obtain a residue comprising the di-PEGylated diene according to formula (II) above, with less than 10% (w / w) impurities; Includes.

[0318] The aqueous solution in the intermediate extraction contains 7.5-16.5 parts water per part PEG-containing material (step a). The total amount of PEG-containing material can be estimated as the sum of the masses of PEG-containing compounds introduced into the reaction mixture when the aqueous solution is obtained from a reaction mixture derived from the PEGylation of a diene. In many cases, this is simply the sum of the masses of the PEG-containing compounds introduced into the reaction mixture. 7 / 8 - the mass of PEG-L. Alternatively, the amount of PEG-containing material can be estimated from the mass fraction of PEG in the material dissolved in aqueous solution. The mass fraction of PEG is determined by the quantitative 1 It can be estimated by a number of methods known to those skilled in the art, such as 1 H-NMR.

[0319] The salt used to adjust the polarity of the aqueous phase is NaCl, and the concentrations given herein are for NaCl. However, the salt may be essentially any inorganic salt. The use of other salts such as KBr, LiCl, Na2SO4, or MgCl2 may also be contemplated. If a salt other than NaCl is used to adjust the polarity of the aqueous solution, recalibration of the associated concentrations is required. Example 20 provides an example of how to recalibrate the salt concentrations.

[0320] The amount of NaCl in the aqueous solution at the start of the intermediate extraction step is 6% to 9% (weight / volume) of the amount of water (step a)).

[0321] The aqueous phase of the intermediate extraction is extracted with 2-5 portions of the primary extraction solvent at an initial concentration of salt, which is carried out at a temperature between 40°C and 70°C (step b)).

[0322] In one embodiment, the aqueous phase is first extracted with 2-5 portions of a primary extraction solvent which is a carboxylic acid ester solvent (steps b2) and b3)) before the amount of salt in the aqueous phase is increased to a concentration higher than the starting concentration but still less than 9% (w / v) of the amount of water in the aqueous solution of step a) (step b1)), after which the aqueous phase is extracted with a further 2-5 portions of the primary extraction solvent (step b2).

[0323] The primary extraction solvent is a carboxylic acid ester (ie, an alkyl ester of a carboxylic acid), such as ethyl acetate or isopropyl acetate.

[0324] Primary extraction solvents other than carboxylic acid esters may be contemplated, such as ketones, such as methyl ethyl ketone, methyl propyl ketone, or diethyl ketone. Mixed solvents having similar solvent properties to the carboxylic acid esters may also be contemplated. Such solvent mixtures may include mixtures of aliphatic or aromatic hydrocarbons and chlorinated solvents.

[0325] The elevated temperature in the extraction of step b) is necessary both to achieve the desired selectivity in the extraction and to promote phase separation. At room temperature, the separation of the phases is impractically slow. At temperatures below 40° C., the selectivity in the extraction is insufficient. Temperatures between 50° C. and 70° C., such as 60° C., have been found to be particularly suitable.

[0326] The amount of NaCl in the aqueous solution at the start of the product extraction step (step c)) is 8% to 12% (weight / volume) of the amount of water.

[0327] The aqueous phase is extracted 2 to 5 times in the product extraction (step c)).

[0328] The organic phases from the product extraction are pooled (step d)), concentrated (step e)), or concentrated and then pooled. The organic phases may be subjected to a step of drying prior to concentration (step e). This can be achieved by a number of methods known to those skilled in the art, such as drying over a drying agent such as magnesium sulfate or using molecular sieves.

[0329] The residue obtained from the product extraction contains a certain amount of L - or HL. It may also contain some amount of NaCl used to adjust the polarity of the aqueous phase.

[0330] In step g), the residue from step e) is dissolved in an aqueous buffer (step f) and then subjected to a polishing extraction step (step g)). In step f), the residue from the product extraction step is dissolved in a neutral or slightly basic aqueous buffer with a pH of 6-9. The aqueous solution is subsequently extracted 2-4 times with a secondary extraction solvent, which is a chlorinated solvent (step g)).

[0331] In the finishing extraction step (step g), the di-PEGylated diene is mixed with only a small amount of L - salt or HL and only a small amount of NaCl is extracted into the organic phase.

[0332] The secondary extraction solvent is a chlorinated organic solvent such as dichloromethane, chloroform, tetrachloroethane, or a chlorinated aromatic solvent. Dichloromethane is particularly useful as a secondary extraction solvent.

[0333] A suitable buffer for use in the final extraction step (step f)) is aqueous sodium bicarbonate.

[0334] The organic phases from the work-up extraction are pooled (step h)) and concentrated (step i)) to obtain a residue. The organic phase may be subjected to an additional drying step over a drying agent such as magnesium sulfate or by use of molecular sieves prior to solvent removal.

[0335] The residue obtained in step i) contains a highly pure di-PEGylated diene containing less than 10% w / w of impurities, the amount of which can be measured by HPLC-ELSD.

[0336] Typically, the purity of the diPEGylated diene is greater than 90%, such as greater than 95%, such as greater than 97%, such as greater than 99%. Figure 10B shows a reverse-phase HPLC-ELSD chromatogram of diPEGylated diene 9 purified according to the present disclosure, showing a purity of greater than 99% (area / area).

[0337] The residue obtained after the finishing extraction can be subjected to hydrosilylation to produce a coating precursor according to the present disclosure. Hydrosilylation conditions are known to those skilled in the art.

[0338] The aqueous solution provided in step a) can be achieved by evaporating the reaction solvent from the reaction mixture resulting from the reaction of a dialkenediol according to formula (III) with a PEGylation reagent according to formula (IV) and dissolving the resulting residue in water.

[0339] Considering that the reaction solvents used in the synthesis of the di-PEGylated dienes are immiscible with water, it is often more convenient to generate the aqueous solution used in the intermediate extraction step (step b) by pre-extraction of the reaction mixture. In such pre-extraction, the reaction solvent and hydrophobic impurities are removed from the reaction mixture. In pre-extraction, the reaction mixture is treated with water and salt to form a two-phase system, the organic phase is removed and the aqueous phase, optionally after further addition of salt, is used as the aqueous solution provided in step a) and used for the intermediate extraction.

[0340] In one embodiment of this method, purification of diPEGylated dienes starts from a quenched reaction mixture resulting from reacting a dialkenedioI according to formula (III) with a PEGylation reagent according to formula (IV) under basic conditions in a water-immiscible organic solvent and includes four extraction steps: pre-extraction 100, intermediate extraction 200, product extraction 300, and product polishing 400. The overall process of such a process including all four extraction steps is shown diagrammatically in Figure 3. Details of the extraction steps are detailed below.

[0341] The steps of pre-extraction 100, intermediate extraction 200 and product extraction 300 are carried out at a temperature between 50°C and 70°C, such as between 55°C and 65°C.

[0342] The process of pre-extraction 100 is shown diagrammatically in Figure 4. The reaction mixture (101 in Figure 4) is treated with water and salt (102 in Figure 4) to form a two-phase system (103 in Figure 4).

[0343] The phases are mixed by vigorous agitation and allowed to separate (104 in FIG. 4), again forming a two-phase system (105 in FIG. 4). The organic phase contains most of the reaction solvent and most of the hydrophobic components of the reaction mixture. The hydrophobic components are generally limited to mineral oil from the use of the hydride base as a dispersant in the mineral oil, but may also contain other unwanted non-polar compounds from elsewhere. The organic phase is removed (106 in FIG. 4) and the aqueous phase (107 in FIG. 4) is saved for further processing in an intermediate extraction (108 in FIG. 4).

[0344] The process of intermediate extraction (steps a) and b)) can be carried out as shown diagrammatically in Figure 5. For example, the aqueous phase from the pre-extraction (201 in Figure 5) is treated with a primary extraction solvent (a carboxylic acid ester solvent) resulting in a two-phase system that is mixed by vigorous stirring and separated (202 in Figure 5) to form a two-phase system (203 in Figure 5). The organic phase is removed (204 in Figure 5). The extraction procedure is repeated multiple times (206 in Figure 5) so that step 204 is performed 2-5 times in total.

[0345] Typically, the aqueous phase (205 in FIG. 5) is extracted 3-4 times and then cooled to RT. 7 / 8 This aqueous phase, essentially free of -PEG-L and monoPEGylated dialkenediol reaction intermediates, may be sent to product extraction (214 in FIG. 5).

[0346] Alternatively, a not-enough amount of R 7 / 8If the -PEG-L and mono-PEGylated dialkenediol reaction intermediates remain in the aqueous phase, more NaCl may be added (step b1) and 207 in FIG. 5) and the aqueous phase may be subjected to repeated extractions (208-213 in FIG. 5). The amount of NaCl added in step 207 is such that the total amount of salt added in steps 102 and 207 is less than 9% (w / v) of the water added in step 102. The extraction procedure is repeated multiple times (213 in FIG. 5) such that step 211 is performed a total of 2-5 times.

[0347] The aqueous phase at the end of the intermediate extraction (213 in Figure 5) is R 7 / 8 The aqueous phase at the end of the intermediate extraction (213 in FIG. 5) is essentially free of the di-PEGylated diene product and the dimerization product of the PEGylation reagent (R 7 / 8 Most of the PEG-PEG)O and the hydrolysis products of the PEGylation reagent present in the reaction mixture before pre-extraction, R 7 / 8 -PEG-OH.

[0348] The process of product extraction (step c) may be carried out as shown diagrammatically in Figure 6. The aqueous phase from the intermediate extraction (301 in Figure 6) is treated with an additional amount of NaCl (302 in Figure 6). The amount of NaCl added in step 302 is such that the total amount of salt added in steps 102, 207 and 302 is 8-12% (w / v) of the water added in step 102. The amount of NaCl added in step 302 is at least 1% (w / v) of the water added in step 102.

[0349] The aqueous phase (303 in FIG. 6) is then treated with a portion of the primary extraction solvent (a carboxylic acid ester solvent) and the phases are mixed by vigorous stirring and separated (304 in FIG. 6) resulting in a two-phase system (305 in FIG. 6). The organic layer is drawn off (306 in FIG. 6). The organic phase of the product extraction (309 in FIG. 6) contains the di-PEGylated diene product in some L-formaldehyde. - or HL, and essentially free of other PEGylated species.

[0350] The aqueous phase (307 in FIG. 6) is subjected to further extractions (308 in FIG. 6) such that step 306 is performed 2-5 times in total.

[0351] The organic phase containing the di-PEGylated diene product is concentrated (310 in FIG. 6) to obtain a residue (311 in FIG. 6). This is most conveniently accomplished by distillation of the solvent under reduced pressure. It is often advantageous to dry the organic phase prior to concentration. This can be accomplished by a number of methods known to those skilled in the art, such as drying over a drying agent such as magnesium sulfate or using molecular sieves.

[0352] Product workup may be carried out as shown diagrammatically in Figure 7. The residue from product extraction (401 in Figure 7) is first dissolved in an aqueous buffer buffered to pH 6-9 (402 in Figure 7).

[0353] The buffered aqueous solution (403 in FIG. 7) is extracted (404 in FIG. 7) with a secondary extraction solvent (a chlorinated solvent) resulting in a two-phase system (405 in FIG. 7).

[0354] The organic phase is withdrawn (406 in Figure 7). The product polishing organic phase (409 in Figure 7) contains the di-PEGylated diene product and is essentially free of low molecular weight impurities and essentially free of PEGylated impurities.

[0355] The aqueous phase (407 in FIG. 7) is subjected to further extractions (408 in FIG. 7) such that step 406 is performed a total of 2-4 times.

[0356] The organic phase from the workup step (409 in Figure 7) is pooled and concentrated (410 in Figure 7). Prior to solvent removal, it is advantageous to dry the organic phase over a drying agent such as magnesium sulfate or by use of molecular sieves.

[0357] The residue (411 in FIG. 7) obtained by removal of the solvent from the organic phase (i.e., after step i) contains the di-PEGylated diene of sufficient purity such that when the di-PEGylated diene is used to prepare a coating precursor according to the present disclosure by hydrosilylation, the coating precursor requires only limited purification.

[0358] Typically, the purity of the diPEGylated diene is greater than 90%, such as greater than 95%, such as greater than 97%, such as greater than 99%. Figure 10B shows a reverse-phase HPLC-ELSD chromatogram of diPEGylated diene 9 purified according to the present disclosure, showing a purity of greater than 99% (area / area).

[0359] In one embodiment, in the intermediate extraction step (step b)), the concentration of NaCl is 7%-8% (weight / volume), and in the product extraction step (step c)), the concentration of NaCl is 9%-11% (weight / volume), the primary extraction solvent is ethyl acetate, the intermediate extraction and product extraction are carried out at 55°C-65°C, and the secondary extraction solvent is dichloromethane.

[0360] Use of coating precursors for coating surfaces, in particular surfaces of nanostructures The present disclosure also relates to the use of a coating precursor according to the present disclosure or the product of the above-mentioned method for coating a surface.

[0361] In particular, the coating precursors described herein can be used as intermediates in producing coated nanostructures.

[0362] The surface can be any surface from macroscopic to microscopic to nano-sized objects. Typically, the surface is a surface of a nanostructure, and the product of coating the surface with a coating precursor is a coated nanostructure. Such coated nanostructures and their uses are described below.

[0363] The surface to be coated preferably contains silanol functional groups.

[0364] When the silanol functional groups in the coating precursor contain alkoxy groups, the presence of some water is beneficial for the coating of the surface.

[0365] If the surface to be coated is a nanostructured surface, a suitable method of coating the surface is to dissolve the nanostructures in water or an aqueous mixture of solvents prior to contacting the surface with the coating precursor.

[0366] Suitably, the coating precursor is contacted with the surface to be coated by dissolving it in a solvent and contacting the solution of the coating precursor with a solution of the nanostructures to be coated.

[0367] Suitable solvents for dissolving the coating precursors are water-miscible aprotic polar organic solvents such as dioxane, THF (tetrahydrofuran), DMSO (dimethylsulfoxide), or DMF (dimethylformamide).

[0368] Z 1 and Z 2 R in 1 , R 2 , and R 3 are the same alkoxy group, the alcohol R 1 H is a suitable solvent for dissolving the coating precursor.

[0369] It is advantageous to use an anhydrous solvent to dissolve the coating precursor.

[0370] The use of the coating precursor to coat a surface is advantageously carried out at elevated temperatures, such as above 60° C., such as above 80° C., such as above 100° C., such as above 120° C., such as above 140° C. Coating is therefore preferably carried out at temperatures between 80° C. and 140° C., preferably between 100° C. and 120° C.

[0371] Addition of the coating precursor solution to the surface to be coated is advantageously done slowly, such as by adding the coating precursor solution in multiple portions. Alternatively, the coating precursor solution may be added to the surface to be coated by slow injection of the coating precursor solution.

[0372] The coating precursor may be added as a melt to the surface to be coated.

[0373] Alternatively, the coating precursor may be added as a solid to a solution of the nanostructures to be coated.

[0374] Specifically, a solution of the coating precursor can be slowly injected into a solution of the nanostructures to be coated.

[0375] In a preferred embodiment, a solution of the coating precursor in anhydrous THF or anhydrous dioxane is slowly injected into a solution of the nanostructures to be coated.

[0376] In a specific embodiment, the Z in the coating precursor 1 and Z 2 R in 1 , R 2 , and R 3 is ethoxylated, and a solution of the coating precursor in absolute ethanol is slowly injected into a solution of the nanostructures to be coated.

[0377] In a preferred embodiment, Z in the coating precursor 1 and Z 2 R in 1 , R 2 , and R 3 is ethoxylated, and a solution of the coating precursor in absolute ethanol is slowly injected into a solution of the nanostructures to be coated having a temperature of 100°C to 120°C.

[0378] In a particularly preferred embodiment, the coating precursor is 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45 the coating precursor is dissolved in absolute ethanol or dioxane, the nanostructures to be coated include monomer residues derived from 1,7-bis-(triethoxysilyl)-4,4-bis-(dimethylphosphonato)-heptane, the coating precursor is dissolved in a solvent mixture including ethylene glycol and water, the solution of the nanostructures to be coated is heated to 100° C.-120° C., and the coating precursor is added by slow injection to the solution of the nanostructures to be coated over a period of 10-50 hours, such as 20 hours.

[0379] Example 14 illustrates the use of a coating precursor according to the present disclosure to coat nanostructures.

[0380] Examples 16a and 16b demonstrate that nanostructures coated with precursors according to the present disclosure have longer plasma half-lives and better storage stability than nanostructures coated with reference precursors.

[0381] Nanostructures Comprising Coatings Derived from Coating Precursors - Patent application As mentioned above, coating precursors according to the present disclosure can be used to create coatings on nanostructures.

[0382] Thus, the present disclosure also relates to spherical nanostructures comprising a coating derived from a coating precursor according to the structure of formula (I) above, or derived from the product of a method according to the present disclosure.

[0383] As mentioned above, the coating precursor according to the present disclosure comprises reactive silane functional groups, which allows the coating precursor to form bonds with surfaces that comprise functional groups capable of forming bonds of the structure GO-Si, where G represents an atom at the surface, such as a silicon atom, and Si represents a silicon atom from the coating precursor molecule. In particular, nanostructures that comprise silanol functional groups on the surface are suitable intermediates in the production of coated nanostructures according to the present disclosure.

[0384] The nanostructures to be coated are also referred to as "precursor nanostructures."

[0385] The nanostructures to be coated with the coating precursor according to the present disclosure may be referred to as "core parts". Such core parts typically comprise a polymer having reactive groups on the surface suitable for forming bonds with the coating precursor. The core parts preferably comprise a crosslinked polymer network comprising siloxane bonds. The reactive groups on the surface may comprise silanol groups.

[0386] The precursor nanostructures may have simple structures comprising a single type of polymer, or may have more complex structures comprising a composite of several different materials, such as multiple layers or zones of different materials, or may be composed of several substructures bonded together, which may be layered as desired.

[0387] The coated nanostructures include an outer layer, or coating layer, that comprises residues derived from the coating precursor.

[0388] FIG. 2 shows an example of the structure of a coated nanostructure according to the present disclosure. The coated nanostructure includes three parts: 1) a hydrodynamic diameter D A 2) a central portion having a thickness [(D B -D A ) / 2], and D B is the hydrodynamic diameter between the center and the middle layer, and 3) the thickness [(DC -D B ) / 2] coating layer, C is the hydrodynamic diameter of the coated nanostructure, coating layer.

[0389] The coated nanostructures may further comprise a radionuclide.

[0390] The coating precursor molecules are bonded to the surface groups of the precursor nanostructures via siloxane bonds through the silane groups in the coating precursor. The coating layer serves to protect the core of the nanostructures from aggregation and from interactions with proteins in vivo, thereby improving the biocompatibility and stability of the coated nanostructures under physiological conditions.

[0391] Coated nanostructures whose coatings are derived from coating precursors according to the present disclosure have superior properties compared to coated nanostructures whose coatings are derived from certain other coating precursors. For example, coated ... coating precursors according to the present disclosure, when the coating has the structure mPEG-CH2-CH2-SiR 1 R 2 R 3 wherein R 1 , R 2 , and R 3 exhibits greater storage stability than coated nanostructures that are chloride, bromide, iodide, lower alkoxy, aryloxy, carboxy, amino, or -NH-acyl (see Example 16).

[0392] Coated nanostructures whose coatings are derived from coating precursors according to the present disclosure exhibit superior in vivo properties compared to coated nanostructures whose coatings are derived from certain other coating precursors. In Example 16a, the coating is 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45The coated nanostructures derived from 1-(ω-methyl)-heptane, a compound according to the present disclosure, Compound 10, were prepared by subjecting the coating to 1-(ω-methyl-(ethyleneoxy) 45 The nanostructures are shown to exhibit longer circulation times in vivo compared to similar nanostructures derived from (3-methyl-3,5-bis(3-(triethoxysilyl)propyloxy)-benzene, a compound outside the scope of this disclosure, compound 51.

[0393] Coated nanostructures, where the coating is derived from a coating precursor according to the present disclosure, exhibit high stability with respect to agglomeration (see Example 16b).

[0394] Additionally, coated nanostructures whose coatings are derived from coating precursors according to the present disclosure exhibit increased stability with respect to loss of coating residue from the nanostructures. Example 16b shows that nanostructures whose coatings are derived from coating precursors according to the present disclosure have superior storage stability to nanostructures coated with precursors outside the scope of the present disclosure.

[0395] Coated nanostructures, where the coating is derived from a coating precursor according to the present disclosure, have good solubility in water. Example 21 shows that the solubility of nanostructures coated with a coating according to the present disclosure is at least 25% (weight / volume).

[0396] Specific embodiments of coated nanostructures The hydrodynamic diameter of the coated nanostructures is from 10 nm to 100 nm, such as from 12 nm to 80 nm, such as from 14 nm to 60 nm, such as from 16 nm to 50 nm, such as from 18 nm to 45 nm, such as from 20 nm to 40 nm, such as from 25 nm to 35 nm.

[0397] In one embodiment, the coated nanostructures comprise a chelating group. Preferably, the chelating group is a bisphosphonate group, more preferably a geminal bisphosphonate.

[0398] The coated nanostructures may further comprise a radionuclide.

[0399] In a specific embodiment, the coated nanostructures comprise a central moiety derived from 1,7-bis-(triethoxysilyl)-4,4-bis-(dimethylphosphonato)-heptane.

[0400] In another specific embodiment, the coated nanostructure comprises a central portion derived from 1,7-bis-(triethoxysilyl)-4,4-bis-(dimethylphosphonato)-heptane and has a hydrodynamic diameter that is from 10 nm to 100 nm, such as from 12 nm to 80 nm, such as from 14 nm to 60 nm, such as from 16 nm to 50 nm, such as from 18 nm to 45 nm, such as from 20 nm to 40 nm, such as from 25 nm to 35 nm. Preferably, the hydrodynamic diameter is from 25 nm to 35 nm.

[0401] In a further specific embodiment, the coated nanostructure has a hydrodynamic diameter of 25 nm to 35 nm and comprises a central portion derived from 1,7-bis-(triethoxysilyl)-4,4-bis-(dimethylphosphonato)-heptane and 1,7-bis-(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45 -methyl)-heptane derived coating layer.

[0402] In a preferred embodiment, the coated nanostructures have a hydrodynamic diameter of 25 nm to 35 nm and comprise a central portion derived from 1,7-bis-(triethoxysilyl)-4,4-bis-(dimethylphosphonato)-heptane surrounded by an intermediate layer of a polymer derived from bis(triethoxysilyl)methane, and 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45 -methyl-heptane derived outer coating layer.

[0403] Example 14 shows some examples of coated nanostructures with coatings derived from coating precursors according to the present disclosure.

[0404] Examples 16a and 16b demonstrate that nanostructures coated with precursors according to the present disclosure have longer plasma half-lives and better storage stability than nanostructures coated with reference precursors.

[0405] Pharmaceutical Compositions Comprising Coated Nanostructures The present disclosure also relates to a pharmaceutical composition comprising a plurality of spherical nanostructures according to the present disclosure.

[0406] The present disclosure further relates to a pharmaceutical composition for use in the treatment or imaging of cancer, the pharmaceutical composition comprising a plurality of spherical nanostructures according to the present disclosure, and the nanostructures comprising a radionuclide.

[0407] Such pharmaceutical compositions have the advantage that the coating derived from the coating precursor according to the present disclosure renders the components of the pharmaceutical composition highly biocompatible and / or bioinert.

[0408] The pharmaceutical composition may be used for medical imaging, such as medical imaging for the diagnosis of cancer.

[0409] The medical imaging may be, for example, SPECT or PET imaging.

[0410] When the pharmaceutical composition is used for medical imaging, the pharmaceutical composition further comprises a radioactive isotope (radionuclide).

[0411] Pharmaceutical compositions according to the present disclosure used for SPECT imaging typically contain gallium-67, indium-111, technetium-99m, lutetium-177, and / or thallium-201.

[0412] Pharmaceutical compositions according to the present disclosure used for PET imaging typically contain copper-62, gallium-68, rubidium-82, yttrium-86, and / or zirconium-89.

[0413] The pharmaceutical compositions may be used to treat cancer, such as treating cancer with radionuclide therapy, in which the coated nanostructures include a radionuclide such as Actinium-225, Copper-64, Copper-67, Holmium-166, Lead-212, Lutetium-177, Radium-223, Rhenium-186, Rhenium-188, Samarium-153, Strontium-89, Thorium-227, and / or Yttrium-90.

[0414] In one embodiment, the radionuclide is 177 Lu, 153 Sm, and / or 90 It's Y.

[0415] Pharmaceutical compositions according to the present disclosure exhibit desirable pharmaceutical properties, such as a pharmacokinetic profile suitable for accumulating the coated nanostructures in tumor tissue.

[0416] Examples 17 and 18 demonstrate the use of pharmaceutical compositions comprising coated nanostructures with coatings derived from coating precursors according to the present disclosure.

[0417] Tumor-bearing mice treated with pharmaceutical compositions comprising nanostructures according to the present disclosure showed a significant increase in mean and median survival time compared to the control group (see Example 17). Furthermore, tumor growth was significantly delayed in the treated group (see Example 17 and FIG. 12).

[0418] Nanostructures as carriers of radionuclides The present disclosure also relates to the use of spherical nanostructures according to the present disclosure as carriers of radioisotopes (radionuclides).

[0419] In such cases, the nanostructure further comprises a chelating group. Preferably, the chelating group comprises a phosphonate, such as a geminal bisphosphonate.

[0420] Such carriers for radioisotopes may be used in the diagnosis (including medical imaging) and treatment of cancer, as described above (see Examples 17 and 18).

[0421] In one preferred embodiment, the coated nanostructures include a central portion comprising monomer residues derived from 1,7-bis-(triethoxysilyl)-4,4-bis-(dimethylphosphonato)-heptane and 1,7-bis-(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45 -methyl)-heptane derived coating layer.

[0422] In another preferred embodiment, the coated nanostructure comprises (1) a central portion comprising monomer residues derived from 1,7-bis-(triethoxysilyl)-4,4-bis-(dimethylphosphonato)-heptane, (2) an intermediate layer of a polymer derived from bis(triethoxysilyl)methane, and (3) a polymeric intermediate layer of 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45 -methyl)-heptane.

[0423] As mentioned above, the carrier for the radioisotope may comprise a radioisotope suitable for medical imaging, such as a radioisotope suitable for PET, or a radioisotope suitable for SPECT, and / or a radioisotope suitable for radionuclide therapy.

[0424] Radioisotopes can be, for example, 177 Lu, 153 Sm, and / or 90 It can be Y. EXAMPLES

[0425] Examples of different embodiments of the present disclosure are described below.

[0426] General experimental conditions Materials, reagents, and solvents were obtained commercially and used without further purification unless otherwise noted. Solvents were reagent grade or similar unless otherwise noted. Reactions were run under N2 unless otherwise noted.

[0427] MilliQ water means ultrapure water, for example water purified using a Millipore Milli-Q laboratory water system.

[0428] SIR-200 resin, a thiolated polystyrene resin, was purchased from ResinTech, USA (resintech.com), activated with aqueous NaHCO3, carefully washed with EtOH and toluene, and azeotropically dried before use.

[0429] HPLC was performed on a Hewlett Packard Series 1100 equipped with an Agilent Poroshell 120 EC-C18 4.6 x 50 mm column, a DAD detector (diode array detector) recording at 220 nm, and an ELSD detector (ELSD settings: 40 °C, 1.4 L N2 / min, gain = 4, impactor on) using a non-linear gradient starting from 43% acetonitrile in water at 1 ml / min with an oven temperature of 40 °C.

[0430] DLS was measured using a Malvern Instruments Zetasizer Nano ZEN3600 and processed using the general process settings in the Zetasizer software.

[0431] SEC was performed on a Younglin Instrument YL9100 equipped with an Agilent Bio SEC-5 1000 Å column eluting at 1.2 ml / min at ambient temperature, a DAD detector recording at 220 nm, 280 nm, and 560 nm, and an ELSD detector (ELSD settings: 60° C., 1.2 L N2 / min, gain=4).

[0432] NMR spectra were obtained using a Varian Unity Inova 400MHz ( 1 H is 399.95MHz, 13 C is a 125.68MHz spectrometer, 1 H NMR and 13 C NMR was recorded using the residual solvent peak as the internal standard.

[0433] Compounds 31 (Tanikaga, R. et al. Synthesis, 1977, p. 299–301), 50 (EP 2572736), 51 (WO 2018130713), and 52 (US 2005255514) were synthesized according to literature procedures.

[0434] Abbreviation Tetrahydrofuran (THF), dichloromethane (DCM), dimethylformamide (DMF), ethyl acetate (EtOAc), methanol (MeOH), ethanol (EtOH), potassium acetate (KOAc), acetonitrile (MeCN), lithium aluminum hydride (LAH), methanesulfonyl chloride (MsCl), triethylamine (TEA), tris(hydroxymethyl)aminomethane (Tris), thin layer chromatography (TLC), m-PEG 45 -OTs (m-PEG45 tosylate), GF / A filters (glass microfiber filters, grade GF / A), saturated aqueous solution (sat.aq.), brine (saturated aqueous sodium chloride solution), polyethersulfone (PES), tangential flow filters (TFF filters).

[0435] TIFF2025509109000021.tif109170

[0436] Example 1a: Compound 2, 4-ethoxycarbonyl-1,6-heptadiene Diethyl diallylmalonate 1 was dissolved in DMSO (57 ml), followed by the addition of milliQ water (650 μl) and LiCl (2.98 g, 70.5 mmol). The reaction mixture was stirred under nitrogen at 190° C. for 3 h. The reaction was monitored by TLC until the starting material was completely converted. The solution was diluted with 100 ml of brine and extracted three times with 100 ml of diethyl ether. The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum to give compound 2 as a colorless oil (3.90 g, 72% yield). 1 H NMR(400MHz,CDCl3)δ:5.74(m,J=17.1,Hz,2H),5.04(m,4H),4.13(q,J=7.1Hz,2H),2.50(m,J=8.0,1H),2.31(m,4H),1.24(t,J=7.1Hz,3H)

[0437] Example 1b: Compound 3, 4-hydroxymethyl-1,6-heptadiene In a 50 ml reactor, under nitrogen, at 0° C., LiAlH4 was added to anhydrous THF (26.74 ml). The mixture was cooled to −78° C. and 4-ethoxycarbonyl-1,6-heptadiene 2 (2.34 g, 139 mmol) was added. After 1 h, the mixture was brought to room temperature. The reaction was monitored by TLC until complete conversion of the starting material. The reaction mixture was cooled to 0° C. and 225 μl of milliQ water was added in portions, followed by 225 μl of 15% NaOH and 670 μl of milliQ water. Filtration and evaporation of volatiles gave the product 3 as an oil, which was purified by chromatography on silica (1.272 g, 72% yield). 1 H NMR(400MHz,CDCl3)δ:5.82(m,J=17.2Hz,2H),5.05(t,4H),3.57(d,J=5.6Hz,2H),2.12(t,J=6.1Hz,4H),1.72(hept,J=6.4Hz,1H)

[0438] Example 1c: Compound 4, 4-[ω-methyl-(ethyleneoxy) 45 -Methyl]-1,6-heptadiene In a 100 ml three-neck round-bottom flask, the diallyl alcohol 3 from Example 1b (262 mg, 1.23 mmol) was dissolved in anhydrous toluene (20 ml). The temperature of the reaction medium was set to 0° C., NaH (179.5 mg, 4.5 mmol, 60% dispersion in mineral oil) was added and the mixture was stirred for 1 h. m-PEG in toluene (25 ml) 45 An azeotropically dried solution of -OTs (5.84 g, 2.7 mmol) was added. The mixture was allowed to reach room temperature for 1 h and then heated to reflux. The reaction was monitored by TLC (heptane:ethyl acetate 5:1) and HPLC until complete conversion and then quenched by portionwise addition of milliQ water (330 μl) at 60° C. Toluene was evaporated under vacuum and the remaining solution was diluted with milliQ water (78 ml) followed by addition of NaCl (4.1 g) and EtOAc (25 ml). After vigorous stirring, the two layers were separated and the organic phase was removed. The remaining aqueous phase was extracted twice with EtOAc (50 ml). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum to give compound 4 as a white solid (22% yield). 1 H NMR(400MHz,CDCl3)δ:5.76(m,2H),5.01(m,4H),3.64(s,225H),3.37(s,3H),3.33(d,J=6.1Hz,2H),2.08(m,4H),1.78(m,1H)

[0439] Example 1d: Compound 5, 4-[ω-methyl-(ethyleneoxy) 45 -Methyl]-1,7-bis(triethoxysilyl)heptane To an azeotropically dried solution of compound 4 from Example 1c (595 mg, 0.27 mmol) in dry toluene (7 ml) was added triethoxysilane (205 μl, 0.182 g, 1.11 mmol, 4.0 equiv). The bath temperature was set to 30° C. and Karstedt's catalyst (20.4 μl, 2% in xylene) was added. The reaction mixture was stirred at room temperature overnight. The reaction was monitored for the disappearance of olefinic protons. 1The reaction was monitored by H-NMR. The solvent was then evaporated and the excess silane was removed by coevaporation with anhydrous toluene (4 ml). The product was dissolved in toluene (5 ml), degassed with three vacuum / nitrogen cycles, and stirred with activated SIR-200 resin (1.56 g) at 60° C. for 4 days. Filtration and evaporation of the solvent gave 217.9 mg (36.2% yield) of compound 5 as a colorless solid. 1 H NMR(400MHz,CDCl33)δ:3.72(q,J=7.0Hz,2H),3.64(s,191H),3.38(s,2H),1.24(m,3H)

[0440] TIFF2025509109000022.tif122170

[0441] Example 2a: Compound 6, 2,2-diallyl-1,3-propanediol To a suspension of LiAlH4 (94.93 g, 2.37 mmol, 2.4 equiv) in anhydrous THF (1,000 ml) was added diethyl diallylmalonate 1 (245 g, 1 mmol) dropwise at 0 °C. The rate of addition was adjusted to maintain the internal temperature below 10 °C. The reaction was stirred at room temperature overnight. The reaction was complete by TLC (heptane: EtOAc 7:3, Rf (starting material) 0.6, Rf (product) 0.2, developed with KMnO4). The reaction mixture was cooled to -5 °C and quenched by slow addition of H2O (100 ml) in portions over 4.5 h, followed by slow addition of 15% (wt / vol) aqueous NaOH (100 ml) in portions and 282 ml of H2O and stirred at 20 °C overnight. The suspension was filtered through two GF / A filter papers and the filter cake was washed three times with 300 ml of THF. The volatiles were evaporated under reduced pressure to give the desired product 6 as a yellow oil (158.7 g, yield > 99%). 1 H NMR(400MHz,CDCl3)δ:5.83(m,2H),5.11(m,4H),3.56(s,4H),2.07(d,4H)

[0442] Example 2b: Compound 7, 4,4-bis(ω-methyl-(ethyleneoxy)17 -Methyl)-hepta-1,6-diene Compound 6 from Example 2a (178 mg, 1.13 mmol) was dissolved in anhydrous toluene (15 ml) and cooled in an ice bath. When the internal temperature was below 10° C., NaH (199 mg, 7.9 mmol, 95% w / w in mineral oil, 7 eq.) was added in portions. The mixture was then stirred at room temperature for 30 min and diluted with m-PEG in toluene (25 ml). 17 An azeotropically dried solution of -OTs (4.44 g, 4.74 mmol, 4.2 equiv) was added under N2 at 0 °C. The reaction mixture was heated to reflux overnight. The reaction was monitored by HPLC and after completion, the temperature was reduced to 15 °C and quenched by slow addition of H2O (1 ml). The pH of the crude product was adjusted to pH 5-7 with 1.0 M HCl and the mixture was diluted with H2O (60 ml). NaCl (4.5 g) was added at 60 °C and the reaction mixture was extracted three times with EtOAc (20 ml). To the remaining aqueous phase, NaCl (1.5 g) was added and the mixture was further extracted with EtOAc (20 ml) at 60 °C. Extraction fractions of acceptable product purity were combined and the solvent was evaporated. The resulting residue was purified by flash chromatography (C18 column, H2O:acetonitrile, 60:40) and dissolved in DCM. The mixture was then dried over MgSO4, filtered and evaporated to give the desired product 7 (892 mg, 46% yield). 1 H NMR(400MHz,CDCl3)δ5.79(m,2H),5.04(m,4H),3.65(s,350H),3.38(s,6H),3.23(s,2H),2.05(d,2H)

[0443] Example 2c: Compound 8, 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 17 (Methyl)-heptane To an azeotropically dried solution of compound 7 from Example 2b (0.88 g, 0.528 mmol) in toluene (7 ml) was added triethoxysilane (3.97 g, 21 mmol, 40 equiv.). The bath temperature was set to 30° C. and Karstedt's catalyst (77 μl, 2% w / w in xylene) was added. The reaction mixture was stirred at room temperature overnight.

[0444] The reaction is analyzed for the disappearance of an olefinic proton. 1 The reaction was monitored by H-NMR. The solvent was then evaporated and excess silane was removed by co-evaporation with anhydrous toluene (10 ml). The product was dissolved in toluene (17 ml), degassed with three vacuum / nitrogen cycles and stirred with activated SIR-200 resin (710 mg) at 60° C. for 4 days. The solution was filtered from the resin, the resin was washed with toluene (3×12 ml) and the solvent was evaporated under vacuum to give compound 8 (876 mg, 82.4% yield) as a colorless solid. 1 H NMR(400MHz,CDCl3)δ:3.71-3.60(d,123H),3.56(m,4H),3.39(s,6H),1.26(d,J=2.8Hz,5H)

[0445] TIFF2025509109000023.tif54170

[0446] Example 3a: Compound 9, 4,4-bis(ω-methyl-(ethyleneoxy) 45 -Methyl)-hepta-1,6-diene Diallylpropanediol 6 (22 g, 0.1411 mol) was dissolved in anhydrous toluene (2.61 L) and cooled in an ice bath. When the internal temperature was below 10° C., NaH (23.7 g, 0.593 mol, 60% w / w in mineral oil, 4.2 equiv.) was added in three portions while maintaining the temperature below 10° C. The slurry was then stirred at room temperature for 60 min, followed by m-PEG in anhydrous toluene (2.61 L). 45To an azeotropically dried solution of -OTs (1.071 kg, 0.9877 mmol, 3.5 equiv) was added at 0°C under N2. The reaction mixture was heated to reflux overnight and stirred under N2. The reaction was monitored by HPLC and upon completion, the temperature was reduced to 15°C and the reaction was quenched by dropwise addition of H2O (70 ml). The pH of the crude reaction mixture was adjusted to 5-7 with 1.0 M HCl (100 ml). The crude reaction mixture was divided into two equal parts for practical reasons and the two parts were extracted separately. Each half of the crude mixture was diluted with H2O (7.14 L). The temperature was increased to 60°C and NaCl (540 g) was added. The mixture was then stirred for 45 min and extracted three times with EtOAc (2.1 L). To the remaining aqueous phase, NaCl (200 g) was added and the mixture was extracted again three times with EtOAc (2.1 l). The last three extracted fractions had acceptable product purity (HPLC) and were dried over MgSO4, filtered through dual GF / A filters, and the solvent was evaporated. The resulting residues were pooled, dissolved in H2O (2.0 L), and the pH was adjusted to pH 8 with 0.8 M aqueous NaHCO3 (100 ml). The aqueous phase was extracted three times with DCM (500 mL). The organic phase was dried over MgSO4, filtered, and evaporated to give a white residue.

[0447] The extraction process was repeated for the other half of the crude mixture and the final products of both extractions were pooled to give the desired compound 9 (758 g, 66.36% yield, 96.8% purity (HPLC-ELSD)). 1 H NMR(400MHz,CDCl3)δ5.80(m,2H),5.03(m,4H),3.81(m,4H),3.70-3.60(s,540H),3.37(s,6H),3.22(s,4H),2.04(d,4H)

[0448] Example 3b: Compound 10, 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45 (Methyl)-heptane To an azeotropically dried solution of compound 9 from Example 3a (714 g, 0.172 mol) in toluene (5.5 L) was added triethoxysilane (1,117 g, 6.88 mol, 40 equiv.) under nitrogen at 22° C. Karstedt's catalyst (25.34 ml, 2% w / w in xylene, 1.14 mmol, 0.0066 equiv.) was added in 1 mL portions via syringe over 30 min resulting in an exotherm of ≦2° C. The reaction mixture was stirred overnight at 22° C. under nitrogen.

[0449] The reaction is analyzed for the disappearance of an olefinic proton. 1 The reaction mixture was monitored by H-NMR. The solvent was then evaporated and the excess silane was removed by coevaporation with anhydrous toluene (2.5 L) a total of four times. The residue was redissolved in toluene (4.2 L), degassed with three vacuum / nitrogen cycles, and stirred with activated SIR-200 resin (175 g) at 60 °C for 3 days. The solution was filtered from the resin, the resin was washed with toluene (3 x 2.8 L), and the collected fractions were filtered through a double GF / A filter and pooled. The solvent was evaporated to give compound 10 as a white solid in quantitative yield (783.2 g, ≥ 99%, purity 94.4% (HPLC-ELSD)). 1 H NMR(400MHz,C6D6)δ3.88(q,12H),3.70-3.40(s,400H),3.14(s,6H),1.68(m,4H),1.59(m,4H),1.23(t,18H),0.79(t,4H)

[0450] TIFF2025509109000024.tif59170

[0451] Example 4a: Compound 11, 4,4-bis(ω-methyl-(ethyleneoxy) 67 -Methyl)-hepta-1,6-diene Diallylpropanediol 6 (1.14 g, 7.14 mmol) was dissolved in anhydrous toluene (195 ml) and cooled in an ice bath. When the internal temperature was below 10° C., NaH (717 mg, 17.9 mmol, 60% w / w in mineral oil, 2.5 equiv.) was added in three portions while maintaining the temperature below 10° C. The slurry was stirred at room temperature for 60 min, after which m-PEG in anhydrous toluene (195 ml) was added. 67 To an azeotropically dried solution of -OTs (80 g, 25 mmol, 3.5 equiv) was added at 0°C under N2. The reaction mixture was heated to reflux overnight and stirred under N2. The reaction was monitored by HPLC and upon completion, the temperature was lowered to 15°C and quenched by dropwise addition of H2O (3 ml). The pH of the crude product was adjusted to pH 5-7 with 1.0 M HCl (6.5 ml). The reaction mixture was diluted with H2O (533 ml), the temperature was raised to 60°C and NaCl (80 mg) was added. The mixture was stirred for 45 min and extracted three times with EtOAc (300 ml). To the remaining aqueous phase, NaCl (16 g) was added and the mixture was extracted three more times with EtOAc (300 ml). The fourth and fifth extracted fractions had acceptable product purity (HPLC) and were dried over MgSO4, filtered through dual GF / A filters and the solvent was evaporated. The resulting residue was dissolved in HO (500 ml) and the pH was adjusted to pH 8 with 0.8 M aqueous NaHCO (30 ml). The aqueous phase was extracted three times with DCM (100 mL). The organic phase was dried over MgSO, filtered and evaporated to give the desired compound 11 (11.1 g, 49.0% yield, 98.3% purity (HPLC-ELSD)). 1 H NMR(400MHz,CDCl3)δ5.77(m,2H),5.02(m,4H),3.81(m,4H),3.70-3.60(s,875H),3.37(s,6H),3.22(s,4H),2.04(d,4H)

[0452] Example 4b: Compound 12, 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 67 (Methyl)-heptane To an azeotropically dried solution of compound 11 from Example 4a (10 g, 1.6 mmol) in toluene (77.5 ml) was added triethoxysilane (10.4 g, 64 mmol, 40 equiv.) under nitrogen at 22° C. Karstedt's catalyst (235.6 μl, 2% w / w in xylene, 0.023 mmol, 0.0066 equiv.) was then added via syringe over 30 min resulting in an exotherm of ≦2° C. The reaction mixture was stirred overnight at 22° C. under nitrogen.

[0453] The reaction is analyzed for the disappearance of an olefinic proton. 1 The reaction mixture was monitored by H-NMR. The solvent was then evaporated and the excess silane was removed by co-evaporation with anhydrous toluene (39 ml) for a total of four times. The residue was redissolved in toluene (59 ml), degassed with three vacuum / nitrogen cycles, and stirred with activated SIR-200 resin (1.65 g) at 60 °C for three days. The mixture was filtered through two GF / A filters, and the remaining SIR-200 resin was further stirred in anhydrous toluene (39 ml) to recover the product. This process was repeated three times in total. The collected fractions were filtered through two GF / A filters, pooled, and the solvent was evaporated to give the desired product 12 in quantitative yield (11.22 g, yield > 99%, purity 78.3% (HPLC-ELSD)). 1 H NMR(400MHz,C6D6)δ3.88(q,12H),3.60-3.40(s,583H),3.14(s,6H),1.67(m,4H),1.57(m,4H),1.23(m,18H),0.79(t,4H)

[0454] TIFF2025509109000025.tif58170

[0455] Example 5a: Compound 13, 4,4-bis(ω-methyl-(ethyleneoxy) 90 -Methyl)-hepta-1,6-diene Diallylpropanediol 6 (176.2 mg, 1.102 mmol) was dissolved in anhydrous toluene (42 ml) and cooled in an ice bath. When the internal temperature was below 10° C., NaH (185.2 mg, 4.628 mmol, 60% w / w in mineral oil, 4.2 equiv.) was added in three portions while maintaining the temperature below 10° C. The slurry was stirred at room temperature for 60 min, after which m-PEG in anhydrous toluene (42 ml) was added. 90 To an azeotropic dried solution of -OTs (17 g, 3.86 mmol, 3.5 equiv) was added under N at 0° C. The reaction mixture was heated to reflux overnight and stirred under N.

[0456] The next day, additional NaH (22 mg, 0.917 mmol, 0.5 equiv) was added and the mixture was stirred at reflux for 4 h. Crushed NaOH (50 mg) was added to the mixture and stirring was resumed at reflux under N2 overnight.

[0457] The reaction was monitored by HPLC and upon completion, the temperature was reduced to 15°C and the reaction was quenched by dropwise addition of H2O (1 ml). The pH of the crude product was adjusted to pH 5-7 with 1.0 M HCl (2.7 ml). The reaction mixture was diluted with H2O (113 ml), the temperature was increased to 60°C and NaCl (17 g) was added. The mixture was stirred for 45 min and extracted three times with EtOAc (60 ml). To the remaining aqueous phase, NaCl (6 g) was added and the mixture was extracted three more times with EtOAc (60 ml). The last extracted fraction had acceptable product purity (HPLC) and was dried over MgSO4, filtered through a double GF / A filter and the solvent was evaporated. The resulting residue was dissolved in H2O (30 ml) and the pH was adjusted to pH 8 with 0.8 M aqueous NaHCO3 (10 ml). The aqueous phase was extracted three times with DCM (11 mL). The organic phase was dried over MgSO4, filtered and evaporated to give the desired compound 13 (3.2 g, yield > 35.6%, purity 83% (HPLC-ELSD)). 1H NMR(400MHz,CDCl3)δ5.80(m,2H),5.02(m,4H),3.81(m,4H),3.70-3.60(s,875H),3.38(s,6H),3.23(s,4H),2.05(d,4H)

[0458] Example 5b: Compound 14, 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 90 (Methyl)-heptane To an azeotropically dried solution of compound 13 from Example 5a (3 g, 0.272 mmol) in toluene (23.25 ml) was added triethoxysilane (1.75 g, 10.88 mmol, 40 equiv.) under nitrogen at 22° C. Karstedt's catalyst (40.06 μl, 2% w / w in xylene, 0.00386 mmol, 0.0066 equiv.) was then added via syringe over 30 min resulting in an exotherm of ≦2° C. The reaction mixture was stirred overnight at 22° C. under nitrogen.

[0459] The reaction is analyzed for the disappearance of an olefinic proton. 1 The reaction mixture was monitored by H-NMR. The solvent was then evaporated and excess silane was removed by co-evaporation with anhydrous toluene (11.7 ml) for a total of four times. The residue was redissolved in toluene (17.7 ml), degassed with three vacuum / nitrogen cycles, and stirred with activated SIR-200 resin (300 mg) at 60 °C for three days. The mixture was then filtered through two GF / A filters, and the remaining SIR-200 resin was further stirred in anhydrous toluene (11.7 ml) to recover the product. This process was repeated three times in total. The collected fractions were filtered through two GF / A filters, pooled, and the solvent was evaporated to give the desired product 14 as a white solid (2.73 mg, 32.1% yield, 27.1% purity (HPLC-ELSD)). 1 H NMR(400MHz,C6D6)δ3.94(q,12H),3.60-3.40(s,752H),3.14(s,6H),1.22(m,18H)

[0460] TIFF2025509109000026.tif54170

[0461] Example 6a (hypothetical example): Compound 15, 4,4-bis(ω-methyl-(ethyleneoxy) 112 -Methyl)-hepta-1,6-diene Before the reaction begins, water is removed from the starting material using a Dean-Stark apparatus. The two alcohol groups of compound 6 are deprotonated with a strong base such as NaH to give m-PEG. 112 Coupling with an azeotropic dried solution of a PEGylation reagent bearing a suitable leaving group such as -OTs gives compound 15.

[0462] Example 6b (hypothetical example): Compound 16, 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 112 (Methyl)-heptane Before the reaction begins, water is removed from the starting materials using a Dean-Stark apparatus. The two allyl groups of compound 15 are hydrosilylated using a silane such as (EtO)3SiH and a catalyst such as a platinum compound such as Karstedt's catalyst. If any platinum remains, it is removed by treatment with activated SIR-200 resin, if desired, to give the final compound 16.

[0463] TIFF2025509109000027.tif120170

[0464] Example 7a: Compound 17, methanesulfonic acid 2-allylpent-4-enyl ester In a 100 ml round bottom flask, diallyl alcohol 3 (1.00 g, 7.92 mmol) was dissolved in DCM (40 ml). The temperature of the reaction was set to 0° C. and triethylamine (1.1 ml, 11.9 mmol, 1.5 equiv.) was added. After stirring for 30 min, MsCl (0.914, 9.5 mmol, 1.2 equiv.) was added portionwise. The mixture was allowed to reach room temperature and stirred for another 3 h. The reaction was monitored by TLC until the starting material was completely converted and quenched by adding 0.5 M HCl (36 ml). The two layers were separated and the organic phase was removed. The aqueous phase was extracted three times with DCM (36 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum to give compound 17 as a colorless oil (1.387 g, 85.7% yield). 1 H NMR(400MHz,CDCl3)δ:5.76(m,2H),5.09(d,4H),4.13(d,J=5.6Hz,2H),3.00(s,3H),2.16(t,J=7.0Hz,4H),1.93(hept,J=6.4Hz,1H)

[0465] Example 7b: Compound 18, (2-allyl-pent-4-enyl)-diethyl malonate NaH (48.6 mg, 1.17 mmol, 60% w / w dispersion in mineral oil) was suspended in dry DMF (1.7 ml) and THF (850 μl) and cooled to 0° C. Diethyl diallylmalonate 1 (187 mg, 1.17 mmol) was added dropwise and the reaction was allowed to warm to room temperature. The crude product from Example 7a (80 mg, 0.392 mmol) was added as a solution in dry THF (850 μl) followed by KI (167 mg, 1.17 mmol). The reaction mixture was stirred at reflux under nitrogen at 80° C. overnight. The reaction was monitored by TLC until complete conversion and cooled to room temperature. It was quenched with saturated NH4Cl (3 ml) and extracted with EtOAc (3×2 ml). The organic phases were combined, dried over MgSO4, filtered and the solvent was removed under vacuum. The resulting residue was purified by short flash chromatography (heptane:EtOAc=7:1) to give the desired compound 18 as a yellow oil in quantitative yield. 1 H NMR(400MHz,CDCl3)δ:5.74(m,2H),5.04(m,4H),4.19(m,J=7.1,4H),3.46(t,J=7.7H z,1H),2.07(m,4H),1.87(t,J=7.3Hz,2H),1.54(m,J=13.0,1H),1.26(t,J=7.1Hz,6H)

[0466] Example 7c: Compound 19, 2-(2-allyl-pent-4-enyl)-diethyl-1,3-propanediol A solution of compound 18 (247 mg, 0.92 mmol) from Example 7b in THF (1.5 ml) was added dropwise to a suspension of LiAlH4 (88.24 mg, 2.4 equiv) in THF (3 ml) at 0° C., maintaining the exotherm below 5° C. during the addition. The reaction was allowed to come to room temperature and stirred for 6 h. The reaction was monitored by TLC until complete conversion. The temperature was lowered to 0° C. and the reaction was quenched by adding H2O (1.0 ml) followed by 15% NaOH (0.2 ml), then further diluted with 1 ml of H2O. A white precipitate was observed and the suspension was filtered through two GF / A filters and the filter cake was washed with 2 ml of THF. The volatiles were removed in vacuo and the resulting residue was purified by flash chromatography (heptane:EtOAc 3:2 followed by heptane:EtOAc 1:1) to give the desired product 19 (114 mg, 67.4% yield). 1 H NMR(400MHz,CDCl3)δ:5.83-5.68(m,2H),5.02(d,4H),3.80(dd,J=10.6,3.7Hz,2H),3.63(dd,J=10.6 ,7.6Hz,3H),2.14-1.98(m,4H),1.96-1.85(m,1H),1.57(dq,J=12.9,6.5Hz,1H),1.16(t,J=7.0Hz,2H)

[0467] Example 7d: Compound 20, 2-(2-allyl-pent-4-enyl)-diethyl-1,3-bis(ω-methyl-(ethyleneoxy) 45 (Methyl)-propane Compound 19 from Example 7c (110 mg, 0.6 mmol) was dissolved in anhydrous toluene (15 ml) and cooled in an ice bath. When the internal temperature was below 10° C., NaH (111 mg, 4.2 mmol, 90% (w / w) in mineral oil, 7 eq.) was added in portions. The mixture was then stirred at room temperature for 30 min and diluted with m-PEG in toluene (25 ml). 45 Azeotropically dried solution of -OTs (5.43 g) was added at 0° C. under N2. The reaction mixture was heated to reflux overnight and stirred under N2. The reaction was monitored by HPLC and after completion, the temperature was reduced to 15° C. and quenched by slow addition of H2O (0.3 ml). The solvent was evaporated and the residue was dissolved in H2O (72 ml). NaCl (5.42 g) was added at 60° C. and the reaction mixture was extracted once with EtOAc (25 ml). To the remaining aqueous phase, NaCl (1.80 g) was added and the mixture was extracted with EtOAc (25 ml) at 60° C. The organic phases were combined, dried over MgSO4, filtered and the solvent was evaporated. The resulting residue was purified by flash chromatography (C18 column, H2O:acetonitrile 63:47) to give the desired product 20 (485 mg, 19% yield). 1 H NMR(400MHz,CDCl3)δ5.74(m,2H),5.00(m,4H),3.71-3.60(s,225H),3.39(m,6H),2.20(m,4H),1.25(s,4H)

[0468] Example 7d: Compound 21, 1,7-bis(triethoxysilyl)-4-(2,2-bis(ω-methyl-(ethyleneoxy) 45 -Methyl)-Ethyl)-Heptane To an azeotropically dried solution of compound 20 from Example 7d (0.13 g, 0.035 mmol) in dry toluene (2 ml) was added triethoxysilane (0.22 g, 1.3 mmol, 40 equiv). The bath temperature was set to 30° C. and Karstedt's catalyst (5 μl, 2% w / w in xylene) was added. The reaction mixture was stirred overnight at room temperature. The reaction was monitored for the disappearance of olefinic protons. 1The reaction was monitored by H-NMR. The solvent was then evaporated and the excess silane was removed by coevaporation with anhydrous toluene (2 ml). The product was dissolved in toluene (2 ml), degassed with three vacuum / nitrogen cycles and stirred with activated SIR-200 resin (50 mg) at 60° C. for 2 days. Filtration and evaporation of the solvent gave the final compound 21 as a colorless solid.

[0469] TIFF2025509109000028.tif111170

[0470] Example 8a: Compound 23, 2,2-di-but-3-enyl-malonic acid diethyl ester In a 100 ml round bottom flask, NaH (2.4 g, 0.1 mol, 60% wt / wt dispersion in mineral oil) was suspended in 50 ml dry DMF at 0° C. under nitrogen. Dimethyl malonate 22 (2.3 ml, 0.02 mmol) was added to the mixture at 0° C., followed by 4-bromo-1-butene (5.20 ml, 0.052 mmol, 2.6 equiv). The suspension was stirred at room temperature for 2 h, then gradually heated to 70° C. and stirred overnight. The next day, the reaction was allowed to cool to room temperature and quenched with NH4Cl (50 ml, saturated aqueous solution). The reaction mixture was extracted three times with 100 ml diethyl ether. The organic phases were combined, dried over MgSO4, filtered and the solvent was removed under vacuum. The resulting residue was purified by flash chromatography (heptane:EtOAc=9:1) to give the desired product 23 as a yellow oil (4.06 g, 84.7% yield). 1 H NMR(400MHz,CDCl3)δ:5.77(m,2H),5.00(m,4H),3.72(s,6H),1.98(m,8H)

[0471] Example 8b: Compound 24, 2,2-di(but-3-enyl)propane-1,3-diol A solution of compound 23 (3.59 g, 0.015 mmol) from Example 8a in THF (15 ml) was added dropwise to a suspension of LiAlH4 in THF (30 ml) at 0° C., keeping the exotherm below 5° C. during the addition. The reaction was stirred at room temperature overnight and monitored by TLC until complete conversion. The reaction was quenched by adding H2O (4.0 ml), followed by 15% (wt / vol) NaOH (4.0 ml) and finally 20 ml of H2O. A white precipitate was observed and the suspension was filtered through two GF / A filters and the filter cake was washed twice with 20 ml of THF. The suspension was extracted three times with DCM (50 ml). The combined organic phase was washed with brine (150 ml), dried over MgSO4, filtered and the solvent was removed under vacuum. The resulting residue was purified by flash chromatography (heptane:EtOAc=7:3) to give the desired product 24 (2.0 g, 70% yield). 1 H NMR(400MHz,CDCl3)δ:5.82(m,J=16.8Hz,2H),5.04(d,J=17.26Hz,2H),4.96(d,J=10.15Hz,2H),3.60(s,4H),2.01(m,4H),1.40(m,4H)

[0472] Example 8c: Compound 25, 5,5-bis(ω-methyl-(ethyleneoxy) 45 -Methyl)-nona-1,8-diene NaH (272 mg, 10.8 mmol, 95% in mineral oil, 2.9 equiv.) in 100 ml of anhydrous THF with compound 24 from Example 8b (1.0 g, 3.73 mmol) and m-PEG 45 A mixture of 2H-OTs (19.41 g, 8.9 mmol, 2.4 equiv.) was heated to 40° C. and stirred under N2 overnight. The reaction was monitored by TLC and after completion, it was quenched by slow addition of H2O (5 ml). The reaction mixture was dried over MgSO4, filtered and the solvent was evaporated to give a white residue. To remove impurities from the residue, the crude product was first dissolved in DCM (50 ml) and then precipitated by adding diethyl ether (200 ml). The white solid was collected by filtration and the precipitation process was repeated a total of three times to give the desired product 25. 1 H NMR(400MHz,CDCl3)δ:5.80(m,2H),4.98(m,4H),3.70-3.60(s,659H),3.54(m,4H),3.37(s,6H),2.03(s,4H),1.36(m,4H)

[0473] Example 8d: Compound 26, 1,9-bis(triethoxysilyl)-5,5-bis(ω-methyl-(ethyleneoxy) 45 (Methyl)-nonane To an azeotropically dried solution of compound 25 from Example 8c (3.0 g, 0.724 mmol) in anhydrous toluene (25 ml) was added triethoxysilane (550 μl, 2.94 mmol, 4.0 equiv). The bath temperature was set at 30° C. and Karstedt's catalyst (100 μl, 2% (wt / wt) in xylene) was added. The reaction mixture was stirred at room temperature overnight. The reaction was monitored for the disappearance of olefinic protons. 1 The reaction was monitored by H-NMR. The solvent was then evaporated and the excess silane was removed by coevaporation with anhydrous toluene (40 ml). The product was dissolved in toluene (50 ml), degassed with three vacuum / nitrogen cycles and stirred with activated SIR-200 resin (2.28 g) at 60° C. for 4 days. After filtration and washing three times with toluene (50 ml), the solvent was evaporated to give compound 26 (2.419 g, 75.6% yield) as a colorless solid. 1 H NMR(400MHz,CDCl3)δ:3.88-3.73(m,12H),3.62(s,365H),3.52(m,4H),3.35(s,6H),1.20(q,J=6.9Hz,18H)

[0474] TIFF2025509109000029.tif118170

[0475] Example 9a: Compound 27, 2,2-di-pent-4-enyl-malonic acid diethyl ester In a 100 ml round bottom flask, NaH (2.4 g, 0.1 mol, 60% wt / wt dispersion in mineral oil) was suspended in 50 ml dry DMF under nitrogen at 0° C. Dimethyl malonate 22 (2.3 ml, 0.02 mmol) was added to the mixture at 0° C., followed by 1-bromo-4-pentene (6.2 ml, 0.1 mmol). The suspension was stirred at room temperature for 2 h, then gradually heated to 50° C. and stirred overnight.

[0476] The next day, the reaction was cooled to room temperature and quenched with NH4Cl (50 mL, saturated aqueous solution). The reaction mixture was extracted three times with diethyl ether (100 mL). The organic phases were combined, dried over MgSO4, filtered, and the solvent was removed under vacuum. The resulting residue was purified by flash chromatography to give the desired product 27 (4.0 g, 56% yield). 1 H NMR(400MHz,CDCl3)δ:5.78(m,2H),4.99(m,4H),3.72(s,6H),2.06(m,J=7.50Hz,4H),1.89(m,4H),1.26(m,J=7.50Hz,4H)

[0477] Example 9b: Compound 28, 2,2-di(pent-4-enyl)-propane-1,3-diol A solution of compound 27 (3.59 g, 0.015 mmol) from Example 9a in THF (15 ml) was added dropwise to a suspension of LiAlH4 in THF (30 ml) at 0° C., maintaining the exotherm below 5° C. during the addition. The reaction was stirred overnight and monitored by TLC until complete conversion. The reaction was quenched by adding H2O (4 ml) followed by 15% (wt / vol) NaOH (4 ml) and a white precipitate was observed. The suspension was filtered through two GF / A filters and the filter cake was washed twice with 20 ml of THF. The suspension was transferred to a separatory funnel and extracted three times with DCM (50 ml). The combined organic phase was washed with brine (150 ml), dried over MgSO4, filtered and the solvent was removed under vacuum. The resulting residue was purified by flash chromatography (heptane:EtOAc=9:1) to give the desired product 28 (2.0 g, 70% yield). 1 H NMR(400MHz,CDCl3)δ:5.80(m,2H),4.98(d,4H),3.57(s,4H),2.04(m,4H),1.30(m,8H)

[0478] Example 9c: Compound 29, 6,6-bis(ω-methyl-(ethyleneoxy) 45 -Methyl)-undeca-1,10-diene Compound 28 from Example 9b (1 g, 3.75 mmol) was dissolved in anhydrous toluene (80 ml) and cooled in an ice bath. When the internal temperature was below 10° C., NaH (176 mg, 7 mmol, 95% w / w in mineral oil, 7 eq.) was added in portions. The mixture was then stirred at room temperature for 30 min and dissolved in m-PEG in toluene (100 ml). 45 An azeotropically dried solution of -OTs (13.2 g, 6.08 mmol, 6 equiv) was added at 0° C. under N2. The reaction mixture was heated to reflux overnight and stirred under N2. The reaction was monitored by HPLC and upon completion, the temperature was lowered to 15° C. and quenched by slow addition of H2O (20 ml). The solvent was evaporated and the residue was purified by flash chromatography (C18 column, H2O:acetonitrile 60:40) to give the desired product 29 (2.0 g, 70% yield). 1 H NMR(500MHz,CDCl3)δ:5.78(m,J=16.9Hz,2H),4.94(m,4H),3.69-3.60(s,391H),3.53(m,4H),3.37(s,6H),1.99(m,4H),1.25(m,8H)

[0479] Example 9d: Compound 30, 1,11-bis(triethoxysilyl)-6,6-bis(ω-methyl-(ethyleneoxy) 45 (Methyl)-undecane To an azeotropically dried solution of compound 29 from Example 9c (0.91 g, 0.216 mmol) in toluene (7 ml) was added triethoxysilane (1.47, 7.9 mmol, 40 equiv.). The reaction temperature was set to 30° C. and Karstedt's catalyst (32 μl, 2% (w / w) in xylene) was added. The reaction mixture was stirred at room temperature overnight.

[0480] The reaction is analyzed for the disappearance of an olefinic proton. 1 The reaction mixture was monitored by H-NMR. The solvent was then evaporated and excess triethoxysilane was removed by coevaporation with anhydrous toluene (4 ml). The product was dissolved in toluene (6 ml), degassed with three vacuum / nitrogen cycles, and stirred with activated SIR-200 resin (300 mg) at 60° C. for 4 days. After filtration and washing three times with toluene (10 ml), the solvent was evaporated to give compound 30 as a colorless solid (purity 85.3% (HPLC-ELSD)).

[0481] TIFF2025509109000030.tif110170

[0482] Example 10a: Compound 32, 2,2-divinyl-propane-1,3-diol A solution of compound 31 (214 mg, 1.01 mmol) in THF (2 ml) was added dropwise to a suspension of LiAlH4 in THF (5 ml) at 0 °C, keeping the exotherm below 5 °C during the addition. The reaction was stirred at room temperature overnight and monitored by TLC until complete conversion. The reaction was quenched by adding H2O (1 ml) followed by 15% (wt / vol) NaOH (250 μl). The suspension was filtered and the filter cake was washed with THF (25 ml). The suspension was transferred to a separatory funnel and extracted three times with DCM (2 ml). The combined organic phase was washed with brine (5 ml), dried over MgSO4, filtered and the solvent removed under vacuum to give the desired product 32 in quantitative yield. 1 H NMR(400MHz,CDCl3)δ:5.79(m,2H),5.32(d,J=11.0Hz,2H),5.22(d,J=17.6,Hz,3H),3.75(s,4H)

[0483] Example 10b: Compound 33, 3,3-bis(ω-methyl-(ethyleneoxy) 45 -Methyl)-penta-1,4-diene Divinylpropanediol 32 from Example 10a (152 mg, 1.2 mmol) was dissolved in anhydrous toluene (6 ml) and cooled in an ice bath. When the internal temperature was below 10° C., NaH (149 mg, 5.9 mmol, 95% w / w in mineral oil, 5 eq.) was added in three portions while maintaining the temperature below 10° C. The slurry was stirred at room temperature for 60 min, after which m-PEG in anhydrous toluene (48 ml) was added. 45 To an azeotropically dried solution of -OTs (10.78 g, 4.9 mmol, 4.2 equiv) was added under N2 at 0°C. The reaction mixture was heated to reflux overnight and stirred under N2. The reaction was monitored by HPLC and upon completion, the temperature was reduced to 15°C and quenched by dropwise addition of H2O (3 ml). The solvent was evaporated and the residue was dissolved in DCM (20 ml). MgSO4 was added and the suspension was stirred for 20 min. The volatiles were evaporated under vacuum and the residual MgSO4 was filtered to give the desired product 33 as a colorless solid in quantitative yield.

[0484] Example 10c (hypothetical example): Compound 34, 1,5-bis(triethoxysilyl)-3,3-bis(ω-methyl-(ethyleneoxy) 45 -Methyl)-pentane Before the reaction begins, water is removed from the starting materials using a Dean-Stark apparatus. The two vinyl groups of compound 33 are hydrosilylated using a silane such as (EtO)3SiH and a catalyst such as a platinum compound such as Karstedt's catalyst. If any platinum remains, it is removed by treatment with activated SIR-200 resin, if desired, to give the final compound 34.

[0485] TIFF2025509109000031.tif56170

[0486] Example 11a: Compound 36, 3,4-bis(ω-methyl-(ethyleneoxy) 45)-Hexa-1,5-diene Divinyl glycol 35 (15 mg, 1.3 mmol) was dissolved in anhydrous toluene (20 ml) and cooled in an ice bath. When the internal temperature was below 10° C., NaH (232 mg, 9.2 mmol, 95% w / w in mineral oil, 7 eq.) was added in three portions while maintaining the temperature below 10° C. The slurry was stirred at room temperature for 60 min, after which m-PEG in anhydrous toluene (25 ml) was added. 45 To an azeotropically dried solution of -OTs (8.28 g, 3.8 mmol, 3.2 equiv) was added under N2 at 0°C. The reaction mixture was heated to reflux overnight and stirred under N2. The reaction was monitored by HPLC and upon completion, the temperature was reduced to 15°C and the reaction was quenched by dropwise addition of H2O (3 ml). The solvent was evaporated and the residue was dissolved in DCM (20 ml). MgSO4 was added and the suspension was stirred for 20 min. The volatiles were evaporated under vacuum and the residual MgSO4 was filtered to give the desired product 36 as a colorless solid in quantitative yield.

[0487] Example 11b (hypothetical example): Compound 37, 1,6-bis(triethoxysilyl)-3,4-bis(ω-methyl-(ethyleneoxy) 45 )-Hexane Before the reaction begins, water is removed from the starting materials using a Dean-Stark apparatus. The two vinyl groups of compound 36 are hydrosilylated using a silane such as (EtO)3SiH and a catalyst such as a platinum compound such as Karstedt's catalyst. Any remaining platinum is removed by treatment with activated SIR-200 resin to give the final compound 37.

[0488] TIFF2025509109000032.tif121170The synthesis of compound 43 begins with the activation of the alcohol group of 38 as the mesylate 39, which is then subjected to a nucleophilic displacement reaction with dimethyl malonate to give compound 40. The two ester groups are reduced with a reducing agent such as LiAlH4 to give the diol 41. The two alcohol groups are deprotonated with a strong base such as NaH to give m-PEG 42. 45Coupling with a PEGylation reagent bearing an appropriate leaving group, such as -OTs, gives compound 42. Finally, hydrosilylation of the two allyl groups using (EtO)3SiH and a catalyst, such as Karstedt's catalyst, gives compound 43.

[0489] TIFF2025509109000033.tif116170The synthesis of compound 49 begins with the activation of the alcohol group of 44 as the mesylate 45, which is then subjected to a nucleophilic displacement reaction with dimethyl malonate to give compound 46. The two ester groups are reduced with a reducing agent such as LiAlH4 to give the diol 47. The two alcohol groups are deprotonated with a strong base such as NaH to give m-PEG 48. 45 Coupling with a PEGylation reagent bearing an appropriate leaving group such as -OTs gives compound 48. Finally, hydrosilylation of the two allyl groups using (EtO)3SiH and a catalyst such as Karstedt's catalyst gives compound 49.

[0490] Example 14: Use of compounds according to the present disclosure as coating precursors Compounds 10, 5, 12, and 14 were used as coating precursors for coating nanostructures.

[0491] Example 14a: 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45 -methyl)-heptane, compound 10, as a coating precursor The precursor nanostructures were synthesized by refluxing 93.60 g of 1,7-bis-(triethoxysilyl)-4,4-bis-(dimethylphosphonato)-heptane 52 in 4,501 g of 90.0% (vol / vol) aqueous ethylene glycol for 48 h, resulting in a solution of precursor nanostructures with a hydrodynamic diameter of 17.6 nm and a phosphorus concentration of 69 mM.

[0492] Primed precursor nanostructures were synthesized by heating 4,338 g of the precursor nanostructure solution with 116.48 g of bis(triethoxysilyl)methane at 100° C. for 4 hours, resulting in a solution of primed nanostructures with a hydrodynamic diameter of 19.7 nm and a phosphorus concentration of 64 mM.

[0493] A 10 L jacketed reactor equipped with a mechanical stirrer, temperature probe, a dropping funnel heated to 40 °C with a heating fan, and a reflux condenser with its top connected to a N2 / vacuum manifold was charged with 6,330 g of 90% (vol / vol) aqueous ethylene glycol and 3,902 g of the primer treated precursor nanostructure solution.

[0494] The jacket temperature was set at 125° C. for 1 hour and then reduced to 110° C. 548.2 g of 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 45 A coating solution was prepared by dissolving 100.2 g of 1,2-dimethyl-3,4-hexanediaminetetraacetate in 548.2 g of absolute ethanol with heating to 40° C. When the internal temperature of the reactor was 105° C., 250 ml of coating solution was added. The remaining coating solution was added slowly at 50 ml / hr via a dropping funnel. The jacket temperature was held at 110° C. until 48 hours after the first addition of coating solution to the reactor, and then cooled to 20° C.

[0495] The reaction mixture was transferred to a 20 L jug fitted with a 4-port lid. The reactor was rinsed with ultrapure water (5+4 L) and this rinse was added to the jug. The jug was shaken to mix the contents. The contents were filtered through an autoclaved filter assembly consisting of 1 μm, 0.4 μm, and 0.2 μm filters connected in series into a new 20 L jug. The filtered solution was concentrated at 5,400 cm 2 The solution was purified by ultrafiltration using a 300 kD TFF filter until the ethylene glycol concentration was less than 500 ppm.

[0496] Nanostructures synthesized in this way do not aggregate even when exposed to 20 mM CaCl2.

[0497] TIFF2025509109000034.tif8170

[0498] Example 14b: 4-[ω-methyl-(ethyleneoxy) 45 -methyl]-1,7-bis(triethoxysilyl)heptane, compound 5, as a coating precursor 1,056 mg of 4-[ω-methyl-(ethyleneoxy) 45 A coating solution was prepared by dissolving 1,2-methyl-1,7-bis(triethoxysilyl)heptane in an equal mass of anhydrous dioxane at 40°C. A two-necked pear flask equipped with a reflux condenser topped with a N2 / vacuum manifold was charged with 5 ml of a solution of primed nanostructures with a hydrodynamic diameter of 20.1 nm and a phosphorus concentration of 150 mM, prepared similarly to the solution used in Example 14a, and heated in a 110°C oil bath for 10 minutes. A 200 μl portion of the coating solution was added to the nanostructure solution. An additional 1,700 μl of the coating solution was added via syringe pump over 20 hours, with the syringe and needle heated to approximately 40°C with a heating fan. The reaction temperature was held at 110°C until 48 hours after the first addition of the coating solution, after which it was cooled to ambient temperature. The solution was filtered through a 0.2 μm PES filter, diluted with water, and cooled to 115 cm 2 The mixture was purified by ultrafiltration using a 300 kD TFF filter.

[0499] Nanostructures synthesized in this way do not aggregate even when exposed to 20 mM CaCl2.

[0500] TIFF2025509109000035.tif8170

[0501] Example 14c: 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 67 -methyl)-heptane, compound 12, as a coating precursor A 13.4 mL sample of solution of primed nanostructures with a hydrodynamic diameter of 19.2 nm and a phosphorus concentration of 64 mM, prepared similarly to the solution used in Example 14a, was diluted to 36.1 mL with 90% (vol / vol) aqueous ethylene glycol in a two-neck round-bottom flask fitted with a reflux condenser at the vertical end connected at the top to a N2 / vacuum manifold and the side end plugged with a septum. This solution was heated in a preheated 110° C. oil bath for 20 minutes, followed by dilution with 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 67 1,500 μl of a 50% (weight / weight) solution of 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 67 An additional 5,200 μl of the (-methyl)heptane solution was added via syringe pump at a rate of 266 μl / hr. After a total of 48 hours, the solution was allowed to cool to ambient temperature.

[0502] The resulting nanostructure solution was diluted to 150 ml with water and filtered through a dual glass fiber filter followed by a 0.2 μm polyethersulfone (PES) syringe filter. The resulting solution was diluted to 800 ml with water and concentrated to approximately 20 ml using a tangential flow filtration device with a nominal cutoff of 70 kD. The dilution-concentration procedure was repeated a total of four times, after which the solution was further concentrated to 20 ml with a spin filter with a nominal cutoff of 300 kD.

[0503] Nanostructures synthesized in this way do not aggregate even when exposed to 20 mM CaCl2.

[0504] TIFF2025509109000036.tif8170

[0505] Example 14d: 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 90 -methyl)-heptane, compound 14, as a coating precursor A 4.1 mL sample of solution of primed nanostructures with a hydrodynamic diameter of 19.2 nm and a phosphorus concentration of 64 mM, prepared similarly to the solution used in Example 14a, was diluted to 11 mL with 90% (vol / vol) aqueous ethylene glycol in a two-neck round-bottom flask fitted with a reflux condenser at the vertical end connected at the top to a N2 / vacuum manifold and the side end plugged with a septum. This solution was heated in a preheated 110° C. oil bath for 15 minutes, followed by dilution with 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 91 530 μl of a 50% (w / w) solution of 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy) 90 An additional 2,120 μl of the (-methyl)heptane solution was added via syringe pump at a rate of 109 μl / hr. After a total of 48 hours, the solution was allowed to cool to ambient temperature.

[0506] The resulting nanostructure solution was diluted to 40 ml with water and filtered through a dual glass fiber filter followed by a 0.2 μm polyethersulfone (PES) syringe filter. The resulting solution was diluted to 800 ml with water and concentrated to approximately 20 ml using a tangential flow filtration device with a nominal cutoff of 70 kD. The dilution-concentration procedure was repeated a total of four times, after which the solution was further concentrated to 10 ml with a spin filter with a nominal cutoff of 300 kD.

[0507] Nanostructures synthesized in this way do not aggregate even when exposed to 20 mM CaCl2.

[0508] TIFF2025509109000037.tif7170

[0509] Example 15: Use of compounds outside the scope of this disclosure as coating precursors (reference example) Compounds 51 and 52 are outside the scope of this disclosure and are used as reference examples.

[0510] Example 15a: 1-(ω-methyl-(ethyleneoxy) 45 -methyl)-3,5-bis(3-(triethoxysilyl)propyloxy)-benzene, compound 51, as a coating precursor (Reference Example) 2,500 mg of 1-(ω-methyl-(ethyleneoxy) 45 A coating solution was prepared by dissolving 1,2-dichlorophenyl)-3,5-bis(3-(triethoxysilyl)propyloxy)-benzene, 51, in an equal mass of anhydrous dioxane at 40° C. A two-necked pear flask equipped with a reflux condenser topped with a N2 / vacuum manifold was charged with 8 mL of a solution of primed nanostructures with a hydrodynamic diameter of 15.1 nm and a phosphorus concentration of 99 mM, prepared similarly to the solution used in Example 14a, and heated in a 110° C. oil bath for 5 minutes. A 300 μL aliquot of the coating solution was added to the nanostructure solution. An additional 1,970 μL of the coating solution was added via syringe pump over 20 hours, with the syringe and needle heated to approximately 40° C. with a heating fan. The reaction temperature was held at 110° C. until 48 hours after the initial addition of coating solution, after which it was cooled to ambient temperature. The solution was filtered through a 0.2 μm PES filter, diluted with water, and cooled to ambient temperature at 115 cm. 2 The mixture was purified by ultrafiltration using a 300 kD TFF filter.

[0511] TIFF2025509109000038.tif8170

[0512] Example 15b: 1-(ω-methyl-(ethyleneoxy) 45 )-10-triethoxysilyl-decane, compound 52, as a coating precursor (reference example) 425mg of 1-(ω-methyl-(ethyleneoxy) 45A coating solution was prepared by dissolving 10-triethoxysilyl-decane, 52, in an equal mass of anhydrous dioxane at 40° C. A reaction vial was charged with 2.5 ml of a solution of primed nanostructures with a hydrodynamic diameter of 18.4 nm and a phosphorus concentration of 104 mM, prepared similarly to the solution used in Example 14a, and heated in an oil bath at 110° C. A 70 μl aliquot of the coating solution was added to the nanostructure solution. An additional 700 μl of the coating solution was added via syringe pump over 20 hours, with the syringe and needle heated to approximately 40° C. with a heating fan. The reaction temperature was held at 110° C. for 94 hours after the first addition of coating solution, after which it was cooled to ambient temperature. The solution was filtered through a 0.2 μm PES filter, diluted with water, and then cooled to ambient temperature at 115 cm. 2 The mixture was purified by ultrafiltration using a 300 kD TFF filter.

[0513] TIFF2025509109000039.tif8170

[0514] Example 16: Comparison of nanostructures coated with coating precursors according to the present disclosure to nanostructures coated with reference coating precursors outside the scope of the present disclosure Nanostructures coated with compounds 5 and 10 were compared to nanostructures coated with a compound outside the scope of this disclosure (compound 51).

[0515] Example 16a: Nanostructures coated with precursors according to the present disclosure have longer plasma half-lives than nanostructures coated with reference precursors 1,7-bis(triethoxysilyl)-4,4-bis(ω-methyl-(ethyleneoxy)silyl) prepared according to Examples 14a, 14b, and 15a, respectively. 45 -methyl)-heptane (compound 10) (test sample A); 4-[ω-methyl-(ethyleneoxy) 45 -methyl]-1,7-bis(triethoxysilyl)heptane (compound 5) (test material B): and the reference compound 1-(ω-methyl-(ethyleneoxy) 45Nanostructures coated with (3-methyl)-3,5-bis(3-(triethoxysilyl)propyloxy)-benzene (compound 51) (test article C, a reference compound outside the scope of this disclosure) were loaded with yttrium in the form of YCl3 such that [P] / [Y] was 23 (±1). The test article was formulated for injection by adjusting [Ca], pH, and osmolality to physiological levels with CaCl2, NaOH, and mannitol, respectively. The in vivo behavior was investigated by injecting the test article at a dose of 2 μmol Y / kg into female BALB / c mice. Blood was collected 1, 6, and 24 hours after injection and plasma was analyzed for [Y] and [Si] by ICP-OES. The results are shown in Table 1 in the form of circulating half-lives. TIFF2025509109000040.tif54170

[0516] As can be seen from Table 1, nanostructures (A) and (B) coated with a coating precursor according to the present disclosure exhibit significantly increased circulation times compared to nanostructures (C) coated with a reference coating precursor.

[0517] Example 16b: Nanostructures coated with precursors according to the present disclosure have better storage stability than nanostructures coated with reference precursors Nanostructures coated with compound 51, i.e., coated nanostructures according to Example 15a, were stored for 48 hours at 4° C. Decomposition products associated with shedding of the coating layer were detected at a total concentration of >5% (area / area) as measured by SEC-ELSD.

[0518] Nanostructures coated with compound 10, i.e., coated nanostructures according to Example 14a, were stored at 4° C. for 106 days. Degradation products associated with shedding of the coating layer were detected at a total concentration of <3% (area / area) as measured by SEC-ELSD. This indicates that the storage stability of nanostructures coated with the coating precursor of the present disclosure is increased by approximately two orders of magnitude compared to nanostructures coated with the reference coating precursor.

[0519] Nanostructures coated with compound 10, i.e., nanostructures coated according to Example 14a, were stored at 4° C. for 76 days. DLS was measured before (27.0 nm) and after (26.9 nm) storage, and no significant change in the diameter of the nanostructures could be detected. This indicates that the storage stability of nanostructures coated with the coating precursor of the present disclosure is good with respect to aggregation.

[0520] Example 17: Use of nanostructures coated with coating precursors according to the present disclosure in pharmaceutical compositions At 10 weeks of age, female BALB / c mice were inoculated with 4T1 cells (1 × 10 5 Tumors were induced by subcutaneous inoculation of 1000 cells into the right flank area.

[0521] The coated nanostructures according to Example 14a (the nanostructures coated with compound 10) were treated with approximately 1 atom of 10 per nanostructure. 177 So that the concentration of Lu 177 Lu was loaded and formulated for injection by adding Tris buffer, CaCl2, and saline (150 mM NaCl).

[0522] Tumor volume is 200-300mm 3 On the 14th or 15th day after inoculation, when 177 Lu-loaded nanostructures were injected at a dose of 218 MBq / kg, and the control group (n=10) was administered saline. Antitumor efficacy was monitored by following tumor growth and overall survival.

[0523] The treatment group showed a significant increase in mean and median survival time compared to the control group (see Table 2). Furthermore, tumor growth was significantly delayed in the treatment group (see Figure 12). TIFF2025509109000041.tif51170

[0524] Thus, nanostructures coated with the coating precursor according to the present disclosure can be used in pharmaceutical compositions, which can be used in the treatment of cancer.

[0525] Additionally, it has been demonstrated that nanostructures coated with coating precursors according to the present disclosure can be used as carriers for radionuclides.

[0526] Example 18: Use of nanostructures coated with coating precursors according to the present disclosure as carriers for radionuclides The coated nanostructures according to Example 14a (the nanostructures coated with compound 10) were treated in the same manner as in Example 17. 177 Lu was supported. 177 Lu was not detected by γ-counter-SEC. Less than 2.5% migrated by radio-TLC on silica eluted with citrate buffer. 177 Lu, and the remainder was bound to the nanostructures and was completely retained at the baseline of the TLC plate.

[0527] This demonstrates that nanostructures coated with coating precursors according to the present disclosure can be used as carriers for radionuclides.

[0528] Example 19: 4,4-bis(ω-methyl-(ethyleneoxy)) under standard hydrosilylation conditions, showing the superiority of the hydrosilylation method of the present disclosure 45 Hydrosilylation of (-methyl)-hepta-1,6-diene, compound 9 (reference example outside the scope of this disclosure) A 10 ml round bottom flask was charged with 600 mg of azeotropically dried compound 9 (0.15 mmol), 5 ml of toluene, and 100 mg of freshly distilled triethoxysilane (0.6 mmol, 4 equiv.). The solution was degassed and heated to 30° C., after which 11 μl of solution of Karstedt's catalyst (2% (wt / wt) Pt, 1.1 μmol, 0.07 equiv.) was added. Heating at 40° C. overnight gave a reaction mixture containing only 6% (a / a) compound 10 and 73% (area / area) of a by-product containing only one silyl moiety.

[0529] Notably, synthesis of compound 10 by the method of the present disclosure afforded compound 10 with a purity of over 90%, as shown in Example 3. Thus, the method of the present disclosure is superior to standard methods used for hydrosilylation.

[0530] Example 20 (hypothetical example): Recalibration of salt concentration for the extractive purification of di-PEGylated dienes according to formula (II) when salts other than NaCl are used Salt M of NaCl concentration used for extraction and purification of di-PEGylated diene x A y Recalibration to is achieved by interpolation of representative test samples.

[0531] A mixture containing a di-PEGylated diene according to formula (II) and at least two of the impurities typically found in a reaction mixture when a di-PEGylated diene is synthesized by PEGylation of a diene according to formula (III) is dissolved in water to a concentration similar to that used in the extraction purification method for di-PEGylated diene. The solution is divided into eight portions, A to H.

[0532] Part A is a solution containing a concentration of [NaCl] similar to that used in the intermediate extraction step in the extraction and purification process for di-PEGylated dienes. i Treat with sodium chloride until

[0533] Moieties B, C, and D are [M x A y ] ref-i are 0.75, 1, and 1.25 times [Mx A y ] B , [M x A y ] C , and [M x A y ] D Up to a concentration of M x A y In this case, [M x A y ] ref-i is the concentration [NaCl] assuming that B, C, and D contain pure water. i would result in a solution with the same ionic strength as a solution of NaCl in pure water at 1000 M x A y is the concentration.

[0534] Part E is a solution containing a concentration of [NaCl] similar to that used in the product extraction step in the di-PEGylated diene extraction purification process. p Treat with sodium chloride until

[0535] Moieties F, G, and H are x A y ] ref-p are 0.75, 1, and 1.25 times [M x A y ] F , [M x A y ] G , and [M x A y ] H Up to a concentration of M x A y In this case, [M x A y ] ref-p is the concentration [NaCl] assuming that F, G, and H contain pure water. p would result in a solution with the same ionic strength as a solution of NaCl in pure water at 1000 M x A y is the concentration.

[0536] Each of the portions A to H was extracted once with a primary extraction solvent at a temperature above 50° C. to obtain aqueous phase A. aq ~H aqand organic phase A org ~H org and generate.

[0537] A aq ~H aq and A org ~H org The relative composition of is assessed using an appropriate analytical method such as HPLC.

[0538] Each fraction, Q i , and each impurity present, I j , calculate the ratio. TIFF2025509109000042.tif13170

[0539] For each impurity, r(B org ,I j ), r(C org ,I j ), and r(D org ,I j ) [M x A y ] and use linear regression to determine whether r is a function of r(A org ,I j ) so that [M x A y ] is calculated for all impurities. x A y ], the average value of [M x A y ] average-intermediate-org , is calculated.

[0540] [M x A y ] average-intermediate-aq is calculated in the same way, and [M x A y ] average-intermediate [M x A y ] average-intermediate-org and [M x A y ] average-intermediate-aq The average value of [M x A y ] average-productCalculate in the same manner using fractions D to H. {[NaCl] i :[M x A y ] average-intermediate} and {[NaCl] p :[M x A y ] average-product} points, and then use the model to fit a linear model to calculate the concentration of NaCl as M x A y Recalibrate as a concentration of

[0541] Example 21: Concentration of a solution of coated nanostructures showing high aqueous solubility of nanostructures coated with a coating precursor according to the present disclosure A 20 ml sample of the nanostructures according to Example 14a (compound 10 coated nanostructures) was concentrated on a 300 kDa spin filter. The concentration of P was measured to be 328 mM by ICP-OES, corresponding to approximately 25% (weight / volume) nanostructures in solution. The hydrodynamic diameter was measured to be 27.4 nm and no aggregates were visible upon visual inspection, indicating the absence of aggregation.

[0542] This demonstrates the high solubility and resistance to aggregation of nanostructures coated with the coating precursor according to the present disclosure.

Claims

1. A compound according to formula (I), During the ceremony, Poly １ and Poly ２ are independently selected from the group consisting of hydrogen and a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da; １ or Poly ２ at least one of the groups is a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da; Y １ and Y ２ are independently -A(CH ２ ) ｎ B-, wherein A is bonded to X, Y １ The B stands for Poly １ is bound to Y ２ The B stands for Poly ２ is bound to n is an integer from 0 to 5, A is selected from the group consisting of —O—, —S—, —NH—, —C(═O)O—, —C(═O)NH—, —O(C═O)—, —NH(C═O)—, and a covalent bond; and B is selected from the group consisting of —O—, —S—, —NH—, —C(═O)O—, —C(═O)NH—, —O(C═O)—, —NH(C═O)—, and a covalent bond, with the proviso that Poly １ or Poly ２ Y in the middle １ or Y ２ is not a carbon atom, then B is a covalent bond; Y ３ and Y ４ are independently -E(CH ２ ) ｍ -, wherein E is bonded to X; m is an integer from 2 to 5, and E is independently selected from the group consisting of -S-, -NH-, -C(=O)O-, -C(=O)NH-, -O(C=O)-, -NH(C=O)-, and a covalent bond; X is the structure X １ , X ２ , X ３ , X ４ , and X ５ selected from the group consisting of During the ceremony, The thick bond is Y １ or Y ２ represents a bond to Bonds that are not bold are Y ３ or Y ４ represents a bond to p is an integer from 1 to 5, and Z １ and Z ２ are independently —SiR １ R ２ R ３ where: R １ , R ２ , and R ３ is independently selected from the group consisting of chloride, bromide, iodide, lower alkoxy, aryloxy, carboxy, amino, and -NH-acyl; compound.

2. Poly １ and Poly ２ is a hydrophilic polymer group having a molecular weight of 400 to 10,000 Da.

3. 3. The compound according to claim 1 or 2, wherein n is an integer from 1 to 3, preferably n is 1 or 2, and even more preferably n is 1.

4. Y １ and Y ２ 2. The compound of claim 1, wherein n is 1 in both of the following:

5. X is X １ 2. The compound of claim 1, wherein:

6. Y １ and Y ２ 2. The compound of claim 1, wherein A is a covalent bond, B is —O—, and n is an integer from 1 to 3 in both of the above.

7. Y ３ and Y ４ 2. The compound of claim 1, wherein E is a covalent bond in both of the following formulas:

8. 2. The compound of claim 1, wherein the hydrophilic polymeric group comprises a PEG chain, and optionally the PEG chain is end-capped with a lower alkyl.

9. 9. The compound of claim 8, wherein each hydrophilic polymeric group comprises 20 to 150 ethylene glycol residues.

10. Poly １ and Poly ２ However, ω-methyl-(ethyleneoxy) ｗ wherein w is 20 to 150; Y １ and Y ２ wherein A is a covalent bond, B is —O—, and n is 1; Y ３ and Y ４ But both are -CH ２ -CH ２ -CH ２ - and X is X １ and Z １ and Z ２ is independently selected from the group consisting of triethoxysilyl and trimethoxysilyl; The compound of claim 1.

11. A compound according to formula (II): During the ceremony, R ７ and R ８ is independently selected from the group consisting of lower alkyl; p is an integer from 20 to 150, q is an integer from 20 to 150, r is an integer from 1 to 3, s is an integer from 1 to 3; t is an integer from 0 to 3, u is an integer from 0 to 3, and X is the structure X １ , X ２ , X ３ , X ４ , and X ５ selected from the group consisting of During the ceremony, The bold bond is [CH ２ ] ｒ and [CH ２ ] ｓ represents a bond to Bonds that are not bold are [CH ２ ] ｔ and [CH ２ ] ｕ represents a bond to P is an integer from 1 to 5; compound.

12. 12. Use of a compound according to claim 11 in the manufacture of a compound according to claim 10.

13. A method for purifying the compound of claim 11, comprising: a) providing an aqueous solution of the impure compound of claim 11, said aqueous solution comprising: Water in an amount of 7.5 to 16.5 times the total mass of the impure compound of claim 11; and NaCl in an amount of 6% to 9% (weight / volume) of the amount of said water, and b) subjecting the aqueous solution of step a) to 2 to 5 intermediate extractions carried out at a temperature between 40°C and 70°C, each intermediate extraction comprising the following steps: b1) optionally adding further portions of NaCl so that the total amount of NaCl added corresponds to an amount of NaCl of less than 9% (w / v) of the amount of water in the aqueous solution of step a); b2) extracting the aqueous solution with a carboxylic acid ester solvent; and b3) obtaining an aqueous phase by removing the organic phase; and c) adding NaCl to the aqueous phase from step b3) in an amount of at least 1% of the amount of water in step a) so that the total amount of NaCl corresponds to an amount of NaCl of 8% to 12% and subjecting the aqueous phase to 2 to 5 product extractions carried out at a temperature of 40°C to 70°C, each product extraction comprising the following steps: c1) extracting the aqueous phase with a carboxylic acid ester solvent; and c2) removing the organic phase; and d) pooling the organic phases from each step c2); e) concentrating the pooled organic phase from step d) to obtain a residue; f) dissolving the residue from step e) in an aqueous buffer solution of pH 6-9 to obtain an aqueous phase; g) subjecting the aqueous phase from step f) to 2 to 4 finishing extractions, each finishing extraction comprising the following steps: g1) extracting the aqueous phase from step f) with a chlorinated solvent; and g2) removing the organic phase; and h) pooling the organic phases from each step g2); i) concentrating the pooled organic phase from step h) to obtain a residue comprising the di-PEGylated diene of claim 11 having less than 10% (wt / wt) impurities; A purification method comprising:

14. Poly １ and Poly ２ and wherein both of said PEG chains are end-capped with a lower alkyl, said method comprising: i) providing the diene of claim 11, optionally purified according to the method of claim 13; ii) converting said diene into a compound having the structure HSiR １ R ２ R ３ wherein R １ , R ２ , and R ３ with at least 30 equivalents of a hydrosilylation reagent, independently selected from the group consisting of lower alkoxy groups, in the presence of a platinum catalyst and an aromatic hydrocarbon solvent at a temperature of 10-35°C; iii) removing excess hydrosilylation reagent; iv) removing platinum from the product; A method comprising:

15. 16. Use of a compound according to any one of claims 1 or 11, or of the product of the method according to any one of claims 12, 13 or 14, as an intermediate in the manufacture of coated nanostructures.

16. 15. Spherical nanostructures having a hydrodynamic diameter of 10 to 100 nm and having a coating derived from a compound according to any one of claims 1 or 11 or from the product of the method according to any one of claims 12, 13 or 14.

17. 17. The spherical nanostructure of claim 16, further comprising a radionuclide.

18. A pharmaceutical composition comprising a plurality of spherical nanostructures according to claim 16.

19. 20. A pharmaceutical composition comprising a plurality of spherical nanostructures according to claim 17 for use in the treatment or imaging of cancer.

20. 17. Use of the spherical nanostructures of claim 16 as carriers of radionuclides.

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