Polymers having upper critical solution temperature in aqueous solutions

Abstract

Aspects relate generally to temperature-responsive polymers, and more particularly to polymers that exhibit an upper critical solution temperature (UCST) in aqueous solutions. In one aspect, a monomeric compound includes: one or more amide or thioamide groups; one or more urea or thiourea groups; and one or more ethylenically unsaturated groups. In one aspect, polymers, such as homopolymers or copolymers, are made by polymerization of the monomeric compounds. Copolymers are made by polymerization of the monomer compound and comonomers such as hydrophobic comonomers, hydrophilic comonomers, pH-responsive comonomers, photoresponsive comonomers, and combinations thereof. The polymer exhibits a UCST of about 1 DEG C to about 100 DEG C in an aqueous solution at 1 atm.

Description

[0001] This application is a divisional application. The international application number of the original application is PCT / US2020 / 031690, the filing date is May 6, 2020, the application number in the Chinese national phase is 202080036062.1, and the invention title is "Polymers with Upper Critical Solution Temperature in Aqueous Solution".

[0002] Cross - reference to related applications

[0003] The original application is a PCT application, claiming the priority of co-pending U.S. non-provisional patent application No. 16 / 867,955 filed on May 6, 2020, which in turn claims the benefit of U.S. provisional patent application No. 62 / 848,132 filed on May 15, 2019. The above related patent applications are incorporated herein by reference in their entirety. Technical Field

[0004] Aspects generally relate to temperature-responsive polymers, and more particularly to polymers that exhibit an upper critical solution temperature in aqueous solution. Background Art

[0005] Water-soluble thermoresponsive polymers are a class of polymers that change their solubility with temperature. Lower critical solution temperature (LCST) polymers are polymers that have a lower critical solution temperature below which the polymer is soluble in solution. Above the LCST, the polymer is partially soluble or insoluble in solution. Upper critical solution temperature (UCST) polymers are polymers that have an upper critical solution temperature above which the polymer is soluble in solution. Below the UCST, the polymer is partially insoluble or insoluble in solution. Since LCST and UCST polymers can change their physical properties in response to changes in external temperature, LCST and UCST polymers are materials being explored for drug delivery systems, biosensors, and medical applications.

[0006] While there are many examples of LCST polymers, there are few examples of UCST polymers, only a few. One example of a UCST polymer is based on zwitterionic polymers (such as poly(betaine)). However, these polymers may not be suitable for electrolyte solutions. Another example of a UCST polymer is a poly(uracil acrylate) urea-modified polymer. However, even a small amount of hydrolysis of the poly(uracil acrylate) side groups can cause the UCST to be lost over time. Another example of a UCST polymer is poly(N-acryloylglycinamide) (poly(NAGA)) and its derivatives. However, it remains a challenge to synthesize pure N-acryloylglycinamide monomers without acrylic impurities.

[0007] Accordingly, there is a need for UCST polymers suitable for electrolyte solutions. Summary of the Invention

[0008] The various aspects generally relate to temperature-responsive polymers, and more specifically to polymers that exhibit an upper critical solution temperature (UCST) in aqueous solution. In one aspect, the monomer compound includes: one or more amide or thioamide groups; one or more urea or thiourea groups; and one or more ethylenically unsaturated groups. In one aspect, a polymer such as a homopolymer or copolymer includes a plurality of monomer units. Each monomer unit includes one or more amide or thioamide groups and one or more urea or thiourea groups. The polymer exhibits a UCST of about 1 °C to about 100 °C in an aqueous solution at 1 atm. In another aspect, a copolymer includes a plurality of monomer units and a plurality of comonomer units. Each monomer unit includes one or more amide or thioamide groups and one or more urea or thiourea groups. Each comonomer unit is selected from the group consisting of hydrophobic comonomers, hydrophilic comonomers, pH-responsive comonomers, photo-responsive comonomers, and combinations thereof. The copolymer exhibits a UCST of about 1 °C to about 100 °C in an aqueous solution at 1 atm. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] To understand the above features of the present disclosure in detail, a more specific description of the present disclosure outlined above can be made with reference to the various aspects, some of which are shown in the drawings. However, it should be noted that the drawings only show exemplary aspects and should not be considered as limiting its scope, and other equally effective aspects are allowed.

[0010] Figure 1 1H NMR spectrum of the MEGA-BMA copolymer according to certain aspects 1 Figures 2 - 6 is a schematic example of a reaction scheme.

[0011] For ease of understanding, the same reference numerals are used to denote the same elements common to the figures whenever possible. It is contemplated that the elements and features of one aspect can be beneficially incorporated into other aspects without further recitation. DETAILED DESCRIPTION

[0012] Some aspects will be described in more detail below, including specific aspects, versions, and examples, but the present disclosure is not limited to these aspects, versions, or examples, and these aspects, versions, or examples are included so that those of ordinary skill in the art can make and use the various aspects when the information in the present disclosure is combined with available information and technologies.

[0013] The various terms used herein are defined as follows. If a term used in a claim is not defined below, the broadest definition given by those skilled in the relevant art, as reflected in one or more printed publications or issued patents, should be given. ​

[0014] All documents described herein are incorporated herein by reference, including any priority documents and / or test procedures, provided they are not inconsistent with the present disclosure. From the foregoing general description and specific aspects, although the forms of these aspects have been illustrated and described, various modifications can be made without departing from the spirit and scope of the present disclosure. Accordingly, the present disclosure should not be limited thereby. Similarly, the term "comprising" is considered synonymous with the term "including". Also, whenever a composition, element, or combination of elements is preceded by the connective "comprising", it is understood that we also contemplate the same composition or combination of elements preceded by the connectives "consisting essentially of", "consisting of", "selected from the group consisting of", or "I", and vice versa. For example, the terms "comprising", "consisting essentially of", and "consisting of" also include products that are combinations of the elements listed after the term.

[0015] For the sake of brevity, only certain ranges are explicitly disclosed herein. However, a range starting from any lower limit can be combined with any upper limit to enumerate ranges not explicitly recited, and a range starting from any lower limit can be combined with any other lower limit to enumerate ranges not explicitly recited. Similarly, a range starting from any upper limit can be combined with any other upper limit to enumerate ranges not explicitly recited. In addition, each individual value between each point or its endpoints within a range is included even if not explicitly mentioned. Thus, each point or individual value can be combined with any other point or individual value or any other lower limit or upper limit as its own lower or upper limit to enumerate ranges not explicitly recited.

[0016] Certain aspects relate to ureidoamide monomer compounds and methods of preparing ureidoamide monomers, the ureidoamide monomers comprising one or more ureido and / or thioureido groups, one or more amido and / or thioamido groups, and one or more ethylenically unsaturated groups. In certain aspects, the ureidoamide monomer compound comprises one or more ureido groups, one or more amido groups, and one or more ethylenically unsaturated groups.

[0017] Certain aspects relate to homopolymers or copolymers (collectively referred to as "polyureidoamides") of ureidoamide monomer compounds. The copolymers of the present disclosure can be random copolymers or block copolymers. The present polyureidoamides have an upper critical solution temperature (UCST) above which the polymer is soluble in a solution, such as an aqueous solution. The polyureidoamides can exhibit a UCST in the temperature range of a biologically relevant temperature range, such as from about 1 °C to about 100 °C, in an aqueous solution. The polyureidoamides can exhibit a UCST in a biologically relevant electrolyte condition, such as an aqueous solution with a sodium ion concentration of greater than zero to about 160 mM.

[0018] Examples of ureido groups include -NH(CO)NH-, -NR(CO)NH-, -NH(CO)NR-, or -NR(CO)NR'- wherein R and R' are each independently an alkylene or haloalkylene group. Examples of thioureido groups include -NH(CS)NH-, -NR(CS)NH-, -NH(CS)NR-, or -NR(CS)NR'- wherein R and R' are each independently an alkylene or haloalkylene group. In some aspects, the ureido group of the ureidoamide monomer is -NH(CO)NH-. Without being bound by theory, it is believed that the ureido group participates in hydrogen bonding with water molecules below the UCST.

[0019] Examples of amido groups include NH 2 (CO)R-, NHR'(CO)R-, or NR”R’(CO)R- wherein R is an alkylene or haloalkylene group and R' and R” are each independently an alkyl or haloalkyl group. Examples of thioamide groups include NH 2 (CS)R-, NHR'(CS)R-, or NR”R’(CS)R- wherein R is an alkylene or haloalkylene group and R' and R” are each independently an alkyl or haloalkyl group. In some aspects, the amido group of the ureidoamide monomer is NH 2 (CO)R- wherein R is an alkylene or haloalkylene group. Without being bound by theory, it is believed that the amido group participates in hydrogen bonding with water molecules below the UCST.

[0020] The ethylenically unsaturated group of the ureidoamide monomer is any ethylenically unsaturated group that is prone to polymerization. For example, the ethylenically unsaturated groups include derivatives, isomers, and analogs (such as sulfur analogs) of the following substances: methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, α-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, triethylene glycol methacrylate, itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethyl acrylate, acrylic acid N,N-N - diethylaminoethyl ester, triethylene glycol acrylate, methacrylamide, N - methylmethacrylamide, N,N - dimethylmethacrylamide, N - tert - butylmethacrylamide, N - n - butylmethacrylamide, N - hydroxymethylmethacrylamide, N - hydroxyethylmethacrylamide, N - tert - butylacrylamide, N - n - butylacrylamide, N - hydroxymethylacrylamide, N - hydroxyethylacrylamide, vinylbenzoic acid (all isomers), diethylaminostyrene (all isomers), α - methylvinylbenzoic acid (all isomers), diethylaminoα - methylstyrene (all isomers), p - vinylbenzenesulfonic acid, sodium p - vinylbenzenesulfonate, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, tributoxysilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl methacrylate, diisopropoxysilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl methacrylate, diisopropoxysilylpropyl methacrylate, trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate, tributoxysilylpropyl acrylate, dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate, dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate, dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate, dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate, vinyl acetate, vinyl butyrate, vinyl benzoate, vinyl chloride, vinyl fluoride, vinyl bromide, maleic anhydride, N - phenylmaleimide, N - butylmaleimide, N - vinylpyrrolidone, N - vinylcarbazole, functionalized methacrylates, acrylates and styrenes of butadiene, ethylene and chloroprene.,

[0021] The ethylenically unsaturated group may be an ethylenically unsaturated ester group represented by formula (I), including its derivatives, isomers and analogs:

[0022]

[0023] wherein, Q 1 and Q 2 are each independently oxygen or sulfur, R 1 and R 2 are each independently hydrogen or a group of the formula - COOR', - CSOR', - COSR', where R' is hydrogen, alkyl or haloalkyl; R 3 is hydrogen, alkyl or haloalkyl; R 4 is alkylene or haloalkylene. The unsaturated carbon - carbon double bond of the ethylenically unsaturated ester group polymerizes into a polymer chain.

[0024] The ethylenically unsaturated group can be an ethylenically unsaturated ester group represented by formula (I), where Q 1 and Q 2 are both oxygen, which is also represented by formula (II), including its derivatives, isomers, and analogs:

[0025]

[0026] wherein, R 1 and R 2 are each independently hydrogen or a group of the formula COOR', where R' is hydrogen, alkyl, or haloalkyl; R 3 is hydrogen, alkyl, or haloalkyl; R 4 is alkylene or haloalkylene. The ethylenically unsaturated group of the ureidoamide monomer containing all-oxygen ester groups can be more cost-effective in the synthesis of the monomer because esters can be more widely available compared to thioesters.

[0027] In some aspects, the ureidoamide monomer compound comprises an ethylenically unsaturated group head, a ureido body, and an amide group tail. The ethylenically unsaturated group head is incorporated into the main chain of the polymer, while the amide group tail is located on the side chain of the polymer.

[0028] In one example, the ureidoamide monomer compound includes a compound represented by formula (III), including its derivatives, isomers, and analogs:

[0029]

[0030] wherein, Q 1 、Q 2 、Q 3 and Q 4 are each independently oxygen or sulfur; R 2 and R 3 are independently alkylene or haloalkylene; R 3 、R 4 、R 5 and R 6 are each independently hydrogen, alkyl, or haloalkyl. In some aspects, the ureidoamide monomer compound includes a compound represented by formula (III), wherein Q 1 、Q 2 、Q 3 and Q 4 are all oxygen, and R 3 、R 4 、R 5 and R 6 are all hydrogen.

[0031] In another example, the ureidoamide monomer compound includes a compound represented by formula (III), wherein R 1 is -C2 H 4 - and R 2 is -CH 2 -. In at least one aspect, the ureidoamide monomer represented by formula (IV) is:

[0032]

[0033] This monomer compound is called 2-(methacryloyloxy)ethyl ureidoglycinamide (also called "MEGA").

[0034] In certain aspects, the ureidoamide monomer compound represented by formula (III) or (IV) is synthesized by reacting an amide hydrohalide with an acrylate (salt). For example, the ureidoamide monomer compound of formula (IV) is synthesized by reacting the amide hydrohalide of glycine amide hydrochloride with the acrylate of 2-isocyanatoethyl methacrylate. The reaction can be carried out in an organic solvent or a polar solvent (which can be a polar organic solvent) such that the salt impurities formed in the synthesis can precipitate in the solvent and be filtered out.

[0035] The ureidoamide monomer compound can be obtained by precipitation, recrystallization, solvent removal (such as evaporation), filtration, and combinations thereof. In certain aspects, the ureidoamide monomer compound can be obtained or purified without chromatography, such as without column chromatography or liquid chromatography. Purification without chromatography reduces the complexity and cost of producing the monomer compound. In certain aspects, the monomer compound can be synthesized and purified without chromatography in a yield of more than 40%, such as more than 50% or such as more than 60%, because the monomer compound can be dissolved and recrystallized in an organic solvent to remove other impurities.

[0036] In certain aspects, the ureidoamide monomer compound can be synthesized and purified without chromatography to produce a product having less than 1 wt% acrylic acid impurities, such as less than 0.5 wt% acrylic acid impurities or such as no acrylic acid impurities. Low or no acrylic acid impurities can reduce or eliminate irritation and corrosion to biological cells and are environmentally preferred.

[0037] In certain aspects, the poly(ureidoamide) comprises a plurality of ureidoamide monomer compounds, such as the compounds represented by formula (III) or (IV). For example, the poly(ureidoamide) comprises a plurality of monomer units represented by formula (V), including its derivatives, isomers, and analogs:

[0038]

[0039] wherein, Q 1 、Q 2 、Q 3 and Q 4 are each independently oxygen or sulfur; R 1is an alkyl or haloalkyl; R 2 and R 3 are independently an alkylene or haloalkylene; R 4 、R 5 、R 6 and R 7 are each independently hydrogen, an alkyl or a haloalkyl. In some aspects, the polyurea-based amide comprises a plurality of monomer units represented by formula (V), wherein Q 1 、Q 2 、Q 3 and Q 4 are each oxygen and R 4 、R 5 、R 6 and R 7 are each hydrogen, which is also represented by formula (VI), including its derivatives, isomers and analogs:

[0040]

[0041] wherein, R 1 is an alkyl or a haloalkyl, and R 2 and R 3 are independently an alkylene or a haloalkylene. In some aspects, the polyurea-based amide comprises a polymeric monomer unit of MEGA represented by formula (VI), wherein R 1 is -CH 3 ; R 2 is -C 2 H 4 -; R 3 is -CH 2 -.

[0042] In some aspects, the number of repeating units of the polymeric urea-based amide monomer compound or the repeating units (n) of the monomer units of formula (V) or (VI) comprised in the polyurea-based amide is from about 10 to about 200, such as from about 40 to about 110, such as from about 50 to about 100. When polymerized into a polyurea-based amide, the urea-based amide monomer exhibits different properties. The main polymer backbone of the polyurea-based amide is hydrophobic, while the amide tail of the urea-based amide monomer unit is hydrophilic.

[0043] In some aspects, the polyurea-based amide copolymer comprises a plurality of urea-based amide monomer compounds and one or more comonomers. In some aspects, the comonomer can be hydrophobic, hydrophilic, pH-responsive, light-responsive or a combination thereof. In some aspects, the comonomer is a hydrophobic comonomer. The combination of the hydrophobic comonomer unit with the hydrophobic main polymer backbone and the hydrophilic urea-based amide monomer unit can affect the overall hydrophobicity or hydrophilicity of the polyurea-based amide copolymer in response to temperature.

[0044] Examples of hydrophobic comonomers include, but are not limited to, styrene, α-methylstyrene, butyl acrylate, butyl methacrylate (BMA) (n-butyl methacrylate or tert-butyl methacrylate), pentyl methacrylate, hexyl methacrylate, lauryl methacrylate, stearyl methacrylate, 2-ethylhexyl methacrylate, crotyl methacrylate, cinnamyl methacrylate, oleyl methacrylate, ricinoleyl methacrylate, vinyl butyrate, vinyl pivalate, vinyl stearate, vinyl laurate, and their derivatives, isomers, and analogs (such as sulfur analogs). In certain aspects, the hydrophobic comonomer is n-butyl methacrylate.

[0045] Examples of hydrophilic comonomers include, but are not limited to, acrylic acid, methacrylic acid, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, acrylamide, methacrylamide, 2-hydroxyethyl acrylate, N-methylmethacrylamide, N,N-dimethylmethacrylamide, and dimethylaminoethyl methacrylate, and their derivatives, isomers, and analogs (such as sulfur analogs).

[0046] In certain aspects, the plurality of comonomer units of the polyurea amide copolymer are represented by formula (VII) and its derivatives, isomers, and analogs:

[0047]

[0048] wherein, Q 1 and Q 2 are each independently oxygen or sulfur, and R 1 and R 2 are each independently an alkyl or haloalkyl. In certain aspects, the plurality of comonomer units of the polyurea amide copolymer are represented by formula (VII), wherein Q 1 and Q 2 are each independently oxygen, which is also represented by formula (VIII):

[0049]

[0050] wherein, R 1 and R 2 are each independently an alkyl or haloalkyl.

[0051] In certain aspects, the number (m) of repeating units of the comonomer units of formula (VII) or (VIII) contained in the polyurea amide copolymer is from 1 to 100, such as from 10 to 50, such as from 15 to 35.

[0052] In some aspects, the number (m) of repeating units of the polymerized comonomer or the repeating units of the comonomer units of formula (VII) or (VIII) comprised in the polyurea-based amide polymer is any suitable number, such as zero for a homopolymer, such as greater than zero for a copolymer. In some aspects, the percentage of the comonomer units is from about 1% to about 50%, such as from about 5% to about 45%, such as from about 10% to about 40% of the total amount of the repeating units (monomer + comonomer), such as based on n + m, where n > m.

[0053] In some aspects, based on the total amount of the repeating units of (monomer + zero comonomer), such as based on n + 0, the repeating units (n) of the urea-based amide monomer compound or the monomer units of formula (V) or (VI) is 100% for a homopolymer of the urea-based amide monomer. In some aspects, based on the total amount of the repeating units of (monomer + comonomer), such as based on n + m (where n > m), the repeating units (n) of the urea-based amide monomer compound or the monomer units of formula (V) or (VI) is from 50% to 100% for a copolymer and a homopolymer of the urea-based amide monomer. In some aspects, based on the total amount of the repeating units of (monomer + comonomer), such as based on n + m (where n > m), the repeating units (n) of the urea-based amide monomer compound or the monomer units of formula (V) or (VI) is greater than 50% to less than 100% for a copolymer, such as from about 55% to about 95% for a copolymer.

[0054] In some aspects, polyurea-based amides, such as polyurea-based amide homopolymers or polyurea-based amide copolymers, are water-soluble thermoresponsive polymers that change their water solubility in response to temperature changes. In some aspects, the polyurea-based amide has an upper critical solution temperature (UCST) above which the polymer is soluble in a solution, such as an aqueous solution. In some aspects, the polyurea-based amide exhibits a UCST in an aqueous solution within a biologically relevant temperature range, such as from about 1 °C to about 100 °C in an aqueous solution at 1 atm, such as from about 34 °C to about 40 °C (which is the range of human body temperature), such as from about 15 °C to about 25 °C (which is the room temperature range), or other biologically relevant temperature ranges.

[0055] The UCST of the poly(ureido amide) can be adjusted to any temperature within the liquid phase of an aqueous solution by the amounts and ratios of the ureido amide monomer units and comonomer units. In other words, the UCST of the poly(ureido amide) can be adjusted to any temperature that is above the freezing point of the aqueous solution and equal to or below the boiling point of the aqueous solution. The poly(ureido amide) having a UCST of from about 1 °C to about 100 °C in an aqueous solution at 1 atm indicates that the UCST is measured at 1 atm, but does not limit the use of the poly(ureido amide) at 1 atm. The poly(ureido amide) having a UCST of from about 1 °C to about 100 °C in an aqueous solution at 1 atm can be used at pressures less than 1 atm. Examples of environmental pressures less than 1 atm where the poly(ureido amide) having a UCST of from about 1 °C to about 100 °C in an aqueous solution at 1 atm can be used include terrestrial locations above sea level and the exterior of aircraft, spacecraft, space satellites, or space stations, as well as other low-pressure applications where the pressure is less than 1 atm. The poly(ureido amide) having a UCST of from about 1 °C to about 100 °C in an aqueous solution at 1 atm can be used at pressures greater than 1 atm. Examples of environmental pressures greater than 1 atm where the poly(ureido amide) having a UCST of from about 1 °C to about 100 °C in an aqueous solution at 1 atm can be used include terrestrial locations below sea level, the interior and / or exterior of submersible vehicles or underwater structures, within pressurized aircraft cabins, as well as other high-pressure applications where the pressure is greater than 1 atm.

[0056] In some aspects, the poly(ureido amide) can exhibit small UCST changes (ΔT), e.g., below about 20 °C, over a wide range of salt concentrations, e.g., from greater than zero to about 160 mM salt concentration. For example, the poly(ureido amide) can exhibit a ΔT of below about 20 °C, e.g., below about 18 °C, e.g., below about 15 °C, below about 12 °C, e.g., below about 10 °C, as determined by DLS, over a salt concentration range from greater than zero to about 160 mM (in an aqueous solution). The salt of the aqueous solution can be sodium chloride. The small change in UCST over the salt concentration range can be used in applications where the poly(ureido amide) is exposed to saline aqueous solutions.

[0057] The UCST of the poly(ureido amide) homopolymers and copolymers is determined by dynamic light scattering (DLS) analysis. To determine the UCST, the polymer (15 mg) is dissolved in 1.5 mL of Milli-Q water in a vial in a 70 °C water bath. The vial is kept in the water bath for at least 1 hour before measurement. The cuvette is filled with the polymer solution from the vial. The cuvette is loaded into the DLS instrument. DLS measurements of the Z-average particle size of the polymer solution are made at various temperatures by cooling the polymer solution from 70 °C to below 1 °C. The Z-average particle size is plotted as a function of temperature. The UCST is the temperature at which the curve of the Z-average particle size from low temperature to high temperature drops to a very low Z-average particle size value (usually <5 nm), indicating dissociation of the aggregated polymer into single molecular polymer chains dissolved in the solution.

[0058] In some aspects, the polyurea-based amides exhibit UCST in an aqueous electrolyte solution, such as a saline solution. In some aspects, the polyurea-based amides exhibit UCST in an aqueous solution under biologically relevant electrolyte conditions, such as in an aqueous solution with a sodium ion concentration ranging from greater than zero to about 160 mM, such as from 135 mM to about 145 mM sodium ion concentration (which is the sodium concentration range in human blood). As the sodium ion concentration increases within the sodium ion concentration range from zero sodium ion concentration to about 160 mM, the polyurea-based amide homopolymers and copolymers surprisingly exhibit a relatively stable UCST because the sodium ion concentration has a minimal effect on the overall hydrophobicity or hydrophilicity of the polyurea-based amides. In contrast, other known UCST non-polyurea-based amides exhibit very different transition temperatures depending on the sodium ion concentration, and the sodium ion concentration greatly affects the overall hydrophobicity or hydrophilicity of the non-polyurea-based amide polymers.

[0059] In some aspects, the polyurea-based amides exhibit UCST in an aqueous solution under biologically relevant pH conditions, such as a pH of 1.5 to 8, such as a pH of about 1.5 to about 6.5 (which is the pH level in the human stomach), or a pH of about 7.35 to about 7.45 (which is the pH level in human blood), or a pH of about 4.5 to about 6.5 (which is the pH level of human skin) or a pH of about 6.5 to about 7.5 (which is the pH level of saliva in the human mouth), or a pH level of about 4.0 to about 7.0 (which is the pH level of the human large intestine).

[0060] In some aspects, the polyurea-based amides that exhibit UCST can assume different structures, such as (i) a swollen random coil structure above the UCST, which is hydrophilic and easily wetted or solvated by an aqueous liquid medium, (ii) a collapsed spherical structure below the UCST, which is hydrophobic and not easily wetted or solvated by an aqueous liquid medium, and / or (iii) an aggregated structure of multiple polyurea-based amides below the UCST, which is hydrophobic and not easily wetted or solvated by an aqueous liquid medium. In some aspects, the polyurea-based amides are reversible between two or more different structures.

[0061] It is believed that the amide functional groups of the ureidoamide monomer units that make up the polyurea-based amide homopolymers or copolymers participate in hydrogen bonding with water molecules at relatively low temperatures, resulting in the polyurea-based amides being soluble in water at relatively low temperatures. At relatively higher temperatures, the hydrophobicity of the carbon backbone of the polyurea-based amide homopolymers or copolymers dominates over the hydrogen bonding of the amide functional groups, resulting in the polyurea-based amides being insoluble in water at low temperatures.

[0062] The polyurea-based amide copolymer can comprise any suitable amount of comonomers. In certain aspects, compared to the polyurea-based amide homopolymer, the polyurea-based amide copolymer having repeating units of hydrophobic comonomers in a greater percentage exhibits an increase in UCST. In certain aspects, compared to the polyurea-based amide homopolymer, the polyurea-based amide copolymer having repeating units of hydrophilic comonomers in a greater percentage exhibits a decrease in UCST.

[0063] In certain aspects, the polyurea-based amide copolymer can comprise any suitable amount of pH-responsive comonomers. The pH-responsive comonomers of the polyurea-based amide copolymer affect the pH-related UCST. An example of a pH-responsive comonomer includes vinyl monomers such as acrylic acid, methacrylic acid, and other alkyl-substituted acrylic acids, maleic anhydride, maleic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid, N-vinylformamide, N-vinylacetamide, aminoethyl methacrylate, phosphorylethyl acrylate or methacrylate. Another example of a pH-responsive comonomer includes polypeptides derived from amino acids (such as polylysine or polyglutamic acid) or polysaccharides (such as alginic acid, hyaluronic acid, carrageenan, chitosan, carboxymethyl cellulose) or nucleic acids such as DNA. Another example of a pH-responsive monomer includes monomers having pendant pH-sensitive functional groups. Examples of pH-sensitive functional groups include, but are not limited to, -OPO(OH) 2 , -COOH or -NH 2 . In certain aspects, the polyurea-based amide homopolymer or copolymer can include ureidoamide monomers having pendant pH-sensitive functional groups. In certain aspects, the polyurea-based amide copolymer can include comonomers having pendant pH-sensitive functional groups.

[0064] In certain aspects, the polyurea-based amide homopolymer or copolymer can include ureidoamide monomers having pendant chromophoric functional groups and / or comonomers having pendant chromophoric functional groups. A chromophoric functional group is any functional group that is sensitive to electromagnetic radiation (i.e., visible or invisible light). Examples of chromophoric functional groups include: groups that can be or cause isomerization between trans and cis; groups that can be or cause a transition from a relatively non-polar hydrophobic, non-ionized state to a hydrophilic ionic state; and groups that polymerize with other monomer or comonomer units in response to electromagnetic radiation.

[0065] In certain aspects, the polyurea-based amide homopolymer or copolymer is a stimulus-responsive polymer that undergoes a transition from hydrophilic to hydrophobic or from hydrophobic to hydrophilic in response to a change in temperature, such as a reversible or irreversible transition.

[0066] By incorporating one or more sensitivities into a poly(urea-alt-amide) homopolymer or copolymer, the poly(urea-alt-amide) homopolymer or copolymer can respond to one or more stimuli. For example, the poly(urea-alt-amide) homopolymer or copolymer can respond to temperature and to one or more stimuli selected from electrolyte concentration, pH concentration, and electromagnetic radiation. For example, the poly(urea-alt-amide) homopolymer or copolymer can be temperature-responsive and can also respond to electromagnetic radiation. For example, depending on the polymer composition and temperature, photo-stimulation of the chromophoric functional groups along the polymer backbone can cause the polymer to transform into a more hydrophobic or hydrophilic conformation, promoting polymer dissolution / wetting or precipitation. In another example, the chromophoric functional groups absorb light and convert the light into heat energy, causing local heating, which can stimulate a phase transition in the temperature-responsive polymer when the system temperature approaches the phase separation temperature.

[0067] The poly(urea-alt-amide) homopolymer or copolymer can consist of a linear backbone or can consist of more than two backbones. In certain aspects, the number-average molecular weight (Mn) of the poly(urea-alt-amide) homopolymer or copolymer as determined by NMR spectroscopy is from about 6,000 Da to about 35,000 Da, such as from about 12,000 Da to about 29,000 Da. In certain aspects, the Mn of the poly(urea-alt-amide) homopolymer or copolymer as determined by triple detection is from about 7,000 Da to about 40,000 Da, such as from about 14,000 Da to about 33,000 Da. In certain aspects, the Mn of the poly(urea-alt-amide) homopolymer or copolymer as determined by RI detection is from about 30,000 Da to about 72,000 Da, such as from about 38,000 Da to about 64,000 Da. The Mn is the number-average molecular weight of a sample of the poly(urea-alt-amide) homopolymer or copolymer that exhibits UCST.

[0068] In certain aspects, the peak molecular weight (Mp) of the poly(urea-alt-amide) homopolymer or copolymer as determined by triple detection is from about 16,000 Da to about 50,000 Da, such as from about 20,000 Da to about 40,000 Da. In certain aspects, the Mp of the poly(urea-alt-amide) homopolymer or copolymer as determined by RI detection is from about 38,000 Da to about 82,000 Da, such as from about 50,000 Da to about 75,000 Da. The Mp is the molecular weight at the peak of the molecular weight distribution of a sample of the poly(urea-alt-amide) homopolymer or copolymer that exhibits UCST.

[0069] In some aspects, the polydispersity (PDI) of the polyurea-based amide homopolymer or copolymer, as determined by triple detection gel permeation chromatography, is from about 1.00 to about 1.30, such as from 1.03 to about 1.20. In some aspects, the PDI of the polyurea-based amide homopolymer or copolymer, as determined by RI detection, is from about 1.10 to about 1.45, such as from about 1.20 to about 1.35. In some aspects, the polyurea-based amide homopolymer or copolymer has a low PDI of less than 1.30 as determined by triple detection gel permeation chromatography or less than 1.45 by RI detection, which provides a polymer with a more uniform size, shape, and / or mass distribution.

[0070] The polymerization method for forming the polyurea-based amide homopolymer or copolymer can be carried out by a solution polymerization method using a solvent such as an organic solvent or an aqueous solvent. The polymerization method for forming the polyurea-based amide homopolymer or copolymer can be carried out by a bulk polymerization method. During the bulk polymerization process, the monomers (and comonomers, if any) to be polymerized are used as solvents or diluents, while very little or no inert solvent is used as a liquid or diluent. In the bulk polymerization method, a small amount of inert solvent can be used as a carrier and scavenger for the catalyst.

[0071] The polyurea-based amide homopolymer or copolymer can be prepared by polymerizing ethylenically unsaturated monomers / comonomers by free radical, coordination, ionic, or other suitable polymerization techniques. The polymerization method for manufacturing the polyurea-based amide homopolymer or copolymer can be living or non-living. In some aspects, the polymerization method for manufacturing the polyurea-based amide homopolymer or copolymer is by living polymerization. Living polymerization is a form of chain polymerization in which there is substantially no irreversible chain termination. Living polymerization is characterized in that the polymer chains will continue to grow provided that monomers and the reaction conditions to support the polymerization are provided. The polymer chains prepared by living polymerization can exhibit a well-defined molecular structure, a predetermined molecular weight, and / or a narrow molecular weight distribution or low polydispersity. Examples of living polymerization include ionic polymerization and controlled radical polymerization (CRP). Examples of CRP include, but are not limited to, initiator transfer terminator polymerization, stable free radical-mediated polymerization (SFRP), atom transfer radical polymerization (ATRP), and reversible addition-fragmentation chain transfer (RAFT) polymerization.

[0072] In some aspects, the polymerization method for manufacturing the polyurea-based amide homopolymer or copolymer uses the RAFT polymerization method for polymerization. The RAFT polymerization method uses a RAFT reagent. Suitable RAFT reagents contain a thiocarbonylthio group (which is a divalent moiety represented by -C(S)S-). Examples of RAFT reagents include, but are not limited to, xanthates, dithiocarbamates, dithiocarbonates, dithiocarbamates, and trithiocarbonate compounds.

[0073] In some aspects, the RAFT reagent is represented by the general formula (IX):

[0074]

[0075] Wherein, R* is an x-valent group, where x is an integer ≥ 1, and Z is independently selected such that the reagent can function as a RAFT reagent in the polymerization of one or more ethylenically unsaturated monomers. The Z group can independently be an organic group and / or an organic group with substituents, which serves to render the C═S moiety in the RAFT reagent to have a suitable high reactivity towards radical addition. The R* group can be an organic group or an organic group with substituents, which acts as a radical leaving group under the polymerization conditions employed. The R* group can be monovalent, divalent, trivalent or higher valent. In certain aspects, x is an integer from 1 to 20, such as from 1 to 10, or such as from 1 to 5. Thus, R* can be an optionally substituted polymer chain, and the remainder of the RAFT reagent is present as multiple groups pendant from the polymer chain.

[0076] In certain aspects, the RAFT reagent is represented by the general formula (XI):

[0077]

[0078] Wherein, Z* is a y-valent group, where y is an integer ≥ 2, and R is independently selected such that the reagent can function as a RAFT reagent in the polymerization of one or more ethylenically unsaturated monomers. The Z* group can be an organic group or an organic group with substituents, which serves to render the C═S moiety in the RAFT reagent to have a suitable high reactivity towards radical addition. The Z* group can be divalent, trivalent or higher valent. In certain aspects, y will be an integer from 2 to 20, such as from 2 to 10, or from 2 to 5. The R groups can independently be an organic group and / or an organic group with substituents, which acts as a radical leaving group under the polymerization conditions employed.

[0079] In certain aspects, at least a portion of the RAFT reagent is incorporated into the polymer. For example, in certain aspects, at least the C═S moiety of the RAFT reagent of formula (IX) or formula (X) is incorporated into the polymer.

[0080] Examples of R* of formula (IX) and examples of R of formula (X) include optionally substituted alkyl, alkenyl, alkynyl, aryl, acyl, carbocyclic, heterocyclic, heteroaryl, alkylthio, alkenylthio, alkynylthio, arylthio, acylthio, carbocyclicthio, heterocyclicthio, heteroarylthio, alkylalkenyl, alkylalkynyl, alkylaryl, alkylacyl, alkylcarbocyclic, alkylheterocyclic, alkylheteroaryl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, alkylacyloxy, alkylcarbocyloxy, alkylheterocyloxy, alkylheteroaryloxy, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, alkylacylthio, alkylcarbocyclicthio, alkylheterocyclicthio, alkylheteroarylthio, alkylalkenylalkyl, alkylalkynylalkyl, alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylalkenylaryl, arylalkynylaryl, arylacylaryl, arylacyl, arylcarbocyclic, arylheterocyclic, arylheteroaryl, alkenoxyaryl, alkynoxyaryl, aryloxyaryl, alkylthioaryl, alkenylthioaryl, alkynylthioaryl, arylthioaryl, arylacylthio, arylcarbocyclicthio, arylheterocyclicthio, arylheteroarylthio, and polymer chains.

[0081] Examples of R* of formula (IX) and examples of R of formula (X) include: optionally substituted alkyl; saturated, unsaturated or aromatic carbocyclic or heterocyclic; alkylthio; dialkylamino; organometallic species; and polymer chains.

[0082] Specific examples of R* of formula (IX) and R of formula (X) include optionally substituted C 1 -C 18 alkyl, C 2 -C 18 alkenyl, C 2 -C 18 alkynyl, C 6 -C 18 aryl, C 1 -C 18 acyl, C 3 -C 18 carbocyclic, C 2 -C 18 heterocyclic, C 3 -C 18 heteroaryl, C 1 -C 18 alkylthio, C 2 -C 18 alkenylthio, C 2 -C 18 alkynylthio, C 6 -C 18 arylthio, C 1 -C 18 acylthio, C3 -C 18 Carbocyclic thio group, C 2 -C 18 Heterocyclic thio group, C 3 -C 18 Heteroaryl thio group, C 3 -C 18 Alkenyl group, C 3 -C 18 Alkynyl group, C 7 -C 24 Alkylaryl group, C 2 -C 18 Alkyl acyl group, C 4 -C 18 Alkyl carbocyclic group, C 3 -C 18 Alkyl heterocyclic group, C 4 -C 18 Alkyl heteroaryl group, C 2 -C 18 Alkoxyalkyl group, C 3 -C 18 Alkenyloxyalkyl group, C 2 -C 18 Alkynyloxyalkyl group, C 7 -C 24 Aryloxyalkyl group, C 2 -C 18 Alkyl acyloxy group, C 2 -C 18 Alkylthioalkyl group, C 3 -C 18 Alkenylthioalkyl group, C 3 -C 18 Alkynylthioalkyl group, C 7 -C 24 Arylthioalkyl group, C 2 -C 18 Alkyl acylthio group, C 4 -C 18 Alkyl carbocyclic thio group, C 3 -C 18 Alkyl heterocyclic thio group, C 4 -C 18 Alkyl heteroaryl thio group, C 4 -C 18 Alkenylalkyl group, C 4 -C 18 Alkynylalkyl group, C 8 -C 24 Alkylarylalkyl group, C 3 -C 18 Alkyl acylalkyl group, C 13 -C 24 Arylalkylaryl group, C 14-C 24 Arylalkenylaryl, C 14 -C 24 Arylalkynylaryl, C 13 -C 24 Arylacylaryl, C 7 -C 18 Arylacyl, C 9 -C 18 Arylcarbocyclic, C 8 -C 18 Arylheterocyclic, C 9 -C 18 Arylheteroaryl, C 8 -C 18 Alkenyloxyaryl, C 8 -C 18 Alkynyloxyaryl, C 12 -C 24 Aryloxyaryl, C 7 -C 18 Alkylthioaryl, C 8 -C 18 Alkenylthioaryl, C 8 -C 18 Alkynylthioaryl, C 12 -C 24 Arylthioaryl, C 7 -C 18 Arylacylthio, C 9 -C 18 Arylcarbocyclicthio, C 8 -C 18 Arylheterocyclicthio, C 9 -C 18 Arylheteroarylthio and a polymer chain having a number average molecular weight of from about 500 to about 80,000, such as from about 500 to about 30,000.

[0083] Examples of Z of formula (IX) and examples of Z* of formula (X) include F, Cl, Br, I, alkyl, aryl, acyl, amino, carbocyclic, heterocyclic, heteroaryl, alkoxy, aryloxy, acyloxy, acylamino, carbocycloxy, heterocycloxy, heteroaryloxy, alkylthio, arylthio, acylthio, carbocyclicthio, heterocyclicthio, heteroarylthio, alkylaryl, alkylacyl, alkylcarbocyclic, alkylheterocyclic, alkylheteroaryl, alkoxyalkyl, aryloxyalkyl, alkylacyloxy, alkylcarbocycloxy, alkylheterocycloxy, alkylheteroaryloxy, alkylthioalkyl, arylthioalkyl, alkylacylthio, alkylcarbocyclicthio, alkylheterocyclicthio, alkylheteroarylthio, alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylacylaryl, arylacyl, arylcarbocyclic, arylheterocyclic, arylheteroaryl, aryloxyaryl, arylacyloxy, arylcarbocycloxy, arylheterocycloxy, arylheteroaryloxy, alkylthioaryl, arylthioaryl, arylacylthio, arylcarbocyclicthio, arylheterocyclicthio, arylheteroarylthio, dialkoxy-, dicycloxy- or diaryloxy-phosphino, dialkyl-, dicyclic- or diaryl-phosphino, cyano (i.e. -CN) and -S-R, where R is as defined for formula (IX).

[0084] Specific examples of Z of formula (IX) and examples of Z* of formula (X) include F, Cl, C 1 -C 18 alkyl, C 6 -C 18 aryl, C 1 -C 18 acyl, amino, C 3 -C 18 carbocyclic, C 2 -C 18 heterocyclic, C 3 -C 18 heteroaryl, C 1 -C 18 alkoxy, C 6 -C 18 aryloxy, C 1 -C 18 acyloxy, C 3 -C 18 carbocycloxy, C 2 -C 18 heterocycloxy, C 3 -C 18 heteroaryloxy, C 1 -C 18 alkylthio, C 6 -C 18 arylthio, C 1 -C 18 acylthio, C 3-C 18 Carbocyclic thio group, C 2 -C 18 Heterocyclic thio group, C 3 -C 18 Heteroaryl thio group, C 7 -C 24 Alkyl aryl, C 2 -C 18 Alkyl acyl group, C 4 -C 18 Alkyl carbocyclic group, C 3 -C 18 Alkyl heterocyclic group, C 4 -C 18 C 4 -C 18 Alkyl heteroaryl, C 2 -C 18 Alkoxyalkyl, C 7 -C 24 Aryloxyalkyl, C 2 -C 18 Alkyl acyloxy group, C 4 -C 18 Alkyl carbocycloxy group, C 3 -C 18 Alkyl heterocycloxy group, C 4 -C 18 Alkyl heteroaryloxy group, C 2 -C 18 Alkylthioalkyl, C 7 -C 24 Arylthioalkyl, C 2 -C 18 Alkyl acylthio group, C 4 -C 18 Alkyl carbocyclic thio group, C 3 -C 18 Alkyl heterocyclic thio group, C 4 -C 18 Alkyl heteroaryl thio group, C 8 -C 24 Alkyl arylalkyl, C 3 -C 18 Alkyl acylalkyl, C 13 -C 24 Aryl alkyl aryl, C 13 -C 24 Aryl acyl aryl, C 7 -C 18 Aryl acyl group, C 9 -C 18 Aryl carbocyclic group, C 8 -C 18 Aryl heterocyclic group, C 9 -C 18Aryl heteroaryl, C 12 -C 24 Aryloxy aryl, C 7 -C 18 Aryl acyloxy, C 9 -C 18 Aryl carbonyloxy, C 8 -C 18 Aryl heteroonyloxy, C 9 -C 18 Aryl heteroaryloxy, C 7 -C 18 Alkylthio aryl, C 12 -C 24 Arylthio aryl, C 7 -C 18 Aryl acylthio, C 9 -C 18 Aryl carbocyclicthio, C 8 -C 18 Aryl heterocyclicthio, C 9 -C 18 Aryl heteroarylthio, dialkoxy-, diheteroonyloxy- or diaryloxy-phosphino (i.e. -P(=O)OR k 2 ), dialkyl-, diheterocyclic- or diaryl-phosphino (i.e. -P(=O)R k 2 )(wherein R k is selected from optionally substituted C 1 -C 18 alkyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 2 -C 18 heterocyclic and optionally substituted C 7 -C 24 alkylaryl), cyano (i.e. -CN) and -S-R (wherein R is as defined for formula (IX)).

[0085] In the examples of R*, R, Z and Z*, it should be understood that the multi-component groups include the subunits in any order. For example, the multi-component group of alkylaryl includes arylalkyl.

[0086] Z, Z*, R or R* can be branched and / or optionally substituted. When Z, Z*, R or R* contains an optionally substituted alkyl moiety, the optional substituents include those in which the -CH 2 - group in the alkyl chain is replaced by a group selected from -O-, -S-, -NR a -, -C(O)- (i.e. carbonyl), -C(O)O- (i.e. ester group) and -C(O)NR a - (i.e. amide group), wherein Ra may be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclic, heteroaryl, heterocyclic, aralkyl, and acyl.

[0087] As used herein, the reference to an x-valent, y-valent, polyvalent, or divalent “form of...” is intended to indicate that the specified group is an x-valent, y-valent, polyvalent, or divalent group, respectively. For example, when x or y is 2, the specified group is intended to be a divalent group. In that case, a divalent alkyl is actually an alkylene (e.g., -CH 2 -). Similarly, the divalent form of an alkylaryl can be represented, for example, by -(C 6 H 4 )-CH 2 -, the divalent alkylarylalkyl can be represented, for example, by -CH 2 -(C 6 H 4 )-CH 2 -, the divalent alkoxy can be represented, for example, by -CH 2 -O-, and the divalent alkoxyalkyl can be represented, for example, by -CH 2 -O-CH 2 -. When the term “optionally substituted” is used in combination with such an x-valent, y-valent, polyvalent, or divalent group, the group can be substituted or fused as described herein. When an x-valent, y-valent, polyvalent, divalent group contains more than two subunits, e.g., [A group][B group][C group] (e.g., alkylarylalkyl), one or more such subunits can be optionally substituted, if feasible. An example of a RAFT agent is a benzyl-capped cyano RAFT agent, although other RAFT agents can be used.

[0088] In certain aspects, the polyurea-based amide homopolymer or copolymer can retain other components (internally and / or thereon). For example, a drug, therapeutic compound, or bioactive agent can be included in and / or on the polyurea-based amide homopolymer or copolymer below the UCST. By causing a polymer transition at a temperature above the UCST, the drug or therapeutic compound or bioactive agent can be released from the polyurea-based amide homopolymer or copolymer.

[0089] Aspects generally relate to temperature responsive polymers, more specifically to polymers that exhibit an upper critical solution temperature (UCST) in aqueous solution. Certain aspects relate to urea-based amide monomer compounds and methods for preparing urea-based amide monomers, wherein the urea-based amide monomers comprise one or more urea groups and / or thiourea groups, one or more amide groups and / or thioamide groups, and one or more ethylenically unsaturated groups. In some aspects, the urea-based amide monomer compound comprises one or more urea groups, one or more amide groups, and one or more ethylenically unsaturated groups. Polymers of certain aspects, such as homopolymers or copolymers, are manufactured by polymerization of urea-based amide monomer compounds. Copolymers can be manufactured by polymerization of the monomer compound and comonomers such as hydrophobic comonomers, hydrophilic comonomers, pH responsive comonomers, photoresponsive comonomers, and combinations thereof. Homopolymers or copolymers exhibit UCST in aqueous solution within a biologically relevant temperature range. In some aspects, homopolymers or copolymers exhibit UCST in aqueous solution under biologically relevant temperature ranges and biologically relevant electrolyte conditions.

[0090] Item 1: A compound comprising one or more amide or thioamide groups, one or more urea or thiourea groups, and one or more ethylenically unsaturated groups.

[0091] Item 2: The compound as described in any one of Items 1 and 3-6, wherein the one or more ethylenically unsaturated groups are represented by formula (I) or by formula (II).

[0092] Item 3: The compound according to any one of Items 1, 2 and 4 to 6, which is represented by formula (III). 1 , Q 2 , Q 3 and Q 4 are each independently oxygen or sulfur. 1 and R 2 R is independently alkylene or haloalkylene. 3 , R 4 , R 5 and R 6 are independently hydrogen, alkyl or haloalkyl.

[0093] Item 4: The compound according to any one of Items 1 to 3, 5 and 6, which is represented by formula (III). 1 , Q 2 , Q 3 and Q 4 Each is oxygen. 3 , R 4 , R 5 and R 6 Each is hydrogen.

[0094] Item 5: The compound according to any one of Items 1 to 4 and 6, which is represented by formula (III). 1 Yes-C 2 H 4 -, R 2 Yes-CH 2 -.

[0095] Item 6: The compound according to any one of Items 1 to 5, wherein the compound is represented by formula (IV).

[0096] Clause 7: A method of preparing any of the compounds of any of clauses 1-6, comprising purifying the compound without chromatography.

[0097] Item 8: A polymer comprising a plurality of repeating units (n) of a monomer unit. Each monomer unit independently comprises one or more amide groups or thioamide groups, and comprises one or more urea groups or thiourea groups, wherein n is an integer from 10 to 200. The polymer comprises a plurality of repeating units (m) of optional comonomer units, wherein m is an integer from 0 to 100, and n>m. The polymer includes at least a portion of a reversible addition fragmentation chain transfer (RAFT) agent. The polymer is configured to exhibit an upper critical solution temperature of about 1°C to about 100°C when present in an aqueous solution at 1 atm.

[0098] Item 9: The polymer of any one of Items 8 and 10-14, wherein the monomer unit is represented by formula (V). 1 , Q 2 , Q 3 and Q 4 are each independently oxygen or sulfur. 1 is an alkyl group or a halogenated alkyl group. 2 and R 3 R is independently alkylene or haloalkylene. 4 , R 5 , R 6 and R 7 Each is independently hydrogen, alkyl or haloalkyl.

[0099] Item 10: The polymer of any one of Items 8, 9, and 11-14, wherein the monomer unit is represented by formula (V). 1 , Q 2 , Q 3 and Q 4 Each is oxygen. 4 , R 5 , R 6 and R 7 Each is hydrogen.

[0100] Item 11: The polymer of any of items 8-10 and 12-14, wherein the upper critical solution temperature is in aqueous solution at a sodium ion concentration of from above zero to about 160 mM.

[0101] Clause 12: A polymer as described in any one of clauses 8-11, 13 and 14, wherein the number average molecular weight (M) of the polymer determined by triple detection is n ) is from about 7,000 Da to about 40,000 Da.

[0102] Item 13: The polymer of any of Items 8-12 and 14, wherein the polymer has a polydispersity of about 1.0 to about 1.3 as determined by triple detection.

[0103] Clause 14: The polymer of any of Clauses 8-13, wherein the polymer is configured to exhibit an upper critical solution temperature of about 5°C to about 60°C when present in the aqueous solution.

[0104] Item 15: A copolymer comprising a plurality of repeating units (n) of a monomer unit and a plurality of repeating units (m) of a comonomer unit. Each monomer unit independently comprises one or more amide groups or thioamide groups and one or more urea groups or thiourea groups, wherein n is an integer from 10 to 200. Each comonomer unit is selected from the group consisting of a hydrophobic comonomer, a hydrophilic comonomer, a pH responsive comonomer, a photoresponsive comonomer, and a combination thereof, wherein m is an integer from 1 to 100 and n>m. The copolymer includes at least a portion of a reversible addition fragmentation chain transfer (RAFT) agent. The copolymer is configured to exhibit an upper critical solution temperature of about 1°C to about 100°C in an aqueous solution at 1 atm.

[0105] Item 16: The polymer of any one of Items 15 and 17-24, wherein the monomer unit is represented by formula (V). 1 , Q 2 , Q 3 and Q 4 are each independently oxygen or sulfur. 1 is an alkyl group or a halogenated alkyl group. 2 and R 3 R is independently alkylene or haloalkylene. 4 , R 5 , R 6 and R 7 Each is independently hydrogen, alkyl or haloalkyl.

[0106] Item 17: The polymer of any one of Items 15, 16, and 18-24, wherein the monomer unit is represented by formula (V). 1 , Q 2, Q 3 and Q 4 Each is oxygen. R 4 , R 5 , R 6 and R 7 Each is hydrogen.

[0107] Clause 18: A copolymer as described in any one of Clauses 15 - 17 and 19 - 24, wherein the plurality of comonomer units are hydrophobic comonomer units.

[0108] Clause 19: A copolymer as described in any one of Clauses 15 - 18 and 20 - 24, wherein the plurality of comonomer units are hydrophobic comonomer units that lower the UCST.

[0109] Clause 20: A polymer as described in any one of Clauses 15 - 19 and 21 - 24, wherein the comonomer units are represented by formula (VII). Q 1 and Q 2 Each independently is oxygen or sulfur. R 1 and R 2 Each independently is an alkyl or a haloalkyl.

[0110] Clause 21: A polymer as described in any one of Clauses 15 - 20, 22 and 23, wherein the comonomer units are represented by formula (VII). Q 1 and Q 2 Each is oxygen.

[0111] Clause 22: A polymer as described in any one of Clauses 15 - 21 and 23, wherein the upper critical solution temperature is in an aqueous solution with a sodium ion concentration ranging from above zero to about 160 mM.

[0112] Clause 23: A polymer as described in any one of Clauses 15 - 22, wherein the copolymer is configured to exhibit an upper critical solution temperature of about 5°C to about 60°C when present in the aqueous solution.

[0113] Examples

[0114] The following are examples illustrating various aspects of manufacturing polyurea - based amide homopolymers or copolymers. These examples are not meant to limit the scope of the claims unless specifically recited in the claims.

[0115] Example 1: Synthesis of 2-(methacryloyloxy)ethylureidoglycinamide (MEGA)

[0116] Despite various variations and their alternatives, an exemplary synthesis of the ureidoamide monomer compound of MEGA involves adding glycine amide hydrochloride (20 g, 18.1 mmol) and potassium carbonate (50 g, 36.2 mmol), both available from Sigma-Aldrich, St. Louis, Missouri, into 200 mL of anhydrous DMF and stirring for 2 hours. A needle was connected through a septum to maintain an argon atmosphere. The mixture was then transferred to an ice bath and kept for 10 minutes while stirring. Then, 2-isocyanatoethyl methacrylate (30.9 g, 20 mmol), available from Sigma-Aldrich, St. Louis, Missouri, was added dropwise. After the complete addition of 2-isocyanatoethyl methacrylate, the ice bath was removed and the reaction mixture was stirred at room temperature for about 16 hours. The progress of the reaction was monitored by thin layer chromatography using an eluent of DCM / MeOH (9 / 1, v / v). The crude mixture was then added to a large excess of hot acetone (40 °C) and stirred for 30 minutes. The acetone mixture was then filtered to remove salt impurities. The filtered acetone mixture was evaporated using a rotary evaporator to remove acetone. The remaining solid was added to a large excess of cold ether (-20 °C) and stored in the refrigerator for several hours. The ether mixture was filtered and the solid was dried to remove all solvents. The crude solid was added to 100 mL of acetone and shaken at 40 °C for 15 minutes. The soluble portion was collected and the insoluble portion was added to another 100 mL of acetone. This process was repeated at least 3 times. The soluble portions were combined and evaporated to reduce the amount of acetone, leaving approximately 200 mL of solution. The remaining solution was stored in the refrigerator for recrystallization. The recrystallized solid was filtered and dried under high vacuum overnight. The synthesis is represented by the reaction scheme (I) shown in Figure 2 as shown in

[0117] In 1 H and 13 13C nuclear magnetic resonance (NMR) analysis of the dried solid was performed. All NMR spectra were recorded on a Bruker 500 MHz spectrometer using deuterated DMSO.

[0118] Example 2: Synthesis of benzyl - terminated cyano RAFT reagent

[0119] Despite various variations and their alternatives, an exemplary synthesis of the benzyl-capped cyano RAFT reagent involves the synthesis of a disulfide, the synthesis of a benzyl-capped initiator, and the reaction of the disulfide with the benzyl-capped initiator to form the benzyl-capped cyano RAFT reagent.

[0120] An example of disulfide synthesis is the synthesis of bis(butylthiosulfinyl) disulfide. Although there may be various variations and alternatives, an exemplary synthesis involves dropwise adding 1-butanethiol (18 g, 0.2 mol) to a solution of potassium hydroxide (14 g, 0.25 mol) in water (70 mL) and stirring for 30 minutes. Then carbon disulfide (31 g, 0.4 mol) is added to the reaction and stirring is continued for another 40 minutes. p-Toluenesulfonyl chloride (19 g, 0.1 mol) in acetone (110 mL) is added to the reaction in portions, and the reaction is stirred for 2 hours. The solvent is concentrated under reduced pressure, and then the resulting residue is redissolved in CH 2 Cl 2 (100 mL), washed with water (3 × 100 mL) and dried over magnesium sulfate. The product is purified by flash column chromatography (eluent: hexane) to obtain the disulfide intermediate as a red oil. The synthesis is represented by reaction scheme (II) shown in Figure 3 .

[0121] An example of benzyl-capped initiator synthesis is the synthesis of ACVA-benzyl. Although there may be various variations and alternatives, an exemplary synthesis involves dissolving benzyl alcohol, DCC, and DMAP in anhydrous THF (200 mL). The solution is stirred and cooled to 0 °C, and then a solution of ACVA (4,4'-azobis(4-cyanopentanoic acid)) (10.0 g in 50 mL anhydrous THF) is added dropwise. The mixture is stirred at 0 °C for another 30 minutes and then stirred overnight at ambient temperature. The salt is removed by filtration, the volatiles are removed under reduced pressure, and the crude product is purified by column chromatography (ethyl acetate / hexane = 1 / 1) to obtain a white solid. The synthesis is represented by reaction scheme (III) shown in Figure 4 .

[0122] Although there may be various variations and alternatives, an exemplary synthesis of a benzyl-capped cyano RAFT reagent involves the reaction of a disulfide, bis(butylthiosulfinyl) disulfide with a benzyl-capped initiator such as ACVA-benzyl. A solution of bis(butylthiosulfinyl) disulfide (1.5 g, 4.5 mmol) and ACVA-benzyl (1.5 g, 5.4 mmol) in ethyl acetate (20 mL) is heated to reflux for 20 hours. The solvent is removed by rotary evaporation. The crude product is purified by column chromatography using eluent: hexane / ethyl acetate 1 / 1 to obtain the benzyl-capped cyano RAFT reagent as a yellow oil. The synthesis is represented by reaction scheme (IV) shown in Figure 5 . The product is measured under 1 H and 13 C nuclear magnetic resonance (NMR). All NMR spectra are recorded on a Bruker 500 MHz spectrometer using deuterated chloroform.

[0123] Example 3: Synthesis of poly(MEGA) and poly(MEGA)-co-poly(BMA) by RAFT polymerization

[0124] Although there may be various variations and their alternatives, an exemplary synthesis of MEGA homopolymers and copolymers includes the RAFT method. As shown in Table 1, homopolymers (Example A) and copolymers (Examples B - E) of MEGA with different proportions of hydrophobic monomers (such as n-butyl methacrylate (BMA)) were synthesized.

[0125]

[0126] In five different vials equipped with magnetic stir bars, benzyl-capped cyano RAFT (8.5×10 -3 g, 22.3×10 -3 mmol), different proportions of MEGA (100 - 60 mol equivalents) and BMA (0 - 40 mol equivalents), and AIBN (0.73×10 - 3 g, 4.5×10 -3 mmol) were dissolved in 1.5 mL of DMSO. The mixture was deoxygenated by purging with argon for 40 minutes and then heated to 70 °C for 4 hours. The reaction was stopped by cooling to 0 °C in an ice bath and exposing to air. Aliquots were taken to check the conversion by NMR. The crude polymer solution was precipitated in a large amount of acetone / methanol (9 / 1, v / v) (for 1 mL of DMSO polymer mixture, about 50 mL of solvent was used). The precipitated solution was stirred for at least 1 hour and then filtered. Then the polymer was dispersed in a large excess of acetone (50 mL of solvent per 1 g of polymer) and stirred for at least 1 hour. This process was repeated once more to completely remove the solvent and unreacted monomers. The polymer was filtered and dried overnight under high vacuum to obtain a yellow solid product. The synthesis is represented by the reaction scheme (V) shown in Figure 6 below.

[0127] In 1 1H nuclear magnetic resonance (NMR), the dried solid was measured. The NMR spectra were recorded on a Bruker 400 MHz spectrometer using deuterated DMSO. According to certain aspects, the 1H NMR spectrum of a polymer of MEGA monomers and BMA comonomers with a ratio of repeat units of MEGA to BMA of about 89:18 is shown in 1 1H NMR spectra of the solvent hydrogen peaks (*), hydrogen peaks of part of the RAFT reagent (a - b), hydrogen peaks of the BMA comonomer (c - e), and hydrogen peaks of the MEGA monomer (f - j) are shown in Figure 1 below. Figure 1

[0128] The conversions of MEGA and BMA to the polymer were as follows using 1 1H NMR spectral data (e.g., Figure 1 ​)Calculation: Conversion rate = [(Sum of peaks of polymer NH 2 ) / (Sum of peaks of polymer and monomer)]×100%.

[0129] The repeating units of MEGA incorporated into the polymer are used as follows 1 using the H NMR spectral data (such as Figure 1 ) Calculation: (Sum of peaks of polymer NH 2 ) / (Benzyl CH 2 protons (b) as a reference peak).

[0130] The repeating units of BMA incorporated into the polymer are used as follows 1 using the H NMR spectral data (such as Figure 1 ) Calculation: (Sum of peaks (c) and (f) at 3.9 ppm - Sum of peaks (i) at 3.6 ppm) / 2.

[0131] The number-average molecular weight (Mn) of poly MEGA homopolymers and copolymers is calculated using the NMR spectral data of the benzyl CH 2 protons (b) at the chain end (for example Figure 1 ) as a reference: Mn = (Repeating unit × Monomer MW)+(Repeating unit × Comonomer MW)+MW of RAFT reagent.

[0132] The number-average molecular weight (M n ) and peak molecular weight (M p ) of MEGA homopolymers and copolymers are also determined by triple detection GPC and RI detection methods.

[0133] The SEC traces of MEGA homopolymers and copolymers are measured in an eluent DMAc containing 0.03 wt% LiCl, calibrated using PSTY standards, and a refractive index detector is used.

[0134] Triple detection is performed on polymer samples of known concentration, which are prepared by dissolving the dried polymer in an eluent DMAc containing 0.03 wt% LiCl overnight and passing through a 0.45 μm PTFE syringe filter before injection. PSTY standards are used for calibration, and a refractive index detector is used to filter the solution. Calculations are based on d n / d c and polymer concentration.

[0135] Refractive index detection is performed on polymer samples, measured in an eluent DMAc containing 0.03 wt% LiCl, calibrated using PSTY standards, and a refractive index detector is used.

[0136] The molecular weight data are shown in Table 2.

[0137]

[0138] Dynamic light scattering (DLS) analysis was performed on MEGA homopolymers and copolymers to determine the UCST. In vials of water with 0, 50, 100, or 150 mmol of NaCl in a 70 °C water bath, various dry polymers (15 mg) were dissolved in 1.5 mL of Milli-Q water in the 70 °C water bath. The vials were kept in the water bath for at least 1 hour before measurement. Each vial was used to fill a cuvette with the polymer solution. Each cuvette was loaded into a DLS instrument. DLS measurements of the Z-average particle size of various polymer solutions were performed at various temperatures by cooling the polymer solution from 70 °C to below 1 °C. The Z-average particle size was plotted as a function of temperature. The UCST is the temperature at which the curve of the Z-average particle size from low temperature to high temperature drops to zero Z-average particle size. The UCST data at different sodium concentrations are shown in Table 3.

[0139]

[0140] While the foregoing relates to aspects of the present disclosure, other and further aspects of the present disclosure can be devised without departing from its basic scope, and its scope is determined by the appended claims.

Claims

1. A compound, comprising: one or more amide groups or thioamide groups; one or more urea groups or thiourea groups; and one or more ethylenically unsaturated groups.

2. The compound according to claim 1, which is represented by formula (I): Wherein: Q 1 、Q 2 、Q 3 and Q 4 each independently represents oxygen or sulfur; R 1 and R 2 are independently an alkylene or haloalkylene; and R 3 、R 4 、R 5 and R 6 are independently hydrogen, alkyl or haloalkyl.

3. The compound according to claim 2, wherein, Q 1 , Q 2 , Q 3 and Q 4 Each is oxygen, and R 3 , R 4 , R 5 and R 6 Each is hydrogen.

4. The compound according to claim 3, wherein: R 1 is - C 2 H 4 -; and R 2 is -CH 2 -.

5. A method for preparing the compound according to any one of claims 1-4, which comprises purifying the compound without chromatography.

6. A polymer, comprising: a plurality of repeating units (n) of monomer units, each monomer unit independently comprising one or more amide groups or thioamide groups and one or more urea groups or thiourea groups, wherein, n is an integer from 10 to 200; a plurality of repeating units (m) of optional comonomer units, wherein m is an integer from 0 to 100, and n>m; and at least a portion of a reversible addition-fragmentation chain transfer (RAFT) reagent; wherein the polymer is configured to exhibit an upper critical solution temperature of about 1 °C to about 100 °C when present in an aqueous solution at 1 atm.

7. The polymer according to claim 6, wherein, the monomer unit is represented by formula (II): Wherein: Q 1 、 Q 2 、 Q 3 and Q 4 each independently is oxygen or sulfur; R 1 is an alkyl or haloalkyl group; R 2 and R 3 are independently an alkylene or a haloalkylene; and R 4 、R 5 、R 6 and R 7 are each independently hydrogen, alkyl or haloalkyl.

8. A copolymer, comprising: a plurality of repeating units (n) of monomer units, each monomer unit independently comprising one or more amide groups or thioamide groups and one or more urea groups or thiourea groups, wherein, n is an integer from 10 to 200; a plurality of repeating units (m) of comonomer units, each comonomer unit selected from the group consisting of hydrophobic comonomers, hydrophilic comonomers, pH-responsive comonomers, photo-responsive comonomers, and combinations thereof, wherein m is an integer from 1 to 100, and n>m; and at least a portion of a reversible addition-fragmentation chain transfer (RAFT) reagent; wherein the copolymer is configured to exhibit an upper critical solution temperature of about 1 °C to about 100 °C in an aqueous solution at 1 atm.

9. The copolymer according to claim 8, wherein, the monomer unit is represented by formula (II): Wherein: Q 1 、Q 2 、Q 3 and Q 4 each independently represents oxygen or sulfur; R 1 is an alkyl or haloalkyl group; R 2 and R 3 are independently an alkylene or haloalkylene; and R 4 、R 5 、R 6 and R 7 are each independently hydrogen, alkyl or haloalkyl.

10. The copolymer according to claim 8, wherein, the comonomer unit is represented by formula (III): Wherein: Q 1 and Q 2 each independently represents oxygen or sulfur; and R 1 and R 2 are each independently an alkyl or haloalkyl group.

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