CN116003285A - Water-soluble prodrug derivatives of phenolic TRPV1 agonists, compositions, preparation methods and uses thereof - Google Patents

Abstract

Compared with the existing medicines, the water-soluble prodrug derivative, the composition, the preparation method and the application of the novel phenol TRPV1 agonist obviously overcome the defects of strong fat solubility and poor solubility in water of the existing phenol TRPV1 agonist, and have the advantages of stable chemical property, good water solubility, capability of rapidly decomposing and releasing active ingredients in blood plasma or in vivo and high safety.

Description

Water-soluble prodrug derivatives of phenolic TRPV1 agonists, compositions, preparation methods and uses thereof

Technical Field

The present invention relates to water-soluble prodrug derivatives of phenolic TRPV1 agonists, compositions comprising the derivatives, methods of preparation and uses thereof.

Background

Capsaicine (formula A) with molecular formula C ₁₈ H ₂₇ NO ₃ The chemical name is (E) -8-methyl-N-vanillyl-6-nonenamide, which is the main bioactive component in capsicum.

Recent studies indicate that capsaicin binds to TRPV1 and is able to activate membrane ion channels that are directly coupled to receptors. This is a relatively nonspecific cation channel. After the channel is opened, mainly calcium ions (sodium ions are also included) enter cells, potassium ions exit cells, and some chloride ions enter cells correspondingly to balance charges (Wachtel RE. Transition vignete capsaicin [ J ]. Reg Anesth Pain Med,1999,24 (4): 361-363).

Capsaicin and its analogs are TRPV1 agonists with phenolic structures such as cis-capsaicin (formula B), dihydro-capsaicin (formula C), nordihydro-capsaicin (formula D), homodihydro-capsaicin, homocapsaicin, norvanillylamine (formula E), and resiniferatoxin (formula F).

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These substances all activate transient receptor potential vanilloid 1 receptor (TRPV 1) to produce analgesia (Luo XJ, peng J, li YJ.Recent advances in the study on capsaicinoids and canpsinids. Eur J. 20117 Jan 10,650 (1): 1-7; horv th K, bors M, bagoly T, S.angndor V, kil r F, kemeny A, helyes Z, szolcs ny J, pint er E.Analgesic topical capsaicinoid therapy increases somatostatin-like immunoreactivity in the human plasma.neuropetides.2014 Dec,48 (6): 371-8; raithel SJ, sapio MR, laPaglia DM, iadola MJ, mannes A, J.trancriptio Changes in Dorsal Spinal Cord Persist after Surgical Incision Despite Preemptive Analgesia with Peripheral Researoxide.2018 Marol.620-635 (3): 620-620).

However, the substances have strong fat solubility and very poor solubility in water, so that the application range of the substances as medicines is greatly limited. Document 1 (CN 107205961B) reports a class of carbamate water-soluble capsaicin prodrugs, of which CA-008 (vocapsaine) is undergoing clinical studies:

because the carbamate structure is not easy to hydrolyze, another amino group is introduced into the structure so as to promote the release of capsaicin by a intramolecular cyclization mechanism:

such structures suffer from the following drawbacks: 1) The decomposition release rate is lower under the physiological pH condition, and the onset of action is slower; 2) The bicyclic urea released by decomposition is in a structure which is nearly neutral and has strong lipophilicity, and there is a risk of local irritation or toxicity caused by accumulation.

Document 2 (CN 112574061 a) reports a class of capsaicin water-soluble prodrugs substituted with glycine esters:

the structural stability is poor, and clinical compatibility stability data reported in the document show that the prepared solution is strong in acidity, the proportion of the decomposed capsaicin is very high, but the concentration of the hydrogen ions and the free capsaicin in the solution is extremely high, so that the solution has strong local irritation. For example, in example 25 of this document, after dissolution preparation using glucose injection (25 ℃, pH 3.2-3.3), the degradation of capsaicin levels of 2.69-8.32% and total impurity levels of 6.46-12.02% in the relevant substances were examined for 0-8 hours, which is not effective in controlling the quality of the product and is not an actual administration regimen.

Thus, there remains a need for a new class of water-soluble prodrug derivatives of phenolic TRPV1 agonists that are capable of overcoming the poor water solubility of the phenolic TRPV1 agonists of the prior art and further overcoming the deficiencies in stability, safety and drug release properties of the prior art prodrugs described above.

Disclosure of Invention

According to one aspect of the present application there is provided a compound having the structure shown in formula i, II or iii below, or a pharmaceutically acceptable salt, solvate or polymorph thereof:

wherein R is ¹ Is that

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R ² 、R ³ May be the same or different and are each H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ² And R is R ³ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups, wherein when the carbon atoms connected by the substituents have chirality, the substituents can be R or S configuration or a mixture of R and S configuration in any proportion;

x, Y, which may be identical or different, are each independently H, D, substituted or unsubstituted C ₁ -C ₆ Hydrocarbyl, or X and Y are interconnected to form a 3-7 membered cyclic hydrocarbyl, wherein when the carbon atom to which the substituents are attached is chiral, either the R or S configuration or a mixture of R and S configurations in any ratio;

n is an integer of 1 to 10;

m and t are each independently integers of 1 to 3;

w is-N (R) ⁴ R ⁵ ) Wherein R is ⁴ 、R ⁵ May be the same or different and are each independently H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ⁴ And R is R ⁵ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups;

a is-NH-or-N (R) ⁴ ) -, wherein R is ⁴ H, D, substituted or unsubstituted C ₁ -C ₁₀ A hydrocarbon group; and

b is C ₃ -C ₁₀ Cycloalkyl groups of (a).

According to another aspect of the present application there is provided a pharmaceutical composition comprising a compound according to the structure of formulae i, II or iii of the present disclosure, a pharmaceutically acceptable salt thereof, a solvate thereof or a polymorph thereof, optionally together with a local anaesthetic component and pharmaceutically acceptable excipients, osmolality adjusting agents, pH adjusting agents.

According to a further aspect of the present application there is provided the use of a compound of the structure according to the general formulae i, ii or iii of the present disclosure, a pharmaceutically acceptable salt thereof, a solvate thereof or a polymorph thereof in the manufacture of a medicament for use in the treatment of capsaicin-related disorders.

According to a further aspect of the present application, there is also provided a process for the preparation of a compound of the structure according to formula i, II or iii of the present disclosure, or a pharmaceutically acceptable salt, solvate or polymorph thereof.

Drawings

Fig. 1: graph of time post-dose versus hind limb avoidance time for the first group of rats (10 μg/rat);

fig. 2: post-dose time versus hind limb avoidance time for the second group of rats (30 μg/dose);

fig. 3: graph of time post-dose versus hind limb avoidance time for the third group of rats (100 μg/rat);

fig. 4: graph of time post-dose versus hind limb avoidance time for the fourth group of rats (20 μg/rat);

fig. 5: pharmacodynamic profile of compound 1 (20 μg /) on carrageenan-induced inflammatory pain in mice;

fig. 6: drug efficacy profile of capsaicin (12 μg/dose) on carrageenan-induced inflammatory pain in mice.

Detailed Description

According to one embodiment of the present invention there is provided a compound having the structure shown in formula i, II or iii below, or a pharmaceutically acceptable salt, solvate or polymorph thereof:

wherein R is ¹ Is that

R ² 、R ³ May be the same or different and are each H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ² And R is R ³ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups, wherein when the carbon atoms connected by the substituents have chirality, the substituents can be R or S configuration or a mixture of R and S configuration in any proportion;

x, Y, which may be identical or different, are each independently H, D, substituted or unsubstituted C ₁ -C ₆ Hydrocarbyl, or X and Y are interconnected to form a 3-7 membered cyclic hydrocarbyl, wherein when the carbon atom to which the substituents are attached is chiral, either the R or S configuration or a mixture of R and S configurations in any ratio;

n is an integer of 1 to 10;

m and t are each independently integers of 1 to 3;

w is-N (R) ⁴ R ⁵ ) Wherein R is ⁴ 、R ⁵ May be the same or different and are each independently H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ⁴ And R is R ⁵ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups;

a is-NH-or-N (R) ⁴ ) -, wherein R is ⁴ H, D, substituted or unsubstituted C ₁ -C ₁₀ A hydrocarbon group; and

b is C ₃ -C ₁₀ Cycloalkyl groups.

In one embodiment of the present application, R ¹ Is that

In the present application, the term "C ₁ -C ₁₀ Hydrocarbyl radicals "and" C ₁ -C ₆ Hydrocarbyl "means containing 1 to 10(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) or 1-6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms, including alkyl, alkenyl, alkynyl, or aryl groups. For example, they may be methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl or phenyl and substituted phenyl.

The term "3-7 membered cyclic hydrocarbon group" refers to a cyclic hydrocarbon group containing 3-7 ring carbon atoms such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and the like.

The term "C ₃ -C ₁₀ Cycloalkyl "refers to cycloalkyl groups containing 3 to 10 ring carbon atoms such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

For the term "substituted C ₁ -C ₁₀ Hydrocarbyl "," substituted C ₁ -C ₆ Hydrocarbyl "and" substituted phenyl "refer to" C "as described above ₁ -C ₁₀ Hydrocarbyl radicals "and" C ₁ -C ₆ The hydrocarbyl "as well as phenyl groups may be substituted with one or more substituents selected from the group consisting of: c (C) ₁ -C ₄ Alkyl, halogen, hydroxy, and the like.

"D" in the above definition refers to deuterium, an isotope of hydrogen.

According to one embodiment of the present application, the compound may be a compound selected from the group consisting of:

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in the present application, the term "pharmaceutically acceptable salt" may include acid addition salts, for example, addition salts which may be inorganic or organic acids. Inorganic acid salts include, but are not limited to, hydrochloride, dihydrogen phosphate, hydrogen phosphate, hydrogen sulfate, hydrobromide, or nitrate, while organic acid salts include, but are not limited to, formate, acetate, chloroacetate, glycolate, trifluoroacetate, propionate, acrylate, butyrate, isobutyrate, valerate, pivalate, caproate, benzoate, phenylacetate, oxalate, malonate, succinate, maleate, fumarate, D-tartrate, L-tartrate, DL-tartrate, glutarate, adipate, phthalate, isophthalate, terephthalate, citrate, methylsulfonate, ethylsulfonate, benzenesulfonate, p-toluenesulfonate.

According to one embodiment of the present application, there is provided a pharmaceutical composition comprising a compound of the structure of formulae i, ii or iii, a pharmaceutically acceptable salt thereof, a solvate thereof or a polymorph thereof as described herein. The pharmaceutical composition may optionally further comprise a local anesthetic component, a pharmaceutically acceptable excipient, an osmotic pressure regulator, a pH regulator.

In the present disclosure, the pharmaceutically acceptable excipients, osmolytes and pH adjusting agents may be those known to those skilled in the art as long as they do not negatively affect the active ingredient in the drug or pharmaceutical composition.

In the present disclosure, the excipient refers to the main additives in the pharmaceutical formulation other than the main drug, for example, including: binding agent, filler, disintegrating agent and lubricant in the solid preparation; a base portion in a semisolid formulation such as an ointment, cream; preservative, antioxidant, correctant, aromatic, cosolvent, emulsifier, solubilizer, colorant, etc. in liquid preparation; the forming agent in the lyophilized preparation includes, for example, mannitol, lactose, sucrose, glucose, dextran, etc. The osmotic pressure regulator refers to a substance for regulating the osmotic pressure of a pharmaceutical preparation, and comprises sodium chloride, glucose and mannitol. The pH regulator is used for regulating the pH of the pharmaceutical preparation and comprises sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, sodium carbonate, sodium bicarbonate, sodium hydroxide, hydrochloric acid and the like.

In one embodiment of the present application, the local anesthetic component includes, for example, but is not limited to, one of lidocaine, bupivacaine, levobupivacaine, ropivacaine, ateocaine, mepivacaine, prilocaine, procaine, chloroprocaine, tetracaine, and dicaine, or any combination thereof.

In one embodiment of the present application, the mass ratio of the compound of the structure of formula I, II or III to the amount of local anesthetic component in the pharmaceutical composition is 1:2 to 1:1300.

As another embodiment of the pharmaceutical composition of the present invention, the mass ratio of the compound of the structure represented by the general formula I, II or III to the amount of the local anesthetic component is 1:3 to 1:700 (when the local anesthetic component is lidocaine), 1:2 to 1:200 (when the local anesthetic component is dicaine), 1:20 to 1:1300 (when the local anesthetic component is atecan), 1:10 to 1:800 (when the local anesthetic component is bupivacaine), or 1:3 to 1:400 (when the local anesthetic component is ropivacaine).

As a further embodiment of the pharmaceutical composition of the present invention, the mass ratio of the compound of the structure shown in the general formula I, II or III to the amount of lidocaine is 1:100-1:600.

In one embodiment, the pharmaceutical composition is a lyophilized formulation comprising a compound of the structure of formula i, II or iii, a pharmaceutically acceptable salt thereof, a solvate thereof or a polymorph thereof, and optionally a local anesthetic component and pharmaceutically acceptable excipients, osmolytes, pH modifiers.

According to one embodiment of the present application, there is provided a compound of the structure of formula i, II or iii, a pharmaceutically acceptable salt thereof, a solvate thereof or a polymorph thereof for the manufacture of a medicament for use in the therapeutic field associated with capsaicin and analogues thereof, including cis-, dihydro-, nordihydro-, norvanillylamine and resiniferatoxin.

According to one embodiment of the present application, there is also provided the use of the compounds of the structure of formula i, II or iii, their pharmaceutically acceptable salts, their solvates or their polymorphs or pharmaceutical compositions in the therapeutic arts related to capsaicin and its analogs (including cis-capsaicin, dihydro-capsaicin, nordihydro-capsaicin, norvanillamine and resiniferatoxin).

According to one embodiment of the present application, there is also provided a treatment of the compound of the structure of formula i, II or iii, a pharmaceutically acceptable salt thereof, a solvate thereof or polymorph or pharmaceutical composition thereof, in combination with a local anesthetic, for use in the therapeutic field in which capsaicin and analogues thereof (including cis-, dihydro-, nordihydro-, norvanillamine-and resiniferatoxin) are associated.

In one embodiment of the present application, the therapeutic fields related to capsaicin and analogs thereof (including cis-capsaicin, dihydro-capsaicin, norvanilla, and resiniferatoxin) include analgesia, weight loss, cancer resistance, reduction of cardiac ischemia reperfusion injury, anti-platelet aggregation, promotion of digestion, reduction of gastroesophageal reflux symptoms, anti-inflammatory (including gastritis and enteritis), treatment of neurological bladder dysfunction, inhibition of skin itch, prevention or treatment of neurodegenerative diseases (such as Alzheimer's disease), antibacterial (including enterococcus faecalis, staphylococcus aureus, bacillus subtilis, streptococcus mutans, streptococcus pyogenes, pseudomonas aeruginosa and Escherichia coli, and Penicillium expansum, candida albicans, color-changing streptococci, and Myxophyllum).

In another embodiment of the present application, the pain that is analgesic comprises neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, complex regional pain syndrome, cancer, nerve injury, cancer chemotherapy, vulvodynia, trauma, surgery, chronic musculoskeletal pain, lower back pain, osteoarthritis, or rheumatoid arthritis-related pain. In yet another embodiment of the present application, the analgesia is postoperative analgesia, analgesia of postoperative chronic pain, or analgesia for dental or oral treatment.

Synthesis method

The present disclosure also provides a process for preparing the compounds of the structures of formulae I, II or III or pharmaceutically acceptable salts, solvates or polymorphs thereof.

In one embodiment of the preparation method according to the present application, the method comprises: the compounds with the structures of the formulas I, II or III or pharmaceutically acceptable salts, solvates or polymorphs thereof are prepared by esterification of carboxylic acid and derivatives R' CO-L thereof with the formulas A, B, C, D, E or F in one of the following reaction formulas 1-6.

Reaction formula 1:

reaction formula 2:

reaction formula 3:

reaction formula 4:

reaction formula 5:

reaction formula 6:

wherein, the liquid crystal display device comprises a liquid crystal display device,

r' CO is

L is-OH, cl, br, -OCOR ^L 、-OSO ₂ R”；

X, Y, which may be identical or different, are each independently H, D, substituted or unsubstituted C ₁ -C ₆ Hydrocarbyl groups, or X and Y being interconnected to form 3-7 membered cyclic hydrocarbon groups, when the carbon atom to which these substituents are attached hasWhen chiral, the chiral compound can be R or S configuration or a mixture of R and S configuration in any proportion;

R ² 、R ³ may be the same or different and are each H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ² And R is R ³ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups, and when the carbon atoms connected with the substituents have chirality, the substituents can be R or S configuration or a mixture of R and S configuration in any proportion;

n is an integer of 1 to 10;

m and t are each independently integers of 1 to 3;

W ¹ is-N (R) ^4’ R ^5’ ) Wherein R is ^4’ 、R ^5’ May be the same or different and are each independently H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ^4’ And R is R ^5’ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups;

A ¹ is-N (R) ^4’ ) -, wherein R is ^4’ H, D, substituted or unsubstituted C ₁ -C ₁₀ A hydrocarbon group;

b is C ₃ -C ₁₀ Cycloalkyl;

r' is substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, preferably methyl, ethyl, trifluoromethyl, phenyl, 4-methylphenyl;

R ^L is H, trifluoromethyl, trichloromethyl, 2',4, '6' -trichlorophenyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, allyloxy, benzyloxy, tert-butyl.

In one embodiment of the present application, the preparation process is specifically carried out by reacting in three ways:

(A) Acylating the hydroxyl group by carboxylic acid halides, wherein the acid halides include acid chlorides or acid bromides, which are prepared by reacting carboxylic acids with halogenating agents including, but not limited to, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, phosphorus tribromide, the resulting acid halides being acylated with hydroxyl compounds, typically in the presence of acid binding agents including, but not limited to, pyridine, triethylamine, DMAP, potassium carbonate, sodium bicarbonate;

(B) Acylation of hydroxyl groups by carboxylic acid anhydrides, wherein the anhydrides include symmetrical or mixed anhydrides, typically in the presence of acid binding agents, commonly used acid binding agents include, but are not limited to, pyridine, triethylamine, DMAP, potassium carbonate, sodium bicarbonate;

(C) By condensing a carboxylic acid or salt thereof with a hydroxyl group in the presence of a condensing agent, wherein the carboxylic acid or salt thereof undergoes a dehydration esterification reaction with the hydroxyl group in the presence of the condensing agent, including but not limited to DCC, DIC, EDC-HCl (i.e., EDCI), BOP reagent, pyBOP, HBTU, TBTU, HOBt, CDI, hillside reagent (i.e., iodinated 2-chloro-1-methylpyridine salt).

In another embodiment of the process according to the invention, compounds of the formula A, B, C, D, E or F are prepared by condensing a carboxylic acid of the formula R 'COOH (wherein the R' CO moiety is as defined above) or an addition salt thereof with an acid with a hydroxy group in the presence of the condensing agent EDC.HCl (i.e. EDCI) to give the corresponding compounds of the formula I, II or III or an addition salt thereof with an acid.

In one embodiment according to the present application, the addition salts are pharmaceutically acceptable inorganic acid salts and organic acid salts, wherein the inorganic acid salts include, for example, but are not limited to, hydrochloride, dihydrogen phosphate, hydrogen phosphate, hydrogen sulfate, hydrobromide, nitric acid, or any combination thereof, preferably hydrochloride; the organic acid salt includes, for example, but is not limited to, formate, acetate, chloroacetate, glycolate, trifluoroacetate, propionate, acrylate, butyrate, isobutyrate, valerate, pivalate, hexanoate, benzoate, phenylacetate, oxalate, malonate, succinate, maleate, fumarate, D-tartrate, L-tartrate, DL-tartrate, glutarate, adipate, phthalate, isophthalate, terephthalate, citrate, methylsulfonate, ethylsulfonate, benzenesulfonate, p-toluenesulfonate, or any combination thereof.

In one embodiment according to the present application, the preparation method comprises the following reaction steps:

the method comprises the steps of carrying out condensation reaction of carboxylic acid of R' COOH or addition salt thereof with the acid and a compound of formula A/B/C/D/E or F in a solvent A, wherein the reaction temperature is-20-80 ℃, the solvent A comprises one or combination of dichloromethane, trichloromethane, acetonitrile, propionitrile, ethyl acetate, methyl acetate, isopropyl acetate, methyl propionate and ethyl propionate, after the reaction is finished, the acid solution is preferably washed by an acidic aqueous solution, wherein the acidic solution comprises inorganic salt, more preferably an acidic aqueous solution comprising sodium chloride, wherein the content of the sodium chloride is up to the maximum extent that the sodium chloride reaches saturation, and the washed organic phase is dried, filtered and concentrated by a drying agent to obtain the compound of formula H or pharmaceutically acceptable acid addition salt, solvate or polymorph thereof, wherein the pH of the acidic aqueous solution is preferably not more than 2, more preferably not more than 1, and the drying agent comprises one or any combination of magnesium sulfate, calcium chloride, sodium sulfate and calcium sulfate.

Route of administration

In one embodiment of the present application, the route of administration of a pharmaceutical composition or medicament comprising a compound of the structure of formula i, II or iii or a pharmaceutically acceptable salt thereof, solvate thereof or polymorph thereof comprises administration by the gastrointestinal or parenteral route. The gastrointestinal route is oral or rectal; the parenteral route is an external route including inhalation, intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, invasive administration, mucosal and deep tissue or ocular, transdermal, topical.

In one embodiment of the present application, subcutaneous injection is the preferred mode of administration, and the drug can be conveniently and reliably delivered into the peripheral subcutaneous tissue to provide a locally rapid onset of action. For example, administration of a compound or pharmaceutical composition provided by the present invention subcutaneously in the painful area of the body can rapidly produce analgesic effects. Hypodermic syringes including syringes and needles are either specially manufactured or can be used to administer a metered dose of medication using existing commercially available medical devices such as insulin syringes and needles. Needles include a variety of types, e.g., 4mm, 5mm, 6mm, 8mm, 12.7mm, all representing the length of the needle. The choice of a suitable needle length is critical, and as short a needle as possible, e.g. 4-6mm, is generally safer and more tolerant the shorter the needle.

In one embodiment of the present application, invasive administration is a preferred mode of administration. The infiltration administration is to reach the target area such as the operation part, subcutaneous, mucous membrane and deep tissue, and the like, and provide the effect of quick acting in the local area through local diffusion. For example, when the pain is relieved in the stomatology, the herpetic pain is treated or the pain is relieved in the wound after operation, the compound or the pharmaceutical composition provided by the invention can be conveniently administered to the needed pain relieving part/area of a patient through an infiltration administration mode, so that the purpose of effective pain relieving is achieved.

In this application, including the embodiments described above, the single dose range of administration may be 1 μg/kg to 100mg/kg depending on the therapeutic purpose, route of administration and pharmaceutical dosage form.

The beneficial effects of the invention are that

Compared with the existing phenol TRPV1 agonist, the invention obtains the water-soluble phenol TRPV1 agonist prodrug derivative by carrying out structural modification on phenolic hydroxyl in the phenol TRPV1 agonist, has good physical/chemical stability, can release the phenol TRPV1 agonist active drug by in vivo hydrolysis, thereby playing pharmacological roles, generating no genotoxic impurities and having high safety. The phenol TRPV1 agonist prodrug derivative has good water solubility, can be prepared into a proper preparation, is easy to decompose and release active drugs in vivo, is fast to decompose, is not easy to enter other organs of a human body through a circulatory system, and has high safety and small side effect. Therefore, the water-soluble prodrug derivative of the phenolic TRPV1 agonist can obviously improve the water solubility of corresponding raw medicines, has high safety, and can improve the oral bioavailability or reduce the side effect of the raw preparation caused by auxiliary materials.

In addition, the invention adopts the mode of combining the phenol TRPV1 agonist and the local anesthetic component or preparing the compound preparation for administration, can effectively relieve the stimulation to the treatment part when capsaicin and analogues thereof exert analgesic effect, relieves the pain, and is particularly suitable for treating diseases such as herpes, osteoarthritis or rheumatoid arthritis.

Compared with the preparation method without condensing agent, the preparation method provided by the invention has the advantages of simple steps, less pollution, high yield and high purity.

In order to make the objects and technical solutions of the present invention more clear, preferred embodiments of the present invention will be described in detail below. The following are to be described: the following examples are provided for further illustration of the invention and are not to be construed as limiting the scope of the invention. Some insubstantial modifications and adaptations of the invention as described above would be within the scope of the invention.

Example 1: preparation of Compound 1 hydrochloride (acid chloride method)

Taking 508mg of dimethyl aminobutyric acid salt in a 100ml single-port bottle, adding 20ml of thionyl chloride, drying by a drying tube, and slowly heating to 40-80 ℃ for external temperature reaction for 2-5 h; stopping heating, concentrating the sulfoxide chloride under reduced pressure in a water bath at room temperature, and adding anhydrous dichloromethane (25 ml x 3) into the residue to carry the residual sulfoxide chloride in the dry system; adding 25ml of anhydrous dichloromethane into the residue for dissolution, placing the solution in a low-temperature bath at the temperature of-20 ℃ to 0 ℃ for stirring, and drying the solution in a drying tube; taking 314mg of capsaicin and 695ul of triethylamine to dissolve in 25ml of anhydrous dichloromethane, slowly dripping the capsaicin and the triethylamine into an acyl chloride system, reacting overnight (12-24 h), adding 2ml of isopropyl ether hydrochloride solution with the mass fraction of 8.9% into the mixture in an ice bath at the temperature of minus 20-0 ℃ after the reaction is finished, drying the mixture in a drying tube, and stirring the mixture for 10min; pouring the reaction solution into 100ml of acid saturated ammonium chloride solution with pH=1-2, shaking for extraction, extracting the organic phase in the acid saturated ammonium chloride solution with pH=1-2 for 2 times, adding the organic phase into anhydrous sodium sulfate for drying, filtering and concentrating under reduced pressure to obtain a crude product, preparing the purified crude product by an acetonitrile-hydrochloric acid aqueous solution system, and decompressing the collected eluent under a water bath at room temperatureConcentrating, removing acetonitrile in the system, extracting with dichloromethane, washing the organic phase with saturated saline water with pH=1, drying the organic phase over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain 277mg of brown oily substance, yield 60.98%, purity 99.48%, ESI-MS M/z [ M-Cl ]] ⁺ 419.2。

Example 2: preparation of Compound 1 hydrochloride (condensing agent method)

Taking dimethyl aminobutyrate (826 mg), capsaicin (498 mg) and EDCI (2.872 g) in a single-port bottle of 250ml, adding dichloromethane (150 ml), sealing a reverse-port rubber plug, and stirring at room temperature for reaction overnight; after completion of the reaction, the reaction mixture was washed by extraction with half-saturated brine (100 ml. Times.2) containing 0.5M hydrochloric acid and saturated brine (100 ml) containing 0.5M hydrochloric acid, and the organic phase was dried over anhydrous magnesium sulfate (20 g) for 3 hours; filtering, concentrating under reduced pressure at 40deg.C, and vacuum pumping the residual solvent with high vacuum equipment for a long time to obtain white solid 696mg, with yield of 93.42%, purity of more than 99.8%, ESI-MS M/z [ M-Cl ]] ⁺ 419.2。

H ¹ -NMR(Bruker AVANCEⅢ600MHz,CDCl ₃ ,)δppm:12.26(1H,s(br)),6.90-6.89(1H,d),6.85(1H,d),6.79-6.77(1H,dd),6.16(1H,t(br)),5.32-5.22(2H,m),4.34-4.33(2H,d),3.74(3H,s),3.07(2H,s(br)),2.72(6H,d),2.68-2.66(2H,t),2.21-2.13(5H,m),1.94-1.90(2H,q),1.62-1.56(2H,m),1.35-1.30(2H,m),0.88(3H,s),0.87(3H,s)。

Example 3: preparation of Compound 21 hydrochloride

A.3 preparation of (N, N-dimethylamino) isobutyric acid

Adding 1.007g of 3-amino isobutyric acid into a 25ml single-mouth bottle, adding 8ml of pure water for dissolution, adding 3.67ml of formic acid and 2.67ml of formaldehyde, heating to 74 ℃ in an external temperature oil bath for reaction for 1h, and then heating to 85 ℃ for reaction overnight (12-24 h); concentrating under reduced pressure in water bath at 60deg.C to remove solvent, dissolving the residue with water, adding small amount of hydrochloric acid solution, concentrating under reduced pressure to dry to obtain yellow oily substance 1.505g, purity 99.12%, yield 92.88%,ESI-MS m/z[M-Cl] ⁺ 132.1。

B. preparation of Compound 21 hydrochloride

The objective compound was prepared by the method of example 2 using 3- (N, N-dimethylamino) isobutyric acid and capsaicin as raw materials.

Example 4: preparation of Compound 9 hydrochloride

A. 4- [ tert-butylcarbonyl (methyl) amino ] butanoyl capsaicin intermediate was prepared by the method of reference example 2, starting with 4- [ tert-butylcarbonyl (methyl) amino ] butanoyl capsaicin.

B. 4- [ tert-butylcarbonyl (methyl) amino group]Dissolving butyryl capsaicin intermediate in mixed solution of tetrahydrofuran and dichloromethane, introducing dry hydrogen chloride gas under ice bath, stirring overnight, concentrating to dryness to obtain the target compound, and preparing ESI-MS M/z [ M-Cl ]] ⁺ 405.3。

The hydrochloride salts of compounds 2-8, 10-20, 22-28, 33-46 and 53-69 were prepared in a similar manner using capsaicin as the main raw material by the procedure of reference examples 1-4. The ESI-MS test of the obtained compound confirms that the data are as follows:

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compounds 70-82 and the hydrochloride of compound 84 were prepared in a similar manner using cis-capsaicin as the main material by the procedure of reference examples 1-4. The ESI-MS test of the obtained compound confirms that the data are as follows:

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the hydrochloride salts of the compounds 85 to 94 and the compounds 96 to 97 were prepared in a similar manner using dihydrocapsaicin as a main raw material by the procedure of reference examples 1 to 4. The ESI-MS test of the obtained compound confirms that the data are as follows:

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the hydrochloride salt of the compound 98-108 was prepared in a similar manner using nordihydrocapsaicin as the main raw material by the procedure of reference examples 1-4. The ESI-MS test of the obtained compound confirms that the data are as follows:

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compounds 109-124 and the hydrochlorides of compounds 126-130 were prepared in a similar manner using norvanillylamine as the main starting material, by reference to the procedure of examples 1-4. The ESI-MS test of the obtained compound confirms that the data are as follows:

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the hydrochlorides of compounds 131-144 and 146-150 were prepared in a similar manner using resiniferatoxin as the main raw material by the procedure of reference examples 1-4. The ESI-MS test of the obtained compound confirms that the data are as follows:

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the hydrobromide and phosphate compounds of the general formulae I, II and III according to the invention were prepared with reference to examples 1 to 4.

Example 5: composition preparation 1

Compound 1 (1.5 mg) and lidocaine hydrochloride (300 mg) were taken, dissolved in chloroform to obtain a mixed solution, concentrated, and the residue was dried to obtain a composition.

Referring to example 4, a composition comprising compounds having structures according to the present invention represented by general formulas I, II, III was prepared.

Test example 1: solubility determination

To determine the water solubility of the compounds described herein, the following hydrochloride salts of the compounds were dissolved in water at room temperature and their solubility was observed and the results are shown in table 1.

Table 1: solubility results

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Capsaicin, cis-capsaicin, dihydrocapsaicin, nordihydrocapsaicin, norvanillylamine, resiniferatoxin, and the like are known to be poorly water-soluble phenolic compounds, for example, capsaicin has a solubility in water of only 0.064mg/ml (document 1CN 107205961B). As shown by the solubility information in the table 1, the solubility of the hydrochloride of the prodrug compound provided by the invention is greatly improved, the water solubility is good, the drug loading load of the corresponding phenolic compound active ingredient in the aqueous solution is greatly improved, and the drug delivery requirement can be met.

Test example 2: incubation test

The test compounds (hydrochloride of compound 1, compound 21, compound 70, compound 80, compound 85, compound 92, compound 98, compound 106, compound 109, compound 123, compound 131, etc.) were prepared as a solution having a concentration of about 0.05mg/ml, and were used as a stock solution. Rat plasma (0.2 ml) was placed in a 2ml EP tube, preheated in a 37 ℃ water bath for 20s, then a stock solution of the compound (50 μl) was added rapidly, after mixing, the EP tube was placed in a 37 ℃ water bath and timing was started. Acetonitrile (1 ml) was injected at a predetermined time point (60 min), the solution was centrifuged for 5min (15000 rpm), and the supernatant was subjected to HPLC detection, and the results are shown in Table 2.

Table 2 incubation test results

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From the data in table 2, the test compounds can rapidly release the prodrug, thereby exerting pharmacological effects. Test example 3: pain relieving aging relation experiment for normal rat plantar injection

(1) Reagent: 5% glucose injection, DMSO, 5% glucose solutions of compound 1 at different concentrations (0.1 g/L, 0.3g/L, 1g/L, respectively), 10% DMSO solution of capsaicin (0.2 g/L);

experimental animals: male SD rats, body weight: 200-220g, amount: 32.

(2) Test procedure

The 32 rats were divided into 4 groups of 8 rats, 3 of which were experimental groups and 1 of which were control groups. The specific administration conditions are shown in table 3:

TABLE 3 animal dosing conditions

Placing the rat after administration in a fixed groove on a test bench for 5 minutes to stabilize the rat; the pain threshold (i.e., hindlimb avoidance time) of the rats was measured separately for the sole of the rat at the site of drug injection using the heat source of the plant instrument 30min, 2.5h, 24h, 2d, 3d after dosing according to the pre-set measurement points. The experimental data are shown in Table 4, and the results are shown in FIGS. 1 to 4, as the experimental data of the 4 groups are plotted separately.

TABLE 4 average hindlimb avoidance time (N=8, units: seconds)

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The results in table 4 show that: the first group, the right plantar injection of 10 μg/100 μl/compound 1, the left plantar injection of the corresponding 5% glucose solution followed by 2.5h found significant differences between the dosing group and the corresponding vehicle group and continued for 48h; the second group, the right foot sole injected with 30 mug/100 mug of compound 1, the left foot injected with the corresponding 5% glucose solution 24 hours later found a significant difference between the dosing group and the corresponding vehicle group and continued for 48 hours; third, 100 μg/100 μl/compound 1 was injected into the sole of the right foot, and the corresponding 5% glucose solution was injected into the left foot, and a significant difference was found between the administration group and the corresponding vehicle group for 24 hours and continued for 72 hours; in the fourth group, 20. Mu.g/dose, 100. Mu.L/dose capsaicin was injected on the sole of the right foot, and the administration group and the corresponding vehicle group were found to be significantly different 30min after injection of the corresponding 10% DMSO on the left foot and continued for 72h.

As can be seen from Table 4 and FIGS. 1 to 4, the compound 1 prepared by the present invention has a significantly prolonged duration of drug effect with increasing dose, and a duration of up to 72 hours at 100. Mu.g/dose.

Test example 4: effect of compound 1 and capsaicin on carrageenan-induced inflammatory pain in mice

(1) Reagent: 5% glucose injection, DMSO,1% carrageenan, compound 1, capsaicin;

experimental animals: male ICR mice, body weight: 18-20g, amount: 32.

(2) Test procedure

The 32 mice were divided into 4 groups of 8 mice each. Two hours prior to dosing, the mice model of arthritis was induced with 1% carrageenan and then dosing was started, dosing conditions are shown in table 5, and experimental data were recorded to compare the efficacy of the two compounds on the mice model of arthritis.

Table 5 animal dosing profile

Group number	Administration (mode of administration: plantar subcutaneous injection)	Dosage (concentration and quality of administration)
			First group of	Right hind limb: 5% dextrose solution of compound 1	25. Mu.L/L (concentration 0.8g/L, 20. Mu.g/L)
Second group of	Right hind limb: 5% glucose solution	25 mu L/min
			Third group of	Right hind limb: 10% DMSO solution of capsaicin	25. Mu.L/L (concentration 0.48g/L, 12. Mu.g/L)
Fourth group	Right hind limb: 10% DMSO solution	25 mu L/min

Placing the mice after administration in a fixed groove on a test bench for 5 minutes to stabilize the mice; the pain threshold (hindlimb avoidance time) of the mice was measured on the sole of the mice at the site of drug injection using a heat source of a hot plate instrument according to the preset measurement points 1h, 1d, 2d, 3d, 4d, 5d after administration. The experimental data are shown in table 6, and the results are shown in fig. 5 to 6.

TABLE 6 average hindlimb avoidance time (N=8, units: seconds)

As can be seen from the results in Table 6, the pain threshold of the first group (compound 1-20. Mu.g/dose) was significantly increased at 1h post-dose, the efficacy was maintained for 5 days, and there were statistical differences (P < 0.05 or P < 0.01) at 1h, 24 (1 d), 48h (2 d) post-dose; the third group (capsaicin-12 μg/dose) had an elevated pain threshold 1h after dosing, and the efficacy was maintained for 3d, but no statistical differences were seen at each time point. Table 6 shows in connection with fig. 5-6: after the compound 1 and capsaicin are administered in equimolar doses, the analgesic effect of the compound 1 on the joint model can be maintained for 5 days, the pain threshold is obviously improved after the administration for 1-48 hours, and the analgesic effect of the capsaicin can be maintained for 3 days, but the pain threshold is obviously improved after the administration for 1 hour, and other time points are slightly improved, so that the analgesic effect of the compound 1 on the joint model is better.

Test example 5: solution stability

The hydrochloride of the compound 1 is dissolved by using 5% glucose injection solution, the pH value of the solution is regulated by using a small amount of dilute hydrochloric acid or dilute sodium hydroxide to prepare solutions with different pH values and concentrations of 1mg/ml, and the solutions are placed at room temperature of 25 ℃ for 24 hours, so that the non-decomposed compound is detected. The results are shown in Table 7 below.

TABLE 7

pH	3.07	3.62	4.29	7.27
					Compound 1 hydrochloride	99.04％	97.40％	92.72％	84.63％

As is apparent from the results in Table 7, the hydrochloride of Compound 1 provided by the present invention has appropriate stability, and can be effectively decomposed under the condition of near physiological pH7.27 while maintaining sufficient stability.

Test example 6: compound 1 hydrochloride, CA008 rat PK comparative test

(1) Compound 1 hydrochloride, CA008 rat intramuscular injection PK comparative test

6 healthy male SD rats were randomly divided into 2 groups, 3 per group, and each of them was given an equimolar dose (1.32 mM, administration volume 1 ml/kg) of compound 1 hydrochloride and CA008 (CA 008 was prepared according to the method of example 7 of document 1CN 107205961B) by intramuscular injection, and capsaicin blood concentration was measured by LC-MS/MS from the mandibular vein blood sampling test of rats at various time points after the injection. The results are shown in Table 8 below.

Table 8: comparison of capsaicin blood concentration at various time points after intramuscular administration of Compounds

	Compound 1 hydrochloride	CA008
			Capsaicin blood concentration for 5min	46.0ng/ml	24.2ng/ml
Capsaicin blood concentration for 15min	89.4ng/ml	34.9ng/ml

(2) Compound 1 hydrochloride, CA008 rat foot injection PK comparative test

12 healthy male SD rats were randomly divided into 2 groups, 6/group, and equimolar doses (2 mM,0.1 ml) of Compound 1 hydrochloride and CA008 (CA 008 was prepared according to the method of example 7 of document 1CN 107205961B) were administered by foot injection, and capsaicin blood concentration was measured by LC-MS/MS method at various time points after injection by sampling from the feet of the rats. The results are shown in Table 9 below.

Table 9: comparison of capsaicin release at various time points after foot injection administration of each compound

	Compound 1 hydrochloride	CA008
			Capsaicin concentration for 5min	38792ng/ml	20909ng/ml
Capsaicin concentration for 30min	10492ng/ml	7719ng/ml
			Capsaicin concentration for 60min	1232ng/ml	490ng/ml

As can be seen from the results in table 9 above, the compound 1 provided by the present invention can provide significantly higher capsaicin concentration at the same time point after administration as compared with the compound CA008 of the prior document 1, indicating that it can rapidly decompose and release capsaicin, resulting in a stronger drug effect. In other words, smaller doses can be used with greater safety while providing the same potency.

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (11)

1. A compound having a structure represented by the following general formula i, II or iii:

wherein R is ¹ The method comprises the following steps:

R ² 、R ³ may be the same or different and are each H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ² And R is R ³ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups, wherein when the carbon atoms connected by the substituents have chirality, the substituents can be R or S configuration or a mixture of R and S configuration in any proportion;

x, Y, which may be identical or different, are each independently H, D, substituted or unsubstituted C ₁ -C ₆ Hydrocarbyl, or X and Y are interconnected to form a 3-7 membered cyclic hydrocarbyl, wherein when the carbon atom to which the substituents are attached is chiral, either the R or S configuration or a mixture of R and S configurations in any ratio;

n is an integer of 1 to 10;

m and t are each independently integers of 1 to 3;

w is-N (R) ⁴ R ⁵ ) Wherein R is ⁴ 、R ⁵ May be the same or different and are each independently H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ⁴ And R is R ⁵ Interconnect shapeForming a 3-7 membered cyclic hydrocarbon group;

a is-NH-or-N (R) ⁴ ) -, wherein R is ⁴ H, D, substituted or unsubstituted C ₁ -C ₁₀ A hydrocarbon group; and

b is C ₃ -C ₁₀ Cycloalkyl groups.

2. The compound of claim 1, wherein R ¹ Is that

3. A compound according to claim 1, selected from the following compounds or pharmaceutically acceptable salts thereof, solvates thereof or polymorphs thereof:

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4. a pharmaceutical composition comprising a compound of the structure of formula i, II or iii according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a solvate thereof or a polymorph thereof, optionally together with a local anaesthetic component and/or a pharmaceutically acceptable excipient, diluent or binder.

5. The pharmaceutical composition of claim 4, wherein the local anesthetic component comprises one or any combination of lidocaine, bupivacaine, levobupivacaine, ropivacaine, activacaine, mepivacaine, prilocaine, procaine, chloroprocaine, tetracaine, and dicaine, wherein the mass ratio of the compound of formula i, II, or iii to the amount of local anesthetic component is 1:2 to 1:1300.

6. The pharmaceutical composition according to claim 5, wherein the mass ratio of the compound of the structure of formula i, II or iii to the amount of local anesthetic component is: 1:3 to 1:700 (when the local anesthetic component is lidocaine), 1:2 to 1:200 (when the local anesthetic component is dicrotic), 1:20 to 1:1300 (when the local anesthetic component is ateziine), 1:10 to 1:800 (when the local anesthetic component is bupivacaine), or 1:3 to 1:400 (when the local anesthetic component is ropivacaine).

7. Use of a compound of the structure of general formula i, II or iii, a pharmaceutically acceptable salt thereof, a solvate thereof or a polymorph thereof according to any one of claims 1 to 3 for the manufacture of a medicament for use in the therapeutic arts related to capsaicin and analogues thereof including cis-capsaicin, dihydro-capsaicin, nordihydrocapsaicin, norvanillylamine and resiniferatoxin.

8. The use according to claim 7, wherein the capsaicin and its analogs are used in the relevant therapeutic fields including analgesia, weight loss, cancer resistance, reduction of cardiac ischemia reperfusion injury, anti-platelet aggregation, promotion of digestion, reduction of gastroesophageal reflux symptoms, anti-inflammatory (including gastritis and enteritis), treatment of neurological bladder dysfunction, inhibition of skin itch, prevention or treatment of neurodegenerative diseases (such as alzheimer's disease), antibacterial (including enterococcus faecalis, staphylococcus aureus, bacillus subtilis, streptococcus mutans, streptococcus pyogenes, pseudomonas aeruginosa and escherichia coli and penicillium expanse, candida albicans, trametes versicolor and mucosae).

9. The use of claim 8, wherein the analgesia involves pain selected from or caused by: neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, complex regional pain syndromes, cancer, nerve injury, cancer chemotherapy, vulvodynia, trauma, surgery (including post-operative analgesia, post-operative chronic pain, or dental or oral treatment), chronic musculoskeletal pain, lower back pain, osteoarthritis, or rheumatoid arthritis-related pain; preferably, the pain is relieved.

10. A process for the preparation of a compound of the structure of formula i, II or iii, or a pharmaceutically acceptable salt, solvate or polymorph thereof, according to any one of claims 1 to 3, which comprises: esterification of carboxylic acids and their derivatives R' CO-L with formula A, B, C, D, E or F by the following reaction formulas 1-6:

reaction formula 1:

reaction formula 2:

reaction formula 3:

reaction formula 4:

reaction formula 5:

reaction formula 6:

wherein the method comprises the steps of

R' CO is

L is-OH, cl, br, -OCOR ^L 、-OSO ₂ R”；

X, Y, which may be identical or different, are each independently H, D, substituted or unsubstituted C ₁ -C ₆ Hydrocarbyl, or X and Y are mutually connected to form 3-7 membered cyclic hydrocarbyl, when the carbon atoms to which the substituents are connected have chirality, the R or S configuration can be a mixture of R and S configurations in any proportion;

R ² 、R ³ may be the same or different and are each H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ² And R is R ³ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups, and when the carbon atoms connected with the substituents have chirality, the substituents can be R or S configuration or a mixture of R and S configuration in any proportion;

n is an integer of 1 to 10;

m and t are each independently integers of 1 to 3;

W ¹ is-N (R) ^4’ R ^5’ ) Wherein R is ^4’ 、R ^5’ May be the same or different and are each independently H, D, substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, or R ^4’ And R is R ^5’ Are mutually connected to form 3-7 membered cyclic hydrocarbon groups;

A ¹ is-N (R) ^4’ ) -, wherein R is ^4’ H, D, substituted or unsubstituted C ₁ -C ₁₀ A hydrocarbon group;

b is C ₃ -C ₁₀ Cycloalkyl;

r' is substituted or unsubstituted C ₁ -C ₁₀ Hydrocarbyl, preferably methyl, ethyl, trifluoromethyl, phenyl, 4-methylphenyl; and

R ^L is H, trifluoromethyl, trichloromethyl, 2',4',6' -trichlorophenyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, allyloxy, benzyloxy, tert-butyl.

11. The method of manufacturing according to claim 10, wherein:

the esterification reaction is carried out by acylation of the hydroxyl group with carboxylic acid halides, including acid chlorides or acid bromides, typically in the presence of acid binding agents, commonly used acid binding agents include, but are not limited to, pyridine, triethylamine, DMAP, potassium carbonate, sodium bicarbonate; or alternatively

The esterification reaction is carried out by acylation of the hydroxyl group with carboxylic acid anhydride, wherein the anhydride comprises a symmetrical anhydride or mixed anhydride, typically in the presence of acid binding agents, commonly used acid binding agents include, but are not limited to, pyridine, triethylamine, DMAP, potassium carbonate, sodium bicarbonate; or alternatively

The esterification reaction is carried out by condensing a carboxylic acid or salt thereof with a hydroxyl group in the presence of a condensing agent, wherein the carboxylic acid or salt thereof undergoes a dehydration esterification reaction with the hydroxyl group in the presence of the condensing agent, including but not limited to DCC, DIC, EDC-HCl (i.e., EDCI), BOP reagent, pyBOP, HBTU, TBTU, HOBt, CDI, hillside reagent (i.e., iodinated 2-chloro-1-methylpyridine salt).

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