N-acylethanolamide derivatives and their preparation methods and applications

Abstract

The present application belongs to the field of prodrugs, and specifically relates to N-acylethanolamide derivatives, preparation methods, and applications thereof. More specifically, the present invention discloses a novel PEA amino acid derivative prodrug, which can be rapidly converted into PEA after oral administration to beagle dogs. Only PEA is detected in the plasma, and almost no PEA amino acid derivatives, especially PEA-(L)-P and PEA-(L)-P-(L)-V, are detected. The prodrug has unexpected bioavailability and faster conversion rate, and its pharmacokinetic properties are significantly better than those of other PEA amino acid derivatives.

Description

Technical Field

[0001] The present application belongs to the field of prodrugs, and specifically relates to N-acylethanolamide derivatives and their preparation methods and applications. Background Art

[0002] Palmitoylethanolamide (PEA) is an endogenous substance that belongs to the N-acylethanolamine family. It plays a protective role in a variety of disease states, including anti-inflammatory, analgesic, immunomodulatory and neuroprotective effects. In disease states, the synthesis of endogenous PEA is reduced and metabolism is increased, resulting in a decrease in PEA in the body, which is unable to maintain the level required for its anti-inflammatory and analgesic activities in a healthy physiological state. This makes exogenous administration a feasible therapeutic strategy to supplement endogenous PEA levels and restore body homeostasis. It has been shown that exogenous PEA supplementation has high safety and tolerability, and PEA's ability to reduce pain intensity has a clear dose response. However, PEA has poor solubility, a partition coefficient (log P)>5, and extremely poor oral bioavailability, which limits its application and development in the medical field. At present, products containing PEA can only be used as health supplements or medical foods, with large doses, usually 1200 mg / day. Representative products are

[0003] Prodrugs are bioreversible derivatives of drug molecules that release active parent drugs after undergoing enzymatic and / or chemical conversion in vivo, and then exert the desired pharmacological effect. Prodrug technology is often used to improve the poor pharmacokinetic (PK) properties of drugs. US9512091B2 discloses that oxazoline prodrugs of PEA are used to inhibit the activity of enzymes in the body and quickly convert to PEA, but no PK data are disclosed and the oral bioavailability is unknown. European Journal of Pharmaceutical Sciences 62 (2014) 33-39. It discloses that galactose prodrugs of PEA are used to increase the passage of PEA through the blood-brain barrier. In vitro cell-level studies have shown good effects, but there are no in vivo results. PLoS ONE 10 (6): e0128699. It discloses that acyloxymethyl carbonate, amino acid ester and carbamate prodrugs of PEA are synthesized to improve the bioavailability of PEA. The results in rats showed that the absorption of the candidate prodrugs was increased, but not enough PEA was released, resulting in a lower PEA blood concentration than the group directly administered with PEA. EP2742957B discloses a PEG prodrug of PEA for prolonged local anti-inflammatory effects, but there are no oral PK results, and the oral bioavailability is unknown. CN110023308A discloses a glycerol ester prodrug of PEA. PK results in rats show a significant improvement in the oral bioavailability of PEA. However, the PEA glycerol ester prodrug is a viscous semisolid, making it difficult to prepare as a solid formulation.

[0004] PLoS ONE 10(6):e0128699 discloses blood concentration data of PEA amino acid derivatives (D-Val-PEA and L-Val-PEA) in rats after oral administration. Both the PEA amino acid derivatives and PEA were detected in the plasma, but PEA bioavailability was not improved. The present invention aims to significantly improve the oral absorption and systemic exposure of PEA through prodrug technology, replenish endogenous PEA, and ensure sufficient PEA levels to maximize therapeutic efficacy. Summary of the Invention

[0005] To achieve the purpose of the invention, the present invention discloses a formula (I):

[0006]

[0007] The compound or a pharmaceutically acceptable salt form thereof.

[0008] Preferably, the present invention discloses a formula (I1):

[0009]

[0010] Or formula (I2):

[0011]

[0012] The compound or a pharmaceutically acceptable salt form thereof.

[0013] Preferably, R1 is selected from C 1-40 Aliphatic group, preferably C 1-20 Aliphatic group, more preferably C 15-20 Aliphatic, preferably C 15-20 Aliphatic group is C 15-20 Alkyl or C containing 1-5 C=C 15-20 Alkenyl.

[0014] More preferably, Selected from (N-oleoyl) or (N-arachidonic acid).

[0015] Preferably, in formula (I), when Z is H, Y is selected from standard amino acids or non-standard amino acids, excluding glycine, alanine, valine, isoleucine, tryptophan, aspartic acid, glutamine, and asparagine; or Y and Z are selected from the same or different standard amino acids or non-standard amino acids, Y is linked to the hydroxyl group of ethanolamine through the carboxyl group, and Y is linked to the carboxyl group of Z through the amino group;

[0016] Preferably, in formula (I), when Z is H, Y is selected from standard amino acids, non-standard amino acids, and Y optionally does not include glycine, alanine, valine, isoleucine, tryptophan, aspartic acid, glutamine, asparagine, or does not include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, γ-aminobutyric acid, sarcosine, carboline, 2-aminoadipic acid, pantothenic acid, bovine serum albumin, threonine, tryptophan, tyrosine, valine, ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, γ-aminobutyric acid, sarcosine, carbohedrine ... one or more of sulfonic acid, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, β-alanine, β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine, β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine, β-dopa (3,4-dihydroxy-L-phenylalanine), 2-aminoisobutyric acid, isovaline, di-N-ethylglycine, N-methyl-alanine, L-abnictine, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclopropyl-1-carboxylic acid, hydroheterocyclobutane-2-carboxylic acid, or pipecolic acid;

[0017] Preferably, in formula (I), Y and Z are selected from the same or different standard amino acids and non-standard amino acids, Y is connected to the hydroxyl group of ethanolamine through a carboxyl group, and Y is connected to the carboxyl group of Z through an amino group; Y is selected from standard amino acids and non-standard amino acids, preferably, Y is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, γ-aminobutyric acid, sarcosine, carboxylic acid, 2-aminohexane Diac acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, beta-alanine, beta-aminoisobutyric acid, beta-leucine, beta-lysine, beta-arginine, beta-tyrosine, beta-phenylalanine, isoserine, beta-glutamic acid, beta-tyrosine, beta-dopa (3,4-dihydroxy-L-phenylalanine), 2-aminoisobutyric acid, isovaline, di-N-ethylglycine, N-methyl-alanine, L-abnictine, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclopropyl-1-carboxylic acid, hydroheterocyclobutane-2-carboxylic acid, or pipecolic acid.

[0018] Preferably, in formula (I1), X is selected from H, standard amino acids, and non-standard amino acids, and the standard amino acids and non-standard amino acids are linked to the amino group of phenylalanine via a carboxyl group;

[0019] Preferably, in formula (I2), X is selected from standard amino acids and non-standard amino acids, wherein the standard amino acids and non-standard amino acids are connected to the hydroxyl group of ethanolamine via a carboxyl group, and the standard amino acids and non-standard amino acids are connected to the carboxyl group of valine via an amino group;

[0020] Preferably, the standard amino acids are selected from aromatic or aliphatic amino acids, more preferably, the standard amino acids are selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine and valine;

[0021] Preferably, the non-standard amino acids are selected from ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, γ-aminobutyric acid, sarcosine, carcine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, β-amino acids, α,α-disubstituted amino acids, N-methyl acids, hydroxy-amino acids, cyclic amino acids; preferably, the non-standard amino acids are selected from ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, γ-aminobutyric acid, sarcosine, carcine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine , thiocysteine, cystathionine, homocysteine, β-alanine, β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine, β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine, β-dopa (3,4-dihydroxy-L-phenylalanine), 2-aminoisobutyric acid, isovaline, di-N-ethylglycine, N-methyl-alanine, L-abnictine, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclopropyl-1-carboxylic acid, hydrocyclobutane-2-carboxylic acid, or pipecolic acid;

[0022] Preferably, in formula (I), Y and Z are selected from the same or different standard amino acids or non-standard amino acids, Y is linked to the hydroxyl group of ethanolamine via a carboxyl group, Y is linked to the carboxyl group of Z via an amino group, and Z is further condensed with one or two same or different standard amino acids or non-standard amino acids via the amino group;

[0023] Preferably, in formula (I1), the standard amino acid or non-standard amino acid is further condensed with one or two identical or different standard amino acids or non-standard amino acids via the amino group;

[0024] Preferably, in formula (I2), X is selected from a standard amino acid, a non-standard amino acid, or an amino acid formed by condensation of 2-3 identical or different standard amino acids or non-standard amino acids, and the standard amino acid, non-standard amino acid or condensed amino acid is connected to the hydroxyl group of ethanolamine through a carboxyl group and to the carboxyl group of valine through an amino group.

[0025] Furthermore, the compound has the structure of formula (I1') or (I1"):

[0026]

[0027] Or (I2') or (I2") structure:

[0028]

[0029] Preferably, the standard amino acids and non-standard amino acids are selected from the D- or L-configuration.

[0030] More specifically, the present invention discloses compounds or pharmaceutically acceptable salt forms thereof:

[0031]

[0032]

[0033] In another aspect, the present invention relates to a compound of formula II:

[0034] P1-P2

[0035] or a pharmaceutically acceptable salt form thereof;

[0036] P1 is N-acylethanolamide; P2 is a moiety conjugated to the N-acylethanolamide, and P1 is linked to the carboxyl group of P2 via the hydroxyl group.

[0037] Preferably, P1 is selected from

[0038] Preferably, P2 is selected from pregabalin, gabapentin, lipoic acid, diethylaminopropionic acid or

[0039] More specifically, the compound or a pharmaceutically acceptable salt form thereof:

[0040]

[0041]

[0042] Preferably, the pharmaceutically acceptable salt form is selected from hydrochloride, trifluoroacetate, sulfate, pyrosulfate, bisulfate, sulfite, acid sulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrobromide, hydroiodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, hemisuccinate, suberate, sebacate, fumarate One or more of: a salt, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, p-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate.

[0043] Preferably, in any one of the above compounds or pharmaceutically acceptable salt forms thereof, one or more hydrogen atoms are replaced by deuterium atoms.

[0044] Furthermore, the present invention also relates to a pharmaceutical composition comprising any one of the above-mentioned compounds or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier, diluent or excipient.

[0045] Preferably, the composition is a solid preparation, a semisolid preparation, or a liquid preparation, preferably a powder, granules, pills, pellets, tablets, enteric-coated tablets, sustained-release tablets, capsules, soft capsules, films, chewing gum, drops, oral liquids, syrups, emulsions, self-microemulsions, lipid preparations, suspensions, or mixtures.

[0046] Furthermore, the present invention also relates to the use of any of the above-mentioned compounds or pharmaceutically acceptable salt forms thereof and the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing or treating pain, chronic low back pain, sciatica, radiculopathy, radicular pain, neuropathic pain, anxiety, depression, schizophrenia, cancer, amyotrophic lateral sclerosis, multiple sclerosis, nervous system diseases, Parkinson's disease, Alzheimer's disease, Huntington's disease, cerebral ischemia, epilepsy, loss of appetite, toothache, osteoarthritis, decreased gastrointestinal motility, cancer, glaucoma, atopic dermatitis, respiratory tract infection, post-traumatic stress disorder, obesity, insomnia, drowsiness, and idiopathic mast cell activation syndrome, wherein idiopathic mast cell activation syndrome is preferably chronic generalized musculoskeletal plastic pain.

[0047] Explanation of terms:

[0048] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0049] The term "aliphatic" means a straight chain (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon, bicyclic hydrocarbon, or polycyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, which has a single point of attachment to the rest of the molecule. In some embodiments, the aliphatic group contains 1-40 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 15-20 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched substituted or unsubstituted alkyl and alkenyl groups.

[0050] Alkenyl: The term "alkenyl" as used herein refers to an alkyl group, as defined herein, having one or more double bonds.

[0051] Preferably, C 15-20 Aliphatic group is C 15-20 Alkyl or C containing 1-5 C=C 15-20 Alkenyl.

[0052] Standard amino acids:

[0053] Standard amino acids or protein-forming amino acids include, but are not limited to, the 22 currently known amino acids that constitute the unit cell of protein and are encoded in the standard genetic code. Standard amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, and valine.

[0054] The non-standard amino acids are selected from ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, γ-aminobutyric acid, sarcosine, carbocine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, β-amino acids such as β-alanine, β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine, β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine, β- DOPA (3,4-dihydroxy-L-phenylalanine), α,α-disubstituted amino acids such as 2-aminoisobutyric acid, isovaline, di-N-ethylglycine, N-methyl acids such as N-methyl-alanine, L-abrin, hydroxy-amino acids such as 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids such as 1-aminocyclopropyl-1-carboxylic acid, hydrocyclobutane-2-carboxylic acid and pipecolic acid.

[0055] In formula (I), Z is selected from standard amino acids and non-standard amino acids, and the standard amino acids and non-standard amino acids are further condensed with one or two identical or different standard amino acids and non-standard amino acids via the amino group. That is, Z can be further linked to the carboxyl group of one identical or different standard amino acid and non-standard amino acid via the amino group, and further, Z can be linked to the carboxylic acid of a new identical or different standard amino acid and non-standard amino acid via the amino group of the new amino acid.

[0056] In formula (I1), the standard amino acid or non-standard amino acid is further condensed with one or two identical or different standard amino acids or non-standard amino acids via the amino group. That is, the standard amino acid or non-standard amino acid linked to the amino group of phenylalanine can be further linked to the carboxylic acid of another identical or different standard amino acid or non-standard amino acid via the amino group. Furthermore, the standard amino acid or non-standard amino acid can be further linked to the carboxylic acid of a new identical or different standard amino acid or non-standard amino acid via the amino group of the new amino acid.

[0057] In formula (I2), X is selected from a standard amino acid, a non-standard amino acid, or a condensed amino acid of 2-3 identical or different standard amino acids or non-standard amino acids. That is, X can be selected from 1 standard amino acid or non-standard amino acid, or 2 identical or different standard amino acids or non-standard amino acid condensed amino acids, or 3 identical or different standard amino acids or non-standard amino acid condensed amino acids, wherein the standard amino acid, non-standard amino acid, or condensed amino acid is linked to the hydroxyl group of ethanolamine via a carboxyl group and is linked to the carboxyl group of valine via an amino group.

[0058] The term "C0" denotes the maximum plasma concentration extrapolated to t=0.

[0059] The term "T max” indicates the time required to reach peak drug concentration after administration.

[0060] The term "AUC last ” represents the area enclosed by the blood drug concentration curve relative to the time axis.

[0061] Compared with the prior art, the prodrug of the present invention has the following unexpected technical effects:

[0062] (1) The PEA prodrug of the present invention can significantly improve the oral bioavailability of PEA, which is superior to the existing technology;

[0063] (2) After oral administration of certain embodiments of the PEA prodrug of the present invention to beagle dogs, only PEA but no prodrug was detected in the plasma, indicating that the PEA prodrug of the present invention has a fast conversion rate in vivo;

[0064] (3) The PEA prodrug of the present invention is a white solid powder with powder properties suitable for the production of solid preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] The present invention will be further described below with reference to the accompanying drawings.

[0066] Figure 1 This is a graph showing the average drug concentration-time curve of PEA in plasma after oral administration of PEA and PEA-(L)-P to male beagle dogs in Example 14. DETAILED DESCRIPTION

[0067] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0068] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0069] Example 1: Synthesis of PEA-(L)-V hydrochloride

[0070] Synthesis route:

[0071]

[0072] PEA-(L)-V hydrochloride

[0073] The synthesis steps of PEA-(L)-V hydrochloride are as follows:

[0074] N-(2-hydroxyethyl) palmitamide (900 mg, 3.0 mmol, 1.0 eq), (tert-butoxycarbonyl)-L-valine (716 mg, 3.3 mmol, 1.1 eq), HOBt (608 mg, 4.5 mmol, 1.5 eq) and DMAP (73.2 mg, 0.6 mmol, 0.2 eq) were dissolved in 15 mL of dichloromethane, and EDCI (864 mg, 4.5 mmol, 1.5 eq) was added under stirring. The temperature was raised to 50°C and the reaction was allowed to proceed overnight. The reaction was monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-palmitamidoethyl (tert-butoxycarbonyl)-L-valine (550 mg, yield 37%, white solid, R f =0.2(PE:EA=2:1)).

[0075] 2-Palmitamidoethyl(tert-butoxycarbonyl)-L-valine (550 mg, 1.1 mmol, 1.0 eq) was dissolved in 5 mL of methanol. 5 mL of a 4N hydrochloric acid solution in 1,4-dioxane was slowly added dropwise under stirring in an ice bath. The reaction was allowed to react at room temperature for 1 h and monitored by TLC. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography to obtain the target compound PEA-(L)-V hydrochloride (445 mg, yield 93%) as a white solid. f =0.3 (DCM:MeOH=20:1)). 1 H NMR(300MHz,MeOH-d4)δ4.32(t,J=5.3Hz,2H),3.95(brs,1H),3.60–3.46(m,2H),2.35(brs,1H),2.23(t,J=7.3Hz ,2H),1.65–1.62(m,2H),1.34–1.31(m,24H),1.10(d,J=6.5Hz,6H),0.93(t,J=6.5Hz,3H)ppm.HRMS(ESI)m / zCalcd for[C 23 H 47 N2O3] + 399.3581, found 399.3580.

[0076] Example 2: Synthesis of PEA-(L)-V-(L)-V Hydrochloride

[0077] Synthesis route:

[0078]

[0079] The synthesis steps of PEA-(L)-V-(L)-V hydrochloride are as follows:

[0080] PEA-(L)-V hydrochloride (360 mg, 0.77 mmol, 1.0 eq), (tert-butyloxycarbonyl)-L-valine (185 mg, 0.85 mmol, 1.1 eq), HOBt (157 mg, 1.16 mmol, 1.5 eq) and DMAP (18.5 mg, 0.15 mmol, 0.2 eq) were dissolved in 5 mL of dichloromethane. EDCI (223 mg, 1.16 mmol, 1.5 eq) was added with stirring. The temperature was raised to 50°C, and triethylamine (78 mg × 3, 2.3 mmol, 3.0 eq) was added portionwise. The reaction was allowed to react overnight and monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate aqueous solution was added, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-palmitamide ethyl (tert-butoxycarbonyl)-L-valyl-L-valine ester (358 mg, yield 60%, R f =0.5(PE:EA=1:1)).

[0081] 2-Palmitamidoethyl (tert-butoxycarbonyl)-L-valyl-L-valine ester (300 mg, 0.5 mmol, 1.0 eq) was dissolved in 5 mL of methanol. 3 mL of a dioxane solution of hydrochloric acid was slowly added dropwise under stirring in an ice bath. The reaction was allowed to proceed at room temperature for 1 h and monitored by TLC. After the reaction was complete, the reaction solution was directly concentrated and separated by column chromatography to obtain the target compound PEA-(L)-V-(L)-V hydrochloride (140 mg, yield 52%) as a white solid. f =0.3 (DCM:MeOH=20:1)). 1 H NMR(300MHz, Methanol-d4)δ4.37(d,J=5.7Hz,1H),4.28–4.15(m,2H),3.49(t,J=5.4Hz,2H),3.27(d,J=5.5Hz,1H), 2.27–2.16(m,3H),2.08–1.97(m,1H),1.67–1.58(m,2H),1.33–1.31(s,24H),1.03–0.90(m,15H)ppm.HRMS(ESI)m / z Calcd for[C 28 H 56 N3O4] + 498.4265, found 498.4279.

[0082] Example 3: Synthesis of Compound PEA-G-(L)-V Hydrochloride

[0083] Synthesis route:

[0084]

[0085] The synthesis steps of PEA-G-(L)-V hydrochloride are as follows:

[0086] N-(2-hydroxyethyl) palmitamide (6.0 g, 20.0 mmol, 1.0 eq), (tert-butyloxycarbonyl)glycine (3.9 g, 22.0 mmol, 1.1 eq), HOBt (4.1 g, 30.0 mmol, 1.5 eq) and DMAP (1.2 g, 11.0 mmol, 0.5 eq) were dissolved in 50 mL of CHCl3, and EDCI (5.8 g, 30.0 mmol, 1.5 eq) was added under stirring. The temperature was raised to 65°C and the reaction was allowed to proceed overnight. The reaction was monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-palmitamidoethyl (tert-butyloxycarbonyl)glycine ester (7.9 g, yield 86%, white solid, R f =0.7 (DCM:MeOH=10:1)).

[0087] 2-Palmitamidoethyl (tert-butoxycarbonyl) glycine ester (7.9 g, 17.0 mmol, 1.0 eq) was dissolved in 30 mL of DCM. 13 mL of 4N HCl in dioxane was slowly added dropwise under ice-cooling stirring. The reaction was allowed to proceed at room temperature for 2 h and monitored by TLC. After the reaction was complete, the reaction solution was concentrated and slurried in DCM:MeOH = 100:1 to obtain PEA-G hydrochloride (5.5 g, yield 83%) as a white solid. f =0.4 (DCM:MeOH=10:1)).

[0088] PEA-G hydrochloride (5.5 g, 14.0 mmol, 1.0 eq) was dissolved in 30 mL CHCl3 and triethylamine (4.2 g, 42.0 mmol, 3.0 eq) was added dropwise with stirring. After stirring for 10 min, (tert-butyloxycarbonyl)-L-valine (3.6 g, 16.8 mmol, 1.2 eq), HOBt (2.8 g, 21.0 mmol, 1.5 eq) and DMAP (854 mg, 7.0 mmol, 0.5 eq) were added. EDCI (4.0 g, 2.0 mmol, 1.5 eq) was added with stirring. The temperature was raised to 65°C and the reaction was allowed to react overnight. The reaction was monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added, extracted with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-palmitamidoethyl (tert-butoxycarbonyl)-L-valylglycine ester (5.4 g, yield 70%, R f =0.7 (DCM:MeOH=10:1)).

[0089] 2-Palmitamidoethyl (tert-butoxycarbonyl)-L-valylglycine ester (5.4 g, 9.7 mmol, 1.0 eq) was dissolved in 30 mL of DCM. 7 mL of a 4N HCl solution in dioxane was slowly added dropwise with stirring on an ice bath. The reaction was allowed to proceed at room temperature for 2 h, monitored by TLC. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography to obtain 1.6 g of the target product, PEA-G-(L)-V hydrochloride (yield 34%), as a white solid. f =0.4 (DCM:EtOH=10:1)). 1 H NMR (300MHz, DMSO-d6) δ8.87(t,J=5.7Hz,1H),8.09(d,J=5.7Hz,1H),4.05( t,J=5.8Hz,2H),4.04–3.81(m,2H),3.48(d,J=5.3Hz,1H),3.28(q,J=5.8Hz, 2H),3.21–3.69(brs,3H),2.07(t,J=7.5Hz,3H),1.47(t,J=7.1Hz,2H),1.2 4(s,24H),0.94(t,J=7.1Hz,6H),0.88–0.84(m,3H)ppm.HRMS(ESI)m / zCalcd for[C 25 H 50 N3O4] + 456.3801, found 456.3789.

[0090] Example 4: Preparation of compound PEA-G-(L)-V trifluoroacetate

[0091] Synthesis route:

[0092]

[0093] The synthesis steps of PEA-G-(L)-V trifluoroacetate are as follows:

[0094] Under argon protection, compound 2-palmitamidoethyl (tert-butoxycarbonyl)-L-valylglycine ester (3.0 g, 5.4 mmol, 1.0 eq) was dissolved in 20 mL of anhydrous DCM. After cooling to 0°C, trifluoroacetic acid (18.5 g, 162.0 mmol, 30.0 eq) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 h, and monitored by TLC. After the reaction was complete, the reaction solution was directly concentrated and separated by column chromatography to obtain the target product PEA-G-(L)-V trifluoroacetate (1.5 g, yield 48%) as a white solid. f =0.3 (DCM:MeOH=10:1)). 1H NMR (300MHz, Methanol-d4) δ4.19(t,J=5.4Hz,2H),4.04–3.90(m,2H),3.43(t,J=5.4Hz,2H),3.16(d,J=5. 5Hz,1H),2.18(t,J=7.5Hz,2H),2.04–1.93(m,1H),1.64–1.55(m,2H),1.28(s,24H),1.00–0.87(m,9H)ppm. 19 F NMR(282MHz,DMSO-d6)δ-68.8ppm.MS m / zCalcd for[C 25 H 49 N3O4Na] + 478.68,found 478.46.

[0095] Example 5: Synthesis of PEA-(L)-A-(L)-V Hydrochloride

[0096] Synthesis route:

[0097]

[0098] The synthesis steps of PEA-(L)-A-(L)-V hydrochloride are as follows:

[0099] Take N-(2-hydroxyethyl) palmitamide (7.5g, 25.0mmol, 1.0eq), (tert-butoxycarbonyl)-L-alanine (5.67g, 30.0mmol, 1.2eq), HOBt (5.1g, 37.5mmol, 1.5eq) and DMAP (1.5g, 12.5mmol, 0.5eq) and dissolve them in 50mL CHCl3. Add EDCI (7.2g, 37.5mmol, 1.5eq) while stirring, raise the temperature to 65℃, react overnight, and monitor by TLC. After the reaction is complete, add an appropriate amount of saturated sodium bicarbonate solution, extract with DCM, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain 2-palmitamidoethyl (tert-butoxycarbonyl)-L-alanine (9.4g, yield 80%, white solid, R f =0.7 (DCM:MeOH=10:1)).

[0100] The compound 2-palmitamidoethyl (tert-butoxycarbonyl)-L-alanine (9.4 g, 20 mmol, 1.0 eq) was dissolved in 30 mL of DCM. 15 mL of 4N HCl in dioxane was slowly added dropwise under stirring in an ice bath. The reaction was allowed to react at room temperature for 2 h and monitored by TLC. After the reaction was complete, the reaction solution was directly concentrated and slurried in DCM:MeOH = 100:1 to obtain PEA-(L)-A hydrochloride (6.0 g, yield 74%) as a white solid. f =0.4 (DCM:MeOH=10:1)).

[0101] PEA-(L)-A hydrochloride (6.0 g, 15.0 mmol, 1.0 eq) was dissolved in 30 mL of CHCl3 and triethylamine (4.5 g, 45.0 mmol, 3.0 eq) was added dropwise with stirring. After stirring for 10 min, (tert-butyloxycarbonyl)-L-valine (3.9 g, 18 mmol, 1.2 eq), HOBt (3.0 g, 22.0 mmol, 1.5 eq) and DMAP (915 mg, 7.5 mmol, 0.5 eq) were added. EDCI (4.2 g, 22.0 mmol, 1.5 eq) was added with stirring. The temperature was raised to 65°C and the reaction was allowed to react overnight. The reaction was monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added, extracted with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-palmitamidoethyl (tert-butoxycarbonyl)-L-valyl-L-alanine ester (6.2 g, yield 72%, R f =0.7 (DCM:MeOH=10:1)).

[0102] The compound 2-palmitamidoethyl (tert-butoxycarbonyl)-L-valyl-L-alanine ester (4.0 g, 7.0 mmol, 1.0 eq) was dissolved in 20 mL of DCM. 4 mL of 4N HCl in dioxane was slowly added dropwise while stirring on an ice bath. The reaction was allowed to react at room temperature for 2 h and monitored by TLC. After the reaction was complete, the reaction solution was directly concentrated and separated by column chromatography to obtain the target product PEA-(L)-A-(L)-V hydrochloride (1.7 g, yield 48%) as a white solid. f =0.3 (DCM:MeOH=10:1)). 1H NMR(300MHz,DMSO-d6)δ8.95(d,J=6.8Hz,1H),8.16(s,3H),7.98(t,J=5.7Hz ,1H),4.36(p,J=7.2Hz,1H),4.04(td,J=5.7,3.2Hz,2H),3.62(d,J=5.7Hz,1 H),3.27(q,J=5.9Hz,2H),2.14–2.03(m,3H),1.51–1.42(m,2H),1.33(d,J=7 .3Hz,3H),1.23(app.s,24H),0.96(d,J=6.9Hz,6H),0.89–0.80(m,3H)ppm.MS m / z Calcd for[C 26 H 51 N3O4Na] + 492.71,found492.45.

[0103] Example 6: Synthesis of PEA-(L)-P hydrochloride

[0104] Synthesis route:

[0105]

[0106] The synthesis steps of PEA-(L)-P hydrochloride are as follows:

[0107] N-(2-hydroxyethyl) palmitamide (6.0 g, 20.0 mmol, 1.0 eq), (tert-butoxycarbonyl)-L-phenylalanine (4.0 g, 24.0 mmol, 1.2 eq), HOBt (4.1 g, 30.0 mmol, 1.5 eq) and DMAP (1.2 g, 10.0 mmol, 0.5 eq) were dissolved in 50 mL of CHCl3, and EDCI (5.8 g, 30.0 mmol, 1.5 eq) was added under stirring. The temperature was raised to 65°C and the reaction was continued overnight. The reaction was monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-palmitamidoethyl (tert-butoxycarbonyl)-L-phenylalanine ester (6.5 g, yield 73%, white solid, R f =0.7 (DCM:MeOH=10:1)).

[0108] 2-Palmitamidoethyl (tert-butoxycarbonyl)-L-phenylalanine ester (6.5 g, 14.6 mmol, 1.0 eq) was dissolved in 30 mL of DCM. 8 mL of 4N HCl in dioxane was slowly added dropwise while stirring on an ice bath. The reaction was allowed to proceed at room temperature for 2 h and monitored by TLC. After the reaction was complete, the reaction solution was concentrated and slurried in a DCM:MeOH ratio of 100:1 to obtain PEA-(L)-P hydrochloride (6.0 g, yield 85%) as a white solid. f =0.4 (DCM:MeOH=10:1)). 1 H NMR(300MHz, Methanol-d4)δ7.40–7.27(m,5H),4.35(dd,J=7.6,6.0Hz,1H),4.31–4.18(m,2H),3.53–3.37(m,2H),3.35–3.28( m,1H),3.20(dd,J=14.4,7.6Hz,1H),2.20(t,J=7.5Hz,2H),1.64–1.54(m,2H),1.27(app.s,24H),0.89(t,J=6.87Hz,3H)ppm.MS m / z Calcd for[2M+1]894.36,found 894.41.

[0109] Example 7: Preparation of PEA-(L)-P-(L)-V Hydrochloride

[0110] Synthesis route:

[0111]

[0112] The synthesis steps of PEA-(L)-P-(L)-V hydrochloride are as follows:

[0113] PEA-(L)-P hydrochloride (6.0 g, 12.5 mmol, 1.0 eq) was dissolved in 30 mL of CHCl3 and triethylamine (3.8 g, 37.5 mmol, 3.0 eq) was added dropwise under stirring. After stirring for 10 min, (tert-butyloxycarbonyl)-L-valine (3.3 g, 15 mmol, 1.2 eq), HOBt (2.5 g, 18.8 mmol, 1.5 eq) and DMAP (763 mg, 6.3 mmol, 0.5 eq) were added. EDCI (3.6 g, 18.8 mmol, 1.5 eq) was added under stirring. The temperature was raised to 65°C and the reaction was allowed to react overnight. The reaction was monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added, extracted with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-palmitamidoethyl (tert-butyloxycarbonyl)-L-valyl-L-phenylalanine ester (5.6 g, yield 70%, Rf =0.7 (DCM:MeOH=10:1)).

[0114] 2-Palmitamidoethyl (tert-butyloxycarbonyl)-L-valyl-L-phenylalanine ester (4.0 g, 6.2 mmol, 1.0 eq) was dissolved in 20 mL of DCM. 3 mL of 4N HCl in dioxane was slowly added dropwise while stirring in an ice bath. The reaction was allowed to react at room temperature for 2 h, monitored by TLC. After the reaction was complete, the reaction solution was directly concentrated, recrystallized from chloroform, and then separated by column chromatography to obtain the target product, PEA-(L)-P-(L)-V hydrochloride (2.8 g, yield 77%), as a white solid, R f =0.3 (DCM:MeOH=10:1)). 1 H NMR(300MHz, Methanol-d4)δ7.33–7.22(m,5H),4.74(dd,J=9.0,5.4Hz,1H),4.14(hep t,J=5.6Hz,2H),3.67(d,J=5.2Hz,1H),3.40(t,J=5.5Hz,2H),3.24(dd,J=14.2,5.5Hz, 1H),3.03(dd,J=14.1,9.0Hz,1H),2.25–2.15(m,3H),1.62–1.56(m,2H),1.27(app.s,2 6H),1.06(d,J=6.9Hz,3H),1.01(d,J=6.9Hz,3H),0.92–0.87(m,3H)ppm.HRMS(ESI)m / z Calcdfor[C 32 H 56 N3O4] + 546.4271, found 546.4264.

[0115] Example 8: Synthesis of PEA-Pregabalin Hydrochloride

[0116] Synthesis route:

[0117]

[0118] The synthesis steps of PEA-pregabalin hydrochloride are as follows:

[0119] Pregabalin (795 mg, 5 mmol, 1 eq.) and NaOH (600 mg, 15 mmol, 3 eq.) were dissolved in 20 mL of water. A solution of Boc2O (1.96 g, 9 mmol, 1.8 eq.) in 1,4-dioxane (20 mL) was added dropwise at room temperature and stirred at room temperature for 1 hour. The 1,4-dioxane was removed by concentration under reduced pressure, and the excess Boc2O was removed by extraction with ether (30 mL x 3). The aqueous phase was adjusted to pH 2 with saturated citric acid solution. The product was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain N-Boc-protected pregabalin, which was carried on to the next step without purification (1.1 g white solid, 85% yield).

[0120] N-Boc-protected pregabalin (142 mg, 0.55 mmol, 1.1 eq.), N-(2-hydroxyethyl)palmitamide (150 mg, 0.5 mmol, 1.0 eq.), EDCI (144 mg, 0.75 mmol, 1.5 eq.), HOBt (101 mg, 0.75 mmol, 1.5 eq.), and DMAP (12.2 mg, 0.1 mmol, 0.2 eq.) were suspended in 5 mL of dichloromethane and stirred at room temperature for 2 days. The reaction was quenched by the addition of 5 mL of saturated sodium bicarbonate and extracted with chloroform (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the N-Boc-protected pregabalin and N-(2-hydroxyethyl)palmitamide ester (230 mg, 85% yield, white solid).

[0121] N-Boc-protected pregabalin and N-(2-hydroxyethyl) palmitamide ester (108 mg, 0.2 mmol, 1.0 eq.) were dissolved in 2 mL of dichloromethane. A 4N solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2 mmol, 10.0 eq.) was added dropwise under an ice-water bath. After complete conversion, the organic solvent was removed by concentration. The product was purified by silica gel column chromatography to obtain a white solid. Recrystallization afforded the target compound, PEA-pregabalin hydrochloride (53 mg, 56% yield, white solid). 1H NMR(300MHz, CDCl3)δ8.33(brs,2H),6.83(brs,1H),4.26–4.14(m,2H),3.54–3.52(m,2H),3.18–3.13(m,1H),3.06–2.99(m,1H),2.6 7–2.51(m,2H),2.40(app.s,1H),2.24(t,J=7.6Hz,2H),1.70–1.59(m,3H),1.30–1.27(m,26H),0.95–0.88(m,9H)ppm.HRMS(ESI)m / z Calcd for[C 26 H 53 N2O3] + 441.4051, found 441.4080.

[0122] Example 9: Synthesis of PEA-gabapentin hydrochloride

[0123] Synthesis route:

[0124]

[0125] The synthesis steps of PEA-gabapentin hydrochloride are as follows:

[0126] Gabapentin (1.71 g, 10 mmol, 1 eq.) and NaOH (1.2 g, 30 mmol, 3 eq.) were dissolved in 30 mL of water. A solution of Boc2O (4.36 g, 20 mmol, 2.0 eq.) in tetrahydrofuran (30 mL) was added dropwise at room temperature and stirred for 1 hour. The tetrahydrofuran was removed by concentration under reduced pressure, and the excess Boc2O was removed by extraction with ether (30 mL x 3). The aqueous phase was adjusted to pH 2 with saturated citric acid solution. The product was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain N-Boc-protected gabapentin, which was carried on to the next step without purification (2.25 g white solid, 85% yield).

[0127] N-Boc-protected gabapentin (325 mg, 1.2 mmol, 1.2 eq.), N-(2-hydroxyethyl)palmitamide (299 mg, 1.0 mmol, 1.0 eq.), EDCI (288 mg, 1.5 mmol, 1.5 eq.), HOBt (203 mg, 1.5 mmol, 1.5 eq.), and DMAP (24.4 mg, 0.1 mmol, 0.2 eq.) were suspended in 10 mL of dichloromethane and stirred at room temperature for 2 days. The reaction was quenched by the addition of 5 mL of saturated sodium bicarbonate. The mixture was extracted with chloroform (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the ester of N-Boc-protected gabapentin and N-(2-hydroxyethyl)palmitamide (397 mg, 72% yield, white solid).

[0128] N-Boc-protected gabapentin and N-(2-hydroxyethyl) palmitamide ester (276 mg, 0.5 mmol, 1.0 eq.) were dissolved in 5 mL of dichloromethane. A 4N solution of hydrogen chloride in 1,4-dioxane (1.2 mL, 4.8 mmol, 9.6 eq.) was added dropwise under an ice-water bath. After complete conversion, the organic solvent was removed by concentration. The product was purified by silica gel column chromatography to obtain a white solid. Recrystallization afforded the target compound, PEA-gabapentin hydrochloride (159 mg, 65% yield, white solid). 1 H NMR(300MHz, CDCl3)δ8.37(s,3H),6.93(s,1H),4.25(s,2H),3.60(s,2H),3.20(s,2H), 2.70(s,2H),2.30(s,2H),1.69–1.33(m,36H),0.95(t,J=6.5Hz,3H)ppm.HRMS(ESI)m / z Calcd for[C 27 H 53 N2O3] + 453.4051,found 453.4051.

[0129] Example 10: Synthesis of PEA-lipoic acid ester

[0130] Synthesis route:

[0131]

[0132] The steps for synthesizing PEA-lipoic acid ester are as follows:

[0133] R-lipoic acid (453 mg, 2.2 mmol, 1.1 eq.), N-(2-hydroxyethyl)palmitamide (598 mg, 2.0 mmol, 1.0 eq.), and DMAP (24.4 mg, 0.2 mmol, 0.1 eq.) were dissolved in 10 mL of dichloromethane. A solution of DCC (825 mg, 4 mmol, 2.0 eq.) in dichloromethane (5 mL) was added dropwise at room temperature. The mixture was stirred overnight at room temperature. Insoluble matter was removed by filtration, and the filter cake was washed with dichloromethane. The organic phase was washed sequentially with saturated NaHCO₃ solution and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The target compound, PEA-lipoic acid ester, was obtained as a yellow solid (420 mg, 43% yield) after silica gel column chromatography (PE:EA = 5:1 to 1:1). 1 H NMR (300MHz, CDCl3) δ5.91(t,J=5.8Hz,1H),4.13(t,J=5.3Hz,2H),3.59–3.45(m,3H),3.19–3.04(m,2H),2.49–2.39(m,1H),2.31(t,J=7.3Hz ,2H),2.15(t,J=7.6Hz,2H),1.93–1.82(m,1H),1.71–1.52(m,6H),1.50–1.37(m,2H),1.22(s,24H),0.84(t,J=6.6Hz,3H)ppm.HRMS(ESI)m / z Calcd for[C 26 H 50 NO3S2] + 488.3227, found 488.3232.

[0134] Example 11: Synthesis of PEA-diethylaminopropionate

[0135] Synthesis route:

[0136]

[0137] The synthesis steps of PEA-diethylaminopropionate are as follows:

[0138] Dissolve N-(2-hydroxyethyl) palmitamide (6g, 20mmol, 1.0eq.) in 40mL of dichloromethane, add triethylamine (30mmol, 1.5eq.) under ice bath, and add acryloyl chloride (22mmol, 1.1eq.) dropwise. Monitor by TLC plate. After the reaction is complete (about 2h), add 20mL of 1N hydrochloric acid under ice bath to quench the reaction. Extract with dichloromethane, combine the organic layers, and dry over anhydrous sodium sulfate. Filter, concentrate, and separate by silica gel column chromatography to obtain 2-palmitamide ethyl acrylate (5.3g, yield 88%) as a white solid, R f=0.5 (DCM:MeOH=20:1)).

[0139] Dissolve 2-palmitamide ethyl acrylate (3.53 g, 10 mmol, 1.0 eq.) in 20 mL of chloroform, add diethylamine (11 mmol, 1.1 eq.) and 20 μL of acetic acid, and heat to 40°C and stir overnight. Monitor by TLC. After the reaction is complete, concentrate and separate by alumina column chromatography to obtain 2.1 g of the target product, PEA-diethylaminopropionate (yield 49%), as a beige solid. f =0.5 (DCM:MeOH=10:1)). 1 H NMR (300MHz, CDCl3) δ6.01(brs,1H),4.19(t,J=5.2Hz,2H),3.51(q,J=5.4Hz,2H),2.78(t,J=7.0Hz,2H),2.57–2.45(m,6H ),2.17–2.12(m,2H),1.61(p,J=7.2Hz,2H),1.24(s,24H),1.02(t,J=7.2Hz,6H),0.87(t,J=6.6Hz,3H)ppm.HRMS(ESI)m / z Calcd for[C 25 H 51 N2O3] + 427.3900,found 427.3903.

[0140] Example 12: Synthesis of PEA-Py

[0141] Synthesis route:

[0142]

[0143] The synthesis steps of PEA-Py are as follows:

[0144] To 10g of 2-chloronicotinic acid, add 20g of a 40% aqueous methylamine solution, heat to 80°C, and continue stirring for two days. After the reaction is complete, add 10% aqueous sodium hydroxide solution to adjust the pH to 10, and concentrate to remove unreacted methylamine. Then, adjust the pH to 5-6 with 10% hydrochloric acid to obtain the crude product, 2-(methylamino)nicotinic acid, which is carried on to the next step without further treatment.

[0145] Under argon protection, LiAlH4 (1.9 g, 50 mmol, 2.5 eq) was dissolved in 40 mL of THF. 2-(Methylamino)nicotinic acid (3.04 g, 20 mmol, 1.0 eq) was slowly added in portions while stirring on an ice bath. After the addition, the reaction temperature was raised to 50°C and monitored by TLC. After the reaction was complete, Na2SO4·10H2O was added under ice bath to quench the reaction. The mixture was stirred for 30 min, filtered through celite, and the filter cake was washed with chloroform. The filtrate was concentrated and separated by silica gel column chromatography to obtain (2-(methylamino)pyridin-3-yl)methanol (916 mg, 42% yield, as a white solid, R f =0.5 (DCM:MeOH=20:1)).

[0146] (2-(Methylamino)pyridin-3-yl)methanol (695 mg, 5 mmol, 1.0 eq) was dissolved in 15 mL of DCM, and imidazole (680 mg, 10 mmol, 2.0 eq) and TBSCl (904 mg, 6 mmol, 1.2 eq) were added in sequence. The mixture was stirred at room temperature for 4 h and monitored by TLC. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give the crude product 3-((tert-butyldimethylsilyl)oxy)methyl)-N-methylpyridin-2-amine (brown liquid, R f =0.6 (DCM:MeOH=10:1)), and directly carried out to the next step without treatment.

[0147] Triphosgene (742 mg, 2.5 mmol, 1.0 eq) was dissolved in 20 mL of DCM, and pyridine (395 mg, 5 mmol, 1.0 eq) was slowly added dropwise under ice bath. After stirring for 5 min, the crude product of the previous step, 3-((tert-butyldimethylsilyl)oxy)methyl)-N-methylpyridin-2-amine, was added dropwise, stirred for 5 min, warmed to room temperature, and continued to stir for 4 h. The reaction was monitored by TLC plate. After the reaction was complete, the reaction was quenched with saturated copper sulfate solution, extracted with DCM, and the organic phases were combined, dried, and separated by column chromatography to obtain 616.7 mg of the target product (3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(methyl)amino chloride (total yield of two steps was 40%), a yellow transparent liquid, R f =0.8(PE:EA=2:1)).

[0148] N-(2-Hydroxyethyl)palmitamide (508 mg, 1.7 mmol, 1.0 eq), DIPEA (439 mg, 3.4 mmol, 2.0 eq), and DMAP (21 mg, 0.17 mmol, 0.1 eq) were dissolved in 10 mL of DCM and (3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(methyl)amino chloride (617 mg, 1.9 mmol, 1.1 eq) was added under stirring. The mixture was refluxed at 50°C for 72 h and monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The product was filtered, concentrated, and purified by silica gel column chromatography to obtain 2-palmitamideethyl (3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(methyl)carbamate (678 mg, yield 70%, R f =0.3(PE:EA=1:1)).

[0149] 2-Palmitamidoethyl (3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(methyl)carbamate (115.3 mg, 0.2 mmol, 1.0 eq) was dissolved in 2 mL of THF, and 3 mL of 1N hydrochloric acid was slowly added dropwise. The mixture was stirred at room temperature for 30 min and monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added to quench the mixture, and the mixture was extracted with DCM. The organic phases were combined, dried, and concentrated to give the crude product 2-palmitamidoethyl (3-(hydroxymethyl)pyridin-2-yl)(methyl)carbamate (R f =0.5 (DCM:MeOH=20:1)), and directly proceeded to the next step without treatment.

[0150] The crude product of the previous step, 2-palmitamidoethyl (3-(hydroxymethyl)pyridin-2-yl)(methyl)carbamate (713 mg, 1.4 mmol, 1.0 eq), N-Boc glycine (245 mg, 1.4 mmol, 1.0 eq), HOBt (284 mg, 2.1 mmol, 1.5 eq) and DMAP (34 mg, 0.28 mmol, 0.2 eq) were dissolved in 20 mL of DCM, and EDCI (403 mg, 2.1 mmol, 1.5 eq) was added under stirring. The reaction was allowed to proceed overnight at room temperature and monitored by TLC. After the reaction was complete, an appropriate amount of saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM. The organic phases were combined, dried, and separated by column chromatography to obtain the product (2-(methyl((2-palmitamidoethoxy)carbonyl)amino)pyridin-3-yl)methyl(tert-butoxycarbonyl)glycine ester (500 mg, yield 55%) as a light yellow solid, R f =0.5 (DCM:MeOH=20:1)).

[0151] (2-(Methyl((2-palmitoylaminoethoxy)carbonyl)amino)pyridin-3-yl)methyl(tert-butoxycarbonyl)glycine ester (100 mg, 0.15 mmol, 1.0 eq) was added dropwise to 3 mL of DCM under ice-bath stirring. 4 mL of a dioxane solution of hydrochloric acid was added dropwise. The reaction was allowed to proceed for 1 h and monitored by TLC. After the reaction was complete, the mixture was concentrated directly, and an appropriate amount of ether was added, stirred thoroughly, and filtered to obtain a crude product (white solid). The crude product was further purified by PTLC to obtain the target product PEA-Py (60 mg, yield 77%, white solid, R f =0.4 (DCM:MeOH=10:1)). 1 H NMR (300MHz, Methanol-d4) δ8.66(dd,J=5.3,1.6Hz,1H),8.44(d,J=7.7Hz,1H),7.78(dd,J=7.8,5.2Hz,1H),5.35(s,2H),4.2 2(brs,2H),3.97(s,2H),3.36–3.29(m,6H),2.17(s,2H),1.57(s,2H),1.28(app.s,24H),0.97–0.77(m,3H)ppm.HRMS(ESI)m / z Calcd for[C 28 H 49 N4O5] + 521.3697,found 521.3697.

[0152] Example 13: Pharmacokinetics of PEA in male beagle dogs after intravenous injection

[0153] The purpose of this study was to investigate the pharmacokinetic (PK) properties of PEA in male beagle dogs after a single intravenous injection of PEA solution.

[0154] Preparation of drug delivery formulation: PEA powder was weighed and added to a solvent containing 10% HS15, 10% NMP, 10% PEG400 and 70% water. The solution was dissolved by ultrasonication, filtered through a 0.22 μm filter membrane, and dispensed into vials. The solution was sterilized by high-pressure steam at 121°C for 15 minutes. The content of the sample was determined to be 0.47 mg / ml.

[0155] Animal Dosing and Blood Collection: Three male beagle dogs were given free access to water throughout the study. They were fasted for at least 12 hours before dosing and fed 4 hours after dosing. PEA solution was injected intravenously. Blood samples were collected into K2EDTA anticoagulant tubes at 0 hour before dosing and at 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after dosing and stored on ice until centrifugation. Plasma was centrifuged within 30 minutes after blood collection (8000 rpm for 5 minutes at 2-8°C). After centrifugation, the plasma was transferred to a centrifuge tube and stored at ≤-65°C. PEA concentrations in plasma were determined by LC-MS / MS, and pharmacokinetic parameters were calculated.

[0156] Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin™ (Version 8.3, Certara, USA). The PEA concentration was calculated by subtracting the plasma concentration at 0 h. The dose and PK data for intravenous administration of PEA solution in beagle dogs are shown in Table 1.

[0157] Table 1 Dosage and PK data of intravenous PEA solution in beagle dogs

[0158]

[0159] The results in Table 1 show that after beagle dogs were intravenously injected with 0.5 mg / kg PEA solution, T max The C0 was 546.8 ng / ml and the AUC last The data of intravenous administration will be used to calculate the oral bioavailability of PEA.

[0160] Example 14: Pharmacokinetics of PEA and its derivatives after oral administration in male beagle dogs

[0161] The purpose of this study was to investigate the PK properties of PEA, I16 (CN110023308A compound I16), or PEA derivatives in male beagle dogs after a single oral administration.

[0162] Preparation of drug delivery preparation: Fill the drug powder into size 0 gelatin capsules.

[0163] Animal Dosing and Blood Collection: Three beagle dogs were included in each group. The day before the experiment, the beagles were fasted for at least 12 hours and had free access to water. On the day of the experiment, the beagles were first gavage-fed with approximately 150 mL of a specially formulated liquid diet (see Table 2 for ingredients). Thirty minutes after feeding, the beagles were orally administered with pre-filled capsules and 20 mL of water to ensure the capsules entered the stomach. After dosing, the animals were allowed free access to water and then fed normally 4 hours later. Blood samples were collected into K2EDTA-anticoagulant tubes at 0 hour before dosing, and at 10, 30, 1, 2, 3, 4, 6, and 8 hours after dosing. These samples were stored on ice until centrifugation. Plasma was centrifuged within 30 minutes (8000 rpm for 5 minutes at 2-8°C). After centrifugation, 400 μL of plasma was quantitatively collected and added to a centrifuge tube pre-filled with 4 μL of formic acid. The samples were stored at ≤-65°C. Analyte concentrations in plasma were determined by LC-MS / MS, and pharmacokinetic parameters were calculated.

[0164] Table 2 Special meal list

[0165] type bacon Regular dog food whole milk quantity 2 pieces (~60g) 25g 150mL

[0166] The pharmacokinetic parameters of each group were calculated using the non-compartmental model using WinNonlin™ (Version 8.3, Certara, USA). The PEA concentration was calculated by subtracting the plasma concentration at 0 h.

[0167] Bioavailability calculation formula: Bioavailability (%) = (AUC T ·D iv ) / (AUC iv ·D T )×100%, where AUC represents AUC last , subscripts T and iv represent the test preparation and intravenous preparation, respectively, and D represents the dosage. iv The AUC of PEA intravenous injection (dosage 0.5 mg / kg) in Example 14 was used. last The average value of the data was 133.5 ng·h / mL.

[0168] (1) Pharmacokinetic testing of PEA

[0169] PEA was used as the control group. The blood concentration of PEA in beagle dogs was measured after oral administration and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 3.

[0170] Table 3 Oral administration dosage and PK data of PEA in beagle dogs

[0171]

[0172] The results in Table 3 show that the bioavailability of PEA was 0.9% after oral administration to beagle dogs. The results indicate that the oral bioavailability of PEA is low, which is consistent with the literature reports.

[0173] (2) Pharmacokinetics of I16 (CN110023308A compound I16)

[0174] I16 is a PEA prodrug disclosed in patent CN110023308A. This prodrug exhibits the highest oral bioavailability of PEA among existing drugs. Here, I16 served as a control group. Plasma concentrations of I16 and PEA were measured in beagle dogs after oral administration of I16, and pharmacokinetic parameters were calculated. Dosage and PK data are shown in Table 4.

[0175] Table 4 Oral administration dosage and PK data of I16 in beagle dogs

[0176]

[0177] 1 The dosage is calculated based on PEA. ND: Not detected in plasma, pharmacokinetic parameters cannot be calculated.

[0178] After oral administration of I16 to beagle dogs, only PEA was detected in the plasma, but I16 was not detected, so the pharmacokinetic parameters of I16 could not be calculated. The pharmacokinetic parameters of PEA are shown in Table 4. The results showed that after oral administration of I16 to beagle dogs, the bioavailability of PEA was 3.1%, which was significantly improved compared with the bioavailability of PEA in (1).

[0179] (3) Pharmacokinetics of PEA-(L)-V hydrochloride

[0180] PLoS ONE 10(6):e0128699 discloses an L-valine derivative of PEA, which was used as a control group and named PEA-(L)-V hydrochloride. The plasma concentrations of PEA-(L)-V and PEA were measured in beagle dogs after oral administration of PEA-(L)-V hydrochloride, and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 5.

[0181] Table 5 Dosage and PK data of oral administration of PEA-(L)-V hydrochloride in beagle dogs

[0182]

[0183]

[0184] 1 The dosage is calculated based on PEA.

[0185] After oral administration of PEA-(L)-V hydrochloride to beagle dogs, PEA-(L)-V and PEA were detected simultaneously in the plasma. The results in Table 5 show that after oral administration of PEA-(L)-V hydrochloride to beagle dogs, the bioavailability of PEA was 0.5%, which did not increase the bioavailability of PEA compared with (1).

[0186] (4) Pharmacokinetics of PEA-(L)-V-(L)-V hydrochloride

[0187] The plasma concentrations of PEA-(L)-V-(L)-V and PEA were determined after oral administration of PEA-(L)-V-(L)-V hydrochloride to beagle dogs, and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 6.

[0188] Table 6 Dosage and PK data of oral administration of PEA-(L)-V-(L)-V hydrochloride in beagle dogs

[0189]

[0190] 1 The dosage is calculated based on PEA.

[0191] After oral administration of PEA-(L)-V-(L)-V hydrochloride to beagle dogs, PEA-(L)-V-(L)-V and PEA were detected simultaneously in the plasma. The results in Table 6 show that after oral administration of PEA-(L)-V-(L)-V hydrochloride to beagle dogs, the bioavailability of PEA was 1.2%, which was slightly improved compared with the bioavailability of PEA in (1).

[0192] (5) Pharmacokinetics of PEA-G-(L)-V hydrochloride

[0193] The plasma concentrations of PEA-G-(L)-V and PEA were determined after oral administration of PEA-G-(L)-V hydrochloride to beagle dogs, and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 7.

[0194] Table 7 Dosage and PK data of oral administration of PEA-G-(L)-V hydrochloride in beagle dogs

[0195]

[0196] 1 The dosage is calculated based on PEA.

[0197] After oral administration of PEA-G-(L)-V hydrochloride to beagle dogs, PEA-G-(L)-V and PEA were detected simultaneously in the plasma. The results in Table 7 show that after oral administration of PEA-G-(L)-V hydrochloride to beagle dogs, the bioavailability of PEA was 1.4%, which was slightly improved compared with the bioavailability of PEA in (1).

[0198] (6) Pharmacokinetics of PEA-(L)-A-(L)-V hydrochloride

[0199] The plasma concentrations of PEA-(L)-A-(L)-V and PEA were determined after oral administration of PEA-(L)-A-(L)-V hydrochloride to beagle dogs, and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 8.

[0200] Table 8 Dosage and PK data of oral administration of PEA-(L)-A-(L)-V hydrochloride in beagle dogs

[0201]

[0202]

[0203] 1 The dosage is calculated based on PEA.

[0204] The results in Table 8 show that after oral administration of PEA-(L)-A-(L)-V hydrochloride to beagle dogs, the bioavailability of PEA was 1.7%, which was approximately 1 times higher than that of PEA in (1).

[0205] (7) Pharmacokinetics of PEA-(L)-P hydrochloride

[0206] The plasma concentrations of PEA-(L)-P and PEA were determined after oral administration of PEA-(L)-P hydrochloride to beagle dogs, and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 9.

[0207] Table 9 Dosage and PK data of oral administration of PEA-(L)-P hydrochloride in beagle dogs

[0208]

[0209] 1 The dosage is calculated based on PEA. ND: Not detected in plasma, pharmacokinetic parameters cannot be calculated.

[0210] After oral administration of PEA-(L)-P hydrochloride to beagle dogs, no PEA-(L)-P was detected in the plasma, only PEA was detected, indicating that the prodrug PEA-(L)-P was converted rapidly in the body.

[0211] The results in Table 9 show that after oral administration of PEA-(L)-P hydrochloride to beagle dogs, the bioavailability of PEA was 9.4%, which was about 9.4 times higher than that of PEA in (1).

[0212] (8) Pharmacokinetics of PEA-(L)-P-(L)-V hydrochloride

[0213] The plasma concentrations of PEA-(L)-P-(L)-V and PEA were determined after oral administration of PEA-(L)-P-(L)-V hydrochloride to beagle dogs, and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 10.

[0214] Table 10 Dosage and PK data of oral administration of PEA-(L)-P-(L)-V hydrochloride in beagle dogs

[0215]

[0216] 1 The dosage is calculated based on PEA. ND: Not detected in plasma, pharmacokinetic parameters cannot be calculated.

[0217] After beagle dogs were orally administered with PEA-(L)-P-(L)-V hydrochloride, no PEA-(L)-P-(L)-V was detected in the plasma, and only PEA was detected, indicating that the prodrug PEA-(L)-P-(L)-V was converted rapidly in the body.

[0218] The results in Table 10 show that after oral administration of PEA-(L)-P-(L)-V hydrochloride to beagle dogs, the bioavailability of PEA was 2.9%, which was about 2.2 times higher than that of PEA in (1).

[0219] (9) Pharmacokinetics of PEA-diethylaminopropionate

[0220] The plasma concentrations of PEA-diethylaminopropionate and PEA were determined after oral administration of PEA-diethylaminopropionate to beagle dogs, and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 11.

[0221] Table 11 Dosage and PK data of oral administration of PEA-diethylaminopropionate in beagle dogs

[0222]

[0223]

[0224] 1 The dosage is calculated based on PEA.

[0225] After oral administration of PEA-diethylaminopropionate, PEA-diethylaminopropionate and PEA were detected simultaneously in the plasma of beagle dogs.

[0226] The results in Table 11 show that after oral administration of PEA-diethylaminopropionate to beagle dogs, the bioavailability of PEA was 1.5%, which was slightly improved compared with the bioavailability of PEA in (1).

[0227] (10) Pharmacokinetic testing of PEA-Py

[0228] The plasma concentrations of PEA-Py and PEA were determined after oral administration of PEA-Py to beagle dogs, and the pharmacokinetic parameters were calculated. The dosage and PK data are shown in Table 12.

[0229] Table 12 Dosage and PK data of oral administration of PEA-Py in beagle dogs

[0230]

[0231] 1 The dosage is calculated based on PEA.

[0232] After oral administration of PEA-Py to beagle dogs, PEA-Py and PEA were detected simultaneously in the plasma.

[0233] The results in Table 12 show that after oral administration of PEA-Py to beagle dogs, the bioavailability of PEA was 0.3%, which did not improve the bioavailability of PEA.

[0234] (11) The above PK examples were summarized and compared, and the results are shown in Table 13.

[0235] Table 13 summarizes the PK data of PEA and PEA derivatives after oral administration to beagle dogs

[0236]

[0237]

[0238] NA: Not applicable.

[0239] Compound PEA-(L)-V has been disclosed in the literature PLoS ONE 10(6):e0128699. However, this prodrug failed to improve the bioavailability of PEA. The results in Table 13 show that the derivatives of the present invention can significantly improve the bioavailability of PEA, up to 10 times, and the effect is significantly better than PEA (raw material) and I16 (the best disclosed PEA prodrug), with unexpected effects. Whether the prodrug can be detected in plasma indirectly reflects the conversion rate of the prodrug in the body. As shown in Table 13, compounds I16, PEA-(L)-P, and PEA-(L)-P-(L)-V were not detected in plasma, suggesting that their conversion rates in the body are fast.

[0240] The goal of the present invention is to obtain an ideal PEA derivative that can be rapidly converted to PEA in vivo and can increase the oral bioavailability of PEA. Those skilled in the art generally believe that the smaller the steric hindrance, the easier the ester bond is to hydrolyze. The PEA derivative PEA-G-(L)-V in Table 13 has the smallest steric hindrance of the ester bond, but the conversion in vivo is not fast. Unexpectedly, no derivatives were detected in the plasma of the PEA-(L)-P and PEA-(L)-P-(L)-V groups, the prodrug conversion rate was fast, and the bioavailability of PEA was significantly improved, showing ideal prodrug PK characteristics.

[0241] The above describes exemplary embodiments of the present invention. However, the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound of formula (I1) or formula (I2) or a pharmaceutically acceptable salt thereof: ； in, R1 is selected from C 15-20 alkyl; In formula (I1), X is selected from H, a standard amino acid, and the standard amino acid is linked to the amino group of phenylalanine via a carboxyl group; In formula (I2), X is selected from standard amino acids, the standard amino acids are linked to the hydroxyl group of ethanolamine through the carboxyl group, and the standard amino acids are linked to the carboxyl group of valine through the amino group; The standard amino acids are selected from the group consisting of alanine, glycine, isoleucine, leucine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Selected from .

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound has the formula (I1') or (I1") structure or (I2') or (I2") structure:

4. The compound according to claim 1, characterized in that: Standard amino acids are selected from the D- or L-configuration.

5. Compound or its pharmaceutically acceptable salt form:

6. Compound or its pharmaceutically acceptable salt form:

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that: Pharmaceutically acceptable salt forms are selected from hydrochloride, trifluoroacetate, sulfate, pyrosulfate, bisulfate, sulfite, acid sulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrobromide, hydroiodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, hemisuccinate, suberate, sebacate, fumarate, One or more of maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, p-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt form thereof, wherein one or more hydrogen atoms are replaced by a deuterium atom.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier, diluent or excipient.

10. The pharmaceutical composition according to claim 9, characterized in that The composition is a solid preparation, a semisolid preparation, a liquid preparation, and is a powder, a granule, a pill, a micropill, a tablet, an enteric-coated tablet, a sustained-release tablet, a capsule, a soft capsule, a film, a chewing gum, a drop, an oral liquid, a syrup, an emulsion, a self-microemulsion, a lipid preparation, a suspension or a mixture.

11. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition according to any one of claims 9 to 10 in the preparation of a medicament for preventing or treating pain, anxiety, depression, schizophrenia, cancer, nervous system diseases, loss of appetite, osteoarthritis, decreased gastrointestinal motility, glaucoma, atopic dermatitis, respiratory tract infection, post-traumatic stress disorder, obesity, insomnia, drowsiness, and idiopathic mast cell activation syndrome.

12. The use according to claim 11, wherein: The pain includes chronic low back pain, sciatica, radiculopathy, radiating pain, neuropathic pain, and toothache.

13. The use according to claim 11, wherein: Neurological diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, cerebral ischemia, and epilepsy.

14. The use according to claim 11, wherein: Idiopathic mast cell activation syndrome is a chronic, widespread, musculoskeletal, and recurrent pain syndrome.

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