CN118125936A - N-acyl ethanolamide derivative, preparation method and application thereof - Google Patents

N-acyl ethanolamide derivative, preparation method and application thereof Download PDF

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CN118125936A
CN118125936A CN202311573352.1A CN202311573352A CN118125936A CN 118125936 A CN118125936 A CN 118125936A CN 202311573352 A CN202311573352 A CN 202311573352A CN 118125936 A CN118125936 A CN 118125936A
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pea
acid
amino acid
standard amino
pharmaceutically acceptable
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王青松
陈玉林
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Nanjing Delova Biotech Co ltd
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Nanjing Delova Biotech Co ltd
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Abstract

The application belongs to the field of prodrugs, in particular to an N-acyl ethanol amide derivative, a preparation method and application thereof, and more particularly discloses a novel PEA amino acid derivative prodrug which can be rapidly converted into PEA compared with a beagle after oral administration, only PEA is detected in plasma, and PEA amino acid derivatives, in particular PEA- (L) -P, PEA- (L) -P- (L) -V, are hardly detected, have unexpected bioavailability and faster conversion rate, and have pharmacokinetics characteristics which are obviously superior to other PEA amino acid derivatives.

Description

N-acyl ethanolamide derivative, preparation method and application thereof
Technical Field
The application belongs to the field of prodrugs, and particularly relates to an N-acyl ethanol amide derivative, a preparation method and application thereof.
Background
Palmitoylethanolamide (Palmitoylethanolamide, PEA) is an endogenous substance belonging to the family of N-acylethanolamines, which exerts protective effects in various disease states, including anti-inflammatory, analgesic, immunomodulating and neuroprotection effects. In a disease state, decreased synthesis of endogenous PEA, increased metabolism, resulting in decreased PEA in vivo, fails to maintain the level required for its anti-inflammatory and analgesic activities in healthy physiological state, which makes exogenous administration a viable therapeutic strategy for supplementing endogenous PEA levels and restoring body homeostasis. Supplementation with exogenous PEA has proved to be highly safe and tolerant, and the PEA's ability to reduce pain intensity has a well-defined dose response. However, PEA has poor solubility, partition coefficient (log P) >5, and extremely poor oral bioavailability, limiting its application development in the pharmaceutical field. At present, PEA-containing products can only be used as health products or medical food, the dosage is large, usually 1200 mg/day, and the representative products are
Prodrugs are biologically reversible derivatives of drug molecules that undergo in vivo enzymatic and/or chemical transformations to release the active parent drug and then exert the desired pharmacological effect. Prodrug technology is often used to improve the adverse pharmacokinetic (Pharmacokinetics, PK) profile of drugs. US9512091B2 discloses that oxazoline prodrugs of PEA are useful for inhibiting the activity of enzymes in vivo and rapidly converting to PEA, but does not disclose PK data, and the oral bioavailability is unknown. European Journal of Pharmaceutical Sciences 62 (2014) 33-39 discloses that galactose prodrugs of PEA are useful for increasing PEA transit through the blood brain barrier, and studies of in vitro cell levels show good effects but no in vivo results. PLoS ONE 10 (6): E0128999 discloses that acyloxymethyl carbonates, amino acid esters and carbamate prodrugs of PEA are synthesized to enhance the bioavailability of PEA, and that in vivo results in rats show increased absorption of candidate prodrugs, but do not release sufficient amounts of PEA, resulting in lower blood levels of PEA than in the PEA group administered directly. EP2742957B discloses PEG prodrugs of PEA for prolonged local anti-inflammatory effects, but without oral PK results, the oral bioavailability is unknown. CN110023308a discloses glyceride prodrugs of PEA, rat PK results show a significant improvement in oral bioavailability of PEA, but PEA glyceride prodrugs are viscous semi-solids, which are difficult to prepare solid formulations.
PLoS ONE 10 (6): e0128699 discloses blood concentration data of PEA amino acid derivatives (D-Val-PEA and L-Val-PEA) after lavage of rats, and PEA amino acid derivatives and PEA are detected in plasma at the same time, without improving PEA bioavailability. The present invention aims to significantly improve the oral absorption and systemic exposure of PEA by prodrug technology, supplement endogenous PEA, ensure that sufficient PEA levels are reached to maximize therapeutic effect.
Disclosure of Invention
To achieve the object, the invention discloses a compound of formula (I):
a compound or a pharmaceutically acceptable salt form thereof.
Preferably, the present invention discloses a compound of formula (I 1):
or formula (I 2):
a compound or a pharmaceutically acceptable salt form thereof.
Preferably, R 1 is selected from C 1-40 aliphatic, preferably C 1-20 aliphatic, more preferably C 15-20 aliphatic, preferably C 15-20 aliphatic is C 15-20 alkyl or C 15-20 alkenyl containing 1-5 c=c.
More preferably, the method further comprises the steps of,Selected from(N-oleoyl) or(N-arachidonyl).
Preferably, in formula (I), when Z is H, Y is selected from standard amino acids, non-standard amino acids, excluding glycine, alanine, valine, isoleucine, tryptophan, aspartic acid, glutamine, asparagine; or Y, Z is selected from the same or different standard amino acid and nonstandard amino acid, Y is connected with the hydroxyl of the ethanolamine through carboxyl, and Y is connected with the carboxyl of Z through amino;
Preferably, in formula (I), when Z is H, Y is selected from standard amino acids, non-standard amino acids, Y optionally excluding 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, homocysteine, homoserine, theanine, gamma-aminobutyric acid, sarcosine, casamino acid, 2-aminoadipic acid, pantothenic acid, taurine, sulfinic acid, 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-coumaric acid, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxyisopropyl-tryptophan, 1-cyclopropyl-amino acid, one or more of a oxetane-2-carboxylic acid or a pipecolic acid;
Preferably, in formula (I), Y, Z is selected from the same or different standard amino acids, non-standard amino acids, Y is linked to the hydroxyl group of ethanolamine by a carboxyl group, Y is linked to the carboxyl group of Z by an amino group; y is selected from standard amino acids, 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, homocysteine, homoserine, theanine, gamma-aminobutyric acid, sarcosine, casamino acid, 2-aminoadipic 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-abrine, 4-hydroxy proline, 5-hydroxy proline, 3-hydroxy-L-amino-4-tryptophan, or 2-hydroxy-amino-alanine, and 1-hydroxy-amino-alanine.
Preferably, in formula (I 1), X is selected from H, a standard amino acid, a non-standard amino acid, the non-standard amino acid being linked to the amino group of phenylalanine by a carboxyl group;
Preferably, in formula (I 2), X is selected from the group consisting of a standard amino acid, a non-standard amino acid, the non-standard amino acid being attached to the hydroxyl group of ethanolamine by a carboxyl group, the standard amino acid, the non-standard amino acid being attached to the carboxyl group of valine by an amino group;
Preferably, the standard amino acid is selected from aromatic or aliphatic amino acids, more preferably, the standard amino acid 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 and valine;
Preferably, the non-standard amino acid is selected from ornithine, homoarginine, citrulline, homocysteine, homoserine, theanine, gamma-aminobutyric acid, sarcosine, casamino acid, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, beta-amino acid, alpha-disubstituted amino acids, N-methyl acid, hydroxy-amino acids, cyclic amino acids; preferably, the non-standard amino acid is selected from ornithine, homoarginine, citrulline, homocysteine, homoserine, theanine, gamma-aminobutyric acid, sarcosine, casamino acid, 2-aminoadipic 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-abrine, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclopropyl-1-carboxylic acid, hydrogen-cyclobutane-2-carboxylic acid or percarboxylic acid;
Preferably, in formula (I), Y, Z is selected from the same or different standard amino acids, 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, Z is further condensed with 1 or 2 same or different standard amino acids, non-standard amino acids via an amino group;
Preferably, in formula (I 1), the standard amino acid, the non-standard amino acid is further condensed with 1 or 2 identical or different standard amino acids, non-standard amino acids by amino groups;
preferably, in formula (I 2), X is selected from a standard amino acid, a non-standard amino acid, or an amino acid formed by condensing 2-3 identical or different standard amino acids and non-standard amino acids, wherein the standard amino acid, the non-standard amino acid or the condensed amino acid is connected with the hydroxyl of ethanolamine through carboxyl, and is connected with the carboxyl of valine through amino.
Further, the compound has the structure of formula (I 1') or (I 1 "):
or (I 2 ') or (I 2') structure:
preferably, the standard amino acid, non-standard amino acid is selected from the D-or L-configuration.
More specifically, the present invention discloses a compound or a pharmaceutically acceptable salt form thereof:
In another aspect, the invention relates to a compound of formula II:
P1-P2
Or a pharmaceutically acceptable salt form thereof;
P 1 is N-acyl ethanolamide; p 2 is a moiety conjugated to the N-acyl ethanolamide and P 1 is linked to the carboxyl group of P 2 through a hydroxyl group.
Preferably, P 1 is selected from
Preferably, P 2 is selected from pregabalin, gabapentin, lipoic acid, diethylaminopropionic acid or
More specifically, a compound or a pharmaceutically acceptable salt form thereof:
Preferably, the pharmaceutically acceptable salt form is selected from one or more of hydrochloride, trifluoroacetate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, 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, 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.
Preferably, the compound of any one of the above claims, or a pharmaceutically acceptable salt form thereof, wherein one or more hydrogen atoms are replaced with deuterium atoms.
Further, the present invention also relates to a pharmaceutical composition comprising a compound according to any one of the above, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
Preferably, the composition is a solid preparation, a semisolid preparation, a liquid preparation, preferably a powder, a granule, a pill, a pellet, 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.
Further, the present invention also relates to the use of a compound according to any one of the above or a pharmaceutically acceptable salt form thereof and a pharmaceutical composition as described above for the manufacture of a medicament for the prevention or treatment of pain, chronic low back pain, sciatica, radiculopathy, radiological pain, neuropathic pain, anxiety, depression, schizophrenia, cancer, amyotrophic lateral sclerosis, multiple sclerosis, neurological diseases, parkinson's disease, alzheimer's disease, huntington's disease, cerebral ischemia, epilepsy, anorexia, dental pain, osteoarthritis, reduced gastrointestinal motility, cancer, glaucoma, atopic dermatitis, respiratory tract infections, post-traumatic stress disorders, obesity, insomnia, somnolence, idiopathic mast cell activation syndrome, preferably chronic broad musculoskeletal plastic pain.
Term interpretation:
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures of compounds should fall within the scope of the present description.
The term "aliphatic" means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a mono-, bi-or multi-cyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, having a single point of attachment to the remainder of the molecule. In some embodiments, the aliphatic group contains 1 to 40 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 20 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 15 to 20 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched substituted or unsubstituted alkyl, alkenyl groups.
Alkenyl: the term "alkenyl" as used herein refers to an alkyl group, as defined herein, having one or more double bonds.
Preferably, the C 15-20 aliphatic group is a C 15-20 alkyl group or a C 15-20 alkenyl group containing 1-5 c=c.
Standard amino acids:
Standard amino acids or protein-producing amino acids include, but are not limited to, the 22 amino acids currently known, which constitute a single-segment unit of a 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.
Non-standard amino acids are selected from ornithine, homoarginine, citrulline, homocysteine, homoserine, theanine, gamma-aminobutyric acid, sarcosine, casamino acid, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, beta-amino acids such as 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), alpha-disubstituted amino acids such as 2-aminoisobutyric acid, isovaline, di-N-ethylglycine, N-methylacid such as N-methyl-alanine, L-abrine, 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, hydrogen heterocyclic-2-carboxylic acid, and cocoa-carboxylic acid.
In formula (I), Z is selected from a standard amino acid, a non-standard amino acid, which is further condensed with 1 or 2 identical or different standard amino acids, non-standard amino acids by amino groups. That is, Z can be further connected with the carboxyl of 1 identical or different standard amino acid and non-standard amino acid through the amino group, and can be further connected with the new identical or different standard amino acid and non-standard amino acid through the amino group of the new amino acid.
In formula (I 1), the standard amino acid and the nonstandard amino acid are further condensed with 1 or 2 identical or different standard amino acids and nonstandard amino acids through amino groups. That is, the amino group of the standard amino acid or the nonstandard amino acid linked to the amino group of phenylalanine may be further linked to the carboxylic acid of another standard amino acid or nonstandard amino acid, which is the same or different, and further, the amino group of the new amino acid may be further linked to the carboxylic acid of a new standard amino acid or nonstandard amino acid, which is the same or different.
In formula (I 2), X is selected from standard amino acids, nonstandard amino acids, or 2-3 identical or different standard amino acids, nonstandard amino acid condensed amino acids. That is, X is 1 standard amino acid or nonstandard amino acid, or 2 identical or different standard amino acids or nonstandard amino acid condensed amino acids, or 3 identical or different standard amino acids or nonstandard amino acid condensed amino acids, wherein the standard amino acid, nonstandard amino acid or condensed amino acid is connected with hydroxyl of ethanolamine through carboxyl, and is connected with carboxyl of valine through amino.
The term "C 0" denotes the maximum plasma concentration extrapolated to t=0.
The term "T max" refers to the time required to reach peak drug concentrations following administration.
The term "AUC last" represents the area enclosed by the plasma concentration curve versus the time axis.
Compared with the prior art, the prodrug has the following unexpected technical effects:
(1) The PEA prodrug of the invention can obviously improve the oral bioavailability of PEA, and is superior to the prior art;
(2) The fact that only PEA was detected in plasma and no prodrug was detected after oral administration of certain example PEA prodrugs of the invention to beagle, demonstrated that PEA prodrugs of the invention have a fast in vivo conversion rate;
(3) The PEA prodrugs of the invention are white solid powders with powder properties suitable for the production of solid formulations.
Drawings
The invention is further described below with reference to the accompanying drawings.
Figure 1 is a graph of mean drug concentration versus time for PEA in plasma after oral PEA, PEA- (L) -P administration in male beagle dogs of example 14.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
EXAMPLE 1 Synthesis of PEA- (L) -V hydrochloride
The synthetic route is as follows:
PEA- (L) -V hydrochloride
The PEA- (L) -V hydrochloride synthesis steps are as follows:
N- (2-hydroxyethyl) palmitoamide (900 mg,3.0mmol,1.0 eq), (t-butoxycarbonyl) -L-valine (7196 mg,3.3mmol,1.1 eq), HOBt (608 mg,4.5mmol,1.5 eq) and DMAP (73.2 mg,0.6mmol,0.2 eq) were dissolved in 15mL dichloromethane, EDCI (864 mg,4.5mmol,1.5 eq) was added with stirring, the reaction was warmed to 50℃overnight, and the TLC spot plate monitored. After completion of the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, DCM was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 2-palmitoylaminoethyl (tert-butoxycarbonyl) -L-valine (550 mg, yield 37%, white solid, R f =0.2 (PE: ea=2:1)).
2-Palmitoylethyl (t-butoxycarbonyl) -L-valine (550 mg,1.1mmol,1.0 eq) was dissolved in 5mL of methanol, 5mL of a 1, 4-dioxane solution of 4N hydrochloric acid was slowly added dropwise with stirring in an ice bath, reacted at room temperature for 1h, and monitored by TLC plate. After the reaction was completed, the reaction mixture was concentrated, and the objective compound PEA- (L) -V hydrochloride (445 mg, yield 93% and white solid) was obtained by column chromatography separation ,Rf＝0.3(DCM:MeOH＝20:1)).1H 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[C23H47N2O3]+399.3581,found 399.3580.
EXAMPLE 2 Synthesis of PEA- (L) -V- (L) -V hydrochloride
The synthetic route is as follows:
The PEA- (L) -V- (L) -V hydrochloride is synthesized as follows:
PEA- (L) -V hydrochloride (360 mg,0.77mmol,1.0 eq), (t-butoxycarbonyl) -L-valine (185 mg,0.85mmol,1.1 eq), HOBt (157 mg,1.16mmol,1.5 eq) and DMAP (18.5 mg,0.15mmol,0.2 eq) were dissolved in 5mL dichloromethane, EDCI (223 mg,1.16mmol,1.5 eq) was added with stirring, the temperature was raised to 50℃and triethylamine (78 mg. Times.3, 2.3mmol,3.0 eq) was added in portions and the reaction was carried out overnight, as monitored by TLC. After the completion of the reaction, an appropriate amount of saturated aqueous sodium hydrogencarbonate solution was added, extracted with methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated, and the 2-palmitoylethyl (t-butoxycarbonyl) -L-valyl-L-valine ester (358 mg, yield 60%, R f =0.5 (PE: ea=1:1)) was separated by column chromatography.
2-Palmitoylaminoethyl (t-butoxycarbonyl) -L-valyl-L-valine ester (300 mg,0.5mmol,1.0 eq) was dissolved in 5mL of methanol, 3mL of dioxane solution of hydrochloric acid was slowly added dropwise with stirring in an ice bath, reacted at room temperature for 1h, and monitored by TLC plate. Directly concentrating the reaction solution after the reaction is completed, and separating by column chromatography to obtain the target compound PEA- (L) -V- (L) -V hydrochloride (140 mg, yield 52 percent) as white solid ,Rf＝0.3(DCM:MeOH＝20:1)).1H 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[C28H56N3O4]+498.4265,found 498.4279.
EXAMPLE 3 Synthesis of the Compound PEA-G- (L) -V hydrochloride
The synthetic route is as follows:
The PEA-G- (L) -V hydrochloride is synthesized as follows:
N- (2-hydroxyethyl) palmitoamide (6.0 g,20.0mmol,1.0 eq), (t-butoxycarbonyl) glycine (3.9 g,22.0mmol,1.1 eq), HOBt (4.1 g,30.0mmol,1.5 eq) and DMAP (1.2 g,11.0mmol,0.5 eq) were dissolved in 50mL CHCl 3, EDCI (5.8 g,30.0mmol,1.5 eq) was added with stirring, the temperature was raised to 65℃and the reaction was monitored overnight by TLC. After completion of the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, DCM was used for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 2-palmitoylethyl (tert-butoxycarbonyl) glycinate (7.9 g, 86% yield, white solid, R f =0.7 (DCM: meoh=10:1)).
2-Palmitoylethyl (t-butoxycarbonyl) glycinate (7.9 g,17.0mmol,1.0 eq) was dissolved in 30mLDCM and added dropwise with ice bath stirring 4N HCl in dioxane 13mL, reacted at normal temperature for 2h and monitored by TLC plate. The reaction was concentrated directly after completion of the reaction and DCM: meoh=100:1 was slurried to give PEA-G hydrochloride (5.5G, 83% yield, white solid, R f =0.4 (DCM: meoh=10:1)).
PEA-G hydrochloride (5.5G, 14.0mmol,1.0 eq) was taken and dissolved in 30mLCHCl 3, triethylamine (4.2G, 42.0mmol,3.0 eq) was added dropwise with stirring, after stirring for 10min, (tert-butoxycarbonyl) -L-valine (3.6G, 16.8mmol,1.2 eq), HOBt (2.8G, 21.0mmol,1.5 eq) and DMAP (254 mg,7.0mmol,0.5 eq) were added with stirring, EDCI (4.0G, 2.0mmol,1.5 eq) was added with stirring, the reaction was allowed to stand overnight, TLC plate monitoring. After completion of the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, DCM was used for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 2-palmitoylethyl (tert-butoxycarbonyl) -L-valylglycine ester (5.4 g, yield 70%, R f = 0.7 (DCM: meOH = 10:1)).
2-Palmitoylaminoethyl (tert-butoxycarbonyl) -L-valylglycine (5.4 g,9.7mmol,1.0 eq) was dissolved in 30mL DCM and 7mL of a 4N HCl dioxane solution was slowly added dropwise with ice-bath stirring and reacted at normal temperature for 2h, monitored by TLC plates. Directly concentrating the reaction solution after the reaction is completed, and separating by column chromatography to obtain 1.6G of target product PEA-G- (L) -V hydrochloride (yield 34%, white solid) ,Rf＝0.4(DCM:EtOH＝10:1)).1H 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),1.24(s,24H),0.94(t,J＝7.1Hz,6H),0.88–0.84(m,3H)ppm.HRMS(ESI)m/z Calcd for[C25H50N3O4]+456.3801,found 456.3789.
EXAMPLE 4 preparation of the compound PEA-G- (L) -V trifluoroacetate salt
The synthetic route is as follows:
the synthesis steps of PEA-G- (L) -V trifluoroacetate are as follows:
Under the protection of argon, 2-palmitoylamide ethyl (tert-butoxycarbonyl) -L-valylglycine (3.0 g,5.4mmol,1.0 eq) was dissolved in 20mL of anhydrous DCM, trifluoroacetic acid (18.5 g,162.0mmol,30.0 eq) was slowly added dropwise after cooling to 0deg.C, the reaction was continued for 2h at normal temperature, and TLC plate monitoring was performed. Directly concentrating the reaction solution after the reaction is completed, and separating by column chromatography to obtain the target product PEA-G- (L) -V trifluoroacetate (1.5G, yield 48 percent) as white solid ,Rf＝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.19F NMR(282MHz,DMSO-d6)δ-68.8ppm.MS m/z Calcd for[C25H49N3O4Na]+478.68,found 478.46.
EXAMPLE 5 Synthesis of PEA- (L) -A- (L) -V hydrochloride
The synthetic route is as follows:
The PEA- (L) -A- (L) -V hydrochloride is synthesized as follows:
n- (2-hydroxyethyl) palmitoylamide (7.5 g,25.0mmol,1.0 eq), (t-butoxycarbonyl) -L-alanine (5.67 g,30.0mmol,1.2 eq), HOBt (5.1 g,37.5mmol,1.5 eq) and DMAP (1.5 g,12.5mmol,0.5 eq) were dissolved in 50mL CHCl 3, EDCI (7.2 g,37.5mmol,1.5 eq) was added with stirring, warmed to 65℃and reacted overnight, monitored by TLC plates. After completion of the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, DCM was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 2-palmitoylethyl (t-butoxycarbonyl) -L-alanine (9.4 g, 80% yield as a white solid, R f =0.7 (DCM: meoh=10:1)).
The compound 2-palmitoylaminoethyl (tert-butoxycarbonyl) -L-alanine (9.4 g,20mmol,1.0 eq) was taken in 30mL DCM and added dropwise slowly with ice-bath stirring 4N HCl in dioxane 15mL, reacted at normal temperature for 2h, monitored by TLC plate. The reaction was concentrated directly after completion of the reaction and DCM: meoh=100:1 was slurried to afford PEA- (L) -a hydrochloride (6.0 g, yield 74%, white solid, R f =0.4 (DCM: meoh=10:1)).
PEA- (L) -A hydrochloride (6.0 g,15.0mmol,1.0 eq) was dissolved in 30mL of CHCl 3, triethylamine (4.5 g,45.0mmol,3.0 eq) was added dropwise with stirring, after stirring for 10min, (tert-butoxycarbonyl) -L-valine (3.9 g,18mmol,1.2 eq), HOBt (3.0 g,22.0mmol,1.5 eq) and DMAP (910 mg,7.5mmol,0.5 eq) were added with stirring, EDCI (4.2 g,22.0mmol,1.5 eq) was added and the reaction was warmed to 65℃overnight with TLC spot plate monitoring. After completion of the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, DCM was used for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 2-palmitoylethyl (tert-butoxycarbonyl) -L-valyl-L-alanine ester (6.2 g, yield 72%, R f =0.7 (DCM: meoh=10:1)).
The compound 2-palmitoylamide ethyl (tert-butoxycarbonyl) -L-valyl-L-alanine ester (4.0 g,7.0mmol,1.0 eq) was dissolved in 20mL DCM and added dropwise slowly 4N HCl in dioxane 4mL with ice-bath stirring and reacted at normal temperature for 2h, monitored by TLC plate. Directly concentrating the reaction solution after the reaction is completed, and separating by column chromatography to obtain the target product PEA- (L) -A- (L) -V hydrochloride (1.7 g, yield 48 percent) as white solid ,Rf＝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,1H),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[C26H51N3O4Na]+492.71,found 492.45.
EXAMPLE 6 Synthesis of PEA- (L) -P hydrochloride
The synthetic route is as follows:
The PEA- (L) -P hydrochloride synthesis steps are as follows:
N- (2-hydroxyethyl) palmitoamide (6.0 g,20.0mmol,1.0 eq), (t-butoxycarbonyl) -L-phenylalanine (4.0 g,24.0mmol,1.2 eq), HOBt (4.1 g,30.0mmol,1.5 eq) and DMAP (1.2 g,10.0mmol,0.5 eq) were dissolved in 50mL CHCl 3, EDCI (5.8 g,30.0mmol,1.5 eq) was added with stirring, the temperature was raised to 65℃and the reaction was allowed to stand overnight with TLC plate monitoring. After completion of the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, DCM was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 2-palmitoylethyl (tert-butoxycarbonyl) -L-phenylalanine ester (6.5 g, 73% yield, as a white solid, R f = 0.7 (DCM: meOH = 10:1)).
2-Palmitoylaminoethyl (tert-butoxycarbonyl) -L-phenylalanine ester (6.5 g,14.6mmol,1.0 eq) was dissolved in 30mL DCM and 4N HCl in dioxane 8mL was slowly added dropwise with ice-bath stirring and reacted at normal temperature for 2h, monitored by TLC plate. After completion of the reaction, the reaction mixture was concentrated directly and DCM: meoh=100:1 was slurried to afford PEA- (L) -P hydrochloride (6.0 g, 85% yield) as a white solid ,Rf＝0.4(DCM:MeOH＝10:1)).1H 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.
EXAMPLE 7 preparation of PEA- (L) -P- (L) -V hydrochloride
The synthetic route is as follows:
The PEA- (L) -P- (L) -V hydrochloride is synthesized as follows:
PEA- (L) -P hydrochloride (6.0 g,12.5mmol,1.0 eq) was taken and dissolved in 30mLCHCl 3, triethylamine (3.8 g,37.5mmol,3.0 eq) was added dropwise with stirring, after stirring for 10min, (tert-butoxycarbonyl) -L-valine (3.3 g,15mmol,1.2 eq), HOBt (2.5 g,18.8mmol,1.5 eq) and DMAP (763 mg,6.3mmol,0.5 eq) were added with stirring, EDCI (3.6 g,18.8mmol,1.5 eq) was added with stirring, the reaction was allowed to stand overnight, TLC plate monitored. After completion of the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, DCM was used for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 2-palmitoylethyl (t-butoxycarbonyl) -L-valyl-L-phenylalanine ester (5.6 g, yield 70%, R f =0.7 (DCM: meoh=10:1)).
2-Palmitoylaminoethyl (t-butoxycarbonyl) -L-valyl-L-phenylalanine ester (4.0 g,6.2mmol,1.0 eq) was dissolved in 20mL DCM and was slowly added drop wise to 4N HCl in dioxane 3mL under ice-bath stirring and reacted at normal temperature for 2h, monitored by TLC plate. After the reaction is completed, the reaction solution is directly concentrated, chloroform is recrystallized, and then the target product PEA- (L) -P- (L) -V hydrochloride (2.8 g, yield 77 percent) is obtained by column chromatography separation ,Rf＝0.3(DCM:MeOH＝10:1)).1H NMR(300MHz,Methanol-d4)δ7.33–7.22(m,5H),4.74(dd,J＝9.0,5.4Hz,1H),4.14(hept,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,26H),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 Calcd for[C32H56N3O4]+546.4271,found 546.4264.
Example 8: synthesis of PEA-pregabalin hydrochloride
The synthetic route is as follows:
the PEA-pregabalin hydrochloride synthesis steps are as follows:
pregabalin (795 mg,5mmol,1 eq.) and NaOH (600 mg,15mmol,3 eq.) are dissolved in 20mL water and a solution of Boc 2 O (1.96 g,9mmol,1.8 eq.) in 1, 4-dioxane (20 mL) is added dropwise at room temperature and stirred for 1 hour at room temperature. The 1, 4-dioxane was removed by concentration under reduced pressure, excess Boc 2 O was removed by extraction with diethyl ether (30 ml x 3) and the aqueous phase was adjusted to pH 2 with saturated solution of citric acid. Dichloromethane (30 ml x 3), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give N-Boc protected pregabalin which was carried forward without purification (1.1 g white solid, 85% yield).
N-Boc protected pregabalin (142 mg,0.55mmol,1.1 eq.) and N- (2-hydroxyethyl) palmitamide (150mg,0.5mmol,1.0eq.),EDCI(144mg,0.75mmol,1.5eq.),HOBt(101mg,0.75mmol,1.5eq.),DMAP(12.2mg,0.1mmol,0.2eq.) were suspended in 5mL dichloromethane and stirred at room temperature for 2 days. The reaction was quenched by the addition of 5mL of saturated sodium bicarbonate, extracted with chloroform (10 mL. Times.3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on silica gel to give N-Boc-protected pregabalin and N- (2-hydroxyethyl) palmitoylamide esterified material (230 mg of white solid, 85% yield).
N-Boc protected pregabalin and N- (2-hydroxyethyl) palmitoamide ester (108 mg,0.2mmol,1.0 eq.) were dissolved in 2mL dichloromethane and a 4N solution of 1, 4-dioxane (0.5 mL,2mmol,10.0 eq.) of hydrogen chloride was added dropwise under an ice water bath. After the raw materials are completely converted, concentrating and removing the organic solvent, performing silica gel column chromatography to obtain a white solid, and recrystallizing to obtain the target compound PEA-pregabalin hydrochloride (53 mg white solid, yield) 56％).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),2.67–2.51(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[C26H53N2O3]+441.4051,found 441.4080.
Example 9: synthesis of PEA-gabapentin hydrochloride
The synthetic route is as follows:
The synthesis steps of PEA-gabapentin hydrochloride are as follows:
Gabapentin (1.71 g,10mmol,1 eq.) and NaOH (1.2 g,30mmol,3 eq.) were dissolved in 30mL water and a solution of Boc 2 O (4.36 g,20mmol,2.0 eq.) in tetrahydrofuran (30 mL) was added dropwise at room temperature and stirred at room temperature for 1 hour. Tetrahydrofuran was removed by concentration under reduced pressure, excess Boc 2 O was removed by extraction with diethyl ether (30 ml x 3) and the aqueous phase was adjusted to pH 2 with saturated solution of citric acid. Dichloromethane (30 ml x 3), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give N-Boc protected gabapentin which was carried forward without purification (2.25 g white solid, 85% yield).
N-Boc protected gabapentin (325 mg,1.2mmol,1.2 eq.) and N- (2-hydroxyethyl) palmitamide (299mg,1.0mmol,1.0eq.),EDCI(288mg,1.5mmol,1.5eq.),HOBt(203mg,1.5mmol,1.5eq.),DMAP(24.4mg,0.1mmol,0.2eq.) are suspended in 10mL dichloromethane and stirred at room temperature for 2 days. The reaction was quenched by the addition of 5mL of saturated sodium bicarbonate, extracted with chloroform (30 mL x 3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on silica gel to give N-Boc-protected gabapentin and N- (2-hydroxyethyl) palmitoylamide esterified product (397 mg of a white solid, 72% yield).
N-Boc protected gabapentin and N- (2-hydroxyethyl) palmitoamide ester (276 mg,0.5mmol,1.0 eq.) were dissolved in 5mL dichloromethane and a 4N solution of 1, 4-dioxane (1.2 mL,4.8mmol,9.6 eq.) of hydrogen chloride was added dropwise under ice water. After the raw materials are completely converted, concentrating and removing the organic solvent, performing silica gel column chromatography to obtain a white solid, and recrystallizing to obtain the target compound PEA-gabapentin hydrochloride (159 mg of white solid, yield) 65％).1H 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[C27H53N2O3]+453.4051,found 453.4051.
Example 10: synthesis of PEA-lipoic acid esters
The synthetic route is as follows:
the PEA-lipoic acid ester synthesis steps are as follows:
r-lipoic acid (457 mg,2.2mmol,1.1 eq.) and N- (2-hydroxyethyl) palmitoamide (598 mg,2.0mmol,1.0 eq.) were dissolved in 10mL of dichloromethane, and a solution of DCC (823mg, 4mmol,2.0 eq.) in dichloromethane (5 mL) was added dropwise at room temperature and stirred overnight at room temperature. Insoluble matter was removed by suction filtration, the filter cake was washed with dichloromethane, and the organic phase was washed with saturated NaHCO 3 solution, saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating under reduced pressure to obtain crude product, and subjecting to silica gel column chromatography (PE: EA=5:1-1:1) to obtain target compound PEA-lipoic acid ester (420 mg yellow solid, yield) 43％).1H 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[C26H50NO3S2]+488.3227,found 488.3232.
Example 11: synthesis of PEA-diethylaminopropionate
The synthetic route is as follows:
The PEA-diethylaminopropionate was synthesized as follows:
N- (2-hydroxyethyl) palmitoamide (6 g,20mmol,1.0 eq.) was dissolved in 40mL dichloromethane, triethylamine (30 mmol,1.5 eq.) was added under ice-bath, and acryloyl chloride (22 mmol,1.1 eq.) was added dropwise. The TLC plate was monitored and after the reaction was complete (about 2 h), the reaction was quenched by addition of 20mL of 1N hydrochloric acid in an ice bath, extracted with dichloromethane, the organic layers combined and dried over anhydrous sodium sulfate. After filtration, concentration and separation by silica gel column chromatography, 2-palmitoyl ethyl acrylate (5.3 g, 88% yield, white solid, R f =0.5 (DCM: meoh=20:1)) was obtained.
2-Palmitoylamide ethyl acrylate (3.53 g,10mmol,1.0 eq.) was dissolved in 20mL chloroform, diethylamine (11 mmol,1.1 eq.) and 20. Mu.L acetic acid were added, and the temperature was raised to 40℃and stirred overnight. TLC plate monitoring, after reaction is completed, concentrating, separating by alumina column chromatography to obtain 2.1g target product PEA-diethylaminopropionate (yield 49%, beige solid) ,Rf＝0.5(DCM:MeOH＝10:1)).1H 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[C25H51N2O3]+427.3900,found 427.3903.
Example 12: synthesis of PEA-Py
The synthetic route is as follows:
The synthesis steps of PEA-Py are as follows:
10g of 2-chloronicotinic acid is taken, 20g of 40% methylamine water solution is added, the temperature is raised to 80 ℃, and stirring is continued for two days. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to adjust the pH to 10, and the mixture was concentrated to remove unreacted methylamine. Then 10% hydrochloric acid is used for adjusting the pH value to 5-6, thus obtaining the crude product 2- (methylamino) nicotinic acid, which is directly carried out in the next step without treatment.
LiAlH 4 (1.9 g,50mmol,2.5 eq) was dissolved in 40mL THF under argon protection, 2- (methylamino) nicotinic acid (3.04 g,20mmol,1.0 eq) was added slowly in portions with stirring in an ice bath, and after the addition the reaction was warmed to 50℃and monitored by TLC plate. After the reaction is completed, na 2SO4·10H2 O is added in an ice bath to quench the reaction, the mixture is stirred for 30min, diatomite is filtered by suction, and a filter cake is washed by chloroform. The filtrate was concentrated and separated by column chromatography on silica gel to give (2- (methylamino) pyridin-3-yl) methanol (916 mg, 42% yield as a white solid, R f =0.5 (DCM: meoh=20:1)).
(2- (Methylamino) pyridin-3-yl) methanol (695 mg,5mmol,1.0 eq) was dissolved in 15mL DCM and imidazole (680 mg,10mmol,2.0 eq) and TBSCl (284 mg,6mmol,1.2 eq) were added sequentially and stirred at room temperature for 4h and monitored by TLC plate. After completion of the reaction, quench with water, extract with DCM, combine the organic phases and dry over anhydrous sodium sulfate. Filtration and concentration gave the crude product 3- ((tert-butyldimethylsilyloxy) methyl) -N-methylpyridin-2-amine (brown liquid, R f =0.6 (DCM: meoh=10:1)) which was carried forward directly without work-up.
Triphosgene (742 mg,2.5mmol,1.0 eq) was dissolved in 20mL DCM, pyridine (399mg, 5mmol,1.0 eq) was slowly added dropwise under ice-bath, after stirring for 5min, the crude product 3- ((tert-butyldimethylsilyloxy) methyl) -N-methylpyridin-2-amine of the previous step was added dropwise, stirring for 5min, rising to room temperature and stirring continued for 4h, TLC plate monitoring. After completion of the reaction, the reaction was quenched with saturated copper sulfate solution, extracted with DCM, the organic phases were combined, dried, and separated by column chromatography to give 616.7mg of the desired product (3- (((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) (methyl) amino chloride (40% total yield in two steps, yellow clear liquid, R f =0.8 (PE: ea=2:1)).
N- (2-hydroxyethyl) palmitoamide (508 mg,1.7mmol,1.0 eq), DIPEA (439 mg,3.4mmol,2.0 eq), DMAP (21 mg,0.17mmol,0.1 eq) were dissolved in 10mL DCM and (3- (((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) (methyl) amino chloride (6277 mg,1.9mmol,1.1 eq) was added with stirring. Reflux was condensed at 50 ℃, reaction 72h, monitored by tlc plate. After completion of the reaction, the reaction was quenched by addition of an appropriate amount of saturated sodium bicarbonate solution, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration, silica gel column chromatography gave the product 2-palmitoylethyl (3- (((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) (methyl) carbamate (678 mg, 70% yield, R f =0.3 (PE: ea=1:1)).
2-Palmitoylethyl (3- (((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) (methyl) carbamate (115.3 mg,0.2mmol,1.0 eq) was dissolved in 2mL THF, 3mL 1N hydrochloric acid was slowly added dropwise, stirred at room temperature for 30min, and monitored by TLC plate. After completion of the reaction, quenched with an appropriate amount of saturated sodium bicarbonate solution, extracted with DCM, the organic phases were combined, dried and concentrated to give the crude 2-palmitoylethyl (3- (hydroxymethyl) pyridin-2-yl) (methyl) carbamate (R f =0.5 (DCM: meoh=20:1)) which was carried forward directly without work-up.
The crude product of the previous step, 2-palmitoylethyl (3- (hydroxymethyl) pyridin-2-yl) (methyl) carbamate (7193 mg,1.4mmol,1.0 eq), N-Boc glycine (245 mg,1.4mmol,1.0 eq), HOBt (284 mg,2.1mmol,1.5 eq) and DMAP (34 mg,0.28mmol,0.2 eq) were taken up in 20mL DCM, EDCI (403 mg,2.1mmol,1.5 eq) was added with stirring, the reaction was allowed to proceed overnight at room temperature, the TLC plate was monitored, after completion of the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, DCM was extracted, the organic phases were combined, dried and the product (2- (methyl ((2-palmitoylethoxy) carbonyl) amino) pyridin-3-yl) glycine ester (500 mg, yield 55%, pale yellow solid, R f = 0.5 (DCM: 20:1)).
(2- (Methyl ((2-palmitoylamino ethoxy) carbonyl) amino) pyridin-3-yl) methyl (tert-butoxycarbonyl) glycinate (100 mg,0.15mmol,1.0 eq) in 3mL DCM was added dropwise with ice bath stirring to 4mL of dioxane solution of hydrochloric acid, the reaction was allowed to proceed for 1h, the TLC plate was monitored, after completion of the reaction, the reaction was concentrated directly, and after sufficient stirring with appropriate amount of diethyl ether, the crude product (white solid) was obtained by suction filtration. The crude product was further purified by PTLC to give the desired product PEA-Py (60 mg, yield 77%, white solid) ,Rf＝0.4(DCM:MeOH＝10:1)).1H 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),4.22(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[C28H49N4O5]+521.3697,found 521.3697.
Example 13: pharmacokinetic testing after intravenous PEA injection in male beagle dogs
The present experiment was aimed at studying the Pharmacokinetic (PK) profile of PEA in beagle dogs after a single intravenous injection of PEA solution in male beagle dogs.
Preparation of the administration preparation: the PEA powder is weighed and added into a solvent containing 10% of HS15, 10% of NMP, 10% of PEG400 and 70% of water, the solvent is dissolved by ultrasonic, the solvent is filtered by a 0.22 mu m filter membrane, the solvent is packaged into penicillin bottles, the penicillin bottles are sterilized by high-pressure steam at 121 ℃ for 15min, and the content of the PEA powder is measured by sampling to be 0.47mg/ml.
Dosing and blood sampling of animals: 3 male beagle dogs were free to drink water throughout the trial, fasted for more than 12 hours prior to dosing, and fed 4 hours after dosing. The PEA solution was injected intravenously. Blood samples were collected into K 2 EDTA anticoagulant tubes 0h before, 5min, 10min, 30min, 1h, 2h, 4h, and 6h after dosing, and buffered on ice until centrifugation. Centrifuging the blood plasma within 30min after blood sampling (centrifuging at 8000rpm for 5min at 2-8deg.C), transferring the blood plasma into a centrifuge tube, preserving at-65deg.C, detecting PEA concentration in the blood plasma by LC-MS/MS, and calculating pharmacokinetic parameters.
Pharmacokinetic parameters were calculated using a non-compartmental model of software WinNonlinTM (version 8.3, certara, USA). PEA concentration was calculated by subtracting 0h plasma concentration. The dose and PK data for the beagle intravenous PEA solution are shown in table 1.
Table 1 dosing and PK data for intravenous PEA solutions for beagle dogs
Table 1 the results show that: after intravenous injection of PEA solution at 0.5mg/kg, beagle was 5min for T max, 546.8ng/mL for C 0, and 133.5 ng.h/mL for AUC last. Intravenous data will be used for calculation of the oral bioavailability of PEA.
Example 14 pharmacokinetic testing of Male beagle oral PEA and its derivatives
The present experiment was aimed at studying the PK profile of the test subjects in beagle dogs after single oral administration of PEA, I16 (CN 110023308a compound I16) or PEA derivatives to male beagle dogs.
Preparation of the administration preparation: the powder charge was filled into size 0 gelatin capsules.
Dosing and blood sampling of animals: 3 beagle dogs in each group fasted for at least 12 hours the day before the experiment, and were free to drink water. On the day of the experiment, beagle dogs were first fed a special meal of about 150mL (ingredients see table 2), and after 30min feeding, pre-filled capsules were each orally administered, and 20mL of water was administered to ensure that the capsules entered the stomach. Can drink water freely after the administration is completed, and can be eaten normally after 4 hours. Blood samples were collected into K 2 EDTA anticoagulant tubes 0h before, 10min, 30min, 1h, 2h, 3h, 4h, 6h, and 8h after dosing, and buffered on ice until centrifugation. After blood collection, blood plasma is centrifuged (at 8000rpm for 5min at 2-8 ℃) within 30min, 400 mu L of blood plasma is quantitatively taken after centrifugation and added into a centrifuge tube with 4 mu L of formic acid added in advance, the blood plasma is preserved at less than or equal to-65 ℃, and the concentration of an object to be detected in the blood plasma is detected by LC-MS/MS, and the pharmacokinetic parameters of the object to be detected are calculated.
Table 2 special meal table
Type(s) Bacon Common dog food Whole milk
Quantity of 2 Strips (60 g) 25g 150mL
Pharmacokinetic parameters for each group were calculated using a non-compartmental model of software WinNonlinTM (version 8.3, certara, USA). PEA concentration was calculated by subtracting 0h plasma concentration.
The bioavailability calculation formula: bioavailability (%) = (AUC T·Div)/(AUCiv·DT) ×100%, where AUC represents AUC last, subscripts T and iv represent test and intravenous formulations, respectively, and D represents the dose administered. AUC iv in the formula the average 133.5ng h/mL of AUC last data for intravenous injection of PEA (administered at a dose of 0.5 mg/kg) in example 14 was used.
(1) Pharmacokinetic testing of PEA
PEA was used as a control group to determine blood concentration after oral PEA administration to beagle dogs and calculate pharmacokinetic parameters, and dosing and PK data are shown in table 3.
Table 3 dose and PK data for beagle oral PEA
Table 3 the results show that: after oral administration of PEA to beagle dogs, the bioavailability of PEA was 0.9%. The results show that the PEA has lower oral bioavailability and is consistent with the literature report.
(2) Pharmacokinetic testing of I16 (CN 110023308A Compound I16)
I16 is a PEA prodrug disclosed in patent CN110023308a, which has the highest oral bioavailability of PEA after administration of the prodrug of the prior art. Here I16 was used as a control group to determine the plasma concentrations of I16 and PEA in beagle dogs after oral administration of I16 and calculate pharmacokinetic parameters, dosing and PK data are shown in table 4.
Table 4 dose and PK data for beagle oral I16
1 The dosage is calculated by PEA. ND: the pharmacokinetic parameters could not be calculated without detection in plasma.
After oral administration of I16 to beagle dogs, PEA was only detected in plasma, I16 was not detected, and thus pharmacokinetic parameters of I16 could not be calculated. The pharmacokinetic parameters of PEA are shown in table 4, and the results show that after oral administration of I16 to beagle, the bioavailability of PEA is 3.1%, and compared with PEA in (1), the bioavailability is significantly improved.
(3) Pharmacokinetic testing of PEA- (L) -V hydrochloride
PLoS ONE 10 (6): e0128699 discloses L-valine derivatives of PEA, herein designated PEA- (L) -V hydrochloride as a control group, and plasma concentrations of PEA- (L) -V and PEA after oral administration of PEA- (L) -V hydrochloride to beagle dogs were determined and pharmacokinetic parameters were calculated and dosing and PK data are shown in Table 5.
Table 5 dose and PK data for beagle oral PEA- (L) -V hydrochloride
1 The dosage is calculated by PEA.
PEA- (L) -V and PEA were detected simultaneously in plasma after oral PEA- (L) -V hydrochloride administration to beagle dogs. The results in table 5 show that PEA bioavailability was 0.5% after oral PEA- (L) -V hydrochloride administration to beagle dogs, without increasing bioavailability compared to PEA in (1).
(4) Pharmacokinetic testing of PEA- (L) -V hydrochloride
Plasma concentrations of PEA- (L) -V and PEA after oral PEA- (L) -V hydrochloride were determined and pharmacokinetic parameters were calculated and dosing and PK data are shown in table 6.
Table 6 dose and PK data for beagle oral PEA- (L) -V hydrochloride
1 The dosage is calculated by PEA.
PEA- (L) -V and PEA were detected simultaneously in plasma after oral PEA- (L) -V hydrochloride in beagle dogs. 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% with slightly improved bioavailability compared to PEA in (1).
(5) Pharmacokinetic testing of PEA-G- (L) -V hydrochloride
Plasma concentrations of PEA-G- (L) -V and PEA were determined after oral PEA-G- (L) -V hydrochloride administration to beagle dogs and pharmacokinetic parameters were calculated and dosing and PK data are shown in Table 7.
TABLE 7 oral PEA-G- (L) -V hydrochloride dose and PK data for beagle dogs
1 The dosage is calculated by PEA.
PEA-G- (L) -V and PEA were detected simultaneously in plasma after oral PEA-G- (L) -V hydrochloride administration to beagle dogs. The results in Table 7 show that PEA has a bioavailability of 1.4% after oral administration of PEA-G- (L) -V hydrochloride to beagle dogs, which is slightly improved over PEA in (1).
(6) Pharmacokinetic testing of PEA- (L) -a- (L) -V hydrochloride
Plasma concentrations of PEA- (L) -a- (L) -V and PEA were determined after oral PEA- (L) -a- (L) -V hydrochloride administration to beagle dogs and pharmacokinetic parameters were calculated and dosing and PK data are shown in table 8.
Table 8 dose and PK data for beagle oral PEA- (L) -a- (L) -V hydrochloride
1 The dosage is calculated by PEA.
The results in table 8 show that PEA bioavailability is 1.7% after oral PEA- (L) -a- (L) -V hydrochloride administration to beagle dogs, which is about 1-fold improved compared to PEA in (1).
(7) Pharmacokinetic testing of PEA- (L) -P hydrochloride
Plasma concentrations of PEA- (L) -P and PEA were determined after oral PEA- (L) -P hydrochloride administration to beagle dogs and pharmacokinetic parameters were calculated and dosing and PK data are shown in table 9.
Table 9 dose and PK data for beagle oral PEA- (L) -P hydrochloride
1 The dosage is calculated by PEA. ND: the pharmacokinetic parameters could not be calculated without detection in plasma.
PEA- (L) -P was not detected in plasma but only PEA was detected after oral PEA- (L) -P hydrochloride in beagle dogs, indicating a fast in vivo conversion rate of the prodrug PEA- (L) -P.
Table 9 the results show that PEA bioavailability is 9.4% after oral PEA- (L) -P hydrochloride administration to beagle dogs, which is about 9.4-fold improved compared to PEA in (1).
(8) Pharmacokinetic testing of PEA- (L) -P- (L) -V hydrochloride
Plasma concentrations of PEA- (L) -P- (L) -V and PEA were determined after oral PEA- (L) -P- (L) -V hydrochloride administration to beagle dogs and pharmacokinetic parameters were calculated and dosing and PK data are shown in table 10.
Table 10 dose and PK data for beagle oral PEA- (L) -P- (L) -V hydrochloride
1 The dosage is calculated by PEA. ND: the pharmacokinetic parameters could not be calculated without detection in plasma.
PEA- (L) -P- (L) -V was not detected in plasma but only PEA was detected after oral PEA- (L) -P- (L) -V hydrochloride in beagle dogs, indicating a fast in vivo conversion rate of the prodrug PEA- (L) -P- (L) -V.
Table 10 the results show that PEA bioavailability is 2.9% after oral PEA- (L) -P- (L) -V hydrochloride administration to beagle dogs, which is about 2.2-fold improved compared to PEA in (1).
(9) Pharmacokinetic testing of PEA-diethylaminopropionate
Plasma concentrations of PEA-diethylaminopropionate and PEA were determined after oral PEA-diethylaminopropionate administration to beagle dogs and pharmacokinetic parameters were calculated and dosing and PK data are shown in table 11.
Table 11 dose and PK data for beagle oral PEA-diethylaminopropionate
1 The dosage is calculated by PEA.
After oral administration of PEA-diethylaminopropionate to beagle dogs, PEA-diethylaminopropionate and PEA were detected simultaneously in plasma.
The results in Table 11 show that PEA has a bioavailability of 1.5% after oral administration of PEA-diethylaminopropionate to beagle dogs, which is slightly higher than PEA in (1).
(10) Pharmacokinetic testing of PEA-Py
Plasma concentrations of PEA-Py and PEA were measured after oral PEA-Py administration to beagle dogs and pharmacokinetic parameters were calculated and the dosing and PK data are shown in Table 12.
Table 12 dose and PK data for beagle oral PEA-Py
1 The dosage is calculated by PEA.
PEA-Py and PEA were detected simultaneously in plasma after oral administration of PEA-Py to beagle dogs.
The results in Table 12 show that PEA bioavailability was 0.3% after oral administration of PEA-Py to beagle dogs without increasing the bioavailability of PEA.
(11) The PK examples above were summarized and compared and the results are shown in Table 13.
TABLE 13 summary PK data after oral administration of PEA and PEA derivatives to beagle dogs
NA: is not applicable.
The compound PEA- (L) -V is disclosed in document PLoS ONE 10 (6): e 012899 but this prodrug fails to improve the bioavailability of PEA. The results in table 13 show that the derivatives of the invention can significantly improve PEA bioavailability, up to 10-fold, and have an unexpected effect significantly better than PEA (drug substance) and I16 (the disclosed optimal PEA prodrug). Whether the prodrug indirectly reflects the conversion rate of the prodrug in vivo was detected in plasma, and as can be seen from Table 13, compounds I16, PEA- (L) -P and PEA- (L) -P- (L) -V were not detected in plasma, suggesting a fast conversion rate in vivo.
The aim of the present invention is to obtain the desired PEA derivatives which can be rapidly converted into PEA in vivo and which are able to increase the oral bioavailability of PEA. Those skilled in the art generally recognize that the less sterically hindered the more readily the ester bond is hydrolyzed. The PEA derivative PEA-G- (L) -V in Table 13 has minimal steric hindrance to the ester linkage, but does not convert in vivo rapidly. Unexpectedly, no derivatives were detected in PEA- (L) -P and PEA- (L) -P- (L) -V group plasma, the prodrug conversion rate was fast, and PEA bioavailability was significantly improved, exhibiting the desirable prodrug PK profile.
The above description has been given of exemplary embodiments of the present invention. The scope of protection of the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (16)

1. A compound of formula (I):
a compound or a pharmaceutically acceptable salt form thereof;
Preferably, the method comprises the steps of,
A compound of formula (I 1):
or formula (I 2):
a compound or a pharmaceutically acceptable salt form thereof.
2. A compound according to claim 1, or a pharmaceutically acceptable salt form thereof, wherein: r 1 is selected from C 1-40 aliphatic, preferably C 1-20 aliphatic, more preferably C 15-20 aliphatic, preferably C 15-20 aliphatic is C 15-20 alkyl or C 15-20 alkenyl containing 1-5 c=c.
3. A compound according to claim 1, or a pharmaceutically acceptable salt form thereof, wherein: Selected from/>
4. A compound according to claim 1, or a pharmaceutically acceptable salt form thereof, wherein:
In formula (I), when Z is H, Y is selected from standard amino acids, non-standard amino acids, excluding glycine, alanine, valine, isoleucine, tryptophan, aspartic acid, glutamine, asparagine; or Y, Z is selected from the same or different standard amino acid and nonstandard amino acid, Y is connected with the hydroxyl of the ethanolamine through carboxyl, and Y is connected with the carboxyl of Z through amino;
in formula (I 1), X is selected from H, a standard amino acid, a non-standard amino acid, the non-standard amino acid being linked to the amino group of phenylalanine through a carboxyl group;
in the formula (I 2), X is selected from standard amino acid and nonstandard amino acid, wherein the standard amino acid and the nonstandard amino acid are connected with the hydroxyl of ethanolamine through carboxyl, and the standard amino acid and the nonstandard amino acid are connected with the carboxyl of valine through amino;
Preferably, the standard amino acid is selected from aromatic or aliphatic amino acids, more preferably, the standard amino acid 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 and valine;
Preferably, the non-standard amino acid is selected from ornithine, homoarginine, citrulline, homocysteine, homoserine, theanine, gamma-aminobutyric acid, sarcosine, casamino acid, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine, cystathionine, homocysteine, beta-amino acid, alpha-disubstituted amino acids, N-methyl acid, hydroxy-amino acids, cyclic amino acids; preferably, the non-standard amino acid is selected from ornithine, homoarginine, citrulline, homocysteine, homoserine, theanine, gamma-aminobutyric acid, sarcosine, casamino acid, 2-aminoadipic 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-abrine, 4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, 1-aminocyclopropyl-1-carboxylic acid, hydrogen-cyclobutane-2-carboxylic acid or percarboxylic acid;
Preferably, in formula (I), Y, Z is selected from the same or different standard amino acids, 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, Z is further condensed with 1 or 2 same or different standard amino acids, non-standard amino acids via an amino group;
Preferably, in formula (I 1), the standard amino acid, the non-standard amino acid is further condensed with 1 or 2 identical or different standard amino acids, non-standard amino acids by amino groups;
preferably, in formula (I 2), X is selected from a standard amino acid, a non-standard amino acid, or an amino acid formed by condensing 2-3 identical or different standard amino acids and non-standard amino acids, wherein the standard amino acid, the non-standard amino acid or the condensed amino acid is connected with the hydroxyl of ethanolamine through carboxyl, and is connected with the carboxyl of valine through amino.
5. The compound of claim 1, or a pharmaceutically acceptable salt form thereof, wherein the compound has the structure of formula (I 1') or (I 1 "):
or (I 2 ') or (I 2') structure:
6. a compound according to claim 4, characterized in that: the standard amino acid and the nonstandard amino acid are selected from D-or L-configuration.
7. A compound or a pharmaceutically acceptable salt form thereof:
8. a compound of formula II:
P1-P2
Or a pharmaceutically acceptable salt form thereof;
P 1 is N-acyl ethanolamide; p 2 is a moiety conjugated to the N-acyl ethanolamide and P 1 is linked to the carboxyl group of P 2 through a hydroxyl group.
9. The compound of claim 8, or a pharmaceutically acceptable salt form thereof, wherein P 1 is selected from
10. The compound of claim 8, or a pharmaceutically acceptable salt form thereof, wherein P 2 is selected from pregabalin, gabapentin, lipoic acid, diethylaminopropionic acid, or
11. A compound or a pharmaceutically acceptable salt form thereof:
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt form thereof, wherein the pharmaceutically acceptable salt form is selected from one or more of 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, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, para-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or the like.
13. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt form thereof, wherein one or more hydrogen atoms are replaced with deuterium atoms.
14. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
15. The pharmaceutical composition according to claim 14, wherein the composition is a solid, semi-solid, liquid, preferably a powder, granule, pill, pellet, tablet, enteric-coated tablet, sustained release tablet, capsule, soft capsule, film, chewing gum, drop, oral liquid, syrup, emulsion, self-microemulsion, lipid formulation, suspension or mixture.
16. Use of a compound according to any one of claims 1-11 or a pharmaceutically acceptable salt form thereof and a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the prevention or treatment of pain, chronic lower back pain, sciatica, radiculopathy, radiological pain, neuropathic pain, anxiety, depression, schizophrenia, cancer, amyotrophic lateral sclerosis, multiple sclerosis, neurological diseases, parkinson's disease, alzheimer's disease, huntington's disease, cerebral ischemia, epilepsy, anorexia, dental pain, osteoarthritis, reduced gastrointestinal motility, cancer, glaucoma, atopic dermatitis, respiratory tract infections, post-traumatic stress disorders, obesity, insomnia, somnolence, idiopathic mast cell activation syndrome, preferably chronic extensive musculoskeletal plastic pain.
CN202311573352.1A 2022-11-25 2023-11-23 N-acyl ethanolamide derivative, preparation method and application thereof Pending CN118125936A (en)

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CN202211488061 2022-11-25
CN2022114880618 2022-11-25
CN2022115927753 2022-12-13
CN202211592775 2022-12-13

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CN118125936A true CN118125936A (en) 2024-06-04

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