CN115894371B - Sinomenine amide derivative, preparation method and application thereof, and analgesic drug - Google Patents
Sinomenine amide derivative, preparation method and application thereof, and analgesic drug Download PDFInfo
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- CN115894371B CN115894371B CN202211719767.0A CN202211719767A CN115894371B CN 115894371 B CN115894371 B CN 115894371B CN 202211719767 A CN202211719767 A CN 202211719767A CN 115894371 B CN115894371 B CN 115894371B
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- sinomenine
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- RARWEROUOQPTCJ-RBUKOAKNSA-N cepharamine Natural products C1CC2=CC=C(OC)C(O)=C2[C@@]2(CCN3C)[C@]13C=C(OC)C(=O)C2 RARWEROUOQPTCJ-RBUKOAKNSA-N 0.000 title claims abstract description 45
- 229930002966 sinomenine Natural products 0.000 title claims abstract description 45
- -1 Sinomenine amide Chemical class 0.000 title claims abstract description 37
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides sinomenine amide derivatives, a preparation method and application thereof, and analgesic drugs, belonging to the technical field of medicines. The sinomenine amide derivative provided by the invention is a novel compound, has good stability, is not easy to decompose in vivo, and shows that the sinomenine amide derivative is not a prodrug but plays a self analgesic effect in a compound form in a non-decomposed state. The test example shows that the sinomenine amide derivative provided by the invention has good analgesic effect on peripheral pain and peripheral neuropathic pain animal models.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to sinomenine amide derivatives, a preparation method and application thereof, and an analgesic drug.
Background
Chronic pain refers to pain that persists for more than one month, and common chronic pain mainly includes chronic back pain, fibromyalgia, chronic arthritic pain, and various neuropathic pain. Chronic pain is characterized by the following aspects: firstly, the incidence rate of chronic pain is high, and patients are widely distributed; secondly, chronic pain seriously jeopardizes the physical and mental health of the patient; third, chronic pain is a great challenge to public medical systems. The current drugs available for treating chronic pain have poor general effects, and the lack of effective treatment modes for patients with chronic pain has become a social problem to be solved urgently.
Antiepileptic GABA drugs such as gabapentin and pregabalin are the first drugs to treat chronic pain. However, gabapentin and pregabalin have limited therapeutic effects on chronic pain: international literature reports that less than 50% of patients can have moderate pain relief for traumatic nerve injury; for mixed neuropathic pain, only 21% of patients are effective; for herpetic neuralgia, only 32-34% of patients are effective. Recent years have seen an increase in reports of gabapentin and pregabalin failures, and attention has been paid to the failure of gabapentin and pregabalin, and the main failures include: calm, cognitive dullness, dizziness, somnolence (20-30% of patients taking the drug) and weight gain (1/6 of patients taking the drug for more than 7% of weight gain after one year). And the side effect of GABA drugs is positively correlated with the dosage.
Tricyclic antidepressants block the reuptake of Norepinephrine (NA) and 5-hydroxytryptamine (5-HT) energy nerve endings to NA and 5-HT, but their analgesic mechanisms are unknown; although the effective rate for chronic pain is about 40%, tricyclic antidepressants usually have mild effects and slow onset of action, and take effect only after at least 1-2 weeks. And the common adverse reactions of tricyclic antidepressants are as follows: sedation, mild cognitive impairment, blurred vision, dry mouth, tachycardia, orthostatic hypotension, delayed urination, constipation, weight gain, and the like.
Although the opioid can achieve a strong analgesic effect, tolerance and dependence are easy to generate, and continuous use of opioid after dependence can cause vicious circle and cause addiction to cause great changes of emotion of patients. The opinion of doctors is very divergent as to when to prescribe such drugs to patients. Currently, over 800 tens of thousands of americans commonly use opioid analgesics, and 200 tens of thousands of people are dependent on opioid drugs. Abuse of highly addictive pain-relieving drugs such as opioids has become a chronic illness that afflicts the united states society.
According to the newest data of NIH, clinical trials worldwide with chronic pain as an indication are currently accumulating up to 2488 (clinicaltrial. Org in 2020). Unfortunately, none of the 59 new drugs and therapies (which is the most year since 1993) were co-approved by the U.S. FDA in 2018, but were directed to chronic pain. In 2005-2009, few varieties of arthritis and fibromyalgia are approved by the FDA, and the medicines are either modified from the existing medicines (such as pregabalin, duloxetine and the like) or are new dosage forms of the existing medicines (such as various slow-release opioid pain relieving medicines). Therefore, the development of novel clinical intervention drugs is urgent.
Disclosure of Invention
The invention aims to provide sinomenine amide derivatives, a preparation method and application thereof, and an analgesic drug.
In order to achieve the above object, the present invention provides the following technical solutions:
The invention provides sinomenine amide derivatives or trifluoroacetate thereof, wherein the sinomenine amide derivatives have a structure shown in a formula I:
the invention provides a preparation method of sinomenine amide derivatives, which comprises the following steps:
Mixing a compound 6, a compound 7, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine and triethylamine with an organic solvent for condensation reaction to obtain a compound 8;
Mixing the compound 8, trifluoroacetic acid and an organic solvent to perform deamination protecting group reaction, so as to obtain the trifluoroacetate of sinomenine amide derivatives with the structure shown in the formula I;
the structural formulas of the compound 6, the compound 7 and the compound 8 are shown in the formulas 6-8 in sequence:
preferably, the mass ratio of the compound 6 to the compound 7 is (1.9-3.8): 2.
Preferably, the temperature of the condensation reaction is room temperature and the time is 24-72 hours.
Preferably, the mass ratio of the compound 8 to trifluoroacetic acid is 1.9: (1.42-5.68).
Preferably, the deamination protecting group reaction temperature is room temperature and the time is 8-24 h.
The invention provides application of sinomenine amide derivatives and/or pharmaceutically acceptable salts thereof in preparing analgesic drugs.
Preferably, the pain for which the analgesic is applicable includes acute pain, peri-operative pain or chronic pain.
Preferably, the chronic pain includes at least one of rheumatoid arthritis pain, diabetic peripheral nerve injury pain, aids peripheral nerve injury pain, or chronic pain caused by tissue injury, facial nerve injury, ischemic injury, perioperative pain, cancer pain, spinal cord injury, or stroke.
The invention provides an analgesic drug, which comprises the sinomenine amide derivative and/or pharmaceutically acceptable salts thereof as active ingredients.
The sinomenine amide derivative is a novel compound, has good stability and is not easy to decompose in vivo, and the sinomenine amide derivative is not a prodrug but plays a self analgesic effect in a compound form in a non-decomposed state. The results of the test examples show that the compound SONP provided by the invention has good analgesic effect on the animal model of peri-operative pain and peripheral neuropathic pain.
Specifically, the compound SONP provided by the invention has excellent stability under room temperature or solution state, and does not decompose for more than four weeks. In a peripheral neuralgia mouse model, under the condition of single administration, the compound SONP can generate the effect of inhibiting mechanical pain sensitivity and cold pain sensitivity of the model mouse in a dose-dependent manner; the compound SONP has similar drug effects when mixed and combined with the optimal analgesic combination S+P (sinomenine+pregabalin) drug discovered by the research group; after repeated administration (1 time a day, 5 consecutive days), compound SONP had a phenomenon of threshold rise before administration and accumulated efficacy, indicating no drug tolerance and better efficacy effect for repeated administration than for single administration. In the incision pain mouse model, compound SONP produces a dose-dependent effect that inhibits mechanical pain, cold pain, and thermal pain in the model mouse; compound SONP has a slightly stronger effect on incision pain than on peripheral neuralgia; the compound SONP has similar drug effects when combined with S+P (sinomenine+pregabalin) drugs.
In order to explore the stability of compound SONP in vivo after administration, the present invention uses microdialysis sampling-mass spectrometry technology to study the metabolic status of compound SONP in blood or brain extracellular fluid after intravenous injection or gastric lavage administration. The results show that most of the compound SONP can exist stably in blood or brain extracellular fluid for 0-6 h, and only a small part (probably less than 1/4 of the original blood component) is hydrolyzed to generate sinomenine and other metabolites.
Drawings
FIG. 1 is a 1 HNMR profile of compound SONP prepared in example 1;
FIG. 2 is a MS mass spectrum of compound SONP prepared in example 1;
FIG. 3 is a chromatogram of compound SONP prepared in example 1;
FIG. 4 is a physical diagram of compound SONP prepared in example 1;
FIG. 5 is a MS mass spectrum of the compound SONP prepared in example 1 after being left at room temperature for four weeks;
FIG. 6 is a MS mass spectrum showing that the compound SONP prepared in example 1 was left as an aqueous solution at room temperature for four weeks;
FIG. 7 is a graph showing the effect of SONP single intraperitoneal injection on mechanical pain sensitivity in peripheral neuralgia mice;
FIG. 8 is a graph showing the effect of SONP single gastric lavage administration on mechanical pain in peripheral neuralgia mice;
FIG. 9 is a graph comparing area under the curve (AUC) of the analgesic effect of SONP single doses for 0-8 h on mechanical pain;
FIG. 10 is a graph showing the effect of SONP single intraperitoneal injection administration on cold pain (score) in mice with peripheral nerve injury;
FIG. 11 is a graph showing the effect of SONP single gastric lavage (i.e., equivalent to oral administration) on cold pain (score) in mice with peripheral nerve injury;
FIG. 12 is a graph comparing area under the curve of analgesic effect of SONP single doses for 0-8 h on cold pain sensitivity (score);
FIG. 13 is a graph showing the effect of SONP single intraperitoneal injection administration on thermal pain in a peripheral neuralgia mouse;
FIG. 14 is a graph showing the effect of SONP single gastric lavage doses on thermal pain in peripheral neuralgia mice;
FIG. 15 is a graph showing the area under the curve for the analgesic effect of SONP single doses of 0-8 h on thermal pain sensitivity (response time);
FIG. 16 is a graph showing the effect of SONP single doses on mechanical pain in incision-pain mice;
FIG. 17 is a graph showing the effect of SONP single doses on cold pain (scoring) in incision pain mice;
FIG. 18 is a graph showing the effect of SONP single doses on thermal pain sensitivity (response time) in incision pain mice;
FIG. 19 is a graph showing the results of drug effect-mechanical pain sensitivity of SONP repeated administrations in a peripheral neuralgia model;
FIG. 20 is a graph showing the results of drug efficacy-cold pain response (score) of SONP repeated doses in a peripheral neuralgia model;
FIG. 21 is a graph showing the results of drug efficacy-thermal pain sensitivity (duration of response) of SONP repeated administrations in a peripheral neuralgia model;
FIG. 22 is a graph showing the change in the concentration of a compound SONP in blood after administration;
FIG. 23 is a graph showing the change in drug concentration of compound SONP in brain extracellular fluid after administration;
FIG. 24 is a graph showing changes in blood concentration of SONP after intravenous or intragastric administration (20 mg/kg);
FIG. 25 is a graph of bioavailability analysis of compound SONP;
FIG. 26 is a graph of blood-brain concentration contrast analysis following administration of compound SONP.
Detailed Description
The invention provides sinomenine amide derivatives or trifluoroacetate thereof, wherein the sinomenine amide derivatives have a structure shown in a formula I:
the invention provides a preparation method of sinomenine amide derivatives, which comprises the following steps:
Mixing a compound 6, a compound 7, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine and triethylamine with an organic solvent for condensation reaction to obtain a compound 8;
Mixing the compound 8, trifluoroacetic acid and an organic solvent to perform deamination protecting group reaction, so as to obtain the trifluoroacetate of sinomenine amide derivatives with the structure shown in the formula I;
the structural formulas of the compound 6, the compound 7 and the compound 8 are shown in the formulas 6-8 in sequence:
In the present invention, unless otherwise specified, all materials are commercially available or prepared by methods well known to those skilled in the art.
The invention mixes compound 6, compound 7, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine and triethylamine with organic solvent for condensation reaction to obtain compound 8. The present invention first describes a method for producing the compound 6. In the present invention, the preparation method of the compound 6 preferably comprises the steps of:
mixing the compound 1, the di-tert-butyl carbonate, the sodium hydroxide and the dioxane with water, and performing an amino protection reaction to obtain a compound 2;
mixing the compound 3, sulfoxide chloride and methanol for esterification reaction to obtain a compound 4;
Mixing the compound 2, the compound 4, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the 1-hydroxybenzotriazole and the triethylamine with methylene dichloride, and performing condensation reaction (marked as first condensation reaction) to obtain a compound 5;
mixing the compound 5, lithium hydroxide aqueous solution and tetrahydrofuran, and carrying out hydrolysis reaction to obtain a compound 6;
the structural formulas of the compound 1, the compound 2, the compound 3, the compound 4 and the compound 5 are shown in the formulas 1-5 in sequence:
The invention mixes the compound 1, the carbonic anhydride di-tert-butyl ester, the sodium hydroxide and the dioxane with water to carry out amino protection reaction to obtain the compound 2. In the present invention, the compound 1 (i.e., pregabalin), di-tert-butyl carbonate, sodium hydroxide, dioxane and water are preferably used in an amount ratio of 2g:3.02g:1.11g:15mL:15mL. In the invention, sodium hydroxide is preferably added into a mixed solvent of dioxane and water under ice bath condition, compound 1 is added, and then di-tert-butyl carbonate anhydride is dropwise added for amino protection reaction. In the invention, the temperature of the amino protection reaction is preferably room temperature, the time of the amino protection reaction is preferably 16 hours, and the time of the amino protection reaction is counted by the beginning of the di-tert-butyl carbonate dripping. After the amino protection reaction, the invention preferably adds water into the obtained product system to dilute, uses hydrochloric acid with the concentration of 1mol/L to adjust the pH value of the system to 5, then uses methylene dichloride to extract, uses saturated sodium chloride solution to wash an organic phase, then uses anhydrous sodium sulfate to dry, filters, decompresses filtrate to remove solvent, obtains colorless oily matter, and places the colorless oily matter in a refrigerator with the temperature of minus 20 ℃ to form solid, namely the compound 2.
The invention mixes the compound 3, sulfoxide chloride and methanol to carry out esterification reaction to obtain the compound 4. In the present invention, the amount ratio of the compound 3 (i.e., gamma-aminobutyric acid), thionyl chloride and methanol is preferably 5g:28.84g:50mL. In the invention, the compound 3 is preferably added into methanol under the protection of argon, and then thionyl chloride is dropwise added for esterification reaction. In the present invention, the temperature of the esterification reaction is preferably 80 ℃, the time of the esterification reaction is preferably 6 hours, and the time of the esterification reaction is calculated by starting from the end of the thionyl chloride. After the esterification reaction, the obtained product system is preferably decompressed and concentrated to remove the solvent, so that transparent solid, namely the crude product of the compound 4, is obtained, and the next reaction is directly carried out.
After compound 2 and compound 4 are obtained, the present invention mixes the compound 2, compound 4, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine and methylene chloride, and performs a condensation reaction (denoted as a first condensation reaction) to obtain compound 5. In the present invention, the amount ratio of the compound 2, the compound 4, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the 1-hydroxybenzotriazole, the triethylamine and the dichloromethane is preferably 2g:1.42g:2.96g:2.08g:3.9g:30mL. The present invention preferably involves a first condensation reaction by dissolving compound 4 in methylene chloride with stirring, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine, and finally adding compound 2. In the present invention, the temperature of the first condensation reaction is preferably room temperature, and the time is preferably 48 hours. After the first condensation reaction, methylene dichloride is preferably added into the obtained product system for dilution, then hydrochloric acid with the concentration of 1mol/L and saturated sodium bicarbonate solution are sequentially used for washing, then anhydrous sodium sulfate is used for drying, filtration is carried out, the filtrate is decompressed and concentrated to remove the solvent, and the residue is purified by silica gel column chromatography (the eluent used is preferably petroleum ether: ethyl acetate=2:1 according to the volume ratio), so as to obtain colorless oily matter, namely the compound 5.
After the compound 5 is obtained, the compound 5, the lithium hydroxide aqueous solution and tetrahydrofuran are mixed for hydrolysis reaction to obtain the compound 6. In the present invention, the amount ratio of lithium hydroxide to tetrahydrofuran in the aqueous solution of compound 5, lithium hydroxide is preferably 2.3g:323mg:25mL; the concentration of the lithium hydroxide aqueous solution is preferably 1mol/L. In the present invention, the compound 5 is preferably added to tetrahydrofuran, and an aqueous lithium hydroxide solution is added with stirring to carry out hydrolysis reaction. In the present invention, the temperature of the hydrolysis reaction is preferably room temperature, and the time is preferably 16 hours. After the hydrolysis reaction, the pH value of the obtained product system is preferably regulated to be 4-5 by hydrochloric acid with the concentration of 1mol/L, then the solvent is removed by decompression concentration, the obtained system is extracted by methylene dichloride, an organic phase is washed by saturated sodium chloride solution, and then the organic phase is dried by anhydrous sodium sulfate, filtered, and the filtrate is decompressed and concentrated to remove the solvent, so that a crude product of the compound 6 is obtained, and then the crude product is directly used in the next step.
After the compound 6 is obtained, the invention mixes the compound 6, the compound 7, the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the 4-dimethylaminopyridine and the triethylamine with an organic solvent for condensation reaction (second condensation reaction) to obtain the compound 8. In the present invention, the mass ratio of the compound 6, the compound 7 (i.e., sinomenine hydrochloride), the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the 4-dimethylaminopyridine and the triethylamine is preferably (1.9 to 3.8): 2: (2.1-4.2): (1.4-2.7): (1.7 to 3.3), more preferably 2.26:2:3.14:2:2.77. in the present invention, the organic solvent is preferably methylene chloride, and the ratio of the organic solvent to the compound 7 is preferably (10 to 40) mL:2g, more preferably 30mL:2g. The present invention preferably carries out the second condensation reaction by adding compound 6 to an organic solvent with stirring, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine and triethylamine, and finally adding compound 7. In the present invention, the temperature of the second condensation reaction is preferably room temperature, and the time is preferably 24 to 72 hours, more preferably 48 hours. After the second condensation reaction, the obtained product system is preferably washed with hydrochloric acid with the concentration of 1mol/L, an organic phase is collected, the organic phase is washed with saturated sodium bicarbonate and then dried with anhydrous sodium sulfate, the filtrate is filtered, the solvent is removed by decompression concentration, and the residue is purified by silica gel column chromatography (the eluent used is preferably dichloromethane: methanol=30:1 according to the volume ratio), so that white solid is obtained, namely the compound 8.
After the compound 8 is obtained, the compound 8, trifluoroacetic acid and an organic solvent are mixed for deamination protecting group reaction, so that the trifluoroacetate of sinomenine amide derivative with the structure shown in the formula I is obtained. In the present invention, the mass ratio of the compound 8 to trifluoroacetic acid is preferably 1.9: (1.42 to 5.68), more preferably 1.9:2.84. in the present invention, the organic solvent is preferably methylene chloride, and the ratio of the organic solvent to the compound 8 is preferably (10 to 40) mL:1.9g, more preferably 20mL:1.9g. In the invention, the compound 8 is added into an organic solvent under stirring, and then trifluoroacetic acid is added to carry out deamination protecting group reaction. In the present invention, the temperature of the deamination protecting group reaction is preferably room temperature, and the time is preferably 8 to 24 hours, more preferably 16 hours.
In the invention, the reaction formula for preparing the trifluoroacetate of the sinomenine amide derivative is shown as follows:
The invention provides application of sinomenine amide derivatives and/or pharmaceutically acceptable salts thereof in preparing analgesic drugs. In the present invention, the pain to which the analgesic is applied preferably includes acute pain, perioperative pain, or chronic pain; the chronic pain preferably includes at least one of rheumatoid arthritis pain, diabetic peripheral nerve injury pain, aids peripheral nerve injury pain, or chronic pain caused by tissue injury, facial nerve injury, ischemic injury, perioperative pain, cancer pain, spinal cord injury, or stroke. The specific type of the pharmaceutically acceptable salt of the sinomenine amide derivative is not particularly limited, and pharmaceutically acceptable salts of the type well known to those skilled in the art are adopted; in the examples of the present invention, the trifluoroacetate salt of sinomenine amide derivatives is specifically described as an example.
The invention provides an analgesic drug, which comprises the sinomenine amide derivative and/or pharmaceutically acceptable salts thereof as active ingredients. In the present invention, the content of the active ingredient in the analgesic is preferably 1 to 40wt%. In the present invention, the analgesic drug further includes pharmaceutically acceptable auxiliary materials, and the specific types of the pharmaceutically acceptable auxiliary materials are not particularly limited, and may be selected according to dosage forms, and in particular, if the analgesic drug is an oral dosage form, the pharmaceutically acceptable auxiliary materials are preferably cyclodextrin compounds, and more preferably beta-cyclodextrin. In the present invention, the dosage form of the analgesic drug preferably includes an oral dosage form, a sublingual tablet dosage form, an intramuscular injection dosage form or an intravenous injection dosage form. In the invention, the analgesic drug is taken as an oral dosage form, the dosage for clinically treating chronic pain can be orally taken for 1-2 times per day, and the content of active ingredients in each time is 20-500 mg.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
(1) Compound 2 was prepared as follows:
1.11g of sodium hydroxide is added into a mixed solvent of 15mL of dioxane and 15mL of water under ice bath condition, 2g of pregabalin (compound 1) is added, then 3.02g of di-tert-butyl carbonate (Boc 2 O) is added dropwise, amino protection reaction is carried out for 16h under stirring condition at room temperature after the dripping, TLC detection is carried out after the reaction, 50mL of water is added into the obtained product system for dilution, 1mol/L hydrochloric acid is used for adjusting the pH value of the system to 5, dichloromethane is used for extraction, an organic phase is washed with saturated sodium chloride solution, then anhydrous sodium sulfate is used for drying, filtration is carried out, the filtrate is decompressed and concentrated to remove the solvent, and 3.2g of colorless oily matter is obtained, and the colorless oily matter is placed in a refrigerator at-20 ℃ to form solid, namely the compound 2 (yield 98.23%).
Compound 4 was prepared as follows:
5g of gamma-aminobutyric acid (compound 3) is added into 50mL of methanol under the protection of argon, 28.84g of thionyl chloride is added dropwise, esterification reaction is carried out for 6h at 80 ℃ after the completion of the addition, TLC detection is carried out after the completion of the reaction, and the obtained product system is decompressed and concentrated to remove the solvent, thus obtaining 7.5g of transparent solid (namely crude product of compound 4).
(2) Compound 5 was prepared as follows:
1.42g of Compound 4 was dissolved in 30mL of methylene chloride with stirring, then 2.96g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2.08g of 1-Hydroxybenzotriazole (HOBT) and 3.9g of triethylamine were added, and 2g of Compound 2 was added with stirring and mixing uniformly, condensation reaction was carried out for 48 hours with stirring at room temperature, TLC detection was completed, 100mL of methylene chloride was added to the resulting product system for dilution, then washing with hydrochloric acid at a concentration of 1mol/L and saturated sodium bicarbonate solution in sequence, followed by drying over anhydrous sodium sulfate, filtration, the solvent was removed by concentrating the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (in terms of volume ratio, eluent used was petroleum ether: ethyl acetate=2:1), to obtain 2.3g of colorless oily substance, namely Compound 5, the yield was 83.2%.1HNMR(600MHz,CDCl3)δ6.81(s,1H),4.89(s,1H),3.69(s,3H),3.31(dd,J=12.7,6.7Hz,2H),3.27–2.97(m,2H),2.41(t,J=7.3Hz,2H),2.16–2.08(m,2H),2.03(d,J=3.1Hz,1H),1.88(p,J=7.1Hz,2H),1.66(dp,J=13.4,6.7Hz,1H),1.45(s,9H),1.20–1.10(m,2H),0.90(dd,J=6.6,2.8Hz,6H).
(3) Compound 6 was prepared as follows:
2.3g of compound 5 is added into 25mL of Tetrahydrofuran (THF), a lithium hydroxide aqueous solution with the concentration of 1mol/L (containing 323mg of LiOH) is added under stirring, hydrolysis reaction is carried out for 16h under the condition of stirring at room temperature, TLC detection is carried out after reaction, the pH value of the obtained product system is regulated to be 4-5 by hydrochloric acid with the concentration of 1mol/L, THF is removed by decompression concentration, the obtained system is extracted by methylene dichloride, an organic phase is washed by saturated sodium chloride solution, and then dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to remove a solvent, thus obtaining a crude product of the compound 6, and then the crude product is directly used in the next step.
(4) Compound 8 was prepared as follows:
Adding 2.26g of compound 6 into 30mL of dichloromethane under stirring, adding 3.14gEDCI g of 4-Dimethylaminopyridine (DMAP) and 2.77g of triethylamine, stirring and mixing uniformly, adding 2g of sinomenine hydrochloride (compound 7), carrying out condensation reaction for 48h under room temperature stirring, detecting the reaction completion by TLC, washing the obtained product system with hydrochloric acid with the concentration of 1mol/L, collecting an organic phase, washing the organic phase with saturated sodium bicarbonate, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to remove the solvent, purifying the residue by silica gel column chromatography (the eluent used is dichloromethane: methanol=30:1 by volume ratio), and obtaining 1.9g of white solid, namely compound 8, wherein the yield is high 53%.1HNMR(600MHz,CDCl3)δ7.09(s,1H),6.95(d,J=8.5 Hz,1H),6.79(d,J=8.4 Hz,1H),5.51(s,1H),5.32(s,1H),3.86–3.78(m,1H),3.75(s,3H),3.60–3.53(m,1H),3.51(s,3H),3.37(d,J=20.3 Hz,3H),3.23(dd,J=16.8,12.3 Hz,3H),3.06(dt,J=14.6,13.1 Hz,3H),2.91–2.83(m,1H),2.78–2.57(m,4H),2.53(s,3H),2.39(dd,J=14.1,7.5 Hz,1H),2.26–2.08(m,6H),2.08–1.92(m,3H),1.92–1.83(m,1H),1.72–1.63(m,2H),1.45(s,9H),1.23–1.11(m,3H),0.91(d,J=6.6 Hz,6H).
(5) Preparation of trifluoroacetate of sinomenine amide derivatives
Adding 1.9g of compound 8 into 20mL of dichloromethane under stirring, then adding 2.84g of trifluoroacetic acid, carrying out deamination protecting group reaction for 16h under stirring at room temperature, carrying out TLC detection on the reaction completion, concentrating the obtained product system under reduced pressure to remove a solvent, dissolving with a small amount of dichloromethane, dispersing in methyl tertiary butyl ether, separating out solids, drying to obtain 1.5g of white solid crude product, purifying by silica gel column chromatography (eluting agent used is dichloromethane, methanol and trifluoroacetic acid, the volume fraction of the trifluoroacetic acid in the eluting agent is 5 per mill, the volume ratio of the dichloromethane to the methanol is 15:1), and obtaining 200mg of pure product, namely the trifluoroacetate (recorded as compound) of the sinomenine amide derivative of the target compound SONP).1H NMR(600 MHz,MeOD)δ7.12(t,J=11.2 Hz,1H),7.03(d,J=8.6 Hz,1H),5.81(s,1H),4.07(s,1H),3.81–3.78(m,1H),3.77(s,3H),3.52(s,3H),3.42–3.34(m,4H),3.03–2.96(m,5H),2.81–2.66(m,4H),2.49–2.31(m,4H),2.24–2.15(m,2H),2.04–1.94(m,2H),1.86–1.66(m,3H),1.27(dd,J=12.5,5.7Hz,2H),0.96–0.93(m,6H).
In the embodiment, the chemical formula of the sinomenine amide derivative is C 31H45N3O6, and the molecular weight is 555.7160; the characterization method used by the english name (4bR,8aS,9S)-3,7-dimethoxy-11-methyl-6-oxo-6,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-4-yl4-((S)-3-(aminomethyl)-5-methylhexanamido)butanoate; is specifically shown in table 1.
Table 1 characterization method used in example 1
FIG. 1 is a 1 HNMR profile of compound SONP prepared in example 1; FIG. 2 is a MS mass spectrum of compound SONP; fig. 3 is a chromatogram of compound SONP, wherein HPLC conditions include: preparing an aqueous phase buffer solution: 0.01mol/L sodium dihydrogen phosphate, 1% triethylamine, pH=3 with phosphoric acid, mobile phase: acetonitrile: aqueous buffer = 20%: the specific information of the chromatographic peak (detector A265 nm) is shown in Table 2.
TABLE 2 specific information on chromatographic peaks in the chromatogram of Compound SONP prepared in example 1
Peak number | Retention time | Area of | Height of (1) | Area percent |
1 | 3.015 | 15318 | 2490 | 0.720 |
2 | 4.257 | 38773 | 3634 | 1.821 |
3 | 5.019 | 104370 | 10313 | 4.903 |
4 | 5.708 | 1965871 | 214062 | 92.342 |
5 | 9.068 | 4572 | 409 | 0.215 |
Totals to | / | 2128903 | 230908 | 100.000 |
The stability of the compound SONP prepared in this example was studied as follows:
FIG. 4 is a physical diagram of compound SONP prepared in example 1, as shown in FIG. 4, compound SONP is a pale yellow solid powder at room temperature; it was exposed to 50 ℃ until day 14 where it changed its behavior, forming a viscous mass.
The compound SONP prepared in example 1 was left at room temperature for four weeks, and then its purity was determined by MS mass spectrometry, and fig. 5 is a MS mass spectrum of the compound SONP prepared in example 1 after left at room temperature for four weeks, and specific data are shown in table 3. The results showed that compound SONP had a purity of 95.75% when left at room temperature, which was approximately the same as 92-96% of the original purity. It was demonstrated that compound SONP was relatively stable at room temperature.
Table 3 specific information corresponding to fig. 5
The compound SONP prepared in example 1 was dissolved in water to give SONP aqueous solution at a concentration of 5 mg/mL; the SONP aqueous solution was left at room temperature for four weeks, and then the purity was determined by MS mass spectrometry, and fig. 6 is a MS mass spectrum of the compound SONP prepared in example 1 after left as an aqueous solution at room temperature for four weeks, and specific data are shown in table 4. The results showed that SONP aqueous solutions had a purity of 95% when left at room temperature, which was approximately the same as the initial purities of 92-96%. Indicating that compound SONP is relatively stable in aqueous solution.
Table 4 specific information corresponding to fig. 6
Test example 1 SONP single administration analgesic Activity verification
The model and the behavioral method used in the test example are specifically as follows:
(1) Mechanical pain sensitivity test protocol
The mice were placed in a plastic cage with a metal mesh at the bottom, left hind paw soles of the mice were stimulated with increasing force using Von Frey fiber filaments conforming to the standard after standing for 1h until hind paw of the mice was retracted. The test was performed with 5 (or 10) pressure applications at a frequency of 1/s and the response threshold was reached with at least 3 (or 6) paw withdrawal of the mice.
(2) Cold pain sensitivity test protocol
The mice were tested for cold pain by dripping acetone onto the plantar surface of the hind paw. The mice were observed for immediate response to the application of acetone, the response time was recorded and the extent of the response was scored. The reaction time is the time corresponding to the reactions of lifting feet, rapid shaking, licking soles and the like after the stimulation of the acetone. The scoring criteria were: 0 = no reaction; 1 = startle response, no significant recoil of hind paws; 2 = stimulated hind paw retraction; 3 = stimulated hind paw continuous retraction, with tremor and licking of hind limb.
(3) Thermal pain sensitivity test protocol
Thermal pain was measured by placing a radiant heat source (Ugo basic, italy) on the plantar surface of the hind paw of the mouse. The machine will automatically record the hind paw withdrawal latency. The stimulus intensity was adjusted so that the baseline latency period of the normal animals was set at 2 to 6s, the deadline of the rats was set at 20s, and the deadline of the mice was set at 15s.
(4) Incision pain model
After the mice were anesthetized with chloral hydrate (5%), a 5mm longitudinal incision was made along the central axis at the left hind paw sole of the mice, 3mm near the heel, using a scalpel, the incision penetrating the skin, fascia and muscle. The bent forceps are taken to penetrate the muscles and tendons exposed from the lower part, and are pulled open by force (the integrity of the muscles and tendons is not destroyed). The torn muscle and skin were replaced and the wound was closed using suture No. 5. In surgery, mice were placed on a heating pad to maintain body temperature between 35-38 ℃. The periwound mechanical pain threshold is detected and compared with the preoperative mechanical pain threshold. The mechanical pain sensitivity and cold and hot pain sensitivity reaction of the incision side hind paws reach the peak value after the operation for about 24 hours, and the drug effect detection is carried out in the period of time.
(5) Peripheral neuralgia model
After anesthetizing the mice with chloral hydrate (5%), the skin of the left hind limb of the mice was cut with scissors and the biceps femoris was cut along the femur, exposing the sciatic nerve and its three terminal branches: sural nerve, common sural nerve and tibial nerve. The total fibular and tibial nerves were axonally severed using butterfly scissors and the lower residual nerves were removed 2mm, taking care not to contact or pull the distal fibular nerve. The torn muscle and skin were replaced and sutured using suture No. 5. In surgery, mice were placed on a heating pad to maintain body temperature between 35-38 ℃. After the operation, the hind paws on the same side of the mice can generate mechanical pain sensitivity and cold and hot pain sensitivity reaction within 10 days, and the drug effect detection can be carried out after the pain sensitivity reaction.
1. SONP therapeutic Effect of Single administration on mice with peripheral nerve injury
Test grouping:
Blank control model group: the "Saline" group; after successful molding, physiological saline is injected into the abdominal cavity, and mechanical pain, cold pain sensitivity and heat pain sensitivity thresholds are measured at 0min (baseline), 30min, 60min, 120min, 240min, 360min, 8h and 24 h; n=8 mice.
SONP intraperitoneal injection administration group: SONP 0.06, 0.06mmol/kg, SONP, 0.12mmol/kg, SONP, 0.24 mmol/kg; after successful molding, injecting 0.06-0.24 mmol/kg compound SONP into the abdominal cavity, and measuring mechanical pain, cold pain sensitivity and hot pain sensitivity threshold values in 0min (baseline), 30min, 60min, 120min, 240min, 360min, 8h and 24 h; n=8 mice.
SONP intragastric administration group: group "SONP 0.12.12 mmol/kg", "SONP 0.24.24 mmol/kg"; after successful molding, the compound SONP with the concentration of 0.12-0.24 mmol/kg is administrated by stomach irrigation, and the mechanical pain, cold pain sensitivity and heat pain sensitivity threshold values are measured at 0min (baseline), 30min, 60min, 120min, 240min, 360min, 8h and 24 h; n=8 mice.
Sinomenine+pregabalin (s+p) group: set "sinomenine+pregabalin 0.12 mmol/kg"; after successful molding, 0.12mmol/kg sinomenine and 0.12mmol/kg pregabalin are simultaneously injected and administrated intraperitoneally, and mechanical pain, cold pain sensitivity and thermal pain sensitivity thresholds are measured at 0min (baseline), 30min, 60min, 120min, 240min, 360min, 8h and 24 h; n=8 mice.
1. SONP Single administration therapeutic Effect of mechanical pain sensitivity in mice with peripheral nerve injury
Fig. 7 is a graph showing the effect of SONP single intraperitoneal injection on mechanical pain sensitivity in mice with peripheral neuralgia, and the result shows that after SONP single intraperitoneal injection, the "0.12mmol/kg" group and the "0.24mmol/kg" group have significant inhibition effect on mechanical pain sensitivity (P <0.05, P < 0.01) compared with the baseline within 30-360 min and 30-480 min respectively, and the generation of drug effect shows obvious dose dependency.
Fig. 8 is a graph showing the effect of SONP single gastric administration on mechanical nociception in peripheral neuralgia mice, and the result shows that, after SONP single gastric administration (i.e., corresponding to oral administration), the group "0.24mmol/kg" has a significant inhibitory effect on mechanical nociception in peripheral neuralgia mice within 2-6 hours compared with the baseline (< 0.05, < 0.01) and the generation of drug effect also shows a significant dose dependency.
Fig. 9 is a graph comparing area under the curve (AUC) of the analgesic effect of SONP single doses for 0-8 h on mechanical nociception, wherein statistics (n=8 animals) were obtained using the area under the curve method: after a single dose of SONP within 0-8 h, "SONP 0.12.12 mmol/kg celiac dose/i.p." group, "sonop 0.24mmol/kg celiac dose/i.p." group, "SONP 0.12.12 mmol/kg oral dose/p.o." group, "sonop 0.24mmol/kg oral dose/p.o." group, "s+p 0.12mmol/kg celiac dose/i.p." group has a significant inhibitory effect on mechanical pain sensitivity in peripheral neuralgia mice compared to "model control group" (Saline) (P <0.05, P < 0.01); the "SONP 0.12mmol/kg intraperitoneal administration/i.p." group, "SONP 0.24.24 mmol/kg intraperitoneal administration/p.o." group, "SONP0.24mmol/kg oral administration/p.o." group was not significantly different (P > 0.05) from the "s+p0.12 mmol/kg intraperitoneal administration/p.o." group, revealing that SONP and s+p (sinomenine+pregabalin) drug combination had similar efficacy.
2. SONP A single dose of treatment effect on Cold pain sensitivity of mice with peripheral nerve injury
Fig. 10 is a graph showing the effect of SONP single intraperitoneal injection on cold pain (score) of mice with peripheral nerve injury, and the result shows that, compared with a baseline, the "0.12mmol/kg" group and the "0.24mmol/kg" group have significant inhibitory effects on cold pain (score) within 180-360 min and 180-480 min respectively after SONP single intraperitoneal injection administration (P <0.05, P < 0.01), and the generation of drug effect shows significant dose dependency.
Fig. 11 is a graph showing the effect of SONP single gastric lavage administration (i.e., equivalent to oral administration) on cold pain sensitivity (score) in mice with peripheral nerve injury, and shows that, compared with the baseline, the group "0.24mmol/kg" after SONP single gastric lavage administration has a significant inhibitory effect on cold pain sensitivity (score) in mice with peripheral nerve pain (P < 0.01) within 1-24 hours, and the generation of drug effect also shows a significant dose dependency.
Fig. 12 is a graph comparing area under the curve for the analgesic effect of SONP single doses for 0-8 h on cold pain sensitivity (score), wherein statistics (n=8 animals) were obtained using the area under the curve method: after a single dose of SONP over 0-8 hours, the "SONP 0.12.12 mmol/kg celiac dose/i.p." group, "sonop 0.24mmol/kg celiac dose/i.p." group, "SONP 0.24.24 mmol/kg oral dose/p.o." group, "s+p0.12mmol/kg celiac dose/i.p." group had a significant inhibitory effect on cold pain (score) in peripheral neuralgia mice compared to "model control group" (Saline) (P <0.05, P < 0.01); the "sonop 0.12mmol/kg intraperitoneal administration/i.p." group, "SONP 0.24.24 mmol/kg intraperitoneal administration/i.p." group, "sonop 0.24mmol/kg oral administration/p.o." group was not significantly different (P > 0.05) from the "s+p0.12mmol/kg intraperitoneal administration/i.p." group, and it was also revealed that SONP had similar efficacy when combined with the s+p (sinomenine+pregabalin) drug.
3. SONP single administration of the therapeutic effect on thermal pain sensitivity of mice with peripheral nerve injury
Fig. 13 is a graph showing the effect of SONP single intraperitoneal administration on the thermal pain of the peripheral neuralgia mice, and shows that, although the generation of the drug effect of SONP shows obvious dose dependency after SONP single intraperitoneal administration, each group has no obvious inhibition effect (P > 0.05) on thermal pain sensitivity (response time), which is related to the fact that the thermal pain sensitivity degree is not prominent relative to cold pain sensitivity after the molding of the peripheral neuralgia model.
Fig. 14 is a graph showing the effect of SONP single administration of intragastric administration on thermal pain in peripheral neuralgia mice, and shows that, after SONP single administration of intragastric administration, although the onset of drug effect of SONP exhibited a remarkable dose-dependence, each group had no remarkable inhibitory effect (P > 0.05) on thermal pain (response time), and as such, this was not remarkable in relation to the degree of thermal pain sensitivity after modeling of the peripheral neuralgia model.
Fig. 15 is a graph comparing area under the curve for the analgesic effect of SONP single doses of 0-8 h on thermal pain sensitivity (response time), wherein statistics (n=8 animals) were obtained using the area under the curve: after a single dose of SONP within 0-8 h, only "SONP 0.24.24 mmol/kg intraperitoneal dose/i.p." group has a significant inhibitory effect on cold pain (response time) in peripheral neuralgia mice compared to "model control group" (Saline) (P < 0.05); the "SONP 0.12mmol/kg celiac administration/i.p." group, "SONP 0.24mmol/kg celiac administration/i.p." group, "SONP 0.24mmol/kg oral administration/p.o." group was not significantly different (P > 0.05) from the "s+p 0.12mmol/kg celiac administration/i.p." group.
2. SONP therapeutic Effect of Single administration on incision pain mice
Test grouping:
SONP intraperitoneal injection administration group: group "SONP 0.03.03 mmol/kg", "SONP 0.06.06 mmol/kg"; after the molding is successful, injecting 0.03-0.06 mmol/kg compound SONP into the abdominal cavity, and measuring mechanical pain sensitivity, cold pain sensitivity and thermal pain sensitivity thresholds at 0min (baseline), 30min, 60min, 120min, 240min, 360min, 8h and 24 h; n=8 mice.
SONP intragastric administration group: "SONP 0.12.12 mmol/kg"; after successful molding, the compound SONP was administered at 0.12mmol/kg by lavage, and the mechanical pain, cold pain, and thermal pain thresholds were measured at 0min (baseline), 30min, 60min, 120min, 240min, 360min, 8h, 24 h; n=8 mice.
1. SONP therapeutic Effect of Single administration on mechanical pain sensitivity in incision pain mice
Fig. 16 is a graph showing the effect of single dose SONP on mechanical pain sensitivity of incision pain mice, and the result shows that, after single dose SONP, the group of "0.06mmol/kg intraperitoneal injection" has a significant inhibitory effect on mechanical pain sensitivity (P <0.05, P < 0.01) within 30-120 min compared with a baseline, and the generation of drug effect shows a significant dose dependency.
2. SONP Single dose therapeutic Effect on Cold pain in incision pain mice
Fig. 17 is a graph showing the effect of single dose SONP on cold pain (score) in incision pain mice, and shows that, after single dose SONP, "0.06mmol/kg intraperitoneal injection" group has significant inhibitory effect on cold pain (score) at 180min time point compared with baseline (P < 0.01), and the generation of drug effect shows obvious dose dependency.
3. SONP Single dose therapeutic Effect on incision pain mice Thermodynia
Fig. 18 is a graph of the effect of a single administration of SONP on thermal pain (response time) in incision pain mice, showing that the "0.12mmol/kg oral administration" group had significant inhibitory effect on thermal pain (response time) in incision pain mice at the 360min time point compared to baseline after SONP single administration (< 0.05).
Test example 2SONP therapeutic effects of repeated injections in a peripheral neuralgia mouse model, the present test example was continuously injected for SONP to 5 days (each administration time was 10:00 AM), and a series of pain indexes (mechanical pain sensitivity, cold pain sensitivity and thermal pain sensitivity) were measured before administration (BL) and at the time of administration for 4 hours, and after completion of continuous administration for 0 to 5 days, basic threshold (BL) was measured for 5 to 10 days to observe the continuous effect of the drug effect.
FIG. 19 is a graph of drug effect versus mechanical pain response of SONP repeated doses in a peripheral neuralgia model, showing that SONP significantly increases the response threshold to mechanical stimulation in mice 4h after 0-5 days of dosing in the "0.12mmol/kg intraperitoneal injection" repeated dose mode (significant differences between days 0, 1,3 and BL baseline values, <0.01 for P, < 2-5 days since baseline values have increased, insignificant differences compared to baseline values, P > 0.05); BL baseline values increased significantly (#P <0.05, #P < 0.01) 3 days after dosing until they returned to normal on day 7 after 1 day of dosing had ceased, suggesting SONP effects accumulated after repeated dosing.
FIG. 20 is a graph of the results of drug efficacy-cold pain (score) of SONP repeated doses in a peripheral neuralgia model, showing that SONP significantly decreased cold stimulation scores in mice 4h after 0-5 days of dosing in the "0.12mmol/kg intraperitoneal injection" repeated dose mode (significant differences between days 0-1 and BL baseline values, P <0.01; 2-5 days were not significant compared to baseline values due to decreased baseline values, P > 0.05); BL baseline values decreased significantly (#P <0.05, #P < 0.01) after 2 days of dosing until after cessation of dosing, and were restored to normal on day 10, suggesting SONP effects accumulated after repeated dosing.
FIG. 21 is a graph of the results of drug efficacy versus thermal pain (duration of response) for SONP repeated doses in a peripheral neuralgia model, showing that SONP significantly increases the thermal stimulation response time (significantly different between days 0-2 and BL baseline values, P <0.01; significantly less than the baseline value compared to P >0.05 for days 2-5) in the "0.12mmol/kg intraperitoneal injection" repeated dose mode for mice 4h after 0-5 days of dosing; BL baseline values increased significantly (#P <0.05, #P < 0.01) 2 days after dosing until normal was restored on day 7 after dosing stopped for 1 day, suggesting SONP effects accumulated after repeated dosing.
Test example 3 analysis of the metabolic situation of Compound SONP in the blood/Central Nervous System (CNS)
The experiment uses microdialysis sampling-mass spectrometry detection technology to analyze the metabolic condition of compound SONP in blood/CNS. Specifically, the experiment uses the microdialysis technology, and the characteristic that small molecular drugs can freely pass through a semipermeable membrane is utilized, so that the concentration of the free drugs can be sampled and analyzed at specific parts (such as brain, blood and skin). The microdialysis technique has the following advantages: 1) Long-time sampling without causing a decrease in blood volume; 2) Effects of the Blood Brain Barrier (BBB) on drug metabolism; 3) At the same time, the absorption, distribution and excretion of the medicine are examined; 4) The sample is clean and can be directly injected (mass spectrum detection). In the process of implanting the microdialysis probe, the brain striatum area is selected as a target area for analyzing the extracellular fluid level of the central nervous system target drug in the experiment, and the main reason is that the area is easier to locate and is widely used for drug metabolism analysis of the nervous system; the rat can wake up and move freely during microdialysis sampling, so that the rat can truly realize homozygosity and synchronization; therefore, the required animal amount is smaller and the reliability is higher.
1. The drug concentration of compound SONP in blood varies with time
Fig. 22 is a graph showing the change in the drug concentration of compound SONP in blood after administration, and shows that compound SONP does not decompose immediately into sinomenine and other metabolites, but is stable in blood for more than 6 hours after intravenous (i.v.) or intragastric (p.o.) administration (n=1 to 3 normal rats). The half-life (t 1/2) of compound SONP under intravenous conditions is expected to be 30-140 min; the half-life (t 1/2) of compound SONP under intragastric administration conditions is expected to be 120-300 min. After 300min of intravenous injection, no small rise in SONP blood concentration was observed.
2. Drug concentration of compound SONP in brain extracellular fluid over time
Fig. 23 is a graph showing the change in drug concentration of compound SONP in brain extracellular fluid after administration, and shows that compound SONP was stable in brain extracellular fluid for more than 6 hours after intravenous (i.v.) or intragastric (p.o.) administration (n=1-3 normal rats), again without immediate decomposition to sinomenine and other metabolites. The half-life (t 1/2) of compound SONP under intravenous conditions is expected to be 30-120 min; the half-life (t 1/2) of compound SONP under intragastric administration conditions is expected to be 120-360 min.
3. Bioavailability analysis of compound SONP
Fig. 24 is a graph showing changes in blood concentration of SONP following intravenous or intragastric administration (20 mg/kg), and fig. 25 is an analytical graph showing bioavailability of compound SONP, where the ratio of the area under the blood concentration curve of compound SONP following intragastric administration (p.o.) to the area under the blood concentration curve of compound SONP following intravenous injection (i.v.) predicts the possible bioavailability of compound SONP. According to the present experimental analysis, compound SONP may have a bioavailability of less than 20%.
4. Comparison of blood brain concentration after administration of Compound SONP
Fig. 26 is a graph of blood-brain concentration comparison analysis of compound SONP after administration, showing the trend of blood and brain concentration change after intravenous (i.v.) or intragastric (p.o.) administration of compound SONP. Because of the existence of the aforementioned limiting factors in the study of compound SONP across the blood-brain barrier, it is not precisely given how much proportion of compound SONP can enter the center across the blood-brain barrier after administration, but may provide inaccurate preliminary predictions: this proportion is approximately 2 to 14%.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. A sinomenine amide derivative or a trifluoroacetate thereof, wherein the sinomenine amide derivative has a structure shown in a formula I:
2. The preparation method of sinomenine amide derivatives according to claim 1, comprising the following steps:
Mixing a compound 6, a compound 7, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine and triethylamine with an organic solvent for condensation reaction to obtain a compound 8;
Mixing the compound 8, trifluoroacetic acid and an organic solvent to perform deamination protecting group reaction, so as to obtain the trifluoroacetate of sinomenine amide derivatives with the structure shown in the formula I;
the structural formulas of the compound 6, the compound 7 and the compound 8 are shown in the formulas 6-8 in sequence:
3. The preparation method according to claim 2, wherein the mass ratio of the compound 6 to the compound 7 is (1.9 to 3.8): 2.
4. A method according to claim 2 or 3, wherein the condensation reaction is carried out at room temperature for 24 to 72 hours.
5. The preparation method according to claim 2, wherein the mass ratio of the compound 8 to trifluoroacetic acid is 1.9: (1.42-5.68).
6. The method according to claim 2 or 5, wherein the deamination protecting group is reacted at room temperature for 8 to 24 hours.
7. The use of sinomenine amide derivatives and/or pharmaceutically acceptable salts thereof according to claim 1 in the preparation of analgesic drugs.
8. The use according to claim 7, wherein the pain medication is adapted for pain including acute pain, peri-operative pain or chronic pain.
9. The use according to claim 8, wherein the chronic pain comprises at least one of rheumatoid arthritis pain, diabetic peripheral nerve injury pain, aids peripheral nerve injury pain, or chronic pain caused by tissue injury, facial nerve injury, ischemic injury, perioperative pain, cancer pain, spinal cord injury, or stroke.
10. An analgesic comprising the sinomenine amide derivative and/or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
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