WO2023109599A1 - Medical material for releasing amino acid and derivative drug thereof, and use method therefor - Google Patents

Medical material for releasing amino acid and derivative drug thereof, and use method therefor Download PDF

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WO2023109599A1
WO2023109599A1 PCT/CN2022/137082 CN2022137082W WO2023109599A1 WO 2023109599 A1 WO2023109599 A1 WO 2023109599A1 CN 2022137082 W CN2022137082 W CN 2022137082W WO 2023109599 A1 WO2023109599 A1 WO 2023109599A1
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drug
carboxylic acid
anhydride monomer
reaction
lysine
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PCT/CN2022/137082
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French (fr)
Chinese (zh)
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郎姝瑶
陈有海
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深圳先进技术研究院
中国科学院深圳理工大学(筹)
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Publication of WO2023109599A1 publication Critical patent/WO2023109599A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • 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

Definitions

  • the invention belongs to the technical field of medical materials, and in particular relates to a medical material for releasing amino acid and its derivative drugs and an application method thereof.
  • Amino acids and their derivatives are widely used in clinical practice.
  • 1-methyl-D/L-tryptophan as an indoleamine 2,3-dioxygenase (IDO) inhibitor has been used in clinical research on cancer immunotherapy;
  • Amino acid is used to treat acute leukemia;
  • arginine hydrochloride can be used to reduce blood ammonia and assist in the treatment of acute liver dysfunction;
  • calcium salt of glutamate, ⁇ -tyrosine, and 5-hydroxytryptamine are used Treatment;
  • iodoalanine is used in tumor radiotherapy and so on.
  • Amino acid molecules are also often used as nutritional supplements.
  • Amino acid and its derivative drugs are usually administered orally or intravenously. Since these drugs can participate in human metabolism and are cleared quickly in the body, they are usually given in large doses and frequently. For example, in a phase II clinical study (NCT01042535) of 1-methyl-D/L-tryptophan in the treatment of recurrent breast cancer, patients took orally administered drugs ranging from 100 mg to 1600 mg twice a day.
  • the technical problem to be solved by the present invention is to provide a medical material for releasing amino acid and its derivative drugs and its application method, so as to reduce the frequency of administration of amino acid drugs in clinical practice and maintain long-term blood drug concentration balance.
  • a medical material used to release drugs comprising bistrichloromethyl carbonate dissolved in tetrahydrofuran.
  • the drug refers to amino acid and its derivative drugs.
  • amino acid and its derivative drugs refer to amino acid drugs.
  • amino acid and its derivative drugs include 1-methyl-D/L-tryptophan.
  • a kind of application method of above-mentioned medical material comprises the following steps:
  • step S11 put lysine into the medical material, and obtain the N-carboxylic acid ring acid anhydride monomer of lysine after the reaction; in the step S2, the N-carboxylic acid ring acid anhydride monomer of lysine After the monomer is mixed with the acid anhydride monomer in the N-carboxylic acid ring of the drug, it is polymerized to obtain the polymer material containing the drug.
  • the mass ratio of the acid anhydride monomer in the N-carboxylic acid ring of the lysine to the acid anhydride monomer in the N-carboxylic acid ring of the drug is 1:1-1:9.
  • the lysine in the step S11 first uses a tert-butoxycarbonyl protecting group to protect the free amino group of the lysine, and then deprotects after the polymerization to obtain the N of the lysine.
  • the S1 is specifically adding the toluene-pretreated drug and tetrahydrofuran into a dry reaction bottle, stirring and heating to 45-55°C under an oil bath, and slowly dripping it into the medical bottle after the temperature of the reaction solution is stable.
  • stop the reaction after the reaction solution completely turns into a clear slightly yellow solution concentrate the reaction solution by rotary evaporation, pour the reaction solution into n-hexane to precipitate, and then vacuum filter to obtain the N-carboxylic acid ring of the drug.
  • the S2 specifically weighs the N-carboxylic acid ring internal acid anhydride monomer of the drug under a dry protective atmosphere, adds it to tetrahydrofuran to fully dissolve it, and then adds benzylamine and potassium carbonate powder, The reaction solution is obtained, and the reaction solution is placed in an oil bath at 35-45° C. to react. After the reaction is completed, the solution is concentrated, centrifuged, and dried to obtain the drug-containing polymer material.
  • the amino acid and derivative drugs are prepared into the N-carboxylic acid ring acid anhydride monomer of the drug, and the polymer material containing the amino acid drug unit is obtained by polymerization.
  • the material can slowly degrade and release the drug monomer in the body to achieve one-time drug administration. effects of long-term drug treatment.
  • Figure 1 is the H NMR spectrum (1H 500MHz, DMSO-d6) of the N-carboxylic acid anhydride monomer in the 1-methyl-D/L-tryptophan of the present invention
  • Fig. 3 is the N-carboxylic acid anhydride monomer proton nuclear spectrum (1H) of the lysine protected by the tert-butoxycarbonyl protecting group of the present invention 500MHz, DMSO-d6);
  • Fig. 4 is a polymer material (1H 500MHz, D 2 O) in which the content of the anhydride monomer in the N-carboxylic acid ring of the drug in Example 2 of the present invention is 10%;
  • Fig. 6 is a schematic diagram of the IDO inhibitory effect in Hela cells of the present invention.
  • the amino acid and derivative drugs are prepared into the N-carboxylic acid ring acid anhydride monomer of the drug, and the polymer material containing the amino acid drug unit is obtained by polymerization.
  • the material can slowly degrade and release the drug monomer in the body to achieve one-time drug administration. effects of long-term drug treatment.
  • NCA N-carboxylic acid anhydride monomer
  • reaction solution After the reaction solution has completely turned into a clear and slightly yellow solution (usually about 3 hours), continue the reaction for another 30 minutes to complete the reaction and discharge excess carbonyl chloride, hydrogen chloride and other by-products. After stopping the reaction, the reaction solution was concentrated by rotary evaporation to about 10 mL, then poured into 100 mL of n-hexane for precipitation, and then vacuum filtered to obtain a solid white crude product. The crude product was recrystallized twice in tetrahydrofuran/n-hexane reaction solution, and dried under vacuum at room temperature for 24 h. As shown in Figure 1, the N-carboxylic acid anhydride monomer (denoted as 1- MT NCA monomer) 1.44 g, yield 45%.
  • the N-carboxylic acid anhydride monomer (0.5 g) of the drug prepared in step S1 was weighed, placed in a reaction bottle, and 5 ml of tetrahydrofuran was added to fully dissolve it.
  • the polymer material can be slowly degraded in the body to release the drug monomer (1-methyl-D/L-tryptophan), so as to achieve the effect of long-term treatment with one administration.
  • reaction solution After the reaction solution has completely turned into a clear and slightly yellow solution (usually about 3 hours), continue the reaction for another 30 minutes to complete the reaction and discharge excess carbonyl chloride, hydrogen chloride and other by-products. After stopping the reaction, the reaction solution was concentrated by rotary evaporation to about 10 mL, then poured into 100 mL of n-hexane for precipitation, and then vacuum filtered to obtain a solid white crude product. The crude product was recrystallized twice in tetrahydrofuran/n-hexane reaction solution, and dried under vacuum at room temperature for 24 h to obtain 1.44 g of the N-carboxylic acid anhydride monomer (1-MT NCA monomer) of the drug with a white appearance. Yield 50%.
  • the preparation of the acid anhydride monomer in the N-carboxylic acid ring of lysine is similar to the preparation of the acid anhydride monomer in the N-carboxylic acid ring of the drug.
  • the difference is that lysine has a free amino group, which needs to be protected first with a tert-butoxycarbonyl protecting group, and then deprotected after polymerization to obtain the final product.
  • lysine (10 g, 33.56 mmol) protected by a tert-butoxycarbonyl protecting group and 100 mL of tetrahydrofuran were added into a reaction flask, stirred and heated to 45 °C under an oil bath, and after the temperature of the reaction solution was stabilized, a constant Slowly drip the medical material for drug release (4.6 g, 15.4 mmol bistrichloromethyl carbonate, dissolved in 20 ml tetrahydrofuran) into the pressure drop funnel.
  • the reaction solution is concentrated by rotary evaporation to about 20 mL.
  • the concentrated reaction solution was poured into 200ml of n-hexane for precipitation.
  • reaction solution After the reaction solution has completely turned into a clear and slightly yellow solution (usually about 3 hours), continue the reaction for another 30 minutes to complete the reaction and discharge excess carbonyl chloride, hydrogen chloride and other by-products. After stopping the reaction, the reaction solution was concentrated by rotary evaporation to about 10 mL, then poured into 100 mL of n-hexane for precipitation, and then vacuum filtered to obtain a solid white crude product. The crude product was recrystallized twice in tetrahydrofuran/n-hexane reaction solution, and dried in vacuum at room temperature for 24 h to obtain 1.44 g of an N-carboxylic acid anhydride monomer in a white drug ring with a yield of 50%.
  • the preparation of the acid anhydride monomer in the N-carboxylic acid ring of lysine is similar to the preparation of the acid anhydride monomer in the N-carboxylic acid ring of the drug.
  • the difference is that lysine has a free amino group, which needs to be protected first with a tert-butoxycarbonyl protecting group, and then deprotected after polymerization to obtain the final product.
  • benzyl formate-protected lysine (10 g, 33.56 mmol) and 100 mL of tetrahydrofuran were added into the reaction flask, stirred and heated to 45 °C under an oil bath, and after the temperature of the reaction solution was stabilized, the reaction solution was passed through a constant pressure dropping funnel. Slowly drop the medical material for drug release (4.6 g, 15.4 mmol of bistrichloromethyl carbonate, dissolved in 20 ml of tetrahydrofuran). The reaction solution was poured into 200ml of n-hexane for precipitation.
  • the present invention has obtained the acid anhydride monomer in the N-carboxylic acid ring containing different proportions of medicine (the content of the acid anhydride monomer in the N-carboxylic acid ring of the medicine is 100%, and the content of the acid anhydride monomer in the N-carboxylic acid ring of the medicine is 10% , the content of acid anhydride monomers in the N-carboxylic acid ring of the drug is 50%, corresponding to the polymer materials in Example 1, Example 2, and Example 3).
  • Hela cells were resuspended in complete DMEM medium at a density of 2.5x10 ⁇ 5 cells/ml, seeded in a 96-well plate, and inoculated 200 microliters per well (5x10 ⁇ 4 cells/well), at 37°C, 5% Cultivate overnight under CO 2 concentration to allow it to grow adherently. After removing the supernatant, add 200 ⁇ l of different concentrations of human interferon (IFN- ⁇ ), 1-methyl-D/L-tryptophan or equivalent 1-methyl-D/L-tryptophan to each well The fresh complete DMEM medium of the polymer material in Example 1, Example 2 and Example 3 of the tryptophan concentration.
  • IFN- ⁇ human interferon
  • Complete DMEM medium refers to DMEM medium containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin solution (PS).
  • FBS fetal bovine serum
  • PS penicillin-streptomycin solution
  • IFN- ⁇ human interferon
  • Negative control wells only add complete DMEM medium.
  • Positive control wells add complete DMEM medium containing 10ng/ml human interferon (IFN- ⁇ ).
  • 1-MT group (five concentrations, 3 wells for each concentration): add 10ng/ml human interferon (IFN- ⁇ ), and 200 ⁇ g/ml, 100 ⁇ g/ml, 20 ⁇ g/ml, 2 ⁇ g/ml, 0.2 1-MT complete DMEM medium at ⁇ g/ml.
  • IFN- ⁇ human interferon
  • P-MT 100% group (five concentrations, 3 wells for each concentration): add human interferon (IFN- ⁇ ) containing 10ng/ml, and concentrations of 200 ⁇ g/ml, 100 ⁇ g/ml, 20 ⁇ g/ml, 2 ⁇ g /ml, 0.2 ⁇ g/ml P-MT-Lys 10% polymer material (Example 1) complete DMEM medium;
  • IFN- ⁇ human interferon
  • P-MT-Lys 10% group (five concentrations, 3 wells for each concentration): add 10ng/ml human interferon (IFN- ⁇ ) and 2000 ⁇ g/ml, 1000 ⁇ g/ml, 200 ⁇ g/ml, 20 ⁇ g/ml ml, 2 ⁇ g/ml P-MT-Lys 10% polymer material (Example 2) complete DMEM medium;
  • P-MT-Lys 50% group (five concentrations, 3 wells for each concentration): add 10ng/ml human interferon (IFN- ⁇ ) and 400 ⁇ g/ml, 200 ⁇ g/ml, 40 ⁇ g/ml, 4 ⁇ g/ml ml, 0.4 ⁇ g/ml P-MT-Lys 50% polymer material (Example 3) complete DMEM medium.
  • IFN- ⁇ human interferon
  • P-MT-Lys 50% polymer material (Example 3) complete DMEM medium.
  • Example 1 the polymer materials obtained in Example 1 (P-MT 100%), Example 2 (P-MT-Lys 10%), and Example 3 (P-MT-Lys 50%) are the same as free 1-formazan Similar to the base-D/L-tryptophan small molecule (1-MT), it can inhibit the function of IDO.
  • the inhibitory effects of polymer materials containing anhydride monomers in N-carboxylic acid rings in different proportions of drugs are significantly different.
  • the IDO1 enzyme inhibitory effect of the polymer materials obtained in Example 3 is comparable to that of free 1-methyl-D/L - Tryptophan small molecule is basically the same.
  • a polymer material with a high ratio of acid anhydride monomers in the N-carboxylic acid ring of the drug (such as a polymer material in which the content of an acid anhydride monomer in the N-carboxylic acid ring of the drug in Example 1 is 100%) has an inhibitory effect lower than that of the N-carboxylic acid ring of the drug.
  • the macromolecular material with low acid anhydride monomer ratio in the carboxylic acid ring (such as the N-carboxylic acid anhydride monomer content of the medicine in the embodiment 3 is the polymer material of 50% and the N-carboxylic acid of the medicine in the embodiment 2
  • the difference in the inhibitory effect can be explained by the different degradation speed of the polymer material.
  • the experimental results can show that the polymerized amino acid and derivative drugs can retain their original functions, and the copolymerization of different proportions of lysine can regulate the function of polymer materials.
  • the medical material for releasing amino acid and its derivative drugs of the present invention can control the release speed of the drug, and can be prepared as a subcutaneous embedding medicament, so as to avoid the inconvenience caused by frequent administration and avoid the failure of patients due to poor compliance. resulting in missed doses.

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Abstract

Disclosed are a medical material for releasing an amino acid and a derivative drug thereof and a use method thereof. The medical material for releasing the drug comprises bis(trichloromethyl)carbonate dissolved in tetrahydrofuran. The use method of the medical material comprises the following steps: S1, putting a drug into the medical material for a reaction to obtain an N-carboxylic acid intracyclic anhydride monomer of the drug; and S2, polymerizing the N-carboxylic acid intracyclic anhydride monomer of the drug to obtain a polymer material containing the drug. According to the present invention, the amino acid and the derivative drug are prepared into the N-carboxylic acid intracyclic anhydride monomer of the drug, a polymer material containing the amino acid drug unit is obtained by means of polymerization, and the material can slowly degrade and release the drug monomer in vivo to achieve the effect of one-time drug administration for long-term treatment.

Description

释放氨基酸及其衍生物类药物的医用材料及其应用方法Medical material releasing amino acid and its derivative drug and its application method 技术领域technical field
本发明属于医用材料技术领域，具体涉及一种释放氨基酸及其衍生物类药物的医用材料及其应用方法。The invention belongs to the technical field of medical materials, and in particular relates to a medical material for releasing amino acid and its derivative drugs and an application method thereof.
背景技术Background technique
氨基酸及其衍生物类药物在临床中被广泛应用。例如，1-甲基-D/L-色氨酸作为吲哚胺2,3-双加氧酶（IDO）抑制剂被应用于癌症免疫治疗临床研究；偶氮丝氨酸、重氮氧代正亮氨酸被用于治疗急性白血病；精氨酸盐酸盐可用于降低血氨、辅助治疗急性肝功能障碍；谷氨酸钙盐、γ-酪氨酸、5-羟色胺被用于神经系统疾病的治疗；碘丙氨酸被用于肿瘤放疗等。氨基酸类分子也常作为营养补充剂使用。Amino acids and their derivatives are widely used in clinical practice. For example, 1-methyl-D/L-tryptophan as an indoleamine 2,3-dioxygenase (IDO) inhibitor has been used in clinical research on cancer immunotherapy; Amino acid is used to treat acute leukemia; arginine hydrochloride can be used to reduce blood ammonia and assist in the treatment of acute liver dysfunction; calcium salt of glutamate, γ-tyrosine, and 5-hydroxytryptamine are used Treatment; iodoalanine is used in tumor radiotherapy and so on. Amino acid molecules are also often used as nutritional supplements.
氨基酸及其衍生物类药物目前通常经口服或静脉注射给药，由于这类药物可参与人体代谢，在体内清除较快，通常给药剂量较大且给药频次较为频繁。例如，在一个1-甲基-D/L-色氨酸治疗复发乳腺癌的二期临床研究（NCT01042535）中，病人每日需口服两次100mg至1600mg不等的药物。Amino acid and its derivative drugs are usually administered orally or intravenously. Since these drugs can participate in human metabolism and are cleared quickly in the body, they are usually given in large doses and frequently. For example, in a phase II clinical study (NCT01042535) of 1-methyl-D/L-tryptophan in the treatment of recurrent breast cancer, patients took orally administered drugs ranging from 100 mg to 1600 mg twice a day.
技术问题technical problem
本发明要解决的技术问题是提供一种释放氨基酸及其衍生物类药物的医用材料及其应用方法，以减少临床中氨基酸类药物的给药次数、维持长期血药浓度平衡。The technical problem to be solved by the present invention is to provide a medical material for releasing amino acid and its derivative drugs and its application method, so as to reduce the frequency of administration of amino acid drugs in clinical practice and maintain long-term blood drug concentration balance.
技术解决方案technical solution
为解决上述技术问题，本发明提供的技术方案为：In order to solve the problems of the technologies described above, the technical solution provided by the invention is:
一种用于释放药物的医用材料，包括溶解于四氢呋喃的碳酸双三氯甲酯。A medical material used to release drugs comprising bistrichloromethyl carbonate dissolved in tetrahydrofuran.
进一步地，所述药物是指氨基酸及其衍生物类药物。Further, the drug refers to amino acid and its derivative drugs.
进一步地，所述氨基酸及其衍生物类药物是指氨基酸类药物。Further, the amino acid and its derivative drugs refer to amino acid drugs.
进一步地，所述氨基酸及其衍生物类药物包括1-甲基-D/L-色氨酸。Further, the amino acid and its derivative drugs include 1-methyl-D/L-tryptophan.
一种上述的医用材料的应用方法，包括以下步骤：A kind of application method of above-mentioned medical material, comprises the following steps:
     S1、将所述药物投入到所述医用材料中，反应后得到药物的N-羧酸环内酸酐单体；S1. Put the drug into the medical material, and obtain the N-carboxylic acid ring acid anhydride monomer of the drug after reaction;
     S2、将所述药物的N-羧酸环内酸酐单体聚合，得到含有药物的高分子材料。S2. Polymerize the anhydride monomer in the N-carboxylic acid ring of the drug to obtain a polymer material containing the drug.
进一步地，还包括以下步骤：Further, the following steps are also included:
S11、将赖氨酸投入到所述医用材料中，反应后得到赖氨酸的N-羧酸环内酸酐单体；所述步骤S2中将所述赖氨酸的N-羧酸环内酸酐单体与所述药物的N-羧酸环内酸酐单体混合后聚合，得到含有药物的高分子材料。S11, put lysine into the medical material, and obtain the N-carboxylic acid ring acid anhydride monomer of lysine after the reaction; in the step S2, the N-carboxylic acid ring acid anhydride monomer of lysine After the monomer is mixed with the acid anhydride monomer in the N-carboxylic acid ring of the drug, it is polymerized to obtain the polymer material containing the drug.
进一步地，所述赖氨酸的N-羧酸环内酸酐单体与所述药物的N-羧酸环内酸酐单体的质量比为1：1~1：9。Further, the mass ratio of the acid anhydride monomer in the N-carboxylic acid ring of the lysine to the acid anhydride monomer in the N-carboxylic acid ring of the drug is 1:1-1:9.
进一步地，所述步骤S11中所述赖氨酸先使用叔丁氧羰基保护基团对所述赖氨酸的游离的氨基进行保护，聚合结束后再脱保护得到所述的赖氨酸的N-羧酸环内酸酐单体。Further, the lysine in the step S11 first uses a tert-butoxycarbonyl protecting group to protect the free amino group of the lysine, and then deprotects after the polymerization to obtain the N of the lysine. - Acid anhydride monomer within the carboxylic acid ring.
进一步地，还包括以下步骤：Further, the following steps are also included:
S11、将赖氨酸和/或精氨酸分别投入到所述医用材料中，反应后得到赖氨酸的N-羧酸环内酸酐单体和精氨酸的N-羧酸环内酸酐单体；所述步骤S2中将所述赖氨酸的N-羧酸环内酸酐单体、精氨酸的N-羧酸环内酸酐单体与所述药物的N-羧酸环内酸酐单体混合后聚合，得到含有药物的高分子材料。S11. Put lysine and/or arginine into the medical materials respectively, and obtain the N-carboxylic acid anhydride monomer of lysine and the N-carboxylic acid anhydride monomer of arginine after reaction. body; in the step S2, the acid anhydride monomer in the N-carboxylic acid ring of the lysine, the acid anhydride monomer in the N-carboxylic acid ring of arginine and the acid anhydride monomer in the N-carboxylic acid ring of the drug The polymers are polymerized after being mixed to obtain a drug-containing polymer material.
进一步地，所述S1具体为在干燥反应瓶中加入甲苯预处理过的所述药物和四氢呋喃，油浴下搅拌加热到45-55℃，待反应溶液温度稳定后，缓慢滴入到所述医用材料中，在反应液完全变为澄清略黄溶液后停止反应，旋蒸浓缩反应液，将所述反应液倒入到正己烷中沉淀，然后真空抽滤得到所述药物的N-羧酸环内酸酐单体；所述S2具体为在干燥的保护气氛下称取所述药物的N-羧酸环内酸酐单体，加入到四氢呋喃使之充分溶解，再加入苯甲胺和碳酸钾粉末，得到反应溶液，将反应溶液置于35-45℃油浴中反应，反应结束后，将溶液浓缩、离心、干燥，得到所述含有药物的高分子材料。Further, the S1 is specifically adding the toluene-pretreated drug and tetrahydrofuran into a dry reaction bottle, stirring and heating to 45-55°C under an oil bath, and slowly dripping it into the medical bottle after the temperature of the reaction solution is stable. In the material, stop the reaction after the reaction solution completely turns into a clear slightly yellow solution, concentrate the reaction solution by rotary evaporation, pour the reaction solution into n-hexane to precipitate, and then vacuum filter to obtain the N-carboxylic acid ring of the drug. Internal acid anhydride monomer; the S2 specifically weighs the N-carboxylic acid ring internal acid anhydride monomer of the drug under a dry protective atmosphere, adds it to tetrahydrofuran to fully dissolve it, and then adds benzylamine and potassium carbonate powder, The reaction solution is obtained, and the reaction solution is placed in an oil bath at 35-45° C. to react. After the reaction is completed, the solution is concentrated, centrifuged, and dried to obtain the drug-containing polymer material.
有益效果Beneficial effect
本发明的有益效果：Beneficial effects of the present invention:
本发明将氨基酸及衍生物类药物制备成药物的N-羧酸环内酸酐单体，聚合得到含有氨基酸药物单元的高分子材料，该材料可在体内缓慢降解释放药物单体，以达到一次给药长期治疗的效果。In the present invention, the amino acid and derivative drugs are prepared into the N-carboxylic acid ring acid anhydride monomer of the drug, and the polymer material containing the amino acid drug unit is obtained by polymerization. The material can slowly degrade and release the drug monomer in the body to achieve one-time drug administration. effects of long-term drug treatment.
附图说明Description of drawings
图1为本发明的1-甲基-D/L-色氨酸的N-羧酸环内酸酐单体核磁氢谱（1H 500MHz, DMSO-d6）；Figure 1 is the H NMR spectrum (1H 500MHz, DMSO-d6) of the N-carboxylic acid anhydride monomer in the 1-methyl-D/L-tryptophan of the present invention;
图2为本发明的药物的N-羧酸环内酸酐单体含量为100%的高分子材料（1H 500MHz, D 2O：DMSO-D6 = 1:2）； Fig. 2 is a polymer material (1H 500MHz, D 2 O:DMSO-D6 = 1:2) in which the content of acid anhydride monomer in the N-carboxylic acid ring of the drug of the present invention is 100%;
图3为本发明的叔丁氧羰基保护基团保护的赖氨酸的N-羧酸环内酸酐单体核磁氢谱（1H 500MHz, DMSO-d6）；Fig. 3 is the N-carboxylic acid anhydride monomer proton nuclear spectrum (1H) of the lysine protected by the tert-butoxycarbonyl protecting group of the present invention 500MHz, DMSO-d6);
图4为本发明的实施例2中药物的N-羧酸环内酸酐单体含量为10%的高分子材料（1H 500MHz, D 2O）； Fig. 4 is a polymer material (1H 500MHz, D 2 O) in which the content of the anhydride monomer in the N-carboxylic acid ring of the drug in Example 2 of the present invention is 10%;
图5为本发明的实施例3中药物的N-羧酸环内酸酐单体含量为50%的高分子材料（1H 500MHz, D 2O：DMSO-D6 = 1:1）； Figure 5 is a polymer material (1H 500MHz, D 2 O:DMSO-D6 = 1:1) in which the content of the anhydride monomer in the N-carboxylic acid ring of the drug in Example 3 of the present invention is 50%;
图6为本发明的Hela细胞中IDO抑制效果示意图。Fig. 6 is a schematic diagram of the IDO inhibitory effect in Hela cells of the present invention.
本发明的实施方式Embodiments of the present invention
为了使本发明所要解决的技术问题、技术方案及有益效果更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention clearer, the present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described here are only used to explain the present invention, not to limit the present invention.
本发明将氨基酸及衍生物类药物制备成药物的N-羧酸环内酸酐单体，聚合得到含有氨基酸药物单元的高分子材料，该材料可在体内缓慢降解释放药物单体，以达到一次给药长期治疗的效果。In the present invention, the amino acid and derivative drugs are prepared into the N-carboxylic acid ring acid anhydride monomer of the drug, and the polymer material containing the amino acid drug unit is obtained by polymerization. The material can slowly degrade and release the drug monomer in the body to achieve one-time drug administration. effects of long-term drug treatment.
对于非氨基酸类药物，可首先通过化学反应与氨基酸键合，再通过本发明制备类似的缓释性高分子材料。For non-amino acid drugs, chemical reactions can be used to bond with amino acids first, and then similar slow-release polymer materials can be prepared through the present invention.
通过氨基酸及衍生物类药物共聚赖氨酸、精氨酸等其他氨基酸单体，为材料提供不同数量的蛋白酶切位点，使材料的生物降解具有一定的可控性，可不需反复口服或注射给药，仍满足治疗需求，为医患双方提供便利。By co-polymerizing lysine, arginine and other amino acid monomers with amino acid and derivative drugs, different numbers of protease cleavage sites are provided for the material, so that the biodegradation of the material is controllable, and repeated oral or injection is not required Drug administration still meets the treatment needs and provides convenience for both doctors and patients.
实施例1Example 1
以下实验需在严格无水条件下进行。所有溶剂应经过钠钾合金或氢化钙回流处理后，新鲜蒸馏使用。氨基酸及衍生物类药物与甲苯在减压条件下回流，用分水器分去水分，再减压蒸去甲苯使用。实验操作需在干燥的保护气下（氮气、氩气或压缩空气）进行，玻璃仪器等需经严格干燥后使用。中间产品需保存在干燥釜内。本实施例中所述药物是指氨基酸及其衍生物类药物。本实施例以1-甲基-D/L-色氨酸为例，进行方案的详细描述。The following experiments were carried out under strictly anhydrous conditions. All solvents should be refluxed with sodium potassium alloy or calcium hydride, and then freshly distilled for use. Amino acid and derivative drugs and toluene are refluxed under reduced pressure, the water is separated by a water separator, and the toluene is evaporated under reduced pressure for use. Experimental operations need to be carried out under a dry protective gas (nitrogen, argon or compressed air), and glass instruments must be strictly dried before use. Intermediate products need to be stored in drying kettles. The drugs mentioned in this example refer to amino acids and their derivatives drugs. This embodiment takes 1-methyl-D/L-tryptophan as an example to describe the scheme in detail.
S1、将所述药物投入到所述医用材料中，反应后得到药物的N-羧酸环内酸酐单体（NCA）。具体包括以下步骤：S1. Put the drug into the medical material, and obtain the N-carboxylic acid anhydride monomer (NCA) of the drug after reaction. Specifically include the following steps:
在干燥反应瓶中加入甲苯预处理过的1-甲基-D/L-色氨酸（1-MT, 2.18 g，10mmol）和50 mL 干燥四氢呋喃，油浴下搅拌加热到50℃，待反应溶液温度稳定后，通过恒压滴液漏斗缓慢滴入所述的用于释放药物的医用材料（2 g，6.67mmol的碳酸双三氯甲酯溶于10 ml四氢呋喃中）。应观察到反应液先变稠至凝胶状，后慢慢溶解变清澈。在反应液完全变为澄清略黄溶液后（通常约3小时）再继续反应30 min，以让反应完全和排出多余碳酰氯、氯化氢等副产物。停止反应后，旋蒸浓缩反应液到10 mL左右，再倒入到100 mL的正己烷中沉淀，然后真空抽滤得到固体白色粗产物。所述粗产物在四氢呋喃/正己烷反应溶液中重结晶2次，室温真空干燥24 h，如图1所示，获得外观呈白色的药物的N-羧酸环内酸酐单体（记为1-MT NCA单体）1.44 g，产率45％。Add toluene-pretreated 1-methyl-D/L-tryptophan (1-MT, 2.18 g, 10 mmol) and 50 mL of dry tetrahydrofuran into a dry reaction flask, stir and heat to 50°C under an oil bath, and wait for the reaction After the temperature of the solution was stabilized, the medical material for drug release (2 g, 6.67 mmol of bistrichloromethyl carbonate dissolved in 10 ml of tetrahydrofuran) was slowly dropped in through a constant pressure dropping funnel. It should be observed that the reaction solution first thickens to gel, and then slowly dissolves and becomes clear. After the reaction solution has completely turned into a clear and slightly yellow solution (usually about 3 hours), continue the reaction for another 30 minutes to complete the reaction and discharge excess carbonyl chloride, hydrogen chloride and other by-products. After stopping the reaction, the reaction solution was concentrated by rotary evaporation to about 10 mL, then poured into 100 mL of n-hexane for precipitation, and then vacuum filtered to obtain a solid white crude product. The crude product was recrystallized twice in tetrahydrofuran/n-hexane reaction solution, and dried under vacuum at room temperature for 24 h. As shown in Figure 1, the N-carboxylic acid anhydride monomer (denoted as 1- MT NCA monomer) 1.44 g, yield 45%.
     S2、将所述药物的N-羧酸环内酸酐单体聚合，得到含有药物的高分子材料。S2. Polymerize the anhydride monomer in the N-carboxylic acid ring of the drug to obtain a polymer material containing the drug.
在干燥的保护气氛下称取步骤S1中制备的所述药物的N-羧酸环内酸酐单体（0.5g），置于反应瓶中，加入5ml四氢呋喃使之充分溶解。向反应瓶中加入5μl苯甲胺作为引发剂，以及20mg 碳酸钾粉末平衡pH，随之封闭瓶口，将反应溶液置于40℃油浴中反应72小时。反应结束后溶液浓缩至1ml，滴入20ml乙醚中沉淀产物。然后离心收集沉淀，并将沉淀重新溶解于1ml 四氢呋喃中，再次滴入20ml乙醚中沉淀产物。重复此过程两次，收集最终产物，真空干燥4小时，如图2所示，即可得到药物的N-羧酸环内酸酐单体含量为100%（P-MT 100%）的高分子材料，用于后续使用。Under a dry protective atmosphere, the N-carboxylic acid anhydride monomer (0.5 g) of the drug prepared in step S1 was weighed, placed in a reaction bottle, and 5 ml of tetrahydrofuran was added to fully dissolve it. Add 5 μl of benzylamine as an initiator to the reaction bottle, and 20 mg of potassium carbonate powder to balance the pH, then seal the bottle, and place the reaction solution in an oil bath at 40° C. for 72 hours. After the reaction, the solution was concentrated to 1 ml, and the product was dropped into 20 ml of ether to precipitate the product. Then the precipitate was collected by centrifugation, and the precipitate was redissolved in 1 ml of tetrahydrofuran, and dropped into 20 ml of ether again to precipitate the product. Repeat this process twice, collect the final product, and dry it in vacuum for 4 hours, as shown in Figure 2, you can get a polymer material with an anhydride monomer content of 100% in the N-carboxylic acid ring of the drug (P-MT 100%) , for subsequent use.
该高分子材料可在体内缓慢降解，释放药物单体（1-甲基-D/L-色氨酸），以达到一次给药长期治疗的效果。The polymer material can be slowly degraded in the body to release the drug monomer (1-methyl-D/L-tryptophan), so as to achieve the effect of long-term treatment with one administration.
实施例2Example 2
S1、将所述药物投入到所述医用材料中，反应后得到药物的N-羧酸环内酸酐单体。具体包括以下步骤：S1. Put the drug into the medical material, and obtain the N-carboxylic acid anhydride monomer in the drug ring after reaction. Specifically include the following steps:
在干燥反应瓶中加入甲苯预处理过的1-甲基-D/L-色氨酸（1-MT, 2.18 g，10mmol）和50 mL 干燥四氢呋喃，油浴下搅拌加热到45℃，待反应溶液温度稳定后，通过恒压滴液漏斗缓慢滴入所述的用于释放药物的医用材料（2 g，6.67mmol的碳酸双三氯甲酯溶于10 ml四氢呋喃中）。应观察到反应液先变稠至凝胶状，后慢慢溶解变清澈。在反应液完全变为澄清略黄溶液后（通常约3小时）再继续反应30 min，以让反应完全和排出多余碳酰氯、氯化氢等副产物。停止反应后，旋蒸浓缩反应液到10 mL左右，再倒入到100 mL的正己烷中沉淀，然后真空抽滤得到固体白色粗产物。所述粗产物在四氢呋喃/正己烷反应溶液中重结晶2次，室温真空干燥24 h，获得外观呈白色的药物的N-羧酸环内酸酐单体（1-MT NCA单体）1.44 g，产率50％。Add toluene-pretreated 1-methyl-D/L-tryptophan (1-MT, 2.18 g, 10 mmol) and 50 mL of dry tetrahydrofuran into a dry reaction flask, stir and heat to 45°C under an oil bath, and wait for the reaction After the temperature of the solution was stabilized, the medical material for drug release (2 g, 6.67 mmol of bistrichloromethyl carbonate dissolved in 10 ml of tetrahydrofuran) was slowly dropped in through a constant pressure dropping funnel. It should be observed that the reaction solution first thickens to gel, and then slowly dissolves and becomes clear. After the reaction solution has completely turned into a clear and slightly yellow solution (usually about 3 hours), continue the reaction for another 30 minutes to complete the reaction and discharge excess carbonyl chloride, hydrogen chloride and other by-products. After stopping the reaction, the reaction solution was concentrated by rotary evaporation to about 10 mL, then poured into 100 mL of n-hexane for precipitation, and then vacuum filtered to obtain a solid white crude product. The crude product was recrystallized twice in tetrahydrofuran/n-hexane reaction solution, and dried under vacuum at room temperature for 24 h to obtain 1.44 g of the N-carboxylic acid anhydride monomer (1-MT NCA monomer) of the drug with a white appearance. Yield 50%.
S11、将赖氨酸投入到所述医用材料中，反应后得到赖氨酸的N-羧酸环内酸酐单体（Lys NCA单体）和/或精氨酸的N-羧酸环内酸酐单体（记为Arg NCA单体）。S11. Putting lysine into the medical material, after the reaction, the N-carboxylic acid anhydride monomer of lysine (Lys NCA monomer) and/or the N-carboxylic acid anhydride of arginine are obtained monomer (denoted as Arg NCA monomer).
赖氨酸的N-羧酸环内酸酐单体的制备与药物的N-羧酸环内酸酐单体的制备类同。区别在于，赖氨酸有一个游离的氨基，需要使用叔丁氧羰基保护基团先行保护，聚合结束后再脱保护得最终产物。具体地，在反应瓶中加入叔丁氧羰基保护基团保护的赖氨酸（10 g，33.56 mmol）和100 mL四氢呋喃，油浴下搅拌加热到45℃，待反应溶液温度稳定后，通过恒压滴液漏斗缓慢滴入所述用于释放药物的医用材料（4.6 g，15.4mmol碳酸双三氯甲酯，溶于20 ml四氢呋喃中），反应结束后旋蒸浓缩反应液到20 mL左右，将浓缩后的反应液倒入200ml正己烷中沉淀。粗产物用四氢呋喃/正己烷重结晶两次，可得到呈白色片状晶形产物：如图3所示，叔丁氧羰基保护基团保护的赖氨酸的N-羧酸环内酸酐单体8.05 g，产率73.8％。The preparation of the acid anhydride monomer in the N-carboxylic acid ring of lysine is similar to the preparation of the acid anhydride monomer in the N-carboxylic acid ring of the drug. The difference is that lysine has a free amino group, which needs to be protected first with a tert-butoxycarbonyl protecting group, and then deprotected after polymerization to obtain the final product. Specifically, lysine (10 g, 33.56 mmol) protected by a tert-butoxycarbonyl protecting group and 100 mL of tetrahydrofuran were added into a reaction flask, stirred and heated to 45 °C under an oil bath, and after the temperature of the reaction solution was stabilized, a constant Slowly drip the medical material for drug release (4.6 g, 15.4 mmol bistrichloromethyl carbonate, dissolved in 20 ml tetrahydrofuran) into the pressure drop funnel. After the reaction is completed, the reaction solution is concentrated by rotary evaporation to about 20 mL. The concentrated reaction solution was poured into 200ml of n-hexane for precipitation. The crude product was recrystallized twice with tetrahydrofuran/n-hexane to obtain a white flaky crystal product: as shown in Figure 3, the N-carboxylic acid anhydride monomer of lysine protected by the tert-butoxycarbonyl protecting group was 8.05 g, yield 73.8%.
     S2、将所述药物的N-羧酸环内酸酐单体聚合，得到含有药物的高分子材料。S2. Polymerize the anhydride monomer in the N-carboxylic acid ring of the drug to obtain a polymer material containing the drug.
在干燥的保护气氛下称取步骤S1中制备的所述药物的N-羧酸环内酸酐单体与赖氨酸的N-羧酸环内酸酐单体共0.5g，其中所述赖氨酸的N-羧酸环内酸酐单体0.45g，所述药物的N-羧酸环内酸酐单体0.05g。将所述药物的N-羧酸环内酸酐单体与赖氨酸的N-羧酸环内酸酐单体置于反应瓶中，加入5ml四氢呋喃使之充分溶解。向反应瓶中加入5μl苯甲胺作为引发剂，以及20mg 碳酸钾粉末平衡pH，随之封闭瓶口，将反应溶液置于45℃油浴中反应72小时。反应结束后打开瓶盖，加入0.5ml三氟乙酸，室温继续反应2小时，以脱去叔丁氧羰基保护基。再将溶液浓缩至1ml，滴入20ml乙醚中沉淀产物。然后离心收集沉淀，并将沉淀重新溶解于1ml 四氢呋喃中，再次滴入20ml乙醚中沉淀产物。重复此过程两次，收集最终产物，真空干燥4小时，即可得到药物的N-羧酸环内酸酐单体含量为10%（P-MT-Lys 10%）的高分子材料，如图4所示，用于后续使用。Under a dry protective atmosphere, weigh a total of 0.5 g of the N-carboxylic acid anhydride monomer of the drug prepared in step S1 and the N-carboxylic acid anhydride monomer of lysine, wherein the lysine 0.45g of the acid anhydride monomer in the N-carboxylic acid ring of the drug, and 0.05g of the acid anhydride monomer in the N-carboxylic acid ring of the drug. The N-carboxylic acid anhydride monomer of the drug and the N-carboxylic acid anhydride monomer of lysine are placed in a reaction bottle, and 5ml of tetrahydrofuran is added to fully dissolve them. Add 5 μl of benzylamine as an initiator to the reaction bottle, and 20 mg of potassium carbonate powder to balance the pH, then seal the bottle, and place the reaction solution in an oil bath at 45° C. for 72 hours. After the reaction, the bottle cap was opened, 0.5 ml of trifluoroacetic acid was added, and the reaction was continued at room temperature for 2 hours to remove the tert-butoxycarbonyl protecting group. Then the solution was concentrated to 1ml, and the product was dropped into 20ml of ether to precipitate the product. Then the precipitate was collected by centrifugation, and the precipitate was redissolved in 1 ml of tetrahydrofuran, and dropped into 20 ml of ether again to precipitate the product. Repeat this process twice, collect the final product, and dry it in vacuum for 4 hours to obtain a polymer material with an anhydride monomer content of 10% (P-MT-Lys 10%) in the N-carboxylic acid ring of the drug, as shown in Figure 4 shown for subsequent use.
实施例3Example 3
S1、将所述药物投入到所述医用材料中，反应后得到药物的N-羧酸环内酸酐单体。具体包括以下步骤：S1. Put the drug into the medical material, and obtain the N-carboxylic acid anhydride monomer in the drug ring after reaction. Specifically include the following steps:
在干燥反应瓶中加入甲苯预处理过的1-甲基-D/L-色氨酸（2.18 g，10mmol）和50 mL 干燥四氢呋喃，油浴下搅拌加热到45℃，待反应溶液温度稳定后，通过恒压滴液漏斗缓慢滴入所述的用于释放药物的医用材料（2 g，6.67mmol的碳酸双三氯甲酯溶于10 ml四氢呋喃中）。应观察到反应液先变稠至凝胶状，后慢慢溶解变清澈。在反应液完全变为澄清略黄溶液后（通常约3小时）再继续反应30 min，以让反应完全和排出多余碳酰氯、氯化氢等副产物。停止反应后，旋蒸浓缩反应液到10 mL左右，再倒入到100 mL的正己烷中沉淀，然后真空抽滤得到固体白色粗产物。所述粗产物在四氢呋喃/正己烷反应溶液中重结晶2次，室温真空干燥24 h，获得外观呈白色的药物的N-羧酸环内酸酐单体1.44 g，产率50％。Add toluene-pretreated 1-methyl-D/L-tryptophan (2.18 g, 10 mmol) and 50 mL of dry tetrahydrofuran into a dry reaction flask, stir and heat to 45°C under an oil bath, and wait for the temperature of the reaction solution to stabilize , slowly drop into the medical material for drug release (2 g, 6.67 mmol of bistrichloromethyl carbonate dissolved in 10 ml of tetrahydrofuran) through a constant pressure dropping funnel. It should be observed that the reaction solution first thickens to gel, and then slowly dissolves and becomes clear. After the reaction solution has completely turned into a clear and slightly yellow solution (usually about 3 hours), continue the reaction for another 30 minutes to complete the reaction and discharge excess carbonyl chloride, hydrogen chloride and other by-products. After stopping the reaction, the reaction solution was concentrated by rotary evaporation to about 10 mL, then poured into 100 mL of n-hexane for precipitation, and then vacuum filtered to obtain a solid white crude product. The crude product was recrystallized twice in tetrahydrofuran/n-hexane reaction solution, and dried in vacuum at room temperature for 24 h to obtain 1.44 g of an N-carboxylic acid anhydride monomer in a white drug ring with a yield of 50%.
S11、将赖氨酸投入到所述医用材料中，反应后得到赖氨酸的N-羧酸环内酸酐单体和/或精氨酸的N-羧酸环内酸酐单体。S11. Putting lysine into the medical material, and reacting to obtain the N-carboxylic acid anhydride monomer of lysine and/or the N-carboxylic acid anhydride monomer of arginine.
赖氨酸的N-羧酸环内酸酐单体的制备与药物的N-羧酸环内酸酐单体的制备类同。区别在于，赖氨酸有一个游离的氨基，需要使用叔丁氧羰基保护基团先行保护，聚合结束后再脱保护得最终产物。具体地，在反应瓶中加入甲酸苄酯保护的赖氨酸（10 g，33.56 mmol）和100 mL四氢呋喃，油浴下搅拌加热到45℃，待反应溶液温度稳定后，通过恒压滴液漏斗缓慢滴入所述用于释放药物的医用材料（4.6 g，15.4mmol碳酸双三氯甲酯，溶于20 ml四氢呋喃中），反应结束后旋蒸浓缩反应液到20 mL左右，将浓缩后的反应液倒入200ml正己烷中沉淀。粗产物用四氢呋喃/正己烷重结晶两次，可得到呈白色片状晶形产物赖氨酸的N-羧酸环内酸酐单体8.05 g，产率73.8％。The preparation of the acid anhydride monomer in the N-carboxylic acid ring of lysine is similar to the preparation of the acid anhydride monomer in the N-carboxylic acid ring of the drug. The difference is that lysine has a free amino group, which needs to be protected first with a tert-butoxycarbonyl protecting group, and then deprotected after polymerization to obtain the final product. Specifically, benzyl formate-protected lysine (10 g, 33.56 mmol) and 100 mL of tetrahydrofuran were added into the reaction flask, stirred and heated to 45 °C under an oil bath, and after the temperature of the reaction solution was stabilized, the reaction solution was passed through a constant pressure dropping funnel. Slowly drop the medical material for drug release (4.6 g, 15.4 mmol of bistrichloromethyl carbonate, dissolved in 20 ml of tetrahydrofuran). The reaction solution was poured into 200ml of n-hexane for precipitation. The crude product was recrystallized twice with tetrahydrofuran/n-hexane to obtain 8.05 g of N-carboxylic acid anhydride monomer of lysine in the form of white flaky crystals, with a yield of 73.8%.
     S2、将所述药物的N-羧酸环内酸酐单体聚合，得到含有药物的高分子材料。S2. Polymerize the anhydride monomer in the N-carboxylic acid ring of the drug to obtain a polymer material containing the drug.
在干燥的保护气氛下称取步骤S1中制备的所述药物的N-羧酸环内酸酐单体与赖氨酸的N-羧酸环内酸酐单体共0.5g，其中所述赖氨酸的N-羧酸环内酸酐单体0.25g，所述药物的N-羧酸环内酸酐单体0.25g。将所述药物的N-羧酸环内酸酐单体与赖氨酸的N-羧酸环内酸酐单体置于反应瓶中，加入5ml四氢呋喃使之充分溶解。向反应瓶中加入5μl苯甲胺作为引发剂，以及20mg 碳酸钾粉末平衡pH，随之封闭瓶口，将反应溶液置于45℃油浴中反应72小时。反应结束后打开瓶盖，加入0.5ml三氟乙酸，室温继续反应2小时，以脱去叔丁氧羰基保护基。再将溶液浓缩至1ml，滴入20ml乙醚中沉淀产物。然后离心收集沉淀，并将沉淀重新溶解于1ml 四氢呋喃中，再次滴入20ml乙醚中沉淀产物。重复此过程两次，收集最终产物，真空干燥4小时，如图5所示，即可得到药物的N-羧酸环内酸酐单体含量为50%（P-MT-Lys 50%）的高分子材料，用于后续使用。Under a dry protective atmosphere, weigh a total of 0.5 g of the N-carboxylic acid anhydride monomer of the drug prepared in step S1 and the N-carboxylic acid anhydride monomer of lysine, wherein the lysine 0.25g of the acid anhydride monomer in the N-carboxylic acid ring of the drug, and 0.25g of the acid anhydride monomer in the N-carboxylic acid ring of the drug. The N-carboxylic acid anhydride monomer of the drug and the N-carboxylic acid anhydride monomer of lysine are placed in a reaction bottle, and 5ml of tetrahydrofuran is added to fully dissolve them. Add 5 μl of benzylamine as an initiator to the reaction bottle, and 20 mg of potassium carbonate powder to balance the pH, then seal the bottle, and place the reaction solution in an oil bath at 45° C. for 72 hours. After the reaction, the bottle cap was opened, 0.5 ml of trifluoroacetic acid was added, and the reaction was continued at room temperature for 2 hours to remove the tert-butoxycarbonyl protecting group. Then the solution was concentrated to 1ml, and the product was dropped into 20ml of ether to precipitate the product. Then the precipitate was collected by centrifugation, and the precipitate was redissolved in 1 ml of tetrahydrofuran, and dropped into 20 ml of ether again to precipitate the product. Repeat this process twice, collect the final product, and dry it in vacuum for 4 hours, as shown in Figure 5, you can get a high N-carboxylic acid anhydride monomer content of 50% (P-MT-Lys 50%) in the drug ring. Molecular material for subsequent use.
本发明得到了含有不同比例药物的N-羧酸环内酸酐单体（药物的N-羧酸环内酸酐单体含量为100% ，药物的N-羧酸环内酸酐单体含量为10%, 药物的N-羧酸环内酸酐单体含量为50%，分别对应实施例1、实施例2、实施例3）的高分子材料。The present invention has obtained the acid anhydride monomer in the N-carboxylic acid ring containing different proportions of medicine (the content of the acid anhydride monomer in the N-carboxylic acid ring of the medicine is 100%, and the content of the acid anhydride monomer in the N-carboxylic acid ring of the medicine is 10% , the content of acid anhydride monomers in the N-carboxylic acid ring of the drug is 50%, corresponding to the polymer materials in Example 1, Example 2, and Example 3).
对比试验Comparative Test
将Hela细胞以2.5x10^5个/毫升的密度重悬于完全DMEM培养基中，接种于96孔板中，每孔接种200微升（5x10^4细胞/孔），在37℃、5% CO 2浓度下过夜培养使之贴壁生长。除去上清后，向各孔中加入200μl含不同浓度的人干扰素(IFN-γ)、1-甲基-D/L-色氨酸或等价于同等1-甲基-D/L-色氨酸浓度的实施例1、实施例2和实施例3中的高分子材料的新鲜完全DMEM培养基。完全DMEM培养基是指含10% 胎牛血清（FBS）和1% 青霉素-链霉素溶液（PS）的DMEM培养基。人干扰素(IFN-γ)的作用是激活Hela细胞，使之高表达IDO1。 Hela cells were resuspended in complete DMEM medium at a density of 2.5x10^5 cells/ml, seeded in a 96-well plate, and inoculated 200 microliters per well (5x10^4 cells/well), at 37°C, 5% Cultivate overnight under CO 2 concentration to allow it to grow adherently. After removing the supernatant, add 200 μl of different concentrations of human interferon (IFN-γ), 1-methyl-D/L-tryptophan or equivalent 1-methyl-D/L-tryptophan to each well The fresh complete DMEM medium of the polymer material in Example 1, Example 2 and Example 3 of the tryptophan concentration. Complete DMEM medium refers to DMEM medium containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin solution (PS). The role of human interferon (IFN-γ) is to activate Hela cells to highly express IDO1.
1. 阴性对照孔（3孔）：仅加入完全DMEM培养基。1. Negative control wells (3 wells): only add complete DMEM medium.
2. 阳性对照孔（3孔）：加入含有10ng/ml人干扰素(IFN-γ)的完全DMEM培养基。2. Positive control wells (3 wells): add complete DMEM medium containing 10ng/ml human interferon (IFN-γ).
3. 1-MT 组（五个浓度，每个浓度3孔）：加入含有10ng/ml人干扰素(IFN-γ)，以及200μg/ml、100μg/ml、20μg/ml、2μg/ml、0.2μg/ml 的1-MT的完全DMEM培养基。3. 1-MT group (five concentrations, 3 wells for each concentration): add 10ng/ml human interferon (IFN-γ), and 200μg/ml, 100μg/ml, 20μg/ml, 2μg/ml, 0.2 1-MT complete DMEM medium at μg/ml.
4. P-MT 100%组（五个浓度，每个浓度3孔）：加入含有10ng/ml人干扰素(IFN-γ)，以及浓度为200μg/ml、100μg/ml、20μg/ml、2μg/ml、0.2μg/ml的P-MT-Lys 10%的高分子材料（实施例1）的完全DMEM培养基；4. P-MT 100% group (five concentrations, 3 wells for each concentration): add human interferon (IFN-γ) containing 10ng/ml, and concentrations of 200μg/ml, 100μg/ml, 20μg/ml, 2μg /ml, 0.2 μg/ml P-MT-Lys 10% polymer material (Example 1) complete DMEM medium;
5.P-MT-Lys 10%组（五个浓度，每个浓度3孔）：加入含有10ng/ml人干扰素(IFN-γ)以及2000μg/ml、1000μg/ml、200μg/ml、20μg/ml、2μg/ml P-MT-Lys 10%的高分子材料（实施例2）的完全DMEM培养基；5. P-MT-Lys 10% group (five concentrations, 3 wells for each concentration): add 10ng/ml human interferon (IFN-γ) and 2000μg/ml, 1000μg/ml, 200μg/ml, 20μg/ml ml, 2 μg/ml P-MT-Lys 10% polymer material (Example 2) complete DMEM medium;
6. P-MT-Lys 50%组（五个浓度，每个浓度3孔）：加入含有10ng/ml人干扰素(IFN-γ)以及400μg/ml、200μg/ml、40μg/ml、4μg/ml、0.4μg/ml 的P-MT-Lys 50%的高分子材料（实施例3）的完全DMEM培养基。6. P-MT-Lys 50% group (five concentrations, 3 wells for each concentration): add 10ng/ml human interferon (IFN-γ) and 400μg/ml, 200μg/ml, 40μg/ml, 4μg/ml ml, 0.4 μg/ml P-MT-Lys 50% polymer material (Example 3) complete DMEM medium.
Hela细胞与上述含不同组分的培养基继续共培养24小时后，每孔吸取150微升上清，转移至新的96孔板中。向新的96孔板中加入每孔50微升30%（v/v）三氯乙酸的冰醋酸溶液，混匀后在50℃水浴中孵育反应30分钟。反应结束后10000xg离心10分钟，每孔转移100微升反应液上清至另一新96孔板中，再向每孔加入100微升20%二甲氨基苯甲醛的冰醋酸溶液，室温反应10分钟，检测492nm处的吸光度，以阴性对照孔吸收值扣除背景，并按阳性对照孔为1进行归一化处理，以对比不同组别的IDO活性差异，如图6所示。After the Hela cells were co-cultured with the above medium containing different components for 24 hours, 150 microliters of supernatant was drawn from each well and transferred to a new 96-well plate. Add 50 microliters of 30% (v/v) trichloroacetic acid in glacial acetic acid solution to each well of a new 96-well plate, mix well and incubate the reaction in a 50°C water bath for 30 minutes. After the reaction, centrifuge at 10,000×g for 10 minutes, transfer 100 microliters of the supernatant of the reaction solution per well to another new 96-well plate, then add 100 microliters of 20% dimethylaminobenzaldehyde in glacial acetic acid to each well, and react at room temperature for 10 minutes. Minutes, the absorbance at 492nm was detected, the background was subtracted from the absorbance value of the negative control well, and the positive control well was normalized to 1 to compare the difference in IDO activity between different groups, as shown in Figure 6.
实验观察到，实施例1（P-MT 100%）、实施例2（P-MT-Lys 10%）、实施例3（P-MT-Lys 50%）得到的高分子材料同游离1-甲基-D/L-色氨酸小分子（1-MT）类似，可以抑制IDO的功能。含有不同比例药物的N-羧酸环内酸酐单体的高分子材料的抑制效果有明显不同，其中，实施例3得到的高分子材料的IDO1酶抑制效果与游离1-甲基-D/L-色氨酸小分子基本相同。药物的N-羧酸环内酸酐单体比例高的高分子材料（如实施例1中药物的N-羧酸环内酸酐单体含量为100%的高分子材料）抑制效果低于药物的N-羧酸环内酸酐单体比例低的高分子材料（如实施例3中药物的N-羧酸环内酸酐单体含量为50%的高分子材料和实施例2中药物的N-羧酸环内酸酐单体含量为10%的高分子材料），该抑制效果的区别可以被高分子材料降解速度的不同解释。实验结果可以说明，聚合后的氨基酸及衍生物类药物可以保留其原有功能，共聚不同比例的赖氨酸可以对高分子材料的功能进行调控。Experiments have observed that the polymer materials obtained in Example 1 (P-MT 100%), Example 2 (P-MT-Lys 10%), and Example 3 (P-MT-Lys 50%) are the same as free 1-formazan Similar to the base-D/L-tryptophan small molecule (1-MT), it can inhibit the function of IDO. The inhibitory effects of polymer materials containing anhydride monomers in N-carboxylic acid rings in different proportions of drugs are significantly different. Among them, the IDO1 enzyme inhibitory effect of the polymer materials obtained in Example 3 is comparable to that of free 1-methyl-D/L - Tryptophan small molecule is basically the same. A polymer material with a high ratio of acid anhydride monomers in the N-carboxylic acid ring of the drug (such as a polymer material in which the content of an acid anhydride monomer in the N-carboxylic acid ring of the drug in Example 1 is 100%) has an inhibitory effect lower than that of the N-carboxylic acid ring of the drug. -The macromolecular material with low acid anhydride monomer ratio in the carboxylic acid ring (such as the N-carboxylic acid anhydride monomer content of the medicine in the embodiment 3 is the polymer material of 50% and the N-carboxylic acid of the medicine in the embodiment 2 The difference in the inhibitory effect can be explained by the different degradation speed of the polymer material. The experimental results can show that the polymerized amino acid and derivative drugs can retain their original functions, and the copolymerization of different proportions of lysine can regulate the function of polymer materials.
本发明的释放氨基酸及其衍生物类药物的医用材料，其释放药物的速度可以调控，并可制备成皮下包埋型药剂，避免频繁给药带来的不便，也避免患者依从性不好而导致的漏服。The medical material for releasing amino acid and its derivative drugs of the present invention can control the release speed of the drug, and can be prepared as a subcutaneous embedding medicament, so as to avoid the inconvenience caused by frequent administration and avoid the failure of patients due to poor compliance. resulting in missed doses.
以上内容仅为本发明的较佳实施例，对于本领域的普通技术人员，依据本发明的思想，在具体实施方式及应用范围上可以作出许多变化，只要这些变化未脱离本发明的构思，均属于本发明的保护范围。The above content is only a preferred embodiment of the present invention, for those of ordinary skill in the art, according to the idea of the present invention, many changes can be made in the specific implementation and application range, as long as these changes do not depart from the concept of the present invention, all Belong to the protection scope of the present invention.

Claims (10)

  1. 一种用于释放药物的医用材料，其特征在于，包括溶解于四氢呋喃的碳酸双三氯甲酯。 A medical material for releasing medicine is characterized by comprising bistrichloromethyl carbonate dissolved in tetrahydrofuran.
  2. 根据权利要求1所述的用于释放药物的医用材料，其特征在于，所述药物是指氨基酸及其衍生物类药物。The medical material for releasing drugs according to claim 1, wherein the drugs refer to amino acids and derivatives thereof.
  3. 根据权利要求2所述的用于释放药物的医用材料，其特征在于，所述氨基酸及其衍生物类药物是指氨基酸类药物。The medical material for releasing drugs according to claim 2, wherein the amino acid and its derivative drugs refer to amino acid drugs.
  4. 根据权利要求2所述的用于释放药物的医用材料，其特征在于，所述氨基酸及其衍生物类药物包括1-甲基-D/L-色氨酸。The medical material for releasing drugs according to claim 2, characterized in that the amino acid and its derivative drugs include 1-methyl-D/L-tryptophan.
  5. 一种如权利要求1-4任意一项所述的医用材料的应用方法，其特征在于，包括以下步骤：A method for applying the medical material according to any one of claims 1-4, comprising the following steps:
         S1、将所述药物投入到所述医用材料中，反应后得到药物的N-羧酸环内酸酐单体；S1. Put the drug into the medical material, and obtain the N-carboxylic acid ring acid anhydride monomer of the drug after reaction;
         S2、将所述药物的N-羧酸环内酸酐单体聚合，得到含有药物的高分子材料。S2. Polymerize the anhydride monomer in the N-carboxylic acid ring of the drug to obtain a polymer material containing the drug.
  6. 根据权利要求5所述的医用材料的应用方法，其特征在于，还包括以下步骤：The application method of medical materials according to claim 5, further comprising the following steps:
    S11、将赖氨酸投入到所述医用材料中，反应后得到赖氨酸的N-羧酸环内酸酐单体；所述步骤S2中将所述赖氨酸的N-羧酸环内酸酐单体与所述药物的N-羧酸环内酸酐单体混合后聚合，得到含有药物的高分子材料。S11, put lysine into the medical material, and obtain the N-carboxylic acid ring acid anhydride monomer of lysine after the reaction; in the step S2, the N-carboxylic acid ring acid anhydride monomer of lysine After the monomer is mixed with the acid anhydride monomer in the N-carboxylic acid ring of the drug, it is polymerized to obtain the polymer material containing the drug.
  7. 根据权利要求6所述的医用材料的应用方法，其特征在于，所述赖氨酸的N-羧酸环内酸酐单体与所述药物的N-羧酸环内酸酐单体的质量比为1：1~1：9。The application method of medical materials according to claim 6, characterized in that, the mass ratio of the anhydride monomer in the N-carboxylic acid ring of the lysine to the anhydride monomer in the N-carboxylic acid ring of the drug is 1:1~1:9.
  8. 根据权利要求6所述的医用材料的应用方法，其特征在于，所述步骤S11中所述赖氨酸先使用叔丁氧羰基保护基团对所述赖氨酸的游离的氨基进行保护，聚合结束后再脱保护得到所述的赖氨酸的N-羧酸环内酸酐单体。The application method of medical materials according to claim 6, characterized in that, the lysine in the step S11 first uses a tert-butoxycarbonyl protecting group to protect the free amino groups of the lysine, and polymerize After the completion, deprotection is carried out to obtain the N-carboxylic acid anhydride monomer in the lysine ring.
  9. 根据权利要求5所述的医用材料的应用方法，其特征在于，还包括以下步骤：The application method of medical materials according to claim 5, further comprising the following steps:
    S11、将赖氨酸和/或精氨酸分别投入到所述医用材料中，反应后得到赖氨酸的N-羧酸环内酸酐单体和精氨酸的N-羧酸环内酸酐单体；所述步骤S2中将所述赖氨酸的N-羧酸环内酸酐单体、精氨酸的N-羧酸环内酸酐单体与所述药物的N-羧酸环内酸酐单体混合后聚合，得到含有药物的高分子材料。S11. Put lysine and/or arginine into the medical materials respectively, and obtain the N-carboxylic acid anhydride monomer of lysine and the N-carboxylic acid anhydride monomer of arginine after reaction. body; in the step S2, the acid anhydride monomer in the N-carboxylic acid ring of the lysine, the acid anhydride monomer in the N-carboxylic acid ring of arginine and the acid anhydride monomer in the N-carboxylic acid ring of the drug The polymers are polymerized after being mixed to obtain a drug-containing polymer material.
  10. 根据权利要求5所述的医用材料的应用方法，其特征在于，所述S1具体为在干燥反应瓶中加入甲苯预处理过的所述药物和四氢呋喃，油浴下搅拌加热到45-55℃，待反应溶液温度稳定后，缓慢滴入到所述医用材料中，在反应液完全变为澄清略黄溶液后停止反应，旋蒸浓缩反应液，将所述反应液倒入到正己烷中沉淀，然后真空抽滤得到所述药物的N-羧酸环内酸酐单体；所述S2具体为在干燥的保护气氛下称取所述药物的N-羧酸环内酸酐单体，加入到四氢呋喃使之充分溶解，再加入苯甲胺和碳酸钾粉末，得到反应溶液，将反应溶液置于35-45℃油浴中反应，反应结束后，将溶液浓缩、离心、干燥，得到所述含有药物的高分子材料。The application method of medical materials according to claim 5, characterized in that the S1 is specifically adding the drug and tetrahydrofuran pretreated with toluene into a dry reaction bottle, stirring and heating to 45-55°C under an oil bath, After the temperature of the reaction solution is stable, slowly drop it into the medical material, stop the reaction after the reaction solution completely becomes a clear and slightly yellow solution, concentrate the reaction solution by rotary evaporation, pour the reaction solution into n-hexane for precipitation, Then vacuum filtration to obtain the acid anhydride monomer in the N-carboxylic acid ring of the drug; the S2 specifically weighs the acid anhydride monomer in the N-carboxylic acid ring of the drug under a dry protective atmosphere, and adds it to tetrahydrofuran to make After the solution is fully dissolved, benzylamine and potassium carbonate powder are added to obtain a reaction solution, and the reaction solution is placed in an oil bath at 35-45°C for reaction. After the reaction is completed, the solution is concentrated, centrifuged, and dried to obtain the drug-containing drug Polymer Materials.
PCT/CN2022/137082 2021-12-15 2022-12-06 Medical material for releasing amino acid and derivative drug thereof, and use method therefor WO2023109599A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2009105825A (en) * 2009-02-20 2010-08-27 Закрытое Акционерное Общество "Фарма-Синтез" (RU) PEPTIDE COPOLYMER, METHOD OF ITS PRODUCTION AND PHARMACEUTICAL COMPOSITION ON ITS BASIS
CN103910784A (en) * 2014-04-10 2014-07-09 山东大学 Simple and convenient preparation method of copaxone
WO2020116552A1 (en) * 2018-12-07 2020-06-11 国立大学法人 東京大学 Polyamino acid, block copolymer, and polymer particle composition

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2009105825A (en) * 2009-02-20 2010-08-27 Закрытое Акционерное Общество "Фарма-Синтез" (RU) PEPTIDE COPOLYMER, METHOD OF ITS PRODUCTION AND PHARMACEUTICAL COMPOSITION ON ITS BASIS
CN103910784A (en) * 2014-04-10 2014-07-09 山东大学 Simple and convenient preparation method of copaxone
WO2020116552A1 (en) * 2018-12-07 2020-06-11 国立大学法人 東京大学 Polyamino acid, block copolymer, and polymer particle composition

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