CN116874434A - Preparation method of medicinal compound - Google Patents

Preparation method of medicinal compound Download PDF

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CN116874434A
CN116874434A CN202310684032.7A CN202310684032A CN116874434A CN 116874434 A CN116874434 A CN 116874434A CN 202310684032 A CN202310684032 A CN 202310684032A CN 116874434 A CN116874434 A CN 116874434A
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curcumin
conical flask
aminouracil
compound
formula
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邬宝轩
刘巨涛
白淼
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Qize Yunnan Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

The invention relates to a preparation method of a compound shown in a formula (I) or (II), which has the advantages of mild reaction conditions, simple operation, high reaction yield, high product purity and convenient post-treatment, and is suitable for industrial production.

Description

Preparation method of medicinal compound
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a medicinal compound.
Background
Most of the metabolic activities of the human body depend on oxidation reactions, but this may lead to aging, diseases and oxidative stress in the human body. Antioxidants are produced by the body to regulate these reactions, but sometimes the free radical load produced during metabolism is too high, so that more antioxidant substances need to be taken in to delay aging and prevent certain diseases.
Free radicals are a class of highly reactive molecules that are produced during biological metabolism and include those containing superoxide anions (O 2 (-) and hydroxyl (.oh) reactive oxidizing species and reactive derivatives thereof. Reactive Oxygen Species (ROS) may also be induced by phospholipase A2, 5-lipoxygenase (5-LOX), cyclooxygenase 2 (COX-2), inducible Nitric Oxide Synthase (iNOS), and enzymes that produce Reactive Oxygen Species (ROS). The free radicals are responsible for regulating cell growth and signaling,and inhibition of bacteria, viruses, etc. in the body. However, if free radicals accumulate excessively in the body, reactive Oxygen Species (ROS) may have toxic effects on cells. Superoxide and peroxide react with metal ions to promote the production of other free radicals, particularly hydroxyl radicals, which react with all components of the cell, including lipid membranes, DNA and proteins.
Since the 70 s of the 20 th century, curcumin has been recognized as having antioxidant effects and its ability to scavenge free radicals has been studied. Curcumin can prevent oxidation of hemoglobin to methemoglobin, or reduce the amount of active oxygen by inhibiting lipopolysaccharide activated macrophages and reducing nitrate-induced oxidative stress. In 1985, toda et al extracted a portion of curcumin from turmeric root and found that it has a strong free radical scavenging capacity in vitro experiments. Motterlini et al studied the in vivo antioxidant activity of curcumin and found that it can activate a wide variety of enzymes in the liver, including glutathione triphosphate transferase, glutathione peroxidase, epoxide hydrolase and superoxide dismutase (SOD).
According to the modern understanding of the antioxidant mechanism of curcumin, the main part of its antioxidant activity is phenolic hydroxyl and β -diketone units, which are able to provide proton blocking antioxidants against the action of free radicals. In addition, the antioxidant activity of curcumin is also closely related to its ability to inhibit lipid peroxidation and maintain various antioxidant enzyme activities such as SOD, catalase (CAT) and glutathione peroxidase (GTP). Lipid peroxidation is a radical mediated chain reaction that can disrupt cell membrane structure. Curcumin inhibits lipid peroxidation mainly by removing factors involved in radical reactions. Since free radicals and active oxygen are causative factors of many common diseases, it is promising to fully utilize curcumin as an antioxidant and a means of scavenging free radicals to develop potential therapeutic drugs.
However, more intensive studies have found that curcumin has poor water solubility, less systemic absorption, too fast metabolism, and low bioavailability, which greatly limits its use.
Disclosure of Invention
In order to solve or partially solve the problems in the related art, the application provides a medicinal compound, wherein 2 pyrimidine groups are introduced, and after the medicinal compound is derivatized with curcumin, a product with relatively good water solubility and bioavailability is obtained on the basis of not affecting the advantages of the curcumin.
The present invention provides a compound or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, which is characterized in that the compound is selected from compounds shown in a general formula (I) or (Il),
（l）；
(Il)。
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound as described above or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier or excipient.
In a third aspect, the present invention provides the use of a compound as defined above, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of an antioxidant medicament.
In a fourth aspect, the present invention provides a process for the preparation of the above-described compounds.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
The beneficial technical effects of the invention are as follows:
improving the bioavailability of curcumin: one of the reasons for suppressing the bioavailability of curcumin is its low water solubility, thereby limiting the absorption and distribution of curcumin in the human body. By improving the water solubility, the absorption of curcumin can be increased and can function more effectively in the human body.
Increase the drug effect of curcumin: curcumin has a variety of biological activities including antioxidant, anti-inflammatory, anticancer, etc. Improving the bioavailability of curcumin can increase the activity and concentration of curcumin in human body, thereby improving the antioxidant and anti-inflammatory effects and having higher therapeutic potential.
Dose and toxicity reduction: the potency of curcumin may be dose limited, and higher doses may result in toxicity. By increasing the bioavailability of curcumin, lower doses can be used to achieve its therapeutic effect, thereby reducing the risk of side effects and toxicity.
The application range is widened: improving the bioavailability of curcumin can also widen its application in other disease treatment fields.
Drawings
FIG. 1 is a graphic representation of a PDB ligand prior to treatment in test example 4 of the present application;
FIG. 2 is a graphic representation of PDB ligands after treatment in test example 4 of the present application;
FIG. 3 is a diagram showing the parameter setting information of the butt GRID in test example 4 of the present invention;
FIG. 4 is a diagram showing the arrangement of the butt GRID in test example 4 of the present invention;
FIG. 5 is the conformational information of the docking of test example 4 of the present application;
FIG. 6 shows the coloring of the conformation according to Van der Waals force in test example 4 of the present application;
FIG. 7 is the geometric center of the docking configuration of test example 4 of the present application;
FIG. 8 shows the state of the docking conformation in the whole and the interaction with the receptor residue in test example 4 of the present application.
Detailed Description
Alternative embodiments of the present application will be described in more detail below with reference to the accompanying drawings. While the drawings illustrate alternative embodiments of the present application, it should be understood that the present application may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
The terminology used in the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any or all possible combinations of one or more of the associated listed items.
For clarity, the following examples are provided in detail.
Example 1
Weighing 0.635g (5 mmol) of 5-amino uracil, putting into a conical flask, adding 1.9g (5 mmol) of curcumin, then adding 60ml of absolute methanol into the conical flask, heating by a magnetic stirrer, reacting for 1.5h on a condensing reflux device, and steaming out the absolute methanol by a rotary evaporator; washing with diethyl ether to remove impurities, and naturally drying to obtain yellow powder with yield of 79.29%.
1 H NMR(DMSO，ppm)：3.83(s ，6H，-OCH 3 )；6.84-7.56(m，6H，-C 6 H 3 )；9.78(br，2H，Ar-OH)；10.51(s，H，-HN-C）； 13 C NMR(DMSO，ppm)：43.84(＞CH 2 )；61.12(-OCH 3 )；168.72(＞C=NH)；198.56(＞C=O)。
Example 2
Weighing 0.635g (5 mmol) of 6-amino uracil, putting into a conical flask, adding 1.9g (5 mmol) of curcumin, then adding 60ml of absolute methanol into the conical flask, heating by a magnetic stirrer, reacting for 1.5h on a condensing reflux device, and steaming out the absolute methanol by a rotary evaporator; washing with diethyl ether to remove impurities, and naturally drying to obtain yellow powder with yield of 75.73%.
1 H NMR(DMSO，ppm)：3.83(s，6 H，-OCH 3 )；6.79-7.23(m，6H，-C 6 H 3 )；9.76(br，2 H，Ar-OH)；10.50(s，H，-HN-C)； 13 C NMR(DMSO，ppm)：44.78(＞CH2)；60.99(-OCH 3 )；163.77(＞C=NH)；196.41(＞C=O)。
Test example 1
The purpose of the experiment is as follows: curcumin (Curcumin, cur) and two derivatives were compared: the properties of Curcumin 5-aminouracil derivatives (Curcumin-5-Aminouracil Derivative, abbreviated as C5 AUD) and Curcumin 6-aminouracil derivatives (Curcumin-6-Aminouracil Derivative, abbreviated as C6 AUD) in terms of water solubility.
The experimental steps are as follows:
10 mg of Cur, C5AUD and C6AUD were weighed out respectively and added to 10 mL of deionized water.
Each sample was stirred using a magnetic stirrer for 30 minutes.
After the stirring was completed, the mixture was allowed to stand for 10 minutes until undissolved substances in the solution settled.
Each solution was filtered using a 0.22 μm filter to remove undissolved particles.
The solubility of each sample in water was determined by ultraviolet spectrophotometry. Absorbance measurements were performed based on the maximum absorption wavelength of each sample.
Experimental data and conclusions:
sample of Solubility (mg/mL)
Cur 0.012
C5AUD 1.35
C6AUD 1.15
Conclusion: the water solubility of both the C5AUD and the C6AUD is significantly better than Cur.
Summarizing: according to the experimental results, both the curcumin 5-aminouracil derivative (C5 AUD) and the curcumin 6-aminouracil derivative (C6 AUD) show remarkable advantages in terms of water solubility. This means that the C5AUD and the C6AUD are more easily dissolved in an aqueous environment, contributing to an increase in bioavailability of the drug. These experimental data provide a valuable reference for the future development of novel water-soluble curcumin derivatives.
Test example 2
Step 1: three groups of Sprague-Dawley rats were prepared, 5 each. Feeding curcumin group, curcumin 5-amino uracil derivative group and curcumin 6-amino uracil derivative group respectively.
Step 2: curcumin, curcumin 5-aminouracil derivative and curcumin 6-aminouracil derivative are dissolved in appropriate vehicles, respectively, for oral administration. The dosage of the drug is 20mg/kg of each rat. Step 3: rats were orally administered curcumin, curcumin 5-aminouracil derivative or curcumin 6-aminouracil derivative solution daily for 7 consecutive days.
Step 4: blood samples were collected from rats at 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after dosing on day 7. Step 5: the blood sample was centrifuged and plasma was collected.
Step 6: the concentrations of curcumin, curcumin 5-aminouracil derivative and curcumin 6-aminouracil derivative in plasma were determined using spectrophotometry or HPLC.
Step 7: plasma drug concentration versus time curves were plotted and bioavailability parameters such as AUC (area under the curve) and Cmax (maximum plasma concentration) were calculated.
Experimental data and conclusions:
time (hours) Curcumin plasma concentration (μg/mL) C5AUD plasma concentration (μg/mL) C6AUD plasma concentration (μg/mL)
0.5 0.09 0.52 0.62
1 0.17 1.10 1.40
2 0.24 1.75 2.10
4 0.19 1.50 1.90
6 0.13 1.00 1.35
8 0.07 0.70 0.90
12 0.04 0.40 0.50
24 0.02 0.20 0.25
AUC and Cmax:
parameters (parameters) Curcumin C5AUD C6AUD
AUC 4.1 23.0 28.0
Cmax 0.24 1.75 2.10
Conclusion: the bioavailability of both C5AUD and C6AUD is significantly better than Cur.
Summarizing: according to the experimental results, both the curcumin 5-aminouracil derivative (C5 AUD) and the curcumin 6-aminouracil derivative (C6 AUD) show remarkable advantages in terms of bioavailability. This means that the C5AUD and the C6AUD are more easily absorbed and utilized in the body, thereby improving the therapeutic effect of the drug.
Test example 3
The experimental steps are as follows:
step 1: curcumin, C5AUD and C6AUD were dissolved in methanol, respectively, to prepare sample solutions having concentrations of 0.1, 0.5, 1.0, 2.0 and 4.0 mM, respectively.
Step 2: 3mL of 0.1 mM DPPH solution was added to each tube containing 1mL of sample solution.
Step 3: the solution in the tube was reacted at room temperature for 30 minutes in the dark.
Step 4: after the end of the reaction, the absorbance of each cuvette solution at 517nm was measured using a spectrophotometer.
Step 5: DPPH radical scavenging was calculated for each sample.
Sample of 0.1 mM 0.5 mM 1.0 mM 2.0 mM 4.0 mM
Curcumin 15% 40% 60% 75% 85%
C5AUD 22% 41% 62% 78% 90%
C6AUD 16% 45% 60% 78% 91%
Conclusion: from experimental data, it can be observed that curcumin, C5AUD and C6AUD all exhibit equal levels of antioxidant capacity at different concentrations.
Test example 4
1 pretreatment of ligands
Pretreatment of ligand: running Autodock software, opening a PDB file of the Ligand pyrimidyl curcumin derivative, clicking the PDB file of the Ligand in the Ligand-Input-Open, automatically adding hydrogen atoms by Autodock, calculating point charges, adding atom types, and clicking in a dialog box for determination. After pretreatment. The Ligand molecules are stored in Ligand-Output-Saveaspdbqt as a file of pdbqt suffix for later use. The PDB file graph before ligand treatment and the PDBQT file graph after ligand treatment are shown in figures 1 and 2.
2 setting of butt GRID
The Autodock software is opened, the pdbqt file of the G-quadruplex is run inside the Grid-macromolecules-Open, and the determination is performed by clicking in a dialog box. The pdbqt file for uracil curcumin derivatives was then opened inside Grid-setmaps types-openligands.
And opening Grid-GridBox-GridOptions, and adjusting the dimensions of the docking points, the X plane, the Y plane and the Z plane in the dialog box to be 64,72 and 78.X plane, and the central coordinates of the Y plane and the Z plane to be 0.056,1.000-1.806 respectively. After the end, click File-ClosesavingCurrent in GridOption dialog, store the lattice point and close the dialog. Next, click on Grid-Output-Savegpf, stored as gpf file for later use. The information and the image of the setting are as shown in fig. 3 and 4.
3 docking and results
After Grid setting is completed, an autoprid calculation is performed in Run-runautogorid. Three spaces in the pop-up dialog require, in order from top to bottom, auto grid computing software, gpf files automatically generated when starting to set up grid points, and glg files generated simultaneously with gpf files. After that, clicking on the counth will automatically start to calculate autogrid.
The pdqt file of the previously processed receptor molecule is run in the locking-macromolecules-setrig and then the pdqt file of the previously processed ligand molecule is opened in the locking-ligand-open and the Accept is clicked in a pop-up dialog.
Opening the dock-search parameters-genetics generic parameters, then popping up the Docking parameters, using the default parameters of the system, clicking Accept in this test. Opening click on dock-dock parameters-setdock parameters directly clicks on Accept after parameter adjustment is completed.
And then storing the dpf file generated by the dock, and opening the dock-Output-Lamarckian Ga storage file.
The calculation of autodock is started inside Run-RunAutodock. The three blanks in the pop-up dialog box require from top to bottom that an autodock running file, a dpf file generated in the dock, and a dlg file generated together when the dpf file is generated are added. After that, clicking on the counth starts to calculate autoprid.
The dlg file stored while running Docking in Analyze-Docking-Open is then determined by clicking in the pop-up dialog box.
And loading the butted result and the molecular conformation into a graphic window by analysis-formats-Load, and then clicking the conformation sequence number of the corresponding molecule in the list in a pop-up dialog box, wherein the butted data of the molecular conformation is displayed in a display window at the top. At this time, a double click is selected to load the molecular conformation into the molecular display window for subsequent observation and analysis.
The analysis-formats-Play will pop up a dialog box controlling the Play. When the third button is clicked, the following dialog box appears, if the ShowInfo is hooked, the related information of the current sub-conformation can be displayed, and the drop-down menu of Colorby is hooked into vdw, the conformation of coloring according to the Van der Waals force can be obtained.
A Receptor rigid molecule is added to the Analyze-macromolecules-Open, so that the situation of the Ligand in the Receptor molecule can be seen.
All molecular conformational results generated by docking in Analyze-docks-ShowsSphere are shown in pellet form. And obtaining the result of the molecular docking experiment. The following are provided: FIG. 5 is a graph showing the conformational information of the docking, FIG. 6 is an image of the molecular conformation stained according to Van der Waals forces, FIG. 7 is an image of the conformational center of the molecular docking, and FIG. 8 is a graph showing the characterization of the docking conformation and the effect of interactions with receptor residues under computer modeling. From the results, it was found that the 5-aminouracil curcumin derivative had 2 active sites for docking with the G-quadruplex.
G-quadruplexes, which are a square formed by the interactive binding of 4 guanines as a basis, are transient structures, present in large numbers in the cell to be divided, and occur in the chromosome nucleus and chromosome terminal (which can protect the chromosome from damage). Because cancer cells divide very rapidly, defects often occur at the end of the chromosome, and the quadruple helix DNA molecule may be present only in cancer cells.
The results of test example 4 therefore demonstrate that the compounds of the present invention have:
anticancer potential: because g-quadruplexes are ubiquitous in cancer cells, compounds that specifically interact with this structure may have anticancer potential.
Specificity: the specific interaction of the compound with the g-quadruplex may make it more targeted in the cell and produce fewer non-specific side effects. This makes it possible to adapt the medicament more easily to clinical applications and reduces the risk of treatment.
Treatment strategy: based on the specific conditions of presence of g-quadruplexes, the discovery of this compound may drive relevant therapeutic strategies and approaches. This may also provide new directions and ideas for cancer treatment and clinical research.
The foregoing description of the embodiments of the present application is illustrative, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described. The terminology used herein was chosen in order to best explain the principles of the embodiments, the practical application, or the improvement of technology in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.

Claims (2)

1. A preparation method of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof is characterized in that 5-aminouracil is weighed and put into a conical flask, curcumin with the same amount is added, absolute methanol is then added into the conical flask, the conical flask is heated by a magnetic stirrer, the mixture reacts for 1.5 hours on a condensation reflux device, and the absolute methanol is distilled out by a rotary evaporator; washing with diethyl ether to remove impurities, and naturally drying to obtain compound of formula (I)
（l）。
2. A preparation method of a compound shown in a formula (II) or pharmaceutically acceptable salt thereof is characterized in that 6-aminouracil is weighed and put into a conical flask, curcumin with the same amount is added, absolute methanol is then added into the conical flask, the conical flask is heated by a magnetic stirrer, the mixture reacts for 1.5 hours on a condensation reflux device, and the absolute methanol is distilled out by a rotary evaporator; washing with diethyl ether to remove impurities, and naturally drying to obtain compound of formula (II)
（II）。
CN202310684032.7A 2023-04-11 2023-04-11 Preparation method of medicinal compound Withdrawn CN116874434A (en)

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Application publication date: 20231013