Flavonoid triazole derivative as well as preparation method and application thereof
By combining flavonoids and triazoles, flavonoid triazole compounds were designed and synthesized, solving the problems of poor solubility and harsh synthesis conditions of flavonoid compounds, and achieving efficient anticancer drug development with low toxicity.
Patent Information
- Application Number
- CN202511334473.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-18
- Publication Date
- 2025-11-07
AI Technical Summary
Existing flavonoids have complex structures, poor solubility, difficulty in crossing cell barriers, and demanding chemical synthesis conditions, which limits their widespread clinical application.
By combining flavonoids with triazoles according to the principle of drug combination, flavonoid triazole compounds were designed and synthesized. A simplified synthetic route was adopted, using readily available raw materials and mild reaction conditions to prepare flavonoid triazole derivatives with high biological activity.
It improves the solubility and bioavailability of flavonoids, reduces synthesis costs, provides highly effective anticancer drug candidates, and has low toxicity to normal cells.
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Figure CN120904178A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the field of organic drug synthesis, in particular to a class of flavone triazole derivatives and a preparation method and application thereof. BACKGROUND
[0002] Flavonoids (also known as flavonoids) are an important class of natural organic compounds, have a broad spectrum of physiological and pharmacological activities, low toxicity, strong biological activity, are important components of traditional Chinese medicine, and widely exist in fruits, vegetables, pasture, medicinal plants. However, natural flavonoids have complex structures, poor solubility, and low physiological activity utilization rate, which limits their wide clinical application.
[0003] However, the natural active ingredients are subject to high oxidation state of nitrogen atom, and are difficult to pass through the cell barrier. Therefore, researchers strive to introduce nitrogen-containing heterocycles to modify the structure of flavones, on the one hand to enhance the solubility and improve the bioavailability, and on the other hand to develop new flavone compounds with stronger activity and smaller side effects.
[0004] The existing flavonoids have harsh reaction conditions, and usually require specific temperature, pressure, catalyst and other reaction conditions in the chemical synthesis process, which has high requirements for equipment and operation, increases the difficulty and cost of synthesis. SUMMARY
[0005] The purpose of the present application is to provide a new flavone derivative containing a nitrogen-containing heterocycle, i.e. a flavone triazole derivative, and a preparation method and application thereof.
[0006] To achieve the above-mentioned purpose, the technical solution adopted by the present application is: According to one aspect of the present application, a flavone triazole derivative is provided, which comprises a compound as described in general formula I or a geometric isomer thereof or a pharmaceutically acceptable salt thereof;
[0007] The overall concept of the present application is to use the drug splicing principle to splice flavone drugs with triazole, and to design and synthesize a class of novel flavone triazole compounds. In general formula I, R is selected from styryl, 1-naphthyl or 9-anthryl; R1 is selected from hydrogen or hydroxyl; R2 is selected from hydrogen or hydroxyl; R3 is selected from hydrogen or hydroxyl; n = 2, 3, 4…….
[0008] According to another aspect of the present application, a preparation method of the above-mentioned flavone triazole derivative is provided, characterized in that it comprises: Step one, flavonoids, potassium carbonate and dibromo-substituted alkane are fully stirred in acetonitrile to obtain intermediate II, ; Step two, after mixing the triazole compound, inorganic base reagent and organic solvent and fully reacting, adding intermediate II, refluxing and stirring to react until the reaction is completed, a flavone triazole compound shown in general formula I is obtained, .
[0009] Further, in step one, the stirring reaction temperature is 50-60°C.
[0010] Further, in step two, the reaction molar ratio of intermediate II: triazole compound: inorganic base reagent is 1: (1-1.4): (1-2.0).
[0011] Further, in step two, the reaction temperature of the triazole compound, inorganic base reagent and organic solvent is 40-80°C.
[0012] Further, in step two, after adding intermediate II, the reflux reaction temperature is 75-85°C.
[0013] Further, the organic solvent is acetone, acetonitrile or ethanol.
[0014] Further, the inorganic base reagent is potassium carbonate or sodium carbonate.
[0015] According to another aspect of the present application, provided is the use of the flavone triazole derivative described above in the preparation of a medicine for preventing or treating cancer.
[0016] According to another aspect of the present application, provided is a pharmaceutical composition comprising the flavone triazole derivative described above and at least one pharmaceutically acceptable excipient, adjuvant or carrier.
[0017] The present application uses CCK-8 experiments to detect the proliferation inhibition effect of the synthesized flavone triazole derivative (general formula I) on A549 cells, and the synthesized flavone triazole derivative shows certain inhibition effect on A549 cells, and the inhibition rate of the best active compound can reach 92.68%. Therefore, the compound is expected to provide more efficient candidate drugs for cancer treatment, and is helpful to solve the clinical treatment problem.
[0018] In addition, the preparation method of the flavone compound provided by the present application has a short synthesis route, and the preparation process does not require catalysts, high temperature, high pressure, anhydrous and anaerobic harsh conditions, and the preparation method is simple, the raw materials are easy to obtain, and the cost is low. BRIEF DESCRIPTION OF DRAWINGS
[0019] Figure 1 The relative cell viability of compound I-3 obtained by the embodiment of the present application in HEK293 cells is shown. DETAILED DESCRIPTION
[0020] A typical embodiment of the present application is to design and synthesize a novel flavone triazole compound by combining flavone drugs with triazole drugs according to the drug combination principle. The flavone triazole compound comprises a compound as shown in general formula I or a geometric isomer thereof or a pharmaceutically acceptable salt thereof.
[0021] In general formula I, R is selected from styryl, 1-naphthyl or 9-anthryl; R1 is selected from hydrogen or hydroxyl; R2 is selected from hydrogen or hydroxyl; R3 is selected from hydrogen or hydroxyl; and n = 2, 3, 4, ….
[0022] The pharmaceutically acceptable salt is preferably a hydrochloride, nitrate or acetate.
[0023] Another typical embodiment of the present application provides a preparation method of the flavone triazole derivative as described above, which comprises the following steps: Step one, flavone compound III, potassium carbonate and dibromo-substituted alkane are fully stirred and reacted in acetonitrile to obtain intermediate II, In the flavone compound III and the intermediate II, R is selected from styryl, 1-naphthyl or 9-anthryl; R1 is selected from hydrogen or hydroxyl; R2 is selected from hydrogen or hydroxyl; R3 is selected from hydrogen or hydroxyl; and n = 2, 3, 4, ….
[0024] In this step, the stirring reaction temperature is 50-60℃, for example, 50℃, 55℃, 58℃ or 60℃.
[0025] Step two, after mixing and fully reacting the triazole compound, inorganic base reagent and organic solvent, the intermediate II is added, and the stirring reaction is carried out under reflux until the reaction is completed, thereby obtaining the flavone triazole compound as shown in general formula I,
[0026] In step two, the reaction molar ratio of the intermediate II: triazole compound: inorganic base reagent is 1:(1-1.4):(1-2.0), for example, 1:1:1, 1:1.1:1.4, 1:1.2:1.6, 1:1.3:1.8 or 1:1.4:2.0. The reaction system is controlled by the dosage ratio to make the cheap and easily available raw materials slightly excessive, so as to ensure that the intermediate which is not easy to obtain is as completely reacted as possible.
[0027] The reaction temperature of the triazole compound, inorganic base reagent and organic solvent is 40-80℃. For example, 40℃, 50℃, 60℃, 70℃ or 80℃. The reaction is usually carried out for 10-15h, and then cooled to room temperature. The control of temperature can improve the reaction activity and reduce the generation of by-products, thereby improving the yield.
[0028] After adding the intermediate II, the reaction temperature was 75-85°C, and the temperature was 75°C, 78°C, 80°C, and 85°C.
[0029] The organic solvent is preferably acetone, acetonitrile or ethanol. The inorganic base reagent is preferably potassium carbonate or sodium carbonate.
[0030] In the above synthesis route, the synthesis route of the flavonoid compound of general formula III is as follows: The substituted phenol, ZnCl2, chloroacetonitrile and diethyl ether were fully reacted, HCl gas was passed for 2 hours under an ice-salt bath, and the reaction was stopped after standing overnight, and then HCl gas was passed for 2 hours, and then the reaction was stopped, and the white powder was obtained by filtration, and then the hydrochloric acid was refluxed and cooled to obtain the intermediate IV.
[0031]
[0032] The intermediate IV, R-substituted aldehyde, 10% NaOH solution and ethanol solvent were fully reacted at room temperature for 24 hours, and then the solution was acidified with 1 mol / L HCl and filtered to obtain the flavonoid compound of general formula III.
[0033] The technical solutions claimed in the present application are further illustrated by some examples. However, the examples are used to explain the embodiments of the present application, and do not exceed the scope of the subject matter of the present application, and the protection scope of the present application is not limited by the examples. Unless otherwise specified, the materials and reagents used in the present application can be obtained from commercial products in the art.
[0034] Example 1 (synthesis of compound I-1) (1) Preparation of compound III-1
[0035] Into a 100 mL round-bottom flask containing compound IV-1 (0.03 mol, 5.60 g), cinnamaldehyde (0.03 mol, 4.00 g) and an appropriate amount of ethanol (25 mL), 10% NaOH (5 mL) was added dropwise, and the reaction was stirred at room temperature for 24 h. The reaction was neutralized to pH=7 with 1 mol / L dilute hydrochloric acid, and then recrystallized from ethanol and dried to obtain 6.3 g of compound III-1, with a yield of 78.90%.
[0036] (2) Preparation of compound II-1
[0037] In a 100 mL round-bottom flask, compound III-1 (0.01 mol, 2.40 g), potassium carbonate (0.01 mol, 1.38 g), 1,3-dibromopropane (0.01 mol, 2.01 g) and appropriate amount of acetonitrile, temperature control 50 °C, stirring reaction for 16 h. TLC tracking to the end of the reaction, and then concentrated, extracted, column chromatography separation, drying and other post-processing, ie 3.27 g of compound II-1, yield 83.85%.
[0038] (3) Preparation of compound I-1
[0039] In a 100 mL round-bottom flask, 1,2,4-triazole (0.62 g, 9 mmol), potassium carbonate (1.25 g, 9 mmol) and appropriate amount of acetonitrile, temperature control 40 °C, stirring reaction for 1 h, cooling to room temperature, adding compound II-1 (3.10 g, 8 mmol) to 75 °C, continue to stir, TLC tracking to the end of the reaction, and then concentrated, extracted, column chromatography separation, drying and other post-processing, ie 2.15 g of compound I-1, yield 72.15%.
[0040] Compound I-1: yellow powder; melting point 157-158 °C; 1 H NMR (500 MHz, CDCl3) δ 8.05 (s,1H, triazole-5-H), 7.94 (s, 1H, triazole-3-H), 7.62 (s, 1H, flavone-8-H), 7.47(d, J = 7.4 Hz, 2H, Ph-2,6-2H), 7.30 (t, J = 7.3 Hz, 2H, Ph-3,5-2H), 7.27 –7.23 (m, 1H, Ph-4-H), 7.19 (t, J = 7.8 Hz, 2H, flavone-5-H, flavone-6-H), 6.91(d, J = 15.7 Hz, 1H, C H =CH), 6.64 (d, J = 11.6 Hz, 1H, CH=C H ), 6.58 (s, 1H, flavone-3-H), 4.41 (t, J = 6.6 Hz, 2H, C- H 2), 4.03 (t, J = 5.7 Hz, 2H, C- H 2),2.51 – 2.39 (m, 2H, C- H 2) ppm. 13C NMR (126 MHz, CDCl3) δ 182.46, 166.57,165.14, 152.47, 148.56, 143.34, 140.52, 136.38, 134.63, 129.19, 128.88,127.34, 122.42, 120.68, 114.83, 113.12, 95.66, 65.10, 46.40, 35.05 ppm.
[0041] Example 2 (Synthesis of compound I-2) (1) Preparation of compound III-2
[0042] Into a 100 mL round-bottom flask containing compound IV-1 (0.03 mol, 5.60 g), 1- naphthaldehyde (0.03 mol, 4.70 g) and appropriate amount of ethanol (25 mL), 10% NaOH (5 mL) was added dropwise, and the reaction was stirred at room temperature for 24 h. TLC tracking was used to determine the completion of the reaction. The reaction mixture was neutralized to pH = 7 with 1 mol / L dilute hydrochloric acid, and then recrystallized from ethanol and dried to obtain 6.9 g of compound III-2 with a yield of 79.20%.
[0043] (2) Preparation of compound II-2
[0044] In a 100 mL round-bottom flask, compound III-2 (0.01 mol, 2.88 g), potassium carbonate (0.01 mol, 1.38 g), 1,3-dibromopropane (0.01 mol, 2.01 g) and appropriate amount of acetonitrile were stirred at 50°C for 16 h. TLC tracking was used to determine the completion of the reaction. The reaction mixture was concentrated, extracted, column chromatography separated, and dried to obtain 3.55 g of compound II-2 with a yield of 86.66%.
[0045] (3) Preparation of compound I-2
[0046] In a 100 mL round-bottom flask, 1,2,4-triazole (0.35 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and appropriate amount of acetonitrile were stirred at 60°C for 1 h, and then cooled to room temperature. Compound II-2 (2.04 g, 5 mmol) was added and the reaction was stirred at 80°C. TLC tracking was used to determine the completion of the reaction. The reaction mixture was concentrated, extracted, column chromatography separated, and dried to obtain 1.14 g of compound I-2 with a yield of 57.4%.
[0047] Compound I-2: yellow powder; melting point 159-160 °C; 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 7.3 Hz, 1H, triazole-5-H), 8.20 (d, J = 8.5 Hz, 1H, triazole-3-H), 8.01 (s,1H, Nap-4-H), 7.91 (s, 1H, Nap-2-H), 7.77 (d, J = 8.1 Hz, 2H, flavone-8-H, flavone-5-H), 7.64 (s, 1H, flavone-6-H), 7.55 – 7.36 (m, 5H, Nap-3,5,6,7,8-H),6.57 (s, 1H, flavone-3-H), 4.34 (t, J = 6.6 Hz, 2H, C- H 2), 3.94 (t, J = 5.8Hz, 2H, C- H 2), 2.44 – 2.33 (m, 2H, C- H 2) ppm. 13 C NMR (126 MHz, CDCl3) δ183.19, 167.41, 165.25, 152.46, 148.82, 143.36, 134.86, 133.69, 132.19,130.25, 129.98, 128.94, 128.38, 127.01, 126.18, 125.58, 123.45, 122.61,113.97, 107.33, 95.90, 65.19, 46.36, 35.05 ppm.
[0048] Example 3 (synthesis of compound I-3) (1) Preparation of compound III-3 To a 100 mL round-bottom flask containing compound IV-1 (0.03 mol, 5.60 g), 9-anthracene carboxaldehyde (0.03 mol, 6.20 g) and an appropriate amount of ethanol (25 mL), 10% NaOH (5 mL) was added dropwise, and the reaction was stirred at room temperature for 24 h. TLC tracking was used to determine the completion of the reaction. The reaction mixture was neutralized to pH = 7 with 1 mol / L dilute hydrochloric acid, and then recrystallized from ethanol and dried to obtain 7.70 g of compound III-3 with a yield of 75.60%.
[0049] (2) Preparation of compound II-3
[0050] In a 100 mL round-bottom flask, flavone III-3 (0.01 mol, 3.38 g), potassium carbonate (0.01 mol, 1.38 g), 1,3-dibromopropane (0.01 mol, 2.01 g) and an appropriate amount of acetonitrile were stirred at 50°C for 16 h. TLC tracking was used to determine the completion of the reaction. After concentration, extraction, column chromatography separation and drying, 3.62 g of compound II-3 was obtained with a yield of 78.70%.
[0051] (3) Preparation of compound I-3
[0052] In a 100 mL round-bottom flask, 1,2,4-triazole (0.35 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and an appropriate amount of acetonitrile were stirred at 80°C for 1 h, and then cooled to room temperature. Compound II-3 (2.29 g, 5 mmol) was added and the reaction was continued to stir at 85°C. TLC tracking was used to determine the completion of the reaction. After concentration, extraction, column chromatography separation and drying, 1.06 g of compound I-3 was obtained with a yield of 47.2%. Compound I-3: yellow powder; melting point 165-167°C; 1 H NMR (400 MHz, DMSO-d6) δ: 7.55 (d, J = 8.5 Hz, 1H, flavone-5- H ), 7.36 (d, J = 0.8 Hz, 1H, imidazole-4- H ), 7.15(d, J = 0.6 Hz, 1H, imidazole-5- H ), 6.71 (d, J = 1.8 Hz, 1H, flavone-3-H ), 6.66 (dd, J = 8.5, 1.9 Hz, 1H, flavone-6- H ), 6.58 (s, 1H, flavone-8- H ), 4.11(t, J = 7.1 Hz, 2H, imidazole-C H 2), 1.62 (dd, J = 14.1, 7.1 Hz, 2H, C H 2),1.22–1.10 (m, 8H, C H 2), 0.76 (t, J = 6.9 Hz, 3H, C H 3) ppm.
[0053] Example 4 (synthesis of compound I-1) (1) Preparation of compound II-1
[0054] In a 100 mL round-bottom flask, flavone III-1 (0.01 mol, 2.40 g), potassium carbonate (0.01 mol, 1.38 g), 1,3-dibromopropane (0.01 mol, 2.01 g) and an appropriate amount of acetonitrile were stirred at 60°C for 16 h. TLC tracking was performed until the reaction was completed, and then the reaction was treated by concentration, extraction, column chromatography separation, and drying, etc. After that, 3.33 g of compound II-1 was obtained with a yield of 86.49%.
[0055] (2) Preparation of compound I-1
[0056] In a 100 mL round-bottom flask, 1,2,4-triazole (0.62 g, 9 mmol), sodium carbonate (0.95 g, 9 mmol) and an appropriate amount of acetone were stirred at 40°C for 1 h, and then cooled to room temperature. Compound II-1 (3.10 g, 8 mmol) was added and the reaction was continued to be stirred at 75°C. TLC tracking was performed until the reaction was completed, and then the reaction was treated by concentration, extraction, column chromatography separation, and drying, etc. After that, 2.01 g of compound I-1 was obtained with a yield of 67.45%.
[0057] Example 5 (synthesis of compound I-2) (1) Preparation of compound II-2
[0058] In a 100 mL round-bottom flask, flavone III-2 (0.01 mol, 2.88 g), potassium carbonate (0.01 mol, 1.38 g), 1,3-dibromopropane (0.01 mol, 2.01 g) and an appropriate amount of acetonitrile were stirred at 60°C for 16 h. TLC tracking was performed until the reaction was completed, and then the reaction mixture was subjected to post-treatment such as concentration, extraction, column chromatography separation and drying, to obtain 3.21 g of compound II-2, with a yield of 78.48%.
[0059] (2) Preparation of compound I-2
[0060] In a 100 mL round-bottom flask, 1,2,4-triazole (0.35 g, 5 mmol), sodium carbonate (0.53 g, 5 mmol) and an appropriate amount of ethanol were stirred at 60°C for 1 h, and then the reaction mixture was cooled to room temperature. Compound II-2 (2.04 g, 5 mmol) was added, and the reaction mixture was stirred at 80°C. TLC tracking was performed until the reaction was completed, and then the reaction mixture was subjected to post-treatment such as concentration, extraction, column chromatography separation and drying, to obtain 1.21 g of compound I-2, with a yield of 61.11%.
[0061] In vitro CCK-8 cytotoxicity experiment In this experiment, CCK-8 experiment was used to detect the proliferation inhibition effect of the synthesized flavone triazole compounds on A549 cells.
[0062] 1. Experimental steps A certain amount of each of the above compounds I-1, I-2 and I-3 was accurately weighed, a small amount of dimethyl sulfoxide was added to completely dissolve the compounds, and then an appropriate amount of culture solution was added to prepare a mother solution. The cell number was adjusted to 6×10 4 6 / mL according to the cell culture method, 100 μL of the cell suspension was inoculated into a 96-well plate, and the plate was incubated at 37°C and 5% CO2 for 24 h. Then, 0.1% DMSO (control group) and 10 μM / L compound I (drug group) were added. After incubation in an incubator for 72 h, 10% CCK-8 was added according to the instructions, and the plate was incubated in the incubator for another 30 min. The plate was detected by an enzyme-labeled instrument at a wavelength of 450 nm.
[0063] The inhibition rates of the control group and the drug group were calculated according to the following formula: cell inhibition rate = (OD 对照组 – OD 药物组 ) / OD 对照组 ×100%.
[0064] 2. Test results According to the CCK-8 inhibition rate calculation formula: cell inhibition rate = [(Ac-As) / (Ac-Ab)]x100% (wherein, Ac: control hole; As: experimental hole; Ab: blank hole), the obtained experimental data are processed to obtain Table 1.
[0065] Table 1 CCK-8 cell inhibition rate
[0066] As shown in Table 1, the inhibition rates of flavone triazoles compounds I-1, I-2, I-3 on A549 cells are 19.09%, 20.07%, and 92.68%, respectively, indicating that the synthesized compounds all exhibit certain anti-tumor activity, especially the inhibition rate of compound I-3 reaches 92.68%, so it is known that the derivatives synthesized from 9-anthracene formaldehyde have better inhibition effect on cancer cells, can play a good anti-tumor role, and are helpful to solve the clinical treatment problem.
[0067] In vitro cytotoxicity testing of highly active molecules The cells used for testing in the experiment are human embryonic kidney cells HEK293. By using a cell counting kit-8 (CCK8) based on WST-8 reduction assay, the effect of high-activity molecule I-3 on HEK293 cell activity is determined. HEK293 cells are seeded into a 96-well plate (5000 cells per well). Then the cells are incubated in a medium containing a specific concentration of compound I-3 for 24 hours. After that, 10 mL of CCK8 is added to each well. After 4 hours, the unreacted dye is sucked out by a pipette. The optical density is measured by a microplate reader at an absorbance of 570 nm. Finally, the half-inhibitory concentration IC 50 value is calculated by plotting. The OD value is measured by an ELISA plate reader at a wavelength of 450 nm by spectrophotometry.
[0068] The survival rate is represented as follows: cell activity = (treatment group OD / control group OD) x 100%. The results show that compound I-3 still shows low toxicity to HEK293 cells at a high concentration, with an IC 50 value of 332 mg / mL. The above results show that this type of compound has low cytotoxicity to human normal cells.
[0069] Although the present application has been described in connection with the presently preferred exemplary embodiments, it will be understood that the application is not limited to the disclosed embodiments, but instead, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the application. The scope of the following claims is not to be limited to the embodiments set forth in the above description.
Claims
1. A flavonoid triazol derivative, characterized in that, A flavone triazolyl derivative of the general formula I or a geometric isomer thereof or a pharmaceutically acceptable salt thereof. ， In the general formula I, R is selected from styryl, 1-naphthyl or 9-anthryl; R1 is selected from hydrogen or hydroxyl; R2 is selected from hydrogen or hydroxyl; R3 is selected from hydrogen or hydroxyl; and n = 2, 3, 4, ….
2. The method of preparing flavonoid triazoles according to claim 1, characterized in that, The method comprises the following steps: Step 1, stirring flavone compound, potassium carbonate and dibromo-substituted alkane in acetonitrile to obtain intermediate II, ； Step 2, mixing triazolyl compound, inorganic base reagent and organic solvent, adding intermediate II and refluxing and stirring until the reaction is completed to obtain flavone triazolyl derivative of the general formula I, 。 3. The method of claim 2, wherein: In step 1, the stirring reaction temperature is 50-60℃.
4. The method according to claim 2 or 3, characterized in that: In step 2, the molar ratio of intermediate II: triazolyl compound: inorganic base reagent is 1:(1-1.4):(1-2.0).
5. The method of claim 4, wherein: In step 2, the reaction temperature of triazolyl compound, inorganic base reagent and organic solvent is 40-80℃.
6. The method of claim 5, wherein: In step 2, after adding intermediate II, the refluxing reaction temperature is 75-85℃.
7. The method of claim 2 or 6, wherein: The organic solvent is acetone, acetonitrile or ethanol.
8. The method of claim 7, wherein: The inorganic base reagent is potassium carbonate or sodium carbonate.
9. Use of the flavone triazolyl derivative of claim 1 in the preparation of a medicament for preventing or treating cancer.
10. A pharmaceutical composition, characterized by: The method comprises the flavone triazolyl derivative of claim 1 and at least one pharmaceutically acceptable excipient, adjuvant or carrier.