WO2023029814A1 - Cristal de matrine, composition pharmaceutique, agent thérapeutique pour maladies telluriques, pesticide et leurs utilisations - Google Patents

Cristal de matrine, composition pharmaceutique, agent thérapeutique pour maladies telluriques, pesticide et leurs utilisations Download PDF

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Publication number
WO2023029814A1
WO2023029814A1 PCT/CN2022/107823 CN2022107823W WO2023029814A1 WO 2023029814 A1 WO2023029814 A1 WO 2023029814A1 CN 2022107823 W CN2022107823 W CN 2022107823W WO 2023029814 A1 WO2023029814 A1 WO 2023029814A1
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Prior art keywords
matrine
crystal
soil
therapeutic agent
borne diseases
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PCT/CN2022/107823
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English (en)
Chinese (zh)
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何其明
荣波
陈庭倬
龚宝金
刘科
李艳芬
任丹
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成都新朝阳作物科学股份有限公司
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Publication of WO2023029814A1 publication Critical patent/WO2023029814A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a new crystal of matrine.
  • Matrine is a common species of botanical pesticides. At present, the research on matrine mainly focuses on the field of pest control, and no one studies the crystal form of its original drug. Matrine is used in the prevention and control of common soil-borne diseases such as blight, damping-off, fusarium wilt, root rot, blight, root-knot nematode, etc. Because it dissolves quickly, its duration of action is short.
  • the XRPD spectrum of the conventional matrine crystal form shows that the 2 ⁇ ( ⁇ 0.2°) of crystal form I (anhydrous matrine) has diffraction peaks at 11.678°, 14.090°, and 23.006°, and the relative abundance exceeds 50%; There are diffraction peaks at 7.024° and 11.453°, and the relative abundance is between 50% and 30%; there is a diffraction peak at 16.676°, and the relative abundance is between 20% and 10%.
  • Embodiments of the present invention provide a matrine crystal, a pharmaceutical composition, a therapeutic agent for soil-borne diseases, an insecticide, and its use, so as to reduce the solubility of matrine and drugs with matrine as an active ingredient, so as to relieve role of interpretation.
  • the embodiment of the present invention provides a matrine crystal, which shows a diffraction peak at the following diffraction angle 2 ⁇ in the X-ray powder diffraction pattern detected by Cu K ⁇ radiation:
  • the embodiment of the present invention provides a matrine crystal
  • the preparation method of the matrine crystal is a suspension crystallization method
  • the suspension crystallization method includes:
  • the solvent is n-heptane.
  • the stirring temperature of the suspension crystallization method is 50°C.
  • stirring time is 5 days.
  • the ratio of matrine to solvent is 50.53mg:0.2mL.
  • the embodiment of the present invention provides a pharmaceutical composition, which contains the matrine crystals as an active ingredient.
  • embodiments of the present invention provide a therapeutic agent for soil-borne diseases, which contains the matrine crystals described in claim 1 as an active ingredient.
  • the therapeutic agents for soil-borne diseases include those for blight, damping-off, fusarium wilt, root rot, blight or symptoms associated with root-knot nematodes.
  • the embodiment of the present invention provides a use of the matrine crystal as an active ingredient of a slow-release drug.
  • the embodiment of the present invention provides an insecticide, which contains the matrine crystal (crystal form III) as an active ingredient.
  • the embodiment of the present invention has the following advantages and beneficial effects:
  • a matrine crystal, a pharmaceutical composition, a therapeutic agent for soil-borne diseases, an insecticide, and its use according to an embodiment of the present invention due to the low solubility of the matrine crystal, has a lower solubility in water and slower diffusion , when it is used for soil-borne diseases, it can prolong its duration of action, effectively reduce the speed of action of matrine, and prolong the action time, thereby producing drug action in a longer period of time and meeting the demand for long-acting release drugs; at the same time, the The control effect of matrine crystals on aphids is better, and has a good insecticidal effect. At the same concentration, the control effect of matrine crystals (crystal form III) on aphids is significantly higher than that of the original crystal form (crystal form I ).
  • Figure 1 is the XRPD pattern of conventional matrine crystals (form I).
  • Fig. 2 is an XRPD pattern of matrine crystals (form III).
  • Fig. 3 is a TGA diagram of matrine crystals (form III).
  • Fig. 4 is the result data analysis data of Fig. 3 .
  • Fig. 5 is the HNMR chart of matrine crystal (crystal form III).
  • FIG. 6 is the detection condition data of FIG. 5 .
  • Fig. 7 is a DSC chart of matrine crystals (form III).
  • FIG. 8 is the detection parameter data of FIG. 7 .
  • Fig. 9 is a PLM diagram of matrine crystals (form III). Wherein, Fig. 9 (a) is a detection diagram of 90° polarized light; Fig. 9 (b) is a detection diagram of 0° polarized light;
  • Fig. 10 is the broad bean leaf after conventional matrine crystallization (crystal form I);
  • Fig. 11 broad bean leaves after matrine crystallization (crystal form II);
  • Fig. 12 shows broad bean leaves treated with different concentrations of matrine crystallization.
  • an embodiment of the present invention provides a matrine crystal, which is detected by Cu K ⁇ radiation (hereinafter referred to as crystal III).
  • crystal III Cu K ⁇ radiation
  • the diffraction peaks are displayed at the following diffraction angle 2 ⁇ :
  • the crystal form III was analyzed by TGA in NETZSCH TG 209F3TGA209F3A-0652-L, and the crucible used was made of Al 2 O 3 ; as shown in Figure 4, the decomposition temperature started at 40.9°C-50°C, and the mass decreased The temperature range of 7% is 50-150°C; the temperature range of 92.5% mass reduction is 150-344.8°C.
  • Figure 7 is the DSC analysis of Form III.
  • FIG. 9 is a PLM diagram of matrine crystals of crystal form III (form III).
  • the embodiment of the present invention provides a matrine crystal
  • the preparation method of the matrine crystal is a suspension crystallization method
  • the suspension crystallization method includes:
  • the solvent is n-heptane.
  • the stirring temperature of the suspension crystallization method is 50°C.
  • stirring time is 5 days.
  • the ratio of matrine to solvent is 50.53mg:0.2mL.
  • Matrine crystal form II was studied by suspension crystallization. Weigh about 50 mg of raw materials into a sample bottle, add a certain amount of solvent, keep the system in a state of suspension and stirring at a certain temperature, stir for five days and filter, and analyze the obtained solid. The results are shown in Table 1 below.
  • the embodiment of the present invention provides a pharmaceutical composition, which contains the matrine crystals as an active ingredient.
  • an embodiment of the present invention provides a therapeutic agent for soil-borne diseases, which contains the matrine crystals described in claim 1 as an active ingredient.
  • the therapeutic agent for said soil-borne disease includes a therapeutic agent for blight, damping-off, fusarium wilt, root rot, blight or symptoms associated with root-knot nematode.
  • the embodiment of the present invention provides a use of the matrine crystal as an active ingredient of a slow-release drug.
  • crystal form III can slowly release the drug to play a role
  • the delayed and sustained effect can be used in the preparation and use of slow-release medicines that require matrine as an active ingredient.
  • the crystal form III can be used as a slow-release drug in the treatment of soil-borne diseases such as blight, damping-off, fusarium wilt, root rot, blight or symptoms associated with root-knot nematodes.
  • the embodiments of the present invention first analyze the influence of 40% matrine solutions with different concentrations on the indoor activity of aphids
  • test sample has poor spreadability, and the sample needs to be diluted with 0.05% Tween water.
  • test insect sources transfer 15 adult aphids (black and shiny, larger in size) to 6cm-10cm broad bean twigs (the lower end is fixed and vertically cultivated with soaked hydroponics planting cotton), and then use Cover the cultivation with a transparent plastic tank with a hole in the bottom, remove the adult aphids after 24 hours, and then carry out chemical treatment after 48 hours of cultivation (ambient temperature is about 25°C);
  • Soaking medicine Prepare the medicine solution according to Table 1, and treat it according to different settings. Soak the broad bean twigs with aphids in the medicine for 5 seconds. The wells were covered with transparent plastic jars and placed in an environment of 25°C for cultivation.
  • the total number of insect populations after the treatment group refers to the base number of insect populations after the treatment (the sum of the number of live insects and the number of dead insects), not the base number of insect populations recorded before the medicine soaking (some aphids will fall into the treatment solution during the medicine soaking process) In this way, the pre-drug insect population base is larger than the actual treated insect population base).
  • Adopt Duncan's new compound range method to carry out statistical analysis to test data as can be seen from Table 4, after test 48h, 40% matrine solution is at 25 times, 50 times, 100 times, 200 times, 400 times, 800 times dilution degree
  • the following control effects on broad bean aphids were 90.86%, 65.46%, 49.25%, 35.99%, 25.68%, 22.13%, respectively, and the 40% matrine solution was diluted 25 times and 50 times to treat broad bean leaves after serious phytotoxicity.
  • the 40% matrine solution diluted 25 times has the highest activity against faba bean aphids, with a control effect of 90.86%.
  • the next best activity is the dilution of 50 times and 100 times, with a control effect of 65.46% respectively.
  • 49.25%; 0.05% Tween 80 has low activity to aphids, and the control effect is 5.82%.
  • the control effect of 70% imidacloprid (chemical control) diluted 10000 times to faba bean aphids is 98.43%.
  • the 40% matrine solution diluted 100 times has a good control effect on broad bean aphids and has low phytotoxicity to leaves.
  • 40% matrine solution was used to dilute the solution 100 times for detection of indoor activity.
  • An embodiment of the present invention provides an insecticide, which contains the matrine crystal (form III) as an active ingredient.
  • test sample has poor spreadability, and the sample needs to be diluted with 0.05% Tween water.
  • test insect sources transfer 15 adult aphids (black and shiny, larger in size) to 6cm-10cm broad bean twigs (the lower end is fixed and vertically cultivated with soaked hydroponics planting cotton), and then use Cover the cultivation with a transparent plastic tank with a hole in the bottom, remove the adult aphids after 24 hours, and then carry out chemical treatment after 48 hours of cultivation (ambient temperature is about 25°C);
  • Soaking medicine Prepare the medicine solution according to Table 5, and treat it according to different settings. Soak the broad bean twigs with aphids in the medicine for 5 seconds. The wells were covered with transparent plastic jars and placed in an environment of 25°C for cultivation.
  • control effect of each treatment is calculated according to the formulas (1) and (2), and the calculation results are kept to two decimal places.
  • the total number of insect populations after the treatment group refers to the base number of insect populations after the treatment (the sum of the number of live insects and the number of dead insects), not the base number of insect populations recorded before the medicine soaking (some aphids will fall into the treatment solution during the medicine soaking process) In this way, the pre-drug insect population base is larger than the actual treated insect population base).
  • control effect in the above table is the average value of each repetition, and the different lowercase letters in the data in the same column indicate the significance of the difference at the 0.05 level.
  • Adopt Duncan's new compound range method to carry out statistical analysis to test data as can be seen from Table 6, after test 48h, 40% matrine solution (crystal form I), 40% matrine solution (crystal form III) in 100 times The control effects on faba bean aphids were 57.27% and 78.36% respectively at dilutions. 40% matrine solution (crystal form I) and 40% matrine solution (crystal form III) were diluted 100 times to treat broad bean leaves. Slight phytotoxicity; the control effect of 0.05% Tween 80 on aphids is 6.25%, and the control effect of 70% imidacloprid (chemical control) diluted 10000 times on broad bean aphids is 94.28%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des modes de réalisation de la présente invention concernent un cristal de matrine, une composition pharmaceutique, un agent thérapeutique pour maladies telluriques et leurs utilisations, qui peuvent réduire la solubilité de la matrine et un médicament utilisant la matrine comme principe actif, de façon à jouer un rôle de libération retardée. Dans une image de diffraction des rayons X sur poudre faisant appel au rayonnement Cu Kα pour la détection, le cristal de matrine présente des pics de diffraction aux angles de diffraction 2θ 17,951° ± 0,2°; 12,146° ± 0,2° et 14,858° ± 0,2°; 20,333° ± 0,2° et 26,414° ± 0,2°; et 10,754° ± 0,2°, 13,794° ± 0,2°, 18,369° ± 0,2°, 21,054° ± 0,2° et 21,348° ± 0,2°. Le cristal de matrine présente une solubilité plus faible et une diffusion plus lente dans l'eau, en raison de ses caractéristiques de faible solubilité. Lorsqu'il est utilisé pour des maladies telluriques, la période de persistance du cristal de matrine peut être prolongée, sa vitesse d'action peut être efficacement réduite et son temps d'action peut être prolongé, de façon à créer un effet pesticide pendant un temps plus long et à répondre aux besoins en pesticide relatifs à une libération de longue durée.
PCT/CN2022/107823 2021-09-06 2022-07-26 Cristal de matrine, composition pharmaceutique, agent thérapeutique pour maladies telluriques, pesticide et leurs utilisations WO2023029814A1 (fr)

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CN202111037315.XA CN113620953A (zh) 2021-09-06 2021-09-06 苦参碱结晶、药物组合物、土传病害的治疗剂及用途

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CN113620953A (zh) * 2021-09-06 2021-11-09 成都新朝阳作物科学股份有限公司 苦参碱结晶、药物组合物、土传病害的治疗剂及用途
CN113620954A (zh) * 2021-09-06 2021-11-09 成都新朝阳作物科学股份有限公司 苦参碱结晶、药物组合物和用途

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