WO2009074065A1 - Utilisation de daphné primeverosyl genkwanine et de plantes de daphné - Google Patents

Utilisation de daphné primeverosyl genkwanine et de plantes de daphné Download PDF

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Publication number
WO2009074065A1
WO2009074065A1 PCT/CN2008/073216 CN2008073216W WO2009074065A1 WO 2009074065 A1 WO2009074065 A1 WO 2009074065A1 CN 2008073216 W CN2008073216 W CN 2008073216W WO 2009074065 A1 WO2009074065 A1 WO 2009074065A1
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Prior art keywords
scented
genus
formula
scent
leukemia
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PCT/CN2008/073216
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English (en)
Chinese (zh)
Inventor
Wenhua Huang
Quan Pu
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Wenhua Huang
Quan Pu
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Publication of WO2009074065A1 publication Critical patent/WO2009074065A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/83—Thymelaeaceae (Mezereum family), e.g. leatherwood or false ohelo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to the field of botanical drugs. More specifically, it relates to the use of the genus Durian and the Daphnepr imeverosyl-Genkwanine (DPG) extracted from the genus Durian. Background technique
  • the treatment level of leukemia has also been greatly improved. People are not only satisfied with the complete remission of patients, but also committed to the study of patients who have long-term disease-free survival and even recovery.
  • the treatment of leukemia is chemotherapy. , integrated Chinese and Western medicine treatment, and hematopoietic stem cell transplantation.
  • Chemotherapy uses chemical agents to kill leukemia cells, so that patients can achieve long-term survival and even cure. There are many types of leukemia, and different chemotherapy regimens should be chosen for different leukemia types. At present, the success rate of chemotherapy is low. The cause of failure is early death due to infection and bleeding during chemotherapy, or leukemia cells are resistant and have no effect.
  • Hematopoietic stem cell transplantation is arguably the most fundamental method of treating leukemia. However, it has great risks. There are two main points: First, there are many transplant-related complications in HSCT, and second, there is still leukemia recurrence after HSCT: The main transplant-related complications are: Hepatic vein occlusion, its incidence 25%, mortality rate is 80%, graft versus host disease, incidence rate is 10%-80%. The recurrence rate of leukemia after HSCT is about 15%-50%.
  • the present invention is intended to provide a compound of formula I, or a plant extract containing a compound of formula I, or a novel use of a prodrug containing a compound of formula I.
  • a second object of the invention is to provide a pharmaceutical composition.
  • a third object of the invention is to provide a method of treating leukemia.
  • a fragrant primrose-baicalin as shown in Formula I (Daphne primeverosyl-Genkwanine, DPG), or an alcoholic extract of the genus Raytheon of the scent of scented scented scutellaria, as shown in Formula I, or a scented scented sage
  • DPG Diphne primeverosyl-Genkwanine
  • the leukemia is selected from the group consisting of drug-resistant acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome (MDS), or end stage multiple myeloma (Kahler's disease).
  • the genus genus is selected from the group consisting of Phnom Penh scent (/3 ⁇ 4p/7/j e odora Thunb), Tcit (Daphne genkwa Sieb. et Zucc), and white scent (Z?ap?/je papyracea Wall, Ex Steud), Cloud Daphne y arwnsis H F. Zhou); More preferably, the whole grass powder of the genus Durian.
  • the alcohol extract is selected from the group consisting of methanol or ethanol extract.
  • the alcohol extract is obtained by the following steps:
  • step (a) the method further comprises the steps of:
  • the medicament is a dosage form selected from the group consisting of an oral capsule, a powder, a tablet, an elixir, a patch, a plaster, a soup, an injection, a sustained release, a medicinal liquor, or an oral solution.
  • a pharmaceutical composition comprising - (i) as a living ingredient, a fragrant primrose flavonoid as shown in formula I
  • DPG Dermataryosyl-Genkwanine
  • the active ingredient has a weight of from 1 to 99% by weight based on the total weight of the composition.
  • the genus of the genus genus is selected from the group consisting of Z3 ⁇ 4p?/7e odora Thunb, the flower (Z3 ⁇ 4pA/?e genkwaSieb. et Zucc), and the Zfep we papyracea Wall (ex Steud) , or Dap/me yunnar nsis HF Zhou;
  • the alcohol extract is selected from the group consisting of methanol or ethanol extract.
  • a method of preparing a medicament for treating leukemia comprising the steps of: administering Daphne prime verosyl-Genkwanine (DPG) as shown in Formula I, or An alcoholic extract of a genus of the genus eucalyptus containing the scented scent of scented scutellaria as shown in Formula I, or a medicinal material of medicinal medicinal material containing ruthenium scutellaria and scutellarin as shown in Formula I Acceptable carriers are obtained by mixing.
  • DPG Daphne prime verosyl-Genkwanine
  • a method of treating leukemia which comprises administering to a patient a Daphnepr imeverosyl-Genkwanine (DPG) as shown in Formula I, or An alcoholic extract of the genus Durian of the scented scented scutellaria- safflorin as shown in Formula I, or a medicinal material of the genus eucalyptus containing the scented sage of the formula I.
  • DPG Daphnepr imeverosyl-Genkwanine
  • An alcoholic extract of the genus Durian of the scented scented scutellaria- safflorin as shown in Formula I
  • a medicinal material of the genus eucalyptus containing the scented sage of the formula I.
  • Figure 1 shows the condition of the L1210 mouse leukemia cell line.
  • FIG 2 shows the effect of DPG on the L 1210 mouse leukemia cell line.
  • Replacement page Article 26
  • Figure 3 shows the condition of human embryonic normal fibroblasts (HLF).
  • FIG. 4 shows the effect of DPG on human embryonic normal fibroblasts (HLF).
  • the inventors After extensive and intensive research, the inventors have unexpectedly discovered that the whole plant of the genus Durian has a pathological positive effect on human malignant hematological diseases. Further, the inventors have found that a compound of the formula I (5-0- ⁇ -OH- primrose- safflorin, Daphne priraeverosyl-Genkwanine, DPG) can be extracted from the above-mentioned genus Durian. It has obvious anti-proliferative and pro-apoptotic effects on leukemia cells and can inhibit the growth of leukemia cells.
  • a compound of the formula I 5-0- ⁇ -OH- primrose- safflorin, Daphne priraeverosyl-Genkwanine, DPG
  • whole grass refers to the whole grass of the genus Durian, including the roots, stems, branches, and leaves of the plant, and the genus Daphne odora Thunb), Daphne genkwa Sieb. et Zucc) , Daphne papyracea Wall, ex Steud, or Z3 ⁇ 4pj3 ⁇ 4/7e yunnanensis HF Zhou.
  • whole grass powder or “whole grass powder” is used interchangeably to mean that after drying the whole plant of the genus Durian, it is pulverized into 50-200 mesh particles, preferably 70-150 mesh, more preferably 90. - 120 mesh.
  • the " Russian medicinal material” may be a whole plant of the genus Durian, or may be a part of the plant, such as roots, stems, branches, leaves, flowers, and/or fruits.
  • the Durian plant whole grass powder provided by the invention can be used for treating leukemia, and the method is as follows: oral administration 3 times per dose, 2 doses / 50 kg body weight per dose, 1 gram per dose, 6 grams per day. The doctor can make adjustments according to the disease and the specific conditions of the patient.
  • the present invention provides an extract of the genus Durian, the extract being selected from the group consisting of methanol or ethanol extraction.
  • the alcohol extract and/or DPG provided by the present invention can be used for the treatment of leukemia by using 3 times a day, 2 doses per 50 kg body weight, 10 mg alcohol extract or DPG per dose, and a total daily dose of 60 mg.
  • the doctor can make adjustments according to the disease and the specific circumstances of the patient.
  • the leukemias treated by the present invention include drug-resistant acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and end-stage multiple myeloma (Kahler's dise ase ).
  • the natural genus of the genus Rutaceae belongs to the genus Rutaceae, about 70 species, distributed in the temperate and subtropical regions of Europe, North Africa and Asia to Oceania. There are 35 species in China, most of which are in the southwest and northwest. Rarely, some types of bast fiber are the raw materials for papermaking, and some are for viewing.
  • the method for treating leukemia provided by the present invention can be reversed to prolong or prevent the recurrence of leukemia
  • the method for treating leukemia provided by the invention can prevent multidrug resistance of leukemia
  • the method for treating leukemia provided by the present invention has small toxic and side effects.
  • the method for treating multiple myeloma provided by the invention can not only induce remission, but also has obvious analgesic effect.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, Otherwise all percentages and parts are by weight.
  • Standard DPG was purchased from SIGMA, and DPG refined products extracted from four different species of the same genus of scented plants, i.e., DPG (No. 1-4) obtained in Examples 9-12, were subjected to thin plate chromatography analysis.
  • the chromatographic spots were found to be singular, and the migration position was consistent with the control, and the molecular weight was completely consistent with the control.
  • Example 14 The standard and four different species of DPG extracts extracted from the genus of the same genus, that is, the DPG (No. 1-4) obtained in Example 9-12, are fine needle-like crystal powders. , insoluble in ether, chloroform or water, but soluble in methanol or ethanol. The nature is exactly the same.
  • Example 14 The standard and four different species of DPG extracts extracted from the genus of the same genus, that is, the DPG (No. 1-4) obtained in Example 9-12, are fine needle-like crystal powders. , insoluble in ether, chloroform or water, but soluble in methanol or ethanol. The nature is exactly the same.
  • Example 14 The standard and four different species of DPG extracts extracted from the genus of the same genus, that is, the DPG (No. 1-4) obtained in Example 9-12, are fine needle-like crystal powders. , insoluble in ether, chloroform or water, but soluble in methanol or ethanol. The nature
  • the whole grass powder I prepared in Example 1 was used to treat refractory and relapsed acute leukemia in 3 cases (ALL2 cases, AGL1 cases) (volunteers), 1 case of AGL was partially relieved; 1 case of ALL improved, 1 case of ALL invalid.
  • Ruixiang whole grass powder has been shown to have a pathological positive effect on human hematological malignancies, and has anti-primary cell effect on drug-resistant acute leukemia and chronic myeloid leukemia, leukemia cells are significantly reduced, blood picture is improved, Partial or complete relief.
  • the alcohol extract I prepared in Example 5 was subjected to a cell test to observe the in vitro biological effect on the L 1210 mouse leukemia cell line. It was found that alcohol extract I can significantly promote apoptosis and inhibit the growth of leukemia cells.
  • Example 19 The cell assay in Example 15 was repeated using the alcohol extracts I I-IV prepared in Examples 6-8, and it was also found that the alcohol extract I I-IV had a significant pro-apoptotic effect and inhibited the growth of leukemia cells, and Normal cells have no effect.
  • Example 19 The cell assay in Example 15 was repeated using the alcohol extracts I I-IV prepared in Examples 6-8, and it was also found that the alcohol extract I I-IV had a significant pro-apoptotic effect and inhibited the growth of leukemia cells, and Normal cells have no effect. Example 19
  • the cell test was carried out using DPG (No. 1) prepared in Example 9, and the in vitro biological effect on the L1210 mouse leukemia cell line was observed.
  • Figure 1 is a control: without DPG, cultured at 37 °C for 3 days;
  • Figure 2 shows the addition of 2 ug/ml DPG and incubation at 37 °C for 3 days. It was found that DPG can significantly promote apoptosis and inhibit the growth of leukemia cells.
  • DPG (No. 1) prepared in Example 9 was used to treat end-stage multiple myeloma, and myeloma cells were reduced from 37% to 4.5%.
  • the method of administration is: Oral DPG (No. 1), 10 mg each time, 3 times a day, for 14 days for 1 course of treatment.
  • Ig monoclonal paraprotein (M-protein) returned to normal, and the bone pain was obvious.
  • M-protein monoclonal paraprotein
  • Example 23 The DPG (No. 2-4) prepared in Examples 10-12 was repeatedly subjected to the in vitro cell test in Example 19, and the results showed that the standard and four different species but the same genus of the scented plant extract DPG refined product DPG ( No. 1 -4) has the same effect of inhibiting the growth of leukemia, and the dosage is uniform.
  • Example 23 The DPG (No. 2-4) prepared in Examples 10-12 was repeatedly subjected to the in vitro cell test in Example 19, and the results showed that the standard and four different species but the same genus of the scented plant extract DPG refined product DPG ( No. 1 -4) has the same effect of inhibiting the growth of leukemia, and the dosage is uniform.
  • Example 23 The DPG (No. 2-4) prepared in Examples 10-12 was repeatedly subjected to the in vitro cell test in Example 19, and the results showed that the standard and four different species but the same genus of the scented plant extract DPG refined product DPG ( No. 1 -4) has the same effect of inhibiting the growth
  • DPG (No. 1) was fed a white rat at a dose of 0.5 mg/kg/day for 15 days, which also proved to be non-toxic.
  • Example 27 The whole grass powders I I-IV and DPG (No. 2-4) prepared by using Examples 2-4 and Examples 10-12 were repeated for the test of Example 23, and the results were similar.
  • Example 27 The whole grass powders I I-IV and DPG (No. 2-4) prepared by using Examples 2-4 and Examples 10-12 were repeated for the test of Example 23, and the results were similar.
  • composition Formulation one is

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Abstract

La présente invention concerne l'utilisation de la daphné primeverosyl genkwanine (DPG), représentée par la formule (I), ou d'un extrait alcoolique de plantes de daphné contenant ce composé, ainsi que l'utilisation de plantes de daphné contenant ce composé dans la fabrication d'un médicament destiné au traitement de la leucémie. L'invention concerne également des compositions pharmaceutiques à base de daphné primeverosyl genkwanine représentée par la formule (I).
PCT/CN2008/073216 2007-12-10 2008-11-27 Utilisation de daphné primeverosyl genkwanine et de plantes de daphné WO2009074065A1 (fr)

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CN200710171993.9 2007-12-10
CN2007101719939A CN101456886B (zh) 2007-12-10 2007-12-10 瑞香樱草糖-芫花黄素和瑞香属植物的用途

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US20110301102A1 (en) * 2010-06-07 2011-12-08 Telik, Inc. Compositions and methods for treating myelodysplastic syndrome
CN113274438A (zh) * 2021-05-24 2021-08-20 上海交通大学 芫花提取物的制备及其应用

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FR2597751B1 (fr) * 1986-04-24 1990-10-05 Ragot Jacqueline Effet de synergie entre deux molecules d'origine vegetale : senegenine et 5-o-b-d-primeverosyl genkwanine utilisable dans le traitement de maladies liees a des desequilibres immunitaires
FR2867476B1 (fr) * 2004-03-11 2006-05-26 Michel Prost Derives de genkwanine et sakuranetine, utilisation cosmetique et therapeutique, et procede de preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JI CHUNRU ET AL.: "study of flavone compounds in leaf of daphne: the structure of yuankanin", ZHONGCAOYAO(CHINESE), vol. 17, no. 11, 1986, pages 7 - 9 *
ZHANG WEI ET AL.: "phenolic constituents from Daphne odora var. atrocaulis", NATURAL PRODUCT RESEARCH AND DEVELOPMENT(CHINESE), vol. 17, no. 1, 2005, pages 26 - 28 *

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