WO2012079279A1 - Composés prégnane glycosides contenant des groupes ortho-esters et leur utilisation - Google Patents

Composés prégnane glycosides contenant des groupes ortho-esters et leur utilisation Download PDF

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WO2012079279A1
WO2012079279A1 PCT/CN2011/002023 CN2011002023W WO2012079279A1 WO 2012079279 A1 WO2012079279 A1 WO 2012079279A1 CN 2011002023 W CN2011002023 W CN 2011002023W WO 2012079279 A1 WO2012079279 A1 WO 2012079279A1
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sugar
extract
canadian
ethanol
hemp
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PCT/CN2011/002023
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English (en)
Chinese (zh)
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赵维民
左建平
杨以阜
王罗医
杨扬
陈振华
唐炜
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中国科学院上海药物研究所
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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)
    • A61K36/27—Asclepiadaceae (Milkweed family), e.g. hoya
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J17/005—Glycosides

Definitions

  • the present invention relates to a class of pregnane glycosides containing orthoester groups, pharmaceutical compositions comprising such compounds, and their use in the preparation of immunosuppressive agents, and more particularly, a class of (Periploca) pregnane glycosides containing orthoester groups extracted from plants, pharmaceutical compositions comprising the same, and immunological rejection or autoimmunity thereof after preparation for prevention and/or treatment of cell/organ transplantation
  • autoimmune diseases include: rheumatoid arthritis, multiple sclerosis, and autoimmune hepatitis.
  • Immunosuppressors are a class of drugs that have an inhibitory effect on immune response and immune regulation. Different immunosuppressive agents act on different aspects of the immune response or immune regulation process. Clinically, immunosuppressive agents are mainly used to treat and/or prevent autoimmune diseases and rejection after cell/organ transplantation. Immunosuppressive agents are mainly classified into the following types: (1) chemical agents, such as nitrogen mustards of alkylating agents; (2) hormones, such as glucocorticoids; (3) fungal metabolites, such as cyclosporin A (cyclosporin A, CsA); (4) Chinese medicine and its active ingredients.
  • chemical agents such as nitrogen mustards of alkylating agents
  • hormones such as glucocorticoids
  • fungal metabolites such as cyclosporin A (cyclosporin A, CsA)
  • Chinese medicine and its active ingredients Chinese medicine and its active ingredients.
  • immunosuppressive drugs have obvious toxic side effects, mainly myelosuppression and liver and kidney toxicity. Since the action of immunosuppressive drugs is non-specific, it can lead to a decline in the immune function of the entire body, an increase in pathogenic microbial infections, and long-term application may increase the incidence of tumors. Therefore, it is important to find new high-efficiency and low-toxic immunosuppressive agents.
  • the bar willow also known as the snail, the goat's milk bar, etc., its root bark is the traditional Chinese medicine fragrant skin (Northern Five Plus Skin:), can be used for rheumatism, strong bones, strong waist and knee, can be used to treat rheumatoid joints Inflammation, muscle and bone pain and other diseases;
  • Southwest Bars also known as ⁇ ⁇ ⁇ , black bone vine (black bone, black keel:) is the root or whole plant of the plant southwestern bar, can be used to relax, ⁇ Rheumatism, treatment of rheumatoid arthritis, bruises, stomach pain, indigestion, amenorrhea, dysentery, etc. Summary of the invention
  • Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a pregnapide compound containing a orthoester group.
  • a further object of the present invention is to provide a method for extracting a pregnane glycoside compound containing an orthoester group from a genus Perilla.
  • the immunosuppressive agent is used for the treatment and/or prevention of rejection after cell/organ transplantation or autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and autoimmune hepatitis.
  • the present invention separates a series of pregnane glycoside compounds containing orthoester groups from the bark and the soiled bark by biological activity tracking separation, and the compounds are represented by the following formula I:
  • Formula I Can be H or 4,6-dideoxy-3-0-methyl- ⁇ 3 -hexanone
  • R 2 is a sugar chain fragment composed of a sugar unit linked by an ether bond, and the sugar unit may be selected from, but not limited to, cymarose, canarose, Preferably, in the acylation product of the oleandrose, or the above monosaccharide, in the formula I: 11 or R 2 is
  • the specific combination of the orthoester group-containing pregnane glycoside compound of the present invention is as follows:
  • Ri is R 2 is Canadian cannabis kana sugar cannabis oleander nectar
  • the method for extracting a pregnane glucoside compound containing an orthoester group from the genus Perilla of the present invention includes the following steps:
  • the fragrant medicinal herbs are extracted three times with 95% ethanol, and the extract is concentrated under reduced pressure to obtain an ethanol extract.
  • the mixture is suspended in water and extracted with chloroform and n-butanol to obtain a chloroform extract and n-butanol extract, chloroform.
  • the extract was separated by silica gel (200 mesh:) column chromatography and eluted with a petroleum ether-acetone gradient (volume ratio 5:1, 2:1, 1 :1, 0:1) to obtain fractions Frl, Fr2, Fr3 And Fr4;
  • fraction Fr3 was separated by reversed-phase C 18 column chromatography and eluted with a methanol-water gradient (volume ratio of 1:1 ⁇ 1:0) to obtain secondary fractions Fr3.1, Fr3.2, Fr3.3, Fr3.4;
  • reverse phase C 18 column chromatography was performed using a Varian SD-1 model with a Merck NW25 C 18 column (10 ⁇ m, 20 mm 250 mm) and a ProStar 320 UV/Vis detector.
  • Black root vine root is extracted with 95% ethanol at room temperature, concentrated under vacuum distillation to form an extract, and dispersed in water, and then extracted with petroleum ether, ethyl acetate and n-butanol, respectively, to obtain a petroleum ether extract.
  • Fraction Fr5 was separated by Sephadex LH-20 (ie, background interference), and then silica gel column chromatography was carried out using chloroform-acetone (volume ratio 8: 1, 7:1, 6:1) as eluent. P-8, P-9, P-10 and Pl l. Wherein, the same ratio of solvent elution fractions is detected by thin layer chromatography and may contain multiple purified compounds.
  • the progesterate-containing progesterone sugar of the present invention is determined by various in vitro and in vivo experiments.
  • Glycosides have significant in vitro immunosuppressive activity and exhibit significant therapeutic effects in animal models of various autoimmune diseases, for example, they can significantly inhibit T cell proliferation; significantly inhibit dinitrofluorobenzene (DNFB) induction.
  • DTH Delayed type hypersensitivity
  • EAE experimental autoimmune encephalomyelitis
  • the severity and pathological changes of various aspects of the diseased joint tissue effectively weaken the liver damage caused by concanavalin (ConA) and reduce the level of cytokines in serum.
  • the present invention provides a crude extract of fragrant skin, which is obtained by the following method:
  • the fragrant medicinal material is extracted three times with 95% ethanol, and the extract is concentrated under reduced pressure to obtain an ethanol extract, which is added to the ethanol extract.
  • the water was centrifuged, the precipitate was washed with petroleum ether, dissolved in ethanol, allowed to stand, filtered, and the supernatant was taken to prepare a 70% ethanol solution, which was separated by macroporous resin column chromatography, and the eluted fraction of 90% ethanol was collected and concentrated. , that is.
  • Figure 1 shows the effect of compound P-1 on experimental autoimmune meningococcal disease (EAE) in mice (A: incidence of EAE in each group; B: disease score; C: body weight change, * ⁇ 0.05, * * ⁇ 0.01)
  • Figure 2 shows the effect of compound P-2 on experimental autoimmune meningococcal (EAE) symptoms in mice (A: incidence of EAE in each group; B: disease score; C: weight change) , *;? ⁇ 0.05).
  • Figure 3 shows the effect of compound P-1 on the severity of arthritis in mice (*/? ⁇ 0.05, **;? ⁇ 0 ⁇ 01).
  • Figure 4 shows the effect of compound P-1 on the pathological changes of arthritis in mice (A: ankle tissue section of normal group mice (400x); B: ankle joint tissue section of solvent control group (400x); C: P -1 treatment group mice ankle joint tissue section (400x); D: normal group mice ankle joint CT scan; E: solvent control group mice ankle CT tomography; F: P-1 treatment group mice Ankle CT tomography)).
  • Figure 5 shows the effect of Compound P-1 on the pathological changes of arthritis in mice (A: solvent control group mice ankle joint micro-CT; B: P-1 treatment group mice ankle joint ankle micro-CT).
  • Figure 6 shows the protective effect of Compound P-1 on ConA-induced hepatitis (A: serum ALT level; B: mouse survival rate; C: liver histopathology; D: pathology score, *p ⁇ 0.05, * * ⁇ 0.01, *** ⁇ 0 ⁇ 001).
  • Figure 7 shows the effect of compound P-1 on serum cytokine levels in hepatitis mice (A: serum IL-4 levels; B: serum IFN- ⁇ levels, *p ⁇ 0.05, **p ⁇ 0.01) .
  • Figure 8 shows the effect of crude extract of Xiangjiapi WJ-C on the severity of arthritis in mice.
  • the pulverized and dried fragrant medicinal herbs (15 kg) were refluxed with 95% ethanol three times (30 Lx3) for 2 hours each time.
  • the extract was concentrated under reduced pressure to obtain an ethanol extract, and about 2 L of water was suspended, followed by chloroform. Extracted with n-butanol to obtain a chloroform extract (762.5 and n-butanol extract (75.2 g).
  • the chloroform fraction was separated by silica gel (200 mesh:) column chromatography and eluted with a petroleum ether-acetone gradient (volume ratio in order) 5 ⁇ 2: 1, 1 :1, 0:1) The fractions Frl (601.3g), Fr2 (15.8g), Fr3 (48.2g) and Fr4 (3.6g) were obtained.
  • Fr3 was reversed by C 18 column chromatography. , eluted with a methanol-water gradient (volume ratios of 1:1, 2:1, 3:1, 4:1, and 1:0, sub-fractions Fr3.1, Fr3.2, Fr3.3, Fr3.4, wherein Fr3.4 (7.8 g) was prepared by reverse phase C18 preparative liquid chromatography eluting with a methanol-water gradient (volume ratio 2:3, 1:1, 2:1, 3:1, 4:1 and 1:0) give P-1 (2.0g), P-2 (1.5g), P-5 ( 18.7mg), P-6 (14.6mg).
  • Fr4 is prepared by reversed phase C 18 Chromatography, elution with methanol-water gradient (3:7, 2:3, 1 : 1, 2:1, 3:1 and 4:1 by volume) to give P-7 (33.0 mg), P-3 (40.1mg), P-4 ( 13.0mg).
  • methanol-water gradient 3:7, 2:3, 1 : 1, 2:1, 3:1 and 4:1 by volume
  • P-7 33.0 mg
  • P-3 40.1mg
  • P-4 13.0mg
  • the ethyl acetate fraction extract (32.0 g) was subjected to reverse phase C18 column chromatography eluting with a methanol-water gradient (volume ratio 1:9, 2:8, 3:7, 4:6, 5: 5, 6:4, 7:3, 8:2, 9:1 and 1:0, each gradient 1L), get six fractions (Frl-Fr6).
  • Fr5 was used to remove background interferences with Sephadex LH-20, and then subjected to silica gel column chromatography using chloroform-acetone (8:1, 7:1, 6:1 by volume) as the eluent to obtain compound P-8 (14.1 mg). ), P-9 (29.4 mg), P-10 (54.0 mg) and Pl l (35.1 mg).
  • the same ratio of solvent elution fractions is detected by thin layer chromatography and may contain multiple purified compounds.
  • mice were sacrificed by the spine method, the spleen was aseptically taken, ground to make a single cell suspension, and the red blood cells were removed with MTT lysate (10% SDS, 50% DMF), and RPMI containing 10% FBS was used.
  • MTT lysate (10% SDS, 50% DMF)
  • RPMI containing 10% FBS was used.
  • the -1640 medium was adjusted to a cell concentration of 5 x 10 5 /ml.
  • 5 ⁇ 10 5 cell suspension, 200 ⁇ RPMI-1640 medium and appropriate concentration of the sample to be tested were added to the 96-well plate, and cultured in a 37° C., 5 % C0 2 incubator for 48 hours, 5 hours before the end of the culture.
  • 90 ⁇ M of MTT lysate was added to each well, and after standing for 6-7 hours in the incubator, the OD 57 () value was measured at 570 nm using a micro
  • Lymphocyte proliferation assay 5xl0 5 fresh spleen cells according to 37 ° C, 5% C0 2 conditions for 48 hours, the culture was washed with 5 ⁇ ⁇ ⁇ of ConA or LPS induced proliferation, adding the appropriate concentration of sample to be tested To test its inhibitory activity against lymphocyte proliferation.
  • Cell proliferation was quantified by 3 H-TdR infiltration. 25 ⁇ of 3 H-TdR was added to each well 8 hours before the end of the culture, and the culture was completed. The cells were collected on a glass fiber membrane by a cell harvester, scintillation fluid was added, and 3 H-TdR infiltration in the DNA was detected by a liquid scintillation counter. The amount reflects the cell proliferation.
  • CC 5 was calculated based on the toxicity data OD 57Q of the compound against normal mouse spleen lymphocytes. (50% cytotoxic concentration), IC 50 (50% inhibitory concentration) was calculated based on the inhibitory effect of the compound on spleen lymphocyte proliferation in normal mice.
  • the safety index (SI) CC 5 o / IC 5 o is the main parameter for evaluating the safety of a compound. The larger the SI value, the safer the compound.
  • Example 3 Therapeutic effects of compounds P-1 and ⁇ -2 on animal models of autoimmune meningitis
  • Example 4 Therapeutic effect of Compound P-1 on an experimental rheumatoid arthritis animal model
  • the DBA/1 mouse arthritis model was induced using bovine type II collagen (CII).
  • CII bovine type II collagen
  • CII was dissolved in 0.1 M acetic acid solution at 4 ° C overnight.
  • an equal volume of CFA and CII collagen containing Mycobacterium tuberculosis strain H37Rv was fully emulsified and mixed, and 250 ⁇ 8 emulsifier was used for sensitization at the base of DBA/1 mice. After 3 weeks, the same The dose of emulsifier is attacked at the tail.
  • the model mice were confirmed to have an onset one week after the challenge, and oral perfusion administration was started once a day for 2 weeks, and the dose was 20 mg/kg.
  • the P1 treatment group was terminated on the 7th day after the second immunization with CII mice, and the end of the experiment was observed on the 21st day.
  • the severity of arthritis in each of the solvent control group and the P-1 treatment group was observed every day.
  • the severity of joint lesions was graded (0 points: normal; 1 point: mild redness or redness of the toe joints; 2 points: moderate redness and extension to the entire foot; 3 points: heavier redness and extension to the ankle joint; 4 points: toe, foot, and sputum are severely red and swollen, and the joint is straightened after the assessment.
  • each limb arthritis score is between 0 and 4, and the result is limbs.
  • the average form of the sum of the scores is expressed.
  • Figure 3 shows the effect of compound P-1 on the severity of arthritis in mice (*;? ⁇ 0.05, ** ⁇ 0.01).
  • the positive control drug is methotrexate (MTX).
  • FIG 4 and Figure 5 show the effect of P-1 on the pathological changes of arthritis in mice.
  • 4A is the ankle joint tissue section of the normal group (400x);
  • 4B is the ankle joint tissue section of the solvent control group (400x);
  • 4C For the compound P-1 treatment group, the ankle joint tissue section (400x);
  • 4D is the CT scan of the ankle joint of the normal group;
  • 4E is the CT scan of the ankle joint of the solvent control group;
  • 4F is the P-1 treatment Group of mouse ankle CT tomography.
  • Figure 5A shows the ankle joint micro-CT of the solvent control group;
  • Figure 5B shows the ankle joint micro-CT of the P-1 treatment group.
  • ConA was dissolved in physiological saline, ConA was formulated to a concentration of 15 mg/kg in a mouse liver injury test; ConA was formulated to a concentration of 20 mg/kg in a mouse survival rate experiment.
  • the prepared ConA physiological saline solution was passed through a 0.45 ⁇ m filter.
  • Mouse liver injury test Compound P-1 was administered four times in a dose of 10 mg/kg by intraperitoneal injection (ie, countdown 3, 2, 1 and 1 hour before ConA injection). .
  • Mouse sera were collected at various time points after injection of 0.2 ml of 15 mg/kg of ConA into the tail vein of mice, and alanine aminotransferase (ALT) levels were measured.
  • ALT alanine aminotransferase
  • the serum ALT level of the model group began to rise 3 hours after the injection of ConA (15 mg/kg), reached a peak at 12 hours, and then decreased again; the P-1 treatment group was at each time point. Can significantly reduce ALT levels, especially at 6, 12 and 24 hours.
  • mice in the model group After injection of a lethal dose of ConA (20 mg/kg), the mice in the model group all died within 9 hours, while the survival rate of the mice in the P-1 treatment group was 60%; After an hour, the survival rate of the mice in the P-1 treatment group was 40%.
  • NKT cells release a large number of cytokines, including IL-4, IL-5, IFN- ⁇ , and TNF- ⁇ , and the time at which each cytokine appears and peaks is different.
  • IL-4 and IFN- ⁇ have been shown to be key cytokines in the development of ConA-induced liver injury in mice, so we focused on whether P-1 can affect the levels of these two cytokines.
  • the P-1 pre-administered treatment group reduced 70% of IL-4 levels in serum at 2 hours and 6 hours; and reduced serum levels at 6 and 12 hours, respectively. % and 80% IFN- ⁇ levels.
  • Example 6 The crude extract of fragrant skin extract WJ-C for the treatment of experimental rheumatoid arthritis animal model
  • Source of experimental animals purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences, animal production license number: SCXK (Shanghai) 2007-0005
  • RPMI-1640 medium was purchased from Gibco BRL (Life Technologies, Grand Island, NY, USA); fetal bovine serum (FBS) was purchased from Hyclone (Logan, Utah, USA); bovine type II collagen Purchased from Collagen Research Center (Tokyo, Japan); Freund's complete adjuvant containing Mycobacterium tuberculosis strain H37Rv, available from Wako Pure Chemical Industries Ltd (Osaka, Japan).
  • Concanavalin A (Con A) was purchased from Sigma.
  • [Methyl-3H]thymidine (TdR) was purchased from the Shanghai Institute of Applied Physics (formerly Shanghai Institute of Nuclear Research).
  • mice in the model were confirmed one week after the challenge, and oral administration was continued for 2 weeks [WJ-C: 12.5 mg/kg, 25 mg/kg, 52 mg/kg; ammonia Hyperthyroidism (MTX): lmg/kg].
  • WJ-C 12.5 mg/kg, 25 mg/kg, 52 mg/kg
  • MTX ammonia Hyperthyroidism
  • the WJ-C treatment group ended on the 7th day after the second immunization with CII mice, and ended on the 21st day.
  • the solvent control group and WJ-C treatment were observed every day.
  • the severity of arthritic lesions in each mouse in the group were confirmed one week after the challenge, and oral administration was continued for 2 weeks [WJ-C: 12.5 mg/kg, 25 mg/kg, 52 mg/kg; ammonia Hyperthyroidism (MTX): lmg/kg].
  • the WJ-C treatment group ended on the 7th day after the second immunization with CII mice, and

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Abstract

La présente invention concerne des composés prégnane glycosides contenant des groupes ortho-esters, des compositions pharmaceutiques contenant les composés, et leur utilisation dans la préparation d'un immunosuppresseur. Plus particulièrement, l'invention concerne des composés prégnane glycosides contenant des groupes ortho-esters extraits à partir de plantes Periploca, des compositions pharmaceutiques contenant les composés, et leur utilisation dans la préparation d'un immunosuppresseur pour la prévention et/ou le traitement de réactions de rejet immunologique à la suite d'une transplantation de cellules/d'un organe ou de maladies auto-immunes, les maladies auto-immunes comprenant la polyarthrite rhumatoïde, la sclérose en plaques et l'hépatite auto-immune et similaires.
PCT/CN2011/002023 2010-12-15 2011-12-02 Composés prégnane glycosides contenant des groupes ortho-esters et leur utilisation WO2012079279A1 (fr)

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CN201010589234.6A CN102532229B (zh) 2010-12-15 2010-12-15 一类含有原酸酯基团的孕甾烷糖苷类化合物及其用途
CN201010589234.6 2010-12-15

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CN107759653B (zh) * 2016-08-16 2020-05-12 中国科学院上海药物研究所 一类三萜化合物、其制备方法及用途
CN107056855A (zh) * 2017-03-24 2017-08-18 昆明理工大学 一种16,17开环孕甾烷糖苷化合物及其应用
CN108785321B (zh) * 2017-04-28 2021-02-05 南京葆赫生物技术有限公司 黑骨藤c21甾类化合物在制备ido抑制剂中的用途

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CN1593503A (zh) * 2004-07-13 2005-03-16 天津中医学院 香加皮强心作用有效提取物、制备方法及用途
CN1939324A (zh) * 2005-09-29 2007-04-04 中国科学院上海药物研究所 杠柳苷a和e的医学用途

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WANG, LUOYI ET AL.: "Structural revision of periplocosides and periperoxides, natural immunosuppressive agents from the genus Periploca", PHYTOCHEMISTRY, vol. 72, no. 17, 16 August 2011 (2011-08-16), pages 2230 - 2236 *

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