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WO2013029479A1 - Dérivé de l'acide mycophénolique et son procédé de préparation et d'utilisation - Google Patents

Dérivé de l'acide mycophénolique et son procédé de préparation et d'utilisation Download PDF

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WO2013029479A1
WO2013029479A1 PCT/CN2012/080409 CN2012080409W WO2013029479A1 WO 2013029479 A1 WO2013029479 A1 WO 2013029479A1 CN 2012080409 W CN2012080409 W CN 2012080409W WO 2013029479 A1 WO2013029479 A1 WO 2013029479A1
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mpa
methyl
compound
acid
alkyl
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段文虎
左建平
李川
陈炜
唐炜
左理
孔芳园
牛巍
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3

Definitions

  • the present invention relates to a class of mycophenolic acid derivatives having good biological activity, as well as processes for their preparation and their use as immunosuppressive agents.
  • Mycophenolic acid is an immunosuppressive antibiotic belonging to the microbial source. It is produced by the fermentation of Penicillium chrysogenum. In 1896, Gosio first isolated the enzymatic phenolic acid from the corn broth containing Penicillium. And proved that it has antibacterial activity. Since then, studies have shown that it has the advantages of anti-tumor, anti-virus, immunosuppression, anti-psoriatic and anti-inflammatory activities, especially the immunosuppressive activity, but the bioavailability is low. The low bioavailability of mycophenolic acid may be complexation in the stomach and intestine, leading to a narrow absorption window, causing metabolism before absorption. Therefore, researchers are trying to improve the bioavailability or specificity of MPA by making their derivatives.
  • M PA Mycophenolate mofetil is an important mycophenolic acid derivative originally used as an antibacterial and antifungal drug. It was used as an antitumor drug in the clinical practice in the late 1960s. Until the 1980s, Allsion and Nelson found that MPA has the ability to inhibit lymphocytes in vitro when looking for high-selective immunosuppressive agents to treat autoimmune diseases, and they have been used as immunosuppressive agents in clinical practice. In May 1995, the enzyme phenolic acid ester was approved by the US Food and Drug Administration (FDA) to prevent acute rejection of kidney transplantation and achieved good results in later applications. In October 1998, the drug became an immunosuppressive drug officially approved for marketing in the United States. Mycophenolate mofetil increased its bioavailability from 43% of MPA to over 94%.
  • FDA US Food and Drug Administration
  • Sodium mycophenolate is another important mycophenolic acid derivative and was approved by the US FDA in 2004. It is mainly used for the treatment of rejection of allogeneic organ transplantation. Sodium mycophenolate is better tolerated, has bioavailability and stability of concern, and requires a unit dose that is less than MMF, making it more acceptable for patients and improving patient compliance.
  • mycophenolic acid due to the complexation of mycophenolic acid in the gastrointestinal tract, the narrow absorption window, the metabolism before absorption, etc. A series of mycophenolic acid derivatives have been designed and prepared for side effects such as rate and intestinal irritation. We have found that this class of compounds has strong immunosuppressive activity and has not been reported in the literature.
  • An object of the present invention is to provide a class of mycophenolic acid derivatives represented by the following formula V having immunosuppressive activity and pharmaceutically acceptable salts thereof.
  • Another object of the present invention is to provide a process for the preparation of such derivatives and pharmaceutically acceptable salts thereof.
  • It is still another object of the present invention to provide a composition comprising one or more such derivatives and pharmaceutically acceptable salts thereof and pharmaceutically acceptable adjuvants.
  • Another object of the present invention is to provide a medicament for the use of such a derivative and a pharmaceutically acceptable salt thereof as an immunosuppressant, and in particular to provide such a derivative and a pharmaceutically acceptable salt thereof for the preparation of a therapeutic organ Transplants such as skin grafts, kidney transplants, liver transplants, heart transplants, autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, IgA nephritis, glomerulonephritis, etc. Application in .
  • Still another object of the present invention is to provide a metabolic research method for such derivatives and applications thereof.
  • the present invention provides a mycophenolic acid derivative represented by the following formula V, and a pharmaceutically acceptable salt thereof,
  • 1 ⁇ is -0-, -QCOOR 2 or -QCONR 2 R 3 , Q is d do alkylene or CH ⁇ alkenylene, preferably d-C 6 alkylene or d ⁇ C 4 alkenylene, More preferably, it is methylene, ethylene, vinylidene or -CH(CH 3 )CH 2 - ;
  • d alkyl is hydrogen; d alkyl; phenyl; d alkyl substituted with an amine group selected from -NH 2 , an amine group mono- or disubstituted with a Ci-C 4 alkyl group or saturated or unsaturated a five- to six-membered cyclic amine group, the saturated or unsaturated five-membered to six-membered cyclic amine group optionally further containing one hetero atom selected from N, 0, S and optionally by a d-alkyl group or
  • R 2 and R 3 are each independently hydrogen; d ⁇ C 12 alkyl; unsubstituted or substituted phenyl; unsubstituted or substituted naphthyl; unsubstituted or substituted Substituted phenyl d Cs alkyl; d Cs alkoxy d Cs alkyl; C 3 ⁇ C 8 cycloalkyl; or saturated or unsaturated five to six membered heterocyclic C Cs alkyl,
  • the saturated or unsaturated 5- to 6-membered heterocyclic group contains 1 to 2 hetero atoms selected from N, 0, S and is optionally substituted by d Cs alkyl or d Cs alkoxy; preferably, and R 3 is each independently hydrogen, C Cu alkyl, d alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted phenyl d-C 3 alkyl, Naphthyl, ethoxyethyl,
  • the hetero atom in S is optionally substituted by d Cs alkyl or phenyl; preferably, and R 3 is formed together with the nitrogen
  • M is Na, K or Li, etc., preferably Na.
  • the mycophenolic acid derivative represented by the general formula V is as shown in the general formulae (1), (II), (III) and (IV).
  • the mycophenolic acid derivative represented by the general formula V is the following compound: (I):
  • the present invention also provides a method for preparing a mycophenolic acid derivative represented by the formula V and a pharmaceutically acceptable salt thereof, which is carried out as follows:
  • the preparation method of the compound represented by the formula (I) when it is -0-R 2 and the L 2 is -0- includes the following steps:
  • the compound IA is condensed with an alcohol R r OH by an acid or a condensing agent to obtain a compound IB.
  • R 2 is as defined above;
  • the organic base means triethylamine, diisopropylethylamine or pyridine, etc.;
  • the acid means trifluoroacetic acid, acetic acid, concentrated sulfuric acid or p-toluenesulfonic acid,
  • 1-ethyl-3-(3-dimethylpropylamine;) carbodiimide as an example of a compound of formula I prepared by the process of the invention, the following compound is obtained: MPA-1 MPA-2 MPA- 3 MPA-4 MPA-5 MPA-6;
  • R 2 Q is as defined above;
  • organic base means triethylamine, diisopropylethylamine or pyridine, etc.;
  • acid means trifluoroacetic acid, acetic acid, concentrated sulfuric acid or p-toluenesulfonic acid , the condensing agent means 1-ethyl-3-(3-dimethylpropylamine;) carbodiimide hydrochloride;
  • R 2 , R 3 , Q are as defined above;
  • organic base means triethylamine, diisopropylethylamine or pyridine, etc.;
  • acid means trifluoroacetic acid, acetic acid, concentrated sulfuric acid or para a benzenesulfonic acid, a condensing agent means 1-ethyl-3-(3-dimethylpropylamine;) carbodiimide hydrochloride;
  • MPA-30 MPA-31, MPA-32, MPA-33, MPA-34, MPA-35, MPA-36, MPA-37, MPA-38,
  • the mycophenolic acid derivative A reacts with the alcohol R r OH to form a compound D;
  • the mycophenolic acid derivative III is reacted with an organic salt of a metal or an organic amine to obtain a compound IV;
  • R 2 , R 3 , Q and M are as defined above, the metal organic salt is sodium methoxide or sodium ethoxide, and the organic amine is triethylamine, pyridine or diisopropylethylamine. Wait;
  • the compounds of the formula (1), (II), (HI), (IV) prepared by the above method provided by the present invention have strong immunosuppressive activity, and the novel compounds can be applied to the rejection reaction after xenotransplantation, itself Immune disease.
  • Figure 1 is the experimental example 2 dinitrofluorobenzene (DNFB) induced delayed type hypersensitivity (DTH) in mice;
  • DNFB dinitrofluorobenzene
  • DTH delayed type hypersensitivity
  • Figure 2 is the survival rate of experimental example 3 aGVHD mice
  • Figure 3 is a graph showing changes in body weight of agVHD mice in Experimental Example 3;
  • Figure 4 is a heterotopic skin survival rate of a mouse skin graft model of Experimental Example 4.
  • Figure 5 shows the pharmacogene comparison of MMF, MPA, MPA-38, MPA-8, and MPA-6.
  • Nuclear magnetic resonance was measured by Bruker AM-400 and Varian Mecury Plus-300 NMR, and the internal standard used was TMS. Mass spectra were determined by Varian MAT-711, MAT-95 and HT-5989 mass spectrometers.
  • the initial reactants were obtained from Sinopharm Chemical Reagent Co., Ltd., Shanghai Darui Fine Chemicals Co., Ltd., Changzhou Huaren Chemical Co., Ltd. and Shanghai Laiying Chemical Co., Ltd. without further processing.
  • the silica gel used in the rapid column chromatography is Qingdao Ocean Chemical Factory product (200 ⁇ 300 mesh;), petroleum ether (60 ° C ⁇ 90 ° C;), dichloromethane and ethyl acetate are used for analytical or industrial re-steaming.
  • Thin layer chromatography was performed on HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Experimental Factory, and developed with 10% phosphomolybdic acid ethanol solution and 2,4-dinitrophenylhydrazine solution.
  • the drying solvent used in the reaction was treated in a conventional manner, and the anhydrous reaction was carried out under a nitrogen atmosphere in a dry solvent.
  • Example 7 (E)-6-(l,3-Dihydro-4-isobutoxycarbonyl-6-methoxy-7-methyl-3-oxobenzofuran-5-yl) Preparation of -4-methyl-4-hexenoic acid (MPA-3) The same procedure as in Example 5 except that isobutyl chloroformate was used in place of methyl chloroformate gave the title compound (yield: 33%).
  • Example 15 The same procedure as Example 15 was carried out except that 3-(N-2-fluorobenzylcarbamoyl;)propionic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 54%).
  • Example 15 The same procedure as Example 15 was carried out except that 3-(N-4-fluorobenzylcarbamoyl;)propionic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 43%).
  • Example 15 The same procedure as in Example 15 was carried out except that 3-(N-4-methoxybenzylcarbamoyl;)propionic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. (Yield: 51%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-methylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl)propionic acid to give the title compound (yield: 71 %).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-tert-butylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: 48%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-n-butylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: 62%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-cyclohexylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: 63 %).
  • Example 27 (E)-6-(l,3-Dihydro-4-(4-(N-n-undecylcarbamoyl)butyryloxy)-6-methoxy-7-methyl Preparation of -3-oxobenzofuran-5-yl;)-4-methyl-4-hexenoic acid (MPA-22) The same procedure as in Example 15 was carried out except that 4-(N-n-undecylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 67%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-cyclopropylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: 47%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-phenylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: 39 %).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-4-fluorophenylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 39%).
  • Example 15 The same procedure as in Example 15 was carried out except that 4-(N-4-chlorophenylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 37%).
  • Example 15 The same procedure as in Example 15 was carried out except that 4-(N-3-methoxyphenylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. (Yield: 35%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-4-methoxyphenylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. (Yield: 48%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N,N-diethylcarbamoyl;)butyric acid was used in place of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 20%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-benzylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl)propionic acid to give the title compound (yield: 54 %).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-2-fluorobenzylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 38%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-4-fluorobenzylcarbamoyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 48%).
  • Example 15 The same procedure as in Example 15 was carried out except that 4-(indole- ⁇ -furylcarbamoyl;)butyric acid was used instead of 3-(indole-benzylcarbamoyl;)propionic acid to give the title compound (yield : 52%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(pyrrolidinylcarbonyl)butyric acid was used in place of 3-(N-benzylcarbamoyl)propionic acid to give the title compound (yield: 43%).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(1-morpholinylcarbonyl;)pentanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: 12 %).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-methylpiperazinylcarbonyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield : %;).
  • Example 15 The same procedure as Example 15 was carried out except that 4-(N-phenylpiperazinylcarbonyl;)butyric acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield : 69%).
  • Example 15 The same procedure as Example 15 was carried out except that 5-(N-cyclopropylcarbamoyl;)pentanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: %;).
  • Example 15 The same procedure as Example 15 was carried out except that 5-(N-phenylcarbamoyl;)pentanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: 52 %).
  • Example 15 The same procedure as in Example 15 was carried out except that 5-(N-2-methoxyphenylcarbamoyl;)pentanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. (Yield: 36%).
  • Example 15 The same procedure as Example 15 was carried out except that 5-(indole- ⁇ -naphthylcarbamoyl;)pentanoic acid was used instead of 3-(indole-benzylcarbamoyl;)propionic acid to give the title compound (yield : 16%).
  • Example 15 The same procedure as in Example 15 was carried out except that 5-(N,N-diethylcarbamoyl;)pentanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 36%).
  • Example 15 The same procedure as Example 15 was carried out except that 5-(N-benzylcarbamoyl;)pentanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound (yield: 50 %).
  • Example 15 The same procedure as Example 15 was carried out except that 5-(N-2-fluorobenzylcarbamoyl;)pentanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound Rate: 41%).
  • Example 15 The same procedure as Example 15 was carried out except that 5-(indole- ⁇ -furylcarbamoyl;)pentanoic acid was used instead of 3-(indole-benzylcarbamoyl;)propionic acid to give the title compound (yield : 29%).
  • Example 15 The same procedure as Example 15 was carried out except that 5-(piperidinylcarbonyl) pentanoic acid was used instead of 3-(N-benzylcarbamoyl)propionic acid to give the title compound (yield: 40%). .
  • Example 15 The same procedure as in Example 15 was carried out except that 5-(N-phenylpiperazinylcarbonyl) pentanoic acid was used instead of 3-(N-benzylcarbamoyl; : 12%).
  • Example 15 The same procedure as Example 15 was carried out except that 6-(N-4-fluorobenzylcarbamoyl;)hexanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. Rate: 43%).
  • Example 15 The same procedure as Example 15 was carried out except that 6-(N-4-methoxybenzylcarbamoyl;)hexanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. (Yield: 43%).
  • Example 15 The same procedure as Example 15 was carried out except that 6-(N-4-methoxyphenylcarbamoyl;)hexanoic acid was used instead of 3-(N-benzylcarbamoyl;)propionic acid to give the title compound. (Yield: 37%).
  • Example 15 The same procedure as Example 15 was carried out except that 7-(N-benzylcarbamoyl;)heptanoic acid was used instead of 3-(N-benzylcarbamoyl)propionic acid to give the title compound (yield: 63 %).
  • the spleen of the mouse was aseptically prepared, and a single cell suspension was prepared. After the red blood cells were removed, the cell concentration was adjusted with RPMI-1640 medium containing 10% fetal bovine serum (FBS). Cell proliferation was induced by adding 5 ⁇ / ⁇ 1 of ConA to 5x105/well mouse spleen cells, and each compound was tested for activity by adding it at an appropriate concentration. Incubate for 48 hours at 37 ° C, 5% C0 2 incubator, and add 25 ⁇ 3H-TdR to each well 8 hours before the end of the culture. The culture is finished. Collect the cells on the glass fiber membrane with a cell harvester and add scintillation fluid. The amount of 3H-TdR infiltration in DNA was measured by a liquid scintillation counter to reflect cell proliferation.
  • FBS fetal bovine serum
  • MPA-93 ⁇ 0.078 activity data showed that this kind of compound has a good immunosuppressive effect on ConA-induced lymphocyte proliferation in vitro, and its activity is equivalent to mycophenolic acid MPA. Note: The half cytotoxic concentration of the compound is tested for CC 5 . Both were greater than 20 ⁇ , indicating that the compound was less in vitro.
  • DNFB Dinitrofluorobenzene-induced delayed sensitization (DTH) inhibitory activity in mice:
  • the compounds of the present invention significantly inhibit dinitrofluorobenzene (DNFB)-induced delayed type hypersensitivity (DTH) in mice,
  • DNFB dinitrofluorobenzene
  • DTH delayed type hypersensitivity
  • Allogeneic bone marrow transplantation is currently the most effective method for the treatment of hematological malignancies and some severe non-malignant hematological diseases, such as acute and chronic leukemia, malignant lymphoma, multiple myelopathy and other malignant hematological diseases and aplastic anemia, myelodysplastic synthesis
  • Non-malignant hematological diseases such as septic and refractory anemia.
  • acute graft-versus-host disease (aGVHD) is a very serious complication of bone marrow transplantation, which directly affects patient survival and quality of life. Skin, mucous membranes, the gastrointestinal tract and the liver can all be targets of attack.
  • the allogeneic bone marrow transplantation model is a commonly used model for replicating acute GVHD. Using this model, C57BL/6 mice were used as recipients, BABL/C mice were used as donors, and spleen lymphocytes and bone marrow cells were transplanted together to establish aGVHD model. Mycophenolic acid derivatives were administered orally to observe immunity. The adjustment effect, the experimental results are shown in Figures 2 and 3.
  • MPA-38 has an obvious anti-mouse aGVHD effect, which improves the body weight loss of mice and improves the survival rate of mice.
  • a heterologous mouse skin transplantation model was established. BABL/C mice were used as donors, and C57BL/6 mice were used as recipients. The donor mouse tail skin was transplanted to the back of recipient mice, and the compound was observed after oral administration. Survival of grafts after skin transplantation in heterologous mice. MMF combined with continuous low-dose cyclosporine (CsA) is a common treatment for transplant rejection.
  • CsA oral 5mg/Kg
  • MMF oral 40mg/Kg
  • CsA oral 5mg/Kg
  • MPA-38 MPA-38.

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Abstract

La présente invention concerne un dérivé de l'acide mycophénolique représenté par la formule générale (V) et ses sels pharmaceutiquement acceptables, dans laquelle L1 est -O-R2, -QCOOR2 ou -QCONR2R3, Q est alkylidène C1~C10 ou alkénylène C1~C6; L2 est -O-R1 ou -O-·M+. L'invention concerne également une composition pharmaceutique contenant le dérivé de l'acide mycophénolique et ses sels pharmaceutiquement acceptables et des adjuvants médicinaux; le procédé de préparation du dérivé de l'acide mycophénolique et ses sels pharmaceutiquement acceptables; et l'utilisation du dérivé de l'acide mycophénolique et ses sels pharmaceutiquement acceptables comme agents immunosuppresseurs.
PCT/CN2012/080409 2011-08-26 2012-08-21 Dérivé de l'acide mycophénolique et son procédé de préparation et d'utilisation Ceased WO2013029479A1 (fr)

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CN201110247876.2 2011-08-26
CN2011102478762A CN102952105A (zh) 2011-08-26 2011-08-26 一类霉酚酸衍生物、其制备方法和用途

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