WO1994028892A1 - Inhibiteur du rejet accompagnant une transplantation d'organe - Google Patents
Inhibiteur du rejet accompagnant une transplantation d'organe Download PDFInfo
- Publication number
- WO1994028892A1 WO1994028892A1 PCT/JP1994/000925 JP9400925W WO9428892A1 WO 1994028892 A1 WO1994028892 A1 WO 1994028892A1 JP 9400925 W JP9400925 W JP 9400925W WO 9428892 A1 WO9428892 A1 WO 9428892A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- rejection
- pharmaceutically acceptable
- inhibitor
- organ transplantation
- Prior art date
Links
- 210000000056 organ Anatomy 0.000 title claims abstract description 19
- 238000002054 transplantation Methods 0.000 title claims abstract description 19
- 239000003112 inhibitor Substances 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 159000000007 calcium salts Chemical class 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 4
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000002505 iron Chemical class 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 159000000000 sodium salts Chemical group 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical class NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 1
- 239000004472 Lysine Substances 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 206010052779 Transplant rejections Diseases 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- 229910052742 iron Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000006186 oral dosage form Substances 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical class OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 5
- -1 mycophenolate ester Chemical class 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000001506 immunosuppresive effect Effects 0.000 description 4
- 229960000951 mycophenolic acid Drugs 0.000 description 4
- 230000010349 pulsation Effects 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- WLNBMPZUVDTASE-HXIISURNSA-N (2r,3r,4s,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;sulfuric acid Chemical compound [O-]S([O-])(=O)=O.O=C[C@H]([NH3+])[C@@H](O)[C@H](O)[C@H](O)CO.O=C[C@H]([NH3+])[C@@H](O)[C@H](O)[C@H](O)CO WLNBMPZUVDTASE-HXIISURNSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229940030999 antipsoriatics Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002683 reaction inhibitor Substances 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- JZXYEMZTQVSTJC-UHFFFAOYSA-N 4-isocyanatobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(N=C=O)C=C1 JZXYEMZTQVSTJC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- CUWYKVMNNGRAOW-IZZDOVSWSA-N ethyl (e)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound CC1=C(OC)C(C/C=C(C)/CCC(=O)OCC)=C(O)C2=C1COC2=O CUWYKVMNNGRAOW-IZZDOVSWSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 229940014456 mycophenolate Drugs 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
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- 230000001629 suppression Effects 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
Definitions
- the present invention relates to a rejection inhibitor capable of suppressing rejection associated with organ transplantation.
- mycophenolic acid derivative Z or CAM The substance itself of a mycophenolic acid derivative represented by the following formula (I) (hereinafter abbreviated as a mycophenolic acid derivative Z or CAM) itself has already been disclosed in JP-A-48-23756. Are shown and known. On the other hand, regarding the pharmaceutical use of this compound, its effect as an anticancer agent has been known. Also, a wide range of compounds including mycophenolic acid derivative Z (CAM) are disclosed in U.S. Patent No. 4,959,387, and these compounds have anti-inflammatory, anti-tumor, anti-viral, It is described that it can be used for therapeutic drugs such as anti-psoriasis and rheumatism. Also, US Pat. No.
- 4,727,069 discloses similar pharmaceutical uses for similar mycopentanoleic acid derivatives.
- the above-mentioned 2 ⁇ 2 patent gazette states that it can be used as a therapeutic drug for anti-inflammatory, anti-tumor, anti-viral, anti-psoriasis, rheumatic, etc.
- the experimental data showing is not disclosed.
- these US patents do not specifically disclose mycophenolic acid derivative Z (CAM).
- mycophenolic acid derivative Z has a conventional immunosuppressive effect such as anti-inflammatory and anti-dryness
- a description that specifically discloses the effect and shows the efficacy In fact, it is actually effective as a reaction inhibitor in organ transplantation. Had not been proven.
- the mycophenolic acid derivative Z (CAM) is rejected due to organ transplantation. It is by no means easy to assume that it is effective as a reaction inhibitor.
- U.S. Patent No. 4,786,637 describes that mycophenolic acid derivatives having a morpholinoethyl group at the end can be used as an inhibitor of rejection and a therapeutic agent for rheumatism. No mention is made of the mycophenolic acid derivative Z (CAM) itself. Disclosure of the invention
- a mycophenolic acid derivative Z represented by the following formula (I) is a drug having an excellent effect on suppressing rejection reactions associated with organ transplantation.
- the present invention has been completed.
- the present invention provides an agent for suppressing rejection associated with organ transplantation, comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
- Pharmaceutical carriers include, for example, lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethinolecellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, Carboxymethylenocellulose calcium salt, magnesium stearate, Yunorek, acetyl cellulose, sucrose, titanium oxide, benzoic acid, para-hydroxybenzoate, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, White sugar, simple syrup, citric acid, distilled water, ethanol, glycerin, propylene glycol, macrogol, sodium monohydrogen phosphate, glucose, sodium chloride And phenol, thimerosal, paraoxybenzoic acid ester, sodium bisulfite, etc. It is used by mixing with this compound according to the form of the preparation.
- mycophenolic monooleic acid derivative Z As an example of producing the mycophenolic monooleic acid derivative Z (CAM), first, mycophenolic acid ethyl ester and p-isocyanatobenzoyl chloride are added in the presence of an organic amine having no active hydrogen in the molecule. To form a compound in which the hydroxyl group of the mycophenolate ester is converted back to a single O (0) CNHPhCOCl group (wherein, Ph represents a phenyl group), which is then converted to water or alcohol or the like. It can be produced by treating with a hydroxyl group-containing compound.
- Mycophenolic acid derivative Z is administered orally, intravenously, transdermally, etc. to mammals including organ transplant recipients at a dose of 0.1 to 10 Oing / Kg can do. Of these, oral administration is preferred. It is also preferable to administer the mycophenolic acid derivative Z (CAM) continuously after receiving the organ transplant, for example, immediately after receiving the organ transplant. It can also be administered.
- the target organ transplant includes heart, lung, liver, kidney, intestine and skin transplant.
- Intra-abdominal heart transplantation was performed by the Ono-Lindsey method using the F344 rat (RT1-1V-1) as a donor animal (dona one) and the WKAH rat as a transferred plant (recipient).
- Untreated group was group A, mycophenolic acid derivative Z used in the present invention
- the mycophenolic acid derivative Z (CAM) used in the present invention in the in vivo test is significantly more effective in organ transplantation in oral administration than the known mycophenolic acid compound X under development. It can be said that it is the rejection reaction suppression accompanying with. Table 1 1 Medication is given
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
L'invention se rapporte à un agent inhibiteur du rejet accompagnant une transplantation d'organe, cet agent contenant comme principe actif un dérivé d'acide mycophénolique représenté par la formule générale (I) ou un sel pharmaceutiquement acceptable de ce dérivé, et ayant une excellente action d'inhibition des phénomènes de rejet.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5/137965 | 1993-06-08 | ||
| JP13796593 | 1993-06-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994028892A1 true WO1994028892A1 (fr) | 1994-12-22 |
Family
ID=15210877
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1994/000926 WO1994028893A1 (fr) | 1993-06-08 | 1994-06-08 | Remede contre les maladies auto-immunes dites 'systemiques' ou contre des maladies inflammatoires du systeme nerveux |
| PCT/JP1994/000925 WO1994028892A1 (fr) | 1993-06-08 | 1994-06-08 | Inhibiteur du rejet accompagnant une transplantation d'organe |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1994/000926 WO1994028893A1 (fr) | 1993-06-08 | 1994-06-08 | Remede contre les maladies auto-immunes dites 'systemiques' ou contre des maladies inflammatoires du systeme nerveux |
Country Status (1)
| Country | Link |
|---|---|
| WO (2) | WO1994028893A1 (fr) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4886859A (fr) * | 1972-02-24 | 1973-11-15 | ||
| JPS57183777A (en) * | 1981-05-01 | 1982-11-12 | Ajinomoto Co Inc | Preparation of mycophenolic acid derivative |
-
1994
- 1994-06-08 WO PCT/JP1994/000926 patent/WO1994028893A1/fr active Application Filing
- 1994-06-08 WO PCT/JP1994/000925 patent/WO1994028892A1/fr active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4886859A (fr) * | 1972-02-24 | 1973-11-15 | ||
| JPS57183777A (en) * | 1981-05-01 | 1982-11-12 | Ajinomoto Co Inc | Preparation of mycophenolic acid derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994028893A1 (fr) | 1994-12-22 |
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