CN101600435A - 多发性硬化症治疗剂 - Google Patents
多发性硬化症治疗剂 Download PDFInfo
- Publication number
- CN101600435A CN101600435A CNA2008800032965A CN200880003296A CN101600435A CN 101600435 A CN101600435 A CN 101600435A CN A2008800032965 A CNA2008800032965 A CN A2008800032965A CN 200880003296 A CN200880003296 A CN 200880003296A CN 101600435 A CN101600435 A CN 101600435A
- Authority
- CN
- China
- Prior art keywords
- multiple sclerosis
- chlorphenyl
- pyridazin
- benzyl
- administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 201000006417 multiple sclerosis Diseases 0.000 title claims abstract description 39
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 239000012453 solvate Substances 0.000 claims abstract description 14
- HEUAVAATAFEENP-UHFFFAOYSA-N 2-benzyl-5-(4-chlorophenyl)-6-(4-methylsulfanylphenyl)pyridazin-3-one Chemical compound C1=CC(SC)=CC=C1C(C(=CC1=O)C=2C=CC(Cl)=CC=2)=NN1CC1=CC=CC=C1 HEUAVAATAFEENP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000004615 ingredient Substances 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 4
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 13
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 13
- 230000000694 effects Effects 0.000 description 11
- 210000000278 spinal cord Anatomy 0.000 description 10
- 206010070834 Sensitisation Diseases 0.000 description 9
- 230000008313 sensitization Effects 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 108020004999 messenger RNA Proteins 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 6
- 230000008595 infiltration Effects 0.000 description 6
- 238000001764 infiltration Methods 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- -1 sucrose fatty acid ester Chemical class 0.000 description 6
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 102000003777 Interleukin-1 beta Human genes 0.000 description 4
- 108090000193 Interleukin-1 beta Proteins 0.000 description 4
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- 102000006386 Myelin Proteins Human genes 0.000 description 4
- 108010083674 Myelin Proteins Proteins 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- 102000002233 Myelin-Oligodendrocyte Glycoprotein Human genes 0.000 description 3
- 108010000123 Myelin-Oligodendrocyte Glycoprotein Proteins 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010037714 Quadriplegia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 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
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- YLOCGHYTXIINAI-XKUOMLDTSA-N (2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 YLOCGHYTXIINAI-XKUOMLDTSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-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
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 108010072051 Glatiramer Acetate Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 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 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 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
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical class [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 2
- 229940043276 diisopropanolamine Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229940042385 glatiramer Drugs 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 230000001861 immunosuppressant effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000005012 myelin Anatomy 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 125000005274 4-hydroxybenzoic acid group Chemical class 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 229920001817 Agar Polymers 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
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101001054334 Homo sapiens Interferon beta Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000035617 depilation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000009034 developmental inhibition Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000007849 functional defect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 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
- 239000011707 mineral Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 208000020911 optic nerve disease Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001915 proofreading effect Effects 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108020004418 ribosomal RNA Proteins 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
Images
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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种对多发性硬化症具有高的有效性、安全性优异、能够口服给药的多发性硬化症的预防和/或治疗剂。该多发性硬化症的预防和/或治疗剂将2－苄基－5－(4－氯苯基)－6－[4－(甲硫基)苯基]－2H－哒嗪－3－酮或其溶剂化物作为有效成分。
Description
技术领域
本发明涉及一种新型的多发性硬化症的预防和/或治疗剂。
背景技术
多发性硬化症是一种表现为因脑和脊髓的脱髓引起的中枢性功能不全，引起视觉障碍、运动障碍等的疾病，是一种被日本厚生劳动省指定为特殊疾病的原因不明的疑难疾病。在欧美，在困扰年轻成年人的神经疾病中发病率最高，每10万人中有50人左右。在日本的发病率估计每10万人中有8～9人左右，推测大约有1万2000个患者。多发性硬化症发病时，多数情况下，症状是反复缓解和复发(复发缓解型)。多发性硬化症尤其多发于30岁前后，随着年龄增加复发减少，但是一部分患者的病状急剧发展(慢性进行型)。在患者的病变部位可以确认T细胞和巨噬细胞的浸润，这些细胞被认为在中枢神经内破坏髓磷脂蛋白、破坏髓鞘，其结果引起神经障碍(非专利文献1)。脱髓斑在整个中枢神经系统分布广泛，高发部位为视神经、脑干、脊髓、小脑等。病状基于神经障碍引起的部位而不同，表现为四肢麻痹、震颤、疲劳、视神经障碍、排尿·排便障碍等各种症状。发病的详细机制等有很多不明之处，但由于免疫抑制剂显示效果，可以认为不是自身免疫疾病的一种(非专利文献2)。另外，也有报道称，在多发性硬化症的发病中，与伴随病毒、细菌的感染的免疫系统的活化相关(非专利文献3)。
实际上，在多发性硬化症的病变部位，可以发现特征性的T细胞、单核细胞/巨噬细胞的浸润，暗示这些细胞产生的Th1型细胞因子(干扰素γ等)与病状相关联(非专利文献4)。由此，考虑通过抑制这些细胞向病变部位的浸润，能够期待取得对多发性硬化症的治疗效果。
作为目前的治疗方法，在发病期使用类固醇剂，在缓解期使用干扰素β(IFNβ)制剂、格拉默(glatiramer)制剂。IFNβ制剂作用于T细胞并调节干扰素γ的产生量，并且通过使抗原提呈细胞的抗原提呈降低(非专利文献5)而抑制免疫应答的增强，与多发性硬化症的症状的延缓发展以及复发频率的减少相关。但是，即使将这些药剂进行给药，平均每年也有0.8次左右的复发发生，现状是至今仍没有能够确实防止复发的方法(非专利文献6)。另外，这需要频繁地进行皮下给药，存在发热·皮下溃疡等副作用的问题，依从性方面也对患者造成极大的负担，因此，能够通过口服给药的药剂具有极大的意义。另一方面，有报告称对于重症进行性的患者，免疫抑制剂环磷酰胺的脉冲疗法是有效的，但是，白血球减少、脱毛等副作用强，要求谨慎给药。根据这种状况，强烈希望开发一种有效的治疗方法。
另一方面，作为公知物质的2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮，如专利文献1中的记载，具有优异的抑制白介素-1β的产生的作用，适用于风湿、关节炎、骨质疏松症、炎症性肠炎、免疫缺陷综合症、败血症、肝炎、肾炎、虚血性疾病、胰岛素依赖型糖尿病、动脉硬化、帕金森病、阿尔茨海默氏病、白血病等的预防、治疗。但是，至今没有对多发性硬化症的应用进行过报道。
专利文献1：国际公开号WO99/25697号小册子
非专利文献1：Noseworthy等；N Engl J Med.343卷13号938-52页(2000)
非专利文献2：Neuhaus等；Trends Pharmacol Sci.24卷3号131-8页(2003)
非专利文献3：Tejada-Simon等；Ann Neurol.53卷189-97页(2003)
非专利文献4：Bielekova等；Nat Med.6卷1167-75页(2000)
非专利文献5：Joseph等；J Neuroimmunol.20卷1号39-44页(1988)
非专利文献6：The IFNB Multiple Sclerosis Study Group；Neurology43卷4号655-61页(1993)
发明内容
本发明的目的在于提供一种对多发性硬化症具有高的有效性、安全性优异、能够口服给药的多发性硬化症的预防和/或治疗剂。
本发明的发明者们对以上现状进行深入的研究，结果发现通过将2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮进行给药，能够确认优异的对多发性硬化症的症状的抑制作用，从而完成本发明。
即，本发明提供如下的技术方案。
1)一种多发性硬化症的预防和/或治疗剂，其将2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物作为有效成分。
2)一种多发性硬化症的预防和/或治疗用医药组合物，其含有2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物以及药学上可接受的载体。
3)一种多发性硬化症的预防和/或治疗方法，将有效量的2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物进行给药。
4)2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物在制造多发性硬化症的预防和/或治疗药中的使用。
5)2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物用于预防和/或治疗多发性硬化症。
发明效果
本发明的多发性硬化症的预防和/或治疗剂能够口服给药，显示优异的多发性硬化症的抑制作用，对多发性硬化症的预防和/或治疗有效。
附图说明
图1是表示对实验性自身免疫性脑脊髓炎得分的变化的药剂效果的图。
图2是表示对最大发病得分的药剂效果的图。
图3是表示对实验性自身免疫性脑脊髓炎小鼠脊髓中F4/80的mRNA表达量的药剂效果的图。
图4是表示对实验性自身免疫性脑脊髓炎小鼠脊髓中TNF-α的mRNA表达量的药剂效果的图。
图5是表示对实验性自身免疫性脑脊髓炎小鼠脊髓中IL-1β的mRNA表达量的药剂效果的图。
图6是表示对实验性自身免疫性脑脊髓炎小鼠脊髓中IL-6的mRNA表达量的药剂效果的图。
具体实施方式
本发明的多发性硬化症的预防和/或治疗剂中所使用的2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮是公知物质，例如可以利用国际公开第99/25697号公报记载的方法或其类似方法进行制造。
另外，2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮能够在以水合物为代表的溶剂化物的形态下存在，这些溶剂化物也包含于本发明中。
如后述的实施例所示，通过将2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物进行给药，在使用作为多发性硬化症的动物模型而被广泛认可的实验性自我免疫性脑脊髓炎模型小鼠的评价体系中，暗示对脊髓的巨噬细胞浸润的抑制作用，显示优异的多发性硬化症的抑制作用。因此，根据本发明，能够进行多发性硬化症的发病预防、复发预防、发展抑制、治疗，并且能够改善其病况。
本发明的多发性硬化症的预防和/或治疗剂的给药形态，没有特别限定，可以根据治疗目的进行适当选择，例如可以列举片剂、胶囊剂、颗粒剂、薄膜包衣剂、散剂、糖浆剂等口服给药形态或注射剂、栓剂、吸入剂、经皮吸收剂、滴眼剂、滴鼻剂等非口服给药形态。优选作成口服给药制剂。
在适合这些给药形态的医药制剂中，除了药学上可接受的载体，例如淀粉类、乳糖、蔗糖、甘露醇、硅酸等赋形剂以及增量剂；琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、复合硅酸盐等崩解剂；羟基丙基甲基纤维素、甲基纤维素、羧甲基纤维素钠、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖、阿拉伯树胶等结合剂；滑石、硬脂酸钙、硬脂酸镁、固形聚乙二醇类、十二烷基硫酸钠或其混合物等润滑剂；乳糖、玉米淀粉等稀释剂；柠檬酸、磷酸、酒石酸、乳酸等有机酸、盐酸等无机酸、氢氧化钠、氢氧化钾等氢氧化碱、三乙醇胺、二乙醇胺、二异丙醇胺等有机胺类等缓冲剂；对羟基安息香酸酯类、苯扎氯铵等防腐剂；硬脂酸钙、硬脂酸镁、十二烷基硫酸钠等阴离子性表面活性剂，苯扎氯铵、苄索氯铵、西吡氯铵等阳离子性表面活性剂，单硬脂酸甘油酯、蔗糖脂肪酸酯、聚氧乙烯硬化蓖麻油、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧乙烯脂肪酸酯、聚氧化乙烯烷基醚等非离子性表面活性剂等的乳化剂；亚硫酸钠、亚硫酸氢钠、二丁基羟基甲苯、丁基羟基茴香醚、乙二胺四乙酸等稳定剂以外，必要时还可以适当地组合使用矫味剂、分散剂、保存剂、香料等。
本发明中，2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物的给药量，可以考虑患者的体重、年龄、性别、症状等方面适当选择，通常情况下，成人每天给药2～320mg，优选4～160mg，分1次或数次进行给药。
实施例
以下通过列举实施例，对本发明进行更具体的说明，但是本发明的技术范围不被这些实施例限定。
实施例1
对实验性自身免疫性脑脊髓炎模型小鼠给药2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮(以下表示为药剂A)，评价症状。实验性自身免疫性脑脊髓炎模型通过用作为髓鞘的构成蛋白的髓磷脂蛋白免疫小鼠，在中枢神经系统内通过T细胞引发自身免疫性炎症。在该模型中，发生T细胞、单核细胞/巨噬细胞向中枢系统的浸润，可知为显示与多发性硬化症的病状相似的表现的模型。
A材料和方法
动物使用7周龄雌性C57BL/6(日本Charles River(株))。关于使小鼠发生实验性自身免疫性脑脊髓炎的致敏用乳液，将MyelinOligodendrocyte Glycoprotein(MOG)35-55(Alexis Biochemical)和Adjuvant complete freund H37 Ra(DIFCO)以MOG浓度为2mg/mL等量添加，使用Handy Micro Homogenizer((株)Microtec Nition制)，在冰浴下均质化调制。将调制成的乳液0.1mL向小鼠的尾根部进行皮内给药，进行初次致敏。同日，对尾部静脉给药溶解于生理盐水的Purtussis toxin 500ng/0.3mL。初次致敏2天后，同样进行静脉给药Purtussis toxin 500ng/0.3mL，进行追加致敏。从初次致敏的第二天到致敏后42天后，将药剂A以30mg/kg在早晨(9:00～11:00)和傍晚(15:30～17:30)两次口服给药。IFNβ(日本Schering)隔天以10000国际单位/个体进行皮下给药。
实验性自身免疫性脑脊髓炎的症状根据以下项目进行得分评价。
0 没有症状
1 尾部乏力或者步行异常
2 尾部乏力并且步行异常
3 1只的四肢麻痹
4 2只以上的四肢麻痹
5 死亡
B 结果
图1表示得分评价的变化，表1表示各个体的发病时间的解析，图2表示各个体的最大得分的解析结果。结果以全部例数10只的平均值±标准误差表示。检定使用非参数Dunnett试验。
实验中，对照组在致敏后16天后发生死亡例，IFNβ给药组在致敏后12天、37天、40天后发生死亡例。另一方面，药剂A给药组没有出现死亡例。通过药剂A的口服给药，表现与IFNβ大约同等的实验性自身免疫性脑脊髓炎得分的改善(图1)，另外，出现得分2以上的发病延迟的倾向(表1)，并且，各个体的最大实验性自身免疫性脑脊髓炎得分出现降低的倾向(图2)。
[表1]
实验性自身免疫性脑脊髓炎发病开始天数的解析结果
*p＜0.05使用Dunnett与对照组相比(Versus Control using Dunnett)
实施例2
A材料和方法
将实验例1中使用的小鼠在第42天取出脊髓，使用ISOGEN(Nippon Gene)精制RNA。作为比较，同样从没有致敏的正常小鼠中取出脊髓以供测定。由获得的RNA使用逆转录酶合成cDNA，根据Applied Biosystems社的实验方案，通过使用TaqMan探针的real-timePCR方法对各种基因(F4/80、TNF-α、IL-1β、IL-6)的mRNA量进行定量(ABI PRISM7900HT系统；Applied Biosystems社)。同时测定核糖体RNA量，用于校正。
B结果
实验性自身免疫性脑脊髓炎模型中，显示各种基因的mRNA量都比正常小鼠高。相对于此，药剂A给药小鼠中，在单核细胞/巨噬细胞系细胞特异性表达的F4/80的mRNA表达量降低，暗示脊髓中单核细胞/巨噬细胞系细胞的浸润受到抑制。另外，也能够确认主要通过这些细胞产生、显示与多发性硬化症的病状紧密相关性的TNF-α、IL-1β、IL-6等细胞因子量的表达受到抑制。另一方面，IFNβ给药小鼠中，IL-1β、IL-6表达受到抑制，但TNFα的表达没有受到抑制。并且，F4/80的mRNA的表达抑制与药剂A相比较弱。
根据以上结果，本发明的药剂A或其溶剂化物，对多发性硬化症的发病预防、复发预防、发展抑制、治疗、病状改善等有效，作为多发性硬化症的预防和/或治疗剂有效。
Claims (6)
1.一种多发性硬化症的预防和/或治疗剂，其特征在于：
将2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物作为有效成分。
2.如权利要求1所述的多发性硬化症的预防和/或治疗剂，其特征在于：其是口服给药制剂。
3.2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物在制造多发性硬化症的预防和/或治疗药中的使用。
4.如权利要求3所述的使用，其特征在于：
所述预防和/或治疗药是口服给药用医药。
5.一种多发性硬化症的预防和/或治疗方法，其特征在于：
将有效量的2-苄基-5-(4-氯苯基)-6-[4-(甲硫基)苯基]-2H-哒嗪-3-酮或其溶剂化物进行给药。
6.如权利要求5所述的方法，其特征在于：
给药方式是口服给药。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP017328/2007 | 2007-01-29 | ||
| JP2007017328 | 2007-01-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101600435A true CN101600435A (zh) | 2009-12-09 |
Family
ID=39673809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008800032965A Pending CN101600435A (zh) | 2007-01-29 | 2008-01-28 | 多发性硬化症治疗剂 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US20100075972A1 (zh) |
| EP (1) | EP2127653A1 (zh) |
| JP (1) | JPWO2008093495A1 (zh) |
| KR (1) | KR20090114371A (zh) |
| CN (1) | CN101600435A (zh) |
| AU (1) | AU2008211480A1 (zh) |
| BR (1) | BRPI0805841A2 (zh) |
| CA (1) | CA2669563A1 (zh) |
| EA (1) | EA200970720A1 (zh) |
| MX (1) | MX2009008059A (zh) |
| TW (1) | TW200838535A (zh) |
| WO (1) | WO2008093495A1 (zh) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1043317E (pt) * | 1997-11-19 | 2009-05-11 | Kowa Co | Novos derivados de piridazina e fármacos que os contêm como ingrediente activo |
| CN100473647C (zh) * | 2000-09-18 | 2009-04-01 | 卫材R&D管理有限公司 | 哒嗪酮和三嗪酮化合物及其作为药物制剂的用途 |
-
2008
- 2008-01-28 EP EP08710303A patent/EP2127653A1/en not_active Withdrawn
- 2008-01-28 US US12/516,595 patent/US20100075972A1/en not_active Abandoned
- 2008-01-28 WO PCT/JP2008/000099 patent/WO2008093495A1/ja active Application Filing
- 2008-01-28 AU AU2008211480A patent/AU2008211480A1/en not_active Abandoned
- 2008-01-28 EA EA200970720A patent/EA200970720A1/ru unknown
- 2008-01-28 BR BRPI0805841-5A patent/BRPI0805841A2/pt not_active IP Right Cessation
- 2008-01-28 TW TW097103099A patent/TW200838535A/zh unknown
- 2008-01-28 MX MX2009008059A patent/MX2009008059A/es unknown
- 2008-01-28 KR KR1020097015733A patent/KR20090114371A/ko not_active Application Discontinuation
- 2008-01-28 CN CNA2008800032965A patent/CN101600435A/zh active Pending
- 2008-01-28 JP JP2008556026A patent/JPWO2008093495A1/ja active Pending
- 2008-01-28 CA CA002669563A patent/CA2669563A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EA200970720A1 (ru) | 2009-12-30 |
| EP2127653A1 (en) | 2009-12-02 |
| JPWO2008093495A1 (ja) | 2010-05-20 |
| KR20090114371A (ko) | 2009-11-03 |
| AU2008211480A1 (en) | 2008-08-07 |
| CA2669563A1 (en) | 2008-08-07 |
| TW200838535A (en) | 2008-10-01 |
| US20100075972A1 (en) | 2010-03-25 |
| WO2008093495A1 (ja) | 2008-08-07 |
| MX2009008059A (es) | 2009-08-12 |
| BRPI0805841A2 (pt) | 2011-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3240538B1 (en) | Use of masitinib for treatment of an amyotrophic lateral sclerosis patient subpopulation | |
| EP1797882A1 (en) | Preventive and/or therapeutic medicine for rheumatoid arthritis | |
| Abboud et al. | Essential tremor: choosing the right management plan for your patient | |
| US20200375954A1 (en) | Therapeutic agent for food competence disorder in stomach | |
| CN1168441C (zh) | 右旋美托咪定用于制备强化监护单位镇静药物的用途 | |
| JP2018516951A (ja) | 夜間胃酸過分泌に対するベンズイミダゾール誘導体の使用 | |
| EP3132803B1 (en) | Preventive or therapeutic agent for pain associated with herpes zoster in acute phase | |
| Osserman et al. | Studies in myasthenia gravis: preliminary report on therapy with mestinon bromide | |
| JP2020536854A (ja) | 医学療法におけるセマグルチド | |
| CN101600435A (zh) | 多发性硬化症治疗剂 | |
| EP1471916B1 (en) | Treatment of rheumatoid arthritis using imatinib | |
| WO2001000196A2 (en) | Mirtazapine for weight gain in wasting diseases | |
| CN110325214A (zh) | 用于预防和治疗神经元损伤的低剂量药物组合 | |
| CN114869872A (zh) | N1-二氢咖啡酰基-n10-咖啡酰基亚精胺在制备药品、保健品或功能食品中的应用 | |
| JP4448447B2 (ja) | 筋肉疲労若しくは筋肉損傷およびそれらに起因する疾患の予防治療用組成物 | |
| Häupl et al. | SAT0249 reduction of monocyte activation by bowel cleanse and one week fasting suggests permanent pathogenetic triggering from the gut in rheumatoid arthritis | |
| EP1920772A1 (en) | Prophylactic and/or therapeutic method for rheumatoid arthritis | |
| WO2019239963A1 (en) | Pharmaceutical composition for treating chronic constipation | |
| CN110227083A (zh) | 一种含氯化钆和双胍类降糖药的药物组合物及其用途 | |
| JPH0517358A (ja) | 睡眠誘起性無呼吸症治療剤 | |
| Scott | Asymptomatic hyperuricaemia. | |
| CN112641765B (zh) | 丙泊酚的抗疲劳制药用途 | |
| US20230381122A1 (en) | Application of n1-dihydrocaffeoyl-n10-caffeoylspermidine in preparation of drug, health product or functional food | |
| US20230055568A1 (en) | Therapeutic agent for myalgic encephalomyelitis/chronic fatigue syndrome | |
| CN109464441B (zh) | 3-乙酰氨基香豆素在制备治疗或预防高尿酸血症及肾损伤的药物中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20091209 |