WO1997009298A1 - Production of an immunosuppressant using microorganisms - Google Patents
Production of an immunosuppressant using microorganisms Download PDFInfo
- Publication number
- WO1997009298A1 WO1997009298A1 PCT/JP1996/002309 JP9602309W WO9709298A1 WO 1997009298 A1 WO1997009298 A1 WO 1997009298A1 JP 9602309 W JP9602309 W JP 9602309W WO 9709298 A1 WO9709298 A1 WO 9709298A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substance
- salt
- diseases
- transplantation
- agar
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 244000005700 microbiome Species 0.000 title description 3
- 229960003444 immunosuppressant agent Drugs 0.000 title description 2
- 230000001861 immunosuppressant effect Effects 0.000 title description 2
- 239000003018 immunosuppressive agent Substances 0.000 title description 2
- 239000000126 substance Substances 0.000 claims abstract description 51
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 4
- 238000002054 transplantation Methods 0.000 claims description 11
- 241000233866 Fungi Species 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 7
- 208000023275 Autoimmune disease Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 5
- 235000015097 nutrients Nutrition 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims 2
- 238000012258 culturing Methods 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000000975 bioactive effect Effects 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 229920001817 Agar Polymers 0.000 description 10
- 239000008272 agar Substances 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 201000010099 disease Diseases 0.000 description 9
- -1 alkali metal salt Chemical class 0.000 description 8
- 208000006673 asthma Diseases 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 201000004624 Dermatitis Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000000855 fermentation Methods 0.000 description 7
- 230000004151 fermentation Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 230000035584 blastogenesis Effects 0.000 description 5
- 239000006783 corn meal agar Substances 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 229920006008 lipopolysaccharide Polymers 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 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 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 description 4
- 241001529936 Murinae Species 0.000 description 4
- 240000007817 Olea europaea Species 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000001788 irregular Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000009137 Behcet syndrome Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010019663 Hepatic failure Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 3
- 206010023332 keratitis Diseases 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 208000007903 liver failure Diseases 0.000 description 3
- 231100000835 liver failure Toxicity 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
- 229920001296 polysiloxane Polymers 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 208000007788 Acute Liver Failure Diseases 0.000 description 2
- 206010000804 Acute hepatic failure Diseases 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 2
- 208000032467 Aplastic anaemia Diseases 0.000 description 2
- 241000244186 Ascaris Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920000742 Cotton Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010019799 Hepatitis viral Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 206010029240 Neuritis Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000005273 aeration Methods 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 208000010668 atopic eczema Diseases 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
- 230000004071 biological effect Effects 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 208000023589 ischemic disease Diseases 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 2
- 239000000401 methanolic extract Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 201000005962 mycosis fungoides Diseases 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001965 potato dextrose agar Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 201000000306 sarcoidosis Diseases 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 201000010000 Agranulocytosis Diseases 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
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 206010064539 Autoimmune myocarditis Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 206010009657 Clostridium difficile colitis Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 208000006069 Corneal Opacity Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 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
- 206010012442 Dermatitis contact Diseases 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
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010060742 Endocrine ophthalmopathy Diseases 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 206010014954 Eosinophilic fasciitis Diseases 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010015218 Erythema multiforme Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 208000032759 Hemolytic-Uremic Syndrome Diseases 0.000 description 1
- 208000027761 Hepatic autoimmune disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010021074 Hypoplastic anaemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 201000002287 Keratoconus Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 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
- 206010024380 Leukoderma Diseases 0.000 description 1
- 241001123008 Leukoma Species 0.000 description 1
- GWNVDXQDILPJIG-SHSCPDMUSA-N Leukotriene C4 Natural products CCCCCC=C/CC=C/C=C/C=C/C(SCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O)C(O)CCCC(=O)O GWNVDXQDILPJIG-SHSCPDMUSA-N 0.000 description 1
- 208000012309 Linear IgA disease Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 206010027910 Mononeuritis Diseases 0.000 description 1
- 208000024599 Mooren ulcer Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- VZUNGTLZRAYYDE-UHFFFAOYSA-N N-methyl-N'-nitro-N-nitrosoguanidine Chemical compound O=NN(C)C(=N)N[N+]([O-])=O VZUNGTLZRAYYDE-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010051606 Necrotising colitis Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000027771 Obstructive airways disease Diseases 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 208000003100 Pseudomembranous Enterocolitis Diseases 0.000 description 1
- 206010037128 Pseudomembranous colitis Diseases 0.000 description 1
- 208000003670 Pure Red-Cell Aplasia Diseases 0.000 description 1
- 208000006311 Pyoderma Diseases 0.000 description 1
- 206010037779 Radiculopathy Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000002200 Respiratory Hypersensitivity Diseases 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 241000576755 Sclerotia Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000019764 Soybean Meal Nutrition 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- 231100000579 Toxinosis Toxicity 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 208000001445 Uveomeningoencephalitic Syndrome Diseases 0.000 description 1
- 206010047112 Vasculitides Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000034705 Vogt-Koyanagi-Harada syndrome Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000836 acute liver failure Toxicity 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000003915 air pollution Methods 0.000 description 1
- 230000010085 airway hyperresponsiveness Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000001707 blastogenic effect Effects 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical class N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 201000010002 cicatricial pemphigoid Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 210000000918 epididymis Anatomy 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 208000024711 extrinsic asthma Diseases 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002538 fungal effect 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
- 210000004195 gingiva Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000021312 gluten Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 206010019692 hepatic necrosis Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 206010021198 ichthyosis Diseases 0.000 description 1
- 201000002597 ichthyosis vulgaris Diseases 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 201000006334 interstitial nephritis Diseases 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003903 intestinal lesions Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 201000010659 intrinsic asthma Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 208000023569 ischemic bowel disease Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 201000010666 keratoconjunctivitis Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 231100000149 liver necrosis Toxicity 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 231100001016 megaloblastic anemia Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000013734 mononeuritis simplex Diseases 0.000 description 1
- 201000005518 mononeuropathy Diseases 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002897 organic nitrogen compounds Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 210000004261 periodontium Anatomy 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 208000019629 polyneuritis Diseases 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 239000013587 production medium Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 238000011218 seed culture Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 208000004003 siderosis Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 230000003393 splenic effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000036575 thermal burns Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000003582 thrombocytopenic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/001—Amines; Imines
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
Definitions
- This invention relates to a new bioactive compound, hereinafter entitled WF10917 substance or a salt thereof which are useful as a medicament.
- The. present invention relates to a new bioactive compound, WF10917 substance.
- WF10917 substance or a salt thereof which has immunosupressing activity
- a process for preparation thereof to a pharmaceutical composition comprising the same, which is useful as immunosupressing agents, and to a use thereof as a medicament.
- one object of this invention is to provide the novel compound, WF10917 substance or a salt thereof which is of use for treating and preventing rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases, psoriasis, and the like.
- Another object of this invention is to provide a process for production of the WF10917 substance or a salt thereof by fermentation of a WF10917 substance-producing strain belonging to the fungi in a nutrient medium.
- the WF10917 substance of the present invention can be represented by the following formula:
- Suitable salt of the WF10917 substance (I) is conventional pharmaceutically acceptable salt and includes a metal salt such as an alkali metal salt (e. g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'- dibenzylethylenediamine salt, etc.), an organic acid salt (e. g.
- a metal salt such as an alkali metal salt (e. g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-
- an inorganic acid salt e. g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.
- a salt with an amino acid e. g. arginine, aspartic acid, glutamic acid, etc.
- the WF10917 substance can be produced by fermentation of the WF10917 substance-producing strain belonging to the fungi such as Fungus No. 10917 in a nutrient medium.
- the production of the WF10917 substance is not limited to the use of the particular organism described herein, which is given for the illustrative purpose only.
- This invention also includes the use of any mutants which are capable of producing the WF10917 substance including natural mutants as well as artificial mutants which can be produced from the described organism by conventional means such as irradiation of X-ray, ultra-violet radiation, treatment with N-methyl-N'-nitro-N-nitrosoguanidine, 2-aminopurine, and the like.
- strain No.10917 was originally isolated from a soil sample, collected in Shingu-shi, Wakayama-ken, Japan. This organism grew very restrictedly on various culture media, and formed olivaceous colonies. Neither teleomorph nor anamorph of strain No.10917 was observed on various media or on an autoclaved leaf affixed to a corn meal agar plate. This strain did not also form differentiated hyphal structures: sclerotia, bulbils, chlamydospores and clamp connections. The lack of definite characteristics suggests that strain No.10917 might be classified as a member of the Mvcelia Sterilia (Hyphomycetes). Its mycological characteristics were as follows.
- the surface at the center was raised, floccose and brownish gray, while that at the margin was plane, felty, producing colorless exudations and dark gray.
- the reverse was brownish gray and produced small amounts of orange soluble pigment. Both teleomorph and anamorph were not formed.
- vegetative hyphae were rather darker than those on corn meal agar, and sometimes funiculose.
- the hyphal cells were filamentous to cylindrical, sometimes ellipsoidal, and 1 - 5 ⁇ m in width.
- Strain No.10917 was able to grow at the temperature range from 6 to 34°C, with the growth optimum at 28 to 30°C. These temperature data were determined on potato dextrose agar (made by NISSUI).
- Mvcelia Sterilia that is an asporogenic fungal group, is taxonomically heterogeneous. Thus, because of an uncertainty in the classification of this organism, it has been referred to simply as Fungus No.10917.
- This strain was deposited in National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology (1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan) as FERM BP-5223 (deposited date: September 1, 1995).
- Potato dextrose G Very restrictedly, 1.0-1.5 cm agar (Difco 0013) S: Irregular, raised, floccose and brownish gray
- Czapek's solution G Very restrictedly, 1.0-1.5 cm agar* S: Irregular, plane, thin and olive (2E-F3) R: Olive (1F3)
- Emerson Yp Ss agar G Very restrictedly, 1.0-1.5 cm
- Corn meal agar G Very restrictedly, 1.0-1.5 cm (Difco 0386)
- S Circular, plane, felty and dark green (28F4)
- MY20 agar* G Very restrictedly, 1.0-1.5 cm
- the WF10917 substance is produced when the WF10917 substance- producing strain belonging the fungi is grown in a nutrient medium containing sources of assimilable carbon and nitrogen under aerobic conditions (e. g. shaking culture, submerged culture, etc.).
- the preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, sucrose, starch, fructose or glycerin, or the like.
- the preferred sources of nitrogen are yeast extract, peptone, gluten meal, cotton seed flour, soybean meal, corn steep liquor, dried yeast, wheat germ, etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.), urea or amino acid, or the like.
- ammonium salts e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
- urea or amino acid or the like.
- the carbon and nitrogen sources though advantageously employed in combination, need not to be used in their pure form because less pure materials, which contain traces of growth factors and considerable quantities of mineral nutrients, are also suitable for use.
- medium mineral salts such as sodium or calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium salts, copper salts, zinc salts, iron salts, or cobalt salts, or the like.
- a defoaming agent such as liquid paraffin, fatty oil, plant oil, mineral oil or silicone, or the like may be added.
- Agitation and aeration of the culture mixture may be accomplished in a variety of ways, such as agitation by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermenter, and the like.
- the fermentation is usually conducted at a temperature between about 10°C and 40°C, preferably 20°C to 30°C, for a period of about 50 hours to 150 hours, which may be varied according to fermentation conditions and scales.
- the culture broth is then subjected for recovery of the WF10917 substance to various procedures conventionally used for recovery and purification of biological active substance, for instance, solvent extraction with an appropriate solvent or a mixture of some solvents, chromatography or recrystallization from an appropriate solvent or a mixture thereof.
- the salt of the WF10917 substance can be prepared by a conventional manner, during or after the recovery and purification of the WF10917 substance.
- the WF10917 substance as obtained has the following physico- chemical properties:
- the WF10917 substance is inferred to have the following plane structural formula.
- the WF10917 substance (I) possesses pharmacological activities such as immunosuppressive activity, and the like, and therefore are useful for the treatment and prevention of immune-mediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum ***, limb, muscle, nervus, etc.; graft-versus-host diseases by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, psoriasis, and the like.
- immune-mediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum ***, limb, muscle, nervus, etc
- the WF10917 substance (I) is also useful for the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, b ⁇ llous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases such as autoimmune diseases and so on (e.
- keratoconjunctivitis vernal conjunctivitis, uveitis associated with Behcet's diseases, keratitis, he ⁇ etic keratitis, conical cornea, dystrophia epithelialis corneae, comeal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.); reversible obstructive airways disease, which includes conditions such as asthma (e. g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (e.
- asthma e. g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma
- chronic or inveterate asthma e.
- bronchitis and the like inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, leukotriene B ⁇ -mediated diseases; intestinal inflammations/allergies such as Coeliac disease, proctitis, eosnophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food related allergic diseases which have symptomatic manifestation remote from the gastro-intestinal tract, for example migraine, rhinitis and eczema; renal diseases such as interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuriti
- autoimmune myocarditis virus myocarditis
- collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesion of gingiva, periodontium, alveolar bone, substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern alopecia or alopecia senilis; muscular dystrophy; Pyoderma and Sezary's syndrome; Addison's disease; active oxygen-mediated diseases, for example, organ injury such as ischemia-reperfusion injury of organs (e. g.
- ischemic diseases e. g. thrombosis, cardiac infarction
- intestinal diseases such as endotoxin- shock, pseudomembranous colitis, colitis caused by drug or radiation
- renal diseases such as ischemic acute renal insufficiency, chronic renal insufficiency
- pulmonary diseases such as toxinosis caused by lung- oxygen or drug (e. g.
- pulmonary emphysema ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn: dermatitis such as erythema multiforme, linear IgA ballous dermatitis, cement dermatitis: and others such as gingvatis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (e. g. air pollution), aging, carcinogenis, metastasis of carcinoma, hypobaropathy; diseases caused by histamine or leukotriene C4 release; and Behcet's disease such as intestinal-, vasculo-, or neuro-
- ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring
- corneal alkali burn dermatitis such as erythema multiforme, linear IgA ballous dermatiti
- Behcet's disease and also the one which affects oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on; and so on.
- the WF10917 substance (I) may have liver regenerating activity and/or activities of stimulating hypertrophy and hype ⁇ lasia of hepatocytes. Therefore, they are useful for treatment and prevention of hepatic diseases such as immunogenic diseases (e. g. chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e. g.
- immunogenic diseases e. g. chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis
- partial liver resection e. g.
- the WF10917 substance (I) may be useful for various diseases because of its useful pharmaceutical activity such as augmenting activity of chemotherapeutic effect, preventing of treating activity of cytomegalovirus infection, anti-inflammatory activity, and so on.
- Test 1 Suppression of blastogenic responce of murine spleen cells by mitogen stimulation
- the lymphocyte blastogenesis test was perfo ⁇ ned in microtiter plates with each well containing 1 x 10 splenic cells of Balb/c mice in 0.1 ml RPMI1640 medium supplemented with 10% fetal bovine serum, 50mM 2-mercaptoethanol, penicilln (100 units/ml) and streptomycin (lOO ⁇ g/ml), to which lipopolysaccharide of E. coli (LPS) or anti CD3 antibody(2Cll) was added.
- LPS lipopolysaccharide of E. coli
- 2Cll anti CD3 antibody
- the WF10917 was dissolved in methanol and further diluted in RPMI 1640 medium and added to the culture to give final concentrations of lOOOng/ml or less.
- the WF10917 substance suppressed murine lymphocyte blastogenesis induced by anti CD3 antibody but not by LPS.
- mice Female Balb/c mice were immunized with 2,4-dinitrophenylated Ascaris Extract (DNP- ascaris) and alum by intraperitoneal injection.
- DNP- ascaris 2,4-dinitrophenylated Ascaris Extract
- the WF10917 substance was dissolved in 10% (HCO-60 R )/saline and administered subcutaneously for 7 consecutive days, beginning at the day of immunization. Seven days after of immunization, serum were collected and antibody titer against DNP was determined by the ELISA. Briefly, 50ml of DNP conjugated bovine serum albumin was added to each well of microtiter plates and incubated for 16 hours at 4°C. The microtiter plates were washed with PBS containing 0.1% of Tween 80(T-PBS) and blocked with 0.5 % of bovine serum albumin- PBS. After washing with T-PBS, 50 ml of diluted mice sera were added and incubated for a hour at room temperature.
- anti murine IgGl monoclonal antibody horse raddish peroxidase conjugate was added and incubated for one hour. After one hour incubation, plates were washed with T-PBS and added orthophenylenediamine dissolved in citrate buffer (pH4.5). Antibody titer were measured using a microplate abso ⁇ tion spectrophotometer at 492 nm.
- the pharmaceutical composition of this invention can be used in the form of pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the WF10917 substance or its pharmaceutically acceptable salt, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administrations.
- the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, creme, and any other form suitable for use.
- the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, com starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes may be used.
- the composition for applying the composition to human, it is preferable to apply it by intravenous, intramuscular, topical or oral administration.
- the dosage of therapeutically effective amount of the WF10917 substance varies from and also depends upon the age and condition of each individual patient to be treated, in the case of individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 10 mg of the WF10917 substance per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1 - 10 mg of the WF10917 substance per kg weight of human being, in case of oral administration, a daily dose of 0.5 - 50 mg of the WF10917 substance of human being is generally given for treating.
- aqueous seed medium 60 ml containing sucrose (3%), dried yeast (3%), cotton seed flour (1%), CaC0 (0.2%), Adecanol LG-109
- the flasks were shaken on a rotary shaker (220 ⁇ m, 5.1 cm-throw) at 30°C for 4 days.
- the resultant seed culture was inoculated to 20 liters of sterile production medium consisting of sucrose 4%, dried yeast 2%, CaCO? 0.5%,
- the cultured broth (140 liters) was extracted with 140 liters of acetone-methanol (1:1) mixture by intermittent mixing.
- the acetone- methanol extract was filtered with an aid of diatomaceous earth and an equal volume of water was added.
- the resultant cake was reextracted with 70 liters of 80% aqueous methanol.
- the methanol extract was filtered with an aid of diatomaceous earth and 70 liters of water was added.
- These extract was combined and passed through a column (10.5 liters) of Diaion HP-20 (Mitsubishi Chemical Co., Ltd.).
- the column was washed with 50% aqueous methanol, 70% aqueous methanol, water, and ethyl acetate and then eluted with methanol. Twenty liters of water was added to the eluate (30 liters), and applied on a column (4 liters) of YMC gel (ODS-AM 120-S50, YMC Co,. Ltd.). The column was developed with 90% aqueous methanol. An active fraction (2 liters) was concentrated under reduced pressure to give the WF10917 substance in the form of colorless crystals (681 mg).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Dermatology (AREA)
- Transplantation (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to a new bioactive compound, WF10917 substance or a salt thereof, having immunosuppressing activity, to a process for preparation thereof and to a pharmaceutical composition comprising the same, said compound having formula (I).
Description
DESCRIPTION
PRODUCTION OF AN IMMUNOSUPPRESSANT USING MICROORGANISMS
TECHNICAL FIELD
This invention relates to a new bioactive compound, hereinafter entitled WF10917 substance or a salt thereof which are useful as a medicament.
DISCLOSURE OF INVENTION
The. present invention relates to a new bioactive compound, WF10917 substance.
More particularly, it relates to a novel compound, WF10917 substance or a salt thereof which has immunosupressing activity, to a process for preparation thereof, to a pharmaceutical composition comprising the same, which is useful as immunosupressing agents, and to a use thereof as a medicament.
Accordingly, one object of this invention is to provide the novel compound, WF10917 substance or a salt thereof which is of use for treating and preventing rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases, psoriasis, and the like.
Another object of this invention is to provide a process for production of the WF10917 substance or a salt thereof by fermentation of a WF10917 substance-producing strain belonging to the fungi in a nutrient medium.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, the WF10917 substance or a salt thereof.
Still further object of this invention is to provide a use of the WF10917 substance or a salt thereof for treating and preventing rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases, psoriasis, and the like.
The WF10917 substance of the present invention can be represented by the following formula:
( I )
Suitable salt of the WF10917 substance (I) is conventional pharmaceutically acceptable salt and includes a metal salt such as an alkali metal salt (e. g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'- dibenzylethylenediamine salt, etc.), an organic acid salt (e. g. acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e. g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), or a salt with an amino acid (e. g. arginine, aspartic acid, glutamic acid, etc.), and the like.
The WF10917 substance can be produced by fermentation of the WF10917 substance-producing strain belonging to the fungi such as Fungus No. 10917 in a nutrient medium.
It is to be understood that the production of the WF10917 substance
is not limited to the use of the particular organism described herein, which is given for the illustrative purpose only. This invention also includes the use of any mutants which are capable of producing the WF10917 substance including natural mutants as well as artificial mutants which can be produced from the described organism by conventional means such as irradiation of X-ray, ultra-violet radiation, treatment with N-methyl-N'-nitro-N-nitrosoguanidine, 2-aminopurine, and the like.
Particulars of Fungus No. 10917 is as follows:
Characteristics of producing strain No.10917
The fungus strain No.10917 was originally isolated from a soil sample, collected in Shingu-shi, Wakayama-ken, Japan. This organism grew very restrictedly on various culture media, and formed olivaceous colonies. Neither teleomorph nor anamorph of strain No.10917 was observed on various media or on an autoclaved leaf affixed to a corn meal agar plate. This strain did not also form differentiated hyphal structures: sclerotia, bulbils, chlamydospores and clamp connections. The lack of definite characteristics suggests that strain No.10917 might be classified as a member of the Mvcelia Sterilia (Hyphomycetes). Its mycological characteristics were as follows.
Cultural characteristics on various agar media are summarized in Table 1. Culture on corn meal agar grew very restrictedly, attaining 1.0-1.5 cm in diameter two weeks later at 25 °C. The colony surface was plane, felty and dark green. The reverse was the same color. Reproductive structures were not observed. Vegetative hyphae were smooth, septate, hyaline or sometimes dark brown, and branched. The hyphal cells were cylindrical and 1.0 - 4.0 μm in width. Chlamydospores were absent. Colonies on potato dextrose agar grew the similar rate as on corn meal agar. The surface at the center was raised, floccose and brownish gray, while that at the margin was plane, felty, producing colorless exudations and dark gray. The reverse was brownish gray and produced small amounts of orange soluble pigment. Both teleomorph and anamorph were not formed. On this medium, vegetative hyphae were rather darker than those on corn meal agar,
and sometimes funiculose. The hyphal cells were filamentous to cylindrical, sometimes ellipsoidal, and 1 - 5 μm in width.
Strain No.10917 was able to grow at the temperature range from 6 to 34°C, with the growth optimum at 28 to 30°C. These temperature data were determined on potato dextrose agar (made by NISSUI).
Mvcelia Sterilia, that is an asporogenic fungal group, is taxonomically heterogeneous. Thus, because of an uncertainty in the classification of this organism, it has been referred to simply as Fungus No.10917. This strain was deposited in National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology (1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan) as FERM BP-5223 (deposited date: September 1, 1995).
Table 1. Cultural characteristics of strain No.10917.
Media Cultural characteristics
Malt extract agar'1 G: Restrictedly, 2.0 - 2.5 cm S: Circular to irregular, raised, cottony, producing colorless exudations, brownish gray (6F2) at the center and greenish gray (30F2) at the margin R: Dark green (28F3) to greenish gray (28F2)
Potato dextrose G: Very restrictedly, 1.0-1.5 cm agar (Difco 0013) S: Irregular, raised, floccose and brownish gray
(5F2) at the center; plane, felty, producing colorless exudations and dark gray (1F1) at the margin R: Brownish gray (5D-E2) and producing small amounts of orange soluble pigment
Media Cultural characteristics
Czapek's solution G: Very restrictedly, 1.0-1.5 cm agar* S: Irregular, plane, thin and olive (2E-F3) R: Olive (1F3)
Sabouraud dextrose G: Very restrictedly, 1.0-2.0 cm agar (Difco 0190) S: Irregular, raised, felty, olive (2F4) at the center, brownish gray (1F2) at the middle, grayish brown (6F3) at the margin R: Brown (7E4), and grayish brown (6F3) at the margin, producing orange soluble pigment
Emerson Yp Ss agar G: Very restrictedly, 1.0-1.5 cm
(Difco 0739) S: Circular, somewhat raised, felty, dark green
(29F4), and gray (1D1) at the margin R: Dark green (30F2), and olive (3F3) at the margin
Corn meal agar G: Very restrictedly, 1.0-1.5 cm (Difco 0386) S: Circular, plane, felty and dark green (28F4)
R: Dark green (27F4)
MY20 agar* G: Very restrictedly, 1.0-1.5 cm
S: Circular, raised, felty to wet, producing large amount of colorless exudations, pale gray (IB 1) at the center, grayish orange (5B4) at the middle, and orange white (5A2) at the margin
R: Grayish orange (5B3)
Abbreviation G: growth, measuring colony size in diameter, S: colony surface, R: reverse.
*: The compositions of malt extract agar, Czapek's solution agar and MY20 agar were based on JCM Catalogue of Strains (Nakase, T., 5th ed., 503p., Japan Collection of Microorganisms and Life Science Research Information Section of the Institute of Physical and Chemical Research, Saitama, 1992).
These characteristics were observed after 14 days of incubation at 25°C. The color descriptions were based on Methuen Handbook of Colour (Kornerup, A. and J. H. Wanscher, 3rd ed., 525p., Methuen, London, 1978).
Production of the WF10917 substance
The WF10917 substance is produced when the WF10917 substance- producing strain belonging the fungi is grown in a nutrient medium containing sources of assimilable carbon and nitrogen under aerobic conditions (e. g. shaking culture, submerged culture, etc.).
The preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, sucrose, starch, fructose or glycerin, or the like.
The preferred sources of nitrogen are yeast extract, peptone, gluten meal, cotton seed flour, soybean meal, corn steep liquor, dried yeast, wheat germ, etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.), urea or amino acid, or the like.
The carbon and nitrogen sources, though advantageously employed in combination, need not to be used in their pure form because less pure materials, which contain traces of growth factors and considerable quantities of mineral nutrients, are also suitable for use.
When desired, there may be added to the medium mineral salts such as sodium or calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium salts, copper salts, zinc salts, iron salts, or cobalt salts, or the like.
If necessary, especially when the culture medium foams seriously a defoaming agent, such as liquid paraffin, fatty oil, plant oil, mineral oil or silicone, or the like may be added.
Agitation and aeration of the culture mixture may be accomplished
in a variety of ways, such as agitation by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermenter, and the like.
The fermentation is usually conducted at a temperature between about 10°C and 40°C, preferably 20°C to 30°C, for a period of about 50 hours to 150 hours, which may be varied according to fermentation conditions and scales.
When the fermentation is completed, the culture broth is then subjected for recovery of the WF10917 substance to various procedures conventionally used for recovery and purification of biological active substance, for instance, solvent extraction with an appropriate solvent or a mixture of some solvents, chromatography or recrystallization from an appropriate solvent or a mixture thereof.
The salt of the WF10917 substance can be prepared by a conventional manner, during or after the recovery and purification of the WF10917 substance.
The WF10917 substance as obtained has the following physico- chemical properties:
Appearance:
Colorless powder Molecular formula :
C 23 H41N06 Elementary Analysis:
Calcd for C23H41N06 • H20
C 62.00, H 9.73, N 3.14 Found:
C 62.76, H 10.29, N 3.09 Molecular weight:
ESI-MS: m/z 428 (M + H)+ Melting point:
148 - 153 °C (dec.) Specific rotation:
[α]D(23°C) +48 ° (c=0.1, in methanol)
Ultraviolet absoφtion spectrum: λ χ (methanol): 230 nm
Solubility:
Slightly soluble: methanol, chloroform
Insoluble: water, dimethyl sulfoxide Color reaction:
Positive: eerie sulfate reaction, iodine vapor reaction, ninhydrin reaction
Negative: Molish reaction, Ehrlich reaction, ferric chloride reaction Thin layer chromatography (TLC):
Stationary phase Developing solvent Rf value
Silica Gel 60 2-propanol: water: acetic acid 0.4
F254* (90:10:0.1, v/v)
* made by E. Merck
High Performance Liquid Chromatography (HPLC): Condition:
Mobile phase: acetonitrile:water:trifluoroacetic acid (65:35:0.1, v/v)
Column: YMC ODS AM-303** (S-5, 12θA, 4.6mmID x 250mm)
Flow rate: 1.5 ml/minute
Detection: UV at 230 nm
Retention time: 7.7 minutes
** trade name: made by Yamamura Chemical Institute Infrared Spectrum: vmax (KBr): 3560' 3120' 2920' 2850' 1740' 1720' 1670' 1590'
1470, 1400, 1360, 1230, 1040, 1020, 990 cm"1 as shown in Fig. 1
H Nuclear magnetic resonance spectrum: (500 MHz, pyridine-dr) δ-rr
6.40 (IH dd, J=15.5 and 10.5Hz), 6.16 (IH, m), 6.06 (IH, dd, J=15.5 and 10.5Hz), 5.75 (IH, dd, J=15.5 and 7Hz), 5.68 (IH, m), 4.89 (IH, br d, J=llHz), 4.69 (IH, d, J=12Hz), 4.63 (IH, d, J=12Hz), 2.70 (IH, m), 2.35 (IH, m), 2.04 (2H, m), 1.80 (3H, s),
1.38 (2H, m), 1.32 - 1.20 (16H, m), 0.87 (3H, t, J=7Hz) as shown in Fig. 2
13 C Nuclear magnetic resonance spectrum:
(125 MHz, pyridine-d^) SQ
174.56 (s), 170.35 (s), 136.15 (d), 132.63 (d), 130.32 (d), 130.00 (d), 71.77 (d), 69.03 (s), 68.33 (d), 63.19 (t), 37.75 (t), 32.92 (t), 32.11 (t), 29.95 (t), 29.89 (t), 29.89 (t), 29.80 (t), 29.59 (t), 29.52 (t), 29.50 (t), 22.92 (t), 20.93 (q), 14.27 (q) as shown in Fig. 3. Nature:
Amphoteric substance
From the above physical and chemical properties, the WF10917 substance is inferred to have the following plane structural formula.
( I )
Biological properties of the WF10917 substance
The WF10917 substance (I) possesses pharmacological activities such as immunosuppressive activity, and the like, and therefore are useful for the treatment and prevention of immune-mediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nervus, etc.; graft-versus-host diseases by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, psoriasis, and the like.
Further, the WF10917 substance (I) is also useful for the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated
illnesses, such as, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bϋllous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases such as autoimmune diseases and so on (e. g. keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's diseases, keratitis, heφetic keratitis, conical cornea, dystrophia epithelialis corneae, comeal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.); reversible obstructive airways disease, which includes conditions such as asthma (e. g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (e. g. late asthma and airway hyper-responsiveness), bronchitis and the like; inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, leukotriene B^-mediated diseases; intestinal inflammations/allergies such as Coeliac disease, proctitis, eosnophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food related allergic diseases which have symptomatic manifestation remote from the gastro-intestinal tract, for example migraine, rhinitis and eczema; renal diseases such as interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic puφura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin diseases such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa
and myocardosis (e. g. autoimmune myocarditis, virus myocarditis); collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesion of gingiva, periodontium, alveolar bone, substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern alopecia or alopecia senilis; muscular dystrophy; Pyoderma and Sezary's syndrome; Addison's disease; active oxygen-mediated diseases, for example, organ injury such as ischemia-reperfusion injury of organs (e. g. heart, liver, kidney, digestive tract) which occurs on preservation, transplantation or ischemic diseases (e. g. thrombosis, cardiac infarction): intestinal diseases such as endotoxin- shock, pseudomembranous colitis, colitis caused by drug or radiation: renal diseases such as ischemic acute renal insufficiency, chronic renal insufficiency: pulmonary diseases such as toxinosis caused by lung- oxygen or drug (e. g. paracort, bleomycins), lung cancer, pulmonary emphysema: ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn: dermatitis such as erythema multiforme, linear IgA ballous dermatitis, cement dermatitis: and others such as gingvatis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (e. g. air pollution), aging, carcinogenis, metastasis of carcinoma, hypobaropathy; diseases caused by histamine or leukotriene C4 release; and Behcet's disease such as intestinal-, vasculo-, or neuro-
Behcet's disease, and also the one which affects oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on; and so on.
And further, the WF10917 substance (I) may have liver regenerating activity and/or activities of stimulating hypertrophy and hypeφlasia of hepatocytes. Therefore, they are useful for treatment and prevention of hepatic diseases such as immunogenic diseases (e. g. chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e. g. necrosis caused by toxins, viral hepatitis, shock or anoxia), B -virus hepatitis, non-A/non-B hepatitis, cirrhosis and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on-chronic" liver failure (acute liver failure on chronic liver diseases).
And further, the WF10917 substance (I) may be useful for various
diseases because of its useful pharmaceutical activity such as augmenting activity of chemotherapeutic effect, preventing of treating activity of cytomegalovirus infection, anti-inflammatory activity, and so on.
As examples for showing biological activities of the WF10917 substance, some biological data are explained in the following.
Test 1. Suppression of blastogenic responce of murine spleen cells by mitogen stimulation
The lymphocyte blastogenesis test was perfoπned in microtiter plates with each well containing 1 x 10 splenic cells of Balb/c mice in 0.1 ml RPMI1640 medium supplemented with 10% fetal bovine serum, 50mM 2-mercaptoethanol, penicilln (100 units/ml) and streptomycin (lOOμg/ml), to which lipopolysaccharide of E. coli (LPS) or anti CD3 antibody(2Cll) was added. The cells were incubated at 37°C in a humidified atmosphere of 5% CO for 96 hours. After the culture period, suppressive activities of the test samples in lymphocyte blastogenesis were quantitated by a MTT [3-(4,5-dimethylthiazolyl-2- yl)-2,5-diphenyltetrazolium bromide] dye reduction' assay.
The WF10917 was dissolved in methanol and further diluted in RPMI 1640 medium and added to the culture to give final concentrations of lOOOng/ml or less.
The results are shown in Table 2.
The WF10917 substance suppressed murine lymphocyte blastogenesis induced by anti CD3 antibody but not by LPS.
Table 2 Effect of the WF10917 substance on murine lymphocyte blastogenesis induced by anti CD3 antibody and LPS
Concentration Suppression of blastogenesis (%) (ng/ml) anti-CD3 LPS
0 0 0
10 25.2 5.9
20 46.5 -4.2
40 48.7 2.6
80 57.9 7.5
160 55.8 14.8
315 59.0 9.2
630 55.8 25.3
1250 64.5 43.3
2500 63.9 67.5
5000 48.2 91.5
Test 2. Effect of WF10917 substance on antibody production in mice
Female Balb/c mice were immunized with 2,4-dinitrophenylated Ascaris Extract (DNP- ascaris) and alum by intraperitoneal injection.
The WF10917 substance was dissolved in 10% (HCO-60R)/saline and administered subcutaneously for 7 consecutive days, beginning at the day of immunization. Seven days after of immunization, serum were collected and antibody titer against DNP was determined by the ELISA. Briefly, 50ml of DNP conjugated bovine serum albumin was added to each well of microtiter plates and incubated for 16 hours at 4°C. The microtiter plates were washed with PBS containing 0.1% of Tween 80(T-PBS) and blocked with 0.5 % of bovine serum albumin- PBS. After washing with T-PBS, 50 ml of diluted mice sera were added and incubated for a hour at room temperature. One hour later, anti murine IgGl monoclonal antibody horse raddish peroxidase conjugate was added and incubated for one hour. After one hour incubation, plates were washed with T-PBS and added orthophenylenediamine dissolved in citrate buffer (pH4.5). Antibody titer were measured using a microplate absoφtion
spectrophotometer at 492 nm.
As shown in Table 3, the antibody production was markedly suppressed by the administration of the WF10917 substance.
Table 3 Effect of the WF10917 substance on antibody production in mice
: p< 0.05 ** : P<0.01 *** : P<0.005
The pharmaceutical composition of this invention can be used in the form of pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the WF10917 substance or its pharmaceutically acceptable salt, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administrations. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, creme, and any other form suitable for use.
The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, com starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes may be used.
For applying the composition to human, it is preferable to apply it
by intravenous, intramuscular, topical or oral administration. While the dosage of therapeutically effective amount of the WF10917 substance varies from and also depends upon the age and condition of each individual patient to be treated, in the case of individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 10 mg of the WF10917 substance per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1 - 10 mg of the WF10917 substance per kg weight of human being, in case of oral administration, a daily dose of 0.5 - 50 mg of the WF10917 substance of human being is generally given for treating.
Following examples are given for the puφose of illustrating the present invention in more detail.
Example 1
(1) Fermentation
An aqueous seed medium (60 ml) containing sucrose (3%), dried yeast (3%), cotton seed flour (1%), CaC0 (0.2%), Adecanol LG-109
(deforming agent, Asahi Denka Co., Ltd.) (0.05%), and Silicone KM- 70 (deforming agent, Shin-Etsu Chemical Co., Ltd.) (0.05%) (pH 6.3 adjusted with IN NaOH) was poured into a 250-ml Erlenmeyer flask and sterilized at 120°C for 30 minutes. A loopful of Fungus No. 10917 was inoculated from a slant culture into the flask. The flask was cultured on a rotary shaker (220 φm, 5.1 cm-throw) at 30°C for 5 days and then transferred at the rate of 2% to 160 ml of the same sterile seed medium in the 500-ml Erlenmeyer flasks. The flasks were shaken on a rotary shaker (220 φm, 5.1 cm-throw) at 30°C for 4 days. The resultant seed culture was inoculated to 20 liters of sterile production medium consisting of sucrose 4%, dried yeast 2%, CaCO? 0.5%,
Adecanol LG-109 0.05%, and Silicone KM-700.05% (pH 6.3) in a 30- liter jar fermenter. Fermentation was carried out at 25 °C for 4 days under aeration of 20 liters/minute and agitation of 250 φm.
(2) Isolation
The cultured broth (140 liters) was extracted with 140 liters of acetone-methanol (1:1) mixture by intermittent mixing. The acetone- methanol extract was filtered with an aid of diatomaceous earth and an equal volume of water was added. The resultant cake was reextracted with 70 liters of 80% aqueous methanol. The methanol extract was filtered with an aid of diatomaceous earth and 70 liters of water was added. These extract was combined and passed through a column (10.5 liters) of Diaion HP-20 (Mitsubishi Chemical Co., Ltd.). The column was washed with 50% aqueous methanol, 70% aqueous methanol, water, and ethyl acetate and then eluted with methanol. Twenty liters of water was added to the eluate (30 liters), and applied on a column (4 liters) of YMC gel (ODS-AM 120-S50, YMC Co,. Ltd.). The column was developed with 90% aqueous methanol. An active fraction (2 liters) was concentrated under reduced pressure to give the WF10917 substance in the form of colorless crystals (681 mg).
Claims
1. A WF10917 substance of the formula:
( I ) »
or a salt thereof.
2. A process for production of the WF10917 substance or a salt thereof, which comprises culturing Fungus No. 10917 (FERM BP- 5223) in a nutrient medium and recovering the same.
3. Biological pure culture of Fungus No. 10917 (FERM BP-5223).
4. A pharmaceutical composition containing WF10917 substance or a salt thereof.
5. A use of the WF10917 substance or a salt thereof as a medicament.
6. A method for treating or preventing rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases and psoriasis which comprises administrating the WF10917 substance or a salt thereof to human or animal.
7. Use of the WF10917 substance or a salt thereof for the manufacture of a medicament for therapeutic treatment or prevention of rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases and psoriasis in human or animal.
8. A compound of claim 1 for use as a medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9511061A JPH10509187A (en) | 1995-09-08 | 1996-08-16 | Production of immunosuppressants using microorganisms |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9518417.2 | 1995-09-08 | ||
| GBGB9518417.2A GB9518417D0 (en) | 1995-09-08 | 1995-09-08 | Novel compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997009298A1 true WO1997009298A1 (en) | 1997-03-13 |
Family
ID=10780439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1996/002309 WO1997009298A1 (en) | 1995-09-08 | 1996-08-16 | Production of an immunosuppressant using microorganisms |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPH10509187A (en) |
| GB (1) | GB9518417D0 (en) |
| WO (1) | WO1997009298A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0410176A1 (en) * | 1989-07-07 | 1991-01-30 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-Aminopentanoic acid compounds and their use as immunosuppressants |
-
1995
- 1995-09-08 GB GBGB9518417.2A patent/GB9518417D0/en active Pending
-
1996
- 1996-08-16 JP JP9511061A patent/JPH10509187A/en active Pending
- 1996-08-16 WO PCT/JP1996/002309 patent/WO1997009298A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0410176A1 (en) * | 1989-07-07 | 1991-01-30 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-Aminopentanoic acid compounds and their use as immunosuppressants |
Non-Patent Citations (1)
| Title |
|---|
| S. SASAKIM ET AL.: "Fungal metabolites. Novel potent immunosuppressants, mycestericins, produced by mycelia sterilia", JOURNAL OF ANTIBIOTICS, vol. 47, no. 4, 1994, TOKYO JP, pages 420 - 433, XP002018194 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH10509187A (en) | 1998-09-08 |
| GB9518417D0 (en) | 1995-11-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6656905B1 (en) | Cyclic tetrapeptide compound and use thereof | |
| JP3111470B2 (en) | Novel polypeptide compound and method for producing the same | |
| JP3061863B2 (en) | Macrocyclic lactone compound and method for producing the same | |
| WO2000008048A2 (en) | Inhibitor of histone deacetylase | |
| US20130225507A1 (en) | Method of producing fr901228 | |
| HU211514A9 (en) | Fr 901228 substance and preparation thereof | |
| US6291231B1 (en) | Microorganism producing terphenyl compounds | |
| JPH06234693A (en) | New isotetracenone-based substance and its production | |
| WO1997009298A1 (en) | Production of an immunosuppressant using microorganisms | |
| WO1993012125A1 (en) | Phosphoric acid ester of heteroring compound as medicament | |
| JPH0394692A (en) | Physiologically active substances BE-18257 class | |
| US5023079A (en) | Heptaene V-28-3 antibiotic derivative | |
| JP4004567B2 (en) | Immunosuppressant containing WB2663B substance | |
| JPH01246288A (en) | Tan-1030a and its derivative, production and use thereof | |
| JP3124373B2 (en) | Immunosuppressant | |
| EP0818464A1 (en) | Methylsulfomycin l, a process for its production and its use | |
| JPH05271267A (en) | Fr901459 substance, and its production and use | |
| KR900008248B1 (en) | Process for preparing physiologically active substance fa-5859 | |
| WO1992011275A1 (en) | 13-dimethyl fr-900506 derivative and the use as an immunosuppressive agent | |
| JPH09221494A (en) | Ws72545 material | |
| JPH0570470A (en) | Physiologically active substance kanglemycin c, its production and its pharmacological use | |
| JPH09202797A (en) | 5alpha-reductase inhibiting compound d1067331 | |
| AU6007299A (en) | Cyclic tetrapeptide compound and use thereof | |
| WO1999055896A1 (en) | A new glucose-6-phosphate translocase inhibitor l 970885 from an actinomycete sp., and chemical derivatives thereof, a process for the preparation and their use as pharmaceuticals | |
| JPH11290087A (en) | New biologically active substance nf07511, its production and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): JP US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| 122 | Ep: pct application non-entry in european phase |