JP2007510618A - ピリドンの誘導体とその使用 - Google Patents
ピリドンの誘導体とその使用 Download PDFInfo
- Publication number
- JP2007510618A JP2007510618A JP2005510535A JP2005510535A JP2007510618A JP 2007510618 A JP2007510618 A JP 2007510618A JP 2005510535 A JP2005510535 A JP 2005510535A JP 2005510535 A JP2005510535 A JP 2005510535A JP 2007510618 A JP2007510618 A JP 2007510618A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- fibrosis
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- -1 N-substituted-2 (1H) pyridone Chemical class 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 9
- 206010016654 Fibrosis Diseases 0.000 claims description 38
- 230000004761 fibrosis Effects 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 239000003708 ampul Substances 0.000 claims description 2
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 abstract description 36
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 241000700159 Rattus Species 0.000 description 15
- 230000017074 necrotic cell death Effects 0.000 description 15
- 230000007882 cirrhosis Effects 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 11
- 210000003494 hepatocyte Anatomy 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 102000008186 Collagen Human genes 0.000 description 10
- 108010035532 Collagen Proteins 0.000 description 10
- 229920001436 collagen Polymers 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 210000002950 fibroblast Anatomy 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 8
- 210000003462 vein Anatomy 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 238000009825 accumulation Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 208000019423 liver disease Diseases 0.000 description 7
- 229960003073 pirfenidone Drugs 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000003510 anti-fibrotic effect Effects 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 208000002672 hepatitis B Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 241000700721 Hepatitis B virus Species 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 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 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 230000003908 liver function Effects 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 3
- 108010082126 Alanine transaminase Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010019799 Hepatitis viral Diseases 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 description 3
- 201000002793 renal fibrosis Diseases 0.000 description 3
- 201000001862 viral hepatitis Diseases 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- NETTXQJYJRFTFS-UHFFFAOYSA-N 1-(4-hydroxyphenyl)-5-methylpyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C1=CC=C(O)C=C1 NETTXQJYJRFTFS-UHFFFAOYSA-N 0.000 description 2
- XMDITNSOBKTMIO-UHFFFAOYSA-N 1-(4-methoxyphenyl)-5-methylpyridin-2-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)C=CC(C)=C1 XMDITNSOBKTMIO-UHFFFAOYSA-N 0.000 description 2
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 2
- SOHMZGMHXUQHGE-UHFFFAOYSA-N 5-methyl-1h-pyridin-2-one Chemical compound CC1=CC=C(O)N=C1 SOHMZGMHXUQHGE-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010028594 Myocardial fibrosis Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000033809 Suppuration Diseases 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- 206010000269 abscess Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 239000003182 parenteral nutrition solution Substances 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 102000014898 transaminase activity proteins Human genes 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- LDHQCZJRKDOVOX-UHFFFAOYSA-N 2-butenoic acid Chemical compound CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- 208000007848 Alcoholism 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
- 206010003757 Atypical pneumonia Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 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 1
- 206010021531 Impetigo Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010037601 Pyelonephritis chronic Diseases 0.000 description 1
- 206010037888 Rash pustular Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010050207 Skin fibrosis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 238000013245 carbon tetrachloride model Methods 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 201000006368 chronic pyelonephritis Diseases 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 230000011382 collagen catabolic process Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 206010019692 hepatic necrosis Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 231100000149 liver necrosis Toxicity 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000011976 maleic acid Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000024121 nodulation Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000007065 protein hydrolysis Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000029561 pustule Diseases 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity 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
- 208000009852 uremia Diseases 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
【選択図】なし
Description
特許文献3には、ガン、例えば、リンパ腫および白血病などを処置するための、N−置換−2(1H)ピリドンまたはN−置換−3(1H)ピリドンの使用が開示されている。
パーフェニドン(PF)は、1980年代初期に最初に発明された低分子化合物である。これは、コラーゲンの合成を阻害する作用、サイトカインの分泌を減少させる作用、そして線維芽細胞の増殖を妨げる作用を有している。この因子の特異的標的遺伝子は依然不明なままである。その後、これは、種々の動物モデルにおいて、心臓、腎臓、肺、および血管内壁の線維症をうまく阻害するために使用されている。この薬剤は、米国において肺の突発性線維症(IPF)の処置についての第3段階の臨床試験にある。しかし、PFの阻害活性は十分満足できるものではない。
R1は、3、4、5、または6位のメチル、エチル、トリフルオロメチルであり;
R2は、2、3、または4位のヒドロキシル、スルフヒドリル、メチルチオ基、エチルチオ基である。
本発明の第2の態様においては、薬学的に許容される担体と、安全であり有効な量の式Iの化合物またはその薬学的に許容される塩を含む薬学的組成物が提供される。
本発明の第3の態様においては、以下の工程を含む、式Iの化合物を生産するための方法が提供される:
(a)銅粉末と無水アルカリ土類金属炭酸塩(例えば、炭酸カリウム、炭酸ナトリウム)の存在下で、式IIの化合物と式IIIの化合物(約0.8〜1.2:0.8〜1.2のモル比で)を160〜200℃で反応させ、それによって式Iaの化合物を生産する工程であって;
(b)式Iaの化合物をBBr3と、不活性な溶媒(例えば、ジクロロメタン、四塩化炭素、ベンゼン、メチルベンゼン、シクロヘキサン、またはそれらの混合物)中で、−10℃から15℃(より好ましくは、−5℃から10℃)で反応させ、それによって式Iの化合物を生産する工程であって:
本発明の第4の態様においては、式Iの化合物またはその薬学的に許容される塩と薬学的に許容される担体を混合して、全重量を基準として0.01〜99wt%の式Iの化合物を含む薬学的組成物を生産する工程を含む、薬学的組成物を生産するための方法が提供される。
本発明により、また、安全であり有効な量の式Iの化合物またはその薬学的に許容される塩のそれが必要である被験体への投与を含む、線維症疾患を処置するための方法も提供される。
本発明の化合物が上記適用において使用される場合は、これは、1つ以上の薬学的に許容される担体または賦形剤(例えば、溶媒、希釈剤など)と混合され得る。これは、以下の投薬形態で経口投与され得る:錠剤、ペレット剤、カプセル剤、分散させることができる粉末剤、顆粒剤、または懸濁液(例えば、約0.05〜5%の懸濁剤を含む)、シロップ剤(例えば、約10〜50%の糖類を含む)、およびエリキシル剤(例えば、約20〜50%のエタノールを含む)。あるいは、軟膏、ゲル剤、薬剤を含むゴムセメントなどの形態で、外用によって投与され得る。あるいは、滅菌の注射可能な溶液または懸濁液(約0.05〜5%の懸濁剤を等張性の媒体中に含む)の形態で全身的に投与され得る。例えば、これらの薬学的調製物には、約0.01〜99wt%、より好ましくは、約0.1〜90wt%の、担体と混合させられた有効成分が含まれ得る。
工程1:5−メチルピリドンの合成
2.窒化ナトリウム(36g、0.522mol)を、100mlの水に溶解させ、その後、室温にて、1滴ずつ溶液中に添加した。この反応は発熱反応であり、大量の気体が発生した。
3.添加の完了後、溶液を2時間攪拌し、その後、温度を上昇させながら4時間還流させた。薄黄色の溶液が黒くなった。これを自然に室温にまで冷ました。
4.氷浴によって温度を低下させる条件で、炭酸ナトリウムを溶液に添加して中和した。pH値を8に調整した。この反応は発熱反応であり、大量の気体が発生した。
5.反応混合物を、65℃の減圧下で蒸留によって濃縮した。濃縮した溶液をジクロロメタンで抽出した。抽出を、有機相のブロットプレートが生成物のブロットを示さなくなるまで、数回繰り返した。抽出溶液を無水硫酸ナトリウムで乾燥させ、回転によって乾燥させると、粗生成物が得られた。
6.粗生成物をエーテル−ジクロロメタン(10/1)で再結晶させると、27.3g(0.25mol)の標題化合物が、薄黄色の固体として得られた。収率は89%であった。
2.混合物をセライトで濾過し、その後、ジクロロメタンで溶出すると、濃縮溶液が得られた。
3.濃縮溶液を減圧下で蒸留させた。その後、パラ−ブロモアニソールの溶媒を蒸留によって除去した。残渣が所望される粗生成物であった。
4.粗生成物を溶媒エチル酢酸で再結晶させた。エーテルを溶離剤として使用した。28gの標題化合物が得られた。収率は58%であった。
2.400mlのエーテルを溶液に滴下して、エーテルと三臭化ホウ素の錯体化合物を形成させた。これは発熱反応であった。滴下速度は、10℃を超えない系の温度を維持するように制御した。添加の完了後、溶液を0℃で40分間攪拌した。
3.反応を、水を添加することによって停止させた。これは発熱反応であった。添加速度は、15℃を超えない系の温度を維持するように制御した。
4.固形物を減圧濾過によって回収した。
5.固形物を、溶媒エタノールで再結晶させると、40gの標題化合物が得られた。これをF351と命名した。収率は40%であった。
13CNMR(ppm):16.9;118.3;121.0;127.8;129.8;130.5;137.5;142.5;145.4
生体外で培養された線維芽細胞の増殖に対するF351の阻害作用を、以下の方法を使用して試験した。F351を0.5%のDMSOに溶解させた。線維芽細胞を種々の量のF351(図1および図2)で5日間処理した。試薬を、48時間ごとに新しいものにした。パーフェニドンを、これらの2つの試薬の作用を比較するために、平行して行った実験において使用した。
生存率=[(実験ウェルのOD570−実験ウェルのOD630)/(対照ウェルのOD570−対照ウェルのOD630)]×100%
阻害率(または増殖率)=100%−生存率
結果は、線維芽細胞に対するF351の阻害作用がパーフェニドンの阻害作用よりも顕著であることを示している(図1および図2)。
ラットの肝線維症モデルを、それぞれ、CCl4およびDMN(ジメチルニトロサミン)での誘導によって確立させ、4週間、または8週間の間、F351で処置した。動物の肝臓を回収して、病理学的結果を観察した。方法は以下の通りである:
(a)四塩化炭素モデル(油と混合した40%のCCl4を0.4ml/100g用いて、1週間に2回、4週間継続して腹腔内に注射した)と、ジメチルニトロサミン肝線維症モデル(1%のDMNを10mg/Kg用いて、1週間に2回、8週間継続して腹腔内に注射した)を作成した。
(b)これらの2つのモデルの動物に、モデルの確立の0日目から250mg/Kgの用量のF351を用いて、1日に1回、4週間または8週間の間継続して胃内に投与した。
(a)DMNモデル:
正常なラット(図3)と比較して、中心静脈周辺の肝細胞の壊死、出血、およびコラーゲンの蓄積、膿瘻周辺の線維症が、4週間でモデルグループにおいて明らかに観察された。F351で処置したグループの病変は、有意に小さくなっており(P<0.001)、ごく少量のコラーゲンの蓄積と、壊死後の線維性の隔壁の形成が、中心静脈の周辺で観察された(図4および図5)。
(b)CCl4モデル:
実験を4週間行った。モデルグループについての病理学的スコアは、S4〜S6のレベルであったが、F351グループの病理学的変化は、明らかに小さくなり、中心静脈周辺および膿瘻周辺の線維症の直径も明らかに減少した(4週、P=0.001)(図8および図9)。
CCl4およびDMNでの誘導によって確立したラットの肝線維症モデルを、実施例3と同じ様式でF351で処置した。ラットの体重と死亡率を観察した。
CCl4およびDMNでの誘導によって確立したラットの肝線維症モデルを、実施例3と同じ様式でF351で処置した。ラットの血清を抽出し、血清トランスアミナーゼのレベルを測定した。
(a)錠剤
F351
100〜500mg
ポリビニルピロリドン
2〜4mg
サリチル酸
1mg
デンプン
40〜80mg
ステアリン酸マグネシウム
1〜5mg
乳糖
5〜10mg
タルカムパウダー
5〜10mg
F351、乳糖、およびデンプンを、それぞれ、1000個の錠剤用に(上記の処方)量りとり、粉砕し、80メッシュスクリーンで篩にかけ、混合し、次いで、ポリビニルピロリドンとサリチル酸とともに混合した。その後、デンプンを添加した。混合物を水で湿らせ、16〜18メッシュスクリーンを用いて粒子になるように処方し、60℃で乾燥させ、顆粒状にし、タルカムパウダーと共に均一になるように混合し、錠剤へと圧縮した。
(b)非経口用溶液
F351
20〜100mg
塩化ナトリウム
1〜5mg
注射用水
10mlになるように
上記の処方にしたがって、F351と塩化ナトリウムを量りとり、溶液になるように処方し、その後、10mlの非経口溶液用バイアルに注ぎ、滅菌後にパックし、注射に使用した。
(c)カプセル剤
F351 50
200mg
ポリビニルピロリドン 2
10mg
デンプン 50
100mg
乳糖 2
10mg
上記の成分を、それぞれ、1000個のカプセル剤用の量で量りとり、粉砕し、そして篩にかけ、均一になるように混合した。次いで、F351を等量の増分で徐々に増加する様式で添加し、均一に分散するように完全に粉砕し、80メッシュスクリーンを用いて篩にかけ、カプセルに充填した。
Claims (10)
- R1がメチルであり、R2がヒドロキシルである、請求項1に記載の化合物。
- R1が5位のメチルであり、R2が4位のヒドロキシルである、請求項1に記載の化合物。
- 薬学的に許容される担体と、安全であり有効な量の式Iの化合物またはその薬学的に許容される塩を含む、薬学的組成物。
- 組成物の全重量を基準として、0.01〜99%の前記式Iの化合物またはその薬学的に許容される塩を含む、請求項3に記載の薬学的組成物。
- 前記薬学的組成物の投薬形態が、錠剤、カプセル剤、アンプル剤、または丸剤である、請求項3に記載の薬学的組成物。
- 以下の工程:
(a)銅粉末と無水アルカリ土類金属炭酸塩の存在下で、式IIの化合物と式IIIの化合物を160〜200℃で反応させ、それによって式Iaの化合物を生産する工程であって;
(b)式Iaの化合物とBBr3を、不活性な溶媒中で−10℃から15℃で反応させ、それによって式Iの化合物を生産する工程であって:
を含む、式Iの化合物を生産するための方法。 - 請求項1に記載の式Iの化合物またはその薬学的に許容される塩を薬学的に許容される担体と混合して、全重量を基準として0.01〜99wt%の式Iの化合物を含む薬学的組成物を生産する工程を含む、薬学的組成物を生産するための方法。
- 請求項1に記載の式Iの化合物またはその薬学的に許容される塩の、線維症を予防するための薬剤の製造における使用。
- 安全であり有効な量の請求項1に記載の式Iの化合物またはその薬学的に許容される塩を、それが必要である被験体へ投与することを含む、線維症疾患を処置するための方法。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2003/000968 WO2005047256A1 (fr) | 2003-11-14 | 2003-11-14 | Derives de pyridone, et utilisation correspondante |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2007510618A true JP2007510618A (ja) | 2007-04-26 |
JP4614884B2 JP4614884B2 (ja) | 2011-01-19 |
Family
ID=34578657
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2005510535A Expired - Lifetime JP4614884B2 (ja) | 2003-11-14 | 2003-11-14 | ピリドンの誘導体とその使用 |
Country Status (7)
Country | Link |
---|---|
US (3) | US7825133B2 (ja) |
EP (1) | EP1683788B1 (ja) |
JP (1) | JP4614884B2 (ja) |
CN (1) | CN100358872C (ja) |
AU (1) | AU2003284808B2 (ja) |
CA (1) | CA2545813C (ja) |
WO (1) | WO2005047256A1 (ja) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012121931A (ja) * | 2005-05-10 | 2012-06-28 | Intermune Inc | ストレス活性化蛋白質キナーゼ系をモジュレートするためのピリドン誘導体 |
JP2012527488A (ja) * | 2009-05-25 | 2012-11-08 | 中南大学 | 1−(置換ベンジル)−5−トリフルオロメチル−2−(1h)ピリドン化合物及びその塩、並びにその製造方法及びその用途 |
JP2012527487A (ja) * | 2009-05-25 | 2012-11-08 | 中南大学 | 1−(置換アリール)−5−トリフルオロメチル−2−(1h)ピリドン化合物及びその塩、並びにその製造方法及びその用途 |
JP2019524811A (ja) * | 2016-08-08 | 2019-09-05 | ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド | ヒドロニドンの製造方法 |
JP2019525946A (ja) * | 2016-08-08 | 2019-09-12 | ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド | ヒドロニドンの製造方法 |
JP2021169516A (ja) * | 2014-08-25 | 2021-10-28 | アイミューン セラピューティクス,インコーポレイテッド | タマゴのタンパク質製剤およびその製造方法 |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002060446A1 (en) | 2001-01-29 | 2002-08-08 | Shionogi & Co., Ltd. | Medicinal preparation containing 5-methyl-1-phenyl-2-(1h)-pyridone as active ingredient |
WO2005027834A2 (en) * | 2003-09-12 | 2005-03-31 | Z-Medica Corporation | Partially hydrated hemostatic agent |
EP1683788B1 (en) | 2003-11-14 | 2012-03-21 | Shanghai Genomics, Inc. | Derivatives of pyridone and use thereof |
US20060178609A1 (en) | 2005-02-09 | 2006-08-10 | Z-Medica, Llc | Devices and methods for the delivery of molecular sieve materials for the formation of blood clots |
AU2006214371A1 (en) | 2005-02-15 | 2006-08-24 | Virginia Commonwealth University | Mineral technologies (MT) for acute hemostasis and for the treatment of acute wounds and chronic ulcers |
NZ591443A (en) | 2005-09-22 | 2013-04-26 | Intermune Inc | Granule formation of pirfenidone and pharmaceutically acceptable excipients |
US8938898B2 (en) | 2006-04-27 | 2015-01-27 | Z-Medica, Llc | Devices for the identification of medical products |
US8202532B2 (en) | 2006-05-26 | 2012-06-19 | Z-Medica Corporation | Clay-based hemostatic agents and devices for the delivery thereof |
US7968114B2 (en) | 2006-05-26 | 2011-06-28 | Z-Medica Corporation | Clay-based hemostatic agents and devices for the delivery thereof |
US7604819B2 (en) | 2006-05-26 | 2009-10-20 | Z-Medica Corporation | Clay-based hemostatic agents and devices for the delivery thereof |
WO2007147297A1 (en) * | 2006-06-15 | 2007-12-27 | Shanghai Genomics, Inc. | The use of derviate of pyridone for preventing and treating radioactive injury of lungs |
CN102099036B (zh) | 2008-06-03 | 2015-05-27 | 英特芒尼公司 | 用于治疗炎性疾患和纤维化疾患的化合物和方法 |
US7635707B1 (en) | 2008-11-10 | 2009-12-22 | Intermune, Inc. | Pirfenidone treatment for patients with atypical liver function |
AU2010206543A1 (en) * | 2009-01-26 | 2011-07-07 | Intermune, Inc. | Methods for treating acute myocardial infarctions and associated disorders |
AU2010248758A1 (en) * | 2009-05-15 | 2011-11-24 | Intermune, Inc. | Methods of treating HIV patients with anti-fibrotics |
US8858969B2 (en) | 2010-09-22 | 2014-10-14 | Z-Medica, Llc | Hemostatic compositions, devices, and methods |
US10105356B2 (en) | 2011-01-31 | 2018-10-23 | Avalyn Pharma Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
AU2012212269B2 (en) | 2011-01-31 | 2016-05-19 | Avalyn Pharma Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
WO2012107831A1 (en) | 2011-02-11 | 2012-08-16 | Signa S.A. De C.V. | Method of making a pyridone compound, 5-ethyl-1-phenyl-2-(1h)-pyridone, and intermediates thereof |
AU2012340698A1 (en) | 2011-11-22 | 2014-04-24 | Intermune, Inc. | Methods of diagnosing and treating idiopathic pulmonary fibrosis |
JP6001169B2 (ja) | 2012-06-22 | 2016-10-05 | ゼット−メディカ,エルエルシー | 止血デバイス |
RU2701156C9 (ru) | 2012-07-18 | 2019-12-18 | Саншайн Лейк Фарма Ко., Лтд. | Азотсодержащие гетероциклические производные и их применение в фармацевтических препаратах |
AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
NZ722927A (en) | 2014-01-10 | 2022-07-29 | Avalyn Pharma Inc | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
CN110452216B (zh) * | 2014-04-02 | 2022-08-26 | 英特穆恩公司 | 抗纤维化吡啶酮类 |
CA2937365C (en) | 2016-03-29 | 2018-09-18 | F. Hoffmann-La Roche Ag | Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same |
WO2022051984A1 (zh) * | 2020-09-10 | 2022-03-17 | 苏州富德兆丰生化科技有限公司 | 吡非尼酮的合成方法 |
CN114790192B (zh) * | 2021-01-26 | 2023-12-08 | 成都阿奇生物医药科技有限公司 | 抗纤维化的化合物及其制备方法和用途 |
CN113173881B (zh) * | 2021-03-17 | 2022-12-20 | 北京康蒂尼药业股份有限公司 | 羟尼酮的晶型及其制备方法和用途 |
EP4326265A1 (en) * | 2021-04-19 | 2024-02-28 | Gyre Therapeutics, Inc. | Pharmaceutical hydronidone formulations for diseases |
CN113476445A (zh) * | 2021-05-14 | 2021-10-08 | 北京康蒂尼药业股份有限公司 | 羟尼酮在制备治疗或预防慢性乙肝伴肝纤维化药物中的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0552814B2 (ja) * | 1989-02-15 | 1993-08-06 | Yamauchi Akitomo | |
JPH08510251A (ja) * | 1993-05-07 | 1996-10-29 | ビー マーゴリン、ソロモン | 線維症の病変の修復と予防のための組成物および方法 |
JPH11501911A (ja) * | 1995-03-03 | 1999-02-16 | ビー マーゴリン、ソロモン | サイトカイン成長因子の引き起こす疾病の治療 |
JPH11512699A (ja) * | 1995-09-19 | 1999-11-02 | ビー マーゴリン、ソロモン | 腫瘍壊死因子アルファの阻止 |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3839346A (en) * | 1972-12-18 | 1974-10-01 | Affiliated Med Res | N-substituted pyridone and general method for preparing pyridones |
GB8621217D0 (en) | 1986-09-03 | 1986-10-08 | Ici Plc | Chemical compounds |
US5716632A (en) | 1989-11-22 | 1998-02-10 | Margolin; Solomon B. | Compositions and methods for reparation and prevention of fibrotic lesions |
US5310562A (en) | 1989-11-22 | 1994-05-10 | Margolin Solomon B | Composition and method for reparation and prevention of fibrotic lesions |
US5789426A (en) | 1995-01-20 | 1998-08-04 | Cornell Research Foundation, Inc. | Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation |
US6090822A (en) * | 1995-03-03 | 2000-07-18 | Margolin; Solomon B. | Treatment of cytokine growth factor caused disorders |
US6114353A (en) * | 1995-03-03 | 2000-09-05 | Margolin; Solomon B. | Compositions and method for treatment of lymphomas, leukemias, and leiomyomas |
US5962478A (en) | 1995-09-19 | 1999-10-05 | Margolin; Solomon B. | Inhibition of tumor necrosis factor α |
ATE315027T1 (de) | 1996-02-02 | 2006-02-15 | Kumiai Chemical Industry Co | Pyridin derivate und herbizide |
US5939439A (en) | 1996-12-30 | 1999-08-17 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
US6294350B1 (en) | 1997-06-05 | 2001-09-25 | Dalhousie University | Methods for treating fibroproliferative diseases |
AU755003B2 (en) | 1998-03-17 | 2002-11-28 | Solomon B. Margolin | Topical antiseptic compositions and methods |
JP2002526447A (ja) | 1998-09-18 | 2002-08-20 | メファ・アクチェンゲゼルシャフト | アルキルフェニルピリドンの局所製剤 |
AU2001230605A1 (en) | 2000-02-09 | 2001-08-20 | Shionogi And Co., Ltd. | Apoptosis inhibitor |
IL151403A0 (en) | 2000-02-21 | 2003-04-10 | Cymar Inc | Compositions and methods for treatment of epilepsy |
US6956044B1 (en) | 2000-02-21 | 2005-10-18 | Margolin Solomon B | Compositions and methods for treatment of epilepsy |
DE10024938A1 (de) * | 2000-05-19 | 2001-11-22 | Bayer Ag | Substituierte Iminoazine |
JP2004504300A (ja) | 2000-07-18 | 2004-02-12 | ビーエーエスエフ アクチェンゲゼルシャフト | 1−アリール−4−ハロアルキル−2−[1h]ピリドン類 |
GB0129260D0 (en) | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
ES2334990T3 (es) | 2002-02-14 | 2010-03-18 | Pharmacia Corporation | Piridinonas sustituidas como moduladores de p38 map quinasa. |
CN1218942C (zh) * | 2002-06-11 | 2005-09-14 | 中南大学湘雅医学院 | 抗纤维化吡啶酮化合物及其生产工艺方法 |
CA2496577A1 (en) | 2002-08-28 | 2004-03-11 | Intermune, Inc. | Combination therapy for treatment of fibrotic disorders |
CH696420A5 (de) | 2002-09-13 | 2007-06-15 | Mepha Ag | Neue stabile Zubereitungen von Alkyl-, Phenyl-Pyridonen für topische Anwendung. |
JP4542743B2 (ja) | 2002-12-26 | 2010-09-15 | Kdl株式会社 | ピリドン誘導体の溶液状医薬組成物 |
EP1683788B1 (en) | 2003-11-14 | 2012-03-21 | Shanghai Genomics, Inc. | Derivatives of pyridone and use thereof |
MY148809A (en) | 2004-07-06 | 2013-05-31 | Eisai R&D Man Co Ltd | Crystals of 1,2-dihydropyridine compound and their production process |
ATE511843T1 (de) | 2005-04-04 | 2011-06-15 | Eisai R&D Man Co Ltd | Dihydropyridin-verbindungen für neurodegenerative erkrankungen und demenz |
JPWO2006109876A1 (ja) | 2005-04-08 | 2008-11-20 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 不随意運動治療剤 |
CN1846699A (zh) | 2005-04-13 | 2006-10-18 | 中南大学湘雅医院 | 1-(取代苯基)-5-甲基-2-(1h) 吡啶酮(i)化合物用于制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的应用 |
JP2006343500A (ja) | 2005-06-08 | 2006-12-21 | Olympus Corp | 光源装置及び投影光学装置 |
-
2003
- 2003-11-14 EP EP03773437A patent/EP1683788B1/en not_active Expired - Lifetime
- 2003-11-14 CA CA2545813A patent/CA2545813C/en not_active Expired - Lifetime
- 2003-11-14 CN CNB2003801106910A patent/CN100358872C/zh not_active Expired - Lifetime
- 2003-11-14 AU AU2003284808A patent/AU2003284808B2/en not_active Expired
- 2003-11-14 JP JP2005510535A patent/JP4614884B2/ja not_active Expired - Lifetime
- 2003-11-14 WO PCT/CN2003/000968 patent/WO2005047256A1/zh active Application Filing
- 2003-11-14 US US10/579,288 patent/US7825133B2/en active Active
-
2010
- 2010-09-17 US US12/885,353 patent/US8022087B2/en not_active Expired - Lifetime
- 2010-09-17 US US12/885,343 patent/US8084465B2/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0552814B2 (ja) * | 1989-02-15 | 1993-08-06 | Yamauchi Akitomo | |
JPH08510251A (ja) * | 1993-05-07 | 1996-10-29 | ビー マーゴリン、ソロモン | 線維症の病変の修復と予防のための組成物および方法 |
JPH11501911A (ja) * | 1995-03-03 | 1999-02-16 | ビー マーゴリン、ソロモン | サイトカイン成長因子の引き起こす疾病の治療 |
JPH11512699A (ja) * | 1995-09-19 | 1999-11-02 | ビー マーゴリン、ソロモン | 腫瘍壊死因子アルファの阻止 |
Non-Patent Citations (1)
Title |
---|
JPN6009068593, LI,C.S. et al, "An efficient copper−catalyzed coupling reaction of pyridin−2−ones with aryl and heterocyclic halides", Tetrahedron Letters, 2004, Vol.45, No.22, p.4257−4260 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012121931A (ja) * | 2005-05-10 | 2012-06-28 | Intermune Inc | ストレス活性化蛋白質キナーゼ系をモジュレートするためのピリドン誘導体 |
JP2012527488A (ja) * | 2009-05-25 | 2012-11-08 | 中南大学 | 1−(置換ベンジル)−5−トリフルオロメチル−2−(1h)ピリドン化合物及びその塩、並びにその製造方法及びその用途 |
JP2012527487A (ja) * | 2009-05-25 | 2012-11-08 | 中南大学 | 1−(置換アリール)−5−トリフルオロメチル−2−(1h)ピリドン化合物及びその塩、並びにその製造方法及びその用途 |
JP2021169516A (ja) * | 2014-08-25 | 2021-10-28 | アイミューン セラピューティクス,インコーポレイテッド | タマゴのタンパク質製剤およびその製造方法 |
JP2019524811A (ja) * | 2016-08-08 | 2019-09-05 | ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド | ヒドロニドンの製造方法 |
JP2019525946A (ja) * | 2016-08-08 | 2019-09-12 | ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド | ヒドロニドンの製造方法 |
Also Published As
Publication number | Publication date |
---|---|
CN1878757A (zh) | 2006-12-13 |
US8022087B2 (en) | 2011-09-20 |
CA2545813C (en) | 2011-01-04 |
AU2003284808A1 (en) | 2004-06-06 |
CA2545813A1 (en) | 2005-05-26 |
EP1683788A4 (en) | 2010-06-02 |
WO2005047256A1 (fr) | 2005-05-26 |
CN100358872C (zh) | 2008-01-02 |
US20110124872A1 (en) | 2011-05-26 |
AU2003284808B2 (en) | 2009-01-22 |
US7825133B2 (en) | 2010-11-02 |
EP1683788A1 (en) | 2006-07-26 |
AU2003284808A8 (en) | 2005-06-06 |
EP1683788B1 (en) | 2012-03-21 |
US20070049624A1 (en) | 2007-03-01 |
US20110123495A1 (en) | 2011-05-26 |
JP4614884B2 (ja) | 2011-01-19 |
US8084465B2 (en) | 2011-12-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4614884B2 (ja) | ピリドンの誘導体とその使用 | |
CN106008488B (zh) | 氰基吲哚类衍生物及其制备方法和用途 | |
US20050171104A1 (en) | Novel thyroid receptor ligands | |
US20040235877A1 (en) | Novel use of tricyclic compound | |
WO2000015603A1 (fr) | Derives de benzene et leur utilisation medicale | |
TW201808284A (zh) | 用於治療或預防高尿酸血症或痛風的化合物及其用途 | |
KR102005068B1 (ko) | 1,2 나프토퀴논 유도체 및 이의 제조방법 | |
WO2017189613A1 (en) | Methods of using fasn inhibitors | |
JP2003531856A (ja) | リン酸輸送阻害剤 | |
US7279593B2 (en) | Prime ring substituted thyroid receptor antagonists for the treatment of cardiac and metabolic disorders | |
KR20150080425A (ko) | 1,2 나프토퀴논 유도체 및 이의 제조방법 | |
JPH10513158A (ja) | エンドセリンアンタゴニストとしての置換されたフェニル化合物 | |
JP4309652B2 (ja) | 抗炎症剤 | |
JPWO2002053550A1 (ja) | ベンゾフラン誘導体及びそれを含有する医薬組成物 | |
JP2023511679A (ja) | 二置換アダマンチル誘導体、その薬学的に許容される塩、およびこれを有効成分として含む癌の増殖抑制用薬学的組成物 | |
KR20010075287A (ko) | 피리도피라진 화합물의 신규한 염 및 그의 결정 | |
JP2002538147A (ja) | 多環2−アミノジヒドロチアゾール系、その製造方法および医薬としての使用 | |
JPS60226877A (ja) | ピペリジン誘導体 | |
CN112824394A (zh) | PPARs-FXR多靶点小分子激动剂及其制备方法和用途 | |
KR20230134994A (ko) | 디메틸칼콘 유도체를 유효성분으로 포함하는 섬유화 질환 예방 또는 치료용 조성물 | |
JPH0480005B2 (ja) | ||
EP3632893A1 (en) | Vinylarene derivative and use thereof | |
JP2019531348A (ja) | アセトフェノン系化合物、その調製方法及び血中脂質調整への使用 | |
JP2011190257A (ja) | 組織線維化疾患の予防または治療剤 | |
JPH0449B2 (ja) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20070604 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20070619 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20070619 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20070604 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100114 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100402 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20100427 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100624 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20100722 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100813 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100922 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20101015 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20101019 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4614884 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131029 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131029 Year of fee payment: 3 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R314533 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131029 Year of fee payment: 3 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131029 Year of fee payment: 3 |
|
S211 | Written request for registration of transfer of exclusive licence |
Free format text: JAPANESE INTERMEDIATE CODE: R314214 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131029 Year of fee payment: 3 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S211 | Written request for registration of transfer of exclusive licence |
Free format text: JAPANESE INTERMEDIATE CODE: R314213 |
|
S534 | Written request for registration of change of nationality |
Free format text: JAPANESE INTERMEDIATE CODE: R313534 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R360 | Written notification for declining of transfer of rights |
Free format text: JAPANESE INTERMEDIATE CODE: R360 |
|
R360 | Written notification for declining of transfer of rights |
Free format text: JAPANESE INTERMEDIATE CODE: R360 |
|
R371 | Transfer withdrawn |
Free format text: JAPANESE INTERMEDIATE CODE: R371 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
EXPY | Cancellation because of completion of term |