JP3867196B2 - TNF−α産生阻害物質 - Google Patents
TNF−α産生阻害物質 Download PDFInfo
- Publication number
- JP3867196B2 JP3867196B2 JP2001164523A JP2001164523A JP3867196B2 JP 3867196 B2 JP3867196 B2 JP 3867196B2 JP 2001164523 A JP2001164523 A JP 2001164523A JP 2001164523 A JP2001164523 A JP 2001164523A JP 3867196 B2 JP3867196 B2 JP 3867196B2
- Authority
- JP
- Japan
- Prior art keywords
- ethyl
- pyridyl
- adamantyl
- propyl
- urea
- 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.)
- Expired - Fee Related
Links
- 230000006433 tumor necrosis factor production Effects 0.000 title claims description 11
- 239000003112 inhibitor Substances 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 63
- -1 1-adamantyl Chemical group 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- QDYISHPTUNJPHS-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-3-(2-methyl-3-pyridin-4-ylpropyl)-1-pentylurea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NCC(C)CC1=CC=NC=C1 QDYISHPTUNJPHS-UHFFFAOYSA-N 0.000 claims description 10
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 8
- YWJSTJKZGMYFRH-WAYWQWQTSA-N 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[(z)-3-pyridin-4-ylprop-2-enyl]urea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NC\C=C/C1=CC=NC=C1 YWJSTJKZGMYFRH-WAYWQWQTSA-N 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- BLAKNPNOJHFMIQ-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-1-but-2-enyl-3-(3-pyridin-4-ylpropyl)urea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CC=CC)C(=O)NCCCC1=CC=NC=C1 BLAKNPNOJHFMIQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- BXUVXRODAMZIAZ-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-pentyl-2-(2-pyridin-4-ylethylsulfanyl)acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)CSCCC1=CC=NC=C1 BXUVXRODAMZIAZ-UHFFFAOYSA-N 0.000 claims description 5
- HVPRNDSHZDOEKF-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-pentyl-3-(pyridin-4-ylmethylsulfanyl)propanamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)CCSCC1=CC=NC=C1 HVPRNDSHZDOEKF-UHFFFAOYSA-N 0.000 claims description 5
- RAPHLBWFMHYIDV-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-pentyl-5-pyridin-4-ylpentanamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)CCCCC1=CC=NC=C1 RAPHLBWFMHYIDV-UHFFFAOYSA-N 0.000 claims description 5
- AIUJHENHBJHHMY-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-(3-pyridin-4-ylpropyl)urea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NCCCC1=CC=NC=C1 AIUJHENHBJHHMY-UHFFFAOYSA-N 0.000 claims description 4
- MHBZVASHZYXXNB-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-(4-pyridin-4-ylbutan-2-yl)urea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NC(C)CCC1=CC=NC=C1 MHBZVASHZYXXNB-UHFFFAOYSA-N 0.000 claims description 4
- YWJSTJKZGMYFRH-AATRIKPKSA-N 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[(e)-3-pyridin-4-ylprop-2-enyl]urea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NC\C=C\C1=CC=NC=C1 YWJSTJKZGMYFRH-AATRIKPKSA-N 0.000 claims description 4
- KLVNJZLUOJMGAR-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-3-(3-pyridin-4-ylpropyl)-1-(3,3,3-trifluoropropyl)urea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCC(F)(F)F)C(=O)NCCCC1=CC=NC=C1 KLVNJZLUOJMGAR-UHFFFAOYSA-N 0.000 claims description 4
- MGONZICZEFZNQG-UHFFFAOYSA-N 1-[3-(1-adamantyl)propyl]-1-propyl-3-(3-pyridin-4-ylpropyl)urea Chemical compound C1C(C2)CC(C3)CC2CC13CCCN(CCC)C(=O)NCCCC1=CC=NC=C1 MGONZICZEFZNQG-UHFFFAOYSA-N 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- RWMRTGBPXPWRIZ-UHFFFAOYSA-N tert-butyl n-[2-[2-(1-adamantyl)ethyl-(3-pyridin-4-ylpropylcarbamoyl)amino]ethyl]-n-methylcarbamate Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCN(C)C(=O)OC(C)(C)C)C(=O)NCCCC1=CC=NC=C1 RWMRTGBPXPWRIZ-UHFFFAOYSA-N 0.000 claims description 4
- VOPFBQTUENFBFS-UHFFFAOYSA-N tert-butyl n-[2-[2-(1-adamantyl)ethyl-[(2-methyl-3-pyridin-4-ylpropyl)carbamoyl]amino]ethyl]-n-methylcarbamate Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCN(C)C(=O)OC(C)(C)C)C(=O)NCC(C)CC1=CC=NC=C1 VOPFBQTUENFBFS-UHFFFAOYSA-N 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000003435 antirheumatic agent Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000000203 mixture Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000004519 manufacturing process Methods 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 17
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 239000002158 endotoxin Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229920006008 lipopolysaccharide Polymers 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 150000003141 primary amines Chemical class 0.000 description 5
- 150000003335 secondary amines Chemical class 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000002198 insoluble material Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- DOHBWNHTMAUNTK-UHFFFAOYSA-N 2-methyl-3-pyridin-4-ylpropan-1-amine Chemical compound NCC(C)CC1=CC=NC=C1 DOHBWNHTMAUNTK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical class CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000007815 allergy Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- ZYIGUOOKJHOVAE-UHFFFAOYSA-N diethyl 2-methyl-2-(pyridin-4-ylmethyl)propanedioate Chemical compound CCOC(=O)C(C)(C(=O)OCC)CC1=CC=NC=C1 ZYIGUOOKJHOVAE-UHFFFAOYSA-N 0.000 description 3
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- QVHCDIXOASJMAN-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]pentan-1-amine Chemical compound C1C(C2)CC3CC2CC1(CCNCCCCC)C3 QVHCDIXOASJMAN-UHFFFAOYSA-N 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- ZZZQLDFHIZXCAA-UHFFFAOYSA-N 2-methyl-3-pyridin-4-ylpropanamide Chemical compound NC(=O)C(C)CC1=CC=NC=C1 ZZZQLDFHIZXCAA-UHFFFAOYSA-N 0.000 description 2
- YGULNNXYUJYOSY-UHFFFAOYSA-N 2-methyl-3-pyridin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=C1 YGULNNXYUJYOSY-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- JURFPUSNTWSSPJ-UHFFFAOYSA-N 3-pyridin-4-ylpropan-1-amine Chemical compound NCCCC1=CC=NC=C1 JURFPUSNTWSSPJ-UHFFFAOYSA-N 0.000 description 2
- ZDHKVKPZQKYREU-UHFFFAOYSA-N 4-(chloromethyl)pyridine;hydron;chloride Chemical compound Cl.ClCC1=CC=NC=C1 ZDHKVKPZQKYREU-UHFFFAOYSA-N 0.000 description 2
- FTFBFLRZEAZBAU-UHFFFAOYSA-N 4-pyridin-4-ylbutan-2-one Chemical compound CC(=O)CCC1=CC=NC=C1 FTFBFLRZEAZBAU-UHFFFAOYSA-N 0.000 description 2
- DFTPIBFPPYDWEC-UHFFFAOYSA-N 5-pyridin-4-ylpentanoic acid Chemical compound OC(=O)CCCCC1=CC=NC=C1 DFTPIBFPPYDWEC-UHFFFAOYSA-N 0.000 description 2
- 0 CC1CC(C2)(C3)C2(CCN(CC=*)C(NCCCc2ccncc2)=O)CC3C1 Chemical compound CC1CC(C2)(C3)C2(CCN(CC=*)C(NCCCc2ccncc2)=O)CC3C1 0.000 description 2
- 206010006895 Cachexia Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- NISLLLKCAMZRRG-UHFFFAOYSA-N ethyl 3-oxo-2-(pyridin-4-ylmethyl)butanoate Chemical compound CCOC(=O)C(C(C)=O)CC1=CC=NC=C1 NISLLLKCAMZRRG-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- WZLFSVMIRVBIDX-UHFFFAOYSA-N n-(4-pyridin-4-ylbutan-2-ylidene)hydroxylamine Chemical compound ON=C(C)CCC1=CC=NC=C1 WZLFSVMIRVBIDX-UHFFFAOYSA-N 0.000 description 2
- HNLXNPWUWRIZRM-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-propyl-5-pyridin-4-ylpentanamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCC)C(=O)CCCCC1=CC=NC=C1 HNLXNPWUWRIZRM-UHFFFAOYSA-N 0.000 description 2
- UOOOCYFGAHYTSG-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]pentan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCCCCC)C3 UOOOCYFGAHYTSG-UHFFFAOYSA-N 0.000 description 2
- UEPYNCNDMALIHK-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]propan-1-amine Chemical compound C1C(C2)CC3CC2CC1(CCNCCC)C3 UEPYNCNDMALIHK-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229920002050 silicone resin Polymers 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- AVQABZVTPWROCF-UHFFFAOYSA-M (2-oxo-2-phenylmethoxyethyl)-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1COC(=O)C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 AVQABZVTPWROCF-UHFFFAOYSA-M 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- TWMKVKIJGLSCJT-UHFFFAOYSA-N 2-(1-adamantyl)-n-methylacetamide Chemical compound C1C(C2)CC3CC2CC1(CC(=O)NC)C3 TWMKVKIJGLSCJT-UHFFFAOYSA-N 0.000 description 1
- QPHKFMOPPHRCKW-UHFFFAOYSA-N 2-(1-adamantyl)-n-methylethanamine Chemical compound C1C(C2)CC3CC2CC1(CCNC)C3 QPHKFMOPPHRCKW-UHFFFAOYSA-N 0.000 description 1
- NORKQDMUHKNJNN-UHFFFAOYSA-N 2-(3-pyridin-4-ylpropyl)isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCC1=CC=NC=C1 NORKQDMUHKNJNN-UHFFFAOYSA-N 0.000 description 1
- VWKLMPOKKGNEFO-UHFFFAOYSA-N 3-(1-adamantyl)-n-propylpropan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCCNCCC)C3 VWKLMPOKKGNEFO-UHFFFAOYSA-N 0.000 description 1
- WSNKEJIFARPOSQ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(1-benzothiophen-2-ylmethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC3=C(S2)C=CC=C3)C=CC=1 WSNKEJIFARPOSQ-UHFFFAOYSA-N 0.000 description 1
- VTNULXUEOJMRKZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2H-tetrazol-5-ylmethyl)benzamide Chemical compound N=1NN=NC=1CNC(C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)=O VTNULXUEOJMRKZ-UHFFFAOYSA-N 0.000 description 1
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-UHFFFAOYSA-N 0.000 description 1
- KOZMKKDQRHAAIG-UHFFFAOYSA-N 3-pyridin-4-ylprop-2-en-1-amine Chemical compound NCC=CC1=CC=NC=C1 KOZMKKDQRHAAIG-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- KLMKQKKMDYLMOF-UHFFFAOYSA-N 4-pyridin-4-ylbutan-2-amine Chemical compound CC(N)CCC1=CC=NC=C1 KLMKQKKMDYLMOF-UHFFFAOYSA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- MFOXLHIPCNHCAX-VOTSOKGWSA-N CCCCCN(CCC1(CC(C2)C3)C=C3CC2C1)C(NC/C=C/C1(C)C=CN=CC1)=O Chemical compound CCCCCN(CCC1(CC(C2)C3)C=C3CC2C1)C(NC/C=C/C1(C)C=CN=CC1)=O MFOXLHIPCNHCAX-VOTSOKGWSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 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
- 101000648290 Rattus norvegicus Tumor necrosis factor Proteins 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- YQYBUJYBXOVWQW-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3,4-dihydro-1H-isoquinolin-2-yl)methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1CC2=CC=CC=C2CC1 YQYBUJYBXOVWQW-UHFFFAOYSA-N 0.000 description 1
- YKKPYMXANSSQCA-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3-pyrazol-1-ylazetidin-1-yl)methanone Chemical compound N1(N=CC=C1)C1CN(C1)C(=O)C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F YKKPYMXANSSQCA-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 108010025899 gelatin film Proteins 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 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
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- WGBGZUMUKVCCSN-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-3,3,3-trifluoropropan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCCC(F)(F)F)C3 WGBGZUMUKVCCSN-UHFFFAOYSA-N 0.000 description 1
- ZFVUGGZMZILACZ-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]but-2-en-1-amine Chemical compound C1C(C2)CC3CC2CC1(CCNCC=CC)C3 ZFVUGGZMZILACZ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- NSTHNVMITOXEJZ-TYYBGVCCSA-N oxalic acid;(e)-3-pyridin-4-ylprop-2-enal Chemical compound OC(=O)C(O)=O.O=C\C=C\C1=CC=NC=C1 NSTHNVMITOXEJZ-TYYBGVCCSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 229940100684 pentylamine Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- NIPDQJPBXRAJPW-UHFFFAOYSA-N tert-butyl n-[2-[2-(1-adamantyl)ethylamino]ethyl]-n-methylcarbamate Chemical compound C1C(C2)CC3CC2CC1(CCNCCN(C)C(=O)OC(C)(C)C)C3 NIPDQJPBXRAJPW-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- 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
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P37/08—Antiallergic agents
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- 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
- C07D213/68—One oxygen atom attached in position 4
-
- 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Transplantation (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
【発明の属する技術分野】
本発明は、慢性関節リウマチ等の自己免疫性疾患の治療剤として有用な新規なTNF−α産生阻害物質に関する。
【0002】
【従来の技術】
TNF−α(Tumor Necrosis Factor-α:腫瘍壊死因子)は、炎症を通した生体防御・免疫機構に広く関わるサイトカインとして認識されており、TNF−αの持続的かつ過剰な産生は組織障害やさまざまな病気を引き起こす原因となることが知られている。例えばTNF−αが関与する病態例として、関節リウマチ、全身性エリテマトーデス(SLE)、悪液質、急性感染症、アレルギー、発熱、貧血、糖尿病など多くの病態が挙げられている(山崎、臨床免疫, 27, 1270, 1995)。また、TNF−αが自己免疫性疾患である慢性関節リウマチおよびクローン病の発症に重要な役割を果たしていることも報告されている(Andreas Eigler et al., Immunology Today, 18, 487, 1997)。
【0003】
このようなことから、TNF−αの産生を阻害または抑制する化合物は、前記疾患の治療に有効であると期待され、種々の研究がなされている(上記文献:山崎、臨床免疫, 27および 1270, 1995、Andreas Eigler et al., Immunology Today, 18)。最近では、蛋白質分解酵素であるメタロプロテアーゼがTNF−αの分泌に関与していることやメタロプロテアーゼ阻害剤がTNF−α産生阻害に重大な影響を及ぼしていることなども報告されている(特表平9−508115号)。また、特開2000−44533号および特開2000−119249号公報には、TNF−αの産生阻害作用を有する化合物が開示されているが、これらの化合物はいずれも側鎖に硫黄原子を有することを特徴とするウレア誘導体である。
【0004】
【発明が解決しようとする課題】
慢性関節リウマチ、アレルギー、糖尿病などの自己免疫性疾患の治療剤として有用なTNF−α産生阻害活性を有する化合物を探索することは意義深い。
【0005】
【課題を解決するための手段】
本発明者等は、種々の化学構造を有する化合物を創製して薬理試験を実施したところ、下記構造を有する新規な化合物が、優れたTNF−α産生阻害活性を有することを見出し本発明に至った。
【0006】
本発明は、
・1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)プロピル]ウレア、
・1−[2−(1−アダマンチル)エチル]−3−[3−(4−ピリジル)プロピル]−1−(3,3,3−トリフルオロプロピル)ウレア、
・1−[2−(1−アダマンチル)エチル]−1−(2−ブテニル)−3−[3−(4−ピリジル)プロピル]ウレア、
・1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[3−(4−ピリジル)プロピル]ウレア、
・1−[3−(1−アダマンチル)プロピル]−1−プロピル−3−[3−(4−ピリジル)プロピル]ウレア、
・(Z)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレア、
・(−)−1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア、
・1−[2−(1−アダマンチル)エチル]−3−[1−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア、
・(+)−1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]ウレア、
・5−(4−ピリジル)吉草酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド、
・3−(4−ピリジルメチルチオ)プロピオン酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド、
・2−[2−(4−ピリジル)エチルチオ]酢酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド、
・6−(4−ピリジル)カプロン酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド、
・cis−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[2−(4−ピリジル)シクロプロピルメチル]ウレア
・1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア、
・1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]ウレア、
・(E)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレアおよび
・(+)−1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア
よりなる群から選ばれる化合物またはその塩類(以下特記なき限り「本化合物」とする)並びにそれらを有効成分とする医薬組成物に関するものである。
【0007】
【発明の実施の形態】
本発明における塩類とは医薬として許容される塩であれば特に制限はなく、塩酸、硝酸、硫酸、リン酸等の無機酸との塩、酢酸、フマル酸、マレイン酸、コハク酸、酒石酸等の有機酸との塩、また、ナトリウム、カリウム、カルシウム等のアルカリ金属またはアルカリ土類金属との塩などが挙げられる。また、本化合物の第四級アンモニウム塩も本発明における塩類に包含される。さらに、本化合物に幾何異性体または光学異性体が存在する場合には、それらの異性体も本発明の範囲に含まれる。なお、本化合物は水和物および溶媒和物の形態をとっていてもよい。
【0008】
本化合物は、それぞれ下記構造を有する。
【0009】
○1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)プロピル]ウレア
【化1】
○1−[2−(1−アダマンチル)エチル]−3−[3−(4−ピリジル)プロピル]−1−(3,3,3−トリフルオロプロピル)ウレア
【化2】
○1−[2−(1−アダマンチル)エチル]−1−(2−ブテニル)−3−[3−(4−ピリジル)プロピル]ウレア
【化3】
○1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[3−(4−ピリジル)プロピル]ウレア
【化4】
○1−[3−(1−アダマンチル)プロピル]−1−プロピル−3−[3−(4−ピリジル)プロピル]ウレア
【化5】
○(Z)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレア
【化6】
○(−)−1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア
【化7】
○1−[2−(1−アダマンチル)エチル]−3−[1−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア
【化8】
○(+)−1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]ウレア
【化9】
○5−(4−ピリジル)吉草酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド
【化10】
○3−(4−ピリジルメチルチオ)プロピオン酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド
【化11】
○2−[2−(4−ピリジル)エチルチオ]酢酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド
【化12】
○6−(4−ピリジル)カプロン酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド
【化13】
○cis−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[2−(4−ピリジル)シクロプロピルメチル]ウレア
【化14】
○1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア
【化15】
○1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]ウレア
【化16】
○(E)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレア
【化17】
○(+)−1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア
【化18】
つぎに、本化合物は例えば下記反応経路1〜3に従って製造できるが、これらの反応経路に限らず種々の反応経路によっても製造できる。なお、詳細な合成方法は後述の実施例で説明する。
【0010】
反応経路1
【化19】
アミド体(A)を還元することにより、また第1アミン(B)と脱離基を有する化合物(C)を反応させることにより、第2アミン(D)を得ることができる(なお、上記化学反応式においてR1とR2を入れ替えて合成することができる。)。同様に脱離基を有する化合物(E)と第1アミン(F)を反応させることにより第2アミン(G)を得ることができる。第1アミン(B)あるいは第2アミン(D)と、第1アミン(F)あるいは第2アミン(G)を縮合剤(H)[例えば1,1’−カルボニルジイミダゾール]の存在下で反応させれば、本化合物[2]が得られる。
【0011】
反応経路2
【化20】
第1アミン(B)あるいは反応経路1で合成した第2アミン(D)とカルボン酸(I)を縮合剤[例えば1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩]の存在下で反応させれば、本化合物[3]が得られる。
【0012】
上記の合成方法によって得られた化合物は、常法により前述の様な塩類とすることができる。
【0013】
上記合成方法によって得られた化合物の有用性を調べるべく、TNF−α産生阻害作用を検討した。詳細については後述の薬理試験の項で示すが、リポポリサッカライド(LPS)の刺激によって引き起こされたTNF−αの遊離に対する抑制効果をin vivo で検討した結果、本化合物は優れたTNF−α産生阻害作用を示した。
【0014】
ところで、「従来の技術」の項で説明したように、TNF−αの産生は慢性関節リウマチ、クローン病、全身エリテマトーデス等の自己免疫性疾患の発症と深く関わり合いがあることが知られており、本化合物のようにTNF−αの産生を阻害する化合物はこれらの疾患の治療に有用である。
【0015】
本化合物は経口でも、非経口でも投与することができる。投与剤型としては、錠剤、カプセル剤、顆粒剤、散剤、注射剤等が挙げられ、汎用されている技術を用いて製剤化することができる。例えば、錠剤、カプセル剤、顆粒剤、散剤等の経口剤であれば、乳糖、結晶セルロース、デンプン、植物油等の増量剤、ステアリン酸マグネシウム、タルク等の滑沢剤、ヒドロキシプロピルセルロース、ポリビニルピロリドン等の結合剤、カルボキシメチルセルロース カルシウム、低置換ヒドロキシプロピルメチルセルロース等の崩壊剤、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコン樹脂等のコーティング剤、ゼラチン皮膜等の皮膜剤などを必要に応じて加えればよい。
【0016】
本化合物の投与量は症状、年令、剤型等によって適宜選択できるが、経口剤であれば通常1日当り0.1〜5000mg、好ましくは1〜1000mgを1回または数回に分けて投与すればよい。
【0017】
以下に、中間体の製造例、本化合物の製造例、製剤例および薬理試験の結果を示すが、これらの例は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。
【0018】
[A]中間体の製造例
製造例1
○2−(1−アダマンチル)−N−ペンチルエチルアミン 塩酸塩(中間体1−1)
メタンスルホン酸 2−(1−アダマンチル)エチルエステル(2.07g,8.01mmol)のエタノール(45.8ml)溶液に、ペンチルアミン(2.69ml,23.2mmol)、炭酸カリウム(2.14g,15.5mmol)、よう化ナトリウム(2.30g,15.3mmol)を加え、17時間加熱還流した。反応溶液を減圧濃縮し、クロロホルム(100ml)で希釈した。これを1N水酸化ナトリウム水溶液(100ml)、飽和塩化ナトリウム水溶液(100ml)で洗浄し、有機層を硫酸マグネシウムで乾燥した。溶媒を減圧留去し、シリカゲルカラムクロマトグラフィーで精製した。得られた標的化合物のフリー体(1.52g,6.10mmol)の酢酸エチル(0.50ml)溶液に、4N塩化水素酢酸エチル溶液(3.1ml)を加えた。析出した固体を酢酸エチルで洗浄し、濾取すると、標的化合物1.33g(60%)が得られた。
【0019】
IR(KBr):2924,2850,2519,1456cm-1
mp:263.0−264.5℃
製造例1と同様の操作を行うことにより、以下の化合物が得られた。なお、標的化合物を塩酸塩として単離しないこともある。
【0020】
○N’−[2−(1−アダマンチル)エチル]−N−(t−ブトキシカルボニル)−N−メチルエチレンジアミン(中間体1−2)
IR(neat):3307,2902,2846,1698cm-1
○N−[2−(1−アダマンチル)エチル]−2−ブテニルアミン(中間体1−3)
IR(neat):2901,1450cm-1
○N−[2−(1−アダマンチル)エチル]−3,3,3−トリフルオロプロピルアミン 塩酸塩(中間体1−4)
IR(KBr):2910,2849,2767,2598,2457cm-1
mp:300.0−310.0℃
2−(1−アダマンチル)−N−プロピルエチルアミン(中間体1−5)
IR(neat):3276,2903,2846,1450cm-1
製造例2
○4−(3−アミノプロピル)ピリジン(中間体2−1)
N−[3−(4−ピリジル)プロピル]フタルイミド(67.1g、252mmol)
とメタノール(504ml)とヒドラジン一水和物(18.3ml、378mmol)を混ぜ、3時間加熱環流した。放冷後不溶物を濾別し、濾液を減圧濃縮した。残留物にクロロホルム(1L)と4N水酸化ナトリウム水溶液(500ml)を加え、分液後、有機層を硫酸ナトリウムで乾燥した。減圧濃縮後減圧蒸留すると、標的化合物20.5g(60%)が無色油状物として得られた。
【0021】
IR(neat):3362,2933,1603cm-1
bp:76.0−79.0℃/40Pa
製造例2と同様の操作を行うことにより、以下の化合物が得られた。
【0022】
○3−(4−ピリジル)−2−プロペニルアミン(中間体2−2)
IR(neat):3280,3024,1599cm -1
製造例3
○2−(1−アダマンチル)−N−メチルエチルアミン(中間体3−1)
水素化リチウムアルミニウム(569mg,15.0mmol)のジエチルエーテル(34.0ml)溶液に、氷冷下、1−アダマンタン酢酸N−メチルアミド(1.54g,7.45mmol)のテトラヒドロフラン(15.0ml)溶液を5分間で滴下した。6時間加熱還流した後、再び氷冷下で撹拌し、酢酸エチルを加えて過剰の水素化リチウムアルミニウムを処理した後、反応溶液を1N塩酸(50ml)で2回抽出した。抽出液を4N水酸化ナトリウム水溶液の添加で塩基性にし、ジエチルエーテル(80ml)で抽出した。有機層を飽和塩化ナトリウム水溶液(60ml)で洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去して、標的化合物890mg(66%)を得た。
【0023】
IR(neat):2902,2845,1449cm-1
製造例3と同様の操作を行うことにより、以下の化合物が得られた。
【0024】
なお、4N塩化水素酢酸エチル溶液により、該化合物を塩酸塩にすることもできた。
【0025】
○3−(1−アダマンチル)−N−プロピルプロピルアミン 塩酸塩(中間体3−2)
IR(KBr):2899,2467,1449cm-1
mp:159.5−162.0℃
製造例4
○5−(4−ピリジル)吉草酸(中間体4−1)
臭化(ベンジルオキシカルボニルメチル)トリフェニルホスホニウム(4.60g、9.36mmol)、β−(4−ピリジル)アクロレインしゅう酸塩(1.90g、8.51mmol)にN,N−ジメチルホルムアミド(17ml)を加え、氷冷下攪拌した。炭酸カリウム(4.70g、34.0mmol)を加え、反応溶液を室温とした。これを一夜攪拌後酢酸エチル(100ml)で希釈し、水(100ml)2回、飽和食塩水(50ml)の順で洗浄した。硫酸ナトリウムで乾燥後酢酸エチルを減圧留去した。残留物をシリカゲルカラムクロマトグラフィーで分離精製すると、5−(4−ピリジル)吉草酸−2,4−ジエンベンジルエステル2.29g(定量的)が淡黄色油状物として得られた。
【0026】
つぎに、5−(4−ピリジル)吉草酸−2,4−ジエンベンジルエステル(2.25g、8.48mmol)にメタノール(42ml)、酢酸(1.0ml、18mmol)を加え、窒素ガスを10分間通気した。触媒量の水酸化パラジウムオンカーボンを加え、水素雰囲気下室温で一夜攪拌した。セライト濾過により不溶物を濾去した後、濾液を減圧濃縮した。固化した残留物に酢酸エチル(50ml)を加え、室温で3時間攪拌した。結晶を濾取すると、標的化合物1.00g(66%)が淡黄色結晶として得られた。
【0027】
IR(KBr):2943,1719,1636,1605cm-1
mp:155.0−180.0℃
製造例5
○(RS)−2−メチル−3−(4−ピリジル)プロピルアミン(中間体5-1)
窒素雰囲気下、水素化ナトリウム(5.36g、134mmol)にN,N−ジメチルホルムアミド(143ml)を加え、氷冷下攪拌した。メチルマロン酸ジエチルエステル(11.7g、67.1mmol)のN,N−ジメチルホルムアミド(40ml)溶液を5分間で滴下し、10分後4−塩化ピコリル塩酸塩(10.0g、61.0mmol)を少しずつ5分間かけて加え室温とした。1時間後飽和重曹水(500ml)を加え、ジエチルエーテル(400ml)で抽出した。有機層を水(100ml)飽和食塩水(50ml)で洗浄し、硫酸マグネシウムで乾燥した。減圧濃縮すると、2−メチル−2−(4−ピリジルメチル)マロン酸ジエチルエステル17.2g(定量的、水素化ナトリウムオイルを含む)が茶色油状物として得られた。
【0028】
つぎに、2−メチル−2−(4−ピリジルメチル)マロン酸ジエチルエステル(17.2g、64.6mmol)に6N塩酸(96.8ml、581mmol)を加え一夜加熱環流した。放冷後ヘキサン(100ml)で洗浄することにより2−メチル−2−(4−ピリジルメチル)マロン酸ジエチルエステルに含まれていた水素化ナトリウムオイルを除去し減圧濃縮した。生じた結晶を酢酸エチルで濾取すると、2−メチル−3−(4−ピリジル)プロピオン酸10.7g(82%)が薄ピンク色結晶として得られた。
【0029】
つぎに、2−メチル−3−(4−ピリジル)プロピオン酸(1.69g、10.2mmol)にクロロホルム(8ml)、塩化チオニル(2.2ml、30.6mmol)、N,N−ジメチルホルムアミド(1滴)を加え、攪拌しながら1時間加熱環流した。減圧濃縮後クロロホルム(8ml)を加え、氷冷下攪拌している28%アンモニア水溶液にゆっくり加えた。10分後室温とし、一夜攪拌した。減圧濃縮後酢酸エチル(100ml)を加え、生じた不溶物を濾去した。濾液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィーで分離精製し、生じた結晶をジエチルエーテルで濾取すると、2−メチル−3−(4−ピリジル)プロピオン酸アミド0.72g(43%)が淡黄色結晶として得られた。
【0030】
つぎに、窒素雰囲気下、水素化リチウムアルミニウム(0.45g、12mmol)に無水ジエチルエーテル(20ml)を加え氷冷下攪拌した。2−メチル−3−(4−ピリジル)プロピオン酸アミド(0.68g、4.1mmol)の無水塩化メチレン(20ml)溶液を5分間で滴下し、室温として一夜攪拌した。再び氷冷下とし、酢酸エチル(5ml)をゆっくり加え、次いで1N水酸化ナトリウム水溶液を初めはゆっくり加え、全量100ml加えた。クロロホルム(100ml)で抽出後、有機層を硫酸ナトリウムで乾燥し減圧濃縮すると、標的化合物0.56g(90%)が淡黄色油状物として得られた。
【0031】
IR(neat):3293,2957,2925,1602cm-1
製造例5と同様の操作を行うことにより、以下の化合物が得られた。また、光学活性な酸を用いて光学分割することにより、光学活性体を得ることができた。
【0032】
○(−)−2−メチル−3−(4−ピリジル)プロピルアミン(中間体5−2)
IR(neat):3362,3301,2958,1603cm-1
[α]20 D:−10.6°(MeOH,C1.0)
○(+)−2−メチル−3−(4−ピリジル)プロピルアミン(中間体5−3)
IR(neat):3362,3294,2958,1603cm-1
[α]20 D:+9.9°(MeOH,C1.0)
製造例6
○4−(3−アミノブチル)ピリジン(中間体6−1)
窒素雰囲気下、水素化ナトリウム(2.81g、70.3mmol)に無水N,N−ジメチルホルムアミド(41ml)を加え、氷水冷下撹拌した。アセト酢酸t−ブチルエステル(6.33g、40.0mmol)のN,N−ジメチルホルムアミド(20ml)溶液を10分間で滴下し、更に10分後窒素気流下として4−(クロロメチル)ピリジン塩酸塩(5.00g、30.5mmol)を少しずつ3分間で加えて室温とした。2時間後飽和重曹水(150ml)を加え、酢酸エチル(100ml)で抽出した。有機層を水(100ml)、飽和食塩水(50ml)で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィーで分離精製すると、2−アセチル−3−(4−ピリジル)プロピオン酸エチルエステル1.34g(18%)が淡黄色油状物として得られた。
【0033】
つぎに、2−アセチル−3−(4−ピリジル)プロピオン酸エチルエステル(1.20g、4.81mmol)に6N塩酸(8ml)を加え、1.5時間加熱還流した。減圧濃縮後2−プロパノール(10ml)を加え、再度減圧濃縮した。生じた固体に酢酸エチルを加え濾取すると、4−(4−ピリジル)−2−ブタノン0.79g(89%)が淡黄色固体として得られた。
【0034】
つぎに、4−(4−ピリジル)−2−ブタノン(736mg、3.96mmol)に水(12ml)、テトラヒドロフラン(1.2ml)を加え、室温で撹拌した。炭酸ナトリウム(483mg、4.56mmol)とヒドロキシルアミン塩酸塩(358mg、5.15mmol)を加え、1.5時間攪拌後酢酸エチル(50ml)を加えて希釈した。炭酸水素ナトリウムを加え分液後飽和食塩水(10ml)で洗浄した。有機層を無水硫酸ナトリウムで乾燥後減圧濃縮した。生じた結晶にシクロヘキサンを加え濾取すると、4−(4−ピリジル)−2−ブタノンオキシム584mg(90%)が淡黄色結晶として得られた。
【0035】
つぎに、窒素雰囲気下、水素化リチウムアルミニウム(257mg、6.77mmol)に無水エーテル(19ml)を加え、氷冷下撹拌した。4−(4−ピリジル)−2−ブタノンオキシム(556mg、3.38mmol)のエーテル(15ml)溶液を7分間で滴下後室温とし一夜撹拌した。更に二日間加熱還流後氷冷下撹拌した。酢酸エチルをゆっくり加えた後1N水酸化ナトリウム水溶液(最初はゆっくり、全20ml)を加えた。クロロホルム(80ml)を加え不溶物をセライトで濾去し、分液後クロロホルムを減圧濃縮した。残留物と水層を合わせ、テトラヒドロフラン(20ml)を加え、室温で撹拌した。炭酸ジ−t−ブチルエステル(1.48g、6.78mmol)を加え一夜撹拌した。クロロホルム(50ml)を加え抽出後無水硫酸マグネシウムで乾燥し減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーで分離精製した。残留物に4N塩化水素酢酸エチル溶液(3ml)とエタノール(1ml)を加え室温で撹拌した。3時間後減圧濃縮し、残留物にクロロホルム(5ml)、メタノール(5ml)、トリエチルアミン(1ml)を加え減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィーで分離精製すると、標的化合物161mg(32%)が茶色油状物として得られた。
【0036】
IR(neat):3354,3280,2958,2925,2866,1602cm-1
[B]本化合物の製造
実施例1
○1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)プロピル]ウレア(化合物1−1)
中間体2−1の4−(3−アミノプロピル)ピリジン(285mg,2.09mmol)のテトラヒドロフラン(10ml)溶液に1,1’−カルボニルジイミダゾール(427mg,2.63mmol)を加え、室温で20分間攪拌した。中間体1−1の2−(1−アダマンチル)−N−ペンチルエチルアミン塩酸塩(571mg,2.00mmol)を加え、1時間加熱還流した。酢酸エチル(50ml)で希釈し、飽和炭酸水素ナトリウム水溶液(50ml)、飽和塩化ナトリウム水溶液(50ml)で洗浄後、硫酸マグネシウムを加え乾燥した。溶媒を減圧留去し、析出した固体をジイソプロピルエーテルで洗浄後濾取すると、標的化合物606mg(73%)が得られた。
【0037】
IR(KBr):2900,2845,1618,1534cm-1
mp:124.0−124.7℃
実施例1と同様の操作を行うことにより、以下の化合物が得られた。
【0038】
○1−[2−(1−アダマンチル)エチル]−3−[3−(4−ピリジル)プロピル]−1−(3,3,3−トリフルオロプロピル)ウレア(化合物1−2)
IR(KBr):3310,2900,2847,1622,1543cm-1
mp:107.5−109.0℃
○1−[2−(1−アダマンチル)エチル]−1−(2−ブテニル)−3−[3−(4−ピリジル)プロピル]ウレア(化合物1−3)
IR(KBr):3328,2900,1619cm-1
mp:89.5−93.5℃
○1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[3−(4−ピリジル)プロピル]ウレア(化合物1−4)
IR(neat):3350,2903,2846,1694,1633,1537cm-1
○1−[3−(1−アダマンチル)プロピル]−1−プロピル−3−[3−(4−ピリジル)プロピル]ウレア(化合物1−5)
IR(neat):3349,2901,1626,1536cm-1
○1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア(化合物1−6)
IR(KBr):3347,2957,2902,2846,1621,1604,1539cm-1
mp:105.3−112.3℃
○1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]ウレア(化合物1−7)
IR(neat):3350,2902,2846,1694,1672,1633,1603,1537cm-1
○(Z)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレア(化合物1−8)
IR(neat):3338,2901,2846,1625,1596,1530cm-1
○(E)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレア(化合物1−9)
IR(KBr):3315,2900,2845,1623,1526cm-1
mp:90−118℃
○(−)−1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア(化合物1−10)
IR(KBr):3337,2900,1616,1526cm-1
mp:103.0−104.0℃
[α]20 D:−4.6°(MeOH,C1.0)
○(+)−1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア(化合物1−11)
IR(KBr):3336,2900,1616,1526cm-1
mp:102.9−103.5℃
[α]20 D:+4.2°(MeOH,C1.0)
○1−[2−(1−アダマンチル)エチル]−3−[1−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア(化合物1−12)
IR(KBr):3338,2902,2847,1615,1533cm-1
mp:128.5−129.0℃
○(+)−1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]ウレア(化合物1−13)
IR(KBr):3345,2910,2848,1693,1622,1602,1538,1248cm-1
mp:122.7−123.7℃
[α]20 D:+2.8°(MeOH,C1.0)
実施例2
○5−(4−ピリジル)吉草酸 N−[2−(1−アダマンチル)エチル]−N−プロピルアミド(化合物2−1)
中間体1−5の2−(1−アダマンチル)−N−プロピルエチルアミン(0.37g、1.7mmol)、中間体4−1の5−(4−ピリジル)吉草酸(0.30g、1.7mmol)にN,N−ジメチルホルムアミド(8.4ml)を加え、室温で攪拌した。N−メチルモルホリン(0.27ml、2.5mmol)、次いで1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(0.38g、2.0mmol)を加えて一夜攪拌した。反応溶液を減圧濃縮し、残留物に酢酸エチル(20ml)を加え、飽和重曹水(20ml)飽和食塩水(5ml)の順で洗浄した。硫酸ナトリウムで乾燥後酢酸エチルを減圧留去した。残留物を塩基性シリカゲルカラムクロマトグラフィーで分離精製すると、標的化合物0.21g(33%)が無色油状物として得られた。
【0039】
IR(neat):2092,2846,1644,1602cm-1
実施例2と同様の操作を行うことにより、以下の化合物が得られた。
【0040】
○5−(4−ピリジル)吉草酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド(化合物2−2)
IR(neat):2903,2847,1736,1643,1602cm-1
○3−(4−ピリジルメチルチオ)プロピオン酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド(化合物2−3)
IR(neat):2903,1643,1599cm-1
○2−[2−(4−ピリジル)エチルチオ]酢酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド(化合物2−4)
IR(neat):2902,1635,1602cm-1
○6−(4−ピリジル)カプロン酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド(化合物2−5)
IR(neat):2903,1644,1602cm-1
実施例3
○cis−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[2−(4−ピリジル)シクロプロピルメチル]ウレア(化合物3−1)
窒素雰囲気氷冷下、化合物1−8の(Z)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレア(0.25g、0.61mmol)の無水1,2−ジクロロエタン(3ml)溶液に、ジエチル亜鉛1.0M ヘキサン溶液(3.1ml、3.1mmol)とクロロヨードメタン(0.44ml、6.1mol)を加え、1時間攪拌した。反応液に氷冷下、飽和塩化アンモニウム水溶液(10ml)を加え、20分間室温で攪拌した後、酢酸エチル(20ml)と飽和塩化アンモニウム水溶液(10ml)で分配した。有機層を飽和塩化ナトリウム水溶液(10ml)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒留去し、得られた残留物をシリカゲルカラムクロマトグラフィーで精製することにより標的化合物9.0mg(3.5%)が無色結晶として得られた。
【0041】
IR(KBr):3340,3025,2903,2847,1617,1603,1525cm-1
mp:128.0−130.0℃
[C]製剤例
本化合物の経口剤および注射剤としての一般的な製剤例を以下に示す。
【0042】
1)錠剤
処方1(100mg中)
本化合物 1 mg
乳糖 66.4mg
トウモロコシデンプン 20 mg
カルボキシメチルセルロース カルシウム 6 mg
ヒドロキシプロピルセルロース 4 mg
ステアリン酸マグネシウム 0.6mg
上記処方の錠剤に、コーティング剤(例えば、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコン樹脂等通常のコーティング剤)2mgを用いてコーティングを施し、目的とするコーティング錠を得る(以下の処方の錠剤も同じ)。また、本化合物および添加物の量を適宜変更することにより、所望の錠剤を得ることができる。
【0043】
2)カプセル剤
処方1(150mg中)
本化合物 5 mg
乳糖 145 mg
本化合物および乳糖の混合比を適宜変更することにより、所望のカプセル剤を得ることができる。
【0044】
3)注射剤
処方1(10ml中)
本化合物 10〜100 mg
塩化ナトリウム 90 mg
水酸化ナトリウム 適量
塩酸 適量
滅菌精製水 適量
本化合物および添加物の混合比を適宜変更することにより、所望の注射剤を得ることができる。
【0045】
[D]薬理試験
辻らの方法[Inflamm.res.46 (1997)193-198]に準じて、リポポリサッカライド(LPS)刺激により引き起こされたTNF−αの産生に対する抑制効果をin vivo試験で検討した。
【0046】
試験動物として体重約200g、8週齢前後の雌性ラット(一群5匹)を使用した。サルモネラ菌由来のLPSを生理食塩水に溶解してLPS溶液(1mg/ml)を調製した。被験物質を1%メチルセルロース水溶液に溶解または均一に懸濁し、被験物質調製液を得た。
【0047】
ラットに上記LPS溶液(0.5ml/kg)を足蹠投与した。LPS投与後直ちに、被験物質調製液(被験物質10mg/kgまたは3mg/kgを含む)を経口投与した。LPS投与2時間後、腹部大動脈より採血し、これを4℃、3000rpmで10分間遠心分離した。得られた血漿中のTNF−αレベルをラットTNF−α特異ELISAキットで測定した。なお、LPS−非投与群(コントロール)では血漿中にTNF−αの産生を認められなかった。
【0048】
被験物質のTNF−αの産生抑制率は、下記の式により求めた。
【0049】
【数1】
A:被験物質非投与群の血漿中のTNF−αレベル
B:被験物質投与群の血漿中のTNF−αレベル
(結果)
被験物質(10mg/kgまたは3mg/kg)をラットに経口投与したときのTNF−αの産生抑制率(%)を算出したところ、本化合物の多くは高い産生抑制率を示した。10mg/kg経口投与時の代表的な試験結果を表1に、また、3mg/kg経口投与時の代表的な試験結果を表2にそれぞれ示す。
【0050】
【表1】
【表2】
【0051】
【発明の効果】
薬理試験の結果から明らかなように、本化合物は優れたTNF−α産生阻害作用を有するので、TNF−αが関与する疾患、例えば慢性関節リウマチ、クローン病、全身エリテマトーデス等の自己免疫性疾患、悪液質、急性感染症、アレルギー、発熱、貧血、糖尿病等の治療剤として広く医薬用途に適用できる。
Claims (5)
- ・1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)プロピル]ウレア、
・1−[2−(1−アダマンチル)エチル]−3−[3−(4−ピリジル)プロピル]−1−(3,3,3−トリフルオロプロピル)ウレア、
・1−[2−(1−アダマンチル)エチル]−1−(2−ブテニル)−3−[3−(4−ピリジル)プロピル]ウレア、
・1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[3−(4−ピリジル)プロピル]ウレア、
・1−[3−(1−アダマンチル)プロピル]−1−プロピル−3−[3−(4−ピリジル)プロピル]ウレア、
・(Z)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレア、
・(−)−1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア、
・1−[2−(1−アダマンチル)エチル]−3−[1−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア、
・(+)−1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]ウレア、
・5−(4−ピリジル)吉草酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド、
・3−(4−ピリジルメチルチオ)プロピオン酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド、
・2−[2−(4−ピリジル)エチルチオ]酢酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド、
・6−(4−ピリジル)カプロン酸 N−[2−(1−アダマンチル)エチル]−N−ペンチルアミド、
・cis−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[2−(4−ピリジル)シクロプロピルメチル]ウレア
・1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア、
・1−[2−(1−アダマンチル)エチル]−1−[2−[N−(t−ブトキシカルボニル)−N−メチルアミノ]エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]ウレア、
・(E)−1−[2−(1−アダマンチル)エチル]−1−ペンチル−3−[3−(4−ピリジル)−2−プロペニル]ウレアおよび
・(+)−1−[2−(1−アダマンチル)エチル]−3−[2−メチル−3−(4−ピリジル)プロピル]−1−ペンチルウレア
よりなる群から選ばれる化合物またはその塩類。 - 請求項1に記載の化合物またはその塩類を有効成分として含有する医薬組成物。
- 請求項1に記載の化合物またはその塩類を有効成分として含有するTNF−α産生阻害剤。
- 請求項1に記載の化合物またはその塩類を有効成分として含有するクローン病または全身エリテマトーデスの治療剤。
- 請求項1に記載の化合物またはその塩類を有効成分として含有する抗リウマチ剤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001164523A JP3867196B2 (ja) | 2000-05-31 | 2001-05-31 | TNF−α産生阻害物質 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000162945 | 2000-05-31 | ||
JP2000-162945 | 2000-05-31 | ||
JP2001164523A JP3867196B2 (ja) | 2000-05-31 | 2001-05-31 | TNF−α産生阻害物質 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006140241A Division JP4482735B2 (ja) | 2000-05-31 | 2006-05-19 | TNF−α産生阻害物質 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2002053555A JP2002053555A (ja) | 2002-02-19 |
JP2002053555A5 JP2002053555A5 (ja) | 2006-07-20 |
JP3867196B2 true JP3867196B2 (ja) | 2007-01-10 |
Family
ID=18666780
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2001164523A Expired - Fee Related JP3867196B2 (ja) | 2000-05-31 | 2001-05-31 | TNF−α産生阻害物質 |
JP2006140241A Expired - Fee Related JP4482735B2 (ja) | 2000-05-31 | 2006-05-19 | TNF−α産生阻害物質 |
JP2009283084A Pending JP2010059204A (ja) | 2000-05-31 | 2009-12-14 | TNF−α産生阻害物質 |
JP2009283085A Pending JP2010059205A (ja) | 2000-05-31 | 2009-12-14 | TNF−α産生阻害物質 |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006140241A Expired - Fee Related JP4482735B2 (ja) | 2000-05-31 | 2006-05-19 | TNF−α産生阻害物質 |
JP2009283084A Pending JP2010059204A (ja) | 2000-05-31 | 2009-12-14 | TNF−α産生阻害物質 |
JP2009283085A Pending JP2010059205A (ja) | 2000-05-31 | 2009-12-14 | TNF−α産生阻害物質 |
Country Status (15)
Country | Link |
---|---|
US (5) | US7098226B2 (ja) |
EP (4) | EP1302461B1 (ja) |
JP (4) | JP3867196B2 (ja) |
KR (2) | KR100880698B1 (ja) |
CN (3) | CN1307159C (ja) |
AT (4) | ATE481385T1 (ja) |
AU (3) | AU2001260674B2 (ja) |
CA (2) | CA2736344A1 (ja) |
CY (1) | CY1107089T1 (ja) |
DE (4) | DE60127595T2 (ja) |
DK (1) | DK1302461T3 (ja) |
ES (4) | ES2284138T3 (ja) |
NO (2) | NO324472B1 (ja) |
PT (1) | PT1302461E (ja) |
WO (1) | WO2001092229A1 (ja) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE60127595T2 (de) * | 2000-05-31 | 2008-01-10 | Santen Pharmaceutical Co., Ltd | Inhibitoren der TNF-Alpha Bildung zur Behandlung von Autoimmunerkrankungen |
WO2003045367A1 (fr) * | 2001-11-30 | 2003-06-05 | Santen Pharmaceutical Co., Ltd. | Inhibiteur d'angiogenese |
EP1496838B1 (en) | 2002-03-12 | 2010-11-03 | Merck Sharp & Dohme Corp. | Substituted amides |
CN101404986B (zh) | 2002-05-17 | 2011-09-28 | 赛奎拉公司 | 用于诊断和治疗感染性疾病的组合物和制药方法 |
US7456222B2 (en) | 2002-05-17 | 2008-11-25 | Sequella, Inc. | Anti tubercular drug: compositions and methods |
US20040033986A1 (en) | 2002-05-17 | 2004-02-19 | Protopopova Marina Nikolaevna | Anti tubercular drug: compositions and methods |
WO2005034857A2 (en) | 2003-09-05 | 2005-04-21 | Sequella, Inc. | Methods and compositions comprising diamines as new anti-tubercular therapeutics |
WO2005102332A1 (ja) * | 2004-04-27 | 2005-11-03 | Santen Pharmaceutical Co., Ltd. | 変形性関節症治療剤 |
WO2005102331A1 (ja) * | 2004-04-27 | 2005-11-03 | Santen Pharmaceutical Co., Ltd. | 骨粗鬆症治療剤 |
UA87854C2 (en) * | 2004-06-07 | 2009-08-25 | Мерк Энд Ко., Инк. | N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators |
WO2006035760A1 (ja) * | 2004-09-27 | 2006-04-06 | Santen Pharmaceutical Co., Ltd. | 皮膚疾患治療剤 |
WO2006035759A1 (ja) * | 2004-09-27 | 2006-04-06 | Santen Pharmaceutical Co., Ltd. | 呼吸器疾患治療剤 |
WO2006043518A1 (ja) * | 2004-10-18 | 2006-04-27 | Santen Pharmaceutical Co., Ltd. | 神経疾患治療剤 |
KR101302627B1 (ko) * | 2005-01-05 | 2013-09-10 | 아비에 인코포레이티드 | 11-베타-하이드록시스테로이드 데하이드로게나제 타입 1 효소의 억제제 |
JP5078621B2 (ja) * | 2005-01-05 | 2012-11-21 | アボット・ラボラトリーズ | 11−β−ヒドロキシステロイドデヒドロゲナーゼ1型酵素の阻害薬としてのアダマンチル誘導体 |
US20090192198A1 (en) | 2005-01-05 | 2009-07-30 | Abbott Laboratories | Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme |
US8562629B2 (en) * | 2006-10-24 | 2013-10-22 | Arthrocare Corporation | Suture device having selective needle actuation and related method |
EP1935420A1 (en) | 2006-12-21 | 2008-06-25 | Merck Sante | 2-Adamantyl-butyramide derivatives as selective 11beta-HSD1 inhibitors |
WO2009020603A2 (en) * | 2007-08-08 | 2009-02-12 | The Scripps Research Institute | Upp amphiphilic alpha-helix mimetics |
US20100261911A1 (en) * | 2007-10-16 | 2010-10-14 | Kenji Oki | Therapeutic agent for trpv1-mediated disease |
US8686006B2 (en) * | 2008-10-22 | 2014-04-01 | Santen Pharmaceutical Co., Ltd. | Pharmaceutical composition for improving intestinal absorption |
HRP20090186A2 (hr) | 2009-03-31 | 2010-10-31 | Institut Ruđer Bošković | Adamantanski bisureidni derivati, metoda priprave i primjena u detekciji aniona |
US8357939B2 (en) * | 2009-12-29 | 2013-01-22 | Siltronic Ag | Silicon wafer and production method therefor |
US9856214B2 (en) | 2013-11-15 | 2018-01-02 | The Wistar Institute Of Anatomy And Biology | EBNA1 inhibitors and their method of use |
BR112017024481B1 (pt) | 2015-05-14 | 2020-11-17 | The Wistar Institute Of Anatomy And Biology | composto inibidor de ebna1, composição farmacêutica compreendendo dito composto e usos terapêuticos do mesmo |
US11242338B2 (en) | 2018-05-17 | 2022-02-08 | The Wistar Institute | EBNA1 inhibitor crystalline forms, and methods of preparing and using same |
CN110423216B (zh) * | 2019-08-26 | 2021-01-05 | 浙江工业大学 | 一种2-(1-金刚烷甲酰胺基)乙基甲酸酯类化合物及其制备方法和应用 |
WO2024084056A1 (en) * | 2022-10-21 | 2024-04-25 | Etherna Immunotherapies Nv | Ionizable lipids |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2640055A (en) * | 1951-01-06 | 1953-05-26 | Warner Hudnut Inc | Amides |
CH509314A (de) * | 1967-02-16 | 1971-06-30 | Shimamoto Takio | Verfahren zur Herstellung von Pyridinmethylcarbamaten |
US3682922A (en) * | 1969-01-16 | 1972-08-08 | Searle & Co | N-acyl-n-{8 (n{40 ,n{40 -disubstituted amino)-alkyl{9 -1-adamantylmethylamines |
US4597902A (en) | 1981-05-20 | 1986-07-01 | A. H. Robins Company, Incorporated | N-(arylthioalkyl)-N'-(aminoalkyl)ureas |
US4724235A (en) | 1981-05-20 | 1988-02-09 | A. H. Robins Company, Incorporated | N-(arylthioalkyl)-N'-(aminoalkyl)ureas useful in the treatment of arrhythmia |
US4555515A (en) * | 1985-02-25 | 1985-11-26 | Stauffer Chemical Co. | Pyridylpropyl carbamates as insect repellents |
US5599944A (en) * | 1987-03-24 | 1997-02-04 | Bayer Aktiengesellschaft | Intermediates for herbicidal sulphonylaminocarbonyltriazolinones having substituents which are bonded via sulphur |
US5776963A (en) * | 1989-05-19 | 1998-07-07 | Hoechst Marion Roussel, Inc. | 3-(heteroaryl)-1- (2,3-dihydro-1h-isoindol-2-yl)alkyl!pyrrolidines and 3-(heteroaryl)-1- (2,3-dihydro-1h-indol-1-yl)alkyl!pyrrolidines and related compounds and their therapeutic untility |
FR2664269B1 (fr) | 1990-07-05 | 1992-10-02 | Roussel Uclaf | Nouveaux derives n-substitues d'alpha-mercapto alkylamines, leur procede de preparation, leur application a titre de medicaments et les compositions les renfermant. |
US5173506A (en) | 1990-08-16 | 1992-12-22 | Schering Corporation | N-(mercaptoalkyl)ureas and carbamates |
IE913855A1 (en) * | 1990-11-06 | 1992-05-22 | Smithkline Beecham Corp | Imidazolidinone compounds |
NZ242054A (en) * | 1991-03-22 | 1993-11-25 | British Tech Group | Pyridine derivatives having a bridged alicyclic group; medicaments |
GB9401129D0 (en) | 1994-01-21 | 1994-03-16 | British Bio Technology | Hydroxamic acid derivatives as metalloproteinase inhibitors |
ES2223049T3 (es) * | 1994-04-29 | 2005-02-16 | Pfizer Inc. | Amidas aciclicas y ciclicas novedosas como estimuladores de la liberacion de neurotransmisores. |
KR100284382B1 (ko) * | 1995-08-22 | 2001-03-02 | 미즈노 마사루 | 아미드화합물 및 그의 용도 |
GB9526560D0 (en) | 1995-12-27 | 1996-02-28 | Bayer Ag | Use of 2-Amino-Heterocycles |
GB9526558D0 (en) * | 1995-12-27 | 1996-02-28 | Fujisawa Pharmaceutical Co | Heterobicyclic derivatives |
CA2242877A1 (en) * | 1996-01-16 | 1997-07-24 | Merck & Co., Inc. | Integrin receptor antagonists |
IT1283637B1 (it) | 1996-05-14 | 1998-04-23 | Italfarmaco Spa | Composti ad attivita' antinfiammatoria ed immunosoppressiva |
US6333324B1 (en) | 1996-12-17 | 2001-12-25 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine compounds as inhibitors of MMP or TNF |
EP0903434B1 (de) | 1997-09-17 | 2002-11-27 | Lenzing Aktiengesellschaft | Verfahren zur Behandlung von Cellulosefasern |
ATE228590T1 (de) | 1997-09-17 | 2002-12-15 | Chemiefaser Lenzing Ag | Verfahren zur behandlung von cellulosefasern |
KR100589474B1 (ko) | 1998-03-26 | 2006-06-14 | 산텐 세이야꾸 가부시키가이샤 | 신규한 우레아 유도체 |
JP3603177B2 (ja) | 1998-03-26 | 2004-12-22 | 参天製薬株式会社 | 新規ウレア誘導体 |
JP3472917B2 (ja) | 1998-08-05 | 2003-12-02 | 参天製薬株式会社 | 含窒素芳香族複素環を有する新規ウレア誘導体 |
KR100663143B1 (ko) * | 1998-08-05 | 2007-01-02 | 산텐 세이야꾸 가부시키가이샤 | 질소 포함 방향족 헤테로고리를 갖는 신규 우레아 유도체 |
CA2362705A1 (en) * | 1999-03-19 | 2000-09-28 | Joseph B. Santella, Iii | N-adamant-1-yl-n'-¬4-chlorobenzothiazol-2-yl| urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent |
WO2000061552A1 (fr) * | 1999-04-07 | 2000-10-19 | Santen Pharmaceutical Co., Ltd. | DERIVE D'UREE N-SUBSTITUE-N'-SUBSTITUE, ET SON UTILISATION COMME INHIBITEUR DE LA PRODUCTION DE TNF-$g(a) |
DE29910780U1 (de) * | 1999-06-21 | 1999-09-16 | Hahn Schickard Ges | Halte- und Betätigungsvorrichtung |
DE60127595T2 (de) * | 2000-05-31 | 2008-01-10 | Santen Pharmaceutical Co., Ltd | Inhibitoren der TNF-Alpha Bildung zur Behandlung von Autoimmunerkrankungen |
WO2003045367A1 (fr) * | 2001-11-30 | 2003-06-05 | Santen Pharmaceutical Co., Ltd. | Inhibiteur d'angiogenese |
-
2001
- 2001-05-31 DE DE60127595T patent/DE60127595T2/de not_active Expired - Lifetime
- 2001-05-31 AT AT05290274T patent/ATE481385T1/de not_active IP Right Cessation
- 2001-05-31 EP EP01934447A patent/EP1302461B1/en not_active Expired - Lifetime
- 2001-05-31 DE DE60130658T patent/DE60130658T2/de not_active Expired - Lifetime
- 2001-05-31 AU AU2001260674A patent/AU2001260674B2/en not_active Ceased
- 2001-05-31 EP EP05290275A patent/EP1561749B1/en not_active Expired - Lifetime
- 2001-05-31 AT AT01934447T patent/ATE374186T1/de active
- 2001-05-31 ES ES05290275T patent/ES2284138T3/es not_active Expired - Lifetime
- 2001-05-31 AT AT06076696T patent/ATE448204T1/de not_active IP Right Cessation
- 2001-05-31 CA CA2736344A patent/CA2736344A1/en not_active Abandoned
- 2001-05-31 JP JP2001164523A patent/JP3867196B2/ja not_active Expired - Fee Related
- 2001-05-31 EP EP06076696A patent/EP1743885B1/en not_active Expired - Lifetime
- 2001-05-31 DK DK01934447T patent/DK1302461T3/da active
- 2001-05-31 DE DE60140495T patent/DE60140495D1/de not_active Expired - Lifetime
- 2001-05-31 ES ES05290274T patent/ES2353020T3/es not_active Expired - Lifetime
- 2001-05-31 AU AU6067401A patent/AU6067401A/xx active Pending
- 2001-05-31 CN CNB2004100546746A patent/CN1307159C/zh not_active Expired - Fee Related
- 2001-05-31 KR KR1020027016230A patent/KR100880698B1/ko not_active IP Right Cessation
- 2001-05-31 CN CNB200410054677XA patent/CN1324012C/zh not_active Expired - Fee Related
- 2001-05-31 CN CNB018102336A patent/CN1284771C/zh not_active Expired - Fee Related
- 2001-05-31 US US10/168,777 patent/US7098226B2/en not_active Expired - Fee Related
- 2001-05-31 CA CA2409741A patent/CA2409741C/en not_active Expired - Fee Related
- 2001-05-31 WO PCT/JP2001/004586 patent/WO2001092229A1/ja active IP Right Grant
- 2001-05-31 PT PT01934447T patent/PT1302461E/pt unknown
- 2001-05-31 KR KR1020087023872A patent/KR100978304B1/ko not_active IP Right Cessation
- 2001-05-31 EP EP05290274A patent/EP1568692B1/en not_active Expired - Lifetime
- 2001-05-31 ES ES01934447T patent/ES2293993T3/es not_active Expired - Lifetime
- 2001-05-31 AT AT05290275T patent/ATE358122T1/de not_active IP Right Cessation
- 2001-05-31 ES ES06076696T patent/ES2339141T3/es not_active Expired - Lifetime
- 2001-05-31 DE DE60143098T patent/DE60143098D1/de not_active Expired - Lifetime
-
2002
- 2002-11-28 NO NO20025718A patent/NO324472B1/no not_active IP Right Cessation
-
2006
- 2006-02-28 AU AU2006200864A patent/AU2006200864B2/en not_active Ceased
- 2006-05-19 JP JP2006140241A patent/JP4482735B2/ja not_active Expired - Fee Related
- 2006-06-07 US US11/448,634 patent/US7491739B2/en not_active Expired - Fee Related
- 2006-06-22 US US11/472,603 patent/US7345064B2/en not_active Expired - Fee Related
-
2007
- 2007-06-29 NO NO20073371A patent/NO20073371L/no not_active Application Discontinuation
- 2007-08-15 US US11/893,238 patent/US20080182881A1/en not_active Abandoned
- 2007-12-14 CY CY20071101588T patent/CY1107089T1/el unknown
-
2009
- 2009-09-23 US US12/586,515 patent/US7923461B2/en not_active Expired - Fee Related
- 2009-12-14 JP JP2009283084A patent/JP2010059204A/ja active Pending
- 2009-12-14 JP JP2009283085A patent/JP2010059205A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP3867196B2 (ja) | TNF−α産生阻害物質 | |
EP1536797B1 (en) | 1-amido-4-phenyl-4-benzyloxymethyl-piperidine derivatives and related comounds as neurokinin-1 (nk-1) antagonsists for the treatment of emesis, depression, anxiety and cough | |
JP4018545B2 (ja) | Fsadのためのnep阻害剤としてのn−フェンプロピルシクロペンチル−置換グルタルアミド誘導体 | |
JP2000515167A (ja) | 基質メタロプロテアーゼ インヒビターとしてのホスフィン酸アミド | |
JP2000515150A (ja) | 置換ベンジルアミン誘導体:新規な種類の神経ペプチドy1特異的リガンド | |
JP2004067635A (ja) | Dgat阻害剤 | |
JPWO2003002554A1 (ja) | ピペラジン化合物 | |
JP2002538146A (ja) | ジヘテロ−置換メタロプロテアーゼ阻害剤 | |
WO2024060911A1 (zh) | 苯并异噻唑化合物及其药物组合物和应用 | |
JP2691679B2 (ja) | オキシム誘導体およびそれを含有する医薬品 | |
JP2856548B2 (ja) | チオナフタレン誘導体およびその製法並びにそれを含む抗アレルギー剤 | |
JPH0899913A (ja) | 置換シクロペンタン−ジ−及び−トリオン類の利用 | |
JP3295277B2 (ja) | 抗腎疾患剤及びベンズイミダゾール誘導体 | |
US8076485B2 (en) | Methylphenidate derivatives and uses of them | |
JP6758374B2 (ja) | Idh2突然変異を標的とする抗腫瘍化合物及びその使用方法 | |
JPS6338026B2 (ja) | ||
KR20080023758A (ko) | 비만 및 관련 질환의 치료를 위한 신규한 아미노산 유도체 | |
JPH02229168A (ja) | ピラゾロン誘導体 | |
JP2024509587A (ja) | Jak媒介性障害の治療に使用するためのlorpucitinib | |
JP2003519100A (ja) | ベータ二置換メタロプロテアーゼ阻害剤 | |
JPH0692948A (ja) | 新規なアセタミド誘導体及びその用途 | |
JPWO2006082820A1 (ja) | 性器ヘルペス治療剤 | |
KR100503518B1 (ko) | 2-(4-알킬-1-피페라지닐)-벤즈알데하이드 및 -벤질리데닐화합물의 제조 방법 | |
JPH06135943A (ja) | 新規なウラシル誘導体及びそれを有効成分とするアレルギー疾患治療薬 | |
JP2756740B2 (ja) | 2−シクロヘキセノン化合物及び該化合物を有効成分とする脳機能改善薬 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20060329 |
|
A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20060427 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060519 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060522 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20060606 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060802 |
|
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: 20060829 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20060925 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20091020 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121020 Year of fee payment: 6 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131020 Year of fee payment: 7 |
|
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: R313111 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
LAPS | Cancellation because of no payment of annual fees |