CN101068774B - 抑制TNF-α形成的2-环戊烯-1-酮肟衍生物 - Google Patents
抑制TNF-α形成的2-环戊烯-1-酮肟衍生物 Download PDFInfo
- Publication number
- CN101068774B CN101068774B CN2005800414947A CN200580041494A CN101068774B CN 101068774 B CN101068774 B CN 101068774B CN 2005800414947 A CN2005800414947 A CN 2005800414947A CN 200580041494 A CN200580041494 A CN 200580041494A CN 101068774 B CN101068774 B CN 101068774B
- Authority
- CN
- China
- Prior art keywords
- cyclopentenes
- ketoxime
- butyl
- phenyl
- cyclopentyl
- 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
- 108060008682 Tumor Necrosis Factor Proteins 0.000 title abstract description 47
- YIDCWHAQPYBNHT-UHFFFAOYSA-N n-cyclopent-2-en-1-ylidenehydroxylamine Chemical class ON=C1CCC=C1 YIDCWHAQPYBNHT-UHFFFAOYSA-N 0.000 title abstract 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 title description 48
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 title description 45
- 230000002401 inhibitory effect Effects 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 14
- 230000001404 mediated effect Effects 0.000 claims abstract description 10
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims abstract 6
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims abstract 6
- 150000001875 compounds Chemical class 0.000 claims description 87
- -1 indyl Chemical group 0.000 claims description 39
- 201000010099 disease Diseases 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 12
- 201000004681 Psoriasis Diseases 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 10
- 208000011231 Crohn disease Diseases 0.000 claims description 9
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
- 201000002661 Spondylitis Diseases 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 206010025135 lupus erythematosus Diseases 0.000 claims description 7
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 6
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 6
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 6
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 6
- 201000008937 atopic dermatitis Diseases 0.000 claims description 6
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims description 6
- 230000009885 systemic effect Effects 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 206010040047 Sepsis Diseases 0.000 claims description 5
- 206010040070 Septic Shock Diseases 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 208000006454 hepatitis Diseases 0.000 claims description 5
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 231100000283 hepatitis Toxicity 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 claims description 3
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 claims description 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- 208000006673 asthma Diseases 0.000 claims 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 abstract description 3
- 102100040247 Tumor necrosis factor Human genes 0.000 abstract 2
- 208000026278 immune system disease Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 72
- 238000000034 method Methods 0.000 description 40
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 230000006837 decompression Effects 0.000 description 33
- 235000002639 sodium chloride Nutrition 0.000 description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 239000000706 filtrate Substances 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 239000012141 concentrate Substances 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- 229960001866 silicon dioxide Drugs 0.000 description 26
- 238000005406 washing Methods 0.000 description 25
- 238000003756 stirring Methods 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000004327 boric acid Substances 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 18
- 230000005764 inhibitory process Effects 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 13
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 13
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000002158 endotoxin Substances 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 9
- 238000004611 spectroscopical analysis Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- PHBVXHIVWULVNF-UHFFFAOYSA-N (4-fluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(F)C=C1 PHBVXHIVWULVNF-UHFFFAOYSA-N 0.000 description 7
- 108010044467 Isoenzymes Proteins 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- ZNRGSYUVFVNSAW-UHFFFAOYSA-N 3-nitrophenylboronic acid Chemical compound OB(O)C1=CC=CC([N+]([O-])=O)=C1 ZNRGSYUVFVNSAW-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 108010008165 Etanercept Proteins 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 6
- 229950005741 rolipram Drugs 0.000 description 6
- MVWAWWOKSVNOJG-UHFFFAOYSA-N (3,4-difluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(F)C(F)=C1 MVWAWWOKSVNOJG-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 210000001015 abdomen Anatomy 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 150000001345 alkine derivatives Chemical class 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 229960000403 etanercept Drugs 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- WDCIDFWOIGUFBT-UHFFFAOYSA-N (3-chloro-4-fluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(F)C(Cl)=C1 WDCIDFWOIGUFBT-UHFFFAOYSA-N 0.000 description 3
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 3
- RMJHGWFYNDUDRZ-UHFFFAOYSA-N 1,3-benzodioxol-5-yloxyboronic acid Chemical compound OB(O)OC1=CC=C2OCOC2=C1 RMJHGWFYNDUDRZ-UHFFFAOYSA-N 0.000 description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960002964 adalimumab Drugs 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 229960000598 infliximab Drugs 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 238000002821 scintillation proximity assay Methods 0.000 description 3
- 229960001940 sulfasalazine Drugs 0.000 description 3
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229960003433 thalidomide Drugs 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- XUPPFPAAYGASPH-UHFFFAOYSA-N (3-cyanophenoxy)boronic acid Chemical compound OB(O)OC1=CC=CC(C#N)=C1 XUPPFPAAYGASPH-UHFFFAOYSA-N 0.000 description 2
- KNXQDJCZSVHEIW-UHFFFAOYSA-N (3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(F)=C1 KNXQDJCZSVHEIW-UHFFFAOYSA-N 0.000 description 2
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
- 208000006313 Delayed Hypersensitivity Diseases 0.000 description 2
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 229920001917 Ficoll Polymers 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000012826 P38 inhibitor Substances 0.000 description 2
- 238000006647 Pauson-Khand annulation reaction Methods 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 description 2
- 229950001653 cilomilast Drugs 0.000 description 2
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 229940073621 enbrel Drugs 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- JQKOHNUZHGRKOY-UHFFFAOYSA-N hexane;tribromoborane Chemical compound BrB(Br)Br.CCCCCC JQKOHNUZHGRKOY-UHFFFAOYSA-N 0.000 description 2
- 229940048921 humira Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 2
- 229960004963 mesalazine Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229940116176 remicade Drugs 0.000 description 2
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 2
- 229960002586 roflumilast Drugs 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 2
- DWSBPCLAELVSFD-UHFFFAOYSA-N (2-fluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=CC=C1F DWSBPCLAELVSFD-UHFFFAOYSA-N 0.000 description 1
- RSTJSDURHPZXEP-UHFFFAOYSA-N (3,4-dichlorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(Cl)C(Cl)=C1 RSTJSDURHPZXEP-UHFFFAOYSA-N 0.000 description 1
- GNUFQJQCEBFWDQ-UHFFFAOYSA-N (3,5-difluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC(F)=CC(F)=C1 GNUFQJQCEBFWDQ-UHFFFAOYSA-N 0.000 description 1
- IBTSWKLSEOGJGJ-UHFFFAOYSA-N (3-acetamidophenyl)boronic acid Chemical compound CC(=O)NC1=CC=CC(B(O)O)=C1 IBTSWKLSEOGJGJ-UHFFFAOYSA-N 0.000 description 1
- UTHULKKJYXJZLV-UHFFFAOYSA-N (3-aminophenoxy)boronic acid Chemical compound NC1=CC=CC(OB(O)O)=C1 UTHULKKJYXJZLV-UHFFFAOYSA-N 0.000 description 1
- ITZYPLMJTLJHGZ-UHFFFAOYSA-N (3-bromophenoxy)boronic acid Chemical compound OB(O)OC1=CC=CC(Br)=C1 ITZYPLMJTLJHGZ-UHFFFAOYSA-N 0.000 description 1
- REHVCPNQQBDOJJ-UHFFFAOYSA-N (3-ethoxycarbonylphenyl)boronic acid Chemical compound CCOC(=O)C1=CC=CC(B(O)O)=C1 REHVCPNQQBDOJJ-UHFFFAOYSA-N 0.000 description 1
- HJBGZJMKTOMQRR-UHFFFAOYSA-N (3-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(C=O)=C1 HJBGZJMKTOMQRR-UHFFFAOYSA-N 0.000 description 1
- BJQCPCFFYBKRLM-UHFFFAOYSA-N (3-methylphenyl)boronic acid Chemical compound CC1=CC=CC(B(O)O)=C1 BJQCPCFFYBKRLM-UHFFFAOYSA-N 0.000 description 1
- PNEPCOGYYNOQDJ-UHFFFAOYSA-N (4-butylphenoxy)boronic acid Chemical compound CCCCC1=CC=C(OB(O)O)C=C1 PNEPCOGYYNOQDJ-UHFFFAOYSA-N 0.000 description 1
- QWMJEUJXWVZSAG-UHFFFAOYSA-N (4-ethenylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=C)C=C1 QWMJEUJXWVZSAG-UHFFFAOYSA-N 0.000 description 1
- OASVXBRTNVFKFS-UHFFFAOYSA-N (4-methyl-3-nitrophenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1[N+]([O-])=O OASVXBRTNVFKFS-UHFFFAOYSA-N 0.000 description 1
- DMJHEIDWSIAXCS-UHFFFAOYSA-N (4-phenylmethoxyphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1OCC1=CC=CC=C1 DMJHEIDWSIAXCS-UHFFFAOYSA-N 0.000 description 1
- CRUILBNAQILVHZ-UHFFFAOYSA-N 1,2,3-trimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1OC CRUILBNAQILVHZ-UHFFFAOYSA-N 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- KLWOQYCCSXYCSV-UHFFFAOYSA-N 1-fluoro-2-nonylbenzene Chemical compound CCCCCCCCCC1=CC=CC=C1F KLWOQYCCSXYCSV-UHFFFAOYSA-N 0.000 description 1
- KGNQDBQYEBMPFZ-UHFFFAOYSA-N 1-fluoro-4-iodobenzene Chemical class FC1=CC=C(I)C=C1 KGNQDBQYEBMPFZ-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- NIBFJPXGNVPNHK-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde Chemical group C1=CC(C=O)=C2OC(F)(F)OC2=C1 NIBFJPXGNVPNHK-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- HTFXWAOSQODIBI-UHFFFAOYSA-N 2-benzyl-1,3-dihydropyrrolo[3,4-c]pyridine Chemical compound C1C2=CC=NC=C2CN1CC1=CC=CC=C1 HTFXWAOSQODIBI-UHFFFAOYSA-N 0.000 description 1
- ZUUZNOFTKGDLLN-UHFFFAOYSA-N 3-(1,3,2-dioxaborinan-2-yl)pyridine Chemical compound O1CCCOB1C1=CC=CN=C1 ZUUZNOFTKGDLLN-UHFFFAOYSA-N 0.000 description 1
- FFVBEUUHAYUHTK-UHFFFAOYSA-N 3-boronooxybenzoic acid Chemical compound OB(O)OC1=CC=CC(C(O)=O)=C1 FFVBEUUHAYUHTK-UHFFFAOYSA-N 0.000 description 1
- SDCPFJIHUUMVDR-UHFFFAOYSA-N 4-boronooxybenzoic acid Chemical compound OB(O)OC1=CC=C(C(O)=O)C=C1 SDCPFJIHUUMVDR-UHFFFAOYSA-N 0.000 description 1
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000009346 Adenosine receptors Human genes 0.000 description 1
- 108050000203 Adenosine receptors Proteins 0.000 description 1
- 229940122869 Adenylate cyclase stimulant Drugs 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- ZZMWBNRRBRSQMB-KAMYIIQDSA-N CC(CC/C1=N/O)=C1c(cc1)ccc1F Chemical compound CC(CC/C1=N/O)=C1c(cc1)ccc1F ZZMWBNRRBRSQMB-KAMYIIQDSA-N 0.000 description 1
- PAOANWZGLPPROA-RQXXJAGISA-N CGS-21680 Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC(NCCC=3C=CC(CCC(O)=O)=CC=3)=NC(N)=C2N=C1 PAOANWZGLPPROA-RQXXJAGISA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- IAFXIHKSTAWRIX-UHFFFAOYSA-L ClC(C(=O)[O-])(O)C(O)C(=O)[O-].[Na+].[Na+] Chemical compound ClC(C(=O)[O-])(O)C(O)C(=O)[O-].[Na+].[Na+] IAFXIHKSTAWRIX-UHFFFAOYSA-L 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 1
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 1
- 102000008379 I-kappa B Proteins Human genes 0.000 description 1
- 108010021699 I-kappa B Proteins Proteins 0.000 description 1
- 229940122696 MAP kinase inhibitor Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101100460844 Mus musculus Nr2f6 gene Proteins 0.000 description 1
- PSPFQEBFYXJZEV-UHFFFAOYSA-N N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine Chemical compound C1=C(C)C=C2N3C(C)=CN=C3C(NCCN)=NC2=C1 PSPFQEBFYXJZEV-UHFFFAOYSA-N 0.000 description 1
- JADDQZYHOWSFJD-FLNNQWSLSA-N N-ethyl-5'-carboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 JADDQZYHOWSFJD-FLNNQWSLSA-N 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- PSBABBDEUFNFKJ-UHFFFAOYSA-N OC1C=CCC1 Chemical compound OC1C=CCC1 PSBABBDEUFNFKJ-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 101000648290 Rattus norvegicus Tumor necrosis factor Proteins 0.000 description 1
- 206010038063 Rectal haemorrhage Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 102100023132 Transcription factor Jun Human genes 0.000 description 1
- 102000009270 Tumour necrosis factor alpha Human genes 0.000 description 1
- 108050000101 Tumour necrosis factor alpha Proteins 0.000 description 1
- SJEYGBBCWPHBFW-UHFFFAOYSA-N [3-(dimethylamino)phenoxy]boronic acid Chemical compound CN(C=1C=C(C=CC1)OB(O)O)C SJEYGBBCWPHBFW-UHFFFAOYSA-N 0.000 description 1
- WOAORAPRPVIATR-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC=CC(C(F)(F)F)=C1 WOAORAPRPVIATR-UHFFFAOYSA-N 0.000 description 1
- QASKCGNZJHBTDJ-UHFFFAOYSA-N [SiH4].BrCCCCC Chemical compound [SiH4].BrCCCCC QASKCGNZJHBTDJ-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- VZRJNLFAIIISJP-UHFFFAOYSA-N boric acid 1-phenylethanone Chemical compound B(O)(O)O.C(C)(=O)C1=CC=CC=C1 VZRJNLFAIIISJP-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- VJQIPKNMASGCOC-UHFFFAOYSA-N butan-2-yloxybenzene Chemical compound CCC(C)OC1=CC=CC=C1 VJQIPKNMASGCOC-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical class C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BBWMASBANDIFMV-UHFFFAOYSA-N ethyl 4-phenylpiperidine-4-carboxylate;hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C1(C(=O)OCC)CC[NH2+]CC1 BBWMASBANDIFMV-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 210000003677 hemocyte Anatomy 0.000 description 1
- 229940000351 hemocyte Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical class CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 108010072415 tumor necrosis factor precursor Proteins 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P17/06—Antipsoriatics
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/61—Carboxylic acid nitriles containing cyano groups and nitrogen atoms being part of imino groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
- C07C323/47—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/08—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Furan Compounds (AREA)
- Pyridine Compounds (AREA)
- Indole Compounds (AREA)
Abstract
式I表示的2-环戊烯-1-酮肟衍生物或药物学可接受的盐抑制TNF-α或PDE4的形成,并因此在由TNF-α或PDE4介导的炎性或免疫学疾病中具有治疗作用。
Description
技术领域
本发明涉及一类体外和体内强效抑制TNF-α之形成的化合物。本发明还涉及此等化合物或其药物学可接受的盐在经由TNF-α介导的炎性疾病和免疫学疾病中的治疗性应用。
背景技术
肿瘤坏死因子-alpha(TNF-α)是一种在数十年前发现的前炎性细胞因子。TNF-α是由多种类型的细胞在应答炎性和免疫刺激时产生的[Trends Cell.Biol.vol 5,392-399(1995)]。例如,用脂多糖(LPS)处理的单核细胞显著增加了TNF-α的形成。虽然TNF-α通过凋亡使肿瘤缩小也是已知的,但其在炎症和免疫学中扮演着中心角色的作用。
在多种免疫学疾病中已观察到存在有大量的TNF-α,所述疾病包括但不限于类风湿性关节炎、牛皮癣、湿疹、Crohn病、慢性阻塞性肺病(COPD)、***性红斑狼疮(SLE)、脓毒症、内毒素休克、多发性硬化、慢性肝炎等[J.Med.Chem.vol 42,2295-2314(1999);Am.J.Respir.Crit.Care Med.vol 153,633-637(1996);Lupus vol 11,102-108(2002);Hepatogastroenterology.vol 47,1675-1679(2000)]。
如使用英夫利昔单抗(RemicadeTM)和阿达木单抗(HumiraTM)时可以看到的,已发现用TNF-α单克隆抗体阻断或中和TNF-α活性可有效治疗免疫学疾病,包括但不限于类风湿性关节炎、关节强直性脊椎炎、Crohn病以及牛皮癣关节炎[RemicadeTM(英夫利昔单抗)Prescribing Information.Centocor Inc.September 2005;HumiraTM(阿达木单抗)Prescribing Information.Abbott Lab.October 2005]。依那西普(EnbrelTM)是一种融合蛋白,其具有用于TNF-α的诱饵受体部分,并因此可中和TNF-α的生物活性。依那西普在美国可用于类风湿性关节炎、关节强直性脊椎炎、牛皮癣、以及牛皮癣关节炎[EnbrelTM(依那西普)Prescribing Information.Immunex Corporation.July2005]。这些蛋白药物目前仅能够以注射制剂得到。
到目前为止,已知许多生物目标可抑制的TNF-α细胞形成。Pro-TNF-α被TNF-α转化酶(TACE)断裂为活性、可溶形式的TNF-α[Nature vol 385,729-733(1997)]。cAMP胞质水平的增加可降低TNF-α的形成。因为抑制磷酸二酯酶4(PDE4)可增加cAMP的胞质水平,所以诸如咯利普兰、cilomilast和罗氟司特的PDE4抑制剂减弱TNF-α的形成[Curr.Pharm.Design vol 8,1255-1296(2002)]。腺苷受体A2a与腺苷酸环化酶偶联,而且其激动剂如CGS21680和NECA抑制TNF-α的合成[DrugDevel.Res.vol 45,103-112(1998)]。已知诸如NIK、IKK和PKB的在NF-κB的信号传递中涉及的激酶压抑TNF-α的形成,如果有抑制的话。IKK抑制剂如BMS-345541阻断IκB上的磷酸化作用并抑制NFκB依赖性的转录[J.Biol.Chem.vol 278,1450-1456(2003)]。已知5-氨基水杨酸在对于炎性肠疾病(IBD)而言治疗相关的剂量下抑制IKK。还已知阿司匹林(一种传统的非甾体抗炎药)在高剂量水平下抑制IKK[Nature vol396,77-80(1998)]。抑制MAP激酶如p38和c-Jun N-端激酶(JNK)可压抑TNF-α的形成。p38抑制剂如VX-745和SB203580在用LPS处理的细胞中抑制TNF-α形成,并且在用于类风湿性关节炎的动物模型中显示了治疗作用[Curr.Opin.Investig.Drugs vol 5,566-571(2003)]。Thalidomide适用于***性红斑狼疮(SLE),但是thalidomide在细胞水平上较弱地抑制TNF-α的合成。似乎thalidomide使TNF-αmRNA失去稳定,降低了TNF-α的形成[Clin.Exp.Immunol.vol 110,151-154(1997)]。甾体也强效地抑制TNF-α的形成[J.Exp.Med.vol 172,391-394(1990)]。
由于认为TNF-α在炎症和免疫学中扮演着中心角色,所以抑制TNF-α的生物活性或形成的药物被期望在以下各种疾病中具有治疗作用:类风湿性关节炎、牛皮癣、牛皮癣关节炎、特应性皮炎、包括溃疡性结肠炎和Crohn病的炎性肠病、关节强直性脊椎炎、脓毒症、肝炎、多发性硬化、***性红斑狼疮(SLE)、慢性阻塞性肺病(COPD)、内毒素休克、I型糖尿病等。发现一些类型的药物对于一些疾病比其他的更为有效,这取决于作用模式以及它们的生化性质。已广泛研制PDE4抑制剂如罗氟司特和cilomilast用于COPD中。另一方面,抗-TNF-α生物制品原是适用于类风湿性关节炎,而且它们的适应症正扩展至包括关节强直性脊椎炎、牛皮癣和Crohn病。5-氨基水杨酸以及柳氮磺吡啶用于治疗中度至轻度的炎性肠疾病,而甾体和抗-TNF-α生物制剂则适用于严重的情况。已有人试图通过使用PDE4抑制剂来治疗炎性肠病[Ann.Rev.Med.Chem.vol 38,141-152(2003)]。虽然p38抑制剂如VX-702已被评估对人类风湿性关节炎的作用,但是它们的治疗作用对于MAP激酶抑制剂仍有待确认[Curr.Opin.Drug Discov.Devel.vol 8,421-430(2005)]。甾体药物原来对于各种免疫学疾病是有效的,然而由于副作用强烈地限制了这些药物的长期使用。
虽然抗-TNF-α的生物制品如英夫利昔单抗、阿达木单抗和依那西普广泛用于治疗免疫学疾病如类风湿性关节炎和牛皮癣,但是这些蛋白药物由于价格昂贵以及需要注射给药而前景暗淡。在此方面,由于费用以及避免注射的便利性,强烈需要抑制TNF-α作用和形成的小分子。
发明内容
本发明提供涉及以下技术方案:式I表示的2-环戊烯-1-酮肟衍生物或其药物学可接受的盐或其组合物,以及它们在由TNF-α或PDE4介导的炎性疾病和免疫学疾病方面的治疗作用。本发明还提供用于合成该式I化合物的方法。
在本发明的一个实施方案中,提供以下的式I化合物,其中:
R1代表直链或支链C1-C10烷基或C3-C7环烷基;以及
R2代表有或没有取代基的芳香基团。
在本发明的另一个实施方案中,式I的化合物被证实可在经刺激用于形成TNF-α的细胞中抑制TNF-α的形成。还证实式I化合物可强效地抑制磷酸二酯酶4的同工酶。
在本发明的再一个方面中,证实式I化合物抑制TNF-α的体内形成,并且抑制动物模型中的炎症或免疫应答。
因此,式I的化合物可用于预防或治疗由TNF-或PDE4介导的炎性或免疫学疾病。此等疾病的例子包括类风湿性关节炎、牛皮癣、牛皮癣关节炎、特应性皮炎、包括溃疡性结肠炎和Crohn病的炎性肠病、关节强直性脊椎炎、多法性硬化、***性红斑狼疮(SLE)、慢性阻塞性肺病(COPD)、脓毒症、内毒素休克、肝炎、I型糖尿病等。
式I的化合物可用等量的合适的药物学可接受的酸或碱通过中和该化合物而被转化为药物学可接受的盐,这取决于该化合物中存在酸性基团或者碱性基团。所述酸或碱例如是氢氧化钾、氢氧化钠、盐酸、甲磺酸、柠檬酸等。式I的化合物或其药物学可接受的盐可与药物学可接受的辅助成分一起给药,该辅助成分包括但不限于柠檬酸、氯化钠、酒石酸、硬脂酸、淀粉、明胶、滑石、芝麻油、抗坏血酸、甲基纤维素、羧基甲基纤维素钠、聚乙二醇(PEG)、聚丙二醇、甜味剂、防腐剂、水、乙醇、氧化钛、碳酸氢钠、硅化微晶纤维素、大豆卵磷脂等。式I的化合物或其药物学可接受的盐可配制成各种机型,如片剂、粉末、颗粒、硬胶囊、软胶囊、口服混悬剂、用于吸入给药的喷雾溶液、注射液、用于局部给药的乳膏、透皮药帖等。式I的化合物或其药物学可接受的盐向人和动物个体给药的日剂量可以是高至100mg/kg体重,但优选最高至10mg/kg体重,这取决于适应症、症状以及所述个体的情况。
在本发明的优选实施方案中,提供如下有利的式I化合物,其中:
R1代表直链或支链C1-C6烷基、环戊基或环己基;以及
R2代表有或没有取代基的芳香基团,其中该芳香基团选自苯基、吡啶基、萘基、吲哚基、噻吩基、苯并[b]噻吩基、氧芴基或噻蒽基。
在本发明的另一个优选实施方案中,提供如下更为有利的式I化合物,其中:
R1代表直链或支链C1-C6烷基、环戊基或环己基;以及
R2代表选自以下组中的芳香基团:吡啶基、萘基、吲哚基、噻吩基、苯并[b]噻吩基、氧芴基或噻蒽基;或R2代表如下具有一个或多个取代基的苯基:
其中,R3-R7独立地选自氢、直链或支链C1-C9烷基、烯基、卤代烷基、芳基、卤素、硝基、氨基、烷基氨基、烷基氨基烷基、亚甲二氧基、烷氧基、卤代烷氧基、苄氧基、烷硫基、烷基磺酰基、烷基亚磺酰基、氰基、羧基、烷氧基羰基、烷氧基烷基、羟基、羟基烷基氨甲酰基、N-羟基-亚氨基烷基或N-(N-羟基-亚氨基烷基)氨基。
在本发明再一个优选的实施方案中,有利的具体式I化合物是以下组中的化合物:
3-环戊基-2-(4-氟苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(3,4-二氟苯基)-2-环戊烯-1-酮肟;
2-(3-氯-4-氟苯基)-3-环戊基-2-环戊烯-1-酮肟;
3-环戊基-2-(3-硝基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(4-甲基-3-硝基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(3,4-二甲氧基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(3-甲氧基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-{4-甲氧基-3-(甲氧基甲基)苯基}-2-环戊烯-1-酮肟;
2-{4-(苄氧基)苯基}-3-环戊基-2-环戊烯-1-酮肟;
3-环戊基-2-(3,4-亚甲二氧基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-{3-(三氟甲氧基)苯基}-2-环戊烯-1-酮肟;
2-(3-氰基苯基)-3-环戊基-2-环戊烯-1-酮肟;
2-(3-氰基-4-氟苯基)-3-环戊基-2-环戊烯-1-酮肟;
3-环戊基-2-{3-(N,N-二甲基氨基甲基)苯基}-2-环戊烯-1-酮肟;
3-环戊基-2-{3-(N,N-二甲基氨基)苯基}-2-环戊烯-1-酮肟;
3-环戊基-2-{5-(1H)-吲哚基}-2-环戊烯-1-酮肟;
3-环戊基-2-(6-甲氧基萘基)-2-环戊烯-1-酮肟;
3-环戊基-2-(4-乙烯基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(4-氧芴基)-2-环戊烯-1-酮肟;
3-环戊基-2-(2-噻蒽基)-2-环戊烯-1-酮肟;
3-环戊基-2-(3-氨甲酰基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-{3-(甲硫基)苯基}-2-环戊烯-1-酮肟;
3-环戊基-2-{3-(甲基磺酰基)苯基}-2-环戊烯-1-酮肟;
3-环戊基-2-(3-羟基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-{3-(羟基甲基)苯基}-2-环戊烯-1-酮肟;
3-环戊基-2-{4-(羟基甲基)苯基}-2-环戊烯-1-酮肟;
3-环己基-2-(4-氟苯基)-2-环戊烯-1-酮肟;
2-(3-氯-4-氟苯基)-3-环己基-2-环戊烯-1-酮肟;
3-环己基-2-(3-氟苯基)-2-环戊烯-1-酮肟;
3-环己基-2-(3,4-二氟苯基)-2-环戊烯-1-酮肟;
3-环己基-2-(3-硝基苯基)-2-环戊烯-1-酮肟;
3-环己基-2-(3-甲氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(4-氟苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二氟苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(2-氟苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(2,4-二氟苯基)-2-环戊烯-1-酮肟;
2-(3-溴苯基)-3-丁基-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二氯苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-硝基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-氟-4-甲氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-氟-4-羟基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-乙氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二甲氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-甲氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-亚甲二氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-{4-(三氟甲氧基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-{3-(羟基甲基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二羟基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-羟基苯基)-2-环戊烯-1-酮肟;
2-(3-氨基苯基)-3-丁基-2-环戊烯-1-酮肟;
3-丁基-2-{3-(乙氧基羰基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-(3-羧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(4-羧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二甲基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-甲基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(4-丁基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-氟-4-苯基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-{3-(三氟甲基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-{4-(甲亚磺酰基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-{4-(甲磺酰基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-{3-(N-羟基亚氨代乙酰基)氨基苯基}-2-环戊烯-1-酮肟;
3-丁基-2-{3-(1-N-羟基亚氨基乙基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-{3-(N-羟基亚氨基甲基)苯基}-2-环戊烯-1-酮肟;
2-(2-苯并[b]噻吩基)-3-丁基-2-环戊烯-1-酮肟;
3-戊基-2-苯基-2-环戊烯-1-酮肟;
2-(4-氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3-氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3,5-二氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3-氯-4-氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3-硝基苯基)-3-戊基-2-环戊烯-1-酮肟;
3-戊基-2-(3,4,5-三甲氧基苯基)-2-环戊烯-1-酮肟;
2-(4-联苯基)-3-戊基-2-环戊烯-1-酮肟;
3-戊基-2-{4-(三氟甲基)苯基}-2-环戊烯-1-酮肟;
2-(1-萘基)-3-戊基-2-环戊烯-1-酮肟;
3-戊基-2-(3-吡啶基)-2-环戊烯-1-酮肟;
3-戊基-2-(3-噻吩基)-2-环戊烯-1-酮肟;
2-(4-氟苯基)-3-丙基-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-丙基-2-环戊烯-1-酮肟;
2-(3-硝基苯基)-3-丙基-2-环戊烯-1-酮肟;
3-乙基-2-(4-氟苯基)-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-乙基-2-环戊烯-1-酮肟;
2-(4-氟苯基)-3-甲基-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-甲基-2-环戊烯-1-酮肟;
2-(4-氟苯基)-3-异丁基-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-异丁基-2-环戊烯-1-酮肟;
2-(3,4-亚甲二氧基苯基)-3-异丁基-2-环戊烯-1-酮肟;
3-异丁基-2-(3-硝基苯基)-2-环戊烯-1-酮肟;
2-(3-氰基苯基)-3-异丁基-2-环戊烯-1-酮肟;
2-(3-氟-4-正壬基苯基)-3-异丁基-2-环戊烯-1-酮肟;以及
2-(3-丁氧基苯基)-3-异丁基-2-环戊烯-1-酮肟。
本发明中所用的术语和缩写示于以下表1中。
表1:本发明中所用的术语和缩写
术语或缩写 | 定义或释义 |
烷基 | 直链或支链烷基 |
烷氧基 | 其上连接有烷基的氧基,例如甲氧基、乙氧基、异丙氧基等 |
烯基 | 其中具有至少一个碳-碳双键的烷基 |
烷氧基烷基 | 被一个烷氧基取代的烷基 |
烷氧基羰基 | 被一个烷氧基取代的″-C(O)-″ |
烷基亚磺酰基 | 被一个烷基取代的″-S(O)-″ |
烷基磺酰基 | 被一个烷基取代的″-S(O)2-″ |
烷硫基 | 被一个烷基取代的″-S-″ |
氨基烷基 | 其上连接有一个氨基(NH2)的烷基 |
氨甲酰基 | ″-C(O)-NH2″基团 |
卤素 | 卤素,如F、Cl、Br或I |
卤代烷基 | 被一个或多个卤素原子取代的烷基,例如氟甲基(F-CH2-)、1-氯乙基(CH3-CHCl-)、三氟甲基(CF3-)等 |
氢基 | 单个氢原子 |
IFN-γ | 干扰素gamma |
N-烷基氨基 | 被烷基取代的″-NH-″,例如N-甲基氨基(CH3-NH-)、N-乙基氨基(CH3CH2-NH-)等 |
N-羟基亚氨基烷基 | 被氢基或烷基取代的″-C(N-OH)-″ |
N-(N-羟基-亚氨基烷基)氨基 | 被(N-羟基亚氨基烷基)取代的″-NH-″ |
甲酰基 | ″CHO-″基团 |
LPS | 脂多糖 |
亚甲二氧基 | ″-O-CH2-O-″基团 |
PDE4 | 磷酸二酯酶4 |
PBMC | 外周单核细胞 |
TNF-α | 肿瘤坏死因子α |
式I化合物的合成
式I化合物的合成总结于以下合成路线1中,其中R1和R2如式I中所定义。在某些情况下,在执行合成路线1期间有小的改变,而这些改变对于本领域技术人员而言应是显而易见的并在适用时提供。
合成路线1
在四氯化碳中用三乙胺或吡啶的卤素复合物进行处理,由此将2-环戊烯-1-酮衍生物A卤化,得到2-卤代环戊烯-1-酮B[Tetrahedron Lett.vol 33,917-920(1992)]。该卤化物与芳香硼酸进行Suzuki偶联,得到偶联产物C,接着使其与盐酸羟胺在吡啶中反应,由此缩合为式I的化合物[Chem.Rev.vol 95,2457-2483(1995)]。
合成路线2
合成路线1中的2-环戊烯-1-酮衍生物A是用合成路线2中描述的三种不同方法制备的。在一个方法中,将烷基或环烷基金属(M=Li、MgBr或MgCl)试剂添加至2-环戊烯-1-酮中,用氯铬酸吡啶(PCC)使所得的烯丙基醇进行氧化性重排,得到2-环戊烯-1-酮衍生物A[Tetrahedron Lett.vol 30,1033-1036(1989)]。另一个方法是使3-乙氧基-2-环戊烯-1-酮或3-甲氧基-2-环戊烯-1-酮与烷基或环烷基金属(M=Li、MgBr或MgCl)反应,然后将所得产物通过用盐酸处理转化为2-环戊烯-1-酮衍生物A[J.Am.Chem.Soc.vol 110,4625-4633(1988)]。在第三种方法中,在六甲基磷酰胺(HMPA)存在下,用三甲基甲硅烷基氯(TMSCl)促进烷基或环烷基铜酸酯在3-烷氧基-2-环戊烯-1-酮上的1,4-加成,而所得的加成物通过用盐酸处理被转化为2-环戊烯-1-酮衍生物A[Tetrahedron vol 45,349-362(1989)]。
或者,式I的化合物也可如合成路线3中所述进行制备,其中主要的中间产物环戊烯-1-酮衍生物C是通过炔D和乙烯之间的分子间Pauson-Khand反应而制得的[Angew.Chem.Int.Ed.vol 39,636-638(2000)以及其中的参考文献]。炔D是通过钯催化的炔和芳基卤化物的偶联而合成的[Chem.Rev.vol 103,1979-2017(2003)]。炔D的Pauson-Khand反应在高压一氧化碳和乙烯下在存在非化学计量量的八羰基二钴和二甲基亚砜作为促进剂时实现的。环戊烯酮C接着根据合成路线1被转化为式1的化合物。
合成路线3
虽然如下制备了式I的化合物,但是本发明化合物的范围绝非仅限于以下的化合物中。这些化合物仅是用作实施例。
实施例1:3-环戊基-2-(4-氟苯基)-2-环戊烯-1-酮肟:根据如下描述的4个步骤的方法制备标题化合物。
步骤1(合成3-环戊基-2-环戊烯-1-酮):在惰性气氛下,向经搅拌并平衡至-78℃的800mg溴化铜二甲基硫在100ml四氢呋喃(THF)中的悬浮液内顺序地添加24ml在***中的2.0M环戊基氯化镁和8ml六甲基磷酰胺(HMPA)。向该化合物内添加5.4ml三甲基甲硅烷基氯(TMSCl)和4.3g 3-甲氧基-2-环戊烯-1-酮在20ml THF中的溶液。该反应混合物缓慢温热至室温并搅拌3小时,接着向其中添加50ml 10%盐酸。所得的反应混合物再搅拌10分钟,然后用乙酸乙酯萃取。有机层用水和盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=3∶1),得到4.5g油状的3-环戊基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ5.94(m,1H),2.82(m,1H),2.61(m,2H),2.41(m,2H),1.96(m,2H),1.77-1.5(m,6H)。
步骤2(合成3-环戊基-2-碘-2-环戊烯-1-酮):在搅拌下向4.35g 3-环戊基-2-环戊烯-1-酮在50ml四氯化碳中的溶液内添加15g碘和2.4ml吡啶,而且该反应混合物搅拌过夜。该反应混合物首先用***稀释,顺序地用饱和硫代硫酸钠水溶液、碳酸氢钠水溶液、和盐水洗涤。有机层在无水硫酸镁上干燥并过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=6∶1),得到4g油状的3-环戊基-2-碘-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ3.23(m,1H),2.74(m,2H),2.57(m,2H),1.98(m,2H),1.78(m,4H),1.55(m,2H)。
步骤3(合成3-环戊基-2-(4-氟苯基)-2-环戊烯-1-酮):65mg 3-环戊基-2-碘-2-环戊烯-1-酮、40mg 4-氟苯基硼酸、10mg四(三苯基膦)钯、4ml甲苯、2ml乙醇和1.5ml 2N碳酸氢钠水溶液的混合物通过在80℃下搅拌过夜进行Suzuki偶联。该反应混合物用乙酸乙酯稀释,用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=4∶1),得到52mg固体的3-环戊基-2-(4-氟苯基)-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ7.22(m,2H),7.09(m,2H),3.15(m,1H),2.68(m,2H),2.55(m,2H),1.81(m,4H),1.64(m,4H)。
步骤4(合成3-环戊基-2-(4-氟苯基)-2-环戊烯-1-酮肟):50mg 3-环戊基-2-(4-氟苯基)-2-环戊烯-1-酮和20mg盐酸羟胺在5ml吡啶中的混合物在60℃下搅拌过夜。减压除去吡啶,而所得的残留物用用乙酸乙酯和10%盐酸萃取。有机层用碳酸氢钠水溶液和盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=4∶1),得到40mg固体的3-环戊基-2-(4-氟苯基)-2-环戊烯-1-酮肟。mp=204-205℃;1H NMR(CDCl3,300MHz):δ7.24-7.19(m,2H),7.11-7.04(m,2H),6.73(bs,1H),2.89(m,1H),2.80(m,2H),2.61(m,2H),1.70(m,4H),1.55(m,4H);APCI MS:m/z 260.1(M+1)。
实施例2~22:根据与实施例1类似的方法制备以下表2中所列的化合物。在实施例2~22中的步骤3中使用以下芳基或杂芳基硼酸化合物用于Suzuki偶联反应:3,4-二氟苯基硼酸用于实施例2;3-氯-4-氟苯基硼酸用于实施例3;3-硝基苯基硼酸用于实施例4;4-甲基-3-硝基苯基硼酸用于实施例5;3,4-二甲氧基苯基硼酸用于实施例6;3-甲氧基苯基硼酸用于实施例7;4-甲氧基-3-甲氧基甲基苯基硼酸用于实施例8;4-苄氧基苯基硼酸用于实施例9;3,4-亚甲二氧基苯基硼酸用于实施例10;3-三氟甲氧基苯基硼酸用于实施例11;3-氰基苯基硼酸用于实施例12;3-氰基-4-氟苯基硼酸用于实施例13;N,N-二甲基氨基甲基苯基-3-硼酸频那醇酯用于实施例14;3-二甲基氨基苯基硼酸用于实施例15;5-吲哚基硼酸用于实施例16;6-甲氧基-2-萘硼酸用于实施例17;4-乙烯基苯硼酸用于实施例18;氧芴-4-硼酸用于实施例19;噻蒽-1-硼酸用于实施例20;苯甲酰胺-3-硼酸用于实施例21;以及3-甲硫基苯基硼酸用于实施例22。实施例2~22的光谱数据以及它们的熔点都列于表2至。
表2:实施例2~22的物理表征数据
实施例23:3-环戊基-2-(3-甲基磺酰基苯基)-2-环戊烯-1-酮肟:
向120mg 3-环戊基-2-(3-甲硫基苯基)-2-环戊烯-1-酮在12ml 1∶1∶1 THF/甲醇/水的混合物中的溶液内添加800mg然后该反应混合物搅拌3小时。该反应混合物减压浓缩并用水/乙酸乙酯萃取。有机层用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=3∶1),得到120mg 3-环戊基-2-(3-甲基磺酰基苯基)-2-环戊烯-1-酮。该甲基砜化合物根据与实施例1之步骤4类似的方法与盐酸羟胺缩合,得到80mg固体的3-环戊基-2-(3-甲基磺酰基苯基)-2-环戊烯-1-酮肟。mp=164-165℃;1H NMR(CDCl3,300MHz):δ7.90-7.85(m,2H),7.62-7.52(m,2H),7.19(bs,1H),3.08(s,3H),2.85(m,1H),2.80(m,2H),2.64(m,2H),1.73(m,4H),1.58(m,4H);APCI MS:m/z 320.1(M+1).
实施例24:3-环戊基-2-(3-羟基苯基)-2-环戊烯-1-酮肟:
在搅拌、-78℃和惰性气氛下向27mg 3-环戊基-2-(3-甲氧基苯基)-2-环戊烯-1-酮肟(实施例7)在5ml二氯甲烷中的溶液内滴加0.5ml 1.0M三溴化硼己烷溶液。该反应混合物搅拌2小时,并同时使其温热至室温。接着将该反应混合物倾倒在饱和的碳酸氢钠水溶液中,并用乙酸乙酯萃取。有机层用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=1∶1),得到12mg固体的3-环戊基-2-(3-羟基苯基)-2-环戊烯-1-酮肟。mp=207-209℃;1H NMR(CDCl3,300MHz):δ7.26-7.21(m,2H),6.79-6.70(m,3H),2.93(m,1H),2.80(m,2H),2.61(m,2H),1.70(m,4H),1.54(m,4H);APCI MS:m/z 258.1(M+1).
实施例25:3-环戊基-2-(3-羟基甲基苯基)-2-环戊烯-1-酮肟:
在80℃下搅拌120mg 3-环戊基-2-碘-2-环戊烯-1-酮、80mg 3-甲酰基苯基硼酸和20mg四(三苯基膦)钯在8ml甲苯、4ml乙醇和4ml 2N碳酸氢钠水溶液中的混合物过夜。该反应混合物用乙酸乙酯稀释,用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=2∶1),得到70mg的3-环戊基-2-(3-甲酰基苯基)-2-环戊烯-1-酮。3-环戊基-2-(3-甲酰基苯基)-2-环戊烯-1-酮在苯中与一滴乙酸和100mg三乙酰氧基硼氢化钠在70-80℃下搅拌2小时。将该反应混合物接着倾倒在饱和氯化钠水溶液中,然后用乙酸乙酯萃取。有机层用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=2∶1),得到40mg的3-环戊基-2-(3-羟基甲基苯基)-2-环戊烯-1-酮,其根据与实施例1之步骤4类似的方法与盐酸羟胺缩合,得到20mg固体的3-环戊基-2-(3-羟基甲基苯基)-2-环戊烯-1-酮肟。1H NMR(CDCl3,300MHz):δ8.75(bs,1H),7.40-7.29(m,3H),7.12(d,J=7.2Hz,1H),4.66(s,2H),2.98(m,1H),2.75(m,2H),2.61(m,2H),1.71(m,4H),1.55(m,4H).
实施例26:3-环戊基-2-(4-羟基甲基苯基)-2-环戊烯-1-酮肟:
标题化合物是根据类似于实施例25的方法制得的。应注意的是,对于实施例26使用4-甲酰基苯基硼酸替代实施例25所用的3-甲酰基苯基硼酸。mp=187-190℃;1HNMR(CDCl3,300MHz):δ7.39(d,J=7.5Hz,2H),7.25(d,J=7.5Hz,2H),6.79(bs,1H),4.70(s,2H),2.91(m,1H),2.80(m,2H),2.61(m,2H),1.70(m,4H),1.55(m,4H);APCIMS:m/z 272.2(M+1).
实施例27:3-环己基-2-(4-氟苯基)-2-环戊烯-1-酮肟:标题化合物是根据以下4个步骤的方法制备的。
步骤1(合成3-环己基-2-环戊烯-1-酮):在搅拌、0℃和惰性气氛下向45ml 2.0M环己基氯化镁在***中的溶液以及15ml***中滴加4.8g 2-环戊烯-1-酮在10ml***中的溶液。该反应混合物搅拌1小时,并同时温热至室温,倾倒在饱和氯化铵水溶液中,然后用乙酸乙酯萃取。有机层用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩,所得的残留物接着与15g氯铬酸吡啶(PCC)在适量的celite存在下于100ml二氯甲烷中反应4小时。该反应混合物用100ml***稀释,然后通过硅胶垫过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=5∶1),得到1.5g油状的3-环己基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ5.93(m,1H),2.61(m,2H),2.39(m,2H),2.30(m,1H),1.91-1.19(m,10H).
步骤2(合成3-环己基-2-碘-2-环戊烯-1-酮):在搅拌下向1.05g3-环己基-2-环戊烯-1-酮在20ml四氯化碳中的溶液内顺序添加5g碘和0.6ml吡啶,然后该混合物搅拌过夜。该反应混合物用***稀释,顺序地用饱和硫代硫酸钠水溶液、碳酸氢钠水溶液、和盐水洗涤。有机层接着在无水硫酸镁上干燥并过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=6∶1),得到850mg油状的3-环己基-2-碘-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ2.81(m,1H),2.72(m,2H),2.55(m,2H),1.90-1.20(m,10H).
步骤3(合成3-环己基-2-(4-氟苯基)-2-环戊烯-1-酮):160mg 3-环己基-2-碘-2-环戊烯-1-酮、100mg 4-氟苯基硼酸、和25mg四(三苯基膦)钯在5ml甲苯、2.5ml乙醇、和2ml 2N碳酸氢钠水溶液中于80℃下搅拌过夜。该反应混合物用乙酸乙酯稀释,用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液接着减压浓缩并通过柱色谱进行纯制(硅胶,己烷/乙酸乙酯=4∶1),得到120mg油状的3-环己基-2-(4-氟苯基)-2-环戊烯-1-酮。1HNMR(CDCl3,300MHz):δ7.18(m,2H),7.10(m,2H),2.76(m,1H),2.66(m,2H),2.52(m,2H),1.82-1.20(m,10H).
步骤4(合成3-环己基-2-(4-氟苯基)-2-环戊烯-1-酮肟):120mg 3-环己基-2-(4-氟苯基)-2-环戊烯-1-酮和60mg盐酸羟胺的混合物在10ml吡啶中于60℃下搅拌过夜。减压除去吡啶,而所得的残留物溶解在乙酸乙酯中,并用10%盐酸洗涤。有机层用碳酸氢钠水溶液和盐水洗涤,在硫酸镁上干燥,然后干燥。滤液接着减压浓缩并通过重结晶进行纯制(乙酸乙酯-己烷),得到40mg固体的3-环己基-2-(4-氟苯基)-2-环戊烯-1-酮肟。mp=173-176℃;1H NMR(CDCl3,300MHz):δ7.20(m,2H),7.08(m,2H),6.78(bs,1H),2.77(m,2H),2.59(m,2H),2.47(m,1H),1.75-1.16(m,10H);APCI MS:m/z 274.2(M+1).
实施例28~32:根据与实施例27类似的方法制备以下表3中所列的化合物。在实施例28~32中的步骤3中使用以下芳基硼酸化合物用于Suzuki偶联反应:3-氯-4-氟苯基硼酸用于实施例28;3-氟苯基硼酸用于实施例29;3,4-二氟苯基硼酸用于实施例30;3-硝基苯基硼酸用于实施例31;以及3-甲氧基苯基硼酸用于实施例32。实施例28~32的光谱数据以及它们的熔点列于表3中。
表3:实施例28~32的物理表征数据
实施例33:3-丁基-2-(4-氟苯基)-2-环戊烯-1-酮肟:标题化合物是根据以下4个步骤的方法制备的。
步骤1(合成3-丁基-2-环戊烯-1-酮):在搅拌、0℃和惰性气氛下向690mg 3-乙氧基-2-环戊烯-1-酮在10ml THF中的溶液内滴加3ml 2.5M n-丁基锂在己烷中的溶液。该反应混合物温热至室温,并再搅拌2小时。反应通过添加3N盐酸而被淬灭。该混合物再搅拌10分钟,接着用萃取乙酸乙酯。有机层用水和盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=5∶1),得到440mg油状的3-丁基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ5.95(m,1H),2.58(m,2H),2.41(m,4H),1.57(m,2H),1.38(m,2H),0.94(t,J=7.5Hz,3H).
步骤2(合成3-丁基-2-碘-2-环戊烯-1-酮):在搅拌下向400mg 3-丁基-2-环戊烯-1-酮在10ml四氯化碳中的溶液内添加1g碘和0.3ml吡啶。搅拌过夜后,该反应混合物用***稀释,顺序地用饱和硫代硫酸钠水溶液、碳酸氢钠水溶液、以及盐水洗涤。有机层在无水硫酸镁上干燥并过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=5∶1),得到500mg油状的3-丁基-2-碘-2-环戊烯-1-酮。1HNMR(CDCl3,300MHz):δ2.77(m,2H),2.59(m,4H),1.58(m,2H),1.43(m,2H),0.97(t,J=7.2Hz,3H).
步骤3(合成3-丁基-2-(4-氟苯基)-2-环戊烯-1-酮):混合500mg 3-丁基-2-碘-2-环戊烯-1-酮、320mg 4-氟苯基硼酸、以及90mg四(三苯基膦)钯,然后在20ml甲苯、10ml乙醇和10ml 2N碳酸氢钠水溶液中于80℃下搅拌过夜。该反应混合物用乙酸乙酯稀释,然后用盐水洗涤。有机层在无水硫酸镁上干燥并过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=5∶1),得到420mg油状的3-丁基-2-(4-氟苯基)-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ7.21(m,2H),7.10(m,2H),2.68(m,2H),2.56(m,2H),2.51(m,2H),1.55(m,2H),1.34(m,2H),0.89(t,J=7.2Hz,3H).
步骤4(合成3-丁基-2-(4-氟苯基)-2-环戊烯-1-酮肟):使100mg 3-丁基-2-(4-氟苯基)-2-环戊烯-1-酮和50mg盐酸羟胺在10ml吡啶中的混合物在60℃下搅拌过夜。减压除去吡啶,而残留物用乙酸乙酯和10%盐酸萃取。有机层用碳酸氢钠水溶液和盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过重结晶进行纯制(己烷/乙酸乙酯),得到80mg固体的3-丁基-2-(4-氟苯基)-2-环戊烯-1-酮肟。mp=115-116℃;1H NMR(CDCl3,300MHz):δ7.20(m,2H),7.07(m,2H),2.79(m,2H),2.59(m,2H),2.26(t,J=7.8Hz,2H),1.45(m,2H),1.26(m,2H),0.85(t,J=7.4Hz,3H);APCI MS:m/z248.2(M+1).
实施例34~64,不包括实施例41和47~49:这些化合物是根据类似于实施例33的方法制得的。在实施例34~64中的步骤3中使用以下芳基或杂芳基硼酸化合物用于Suzuki偶联反应:3,4-二氟苯基硼酸用于实施例34;2-氟苯基硼酸用于实施例35;2,4-二氟苯基硼酸用于实施例36;3-溴苯基硼酸用于实施例37;3,4-二氯苯基硼酸用于实施例38;3-硝基苯基硼酸用于实施例39;3-氟-4-甲氧基苯基硼酸用于实施例40;3-乙氧基苯基硼酸用于实施例42;3,4-二甲氧基苯基硼酸用于实施例43;3-甲氧基苯基硼酸用于实施例44;3,4-亚甲二氧基苯基硼酸用于实施例45;4-三氟甲氧基苯基硼酸用于实施例46;3-氨基苯基硼酸用于实施例50;3-乙氧基羰基苯基硼酸用于实施例51;3-羧基苯基硼酸用于实施例52;4-羧基苯基硼酸用于实施例53;3,4-二甲基苯基硼酸用于实施例54;3-甲基苯硼酸用于实施例55;4-丁基苯基硼酸用于实施例56;3-氟-4-联苯基硼酸用于实施例57;3-三氟甲基苯基硼酸用于实施例58;4-甲亚磺酰基苯硼酸用于实施例59;4-甲磺酰基苯硼酸用于实施例60;3-乙酰胺基苯硼酸用于实施例61;3-乙酰基苯硼酸用于实施例62;3-甲酰基苯硼酸用于实施例63;以及苯并噻吩-2-硼酸用于实施例64。实施例34~64的光谱数据以及它们的熔点都列于表4中。
实施例41:3-丁基-2-(3-氟-4-羟基苯基)-2-环戊烯-1-酮肟:在搅拌、和惰性气氛下向20mg 3-丁基-2-(3-氟-4-甲氧基苯基)-2-环戊烯-1-酮肟(实施例40)在5ml二氯甲烷中的溶液内添加0.5ml 1.0M三溴化硼己烷溶液。该反应混合物搅拌20小时,倾倒在饱和碳酸氢钠水溶液中,并用乙酸乙酯萃取。有机层用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=2∶1),得到11mg 3-丁基-2-(3-氟-4-羟基苯基)-2-环戊烯-1-酮肟。实施例41的光谱数据以及其熔点都列于表4中。
实施例47:3-丁基-2-(3-羟基甲基苯基)-2-环戊烯-1-酮肟:3-丁基-2-(3-羟基甲基苯基)-2-环戊烯-1-酮肟是根据类似于实施例25的方法制得的。对于实施例47使用3-丁基-2-碘-2-环戊烯-1-酮替代用于实施例25的3-环戊基-2-碘-2-环戊烯-1-酮。实施例47的光谱数据以及其熔点都列于表4中。
实施例48:3-丁基-2-(3,4-二羟基苯基)-2-环戊烯-1-酮肟:3-丁基-2-(3,4-二甲氧基苯基)-2-环戊烯-1-酮肟(实施例43)根据类似于实施例41的方法进行脱甲基化反应,以得到3-丁基-2-(3,4-二羟基苯基)-2-环戊烯-1-酮肟。实施例48的光谱数据以及其熔点都列于表4中。
实施例49:3-丁基-2-(3-羟基苯基)-2-环戊烯-1-酮肟:3-丁基-2-(3-甲氧基苯基)-2-环戊烯-1-酮肟(实施例44)根据类似于实施例41的方法进行脱甲基化反应,以得到3-丁基-2-(3-羟基苯基)-2-环戊烯-1-酮肟。实施例49的光谱数据以及其熔点都列于表4中。
表4:实施例34~64的物理表征数据
实施例65:2-(4-氟苯基)-3-戊基-2-环戊烯-1-酮肟:标题化合物是根据以下4个步骤的方法制备的。
步骤1(合成3-戊基-2-环戊烯-1-酮):在搅拌、室温和惰性气氛下向2.5g镁在100ml***中的悬浮液内添加10ml 1-溴戊烷。1小时后,向该混合物内缓慢添加5ml2-环戊烯-1-酮。该反应混合物再搅拌2小时,倾倒在饱和氯化铵水溶液内并用乙酸乙酯萃取。有机层用盐水洗涤,在硫酸镁上干燥,然后干燥。滤液减压浓缩,而所得的残留物在适量celite存在下在100ml二氯甲烷中与10g PCC反应3小时。该反应混合物用100ml***稀释,然后通过硅胶垫过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=10∶1),得到1.5g油状的3-戊基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ5.92(m,1H),2.57(m,2H),2.39(m,4H),1.57(m,2H),1.32(m,4H),0.88(m,3H).
步骤2(合成2-碘-3-戊基-2-环戊烯-1-酮):在搅拌下向1.0g3-戊基-2-环戊烯-1-酮在20ml四氯化碳中的溶液内顺序地添加1.5g碘和1ml吡啶。该混合物搅拌过夜,用***稀释,顺序地用饱和硫代硫酸钠水溶液、碳酸氢钠水溶液以及盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=7∶1),得到770mg油状的2-碘-3-戊基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ2.76(m,2H),2.58(m,4H),1.59(m,2H),1.37(m,4H),0.92(m,3H).
步骤3(合成2-(4-氟苯基)-3-戊基-2-环戊烯-1-酮):2.45g2-碘-3-戊基-2-环戊烯-1-酮、1.5g 4-氟苯基硼酸、和250mg四(三苯基膦)钯的混合物在50ml甲苯、25ml乙醇、和25ml 2N碳酸氢钠水溶液中于80℃下搅拌过夜。该反应混合物用乙酸乙酯和盐水萃取。有机层在无水硫酸镁上干燥并过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=5∶1),得到2.18g的2-(4-氟苯基)-3-戊基-2-环戊烯-1-酮。1HNMR(CDCl3,300MHz):δ7.22(m,2H),7.10(m,2H),2.67(m,2H),2.55(m,2H),2.50(m,2H),1.57(m,2H),1.28(m,4H),0.87(m,3H).
步骤4(合成2-(4-氟苯基)-3-戊基-2-环戊烯-1-酮肟):2.18g 2-(4-氟苯基)-3-戊基-2-环戊烯-1-酮和800mg盐酸羟胺在100ml吡啶中的混合物在60℃下搅拌过夜。减压除去吡啶,而所得的残留物用乙酸乙酯和10%盐酸萃取。有机层用碳酸氢钠水溶液以及盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过重结晶进行纯制(乙酸乙酯-己烷),得到2g的2-(4-氟苯基)-3-戊基-2-环戊烯-1-酮肟。mp=101-102℃;1H NMR(CDCl3,300MHz):δ9.08(bs,1H),7.19(m,2H),7.04(m,2H),2.72(m,2H),2.54(m,2H),2.24(t,J=7.8Hz,2H),1.45(m,2H),1.22(m,4H),0.84(t,J=6.9Hz,3H);APCI MS:m/z 262.2(M+1).
实施例66~77:根据与实施例65类似的方法制备以下表5中所列的化合物。在实施例66~77中的步骤3中使用以下芳基或杂芳基硼酸化合物用于Suzuki偶联反应:苯基硼酸用于实施例66;3-氟苯基硼酸用于实施例67;3,4-二氟苯基硼酸用于实施例68;3,5-二氟苯基硼酸用于实施例69;3-氯-4-氟苯基硼酸用于实施例70;3-硝基苯基硼酸用于实施例71;3,4,5-三甲氧基苯基硼酸用于实施例72;4-联苯基硼酸用于实施例73;4-三氟甲基苯基硼酸用于实施例74;2-萘硼酸用于实施例75;吡啶-3-硼酸1,3-丙烷二醇环酯用于实施例76;以及噻吩-3-硼酸用于实施例77。实施例66~77的光谱数据以及它们的熔点都列于表5中。
表5:实施例66~77的物理表征数据
实施例78:2-(4-氟苯基)-3-丙基-2-环戊烯-1-酮肟:标题化合物是根据以下4个步骤的方法制备的。
步骤1(合成3-丙基-2-环戊烯-1-酮):在搅拌、0℃和惰性气氛下向1ml 2-环戊烯-1-酮在20ml***中的溶液内滴加10ml 2.0M丙基氯化镁的***溶液。该反应混合物在室温下搅拌1小时,倾倒在饱和氯化铵水溶液中,并用乙酸乙酯萃取。有机层用盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩,而所得的残留物溶解在20ml二氯甲烷中,并与2.7g PCC以及适量的celite一起搅拌3小时。该反应混合物用20ml***稀释,并通过硅胶垫进行过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=4∶1),得到420mg油状的3-丙基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ5.95(m,1H),2.58(m,2H),2.41(m,4H),1.63(m,2H),0.98(t,J=7.2Hz,3H).
步骤2(合成2-碘-3-丙基-2-环戊烯-1-酮):向420mg 3-丙基-2-环戊烯-1-酮在10ml四氯化碳中的溶液内顺序地添加2.5g碘和0.4ml吡啶。搅拌3小时后,该反应混合物用***稀释,顺序地用饱和硫代硫酸钠水溶液、碳酸氢钠水溶液、以及盐水洗涤。有机层在无水硫酸镁上干燥并过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=4∶1),得到690mg油状的2-碘-3-丙基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ2.77(m,2H),2.60(m,4H),1.65(m,2H),0.99(t,J=7.2Hz,3H).
步骤3(合成2-(4-氟苯基)-3-丙基-2-环戊烯-1-酮):230mg 2-碘-3-丙基-2-环戊烯-1-酮、160mg 4-氟苯基硼酸、以及40mg四(三苯基膦)钯的混合物在80℃下于5ml甲苯、2.5ml乙醇、和2.5ml 2N碳酸氢钠水溶液中搅拌过夜。该反应混合物用乙酸乙酯和盐水萃取。有机层在无水硫酸镁上干燥并过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=5∶1),得到170mg油状的2-(4-氟苯基)-3-丙基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ7.21(m,2H),7.10(m,2H),2.67(m,2H),2.55(m,2H),2.50(m,2H),1.61(m,2H),0.94(t,J=7.2Hz,3H).
步骤4(合成2-(4-氟苯基)-3-丙基-2-环戊烯-1-酮肟):170mg 2-(4-氟苯基)-3-丙基-2-环戊烯-1-酮和100mg盐酸羟胺的混合物在20ml吡啶中于60℃下搅拌过夜。减压除去吡啶,而所得的残留物用乙酸乙酯和10%盐酸萃取。有机层用碳酸氢钠水溶液和盐水洗涤,在硫酸镁上干燥,然后过滤。滤液减压浓缩并通过重结晶进行纯制(乙酸乙酯-己烷),得到100mg的2-(4-氟苯基)-3-丙基-2-环戊烯-1-酮肟。mp=165-166℃;1H NMR(CDCl3,300MHz):δ7.24-7.17(m,3H),7.10-7.03(m,2H),2.79(m,2H),2.59(m,2H),2.25(t,J=7.7Hz,2H),1.50(m,2H),0.87(t,J=7.4Hz,3H);APCI MS:m/z234.1(M+1).
实施例79:2-(3,4-二氟苯基)-3-丙基-2-环戊烯-1-酮肟:标题化合物是根据类似于实施例78的方法制备的。在制备实施例79的步骤3中使用3,4-二氟苯基硼酸用于Suzuki偶联反应。mp=136-137℃;1H NMR(CDCl3,300MHz):δ7.83(bs,1H),7.17(dt,J=10.5and 8.4Hz,1H),7.07(ddd,J=2.1,7.8and 11.1Hz,1H),6.96(m,1H),2.78(m,2H),2.58(m,2H),2.25(t,J=7.8Hz,2H),1.50(m,2H),0.87(t,J=7.5Hz,3H);APCI MS:m/z252.1(M+1).
或者,标题化合物是根据如下的3个步骤的方法制备的。
步骤1(合成1,2-二氟-4-戊-1-炔基苯):向300mg二氯二(三苯基膦)钯和160mg碘化铜在200ml THF中的混合物内顺序地添加7ml三乙胺、10g 1,2-二氟-4-碘苯、以及4.5ml戊炔。该反应混合物搅拌8小时,然后通过硅胶垫进行过滤。滤液用乙酸乙酯稀释,然后顺序地用10%盐酸、水以及盐水洗涤。有机层在无水硫酸镁上干燥并过滤。滤液减压浓缩并通过真空蒸馏进行纯制,得到7.15g油状的1,2-二氟-4-戊-1-炔基苯。1H NMR(CDCl3,300MHz):δ7.19(ddd,J=1.8,7.8and 10.8Hz,1H),7.14-7.01(m,2H),2.36(t,J=7.2Hz,2H),1.62(qt,J=7.2and 7.5Hz,2H),1.04(t,J=7.5Hz,3H).
步骤2(合成2-(3,4-二氟苯基)-3-丙基-2-环戊烯-1-酮):装有1g 1,2-二氟-4-戊-1-炔基苯、385mg Co2(CO)8、0.7ml DMSO、以及5ml甲苯的钢制压力反应器用一氧化碳清洗3次,在5bar一氧化碳以及45bar乙烯下密封,然后在160℃下搅拌12小时。该反应混合物在冷却并释放压力后通过celite垫过滤。滤液减压浓缩并通过柱色谱纯制(硅胶,己烷/乙酸乙酯=4∶1),得到1.05g油状的2-(3,4-二氟苯基)-3-丙基-2-环戊烯-1-酮。1H NMR(CDCl3,300MHz):δ7.19(dt,J=10.5 and 8.4Hz,1H),7.09(ddd,J=2.1,7.8and 11.1Hz,1H),6.97(m,1H),2.68(m,2H),2.55(m,2H),2.50(m,2H),1.62(m,2H),0.95(t,J=7.5Hz,3H).
步骤3(合成2-(3,4-二氟苯基)-3-丙基-2-环戊烯-1-酮肟):1.36g 2-(3,4-二氟苯基)-3-丙基-2-环戊烯-1-酮在20ml吡啶中与2.6g盐酸羟胺缩合,得到980mg的2-(3,4-二氟苯基)-3-丙基-2-环戊烯-1-酮肟。
实施例80:2-(3-硝基苯基)-3-丙基-2-环戊烯-1-酮肟:标题化合物是根据类似于实施例78的方法制备的。在制备实施例80的步骤3中使用3-硝基苯基硼酸用于Suzuki偶联反应。mp=128-129℃;1H NMR(CDCl3,300MHz):δ8.19-8.14(m,2H),7.63-7.52(m,2H),7.00(s,1H),2.84(m,2H),2.65(m,2H),2.28(t,J=7.7Hz,2H),1.55(m,2H),0.89(t,J=7.2Hz,3H).
实施例81:3-乙基-2-(4-氟苯基)-2-环戊烯-1-酮肟:3-乙基-2-环戊烯-1-酮是通过用乙基氯化镁替代丙基氯化镁根据类似于实施例78的步骤1的方法制备的。标题化合物接着根据类似于实施例78所用的方法由3-乙基-2-环戊烯-1-酮起始进行制备。mp 168-169℃;1H NMR(CDCl3,300MHz):δ7.24(m,2H),7.08(m,2H),6.89(s,1H),2.81(m,2H),2.61(m,2H),2.30(q,J=7.8Hz,2H),1.08(t,J=7.7Hz,3H);APCI MS:m/z 220.1(M+1).
实施例82:2-(3,4-二氟苯基)-3-乙基-2-环戊烯-1-酮肟:标题化合物是根据类似于实施例81所用的方法制备的。在Suzuki偶联反应中,使用3,4-二氟苯基硼酸替代实施例81中所用的4-氟苯基硼酸。mp=136-137℃;1H NMR(CDCl3,300MHz):δ7.16(m,1H),7.11(m,1H),6.99(m,1H),6.88(s,1H),2.81(m,2H),2.62(m,2H),2.31(q,J=7.8Hz,2H),1.08(t,J=7.8Hz,3H).
实施例83:2-(4-氟苯基)-3-甲基-2-环戊烯-1-酮肟:3-甲基-2-环戊烯-1-酮是通过用甲基溴化镁替代丙基氯化镁根据类似于实施例78的步骤1的方法制备的。标题化合物接着根据类似于实施例78所用的方法由3-甲基-2-环戊烯-1-酮起始进行制备。mp 170-171℃;1H NMR(CDCl3,300MHz):δ7.26(m,2H),7.08(m,2H),6.77(s,1H),2.81(m,2H),2.60(m,2H),1.92(m,3H);APCI MS:m/z 206.1(M+1).
实施例84:2-(3,4-二氟苯基)-3-甲基-2-环戊烯-1-酮肟:标题化合物是根据类似于实施例83所用的方法制备的。在Suzuki偶联反应中,使用3,4-二氟苯基硼酸替代实施例83中所用的4-氟苯基硼酸。mp=155-156℃;1H NMR(CDCl3,300MHz):δ7.19-7.10(m,2H),7.04(m,1H),6.75(s,1H),2.81(m,2H),2.60(m,2H),1.94(m,3H).
实施例85:2-(4-氟苯基)-3-异丁基-2-环戊烯-1-酮肟:3-异丁基-2-环戊烯-1-酮是通过用仲丁基锂替代正丁基锂根据类似于实施例33的步骤1的方法制备的。标题化合物接着根据类似于实施例33所用的方法由3-异丁基-2-环戊烯-1-酮起始进行制备。mp=154-157℃;1H NMR(CDCl3,300MHz):δ7.22-7.17(m,3H),7.11-7.04(m,1H),2.79(m,2H),2.56(m,2H),2.16(d,J=7.5Hz,2H),1.93-1.81(m,1H),0.83(d,J=6.6Hz,6H);APCI MS:m/z 248.1(M+1).
实施例86~91:以下表6中的化合物是根据类似于实施例85中所用的方法而制备的。使用以下芳基硼酸化合物用于实施例86~90制备中的步骤3中的Suzuki偶联反应:3,4-二氟苯基硼酸用于实施例86;3,4-亚甲二氧基苯基硼酸用于实施例87;3-硝基苯基硼酸用于实施例88;3-氰基苯基硼酸用于实施例89;3-氟-4-n-壬基苯基硼酸用于实施例90;以及3-n-丁氧基苯基硼酸用于实施例91。实施例86~91的光谱数据以及它们的熔点列于表6中。
表6:实施例86~91的物理表征数据
生物学评估
对本发明化合物在经刺激的免疫细胞中抑制TNF-α形成的能力进行评估。从剂量-应答曲线中读出IC50值(TNF-α形成被抑制50%时的浓度)。该体外抑制测试是用PDE4抑制剂咯利普兰作为阳性对照来进行的。评估本发明的化合物在炎性或免疫学疾病的动物模型中的治疗活性。还测试了本发明化合物在抑制PDE4同工酶上的能力。
抑制TNF-α在大鼠PBMC中的形成:如文献中所述[Exp.Geront.vol 37,235-247(2002)]在大鼠外周单核血细胞(PBMC)中对本发明的化合物抑制TNE-α形成的能力进行评估。简而言之,从用ACD(酸/柠檬酸盐/葡萄糖)处理的大鼠腹静脉中抽取6ml血液,并小心地将其添加至包含6ml Ficoll 1077的试管中,然后在室温下使该试管在1500rpm(415G)离心30分钟。将细胞部分(中间部分)悬浮在包含经磷酸盐缓冲的盐水(PBS)的50ml试管中。该试管在2000rpm(737G)离心5分钟。所得的沉淀物悬浮在6ml PBS和6ml Ficoll 1077中,然后在室温下于1500rpm(415G)离心30分钟,以除去残留的血浆。将细胞部分悬浮在PBS中并在2000rpm离心5分钟。重复此等洗涤过程2次。将收集到的细胞悬浮在10ml包含10%FBS的RPMI-1640中,并进一步稀释至每ml包含4x106个细胞。将该细胞悬浮液以每孔100μl的量分配在96孔板中,所述孔已预先补充有1μl的DMSO(安慰剂)或包含预定浓度的本发明化合物的DMSO母液。该板在37℃、5%CO2和95%O2下培养1小时。向每个孔中添加100μl包含0.1μg/ml LPS、5U/ml IFN-γ和10%FBS的RPMI-1640。该板接着在37℃、5%CO2和95%O2下培养18小时。每个孔中的等分上清液进行ELISA测试,以测定每个孔中的TNF-α浓度。在表7中总结了本发明的化合物在大鼠PBMC中观察到的抑制TNF-α形成的体外活性。然而,这些体外抑制数据的提供并不是将化合物的范围限制在表7中。
表7:化合物对TNF-α在大鼠PBMC中形成的体外抑制活性
实施例 | IC50,μg/ml或%抑制 | 实施例 | IC50,μg/ml或%抑制 |
1 | 0.12 | 2 | 0.035 |
3 | 0.053 | 4 | 0.02 |
5 | 66%抑制@0.3μg/ml | 10 | 0.097 |
12 | 0.1 | 13 | 0.4 |
18 | 78%抑制@3μg/ml | 19 | 1 |
23 | 1.2 | 25 | 1.5 |
27 | 0.34 | 28 | 0.13 |
30 | <0.1 | 31 | 0.076 |
32 | 0.49 | 33 | 2.0 |
34 | 0.3 | 39 | 0.23 |
45 | 0.69 | 58 | 59%抑制@3μg/ml |
65 | ~1 | 66 | 1~3 |
71 | <1 | 77 | 2.8 |
78 | 0.62 | 79 | 0.18 |
80 | 0.2 | 81 | ~3 |
83 | ~10 | 85 | 0.77 |
86 | 0.27 | 89 | 0.09 |
咯利普兰 | 0.05~0.1 |
在人PBMC中抑制TNF-α的形成:如文献中所述[J.Med.Chem.vol 39,3238-3240(1996)]在人PBMC中对本发明的化合物抑制TNF-α形成的能力进行评估。从经过ACD处理的健康人受试者中新鲜抽取血液,以根据用于大鼠PBMC的方法分离人PBMC。对人TNF-α的ELISA所使用的测试方法基本上与用于大鼠TNF-αELISA测试的方法相同。本发明的化合物在人和大鼠PBMC中显示出可相互比拟的抑制活性。在表8中总结了本发明的某些化合物在人PBMC中的体外抑制活性。
表8:化合物对TNF-α在人PBMC中形成的体外抑制活性
实施例 | IC50,μg/ml | 实施例 | IC50,μg/ml |
2 | 0.072 | 4 | 0.07 |
12 | 0.16 | 45 | 0.8 |
65 | 1.2 | 咯利普兰 | 0.01~0.1 |
体内抑制TNF-α形成:根据与文献[J.Pharmacol.Exp.Therapeut.vol 279,1453-1461(1996)]中类似的方法对本发明的化合物在用LPS刺激的小鼠中抑制TNF-α体内形成的能力进行评估。简而言之,在第0小时向经过整夜禁食的小鼠(Balb/C或ICR,25~30g)通过口服饲药法给药本发明的化合物+载体或者仅给药载体(5%Tween 80)(10ml/kg体重)。在第0.5小时时这些小鼠中每只小鼠都腹膜注射100mg LPS,用CO2麻醉后2小时时从腹静脉抽取血液。通过离心从所抽取的血液中分离血浆,并对其进行ELISA测试,以测定TNF-α的浓度。本发明化合物对TNF-α体内形成的%抑制作用是通过对比接受所述化合物的小鼠中观察到的平均TNF-α浓度和仅接受载体的小鼠中观察到的平均TNF-α浓度来测定的。如表9中所示,本发明的化合物强效抑制经LPS刺激的小鼠中TNF-α的体内形成,与它们对TNF-α形成的体外抑制活性是平行的。
表9:在经LPS刺激的小鼠中化合物对TNF-α形成的体内抑制活性(n=5-6每组)
实施例 | %抑制@剂量 | 实施例 | %抑制@剂量 |
1 | 72%@3mg/kg | 2 | 78%@0.3mg/kg |
4 | 63%@0.01mg/kg | 13 | 70%@0.3mg/kg |
27 | 87%@3mg/kg | 28 | 88%@3mg/kg |
31 | 80%@3mg/kg | 32 | 92%@3mg/kg |
39 | 96%@3mg/kg | 45 | 42%@1mg/kg |
66 | 45%@3mg/kg | 79 | 85%@3mg/kg |
80 | 95%@3mg/kg | 咯利普兰 | ~50%@0.2mg/kg |
在迟发型过敏反应中的治疗效果:根据文献中的方法[J.Immunol.vol 171,3010(2003)]对本发明的化合物在迟发型过敏反应(DTH)的动物模型中治疗炎症的能力进行评估。简而言之,于第0天将Balb/c小鼠的腹部剃毛,并在该腹部皮肤上局部给药溶解在9∶1丙酮/DMSO(载体)中的2%噁唑酮。在第5天,通过在左耳上给药2%噁唑酮而诱发DTH。将本发明的化合物溶解在载体中并局部施用在左耳2次,第一次是在用噁唑酮诱发之前2小时,而第二次是在用噁唑酮诱发之后4小时。在用噁唑酮诱发之后24小时比较经穿孔的左耳(发炎)和右耳(未发炎)的重量,由此对治疗效果进行评分。例如,对于3%的实施例4溶液观察到37%的耳水肿抑制作用(p<0.05),而对于以每剂90mg/kg的量在第5天口服给药环孢菌素2次则观察到76%的抑制作用(p<0.01)。每组评估5只动物。
在DSS诱发的结肠炎中的治疗效果:根据文献中的方法[J.Pharmacol.Exp.Therapeut.vol 292,22-30(2000)]在小鼠中对本发明的化合物治疗由葡聚糖硫酸钠(DSS)诱发的结肠炎的能力进行评估。简而言之,将重量为16-20g的雌性Balb/c小鼠随机分组(每组5~6只),并由第1天起就允许其自由饮用包含5%DSS的水。以10ml/kg的剂量口服给药在5%Tween 80中的本发明的化合物或者柳氮磺吡啶,每日二次。评估粪便粘稠度、体重以及直肠出血,由此每日测量每只动物的临床活动分值。观察本发明化合物的治疗效果。例如,以1mg/kg BID的量接受实施例4的动物在第11天时在临床活动分值方面与对照组(仅载体和DDS)相比显示出43%的改善(p<0.05),而在以50mg/kgBID的量接受柳氮磺吡啶的动物中观察到19%的改善(p>0.05)。
U937细胞中对cAMP Degradation的体外抑制作用:评估本发明的化合物在细胞中抑制由forskolin(一种腺苷酸环化酶刺激剂)诱发的cAMP水解上的能力。简而言之,在96孔板上,每个孔3x105个U937细胞在200μl包含10%FBS的RPMI-1640中于37℃下温育10分钟,该板然后用预定剂量的DMSO或本发明化合物的DMSO母液处理。这些细胞接着在37℃下用10μM forskolin刺激10分钟。该板在1500rpm离心5分钟。小心地从每个孔中取出120μl上清液,然后向每个孔中添加200μl的溶胞剂1B。接着分析细胞溶解物,以通过使用来自Amersham Pharmacia Biotech的cAMP EIA试剂盒(Kit#RPN225)的酶免疫测定(EIA)来测量cAMP浓度。由cAMP浓度的剂量-应答曲线测定本发明化合物的IC50值。本发明的化合物在U937细胞中中强效抑制cAMP的细胞降解。例如,所观察到的IC50值对于实施例2是0.1μg/ml,对于实施例4是0.13μg/ml,并且对于实施例45是0.87μg/ml,而已知的PDE4抑制剂咯利普兰的IC50值是0.27μg/ml。
抑制PDE4同工酶:根据文献中的方法[Biochemistry vol 39,6449-6458(2000)]评估本发明的化合物在抑制磷酸二酯酶4(PDE4)的同工酶(得自Fab Gennix International Inc.(Frisco,Texas/USA))上的能力。简而言之,测定预定剂量的化合物在抑制PDE4同工酶在pH 7.4Tris缓冲液中对cAMP的水解上的能力。使用来自AmershamBiosciences的SPA试剂盒根据供货商的指导手册(TRKQ7090磷酸二酯酶[3H]cAMPSPA酶测定)通过闪烁亲近测定法(SPA)来测定所得的cAMP浓度。如表10中对某些本发明化合物所示,本发明的化合物强效地抑制PDE4的同工酶。
表10:化合物对人PDE4同工酶的抑制活性
Claims (15)
2.如权利要求1所述的化合物或其药物学可接受的盐,其中:
R1代表直链或支链C1-C6烷基、环戊基或环己基。
3.如权利要求1所述的化合物或其药物学可接受的盐,其中所述化合物选自以下组中:
3-环戊基-2-(4-氟苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(3,4-二氟苯基)-2-环戊烯-1-酮肟;
2-(3-氯-4-氟苯基)-3-环戊基-2-环戊烯-1-酮肟;
3-环戊基-2-(3-硝基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(4-甲基-3-硝基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(3,4-二甲氧基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-(3-甲氧基苯基)-2-环戊烯-1-酮肟;
2-{4-(苄氧基)苯基}-3-环戊基-2-环戊烯-1-酮肟;
3-环戊基-2-(3,4-亚甲二氧基苯基)-2-环戊烯-1-酮肟;
3-环戊基-2-{3-(三氟甲氧基)苯基}-2-环戊烯-1-酮肟;
2-(3-氰基苯基)-3-环戊基-2-环戊烯-1-酮肟;
2-(3-氰基-4-氟苯基)-3-环戊基-2-环戊烯-1-酮肟;
3-环戊基-2-{5-(1H)-吲哚基}-2-环戊烯-1-酮肟;
3-环戊基-2-(6-甲氧基萘基)-2-环戊烯-1-酮肟;
3-环戊基-2-(4-氧芴基)-2-环戊烯-1-酮肟;
3-环戊基-2-(2-噻蒽基)-2-环戊烯-1-酮肟;
3-环戊基-2-(3-羟基苯基)-2-环戊烯-1-酮肟;
3-环己基-2-(4-氟苯基)-2-环戊烯-1-酮肟;
2-(3-氯-4-氟苯基)-3-环己基-2-环戊烯-1-酮肟;
3-环己基-2-(3-氟苯基)-2-环戊烯-1-酮肟;
3-环己基-2-(3,4-二氟苯基)-2-环戊烯-1-酮肟;
3-环己基-2-(3-硝基苯基)-2-环戊烯-1-酮肟;
3-环己基-2-(3-甲氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(4-氟苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二氟苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(2-氟苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(2,4-二氟苯基)-2-环戊烯-1-酮肟;
2-(3-溴苯基)-3-丁基-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二氯苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-硝基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-氟-4-甲氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-氟-4-羟基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-乙氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二甲氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-甲氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-亚甲二氧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-{4-(三氟甲氧基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二羟基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-羟基苯基)-2-环戊烯-1-酮肟;
2-(3-氨基苯基)-3-丁基-2-环戊烯-1-酮肟;
3-丁基-2-{3-(乙氧基羰基)苯基}-2-环戊烯-1-酮肟;
3-丁基-2-(3-羧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(4-羧基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3,4-二甲基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(3-甲基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-(4-丁基苯基)-2-环戊烯-1-酮肟;
3-丁基-2-{3-(三氟甲基)苯基}-2-环戊烯-1-酮肟;
2-(2-苯并[b]噻吩基)-3-丁基-2-环戊烯-1-酮肟;
3-戊基-2-苯基-2-环戊烯-1-酮肟;
2-(4-氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3-氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3,5-二氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3-氯-4-氟苯基)-3-戊基-2-环戊烯-1-酮肟;
2-(3-硝基苯基)-3-戊基-2-环戊烯-1-酮肟;
3-戊基-2-(3,4,5-三甲氧基苯基)-2-环戊烯-1-酮肟;
3-戊基-2-{4-(三氟甲基)苯基}-2-环戊烯-1-酮肟;
2-(1-萘基)-3-戊基-2-环戊烯-1-酮肟;
3-戊基-2-(3-吡啶基)-2-环戊烯-1-酮肟;
3-戊基-2-(3-噻吩基)-2-环戊烯-1-酮肟;
2-(4-氟苯基)-3-丙基-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-丙基-2-环戊烯-1-酮肟;
2-(3-硝基苯基)-3-丙基-2-环戊烯-1-酮肟;
3-乙基-2-(4-氟苯基)-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-乙基-2-环戊烯-1-酮肟;
2-(4-氟苯基)-3-甲基-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-甲基-2-环戊烯-1-酮肟;
2-(4-氟苯基)-3-异丁基-2-环戊烯-1-酮肟;
2-(3,4-二氟苯基)-3-异丁基-2-环戊烯-1-酮肟;
2-(3,4-亚甲二氧基苯基)-3-异丁基-2-环戊烯-1-酮肟;
3-异丁基-2-(3-硝基苯基)-2-环戊烯-1-酮肟;
2-(3-氰基苯基)-3-异丁基-2-环戊烯-1-酮肟;以及
2-(3-氟-4-正壬基苯基)-3-异丁基-2-环戊烯-1-酮肟。
4.用于预防或治疗TNF-α介导的疾病的药物组合物,其包含治疗有效量的如权利要求1-3之一所述的化合物或其药物学可接受的盐作为活性成分。
5.如权利要求4所述的药物组合物,其中所述TNF-α介导的疾病是炎性或免疫学疾病。
6.如权利要求4所述的药物组合物,其中所述TNF-α介导的疾病选自以下组中:类风湿性关节炎、牛皮癣、牛皮癣关节炎、特应性皮炎、包括溃疡性结肠炎和Crohn病的炎性肠病、关节强直性脊椎炎、多发性硬化、***性红斑狼疮、慢性阻塞性肺病、脓毒症、内毒素休克、肝炎以及I型糖尿病。
7.如权利要求4所述的药物组合物,其中所述TNF-α介导的疾病是包括溃疡性结肠炎和Crohn病的炎性肠病、牛皮癣或特应性皮炎。
8.用于预防或治疗PDE4介导的疾病的药物组合物,其包含治疗有效量的如权利要求1-3之一所述的化合物或其药物学可接受的盐作为活性成分。
9.如权利要求8所述的药物组合物,其中所述PDE4介导的疾病是气喘或慢性阻塞性肺病。
10.如权利要求1-3之一所述的化合物或其药物学可接受的盐在制备用于预防或治疗TNF-介导的疾病的药物中的应用。
11.如权利要求10所述的应用,其中所述TNF-α介导的疾病是炎性或免疫学疾病。
12.如权利要求10所述的应用,其中所述TNF-α介导的疾病选自以下组中:类风湿性关节炎、牛皮癣、牛皮癣关节炎、特应性皮炎、包括溃疡性结肠炎和Crohn病的炎性肠病、关节强直性脊椎炎、多发性硬化、***性红斑狼疮、慢性阻塞性肺病、脓毒症、内毒素休克、肝炎、和I型糖尿病。
13.如权利要求10所述的应用,其中所述TNF-α介导的疾病是包括溃疡性结肠炎和Crohn病的炎性肠病、牛皮癣或特应性皮炎。
14.如权利要求1-3之一所述的化合物或其药物学可接受的盐在制备用于预防或治疗PDE4介导的疾病的药物中的应用。
15.如权利要求14所述的应用,其中所述PDE4介导的疾病是气喘或慢性阻塞性肺病。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20040100419 | 2004-12-02 | ||
KR10-2004-0100419 | 2004-12-02 | ||
KR1020040100419 | 2004-12-02 | ||
PCT/KR2005/004061 WO2006059867A1 (en) | 2004-12-02 | 2005-11-30 | 2-cyclopenten-1-one oxime derivatives inhibiting production of tnf-alpha |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101068774A CN101068774A (zh) | 2007-11-07 |
CN101068774B true CN101068774B (zh) | 2011-08-10 |
Family
ID=36565283
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2005800414947A Expired - Fee Related CN101068774B (zh) | 2004-12-02 | 2005-11-30 | 抑制TNF-α形成的2-环戊烯-1-酮肟衍生物 |
Country Status (8)
Country | Link |
---|---|
US (1) | US8013187B2 (zh) |
EP (1) | EP1841729B1 (zh) |
JP (1) | JP4903155B2 (zh) |
KR (1) | KR100879423B1 (zh) |
CN (1) | CN101068774B (zh) |
AT (1) | ATE495148T1 (zh) |
DE (1) | DE602005025934D1 (zh) |
WO (1) | WO2006059867A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5273989B2 (ja) * | 2007-11-13 | 2013-08-28 | 株式会社明治 | 消化管潰瘍の予防又は治療剤 |
WO2009072807A2 (en) * | 2007-12-03 | 2009-06-11 | Amorepacific Corporation | Pharmaceutical composition for preventing or treating fat metabolism-related diseases containing 2-cyclopentene-1-one oxime derivatives |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US631286A (en) * | 1899-04-03 | 1899-08-22 | Alexander Euston | Hydraulic press. |
CN1114645A (zh) * | 1994-05-05 | 1996-01-10 | 巴斯福股份公司 | O-(肟基)乙基环己烯酮肟醚及其作为除草剂的用途 |
US5693659A (en) * | 1994-06-23 | 1997-12-02 | Celltech Therapeutics Limited | Substituted oxime derivatives and processes for their preparation |
US5792882A (en) * | 1993-08-19 | 1998-08-11 | Pfizer Inc. | Phenoxyphenyl cyclopentenyl hydroxyureas |
US20030229146A1 (en) * | 2001-12-05 | 2003-12-11 | Dabur Research Foundation | Cyclopentenone derivatives for cancer therapy |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3980700A (en) * | 1971-10-07 | 1976-09-14 | G. D. Searle & Co. | Prostaglandin intermediates and optically active isomers thereof |
IT1226969B (it) * | 1984-01-05 | 1991-02-26 | Istituto Biochimico Italiano | Procedimento perfezionato per la preparazione dell'acido 7-(2)esil-5- idrossi- ciclopentil)-eptanoico |
EP0633775B1 (en) | 1992-04-02 | 2000-05-31 | Smithkline Beecham Corporation | Compounds useful for treating inflammatory diseases and for inhibiting production of tumor necrosis factor |
-
2005
- 2005-11-30 JP JP2007544262A patent/JP4903155B2/ja not_active Expired - Fee Related
- 2005-11-30 CN CN2005800414947A patent/CN101068774B/zh not_active Expired - Fee Related
- 2005-11-30 WO PCT/KR2005/004061 patent/WO2006059867A1/en active Application Filing
- 2005-11-30 EP EP05819104A patent/EP1841729B1/en not_active Not-in-force
- 2005-11-30 AT AT05819104T patent/ATE495148T1/de not_active IP Right Cessation
- 2005-11-30 DE DE602005025934T patent/DE602005025934D1/de active Active
- 2005-11-30 US US11/720,081 patent/US8013187B2/en active Active
- 2005-11-30 KR KR1020077011568A patent/KR100879423B1/ko active IP Right Grant
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US631286A (en) * | 1899-04-03 | 1899-08-22 | Alexander Euston | Hydraulic press. |
US5792882A (en) * | 1993-08-19 | 1998-08-11 | Pfizer Inc. | Phenoxyphenyl cyclopentenyl hydroxyureas |
CN1114645A (zh) * | 1994-05-05 | 1996-01-10 | 巴斯福股份公司 | O-(肟基)乙基环己烯酮肟醚及其作为除草剂的用途 |
US5693659A (en) * | 1994-06-23 | 1997-12-02 | Celltech Therapeutics Limited | Substituted oxime derivatives and processes for their preparation |
US20030229146A1 (en) * | 2001-12-05 | 2003-12-11 | Dabur Research Foundation | Cyclopentenone derivatives for cancer therapy |
Also Published As
Publication number | Publication date |
---|---|
KR100879423B1 (ko) | 2009-01-19 |
EP1841729A4 (en) | 2009-12-23 |
DE602005025934D1 (de) | 2011-02-24 |
CN101068774A (zh) | 2007-11-07 |
JP2008521885A (ja) | 2008-06-26 |
EP1841729B1 (en) | 2011-01-12 |
KR20070085422A (ko) | 2007-08-27 |
WO2006059867A1 (en) | 2006-06-08 |
US20090036501A1 (en) | 2009-02-05 |
JP4903155B2 (ja) | 2012-03-28 |
EP1841729A1 (en) | 2007-10-10 |
ATE495148T1 (de) | 2011-01-15 |
US8013187B2 (en) | 2011-09-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI828649B (zh) | 聯芳基衍生物、其製備方法和在藥學上的應用 | |
JP6603649B2 (ja) | キヌレニン経路の阻害剤 | |
EP2296653B1 (en) | Compounds and methods for treating inflammatory and fibrotic disorders | |
CN101595084B (zh) | 用于调整激酶级联的二芳基组合物和方法 | |
CN103502237B (zh) | Faah抑制剂 | |
CN103479654B (zh) | 作为抗炎药的含硼的小分子 | |
TW202024023A (zh) | 治療性化合物及其使用方法 | |
CN106488910A (zh) | Kras g12c的抑制剂 | |
CN103261160A (zh) | 用于抑制nampt的胍化合物和组合物 | |
JP2018502853A (ja) | 炎症およびがんを処置するための複素環式itk阻害剤 | |
TW201040162A (en) | Inhibitors of JAK | |
TW200413331A (en) | Small molecule PI 3-kinase inhibitors and methods of their use | |
CN103012399B (zh) | 7-氧代吡啶并嘧啶类化合物及其药用组合物和应用 | |
JPH04504576A (ja) | 新規アリールピリダジン、その製造、使用およびこれを含有する医薬品 | |
CN102227424A (zh) | 囊性纤维化跨膜传导调节因子的调节剂 | |
CN103068384A (zh) | 表现出抗癌和抗增生活性的环丙基二甲酰胺以及类似物 | |
CN102643228A (zh) | 间烟碱化合物的羟基苯甲酸盐 | |
CN101636385B (zh) | 作为ep4受体拮抗剂的萘和喹啉磺酰脲衍生物 | |
CN102803269A (zh) | Ampk的噻吩并[2,3-b]嘧啶二酮活化剂及其治疗用途 | |
CN100439365C (zh) | 用作蛋白激酶抑制剂的化合物和组合物 | |
KR20050051658A (ko) | IgE를 조절하고 세포 증식을 억제하기 위한 페닐-인돌화합물 | |
JP2017525765A (ja) | 新規イミノニトリル誘導体 | |
JP2003514898A (ja) | Cox−2の選択的阻害剤としてのピリミジン誘導体 | |
CN108530444A (zh) | 一种新型nampt和ido双重抑制剂及其制备方法和医药用途 | |
CN101068774B (zh) | 抑制TNF-α形成的2-环戊烯-1-酮肟衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110810 Termination date: 20211130 |
|
CF01 | Termination of patent right due to non-payment of annual fee |