TWI360535B - Sulfur-containing compound, method of preparation - Google Patents
Sulfur-containing compound, method of preparation Download PDFInfo
- Publication number
- TWI360535B TWI360535B TW096132313A TW96132313A TWI360535B TW I360535 B TWI360535 B TW I360535B TW 096132313 A TW096132313 A TW 096132313A TW 96132313 A TW96132313 A TW 96132313A TW I360535 B TWI360535 B TW I360535B
- Authority
- TW
- Taiwan
- Prior art keywords
- formula
- group
- compound
- equation
- chemical
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 91
- 238000000034 method Methods 0.000 title claims description 28
- 229910052717 sulfur Inorganic materials 0.000 title claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title description 9
- 239000011593 sulfur Substances 0.000 title description 9
- 238000002360 preparation method Methods 0.000 title description 4
- 239000000126 substance Substances 0.000 claims description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 208000002193 Pain Diseases 0.000 claims description 16
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 claims description 14
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 claims description 14
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 201000001320 Atherosclerosis Diseases 0.000 claims description 11
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 claims description 10
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 claims description 10
- 208000004296 neuralgia Diseases 0.000 claims description 10
- 208000021722 neuropathic pain Diseases 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 238000005886 esterification reaction Methods 0.000 claims description 7
- 206010020718 hyperplasia Diseases 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000000376 reactant Substances 0.000 claims description 7
- 101100516554 Caenorhabditis elegans nhr-5 gene Proteins 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 206010003246 arthritis Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 206010065390 Inflammatory pain Diseases 0.000 claims description 3
- 230000003143 atherosclerotic effect Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000357 manganese(II) sulfate Inorganic materials 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 208000020431 spinal cord injury Diseases 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 10
- 239000000203 mixture Substances 0.000 claims 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 claims 2
- 101100366060 Caenorhabditis elegans snap-29 gene Proteins 0.000 claims 1
- 230000002152 alkylating effect Effects 0.000 claims 1
- 150000001555 benzenes Chemical group 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 230000035622 drinking Effects 0.000 claims 1
- 230000002008 hemorrhagic effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 101150041968 CDC13 gene Proteins 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000000202 analgesic effect Effects 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- 230000001684 chronic effect Effects 0.000 description 6
- 229940035676 analgesics Drugs 0.000 description 5
- 239000000730 antalgic agent Substances 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 210000003497 sciatic nerve Anatomy 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 230000007815 allergy Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000003568 thioethers Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 210000001168 carotid artery common Anatomy 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- GBHCABUWWQUMAJ-UHFFFAOYSA-N 2-hydrazinoethanol Chemical compound NNCCO GBHCABUWWQUMAJ-UHFFFAOYSA-N 0.000 description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 2
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 210000000269 carotid artery external Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000007659 motor function Effects 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- JLIDVCMBCGBIEY-UHFFFAOYSA-N 1-penten-3-one Chemical class CCC(=O)C=C JLIDVCMBCGBIEY-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- 241001108921 Asclepias asperula Species 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
- 101100328518 Caenorhabditis elegans cnt-1 gene Proteins 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 229940122204 Cyclooxygenase inhibitor Drugs 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 102000004020 Oxygenases Human genes 0.000 description 1
- 108090000417 Oxygenases Proteins 0.000 description 1
- 206010033425 Pain in extremity Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- DYAHQFWOVKZOOW-UHFFFAOYSA-N Sarin Chemical compound CC(C)OP(C)(F)=O DYAHQFWOVKZOOW-UHFFFAOYSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- QRSFFHRCBYCWBS-UHFFFAOYSA-N [O].[O] Chemical compound [O].[O] QRSFFHRCBYCWBS-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- -1 argon peroxide Chemical class 0.000 description 1
- WTSAKMSVTHDBCS-UHFFFAOYSA-N benzoic acid;hydrazine Chemical compound [NH3+]N.[O-]C(=O)C1=CC=CC=C1 WTSAKMSVTHDBCS-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000002390 hyperplastic effect Effects 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229940088644 n,n-dimethylacrylamide Drugs 0.000 description 1
- YLGYACDQVQQZSW-UHFFFAOYSA-N n,n-dimethylprop-2-enamide Chemical compound CN(C)C(=O)C=C YLGYACDQVQQZSW-UHFFFAOYSA-N 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- 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
- C07C323/22—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 doubly-bound oxygen atoms bound to the same carbon skeleton
-
- 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
- C07C323/50—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 carboxyl groups bound to the same carbon skeleton
- C07C323/51—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 carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—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 carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- 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
- C07C323/50—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 carboxyl groups bound to the same carbon skeleton
- C07C323/51—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 carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—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 carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
1360535 九、發明說明: 【發明所屬之技術領域】 本發明係關於一種新穎之含硫化合物。該含硫化合物可 抑制誘發型一氧化氮合成酶(inducible nitric oxide synthase,iNOS)及 / 或第二型環氧合酶(cyclooxygenase-2, COX-2)之作用。 【先前技術】 隨著文明進步,人類除延長壽命外,更重視生活品質之 提升。然而至今有許多疾病,例如癌症、慢性疼痛與動脈 粥狀硬化,仍無專一且有效治療或預防之藥物。 許多研究報告證實發炎性反應於許多疾病之發生上扮演 重要角色。這些發炎性相關疾病之發生和許多例如自由 基、污染、飲食及壽命之外在壓力環境所誘發之身體慢性 且長期發炎密切相關。 動脈粥狀硬化(atherosclerosis)作用造成企管重塑 (remolding),進而導致jk管内徑變小。此病變為引起如心 肌梗塞(myocardial infarction)、中風(stroke)及週邊血管病 變之急性且致命心血管疾病之重要原因。心血管疾病亦為 文明進步國家重大死因之一(Libby,Am J Clin Nutr 83:45 6S-460S,2006)。研究報告已證實,動脈粥狀硬化為 一種慢性發炎性心血管疾病(Ross,NEnglJMed 340:115-126,1999),因早期血管内皮細胞受到壓力或破壞,誘發 單核細胞分化為巨嘆細胞並大量聚集在受損組織周圍,經 由一連串發炎性反應,導致血管内平滑肌細胞增生及相關 120871.doc 1360535 發炎性細胞聚集,最後使血管之血流功能受損進而引發心 血管疾病(Lucas與 Greaves,Exp Rev Mol Med 5:1-18, 2001 ; Gordon,Bioessays 17:977-986,1995 ; Majno 與 Joris,Cells,Tissues and Disease : Principles of General Pathology,Blackwell Science,Cambridge,MA,USA, 1996)。於動物實驗之研究結果顯示誘發型一氧化氮合成 酶及第二型環氧合酶此兩種發炎性反應關鍵蛋白質在動脈 粥狀硬化上扮演重要角色(Cipollone,Lupus 14:756-759, 2005 ; Boyle,Curr Vase Pharmacol 3:63-68,2005)。此 外,從人類粥狀硬化組織中(包含巨噬細胞、增生之平滑 肌細胞)亦可發現大量誘發型一氧化氮合成酶及第二型環 氧合酶之表現及大量巨噬細胞聚集(Baker等人, Arterioscler Thromb Vase Biol 19:646-655 » 1999 ; Buttery 等人,Lab Invest 75:77-85,1996)。目前亦證實給予誘發 型一氧化氮合成酶或第二型環氧合酶選擇性抑制劑可顯著 預防粥狀硬化之發生(Burleigh等人,(^1^111&^〇11105:1816-23,2002 ; Hayashi 等人,Atherosclerosis 187:316-324 j 2006 ; Pratico等人,Arterioscler Thromb Vase Biol 19:646-655 , 2001)〇 根據國際疼痛醫學會(International Association for the Study of Pain,IASP)之定義,疼痛是一種伴隨著實質或潛 在組織傷害所引起之不愉快情緒或感官經驗。尤其現今人 類壽命延長,人們遭受各類型疼痛攻擊的機會及時間一再 提高。保守估計全球每年止痛藥消費量約為一千億美元, 120871.doc 1360535 =疼痛控制進而提高生活品質為―重要之課題。於各式 =,神經病理性疼痛之起因取多,如糖尿病所引起之 =環不良或截肢、外傷所導致之神經受損、病毒感染 =起因不明的疼痛。目前臨床上有關止痛藥物可分為且成 瘾性止痛藥與非成癘性止痛藥。成瘾性止痛藥以鵪片、類 /Plate)為主’然而鸦片類藥物對神經病理性疼痛之止痛 效果並不好。非成瘾性止痛藥可分為類固醇型㈣⑽)及 非類固醇型(non_steroid)。類固醇型止痛藥主要經由抗發 炎途徑進而達到止痛的效果,其專一性差、副作用大且無 法長期服用;而非成癌性之非類固醇型藥物又可分成單純 止痛型(如普拿疼)及消炎止痛型(如阿斯匹靈)。目前非類 © # jL M (non-steroid anti-inflammatory drug ; NSAID)是目前咸認副作用較低相對安全之藥物。於各式 類固醇型消炎止痛劑中選擇性較高者之藥理機制主要係藉 由抑制第二型環氧合酶或誘發型一氧化氣合成酶之訊息路 徑,進而達到消炎止痛之作用(Turini與DuB〇is,八仙―
Rev Med 53:35,2002 ; Handy 等人,Br j pha_c〇1 123:11 19-1126,1998,· Osborne 等人,Br j pharmac〇1 126:1840-1846,1999)。目前已有研究報告證實在中樞神 經系統及週邊組織中由誘發型一氧化氮合成酶或第二型環 氧合酶所催化之產物NO或PGE2,對疼痛的產生、維持及 敏感化十分重要(Moalem 及Tracey,Brain Res Rev 51:24()_ 264,2006)。有別於神經阻斷劑使用於止痛作用會影響運 動功能’給予誘發型一氧化氮合成酶或第二型環氧合酶抑 120871.doc '劑並不易產生運動功能下降及神經受損之副作用 目前止痛藥物開發上一重要之方向。 為 【發明内容】 γ本發明之-目的在於提供—種新賴之含硫化合物,其可 丄由化學合成’在離體實驗模式具顯著抑制發炎性蛋白質 婦體實驗亦證日㈣含硫化合物具有治療與誘發 效果乳化II合成酶及/或第二型環氧合酶作用相關疾病之 本發明之另一目的在於提供一種新穎之含硫化合物製造 方法。 本發月X目的在於提供一種醫藥組合物,其包含如上 述之含硫化合物。 ’本發明再一目的在於提供一種如上述含硫化合物於製造 藥物之用it ’該藥物可用於治療與誘發型一氧化氮合成酶 及/或第二型環氧合酶作用相關疾病。 【實施方式】 本發明含硫化合物具有以下式1之結構,
0 式1, 其中: R1係選自由h、r5及r5c(=〇)所级成之群; R2係選自由S及(〇=)s(=〇)所組成之群; 120871.doc 1360535 R3係選自由Η、CH3及CH2CH2C(=0)0R5所組成之群; 選自由 r5、〇r5、-nch2ch2och2ch2 ' N(r5)2、 NH2、NHR5及OH所組成之群; R5係選自由具有一至六個碳之烷基及經取代或未經取代 之苯基所組成之群,較佳地,R5係選自由曱基、乙基及 未經取代之苯基所組成之群; 但當 R3為 CH2CH2C(=0)0R5 時,R4為 OR5 ;及 R1為Η、R2為S及R3為Η時,R4不為CH3。 根據本發明之較佳具體實施例,上述式1化合物具有如 以下所示的化學結構式:
式3, 式4,
式6, 120871.doc •10- 1360535 o' Ο 式7, 〇 式8, 〇、 o 式9, ch3 HO〜Sx^Y、H3 o 式10, 〇、、々〇 ?H3 H0〜S〜^Yn、ch: 〇 式11, f 0 〇 式12, 0、 o o 式13, HO八 〇
NH 2 式14, 120871.doc 1360535
式15,
式16,
式17,
式18, 式19, 式20, 120871.doc -12- 1360535
式21,或
式22。 本發明亦提供式2化合物之製備方法, R3
R4 0 式2, 其中: R1係選自由Η、R5及R5C(=0)所組成之群;
R2係選自由S及(0=)S(=0)所組成之群; R3係選自由Η、CH3及CH2CH2C(=0)0R5所組成之群; R4 係選自由 R5、OR5、-NCH2CH2OCH2CH2、N(R5)2、 NH2、NHR5及OH所組成之群; R5係選自由具有一至六個碳之烷基及經取代或未經取代 之苯基所組成之群; 但當 R3為 CH2CH2C(=0)0R5 時,R4為 OR5 ; 包括: (I) 當R1為Η及R2為S時,以如式23所示結構之化合物 120871.doc -13- 1360535 (II) 當R1為R5C(=0)時,該方法包含將如式25所示結構 之化合物進行醋化反應。 較佳地,該反應係於三乙基胺存在下進行。於本發明之 一具體實施例中,上述反應物係溶解於二氣曱烷中。 於本發明之一較佳具體實施例中,當R1為CH3C(=0) 時,該方法包含將如式25所示結構之化合物與乙酸酐反 應;於本發明之另一較佳具體實施例,當R1為C6H5C(=0) 時,該方法包含將如式25所示結構之化合物與苯甲酸醯氯 (benzoyl chloride)反應 ° (III) 當R1為R5時,該方法包含將如式25所示結構之化 合物進行烧基化反應; 於本發明之一較佳具體實施例中,當R1為CH3時,該方 法包含將如式25所示結構之化合物與CH3I反應。 (IV) 當R2為(0=)S(=0)時,該方法包含將如式25所示結 構之化合物進行氧化反應。 較佳地,氧化反應係以過氧化氬或間氣過氧苯甲酸 (meta-chloroperoxybenzoic acid)進行。於本發明之一具體 實施例中,當使用過氧化氫進行氧化時,該氧化反應係於 MnS04 · Η20催化下進行反應。另一方面,該反應物係溶 解於乙腈中;當使用間氯過氧苯甲酸反應時,反應物係溶 解於二氣甲烷中。 (V) 當R1為R5C(=0)及R2為(0=)S(=〇)時,該方法包含 將如式25所示結構之化合物進行如上所述之酯化 及氧化反應。 120871.doc -16- 1360535 (VI) 當R1為R5及R2為(0=)S(=0)時,該方法包含將如式 2 5所示結構之化合物進行如上所述之烧基化及氧 化反應。 (VII) 當R1為Η、R2為S、R3為Η且R4為CH3時,該方法包 含以如式27所示結構之化合物
式27 與如式24所示結構之2-巯乙醇於三乙基胺存在下反 應而得。 本發明又關於一種醫藥組合物,其包含治療有效量之如 上述式1所示結構之化合物。由於本發明化合物具有抑制 一氧化氮合成酶及/或第二型環氧合酶作用之效果,故可 用以治療與誘發型一氧化氮合成酶及/或第二型環氧合酶 作用相關之疾病。由於先前文獻已報導許多疾病的發生與 一氧化氮合成酶及/或第二型環氧合酶之作用相關,如關 節炎(arthritis)(Cuzzocrea等人,Arthritis Rheum. 52:1929-40,2005)、多發性硬化症(multiple sclerosis)(Misko 等 人,J Neuroimmunol. 61:195-204,1995)、發炎性疼痛 (inflammatory pain)(Toriyabe 等人,Anesthesiology 101, 983-990,2004)及脊體損傷(spinal cord injury)(Lopez-Vales等人,Spine. 31:1100-6,2006),因此較佳地,該疾 病係選自由發炎、動脈粥狀硬化、神經病理性疼痛、發炎 性血管内膜增生、關節炎、多發性硬化症、發炎性疼痛及 脊髓損傷所組成之群。於一活體大白鼠動脈硬化模式中, 120871.doc 17 1360535 證實根據本發明之化合物具抗動脈粥狀硬化之作用。於本 " 發明之另—具體實施例中’從椎管(intmheCal)注射可以有 效治療神經病理性疼痛。 纟發明之醫藥組合物可以口服或注射方式給予,較佳 地,其係為針劑之劑型。 • 本發明之另一目的在於提供-種如上述式1所示結構之 &合物於製備藥物之用途’該藥物係用於治療與誘發型一 • 氧化氮合成酶及/或第二型環氧合酶作用相關的疾病。 本發明茲以下列實例+以# ^ _ nD , 』頁例于以進一步說明,唯不僅侷限於此 等實例所揭示之内容。 實例1 :化合物之合成一 在單口圓底瓶中加入2-巯乙醇(1.8〇 g,98%,27 14
• mmole)以及三乙基胺(0·53 mL,3 77 mm〇le),並以22 mL 丙酮溶解之,於0〇C冰浴下攪拌。再將甲基乙烯基酮 (methyl vinyl ketone)(2.31 mL,2714 mm〇le)溶於 4 灿丙 隹酮中,並將其緩緩滴入上述單口圓底瓶中,待全部加完 後,讓整個反應慢慢回升到室溫。反應進行16個小時之 後’直接減壓濃縮,再以矽膠管柱分離(以hexane/Et〇Ac =2 : 1沖提),以得到如式26所示結構之硫醚類化合物 (3.35 g,產率 1〇〇%)。 式26。 式26所示結構之硫醚類化合物:無色油狀,ir (κβγ) 120871.doc -18- 1360535
Vmax 3405,1713,1416,1362,1161,1045, 1010 cm·1; NMR (CDC13, 300 MHz) δΗ 3.73 (2H, dt, J = 5.6, 5.4 Hz), 2.75 (4H, br s), 2.72 (2H, t, J = 5.4 Hz), 2.46 (1H, t, J = 5.6 Hz, OH) 2.17 (3H, s); 13C NMR (CDC13, 75 MHz) Sc 207.0 (qC), 60.6 (CH2), 43.7 (CH2), 35.6 (CH2), 30.2 (CH3), 25.4 (CH2); ESIMS m/z 171 [M + Na]+; HRESIMS m/z 171.0458 [M + Na]+ (計算為 c6H1202SNa,171.0456)。 實例2 :化合物之合成二 取上述實例一所製得的如式26所示結構之硫醚類化合物 (1.00 g,6.76 mmole)以及 MnS04 · H20(23 mg,0.14 mmole)於500 mL單口圓底瓶中,溶於乙腈(156 mL),整個 反應置於室溫下劇烈攪拌之(稱之為A瓶)。另準備一個250 mL·錐形瓶’在〇°C下於錐形瓶内加入預先製備好的碳酸氫 鈉緩衝液(115 mL,0·2 Μ,pH =8.0)以及30%的過氧化氫 水溶液(3.38 mL),攪拌均勻後用滴管吸取此溶液分批慢慢 加入A瓶中,待加完此溶液,經過兩個小時後直接加入乙 酸乙醋/異丙醇(3 : 1)混合溶劑萃取(2〇〇 mL X 6),合併所 有的有機萃取液,經減壓濃縮後,再以矽膠管柱純化 (hexane/EtOAc = 1 : 3 ),最後得到如式3所示結構之化合 物 1.03 g,產率 84%。 式3所示結構之化合物:無色結晶;= 59 - 60。(: ; IR (KBr) vmax 3416, 1715, 1416, 1366, 1311, 1120, 1009 cm'1; H NMR (CDCI3, 300 MHz) <5 H 4.02 (2H, t, J = 5.4 Hz), 3.36 (2H, t, / = 7.3 Hz), 3.21 (2H, t, J = 5.4 Hz), 2.97 (2H, 120871.doc 19 1360535 t, J = 7.3 Hz), 2.20 (3H, s); 13C NMR (CDC13j 75 MHz) 204.9 (qC), 56.0 (CH2), 55.7 (CH2), 48.7 (CH2), 34.9 (CH2), 29.7 (CH3); ESIMS m/z 203 [M + Na] + ; HRESIMS m/z 203.0354 [M + Na]+ (計算為 C6H1204SNa,203.0354)。 實例3 :化合物之合成三 取上述實例一所製得的如式26所示結構之硫醚類化合物 (1.00 g,6.76 mmole)於125 mL單口圓底瓶中並以二氣甲 烷(64 mL)溶解之,並於室溫下攪拌。接著稱取2.92g的間 氯過氧苯曱酸(meta-chloroperoxybenzoic acid,16.90 mmole)分批·慢慢加入上述單口圓底瓶中,待加完後,以 TLC追蹤直至反應物完全耗完為止,再將二氣曱烷抽乾, 接著加入飽和碳酸氫鈉水溶液1〇〇 mL劇烈搖晃後以乙酸乙 酯萃取(100 mL X 10),合併乙酸乙酯萃取液,經減壓濃 縮後’再以石夕膠管柱純化(hexane/EtOAc = 3 : 2至1 : 3 ),最後得到如式3所示結構之化合物1.00 g,產率82%。 實例4 :化合物之合成四 在20 mL樣品瓶中加入如式3所示結構之化合物(20 mg, 0.114 mmole)以及三乙基胺(25 μΙ〇,並以2 mL二氣甲烷溶 解之,於室溫下攪拌。接著加入乙酸酐40 /iL。反應進行 16個小時之後,直接減壓濃縮,再以矽膠管柱分離 (hexane/EtOAc = 2 : 3 ),得到如式4所示結構之化合物 25.0 mg,產率 98%。
式4所示結構之化合物:無色油狀;IR (KBr) vmax 1743, 1720,1366,1317,1234,1125,1070,1036 cm1;NMR 120871.doc -20· 1360535 (CDC13, 300 MHz) 4.52 (2H, t, J = 5.8 Hz), 3.36 (2H, t, J = 7.2 Hz), 3.34 (2H, t, J = 5.8 Hz), 3.03 (2H, t, J = 7.2
Hz), 2.25 (3H, s), 2.11 (3H, s); 13C NMR (CDC13, 75 MHz)
Sc 204.0 (qC), 170.2 (qC), 57.5 (CH2), 52.8 (CH2), 48.5 (CH2), 34.9 (CH2), 29.8 (CH3), 20.7 (CH3); ESIMS m/z 245 [M + Na]+ 0 實例5 :化合物之合成五 在20 mL樣品瓶中加入如式3所示結構之化合物(2〇 mg, 0.114 mmole)以及三乙基胺(25 ,並以2 mL二氯甲烷溶 解之,於室溫下攪拌。接著加入苯曱酸醯氯5〇 ;iL。反應 進行5個小時之後,直接減壓濃縮,再以矽膠管柱分離 (hexane/EtOAc = 5 : 1 ),得到如式5所示結構之化合物 29.8 mg,產率 92%。 如式5所示結構之化合物:無色結晶;mp = 7 9 - 8 0 °C ; IR (KBr) vmax 1714,1710,1315,1276,1133,1119 cm.1; 4 NMR (CDCI3, 300 MHz) 8.04 (2H, d, J = 7.5 Hz), 7.60 (1H, t, J = 7.5 Hz), 7.47 (2H, t, J = 7.5 Hz), 4.78 (2H, t, J =5.7 Hz), 3.48 (2H, t, J = 5.7 Hz), 3.41 (2H, t, J = 7.2 Hz), 3.03 (2H, t, J = 7.2 Hz), 2.21 (3H, s); 13C NMR (CDC13j 75 MHz) 5C 203.8 (qC), 165.8 (qC), 133.5 (CH), 129.6 (CH x 2), 129.0 (qC), 128.6 (CH x 2), 58.0 (CH2), 53.0 (CH2), 48.6 (CH2), 34.9 (CH2), 29.7 (CH3) ; ESIMS m/z 307 [M + Na]+。 實例6:化合物之合成六 120871.doc •21 · 1360535 如實例一及二之製造方法,分別以共軛不飽和物乙基乙 烯基_ (ethyl vinyl ketone)、丙烯酸乙酯、n,N-二曱基丙 稀酿胺(N,N-dimethylacrylamide)、4-丙烯醯嗎啉(4- acryl〇ylmorpholine)以及丙烯醯胺(acrylamide)和 2 酼乙醇 反應,而知到如式6、8、10、12及14所示結構之硫輕類化 合物。其中只有在製備如式14所示之化合物時,由於丙稀 酿胺溶解度不佳,因此需要在混合溶劑系統(曱醇/丙酮= 1 : 1)下進行。這些反應中間產物再以過氧化氫進行氧化 反應’即可分別得到如式7(總產率87%)、9(總產率85%)、 11(總產率87%)、13(總產率83%)及15(總產率75%)所示結 構之化合物。此外如式16所示之化合物乃是丙烯酸乙酯與 2-巯乙醇在完全不使用溶劑的狀態下所產生,在此一反應 條件下除了得到如式16所示之化合物(產率22%)之外,也 同時得到如式8所示結構之化合物(產率45%) »如式17所示 結構之化合物的製備乃是以如式16所示結構之化合物為反 應物經過氧化氫氧化所製備(產率84%)。 如式6所示結構之化合物:無色油狀;ir (KBr) v_ 3418,1714, 1458,1411,1375, 1361,1113, 1046, 1013 cm-1; !H NMR (CDC13, 300 MHz) 3.75 (2H, t, J = 6.2 Hz), 2.70-2.80 (6H, m), 2.48 (2H, q, J = 7.3 Hz), 1.06 (3H, t, J = 7.3 Hz); 13G NMR (CDC13, 75 MHz) Sc 209.9 (qC), 60.6 (CH2), 42.0 (CH2), 35.9 (CH2), 34.8(CH2), 25.3 (CH2), 7.3 (CH3) ; ESIMS m/z 185 [M + Na]+ 〇 如式7所示結構之化合物:無色針狀;mp = 44 _ 45 ας. 120871.doc -22- 1360535 IR (KBr) vmax 3419, 1715,1312,1280,1123 cnT1;巾 NMR (CDC13, 300 MHz) 4.01 (2H, t, J = 5.2 Hz), 3.36 (2H, t, J = 7.3 Hz), 3.19 (2H, t, J = 5.2 Hz), 2.93 (2H, t, J = 7.3 Hz), 2.47 (2H, q, J = 7.3 Hz), 1.01 (3H, t, J = 7.3 Hz); 13C NMR (CDCI3, 75 MHz) Sc 207.6 (qC), 56.0 (CH2), 55.7 (CH2), 48.8 (CH2), 35.8 (CH2), 33.6 (CH2), 7.5 (CH3); ESIMS m/z 217 [M + Na]+。 如式8所示結構之化合物:無色油狀;IR (KBr) vmax 3440, 1732, 1373, 1249, 1185, 1044 cm'1; 'H NMR (CDC13, 300 MHz) 4.16 (2H, q, J = 7.1 Hz), 3.74 (2H, t, J = 6.1 Hz), 2.82 (2H, t, J = ΊΛ Hz), 2.74 (2H, t, J = 6.1 Hz), 2.62
(2H, t, J ^ 7.1 Hz),1.27 (3H, t, J = 7.1 Hz); 13C NMR (CDCI3, 75 MHz) 172.1 (qC), 60.8 (CH2 x 2), 35.1 (CH2), 34.9 (CH2), 26.8 (CH2), 14.2 (CH3) ; ESIMS m/z 201 [M + Na]+。 如式9所示結構之化合物:無色油狀;IR (KBr) vmax 3503, 1732, 1313, 1281, 1120, 1065 cm'1; 'H NMR (CDC13, 300 MHz) δΗ 4.19 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 5.0 Hz), 3.46 (2H, t, 7 = 7.4 Hz), 3.25 (2H, t, J =5.0 Hz), 2.88
(2H, t, J = 7.4 Hz), 1.28 (3H, t, J = 7.1 Hz); 13C NMR (CDCI3, 75 MHz) Sc 170.7 (qC), 61.5 (CH2), 56.2 (CH2), 55.6 (CH2), 49.9 (CH2), 26.8 (CH2), 14.0 (CH3) ; ESIMS w/2 233 [M + Na]+。 如式10所示結構之化合物:無色油狀;IR (KBr) vmax 120871.doc •23- 1360535
3399, 1630, 1500, 1403, 1143, 1048, 1014 cm'1; !Η NMR (CDC13, 300 MHz) δη 3.77 (2H, t, J =5.9 Hz), 3.02 (3H, s), 2.96 (3H,s),2.87 (2H,t,·/ = 7.2 Hz),2.75 (2H,t,=5.9 Hz), 2.62 (2H, t, J = 7.2 Hz); 13C NMR (CDC13, 75 MHz) 8C 171.1 (qC), 60.8 (CH2), 37.0 (CH3), 35.4 (CH3 x 1, CH2 x 1),33.5 (CH2),26.8 (CH2) ; ESIMS m/z 200 [M + Na]+。 如式11所示結構之化合物:無色油狀;IR (KBr) vmax 3371, 1634, 1503, 1405, 1312, 1278, 1119, 1065 cm'1; !H NMR (CDCI3, 300 MHz) δη 4.06 (2H, t, J =5.2 Hz), 3.49 (2H, t, J = 7.2 Hz), 3.25 (2H, t, J =5.2 Hz), 3.03 (3H, s), 2.94 (3H, s), 2.87 (2H, t, J = 7.2 Hz); 13C NMR (CDC13, 75 MHz) 169.4 (qC), 56.2 (CH2), 56.0 (CH2), 50.3 (CH2), 37.1 (CH3), 35.7 (CH3), 25.7 (CH2) ; ESIMS m/z 232 [M + Na]+。 如式12所示結構之化合物:無色油狀;IR (KBr) vmax 3418, 1633, 1463, 1437, 1271, 1248, 1115, 1067, 1028 cm-1; !H NMR (CDCI3, 300 MHz) δ K 3.76 (2H, t, J = 6.0 Hz), 3.69 (4H, m), 3.63 (2H, m), 3.48 (2H, dd, J = 4.5, 4.9 Hz), 2.87 (2H,t,·/ = 7.2 Hz), 2.74 (2H, t, «/ = 6.0 Hz), 2.63 (2H, t, J = 7.2 Hz); 13C NMR (CDC13, 75 MHz) 5C 169.8 (qC), 66.6 (CH2), 66.3 (CH2), 60.8 (CH2), 45.7 (CH2), 41.9 (CH2), 35.2 (CH2), 33.2 (CH2) 26.8 (CH2); ESIMS m/z 242 [M + Na]+ 0 如式1 3所示結構之化合物:無色針狀;mp = 109-110°C ; 120871.doc ·24· 1360535 IR (KBr) vmax 3420,1637,1452, 1311,1275,1117,1067, 1028 cm·1; NMR (CDC13, 300 MHz) δΗ 4.06 (2H, t, J = 5.2 Hz), 3.57-3.67 (6H, m), 3.49 (2H, t, J = 7.2 Hz), 3.47 (2H,m), 3.25 (2H, t,/ = 5.2 Hz), 2.86 (2H,t,J = 7.2 Hz); 13C NMR (CDC13, 75 MHz) δ〇 168.0 (qC), 66.5 (CH2), 66.3 (CH2), 56.2 (CH2), 56.0 (CH2), 50.2 (CH2), 45.7 (CH2), 42.3 (CH2) 25.3 (CH2); ESIMS m/z 274 [M + Na]+ ° 如式14所示結構之化合物:白色粉末;IR (KBr) vmax 3354, 3196, 1661, 1414 cm1; !H NMR (pyridine-d5, 300 MHz) 4.02 (2H, t, J = 6.7 Hz), 3.13 (2H, t, J = 7.2 Hz), 2.93 (2H, t, J = 6.7 Hz), 2.82 (2H, t, J = 7.2 Hz); 13C NMR (pyridine-d5, 75 MHz) Sc 174.3 (qC), 61.7 (CH2), 36.6 (CH2), 35.2 (CH2), 28.1 (CH2) ; ESIMS m/z 172 [M + Na]+。 如式15所示結構之化合物:白色粉末;IR (KBr) vmax 3370, 3200, 1661, 1395 cm1; *H NMR (pyridine-d5, 300 MHz) 4.35 (2H, t, ·/ = 5.6 Hz),4.06 (2H,t,= 7.6 Hz), 3.64 (2H, t,J= 5.6 Hz), 3.25 (2H, t, J = 7.6 Hz); 13C NMR (pyridine-d5, 75 MHz) Sc 174.3 (qC), 61.7 (CH2), 36.6 (CH2), 35.2 (CH2), 28.1 (CH2) ; ESIMS m/z 204 [M + Na]+。 如式16所示結構之化合物:無色油狀;IR (KBr) vmax 3438, 1731, 1377, 1299, 1206, 1162, 1043 cm'1; ]H NMR (CDCI3, 300 MHz) Su 4.10 (2H, q, J ^ 7.0 Hz), 4.05 (2H, q, 120871.doc -25- 1360535 載之方式,於雄性Wistar大白老鼠枕骨大孔附近打開硬腦 膜後,植入長8.5公分之PE管(外徑0.014英吋,内徑0.008 英吋),藥物作用部位為脊髓腰薦(lumbar)附近,而注射藥 物端則固定在頭部。手術後出現運動功能不全或椎管内有 金液之動物捨去不用。 神經病理性疼痛動物模式
仿自於1988年Bennett及Xie(Pain 33:87-107)所建立之坐 骨神經慢性壓迫(sciatic nerve chronic constriction injury ; CCI)誘發神經病理性疼痛模式,使用4-0羊腸線於大白老 鼠坐骨神經上綁四個結,一週後即可順利誘發對溫度之疼 痛過敏(thermal hyperalgesia)行為。溫度疼痛過敏行為分 析仿Hargreaves等人於1988年(Pain 32:77-88)所建立方式, 並利用腳掌疼痛刺激記錄儀(analgesiometer ; IITC Inc., Woodland Hills,CA,USA),評估如式3所示結構之化合 物對於神經病理性疼痛之止痛作用。
每一隻實驗動物之數據以最大影響作用(maximum percent effect,MPE)呈現,並進行統計分析。 MPE (%)= 給藥後反應時間-基礎反應時間 30秒-基礎反應時間 xl 00% MPE值越大代表止痛效用越好,但最大值為1〇〇。 大白鼠動脈粥狀硬化模式 完全仿自 Berger 等人(Atherosclerosis 175:229-234, 2004)及 Chen 等人(Naunyn Schmiedebergs Arch Pharmacol 120871.doc -29- 1360535 368.127-133 ’ 2003)文獻’實驗動物以2 5%活寧 (isoflurane,空氣和氧氧以1:1混合),利用2F氣球擴張導 管。首先將導管預先以沙林溶液注滿,再把導管由右側頸 部之外頸動脈(external carotid artery)進入右側頸總動脈 (nght common carotid artery),進入右側頸總動脈約15公 分後,隨即將氣球脹起並來回三次磨擦,再把導管抽出, 並迅速把外頸動脈結紮並傷口縫合。三週後隸動物,取 下左右兩侧頸總動脈,並利用4%多聚甲醛 (Paraf〇rmaldehyde)固定一天後,進行組織切片(3 m)及病 理染色(Η & E),最後以光學顯微鏡觀察並照相,計算血 管内媒增生之厚度。每—隻老鼠之右侧定為實驗組,對側 (即左側)為控制組。 治療組在手術後第十天開始給藥則為實驗初步結果發 現’給予藥物每一天一針具有明顯改善血管内壁增生之作 用。 抗動脈粥狀硬化之作用結果示於圖2,利用氣球擴張手 術(balloon induced angioplasty)誘發大白鼠動脈粥狀硬 化,在手術完第二十四天,從頸動脈病理切片可以發現其 頸動脈血管壁增厚。式3所示結構之化合物治療组從手術 完成後第十天至第二十四天,每天皮下注射給予3叫心 後可改善因氣球擴張手術所誘發之血管内膜增生之現象。 利用血管内膜/血管中層數值化分析後發現,式3所示結構 之化合物具顯著改善動脈粥狀硬化之作用。 神經病理性疼痛之鎮痛作用之結果示於圖3。大白老鼠 120871.doc •30- 1360535 坐骨神經破壞後第七天開始會產生溫度異常過敏之神經病 理性之疼痛行為(thermal hyperalgesia),腳掌反廡時門 (paw withdrawal latency)從30秒降至14秒左右,從椎技 (intrathecal)注射式3所不結構之化合物〇.1、〇.5、1或$ 8 皆具有顯著抑制溫度疼痛過敏行為,利用最大影響作用 (MPE)計算後,其百分之五十有效止痛劑量(ED50)為〇 ?5 士 0 05 g 〇 統計分析方法: 所有數據都以平均值±標準偏差S.E.M.呈現。數據資料 以單向ANOVA分析後再以Dunnett's test比較差異,p<〇 〇5 表示具有統af上之差異。在離體抗發炎活性方面,以單獨 給予LPS組當作1 〇〇%。而在動物實驗方面,每組重覆四至 八次。 上述實施例僅為說明本發明之原理及其功效,而非限制 本發明。習於此技術之人士對上述實施例所做之修改及變 化仍不違背本發明之精神。本發明之權利範圍應如後述之 申請專利範圍所列。 【圖式簡單說明】 圖1為不同濃度如式3所示結構之化合物對Lps刺激巨噬 細胞表現發炎性蛋白質誘發型一氧化碳合成酶及第二型環 氧合酶之影響。A為西方墨點法之結果。B為不同濃度如 式3所示結構之化合物對誘發型一氧化碳合成酶表現影響 之統計分析結果。C為不同濃度如式3所示結構之化合物對 第一型%氧合酶蛋白質表現影響之統計分析結果。每組重 120871.doc 31 1360535 覆6次。 圖2為如式3所示結構之化合物對於氣球擴張誘發頸動脈 内膜增生之作用。A為控制組,B為受損組,c為如式3所 示結構之化合物治療組;DEF分別為aBC圖的放大。〇為 利用血管内膜/血管中層數值化分析之統計結果。 圖3為如式3所示結構之化合物對坐骨神經慢性壓迫誘發 神經病理性疼痛之止痛作用。A為椎管注射不同劑量之如 φ 式3所示結構之化合物對於腳掌反應時間之作用,給予如 式3所示結構之化合物後可以延長因坐骨神經慢性壓迫所 誘發之溫度疼痛過敏之作用B為椎管注射如式3所示結構 之化合物後產生最大影響作用數值(MPEo/o)。C為以最大影 響作用數值計算如式3所示結構之化合物之劑量效應曲線 (dose-response curve)及其百分之五十止痛劑量。每點樣品 數至少6。
120871.doc -32-
Claims (1)
1360535 100. Η. 18. 十、申請專利範圍: 1 一種具有式1結構之化合物
R1係選自由Η、R5及R5C(=0)所組成之群;
式1, R2係選自由S及(0 = )S(=0)所組成之群; R3係選自由Η、CH3及CH2CH2C( = 〇)〇r5所組成之群. R4 係選自由 R5、OR5、-NCH2CH2〇CH2CH2、N(R5)2、 NH2、NHR5及OH所組成之群; R5係選自由具有一至六個碳之烷基及苯基所組成之群; 但當 R3 為 CH2CH2C(=0)0R5 時,R4 為 〇r5 ;及 R1為Η、R2為S及R3為Η時,R4不為CH3 ; 且該化合物具有選自由式3、4、5、7、8、9、11、12、 1 3、16、17、18、19、21及22組成之群之化學結構式:
Ο 式3 式4 式5 式7 120871-1001118 1360535
120871-1001118 ·1· 1360535
式21
式22。 _種製造具有式2結構之化合物之方法 R3
其中: R1係選自由Η、R5及R5C(=0)所組成之群;
R係選自由S及(0=)S(=0)所組成之群; R3係選自由H、CH3及CH2CH2C(=〇)〇R、組成 < 群; R4係選自由 R5、OR5、十 CH2CH2〇CH2CH2、NiR5、,、 NH2、NHR5及OH所組成之群; R係選自由具有一至六個碳之烷基及經取代或未經取代 之苯環所組成之群; 但當 R3 為 CH2CH2C(=0)0R5 時,R4 為 OR5 ; 且該化合物具有選自由式3、4、5、7、8、9、11、12、 13、16、17、18' 19、21及22組成之群之化學結構式: 120871-1001118 1360535
12087M001118 -4- 1360535
HO〜s、>Y〇〜/ 〇 式16
〇
式17 式18 式19 式21 式22 該方法包含: (I) 當R1為Η及R2為S時,該方法包含以如式2 3所示結 構之化合物 120871-1001118 ο R3 R4 式23 '、如式24所示結構之2-疏乙醇(2-mercaptoethanol) 式24 反應’以得到如式2 5所示結構之化合物 R3 HO ,R4 ° 式 25 ; (II) 當Rl為r5c(=〇)時,將如式25所示結構 之化合物進 行酯化反應; (III) 當R1為R5時,將如式25所示結構之化合物進行烷 基化反應; (IV) 當R2為(〇=)s(=〇)時,將如式25所示結構之化合物 進行氧化反應; (V) 當R1為代(喝及R、(0=)s(=0)時,將如式25所 不結構之化合物進行酯化及氧化反應; (VD當R1為RjR、(0 = )s㈣時,將如式25所示結構 之化合物進行烷基化及氧化反應;及 (VII)當R丨為Η、R2為s、R3為j^r4為Ch3時以如式 所示結構之化合物 Ο
式27 120871-1001Π8 與如式24所示結構之2-酼乙醇於三乙基胺存在下反 應而得。 3.根據請求項2之方法,其中r3為H。 4·根據凊求項2之方法,其中如式23所示結構之化合物與 如式24所不結構之化合物係於三乙基胺存在下進行。 根據請求項2之方法,其中如式23所示結構之化合物與 如式24所示結構之化合物係溶解於丙酮中。 6. 根據凊求項2之方法,其中當R3為CH2CH2C卜⑺〇r5時, 如式23所示結構之化合物與如式24所示結構之化合物反 應係於不使用溶劑之狀態下進行。 7. 根據請求項2之方法,其中酯化反應係於三乙基胺存在 下進行。 8 ·根據凊求項2之方法,其中酯化反應之反應物係溶解於 二氣甲烷中。 9. 根據請求項2之方法,其中當RlgCH3C(=〇)時該酯化 反應包含將如式25所示結構之化合物與乙酸酐反應。 10. 根據請求項2之方法,其中當111為(:6115(::(=〇)時,該酯化 反應包含將如式25所示結構之化合物與苯甲酸醯氣 (benzoyl Chl0ride)反應。 11. 根據請求項2之方法,其中當R1為CH3時,該烷基化反應 包含將如式25所示結構之化合物與CH3I反應。 12. 根據請求項2之方法’其中該氧化反應係以過氧化氫進 行。 13. 根據請求項12之方法’其中該氧化反應係於MnS〇4 · 120871-1001118 14 H2〇催化下進行。 根據請求項丨2之方法,其中該氧化反應之反應物係溶解 於乙腈中。 15. 16. 17. 根據請求項12之方法’其中該氧化反應係以間氣過氧苯 甲酸(meta-chloroperoxybenzoic acid)進行。 根據請求項1 5之方法,其中該氧化反應之反應物係溶解 於二氯甲烷中。 一種醫藥组合物’其係用以治療與誘發型一氧化氮合成 酶及/或第二型環氧合酶作用相關之疾病,其中該疾病係 選自由發炎、動脈粥狀硬化、神經病理性疼痛、發炎性 血官内膜增生、關節炎、多發性硬化症、發炎性疼痛及 脊髓損傷所組成之群,其包含具有式1結構之化合物, R3 ° 式1, R1係選自由Η、R5及R5C(=0)所組成之群; R2係選自由S及(0=)S(=0)所組成之群; R3係選自由Η、CH3及CH2CH2C( = 〇)〇R5所組成之群; R4 係選自由 R5、OR5、-NCH2CH2〇CH2CH2、N(R5)2、 NH2、NHR5及OH所組成之群; R5係選自由具有一至六個碳之烷基及苯基所組成之群; 但當 R3 為 ch2ch2c(=o)or5 時,R44〇R5 ;及 R1為Η、R2為S及R3為Η時,R4不為CH3。 120871-1001118 1360535 18. 根據請求項17之醫藥組合物,其中R5係選自由甲基、乙 基及未經取代之苯基所組成之群。 19. 根據請求項17之醫藥組合物,其具有如式3所示的化學 結構式: 0、/0 HCT 0 式3 20.根據請求項17之醫藥組合物,其具有如式4所示的化學 結構式: Λ 0 式4。 21.根據請求項17之醫藥組合物,其具有如式5所示的化學 結構式: Ο
σ 0 式5。 22 .根據請求項1 7之醫藥組合物,其具有如式6所示的化學 結構式: 〇 式6。 23 .根據請求項1 7之醫藥組合物,其具有如式7所示的化學 結構式: 0…0
0 式7。 24.根據請求項17之醫藥組合物,其具有如式8所示的化學 120871-1001118 1360535 結構式: HO〜S^Y〇V Ο 式8。 25.根據請求項1 7之醫藥組合物,其具有如式9所示的化學 結構式:
0 式9。 26.根據請求項17之醫藥組合物,其具有如式10所示的化學 •結構式: ch3 Ο 式 10。 27 .根據請求項1 7之醫藥組合物,其具有如式11所示的化學 結構式: 〇、、々〇 ?Η3 ho^^^s^^^n、ch3 〇 式11。 Φ 28.根據請求項17之醫藥組合物,其具有如式12所示的化學 結構式: r? h〇〜s^^n^ Ο 式 12。 29.根據請求項17之醫藥組合物,其具有如式13所示的化學 結構式·
0 式 13。 120871-1001118 •10- 3 ο.根據請求項]7夕殷^ 唄17之醫樂組合物,其具有如 結構式: 如式W所示的化學 /NH 3 1.根據請求項17之 〇 式14 結構式: 醫藥組合物,其具有如式15所 示的化學
2 NH 3 2.根據請求項丨7之 0 式15 結構式: 醫藥組合物,其具有如式16所 示的化學 0^0' 0 式16。 33.=::求項〗7之醫藥组合物’其具有…所 示的化學
0' 0、 式17 34.根據请求項17之 人 甘乱士 诸樂,,且5物,其具有如式18所示的化 結構式: 學 MeO ο 式18 35.根據。月求項17之醫藥組合物’其具有如式Η所示的化學 120871-1001118 1360535 結構式: ,ΟΗ Ο 3 6.根攄請求 結構式: 、17之醫藥組合物,其具有 式19 如式20所示的化學 ΌΗ 式20 Ο 3 7 _根據請求項]7 +紐—. ’ 17之醫樂組合物,复 結構式: 、有如式2 1所示的化學 HO^N^S' Ί. 0 0、 ,0、 式21 3 8 _根據睛求項1 7 +糾# 谓17之醫藥組合物’ 1 結構式: /…、有如式22所示的化學
39. 酋樂組合物 40. 一種化合物^^ ,、劑i係為針劑。 v <用途,其係用、 氮合成酶及/或笛_ ,、’、以製造治療與誘發型一氧化 ——里環氧合酶作 令該疾病係選έ Λ欠 啤作用相關疾病之藥物,其 由發炎、動脈粥狀硬化、神經病理性疼 12087M00JI]8 •12- 1360535 、多發性硬化症、發 其中該化合物包含具 痛、發炎性血管内膜增生、關節炎 k性疼痛及脊趙損傷所組成之群, 有式1結構之化合物,
式1, R係選自由Η、R5及R5C(=〇)所組成之群· R係選自由s及(o=)s(=o)所組成之群; R3係選自由H、CH3及CH2CH2C(=〇)OR5所組成之群; R4 係選自由 R5、OR5、-NCH2CH2QCH2CH2、N(R5)2、 NH2、NHR5及OH所組成之群; R5係選自由具有一至六個碳之烷基及苯基所組成之群; 但當 R3 為 CH2CH2C(=0)0R5 時,R4 為 OR5 ;及 R1為Η、R2為s及R3為Η時,R4不為CH3。 41·根據請求項4〇之用途,其中R5係選自由甲基、乙基及未 經取代之笨基所組成之群。 42 根據請求項40之用途,其具有如式3所示的化學結構 式:
式3。 43 ·根據請求項40之用途,其具有如式4所示的化學結構 式: 120871-1001118 •13· 1360535 〇 Λ 0、/0 cr ο 式4。 44.根據請求項40之用途,其具有如式5所示 式: 的化學結構 0
〇、,〇 0 式5。 45 .根據請求項40之用途,其具有如式6所示 式: 的化學結構
HO 〇 式6。 46.根據請求項40之用途,其具有如式7所示 式:0、,0 的化學結構
0 式7。 47. 根據請求項40之用途,其具有如式8所示 式: 〇 式8。 48. 根據請求項40之用途,其具有如式9所示 式: 的化學結構 的化學結構 HCT 0 式9。 49.根據請求項40之用途,其具有如式10所示 式: 的化學結構 120871-1001118 •14- 1360535 式 項 求 請 據 根 構 結 學 化 的 示 所 1± 式 如 有 具 其 途 用 之 式: ch3 Ησ -C. O 式 11。 5 1.根據請求項40之用途,其具有如式12所示的化學結構 式: Ό N. ΗΟ 0 式 12。 5 2.根據請求項40之用途,其具有如式13所示的化學結構 式: '0 0…0 .N、 HCT Ο 式 13。 53.根據請求項40之用途,其具有如式14所示的化學結構 式: HO NH 2 0 式 14。 54.根據請求項40之用途,其具有如式15所示的化學結構 式: 〇、wP H0 〜^^NH2 〇 式15。 5 5.根據請求項40之用途,其具有如式16所示的化學結構 120871-1001118 -15· ΎΊΕψ 35 式: HO 式16 的化學結構 56,根據請求項40之用途,其具有如式17所示 式.
式17。 的化學結構 57.根據請求項40之用途,其具有如式18所示 式· | MeO^ V 〇 式18。 58.根據請求項40之用途,其具有如式19所示 式: 0…〇 的化學結構 HCT ΌΗ 〇 式 19。 59.根據請求項40之用途,其具有如式20所示 式: 的化學結構 ΗΟ ΌΗ 〇 式20。 60.根據請求項40之用途,其具有如式21所示 式· 的化學結構 120871-1001118 -16 - 1360535 t
〇 HO^^S
式21。 61.根據請求項40之用途,其具有如式22所示 化學結構 式:
62 _根據請求項40之用途,其中該藥物係為針劑。 120871-1001118 -17-
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW096132313A TWI360535B (en) | 2007-08-30 | 2007-08-30 | Sulfur-containing compound, method of preparation |
US12/172,633 US8399661B2 (en) | 2007-08-30 | 2008-07-14 | Sulfur-containing compound, method of preparation and pharmaceutical uses thereof |
JP2008195689A JP5097043B2 (ja) | 2007-08-30 | 2008-07-30 | イオウ含有化合物、その調製方法および薬学的使用 |
EP08015281.2A EP2030968B1 (en) | 2007-08-30 | 2008-08-29 | Sulfur-containing compound, method of preparation and pharmaceutical uses thereof |
US13/760,517 US8722745B2 (en) | 2007-08-30 | 2013-02-06 | Sulfur-containing compound, method of preparation and pharmaceutical uses thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW096132313A TWI360535B (en) | 2007-08-30 | 2007-08-30 | Sulfur-containing compound, method of preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200909401A TW200909401A (en) | 2009-03-01 |
TWI360535B true TWI360535B (en) | 2012-03-21 |
Family
ID=40094452
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW096132313A TWI360535B (en) | 2007-08-30 | 2007-08-30 | Sulfur-containing compound, method of preparation |
Country Status (4)
Country | Link |
---|---|
US (2) | US8399661B2 (zh) |
EP (1) | EP2030968B1 (zh) |
JP (1) | JP5097043B2 (zh) |
TW (1) | TWI360535B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2951166B1 (fr) * | 2009-10-13 | 2011-12-16 | Centre Nat Rech Scient | Nouveau procede de preparation de polyols par thiolisation et produits tels qu'obtenus |
US9238620B1 (en) | 2014-07-09 | 2016-01-19 | National Sun Yat-Sen University | Pharmaceutical uses of sulfur-containing compound |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2416052A (en) | 1945-03-19 | 1947-02-18 | Du Pont | Stabilized soap |
NL299516A (zh) | 1959-05-02 | |||
US3591610A (en) * | 1964-03-24 | 1971-07-06 | Sumitomo Chemical Co | Anthraquinone dyes |
NL128673C (zh) | 1964-03-24 | |||
BE666830A (zh) | 1964-07-13 | 1965-11-03 | ||
FR2071386A5 (en) | 1969-12-26 | 1971-09-17 | Inst Monomerov Deya | Carboalkoxyalkyl esters of alpa, beta-un- - saturated acids |
US3888912A (en) | 1973-08-20 | 1975-06-10 | Minnesota Mining & Mfg | Process for making beta-acryloyloxypropanoic acid |
JPS511733A (ja) | 1974-06-28 | 1976-01-08 | Toyoda Automatic Loom Works | Kyuchakukanenbosekikino kidohoho |
US4093591A (en) | 1976-11-08 | 1978-06-06 | The Goodyear Tire & Rubber Company | 3,5-Ditertiary alkyl-4-hydroxyphenyl (alkyl) 6-acyloxy-4-thia hexanoates and hexenamides as antioxidants |
JPS5941571B2 (ja) | 1977-01-06 | 1984-10-08 | コニカ株式会社 | ハロゲン化銀写真感光材料 |
US4778869A (en) | 1979-05-29 | 1988-10-18 | American Cyanamid Company | Activated ester monomers and polymers |
CA1135712A (en) | 1979-05-29 | 1982-11-16 | Peter J. Schirmann | Activated ester monomers and polymers |
US4656308A (en) | 1979-05-29 | 1987-04-07 | American Cyanamid Company | Ethers of acrylamidoglycolic acid and esters |
DE3004453A1 (de) | 1980-02-07 | 1981-08-13 | Intensiv-Filter Gmbh & Co Kg, 5620 Velbert | Zwei-stufen-injektor zur abgasreinigung von staubfiltern |
JPS62149666A (ja) | 1985-12-25 | 1987-07-03 | Shionogi & Co Ltd | N−ビニルアゾ−ル類 |
JPH0810324B2 (ja) | 1987-10-06 | 1996-01-31 | コニカ株式会社 | 高感度で漂白脱銀性のよいハロゲン化銀カラー写真感光材料 |
JPH0199039A (ja) | 1987-10-12 | 1989-04-17 | Konica Corp | 粒状性及び感度の優れたハロゲン化銀写真感光材料 |
JPH01102461A (ja) | 1987-10-15 | 1989-04-20 | Konica Corp | ハロゲン化銀カラー写真感光材料 |
JP2511101B2 (ja) | 1988-03-16 | 1996-06-26 | 三共有機合成株式会社 | 塩素含有樹脂の安定化法 |
EP0367577B1 (en) | 1988-10-31 | 1994-01-05 | Japan Synthetic Rubber Co., Ltd. | Novel ester group-containing (meth) acrylic acid ester, novel (co)polymer thereof, composition comprising the (co) polymer and composition comprising the ester group- containing (meth) acrylic acid ester |
JP2546887B2 (ja) | 1989-02-07 | 1996-10-23 | 株式会社トクヤマ | チオカルボン酸エステル化合物及びその製造方法 |
US5214116A (en) | 1989-02-07 | 1993-05-25 | Tokuyama Soda Kabushiki Kaisha | Resin derived from sulfur-containing unsaturated compound and having a high refractive index |
JP2782809B2 (ja) | 1989-07-18 | 1998-08-06 | 三菱化学株式会社 | オキシチタニウムフタロシアニンの製造方法 |
FR2663928B1 (fr) | 1990-06-27 | 1994-04-08 | Norsolor | Nouveaux composes acryliques soufres, un procede pour leur preparation et leur application a la synthese de nouveaux polymeres. |
JPH04221329A (ja) | 1990-12-21 | 1992-08-11 | Kuraray Co Ltd | 縮合環含有化合物の製造方法 |
FR2687400A1 (fr) | 1992-02-17 | 1993-08-20 | Atochem Elf Sa | Nouveaux composes (meth)acryliques, leur procede de preparation et leur application a la synthese de nouveaux polymeres. |
JPH07300451A (ja) | 1994-03-11 | 1995-11-14 | Nippon Shokubai Co Ltd | 新規なスルホン化合物 |
JP2891647B2 (ja) | 1994-03-11 | 1999-05-17 | 株式会社日本触媒 | 有機スルフィド化合物及びその製造方法 |
WO1996022238A1 (en) | 1995-01-19 | 1996-07-25 | Tecnocad S.R.L. | A plant and a process for differentiated refuse collection |
JPH08283234A (ja) | 1995-04-17 | 1996-10-29 | Nippon Shokubai Co Ltd | スルフィド化合物の製造方法 |
US5959147A (en) | 1996-11-07 | 1999-09-28 | Nippon Shokubai Co., Ltd. | Organic sulfide compound and method for production thereof |
JP2002121182A (ja) | 2000-10-13 | 2002-04-23 | Idemitsu Kosan Co Ltd | スルフィド誘導体の製造方法 |
WO2003097047A1 (en) | 2002-05-13 | 2003-11-27 | Eli Lilly And Company | Multicyclic compounds for use as melanin concentrating hormone antagonists in the treatment of obesity and diabetes |
ITBZ20030043A1 (it) | 2003-07-04 | 2005-01-05 | Isola Srl | Impianto di raccolta differenziata ed indifferenziata di rifiuti solidi urbani. |
GB0316294D0 (en) | 2003-07-11 | 2003-08-13 | Polytherics Ltd | Conjugated biological molecules and their preparation |
JP4221329B2 (ja) | 2004-04-28 | 2009-02-12 | パナソニック株式会社 | 半導体記憶装置 |
CN101523109B (zh) | 2006-10-10 | 2013-08-21 | 皇家飞利浦电子股份有限公司 | 薄照明设备、显示设备和发光体设备 |
JP2008195689A (ja) | 2007-02-15 | 2008-08-28 | Sakamoto Yakuhin Kogyo Co Ltd | 化粧料製剤及びそれを配合する化粧料 |
-
2007
- 2007-08-30 TW TW096132313A patent/TWI360535B/zh not_active IP Right Cessation
-
2008
- 2008-07-14 US US12/172,633 patent/US8399661B2/en not_active Expired - Fee Related
- 2008-07-30 JP JP2008195689A patent/JP5097043B2/ja not_active Expired - Fee Related
- 2008-08-29 EP EP08015281.2A patent/EP2030968B1/en not_active Not-in-force
-
2013
- 2013-02-06 US US13/760,517 patent/US8722745B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
US8399661B2 (en) | 2013-03-19 |
US20130172355A1 (en) | 2013-07-04 |
EP2030968A2 (en) | 2009-03-04 |
EP2030968A3 (en) | 2010-01-13 |
US8722745B2 (en) | 2014-05-13 |
JP5097043B2 (ja) | 2012-12-12 |
US20090062285A1 (en) | 2009-03-05 |
EP2030968B1 (en) | 2017-02-22 |
TW200909401A (en) | 2009-03-01 |
JP2009108028A (ja) | 2009-05-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2010248209A (ja) | ニトロソ化およびニトロシル化された非ステロイド抗炎症性化合物、組成物および使用方法 | |
WO2021254470A1 (zh) | 6-氧代-3,6-二氢吡啶类衍生物、其制备方法及其在医药上的应用 | |
US9096494B2 (en) | Arachidonic acid analogs and methods for analgesic treatment using same | |
KR102243637B1 (ko) | 바이사이클릭 진통 화합물 | |
TW200900058A (en) | N-(heteroaryl)-1-heteroaryl-1H-indole-2-carboxamide derivatives, their preparation and their therapeutic application | |
TW200530202A (en) | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes | |
PT1877390E (pt) | Compostos benzisoxazole-piridina e métodos para a sua utilização | |
TW201002317A (en) | Cathepsin C inhibitors | |
JP2010519332A (ja) | 新規ホスホジエステラーゼ阻害剤 | |
JP2010513318A (ja) | ヘテロ環状化合物およびその使用方法 | |
JP2017203046A (ja) | ノルイボガインの硫酸エステル | |
TWI360535B (en) | Sulfur-containing compound, method of preparation | |
US20250042870A1 (en) | Dp antagonist | |
WO2008006276A1 (fr) | INHIBITEUR À PETITE MOLÉCULE POUVANT INHIBER LA FIBROSE DU POLYPEPTIDE Aβ DANS LA MALADIE D'ALZHEIMER, PROCÉDÉS DE PRÉPARATION CORRESPONDANTS, COMPOSITIONS PHARMACEUTIQUES ET UTILISATIONS CORRESPONDANTES | |
KR20080081057A (ko) | 진해제 | |
JP2006501161A (ja) | ニトロソ化および/またはニトロシル化シクロオキシゲナーゼ−2選択的阻害剤、組成物ならびに使用方法 | |
EP3911632A1 (en) | Prodrugs of alox-15 inhibitors and methods of using the same | |
EP4326268A1 (en) | Treatment of cns diseases with sgc stimulators | |
JP6173352B2 (ja) | 筋萎縮性側索硬化症の治療方法 | |
CN103374021B (zh) | 含有锌结合基的吡啶并嘧啶类HDAC和mTOR抑制剂 | |
CN108558760B (zh) | 一类芳香酰胺化合物及其制备方法和用途 | |
TW201136922A (en) | New oxadiazole derivatives | |
CN116891457A (zh) | 一种用于雄激素受体蛋白靶向降解的嵌合体化合物、其制备方法及其在医药上的应用 | |
JP7047954B2 (ja) | フェニル酢酸化合物を含有する医薬組成物 | |
ES2258406A1 (es) | Uso de compuestos heterociclicos como agentes neurogenicos. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |