CN110950786A - 新型cyp-类二十烷酸衍生物 - Google Patents
新型cyp-类二十烷酸衍生物 Download PDFInfo
- Publication number
- CN110950786A CN110950786A CN201911170917.5A CN201911170917A CN110950786A CN 110950786 A CN110950786 A CN 110950786A CN 201911170917 A CN201911170917 A CN 201911170917A CN 110950786 A CN110950786 A CN 110950786A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- compound
- fluorine
- optionally substituted
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 127
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 43
- 201000010099 disease Diseases 0.000 claims abstract description 37
- 235000020660 omega-3 fatty acid Nutrition 0.000 claims abstract description 20
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 claims abstract description 11
- -1 hydroxy, amino Chemical group 0.000 claims description 68
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 49
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 48
- 229910052731 fluorine Inorganic materials 0.000 claims description 44
- 239000011737 fluorine Substances 0.000 claims description 39
- 150000003254 radicals Chemical class 0.000 claims description 35
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
- 125000001153 fluoro group Chemical group F* 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
- 150000001720 carbohydrates Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 150000002016 disaccharides Chemical class 0.000 claims description 5
- 150000002772 monosaccharides Chemical class 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 206010047281 Ventricular arrhythmia Diseases 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 230000008901 benefit Effects 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- WVOXLKUUVCCCSU-ZPFDUUQYSA-N Pro-Glu-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WVOXLKUUVCCCSU-ZPFDUUQYSA-N 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 53
- 238000011282 treatment Methods 0.000 abstract description 24
- 239000002207 metabolite Substances 0.000 abstract description 18
- 206010020772 Hypertension Diseases 0.000 abstract description 17
- 206010003119 arrhythmia Diseases 0.000 abstract description 14
- 230000002265 prevention Effects 0.000 abstract description 13
- 206010061218 Inflammation Diseases 0.000 abstract description 12
- 230000004054 inflammatory process Effects 0.000 abstract description 12
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 abstract description 10
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 abstract description 10
- 206010019280 Heart failures Diseases 0.000 abstract description 8
- 208000034038 Pathologic Neovascularization Diseases 0.000 abstract description 8
- 239000004593 Epoxy Substances 0.000 abstract description 7
- 230000035755 proliferation Effects 0.000 abstract description 7
- 102000004190 Enzymes Human genes 0.000 abstract description 6
- 108090000790 Enzymes Proteins 0.000 abstract description 6
- 230000036737 immune function Effects 0.000 abstract description 6
- 230000015271 coagulation Effects 0.000 abstract description 5
- 238000005345 coagulation Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 74
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 235000019439 ethyl acetate Nutrition 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 29
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 29
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 29
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 29
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 28
- 239000002253 acid Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 206010028980 Neoplasm Diseases 0.000 description 26
- 238000004809 thin layer chromatography Methods 0.000 description 26
- 229910001868 water Inorganic materials 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000009472 formulation Methods 0.000 description 22
- 238000000034 method Methods 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 239000004480 active ingredient Substances 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 18
- ZWCQPOBDHYPODJ-UHFFFAOYSA-N methyl 4-(2,4-dimethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]thiophene-3-carboxylate Chemical compound COC(=O)C1=C(NC(=O)C(F)(F)F)SC=C1C1=CC=C(C)C=C1C ZWCQPOBDHYPODJ-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 229940090949 docosahexaenoic acid Drugs 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 101150051438 CYP gene Proteins 0.000 description 14
- 229940024606 amino acid Drugs 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 12
- 230000004071 biological effect Effects 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000000377 silicon dioxide Substances 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 12
- GPQVVJQEBXAKBJ-JPURVOHMSA-N 17(18)-EpETE Chemical compound CCC1OC1C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O GPQVVJQEBXAKBJ-JPURVOHMSA-N 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 229910052681 coesite Inorganic materials 0.000 description 11
- 229910052906 cristobalite Inorganic materials 0.000 description 11
- 239000003995 emulsifying agent Substances 0.000 description 11
- 239000003755 preservative agent Substances 0.000 description 11
- 229910052682 stishovite Inorganic materials 0.000 description 11
- 229910052905 tridymite Inorganic materials 0.000 description 11
- 150000007513 acids Chemical class 0.000 description 10
- 235000014113 dietary fatty acids Nutrition 0.000 description 10
- 229930195729 fatty acid Natural products 0.000 description 10
- 239000000194 fatty acid Substances 0.000 description 10
- 150000004665 fatty acids Chemical class 0.000 description 10
- 239000007832 Na2SO4 Substances 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 150000002632 lipids Chemical class 0.000 description 9
- 230000004060 metabolic process Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 230000006793 arrhythmia Effects 0.000 description 8
- 230000000747 cardiac effect Effects 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 230000001419 dependent effect Effects 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 208000019622 heart disease Diseases 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- NNDIXBJHNLFJJP-UHFFFAOYSA-N 20-Hydroxyeicosatetraenoic acid Chemical compound OCCCCCC=CCC=CCC=CCC=CCCCC(O)=O NNDIXBJHNLFJJP-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 102000001708 Protein Isoforms Human genes 0.000 description 7
- 108010029485 Protein Isoforms Proteins 0.000 description 7
- 239000000443 aerosol Substances 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 7
- 239000011324 bead Substances 0.000 description 7
- 238000010009 beating Methods 0.000 description 7
- 239000003086 colorant Substances 0.000 description 7
- 239000003974 emollient agent Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- OSXOPUBJJDUAOJ-MBYQGORISA-N (4Z,7Z,10Z,13Z,16Z)-19,20-epoxydocosapentaenoic acid Chemical compound CCC1OC1C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O OSXOPUBJJDUAOJ-MBYQGORISA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 108091006146 Channels Proteins 0.000 description 6
- 239000004909 Moisturizer Substances 0.000 description 6
- GDFAOVXKHJXLEI-VKHMYHEASA-N N-methyl-L-alanine Chemical compound C[NH2+][C@@H](C)C([O-])=O GDFAOVXKHJXLEI-VKHMYHEASA-N 0.000 description 6
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 239000002480 mineral oil Substances 0.000 description 6
- 230000001333 moisturizer Effects 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 6
- 230000000699 topical effect Effects 0.000 description 6
- 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 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 150000008575 L-amino acids Chemical class 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 210000004413 cardiac myocyte Anatomy 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 239000003205 fragrance Substances 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000006210 lotion Substances 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 150000003904 phospholipids Chemical class 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 239000003380 propellant Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000004679 31P NMR spectroscopy Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 208000003174 Brain Neoplasms Diseases 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000003288 anthiarrhythmic effect Effects 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 208000010125 myocardial infarction Diseases 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 206010035653 pneumoconiosis Diseases 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
- 230000004224 protection Effects 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- 206010047302 ventricular tachycardia Diseases 0.000 description 4
- 239000004034 viscosity adjusting agent Substances 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- NIZIYBWWWDZXAX-UHFFFAOYSA-N 15-(oxan-2-yloxy)pentadec-5-yn-1-ol Chemical compound O1C(CCCC1)OCCCCCCCCCC#CCCCCO NIZIYBWWWDZXAX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- 102400000345 Angiotensin-2 Human genes 0.000 description 3
- YZTGUQXJEUGIHB-UHFFFAOYSA-N C(C)(C)(C)[Si](OCCCCC#CCCCCCCCCCOC1OCCCC1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C(C)(C)(C)[Si](OCCCCC#CCCCCCCCCCOC1OCCCC1)(C1=CC=CC=C1)C1=CC=CC=C1 YZTGUQXJEUGIHB-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 208000018652 Closed Head injury Diseases 0.000 description 3
- 229910014572 C—O—P Inorganic materials 0.000 description 3
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 3
- 239000004150 EU approved colour Substances 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 239000004166 Lanolin Substances 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 239000000538 analytical sample Substances 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 150000002066 eicosanoids Chemical class 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 150000002121 epoxyeicosatrienoic acids Chemical class 0.000 description 3
- 230000001815 facial effect Effects 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019388 lanolin Nutrition 0.000 description 3
- 229940039717 lanolin Drugs 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 208000002780 macular degeneration Diseases 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 235000020665 omega-6 fatty acid Nutrition 0.000 description 3
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000002053 thietanyl group Chemical group 0.000 description 3
- 239000012049 topical pharmaceutical composition Substances 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- DXOYQVHGIODESM-KROJNAHFSA-N 11,12-EET Chemical compound CCCCC\C=C/CC1OC1C\C=C/C\C=C/CCCC(O)=O DXOYQVHGIODESM-KROJNAHFSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- UCDFPXDWWGVJLA-UHFFFAOYSA-N 20-hydroxyicosa-2,4,6,8,10-pentaenoic acid Chemical compound OCCCCCCCCCC=CC=CC=CC=CC=CC(O)=O UCDFPXDWWGVJLA-UHFFFAOYSA-N 0.000 description 2
- NHVSXXSWVWZPNQ-UHFFFAOYSA-N 22-hydroxydocosa-2,4,6,8,10,12-hexaenoic acid Chemical compound OCCCCCCCCCC=CC=CC=CC=CC=CC=CC(O)=O NHVSXXSWVWZPNQ-UHFFFAOYSA-N 0.000 description 2
- RMTFNDVZYPHUEF-XZBKPIIZSA-N 3-O-methyl-D-glucose Chemical compound O=C[C@H](O)[C@@H](OC)[C@H](O)[C@H](O)CO RMTFNDVZYPHUEF-XZBKPIIZSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 102000005297 Cytochrome P-450 CYP4A Human genes 0.000 description 2
- 108010081498 Cytochrome P-450 CYP4A Proteins 0.000 description 2
- 102100029363 Cytochrome P450 2C19 Human genes 0.000 description 2
- 102100031461 Cytochrome P450 2J2 Human genes 0.000 description 2
- 102100024901 Cytochrome P450 4F3 Human genes 0.000 description 2
- 102000018832 Cytochromes Human genes 0.000 description 2
- 108010052832 Cytochromes Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 150000008574 D-amino acids Chemical class 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 206010013710 Drug interaction Diseases 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 206010016207 Familial Mediterranean fever Diseases 0.000 description 2
- 208000035690 Familial cold urticaria Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 101000941723 Homo sapiens Cytochrome P450 2J2 Proteins 0.000 description 2
- 101000909121 Homo sapiens Cytochrome P450 4F3 Proteins 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 102000016469 Large-Conductance Calcium-Activated Potassium Channels Human genes 0.000 description 2
- 108010092555 Large-Conductance Calcium-Activated Potassium Channels Proteins 0.000 description 2
- 102100025357 Lipid-phosphate phosphatase Human genes 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 108030006933 Soluble epoxide hydrolases Proteins 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010042600 Supraventricular arrhythmias Diseases 0.000 description 2
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000003293 cardioprotective effect Effects 0.000 description 2
- 230000009084 cardiovascular function Effects 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000002057 chronotropic effect Effects 0.000 description 2
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 108010012052 cytochrome P-450 CYP2C subfamily Proteins 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 210000002253 embryonic cardiomyocyte Anatomy 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 235000021323 fish oil Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 230000000762 glandular Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- GOQJMMHTSOQIEI-UHFFFAOYSA-N hex-5-yn-1-ol Chemical compound OCCCCC#C GOQJMMHTSOQIEI-UHFFFAOYSA-N 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 230000003680 myocardial damage Effects 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 238000002663 nebulization Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 230000008816 organ damage Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 150000002924 oxiranes Chemical class 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Chemical group 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 230000009469 supplementation Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000011824 transgenic rat model Methods 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 230000005747 tumor angiogenesis Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- XWKAVQKJQBISOL-ZETCQYMHSA-N (2s)-2-anilinopropanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=C1 XWKAVQKJQBISOL-ZETCQYMHSA-N 0.000 description 1
- UUDAMDVQRQNNHZ-UHFFFAOYSA-N (S)-AMPA Chemical compound CC=1ONC(=O)C=1CC(N)C(O)=O UUDAMDVQRQNNHZ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- BBOLNFYSRZVALD-UHFFFAOYSA-N 1,2-diiodobenzene Chemical compound IC1=CC=CC=C1I BBOLNFYSRZVALD-UHFFFAOYSA-N 0.000 description 1
- MPCAJMNYNOGXPB-SLPGGIOYSA-N 1,5-anhydro-D-glucitol Chemical compound OC[C@H]1OC[C@H](O)[C@@H](O)[C@@H]1O MPCAJMNYNOGXPB-SLPGGIOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- XFUXZHQUWPFWPR-TWVHMNNTSA-N 19-HETE Chemical compound CC(O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O XFUXZHQUWPFWPR-TWVHMNNTSA-N 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- AMRBZKOCOOPYNY-QXMHVHEDSA-N 2-[dimethyl-[(z)-octadec-9-enyl]azaniumyl]acetate Chemical compound CCCCCCCC\C=C/CCCCCCCC[N+](C)(C)CC([O-])=O AMRBZKOCOOPYNY-QXMHVHEDSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- VMKYTRPNOVFCGZ-UHFFFAOYSA-N 2-sulfanylphenol Chemical compound OC1=CC=CC=C1S VMKYTRPNOVFCGZ-UHFFFAOYSA-N 0.000 description 1
- 125000002281 20-HETE group Chemical group 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-aminobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZXVONLUNISGICL-UHFFFAOYSA-N 4,6-dinitro-o-cresol Chemical compound CC1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1O ZXVONLUNISGICL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 1
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-QYESYBIKSA-N 6-deoxyglucose Chemical compound C[C@@H]1O[C@H](O)[C@@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-QYESYBIKSA-N 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 208000020154 Acnes Diseases 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 208000033116 Asbestos intoxication Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-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
- 208000012657 Atopic disease Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000011594 Autoinflammatory disease Diseases 0.000 description 1
- 101100114750 Bacillus megaterium (strain ATCC 14581 / DSM 32 / JCM 2506 / NBRC 15308 / NCIMB 9376 / NCTC 10342 / NRRL B-14308 / VKM B-512) cyp102A1 gene Proteins 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- AAZHTQCVIOJTCN-UHFFFAOYSA-N C(CCCCCCCCCCCCCCC(C)C)CC(C(=O)O)(C)C.C(C(C)(C)C)(=O)OCCCCCCCCCCCCCCCC(C)C Chemical compound C(CCCCCCCCCCCCCCC(C)C)CC(C(=O)O)(C)C.C(C(C)(C)C)(=O)OCCCCCCCCCCCCCCCC(C)C AAZHTQCVIOJTCN-UHFFFAOYSA-N 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- GNOCKUYGCRRLQP-RUCXOUQFSA-N CN[C@@H](C)C(=O)O.CN[C@@H](C)C(=O)O Chemical compound CN[C@@H](C)C(=O)O.CN[C@@H](C)C(=O)O GNOCKUYGCRRLQP-RUCXOUQFSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010049993 Cardiac death Diseases 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 102000010970 Connexin Human genes 0.000 description 1
- 108050001175 Connexin Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 108010074918 Cytochrome P-450 CYP1A1 Proteins 0.000 description 1
- 108010001202 Cytochrome P-450 CYP2E1 Proteins 0.000 description 1
- 102100031476 Cytochrome P450 1A1 Human genes 0.000 description 1
- 102100024889 Cytochrome P450 2E1 Human genes 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 1
- PNNNRSAQSRJVSB-JGWLITMVSA-N D-quinovose Chemical compound C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-JGWLITMVSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 206010011906 Death Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920000064 Ethyl eicosapentaenoic acid Polymers 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 206010017999 Gastrointestinal pain Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 235000009438 Gossypium Nutrition 0.000 description 1
- 241000219146 Gossypium Species 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 241000208681 Hamamelis virginiana Species 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000013875 Heart injury Diseases 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 101000732617 Homo sapiens Angiotensinogen Proteins 0.000 description 1
- 101000579218 Homo sapiens Renin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 206010021137 Hypovolaemia Diseases 0.000 description 1
- 208000024781 Immune Complex disease Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 102000016924 KATP Channels Human genes 0.000 description 1
- 108010053914 KATP Channels Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000007433 Lymphatic Metastasis Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 206010026673 Malignant Pleural Effusion Diseases 0.000 description 1
- 206010025538 Malignant ascites Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 102000044589 Mitogen-Activated Protein Kinase 1 Human genes 0.000 description 1
- 102000046795 Mitogen-Activated Protein Kinase 3 Human genes 0.000 description 1
- 108700027649 Mitogen-Activated Protein Kinase 3 Proteins 0.000 description 1
- 108700015928 Mitogen-activated protein kinase 13 Proteins 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101100456894 Mus musculus Mettl9 gene Proteins 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- AOMUHOFOVNGZAN-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)dodecanamide Chemical compound CCCCCCCCCCCC(=O)N(CCO)CCO AOMUHOFOVNGZAN-UHFFFAOYSA-N 0.000 description 1
- KDFGDPLUSXZGGS-UHFFFAOYSA-N N.N.N.N.N Chemical compound N.N.N.N.N KDFGDPLUSXZGGS-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- AYRXSINWFIIFAE-UHFFFAOYSA-N O6-alpha-D-Galactopyranosyl-D-galactose Natural products OCC1OC(OCC(O)C(O)C(O)C(O)C=O)C(O)C(O)C1O AYRXSINWFIIFAE-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 208000037062 Polyps Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 229910019020 PtO2 Inorganic materials 0.000 description 1
- 208000006311 Pyoderma Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 208000007135 Retinal Neovascularization Diseases 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- JVWLUVNSQYXYBE-UHFFFAOYSA-N Ribitol Natural products OCC(C)C(O)C(O)CO JVWLUVNSQYXYBE-UHFFFAOYSA-N 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 108010081391 Ristocetin Proteins 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 201000010001 Silicosis Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 241000272534 Struthio camelus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046823 Uterine spasm Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 206010065341 Ventricular tachyarrhythmia Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003082 abrasive agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 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
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000004479 aerosol dispenser Substances 0.000 description 1
- 239000007801 affinity label Substances 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 description 1
- 229960003375 aminomethylbenzoic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 208000010123 anthracosis Diseases 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000002763 arrhythmic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 206010003441 asbestosis Diseases 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000003212 astringent agent Substances 0.000 description 1
- 230000003140 astrocytic effect Effects 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000003943 azolyl group Chemical group 0.000 description 1
- 208000025255 bacterial arthritis Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 201000007983 brain glioma Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 206010061592 cardiac fibrillation Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229940073669 ceteareth 20 Drugs 0.000 description 1
- 229940073642 ceteareth-30 Drugs 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 229940119217 chamomile extract Drugs 0.000 description 1
- 235000020221 chamomile extract Nutrition 0.000 description 1
- BGTFCAQCKWKTRL-YDEUACAXSA-N chembl1095986 Chemical compound C1[C@@H](N)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]([C@H]1C(N[C@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(C(=C(O)C=4)C)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@@H](C(=O)N3)[C@H](O)C=3C=CC(O4)=CC=3)C(=O)N1)C(O)=O)=O)C(C=C1)=CC=C1OC1=C(O[C@@H]3[C@H]([C@H](O)[C@@H](O)[C@H](CO[C@@H]5[C@H]([C@@H](O)[C@H](O)[C@@H](C)O5)O)O3)O[C@@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O[C@@H]3[C@H]([C@H](O)[C@@H](CO)O3)O)C4=CC2=C1 BGTFCAQCKWKTRL-YDEUACAXSA-N 0.000 description 1
- CEZCCHQBSQPRMU-UHFFFAOYSA-L chembl174821 Chemical compound [Na+].[Na+].COC1=CC(S([O-])(=O)=O)=C(C)C=C1N=NC1=C(O)C=CC2=CC(S([O-])(=O)=O)=CC=C12 CEZCCHQBSQPRMU-UHFFFAOYSA-L 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000032459 dedifferentiation Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 208000010227 enterocolitis Diseases 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- ITNKVODZACVXDS-YNUSHXQLSA-N ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate Chemical compound CCOC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC ITNKVODZACVXDS-YNUSHXQLSA-N 0.000 description 1
- DTMGIJFHGGCSLO-FIAQIACWSA-N ethyl (4z,7z,10z,13z,16z,19z)-docosa-4,7,10,13,16,19-hexaenoate;ethyl (5z,8z,11z,14z,17z)-icosa-5,8,11,14,17-pentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC.CCOC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC DTMGIJFHGGCSLO-FIAQIACWSA-N 0.000 description 1
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 208000024695 exercise-induced bronchoconstriction Diseases 0.000 description 1
- 208000024711 extrinsic asthma Diseases 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 210000005002 female reproductive tract Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229960004279 formaldehyde Drugs 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 208000020694 gallbladder disease Diseases 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- DLRVVLDZNNYCBX-CQUJWQHSSA-N gentiobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-CQUJWQHSSA-N 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 208000010758 granulomatous inflammation Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 239000012676 herbal extract Substances 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 208000000069 hyperpigmentation Diseases 0.000 description 1
- 230000003810 hyperpigmentation Effects 0.000 description 1
- 208000024326 hypersensitivity reaction type III disease Diseases 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 208000015210 hypertensive heart disease Diseases 0.000 description 1
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical class CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 201000010659 intrinsic asthma Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 description 1
- 230000037427 ion transport Effects 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 235000020978 long-chain polyunsaturated fatty acids Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000021281 monounsaturated fatty acids Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- BOUCRWJEKAGKKG-UHFFFAOYSA-N n-[3-(diethylaminomethyl)-4-hydroxyphenyl]acetamide Chemical compound CCN(CC)CC1=CC(NC(C)=O)=CC=C1O BOUCRWJEKAGKKG-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000007472 neurodevelopment Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 208000007892 occupational asthma Diseases 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000019809 paraffin wax Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940100460 peg-100 stearate Drugs 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000036515 potency Effects 0.000 description 1
- 230000009862 primary prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical compound OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 description 1
- 229950004257 ristocetin Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002210 silicon-based material Substances 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000000050 smooth muscle relaxant Substances 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000001360 synchronised effect Effects 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
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000002446 thrombocytic effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000029387 trophoblastic neoplasm Diseases 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 208000025883 type III hypersensitivity disease Diseases 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 208000001319 vasomotor rhinitis Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004382 visual function Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/44—Amides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3826—Acyclic unsaturated acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/20—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
- C07C309/21—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
-
- 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
- C07C323/31—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 the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—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 the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the 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
- C07C323/23—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
- C07C323/39—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 at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/41—Y being a hydrogen or an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
- C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
- C07D291/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3882—Arylalkanephosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4015—Esters of acyclic unsaturated acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
本发明新型CYP‑类二十烷酸衍生物,更具体地涉及通式(I)的化合物,其为由ω‑3(n‑3)多不饱和脂肪酸(PUFA)通过细胞色素P450(CYP)酶产生的环氧代谢产物的类似物。本发明还涉及含有一种或多种这些化合物的组合物,以及这些化合物或组合物用于治疗或预防与炎症、增殖、高血压、凝血、免疫功能、病理性血管发生、心力衰竭和心律失常相关的病症或疾病的用途。
Description
本申请是2015年1月21日提交的发明名称为“新型CYP-类二十烷酸衍生物”的中国专利申请201580005451.7的分案申请。
本发明涉及通式(I)的化合物,其为由ω-3(n-3)多不饱和脂肪酸(PUFA)通过细胞色素P450(CYP)酶产生的环氧代谢产物的类似物。本发明还涉及含有这些化合物中的一种或多种的组合物,以及这些化合物或组合物用于治疗或预防与炎症、增殖、高血压、凝血、免疫功能、病理性血管发生、心力衰竭和心律失常相关的病症或疾病的用途。
发明背景
ω-6和ω-3多不饱和脂肪酸(n-6和n-3PUFA)是哺乳动物膳食的重要组分。生物学上最重要的n-3PUFA是二十碳五烯酸(EPA,20:5n-3)和二十二碳六烯酸(DHA,22:6n-3)。膳食n-3PUFA对影响正常健康和慢性疾病的各种生理过程具有作用(综述参见,例如Jump,D.B.(2002)J.Biol.Chem.277,8755-8758),诸如血浆脂质水平的调节(Rambjor,G.S.,Walen,A.I.,Windsor,S.L.和Harris,W.S.(1996)Lipid 31,45-49;Harris,W.S.(1997)Am.J.Clin.Nutr.65,1645-1654;Harris,W.S.,Hustvedt,B-E.,Hagen,E.,Green,M.H.,Lu,G.和Drevon,C.A.(1997)J.Lipid Res.38,503-515;Mori,T.A.,Burke,V.,Puddey,I.B.,Watts,G.F.,O'Neal,D.N.,Best,J.D.和Beilen,L.J.(2000)Am.J.Clin.Nutr.71,1085-1094)、心血管(Nordoy,A.(1999)Lipids 34,19-22;Sellmayer,A.,Hrboticky,N.和Weber,P.C.(1999)Lipids 34,13-18;Leaf,A.(2001)J.Nutr.Health Aging 5,173-178)和免疫功能(Hwang,D.(2000)Annu.Rev.Nutr.20,431-456)、炎症(Calder,P.C.(2012)Mol.Nutr.Food Res.56,1073-1080)、胰岛素作用(Storlien,L.,Hulbert,A.J.和Else,P.L.(1998)Curr.Opin.Clin.Nutr.Metab.Care 1,559-563;Storlien,L.H.,Kriketos,A.D.,Calvert,G.D.,Baur,L.A.和Jenkins,A.B.(1997)Prostaglandins LeukotrienesEssent.Fatty Acids 57,379-385;Oh,D.Y.,Talukadar,S.,Bae,E.J.,Imamura,T.,Morinaga,H.,Fan,W.,Li,P.,Lu,W.J.,Watkins,S.M.,Olefsky,J.M.(2010)Cell 142(5),687-98)以及神经元发育和视觉功能(Salem,N.,Jr.,Litman,B.,Kim,H-Y.和Gawrisch,K.(2001)Lipids 36,945-959)。n-3PUFA的摄入会使得它们几乎分布于身体的每个细胞,并且影响膜组分和功能、类二十烷酸合成和信号转导以及基因表达的调控(Salem,N.,Jr.,Litman,B.,Kim,H-Y.和Gawrisch,K.(2001)Lipids 36,945-959;Jump,D.B.和Clarke,S.D.(1999)Annu.Rev.Nutr.19,63-90;Duplus,E.,Glorian,M.和Forest,C.(2000)275,30749-30752;Dubois,R.N.,Abramson,S.B.,Crofford,L.,Gupta,R.A.,Simon,L.S.,Van DePutte,L.B.A.和Lipsky,P.E.(1998)FASEB J.12,1063-1073)。
流行病学、临床和实验研究表明鱼油n-3PUFA (EPA和DHA)保护免于心血管疾病(Kris-Etherton PM,Harris WS,Appel LJ.Fish consumption,fish oil,omega-3fattyacids,and cardiovascular disease.Circulation 2002;106(21):2747–57)。n-3PUFA降低源自冠心病的死亡率和心脏性猝死的比率(Mozaffarian D.Fish and n-3fatty acidsfor the prevention of fatal coronary heart disease and sudden cardiacdeath.Am J Clin Nutr 2008;87(6):1991S–6S)。针对室性心律失常的保护可能是在心肌梗死后以及在心力衰竭患者中n-3PUFA预防心脏性猝死的主要因素(Leaf A,Kang JX,XiaoYF,Billman GE.Clinical prevention of sudden cardiac death by n-3polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3fish oils.Circulation2003;107(21):2646–52和Marchioli R,Barzi F,Bomba E等人Early protection against sudden death by n-3polyunsaturated fatty acids aftermyocardial infarction:time-course analysis of the results of the GruppoItaliano per lo Studio della Sopravvivenza nell’Infarto Miocardico(GISSI)-Prevenzione.Circulation 2002;105(16):1897–903)。还在心房颤动的人体研究中观察到n-3PUFA的显著的抗心律失常作用(Calo L,Bianconi L,Colivicchi F等人N-3fattyacids for the prevention of atrial fibrillation after coronary artery bypasssurgery:a randomized,controlled trial.J Am Coll Cardiol 2005;45(10):1723–8)。n-3PUFA的可能的心脏益处还延伸至充血性心力衰竭和动脉粥样硬化的预防和治疗以及诸如甘油三酯和促炎细胞因子的高血浆水平的一般风险因子的降低(Lavie CJ,Milani RV,Mehra MR,Ventura HO.Omega-3polyunsaturated fatty acids and cardiovasculardiseases.J Am Coll Cardiol 2009;54(7):585–94)。
此外,流行病学和实验研究表明n-3PUFA消费与黄斑变性的降低的风险以及结肠癌、乳腺癌、前列腺癌和其它癌症的较低的发病率相关(Serini S,Piccioni E,CalvielloG.Dietary n-3PUFA vascular targeting and the prevention of tumor growth andage-related macular degeneration.Curr Med Chem.2009;16(34):4511-26)。针对黄斑变性和癌症的保护的主要常见机制在于n-3PUFA抑制病理性血管发生的能力。EPA和DHA抑制异常视网膜新生血管化、血管通透性和炎症(Connor KM,SanGiovanni JP,Lofqvist C,Aderman CM,Chen J,Higuchi A,Hong S,Pravda EA,Majchrzak S,Carper D,HellstromA,Kang JX,Chew EY,Salem N Jr,Serhan CN,Smith LE.Increased dietary intake ofomega-3-polyunsaturated fatty acids reduces pathological retinalangiogenesis.Nat Med.2007年7月;13(7):868-73)。血管发生是肿瘤生长和转移中的关键步骤,其被n-6PUFA和衍生自n-6PUFA的代谢产物促进,但是被n-3PUFA和衍生自n-3PUFA的代谢产物抑制(Kang JX,Liu A.The role of the tissue omega-6/omega-3fatty acidratio in regulating tumor angiogenesis.Cancer Metastasis Rev.2013年6月;32(1-2):201-10)。
此外,PUFA最重要的生物学作用之一是给可以调节许多功能的生物活性脂肪酸代谢物的产生提供前体(Arm,J.P.和Lee,T.H.(1993)Clin.Sci.84:501-510)。例如,花生四烯酸(AA;20:4,n-6)被细胞色素P450(CYP)酶代谢为具有强力生物学活性的数种类型的氧化代谢物(Roman RJ.P-450metabolites of arachidonic acid in the control ofcardiovascular function.Physiol Rev.2002;82:131-85)。主要的代谢产物包括20-羟基二十碳四烯酸(20-HETE)和一系列的区域和立体异构环氧二十碳三烯酸(EET)。CYP4A和CYP4F亚型产生20-HETE和CYP2C以及CYP2J亚型EET。
已知EPA(20:5,n-3)和DHA (22:6,n-3)可用作AA代谢CYP亚型的替代底物。将AA环氧化为EET的CYP2C和CYP2J亚家族成员将EPA代谢为环氧二十碳四烯酸(EEQ)并将DHA代谢为环氧二十二碳五烯酸(EDP)。将EPA和DHA与AA区分开来的ω-3双键是被大部分环氧化物酶攻击的优选部位,其导致作为主要代谢产物的17,18-EEQ和19,20-EDP的形成。将AA羟基化为20-HETE的CYP4A和CYP4F亚型将EPA代谢为20-羟基二十碳五烯酸(20-HEPE)并将DHA代谢为22-羟基二十二碳六烯酸(22-HDHA)。将AA主要转化为19-HETE的CYP1A1、CYP2E1和其它亚型表现出对EPA和DHA的显著的ω-3环氧化物酶活性(Theuer J,Shagdarsuren E,MullerDN,Kaergel E,Honeck H,Park JK,Fiebeler A,Dechend R,Haller H,Luft FC,SchunckWH.Inducible NOS inhibition,eicosapentaenoic acid supplementation,andangiotensin II-induced renal damage.Kidney Int.2005;67:248-58;Schwarz D,Kisselev P,Ericksen SS,Szklarz GD,Chernogolov A,Honeck H,Schunck WH,RootsI.Arachidonic and eicosapentaenoic acid metabolism by human CYP1A1:highlystereoselective formation of 17(R),18(S)-epoxyeicosatetraenoic acid.BiochemPharmacol.2004;67:1445-57;Schwarz D,Kisselev P,Chernogolov A,Schunck WH,RootsI.Human CYP1A1variants lead to differential eicosapentaenoic acid metabolitepatterns.Biochem Biophys Res Commun.2005;336:779-83;Lauterbach B,Barbosa-Sicard E,Wang MH,Honeck H,Kargel E,Theuer J,Schwartzman ML,Haller H,Luft FC,Gollasch M,Schunck WH.Cytochrome P450-dependent eicosapentaenoic acidmetabolites are novel BK channel activators.Hypertension.2002;39:609-13;Barbosa-Sicard E,Markovic M,Honeck H,Christ B,Muller DN,SchunckWH.Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the CYP2Csubfamily.Biochem Biophys Res Commun.2005;329:1275-81)。CYP依赖性n-3PUFA代谢的显著特征是n-3双键的优选环氧化作用,其将EPA和DHA与AA区分开来。所得代谢物,即来自EPA的17,18-EET和来自DHA的19,20-EDP的独特之处在于没有在AA产物系列范围内的同系物。根据CYP亚型的底物特异性,膳食EPA/DHA补充导致在大鼠也可能在人的所有主要器官和组织中由AA-衍生的向EPA-和DHA-衍生的环氧-和ω-羟基-代谢产物的显著转移(ArnoldC,Markovic M,Blossey K,Wallukat G,Fischer R,Dechend R,Konkel A,von Schacky C,Luft FC,Muller DN,Rothe M,Schunck WH.Arachidonic acid-metabolizing cytochromeP450 enzymes are targets of{omega}-3fatty acids.J Biol Chem.2010年10月22日;285(43):32720-33和Keenan AH,Pedersen TL,Fillaus K,Larson MK,Shearer GC,NewmanJW.Basal omega-3fatty acid status affects fatty acid and oxylipin responsesto high-dose n3-HUFA in healthy volunteers.J Lipid Res.2012年8月;53(8):1662-9)。
EET和20-HETE在调节各种心血管功能中起到重要作用(Roman RJ.P-450metabolites of arachidonic acid in the control of cardiovascularfunction.Physiol Rev.2002;82:131-85)。据证实,Ang II诱导的高血压与CYP依赖性AA代谢的下调有关(Kaergel E,Muller DN,Honeck H,Theuer J,Shagdarsuren E,Mullally A,Luft FC,Schunck WH.P450-dependent arachidonic acid metabolism and angiotensinII-induced renal damage.Hypertension.2002;40:273-9)。在Ang II诱导的高血压和终末器官损伤的双转基因的大鼠(dTGR)模型中(Luft FC,Mervaala E,Muller DN,Gross V,Schmidt F,Park JK,Schmitz C,Lippoldt A,Breu V,Dechend R,Dragun D,Schneider W,Ganten D,Haller H.Hypertension-induced end-organ damage:A new transgenicapproach to an old problem.Hypertension.1999;33:212-8)。转基因大鼠带有人肾素和血管紧张素原基因,局部产生Ang II并发展明显的高血压、心肌梗死和清蛋白尿。动物在80周龄前由于心肌和肾衰竭而死亡。模型表明,产生了Ang II诱导的炎症的严重特征。产生了活性氧类别,活化了转录因子NF-κB和AP-1,并且活化了这些转录因子的基因锚定位点。
最近证实,补充二十碳五烯酸(EPA)显著地降低dTGR的死亡率(Theuer J,Shagdarsuren E,Muller DN,Kaergel E,Honeck H,Park JK,Fiebeler A,Dechend R,Haller H,Luft FC,Schunck WH.Inducible NOS inhibition,eicosapentaenoic acidsupplementation,and angiotensin II-induced renal damage.Kidney Int.2005;67:248-58)。另外,据证实,dTGR基于Ang II诱导的电重构(electrical remodeling)发展了室性心律失常(Fischer R,Dechend R,Gapelyuk A,Shagdarsuren E,Gruner K,Gruner A,Gratze P,Qadri F,Wellner M,Fiebeler A,Dietz R,Luft FC,Muller DN,SchirdewanA.Angiotensin II-induced sudden arrhythmic death and electrical remodeling.AmJ Physiol Heart Circ Physiol.2007;293:H1242-1253)。用PPAR-α激活剂治疗dTGR大鼠强烈地诱导CYP2C23依赖性EET产生并保护免受高血压和终末器官损伤(Muller DN,TheuerJ,Shagdarsuren E,Kaergel E,Honeck H,Park JK,Markovic M,Barbosa-Sicard E,Dechend R,Wellner M,Kirsch T,Fiebeler A,Rothe M,Haller H,Luft FC,Schunck WH.Aperoxisome proliferator-activated receptor-alpha activator induces renalCYP2C23 activity and protects from angiotensin II-induced renal injury.Am JPathol.2004;164:521-32)。
长期用纯EPA-乙酯和DHA-乙酯的混合物饲喂dTGR (从4-7周龄)(Omacor fromSolvay Arzneimittel,Hannover,Germany)改善了这种血管紧张素II-诱导的高血压模型中心脏的电重塑。特别地,EPA和DHA降低了死亡率,抑制了心律失常的诱导性并保护免于连接蛋白43-间隙连接重塑(Fischer R,Dechend R,Qadri F,Markovic M,Feldt S,Herse F,Park JK,Gapelyuk A,Schwarz I,Zacharzowsky UB,Plehm R,Safak E,Heuser A,Schirdewan A,Luft FC,Schunck WH,Muller DN.Dietary n-3polyunsaturated fattyacids and direct renin inhibition improve electrical remodeling in a model ofhigh human renin hypertension.Hypertension.2008年2月;51(2):540-6)。通常,CYP依赖性类二十烷酸被视为第二信使:EET和20-HETE由CYP酶在胞外信号诱导的AA从膜磷脂释放后(通过磷脂酶A2)产生,并在调节离子转运、细胞增殖和炎症的信号转导途径中发挥它们的功能。取决于饮食,n-3PUFA部分地在磷脂的sn2位置代替AA,并可以由此成为牵涉入随后信号转导途径中的替代分子。
对心脏中CYP依赖性类二十烷酸的生物学活性的少数几个研究表明了EET和20-HETE在调节L-型Ca2+和肌浆及线粒体ATP敏感性钾(KATP)通道中的重要作用。在心肌细胞中,L-型Ca2+电流和细胞收缩(cell shorting)在EET产生的抑制时降低,并且这些效果可以通过加入11,12-EET而逆转(Xiao YF,Huang L,Morgan JP.Cytochrome P450:a novelsystem modulating Ca2+channels and contraction in mammalian heart cells.JPhysiol.1998;508(Pt3):777-92)。还已知EET激活心脏KATP通道。这种效果是高度立体选择性的:仅11,12-EET的S,R而非R,S-对映体是有效的(Lu T,VanRollins M,LeeHC.Stereospecific activation of cardiac ATP-sensitive K(+)channels byepoxyeicosatrienoic acids:a structural determinant study.Mol Pharmacol.2002;62:1076-83)。产生EET的人CYP2J2的过量表达通过KATP通道的活化导致转基因小鼠心脏改善的缺血后功能性恢复(Seubert J,Yang B,Bradbury JA,Graves J,Degraff LM,GabelS,Gooch R,Foley J,Newman J,Mao L,Rockman HA,Hammock BD,Murphy E,ZeldinDC.Enhanced postischemic functional recovery in CYP2J2 transgenic heartsinvolves mitochondrial ATP-sensitive K+channels and p42/p44 MAPK pathway.CircRes.2004;95:506-14)。20-HETE看起来通过充当内源KATP通道阻断剂而起到相反作用(Gross ER,Nithipatikom K,Hsu AK,Peart JN,Falck JR,Campbell WB,GrossGJ.Cytochrome P450 omega-hydroxylase inhibition reduces infarct size duringreperfusion via the sarcolemmal KATP channel.J Mol Cell Cardiol.2004;37:1245-9;Nithipatikom K,Gross ER,Endsley MP,Moore JM,Isbell MA,Falck JR,Campbell WB,Gross GJ.Inhibition of cytochrome P450omega-hydroxylase:a novel endogenouscardioprotective pathway.Circ Res.2004;95:e65-71)。
衍生自EPA和DHA的CYP代谢产物的目前已知的生物学活性与它们的衍生自AA的相似物的生物学活性部分相似,部分似乎是独特的,或者甚至可产生相反的效力(WestphalC,Konkel A,Schunck WH.Cyp-eicosanoids--a new link between omega-3fatty acidsand cardiac disease?Prostaglandins Other Lipid Mediat.2011;96:99-108)。所有三种PUFA的环氧代谢产物都有舒血管性质,借此在一些血管床中,EEQ和EDP的效力可超过EET的效力(Lauterbach B,Barbosa-Sicard E,Wang MH,Honeck H,Kargel E,Theuer J,Schwartzman ML,Haller H,Luft FC,Gollasch M,Schunck WH.Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channelactivators.Hypertension.2002;39:609-13)。11,12-和14,15-EET的抗炎效力首先被揭示,但是诸如17,18-EEQ的EPA环氧化物也产生抗炎效力(Morin C,Sirois M,Echave V,Albadine R,Rousseau E.17,18-epoxyeicosatetraenoic acid targets ppargamma andp38 mitogen-activated protein kinase to mediate its anti-inflammatory effectsin the lung:Role of soluble epoxide hydrolase.Am J Respir Cell Mol Biol.2010;43:564-575)。17,18-EEQ和19,20-EDP抑制Ca2+诱导的以及异丙肾上腺素诱导的新生心肌细胞的增加的收缩性,表明这些代谢产物可起如上所述的EPA和DHA的抗心律失常作用的内源性调节剂的作用(Arnold C,Markovic M,Blossey K,Wallukat G,Fischer R,Dechend R,Konkel A,von Schacky C,Luft FC,Muller DN,Rothe M,Schunck WH.Arachidonic acid-metabolizing cytochrome P450enzymes are targets of{omega}-3fatty acids.J BiolChem.2010年10月22日;285(43):32720-33)。近期描述了化学合成的化合物,其具有17,18-EEQ在新生心肌细胞中的抗心律失常性质并在心肌梗死的大鼠模型中减少室性快速型心律失常(Falck JR,Wallukat G,Puli N,Goli M,Arnold C,Konkel A,Rothe M,Fischer R,Müller DN,Schunck WH,17(R),18(S)-epoxyeicosatetraenoic acid,a potenteicosapentaenoic acid(EPA)derived regulator of cardiomyocyte contraction:structure-activity relationships and stable analogues.J Med Chem.2011年6月23日;54(12):4109-18;WO 2010/081683 A1,还公开为美国专利公开2012/0122972,将其以其整体通过援引加入本文,本文中引用的所有其它专利和非专利公开亦如此)。17,18-EEQ和19,20-EDP的形成可额外地有助于n-3PUFA的抗血栓形成效力(Jung F,Schulz C,BlaschkeF,Muller DN,Mrowietz C,Franke RP,Lendlein A,Schunck WH.Effect of cytochromeP450-dependent epoxyeicosanoids on Ristocetin-induced thrombocyteaggregation.Clin Hemorheol Microcirc.2012;52(2-4):403-16)。此外,有证据表明CYP-依赖性环氧代谢产物在介导如上所述的n-6和n-3PUFA在病理性血管发生的过程中的相反效力方面的重要作用。因此,衍生自AA的EET促进肿瘤血管发生和转移(Panigrahy D,EdinML,Lee CR,Huang S,Bielenberg DR,Butterfield CE,Barnes CM,Mammoto A,Mammoto T,Luria A,Benny O,Chaponis DM,Dudley AC,Greene ER,Vergilio JA,Pietramaggiori G,Scherer-Pietramaggiori SS,Short SM,Seth M,Lih FB,Tomer KB,Yang J,SchwendenerRA,Hammock BD,Falck JR,Manthati VL,Ingber DE,Kaipainen A,D'Amore PA,KieranMW,Zeldin DC.Epoxyeicosanoids stimulate multiorgan metastasis and tumordormancy escape in mice.J Clin Invest.2012;122:178-191)。相反,19,20-EDP和其它区域异构DHA-环氧化物抑制这些在致癌作用中的关键事件(Zhang G,Panigrahy D,Mahakian LM,Yang J,Liu JY,Stephen Lee KS,Wettersten HI,Ulu A,Hu X,Tam S,HwangSH,InghamES,Kieran MW,Weiss RH,Ferrara KW,Hammock BD.Epoxy metabolites ofdocosahexaenoic acid(dha)inhibit angiogenesis,tumor growth,andmetastasis.Proc Natl Acad Sci U S A.2013;110:6530-6535)。
尽管衍生自n-3PUFA的CYP代谢产物(诸如17,18-EEQ和19,20-EDP)在介导n-3PUFA在哺乳动物身体中的有益效力方面发挥重要作用,但是由于它们有限的生物利用度以及化学和代谢不稳定性,未将它们用作治疗剂。n-3PUFA的这些环氧代谢产物易于自氧化,通过可溶性环氧化物水解酶快速失活,并通过β-氧化降解。最后,用于治疗或预防与炎症、增殖、病理性血管发生、高血压、凝血、免疫功能、心力衰竭和心律失常有关的病症和疾病的新药剂备受关注,因为这些病症导致相当数目患者的死亡,而且许多目前使用的药物的给药与复杂的药物相互作用和许多不良副作用有关。
因此,本发明所要解决的问题是提供n-3PUFA代谢产物的新类似物,其对通过可溶性环氧化物水解酶的失活更稳定和/或较不易自氧化,并且具有抗炎、抗增殖、抗高血压、抗凝、抗血管发生或免疫调节活性,特别是心脏保护活性,包括针对室性心律失常和心房颤动的保护。
发明概述
本发明涉及通式(I)的化合物:
P-E-I (I)
或其药学上可接受的盐,
其中
P为由通式(II)表示的基团:
–(CH2)n-B-(CH2)k-X (II)
其中
B表示碳-碳键;-O-;或-S-;
n为0或3-8的整数;并且
k为0或1;条件是当n为0时,k为1;
X表示基团:
其中
R和R'各自独立地表示氢原子;或者C1-C6烷基,其可被一个或多个氟原子、氯原子或者羟基取代;
R1表示羟基基团、C1-C6烷氧基、—NHCN、—NH(C1-C6烷基)、—NH(C3-C6环烷基)、—NH(芳基)或—O(C1-C6亚烷基)O(C=O)R11;R11为C1-C6烷基,其任选地被一个或多个氟原子、氯原子取代;或者C3-C6环烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;
R2表示-NHR3;-NR20R21;-OR22;-(OCH2-CH2)i-R23;-Xaao;单糖或二糖或者其衍生物,其经所述糖的1-O-、3-O-或6-O-位通过酯键连接至-C(O);
或者
R2选自:
其中
R3表示(SO2R30);(OR31);-C1-C6亚烷基(SO2R32)或者-C1-C6亚烷基(CO2H);
R30为C1-C6烷基或芳基,其中所述C1-C6烷基任选地被下列取代:-NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,C1-C6烷基羰基氧基-,C1-C6烷氧基羰基氧基-,C1-C6烷基羰基硫基-,C1-C6烷基氨基羰基-,二(C1-C6)烷基氨基羰基-,一个、两个或三个氟原子或氯原子,或者羟基;并且其中所述芳基任选地被独立地选自下列的一个、两个或三个取代基取代:C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、氟原子或氯原子、羟基、氨基、—NH(C1-C6烷基)和—N(C1-C6)二烷基;
R31为C1-C6烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;或者C3-C6环烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;
R32为C1-C6烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;或者C3-C6环烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;
R20和R21各自独立地表示氢原子;C1-C6烷基,其可被一个或多个氟原子、氯原子或者羟基取代;C3-C6环烷基,其可被一个或多个氟原子、氯原子或者羟基取代;或者-C1-C6亚烷基(CO2H);
R22为氢原子、C1-C6烷基;或C3-C6环烷基;其中所述C1-C6烷基或所述C3-C6环烷基任选地被下列取代;-NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,—NH(C1-C6)亚烷基-C1-C6烷氧基,一个、两个或三个氟原子或氯原子,羟基或C1-C6烷氧基;
R23为-OH、-O(C1-C3)烷基或-N(C1-C3)二烷基;i为1-10的整数;
R24、R25和R26各自独立地表示氢原子;—C(=O)C11-C21烷基;或—C(=O)C11-C21烯基;
Xaa表示Gly,常见D,L-氨基酸、D-氨基酸或L-氨基酸,非常见D,L-氨基酸、D-氨基酸或L-氨基酸,或者2-至10-肽;并且通过酰胺键连接至-C(O);o为1-10的整数;
R4表示
h为0、1或2;
R5表示氢原子;氟原子或氯原子;-CF3;-C(=O)OR51;–NHC(=O)R52;-C(=O)NR53R54;或者–S(O2)OH;
R51表示氢原子;C1-C6烷基;或者C3-C6环烷基;其中所述C1-C6烷基或者所述C3-C6环烷基任选地被下列取代:-NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,—NH(C1-C6)亚烷基-C1-C6烷氧基,一个、两个或三个氟原子或氯原子,羟基或C1-C6烷氧基;
R52、R53和R54各自独立地表示C1-C6烷基,其任选地被一个或多个氟原子或氯原子取代;C3-C6环烷基,其任选地被一个或多个氟原子或氯原子取代;或者芳基,其任选地被独立地选自下列的一个、两个或三个取代基取代:C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷硫基、氟原子或氯原子、羟基、氨基、—NH(C1-C6烷基)、—N(C1-C6)二烷基和氧代取代基;
R6和R7各自独立地表示羟基;-O(C1-C6)烷基、-O(C2-C6)烯基、-O(C1-C6)亚烷基O(C=O)(C1-C6)烷基或-O(C1-C6)亚烷基O(C=O)(C2-C6)烯基;其中所述C1-C6烷基和所述C2-C6烯基可被下列取代:NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,C1-C6烷基羰基氧基-,C1-C6烷氧基羰基氧基-,C1-C6烷基羰基硫基-,C1-C6烷基氨基羰基-,二(C1-C6)烷基氨基羰基-,或者一个、两个或三个氟原子或氯原子;或者R6表示羟基并且R7表示基团:
R8和R8’各自独立地表示氢原子;C1-C6烷基;–C(=O)C1-C6烷基;–C(=O)C3-C6环烷基;–C(=O)芳基;或者–C(=O)杂芳基;其中所述C1-C6烷基、所述C3-C6环烷基、所述芳基或者所述杂芳基可被一个、两个或三个选自下列的取代基取代:氟原子或氯原子、羟基、-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、—NH(C1-C6)亚烷基-C1-C6烷氧基和C1-C6烷氧基;
R9表示C1-C6烷基或芳基;其中所述C1-C6烷基任选地被下列取代:-NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,—NH(C1-C6)亚烷基-C1-C6烷氧基,一个、两个或三个氟原子或氯原子,羟基,C1-C6烷氧基,芳基,芳基氧基,—C(═O)-芳基,—C(═O)C1-C6烷氧基;并且其中所述芳基任选地被独立地选自下列的一个、两个或三个取代基取代:C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、氟原子或氯原子、羟基、氨基、—NH(C1-C6烷基)、—N(C1-C6)二烷基和氧代取代基;
g为1或2;
X1表示氧原子;硫原子;或NH;
X2表示氧原子;硫原子;NH;或N(CH3);
X3表示氧原子;硫原子;氮原子;碳原子;或C-OH;并且虚线表示碳-碳键或碳-碳双键;
E为由通式(III)或(IV)表示的基团:
其中
环A表示包含至少一个双键的5-元或6-元碳环或杂环;并且L和T各自独立地表示环原子,其中L和T为彼此相邻的;
R12和R13各自独立地表示氢原子、氟原子、羟基、-NH2,C1-C6烷基、C1-C6烷氧基、—C(═O)-芳基、—C(═O)C1-C6烷基或-SO2(C1-C6烷基);或者-SO2芳基;其中任意前述C1-C6烷基、C1-C6烷氧基或芳基任选地被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;或者R12和R13一起形成5-元或6-元环,所述环任选地被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;
I为–(CH2)m-Y,其中
m为3-6的整数,条件是当E为通式(III)的基团时,m为3-5的整数;
Y表示基团:
其中
R40、R41、R43、R44、R46和R48各自独立地表示氢原子、羟基、-NH2、-C1-C6烷基、-C3-C6环烷基、-C1-C6烷氧基、—C(=O)芳基或—C(=O)C1-C6烷基,其中任意前述C1-C6烷基、C3-C6环烷基、C1-C6烷氧基或芳基任选地被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;或者,R40和R41一起或R43和R44一起形成5-元或6-元环,所述环可被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;
R42、R45和R47各自独立地表示-C1-C6烷基,其中所述C1-C6烷基可被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;或者,R41和R42一起、或R44和R45一起、或R46和R47一起形成5-元或6-元环,所述环可被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;
f为0-6的整数;
条件是:
(i)当n为3时,B为O或S,k为1,E为通式(IV)的基团,并且R12和R13各自为氢原子;或者当n为5、6、7或8时,B和k如上所定义,E为通式(IV)的基团,并且R12和R13各自为氢原子;
P表示基团:
–(CH2)3-O-(CH2)-X81;–(CH2)5-O-(CH2)-X81;–(CH2)3-S–(CH2)-X81;–(CH2)5-S-(CH2)-X81;–(CH2)5-O-X82;–(CH2)7-O-X82;-S-X82;–O-X82;–(CH2)5-X83或–(CH2)7-X83;
其中
X81表示基团:
X82表示基团:
X83表示基团:
R和R'如上所定义;
R1’定义为上文的R1;
R2’表示-NHR3’;-OR22’;-(OCH2-CH2)i-R23;单糖或二糖或者其衍生物,其经所述糖的1-O-、3-O-或6-O-位通过酯键连接至-C(O);或者
R2’选自:
其中
R3’表示(SO2R30);(OR31);-C1-C6亚烷基(SO2R32);或者-C2-C6亚烷基(CO2H);
R22’为C3-C6环烷基,其任选地被下列取代:-NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,—NH(C1-C6)亚烷基-C1-C6烷氧基,一个、两个或三个氟原子或氯原子,羟基或C1-C6烷氧基;
R23和i如上所定义,条件是当i=3时,R23不为–OH;
R24、R25、R26和R27如上所定义;
R4’定义为上文的R4;并且h如上所定义;
R6’和R7’定义为上文的R6和R7;
R8”和R8”定义为上文的R8和R8’;
R9’定义为上文的R9;R9”表示芳基,其任选地被独立地选自下列的一个、两个或三个取代基取代:C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、氟原子或氯原子、羟基、氨基、—NH(C1-C6烷基)、—N(C1-C6)二烷基和氧代取代基;并且
(ii)如下所示的化合物(A)和(B)除外
本文中的化合物通常用标准命名法来描述。对于具有不对称中心的化合物,应当理解,除非另外指明,否则涵盖了所有的旋光异构体及其混合物。具有两个或更多个不对称元素的化合物还可以非对映异构体的混合物的形式存在。另外,具有碳-碳双键的化合物可以以Z-和E-形式存在,除非另外指明,本发明包括所有异构形式的化合物。当化合物以各种互变异构形式存在时,所指的化合物并不限于任一具体的互变异构体,而是意图涵盖所有的互变异构形式。所指的化合物还意图涵盖其中一个或多个原子由同位素代替的化合物,所述同位素即具有相同原子数但不同质量数的原子。作为一般性的实例而非限制,氢的同位素包括氚和氘,碳的同位素包括11C、13C和14C。
具有一个或多个手性中心的本文所提供的式的化合物具有至少50%的对映体过量。例如,这样的化合物的对映体过量可以为至少60%、70%、80%、85%、90%、95%、或98%。化合物的一些实施方案的对映体过量为至少99%。明显的是,单一对映体(旋光体)可以得自不对称合成;合成自光学纯的前体;例如利用修饰的CYP102(CYP BM-3)的生物合成;或者通过外消旋物的拆分,如酶促拆分或在拆分试剂的存在下通过诸如结晶的常规方法进行的拆分;或者例如利用手性HPLC柱的色谱法。
本文中使用包含诸如P、E、I、B、R1-R54、X-X83和Y的变量的通式描述了某些化合物。除非另外指明,此类通式中的各变量独立于任意其他变量,并且在一个通式中出现多次的任何变量在每次出现时独立地定义。因此,例如如果一个基团表示为由0-2个R*取代,则该基团可以为未取代的,或者由高达两个R*基团取代,并且R*在每次出现时都独立地选自R*的定义。此外,取代基和/或变量的组合也是可以的,不过仅在此类组合导致稳定的化合物(即可以被分离、表征并测试生物活性的化合物)时如此。
如本文中所使用,“包含”、“包括”、“含有”、“特征在于”及其语法上的等同是包含性或开放性术语,其不排除另外的未记载的要素或方法步骤。“包含”等应解释为包括更加限制性的术语“由...组成”。
如本文中所使用,“由...组成”排除未在权利要求中说明的任何要素、步骤或成分。
当在本文中使用商品名时,其意在独立地包括所述商品名产品制剂、普通药和所述商品名产品的活性药物成分。
通常,除非另有说明,否则本文使用的科学和技术术语具有与本发明所属领域普通技术人员通常理解相同的含义,并且其与一般教科书和词典一致。
本文公开的化合物的“药学可接受的盐”为酸式或碱式盐,其在本领域通常被视为适合用于与人或动物的组织接触而无过量的毒性或致癌性,并且优选没有刺激、变应应答或其他问题或并发症。这样的盐包括诸如胺的碱性残基的无机和有机酸盐以及诸如羧酸的酸性残基的碱或有机盐。
合适的药学盐包括但不限于例如以下酸的盐:盐酸、磷酸、氢溴酸、苹果酸、乙醇酸、富马酸、硫酸、氨基磺酸、对氨基苯磺酸、甲酸、甲苯磺酸、甲磺酸、苯磺酸、乙二磺酸、2-羟乙基磺酸、硝酸、苯甲酸、2-乙酰氧基苯甲酸、柠檬酸、酒石酸、乳酸、硬脂酸、水杨酸、谷氨酸、抗坏血酸、扑酸、琥珀酸、富马酸、马来酸、丙酸、羟基马来酸、氢碘酸、苯乙酸、链烷酸,如乙酸、HOOC-(CH2)n-COOH,其中n为0-6的任意整数,即0、1、2、3、4、5或6等。类似地,药学可接受的阳离子包括但不限于钠、钾、钙、铝、锂和铵。本领域技术人员应当知道本文提供的化合物的其他药学可接受的盐。通常,药学可接受的酸式或碱式盐可以通过任何常规化学方法合成自含有碱或酸部分的母体化合物。简言之,此类盐可以通过将游离酸或碱形式的这些化合物与化学计算量的合适碱或酸在水或有机溶剂或者在水和有机溶剂的混合物中反应来制备。通常,优选使用非水性的介质,如醚、乙酸乙酯、乙醇、异丙醇或乙腈。
明显的是,式(I)的各化合物可以但不是必须作为水合物、溶剂合物或非共价复合物存在。此外,多种晶体形式和多晶型物在本发明的范围内。
如本文中所用的“取代基”指共价键合至所关注分子中的原子的分子部分。例如,“环取代基”可以是卤素、烷基、卤代烷基或本文所述的其他取代基,其共价键合至环成员的原子,优选碳或氮原子。
如本文所用的术语“取代的”表示指定原子上的任何一个或多个氢由指定取代基的选择代替,条件是指定原子的正常价态未被超过,并且取代导致了稳定的化合物,即可以被分离、表征并测试生物活性的化合物。当取代基为氧代,即=O时,则该原子上的2个氢被代替。为芳香碳原子的取代基的氧代基团导致–CH–转化为–C(=O)–,并丧失芳香性。例如,由氧代取代的吡啶基为吡啶酮。
表述“任选地取代的”是指其中一个、两个、三个或更多个氢原子可能相互独立地被各个取代基代替的基团。
如本文所用的术语“氨基酸”指含有诸如α-、β-或γ-氨基的一个或多个氨基取代基的任何有机酸、脂肪族羧酸的衍生物。在本文中所用的多肽符号中,如Xaa5,如Xaa1Xaa2Xaa3Xaa4Xaa5,其中Xaa1至Xaa5各自且独立地选自限定的氨基酸,根据标准使用和方便,左手方向为氨基末端方向,右手方向为羧基末端方向。
术语“常见氨基酸”指20种天然存在的氨基酸,其选自甘氨酸、亮氨酸、异亮氨酸、缬氨酸、丙氨酸、苯基丙氨酸、酪氨酸、色氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、半胱氨酸、甲硫氨酸、精氨酸、赖氨酸、脯氨酸、丝氨酸、苏氨酸和组氨酸,并且包括其所有立体异构同种型,即D,L-、D-和L-氨基酸。本文的这些常见氨基酸可以通过它们的常见3字母或单字母或者按照以下常规使用的缩写来指代(参见,例如Immunology—A Synthesis,第2版,E.S.Golub和D.R.Gren,Eds.,Sinauer Associates,Sunderland Mass.(1991))。
术语“非常见氨基酸”指非天然氨基酸或化学氨基酸类似物,如α,α-二取代的氨基酸、N-烷基氨基酸、高氨基酸、脱氢氨基酸、芳香氨基酸(除了苯基丙氨酸、酪氨酸和色氨酸)以及邻-、间-或对-氨基苯甲酸。非常见氨基酸还包括在1,3或更大取代模式中具有分离的胺和羧基官能团的化合物,如β-丙氨酸、γ-氨基丁酸、Freidinger内酰胺双环二肽(BTD)氨基-甲基苯甲酸和其他本领域已知的的化合物。还可以使用Statine样等排物、羟基亚乙基等排物、还原的酰胺键等排物、硫代酰胺等排物、脲等排物、氨基甲酸酯等排物、硫醚等排物、乙烯基等排物和其他本领域已知的酰胺键等排物。类似物或非常见氨基酸的使用可以改进加入的肽的稳定性和生物半衰期,因为它们对生理条件下的破坏更具抵抗力。本领域技术人员应当了解可以进行的类似类型的取代。可以用作肽的合适构建块(block)的非常见氨基酸的非限制性列表及它们的标准缩写(括号中)如下:α-氨基丁酸(Abu)、L-N-甲基丙氨酸(Nmala)、α-氨基-α-甲基丁酸酯(Mgabu)、L-N-甲基精氨酸(Nmarg)、氨基环丙烷(Cpro)、L-N-甲基天冬酰胺(Nmasn)、羧基化L-N-甲基天冬氨酸(Nmasp)、氨基异丁酸(Aib)、L-N-甲基半胱氨酸(Nmcys)、氨基降冰片基(Norb)、L-N-甲基谷氨酰胺(Nmgln)、羧基化L-N-甲基谷氨酸(Nmglu)、环己基丙氨酸(Chexa)、L-N-甲基组氨酸(Nmhis)、环戊基丙氨酸(Cpen)、L-N-甲基异亮氨酸(Nmile)、L-N-甲基亮氨酸(Nmleu)、L-N-甲基赖氨酸(Nmlys)、L-N-甲基甲硫氨酸(Nmmet)、L-N-甲基正亮氨酸(Nmnle)、L-N-甲基正缬氨酸(Nmnva)、L-N-甲基鸟氨酸(Nmorn)、L-N-甲基苯基丙氨酸(Nmphe)、L-N-甲基脯氨酸(Nmpro)、L-N-甲基丝氨酸(Nmser)、L-N-甲基苏氨酸(Nmthr)、L-N-甲基色氨酸(Nmtrp)、D-鸟氨酸(Dorn)、L-N-甲基酪氨酸(Nmtyr)、L-N-甲基缬氨酸(Nmval)、L-N-甲基乙基甘氨酸(Nmetg)、L-N-甲基-叔丁基甘氨酸(Nmtbug)、L-正亮氨酸(NIe)、L-正缬氨酸(Nva)、α-甲基-氨基异丁酸酯(Maib)、α-甲基-γ-氨基丁酸酯(Mgabu)、D-α-甲基丙氨酸(Dmala)、α-甲基环己基丙氨酸(Mchexa)、D-α-甲基精氨酸(Dmarg)、α-甲基环戊基丙氨酸(Mcpen)、D-α-甲基天冬酰胺(Dmasn)、α-甲基-α-萘基丙氨酸(Manap)、D-α-甲基天冬氨酸(Dmasp)、α-甲基青霉胺(Mpen)、D-α-甲基半胱氨酸(Dmcys)、N-(4-氨基丁基)甘氨酸(NgIu)、D-α-甲基谷氨酰胺(Dmgln)、N-(2-氨基乙基)甘氨酸(Naeg)、D-α-甲基组氨酸(Dmhis)、N-(3-氨基丙基)甘氨酸(Norn)、D-α-甲基异亮氨酸(Dmile)、N-氨基-α-甲基丁酸酯(Nmaabu)、D-α-甲基亮氨酸(Dmleu)、α-萘基丙氨酸(Anap)、D-α-甲基赖氨酸(Dmlys)、N-benzyl甘氨酸(Nphe)、D-α-甲基甲硫氨酸(Dmmet)、N-(2-氨基甲酰基乙基)甘氨酸(NgIn)、D-α-甲基鸟氨酸(Dmorn)、N-(氨基甲酰基甲基)甘氨酸(Nasn)、D-α-甲基苯基丙氨酸(Dmphe)、N-(2-羧基乙基)甘氨酸(NgIu)、D-α-甲基脯氨酸(Dmpro)、N-(羧基甲基)甘氨酸(Nasp)、D-α-甲基丝氨酸(Dmser)、N-环丁基甘氨酸(Ncbut)、D-α-甲基苏氨酸(Dmthr)、N-环庚基甘氨酸(Nchep)、D-α-甲基色氨酸(Dmtrp)、N-环己基甘氨酸(Nchex)、D-α-甲基酪氨酸(Dmty)、N-环癸基甘氨酸(Ncdec)、D-α-甲基缬氨酸(Dmval)、N-环十二烷基甘氨酸(Ncdod)、D-N-甲基丙氨酸(Dnmala)、N-环辛基甘氨酸(Ncoct)、D-N-甲基精氨酸(Dnmarg)、N-环丙基甘氨酸(Ncpro)、D-N-甲基天冬酰胺(Dnmasn)、N-环十一烷基甘氨酸(Ncund)、D-N-甲基天冬氨酸(Dnmasp)、N-(2,2-二苯基乙基)甘氨酸(Nbhm)、D-N-甲基半胱氨酸(Dnmcys)、N-(3,3-二苯基丙基)甘氨酸(Nbhe)、D-N-甲基谷氨酰胺(Dnmgln)、N-(3-胍基丙基)甘氨酸(Narg)、D-N-甲基谷氨酸(Dnmglu)、N-(1-羟基乙基)甘氨酸(Ntbx)、D-N-甲基组氨酸(Dnmhis)、N-(羟基乙基))甘氨酸(Nser)、D-N-甲基异亮氨酸(Dnmile)、N-(咪唑基乙基))甘氨酸(Nhis)、D-N-甲基亮氨酸(Dnmleu)、N-(3-吲哚基乙基)甘氨酸(Nhtrp)、D-N-甲基赖氨酸(Dnnilys)、N-甲基-γ-氨基丁酸酯(Nmgabu)、N-甲基环己基丙氨酸(Nmchexa)、D-N-甲基甲硫氨酸(Dnmmet)、D-N-甲基鸟氨酸(Dnmorn)、N-甲基环戊基丙氨酸(Nmcpen)、N-甲基甘氨酸(NaIa)、D-N-甲基苯基丙氨酸(Dnmphe)、N-甲基氨基异丁酸酯(Nmaib)、D-N-甲基脯氨酸(Dnmpro)、N-(1-甲基丙基)甘氨酸(Nile)、D-N-甲基丝氨酸(Dnmser)、N-(2-甲基丙基)甘氨酸(Nleu)、D-N-甲基苏氨酸(Dnmthr)、D-N-甲基色氨酸(Dnmtrp)、N-(1-甲基乙基)甘氨酸(Nval)、D-N-甲基酪氨酸(Dnmtyr)、N-甲基a-萘基丙氨酸(Nmanap)、D-N-甲基缬氨酸(Dnmval)、N-甲基青霉胺(Nmpen)、γ-氨基丁酸(Gabu)、N-(p-羟基苯基)甘氨酸(Nhtyr)、L-/-丁基甘氨酸(Tbug)、N-(硫甲基)甘氨酸(Ncys)、L-乙基甘氨酸(Etg)、青霉胺(Pen)、L-高苯基丙氨酸(Hphe)、L-α-甲基丙氨酸(Mala)、L-α-甲基精氨酸(Marg)、L-α-甲基天冬酰胺(Masn)、L-α-甲基天冬氨酸(Masp)、L-α-甲基-叔丁基甘氨酸(Mtbug)、L-α-甲基半胱氨酸(Mcys)、L-甲基乙基甘氨酸(Metg)、L-α-甲基谷氨酰胺(MgIn)、L-α-甲基谷氨酸(MgIu)、L-α-甲基组氨酸(Mhis)、L-α-甲基高苯基丙氨酸(Mhphe)、L-α-甲基异亮氨酸(Mile)、N-(2-甲基硫乙基)甘氨酸(Nmet)、L-α-甲基亮氨酸(Mleu)、L-α-甲基赖氨酸(Mlys)、L-α-甲基甲硫氨酸(Mmet)、L-α-甲基正亮氨酸(MnIe)、L-α-甲基正缬氨酸(Mnva)、L-α-甲基鸟氨酸(Morn)、L-α-甲基苯基丙氨酸(Mphe)、L-α-甲基脯氨酸(Mpro)、L-α-甲基丝氨酸(Mser)、L-α-甲基苏氨酸(Mthr)、L-α-甲基色氨酸(Mtrp)、L-α-甲基酪氨酸(Mtyr)、L-α-甲基缬氨酸(Mval)、L-N-甲基高苯基丙氨酸(Nmhphe)、N-(N-(2,2-二苯基乙基)氨基甲酰基甲基)甘氨酸(Nnbhm)、N-(N-(3,3-二苯基丙基)氨基甲酰基甲基)甘氨酸(Nnbhe)、1-羧基-1-(2,2-二苯基-乙基氨基)环丙烷(Nmbc)、L-O-甲基丝氨酸(Omser)、L-O-甲基高丝氨酸(Omhser)。
表述烷基是指饱和的、直链或支链烃基团,其含有1-20个碳原子、优选1-10个碳原子如正辛基,特别是1-6个碳原子,即1、2、3、4、5或6个碳原子,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基或2,2-二甲基丁基。
表述烯基是指至少部分不饱和的直链或直链烃基团,其含有2-21个碳原子,优选2-6个碳原子,即2、3、4、5或6个碳原子,例如乙烯基、丙烯基(烯丙基)、异丙烯基、丁烯基、乙炔基(ethinyl)、丙炔基、丁炔基、乙炔基(acetylenyl)、炔丙基、异戊二烯基或己-2-烯基,或者含有11-21个碳原子,即11、12、13、14、15、16、17、18、19、20或21个碳原子,例如包含被一个双键间断的亚甲基链的烃基,例如,如在包含被亚甲基间断的多烯的单不饱和脂肪酸或烃基中发现的,例如包含两个或更多个以下结构单元–[CH=CH-CH2]-的烃基,例如,如在多不饱和脂肪酸中发现的。烯基具有一个或多个,优选1、2、3、4、5或6个双键。
表述烷氧基是指单键键合至氧的烷基。
表述烷硫基是指单键键合至硫的烷基。
表述环烷基和碳环是指烃的饱和环状基团,其含有一个或多个环(优选1或2个),并含有3-14个环碳原子,优选3-10个,特别是3、4、5、6或7个环碳原子,例如环丙基、环丁基、环戊基、螺[4,5]癸基、降冰片基、环己基、萘烷基、二环[4.3.0]壬基、四氢萘或环戊基环己基。
表述芳基是指芳香性基团,其含有一个或多个环,所述环含有6-14个环碳原子、优选6-10个、特别是6个环碳原子。
表述杂芳基是指这样的芳香性基团,其包含一个或多个环,所述环含有5-14个环原子、优选5-10个、特别是5或6个环原子,并且含有一个或多个(优选1、2、3或4个)氧、氮、磷或硫环原子(优选O、S或N)。实例为吡啶基(如4-吡啶基)、咪唑基(如2-咪唑基)、苯基吡咯基(如3-苯基吡咯基)、噻唑基、异噻唑基、1,2,3-三唑基、1,2,4-三唑基、噁二唑基、噻二唑基、吲哚基、吲唑基、四唑基、吡嗪基、嘧啶基、哒嗪基、噁唑基、异噁唑基、三唑基、四唑基、异噁唑基、吲唑基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、哒嗪基、喹啉基、异喹啉基、吡咯基、嘌呤基、咔唑基、吖啶基、嘧啶基、2,3′-联呋喃基、吡唑基(如3-吡唑基)和异喹啉基。
表述杂环是指如上文所定义的杂芳基以及如上文所定义的环烷基或碳环,其中一个或多个(优选1、2或3个)环碳原子各自独立地被氧、氮、硅、硒、磷或硫原子(优选被氧、硫或氮原子)代替。杂环优选具有1个或2个环,所述环含有3-10个,特别是3、4、5、6或7个环原子,所述环原子优选选自C、O、N和S。实例为氮丙啶基、环氧乙烷基、硫杂环丙烷基、氧氮杂环丙烷基(oxaziridinyl)、二氧杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、二氮杂环丁烷基、二氧杂环丁烷基、二硫杂环丁烷基、吡咯烷基、四氢呋喃基、硫杂环戊烷基、磷杂环戊烷基(phospholanyl)、硅杂环戊烷基(silolanyl)、azolyl、噻唑基、异噻唑基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、二氧戊环基、二硫戊环基、哌嗪基、吗啉基、硫吗啉基、三噁烷基、氮杂环庚烷基(azepanyl)、氧杂环庚烷基(oxepanyl)、硫杂环庚烷基(thiepanyl)、高哌嗪基或乌洛托品基(urotropinyl)。
除非另外说明,如本文中使用的一般术语环包括环烷基或碳环、杂环、芳基和杂芳基。
如本文中使用的表述“卤代”、“卤素”或“卤素原子”意指氟、氯、溴或碘,优选氟和/或氯。
如本文中使用的表述单糖或二糖及其衍生物意指属于或衍生自单糖或二糖的碳水化合物或糖。
单糖、二糖及衍生物的实例包括葡萄糖、3-O-甲基-葡萄糖、1-脱氧-葡萄糖、6-脱氧-葡萄糖、半乳糖、甘露糖、果糖、木糖、核糖、纤维二糖、麦芽糖、乳糖、龙胆二糖、蔗糖、海藻糖和甘露醇、山梨糖醇和核糖醇。优选地,所述糖为D型糖,例如D-葡萄糖、3-O-甲基-D-葡萄糖、1-脱氧-D-葡萄糖或6-脱氧-D-葡萄糖、D-半乳糖、D-甘露糖。
如本文所用,限定长度范围的界限的表述,如“1至5”表示1至5的任何整数,即1、2、3、4和5。换言之,由两个明确提及的整数所限定的任何范围表示包含并公开了限定该范围的任何整数以及该范围内所包含的任何整数。
根据本发明,所述式(I)的化合物可以是这样的化合物,其中E为由通式(IV)表示的基团;R12和R13之一表示氢原子,并且另一个表示氟原子、羟基、-NH2、C1-C6烷基、C1-C6烷氧基、—C(═O)-芳基、—C(═O)C1-C6烷基或-SO2(C1-C6烷基);或者-SO2芳基;其中任意前述C1-C6烷基、C1-C6烷氧基或芳基任选地被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;或者R12和R13一起形成5-元或6-元环,所述环任选地被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;并且P和I如上所定义。
根据本发明,所述式(I)的化合物也可为这样的化合物,其中E为由通式(IV)表示的基团;R12和R13各自独立地表示氟原子、羟基、-NH2、C1-C6烷基、C1-C6烷氧基、—C(═O)-芳基、—C(═O)C1-C6烷基或-SO2(C1-C6烷基);或者-SO2芳基;其中任意前述C1-C6烷基、C1-C6烷氧基或芳基任选地被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;或者R12和R13一起形成5-元或6-元环,所述环任选地被独立地选自下列的一个、两个或三个取代基取代:-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、C1-C6烷基羰基氧基-、C1-C6烷氧基羰基氧基-、C1-C6烷基羰基硫基-、C1-C6烷基氨基羰基-、二(C1-C6)烷基氨基羰基-、氟原子或氯原子和羟基;并且P和I如上所定义。
优选地,所述式(I)的化合物可为这样的化合物,其中E为由通式(IV)表示的基团;I如上所定义;并且P表示基团:–(CH2)3-O-(CH2)-X81;–(CH2)5-O-(CH2)-X81;–(CH2)3-S–(CH2)-X81;–(CH2)5-S-(CH2)-X81;–(CH2)5-O-X82;–(CH2)7-O-X82;-S-X82;–O-X82;–(CH2)5-X83或–(CH2)7-X83;其中X81、X82和X83如上所定义。
在本发明的化合物中,P可表示基团–(CH2)5-X83或–(CH2)7-X83;其中X83如上所定义。
本发明的化合物可以为这样的化合物,其中X83表示选自下列的基团:
其中R1’、R2’、R6’、R7’、R8”和R8”’如上所定义。
优选地,本发明的化合物可以是这样的化合物,其中R1’为羟基;并且R2’表示-NHR3’表示-NHR3’或者基团
其中
R6’和R7’各自独立地表示羟基;-O(C1-C6)烷基;或者-O(CH2)O(C=O)(C1-C6)烷基;并且
R8”为氢原子;并且R8”’为–C(=O)C1-C6烷基。
所述式(I)的化合物也可为这样的化合物,其中E为由通式(III)表示的基团;并且P和I如上所定义。
所述式(I)的化合物可以为这样的化合物,其中E为由通式(III)表示的基团;L和T各自独立地表示碳、氮或硫原子;L和T中的至少一个表示碳原子;P和I如上所定义。
优选地,L和T各自独立地表示碳或氮原子,其中L和T中的至少一个为碳原子。L和T二者都可表示碳原子。
优选地,所述式(I)的化合物可为这样的化合物,其中E为
P和I如上所定义;优选地,P表示基团–(CH2)6-X、–(CH2)7-X、(CH2)8-X或–(CH2)9-X;更优选地,P表示基团–(CH2)6-X或(CH2)9-X;并且最优选地,P表示基团–(CH2)9-X;其中X如上所定义;更优选地,X为
其中R6和R7如上所定义;更优选地,R6和R7各自独立地表示-O(CH2)O(C=O)(C1-C6)烷基。
在本发明的化合物中,I可以为–(CH2)m-Y,其中m为3;并且Y表示基团:
其中
R40、R41、R43和R44各自表示氢原子;并且R42和R45各自独立地表示-C1-C6烷基。
在本发明的化合物中,其中E为由通式(III)表示的基团;I优选为–(CH2)m-Y;m为4;并且Y表示基团:
其中
R40、R41、R43和R44各自表示氢原子;并且R42和R45各自独立地表示-C1-C6烷基。
在本发明的化合物中,R42可优选为甲基;并且R45可优选为乙基。
在本发明的化合物中,R24、R25和R26可各自独立地表示氢原子;—C(=O)(CH2)10CH3、—C(=O)(CH2)12CH3、—C(=O)(CH2)14CH3、—C(=O)(CH2)16CH3、—C(=O)(CH2)18CH3、—C(=O)(CH2)20CH3;-C(=O)(CH2)7CH=CH(CH2)3CH3、-C(=O)(CH2)7CH=CH(CH2)5CH3、-C(=O)(CH2)4CH=CH(CH2)8CH3、-C(=O)(CH2)7CH=CH(CH2)7CH3、-C(=O)(CH2)9CH=CH(CH2)5CH3、-C(=O)(CH2)11CH=CH(CH2)7CH3、-C(=O)(CH2)7CH=CHCH2CH=CH(CH2)4CH3、-C(=O)(CH2)7(CH=CHCH2)3CH3、-C(=O)(CH2)3(CH=CHCH2)4(CH2)3CH3、-C(=O)(CH2)3(CH=CHCH2)5CH3或-C(=O)(CH2)2(CH=CHCH2)6CH3。优选地,R24、R25和R26可各自独立地表示氢原子;—C(=O)(CH2)10CH3、—C(=O)(CH2)12CH3、—C(=O)(CH2)14CH3、—C(=O)(CH2)16CH3;-C(=O)(CH2)7CH=CH(CH2)5CH3、-C(=O)(CH2)7CH=CH(CH2)7CH3、-C(=O)(CH2)7CH=CHCH2CH=CH(CH2)4CH3、-C(=O)(CH2)7(CH=CHCH2)3CH3、-C(=O)(CH2)3(CH=CHCH2)4(CH2)3CH3、-C(=O)(CH2)3(CH=CHCH2)5CH3或-C(=O)(CH2)2(CH=CHCH2)6CH3。
本发明的化合物可为选自下列的化合物:
特别优选的是以任何可能的方式组合式(I)的单独的一般基团的优选实施方案。
本领域技术人员会认识到,本发明的通式(I)的n-3PUFA类似物中的一些代表由ω-3(n-3)多不饱和脂肪酸(PUFA)通过细胞色素P450(CYP)制备的天然存在的环氧代谢产物的“生物电子等排体”。生物电子等排体是由原子或原子团被其它供选择的、非常相似的原子或原子团交换得到的化合物,从而产生具有与母体化合物相似生物学性质的新化合物。例如,生物等排性已被药物化学家用于改善化合物的期望的生物或物理性质,例如用于减弱毒性、改变活性、改变化合物的药物代谢动力学和/或代谢。例如,在化合物中代谢氧化的位点将氢原子用氟代替可防止这样的代谢发生。因为氟在大小上与氢原子相似,所以分子的总体拓扑学未受到显著影响,使得期望的生物学活性未受影响。然而,在阻断的代谢途径下,所述化合物可具有较长的半衰期。另一实例是羧酸基团的生物等排代替,其得到表现出改善的生物利用度、增强的血脑屏障穿透、提高的活性、更好的化学稳定性和/或对靶点更好的选择性的类似物(参见例如教科书“The practice of medicinal chemistry”,由Camille Georges Wermuth编辑,第3版,Academic Press,2008,例如第303-310页;Ballatore C.等人“Carboxylic Acid(Bio)Isosteres in Drug Design”,ChemMedChem 8,385-395(2013))。此外,生物等排性也可用于提供化合物的“前药”,即最初以非活性(或较低活性)形式向个体或患者给药,然后通过身体的正常代谢处理在体内变成其活性形式的化合物。例如,将化合物与脂质和/或糖单元缀合得到表现出与母体化合物相比提高的药物递送的类似物(前药)(参见例如Wong A.和Toth I."Lipid,Sugar and LiposaccharideBased Delivery Systems",Current Medicinal Chemistry 8,1123-1136(2001))。
可以有机合成领域技术人员公知的多种方法制备本发明的通式(I)的n-3PUFA类似物。例如,可根据如下所示的一般反应路线1-4,使用合成有机化学领域已知的合成方法或者本领域技术人员理解的基于其的变体来合成本发明的化合物。除非另外说明,所有变量(例如n、k、R2(也称作R2)、R6、R7、R8、R41、R42、R44和R45)具有上文限定的含义。标准市售等级的原料试剂可在未进一步纯化下使用,或者可由这样的原料通过常规方法容易地制备。有机合成领域的技术人员会认识到,原料和反应条件可变化,包括为了制备本发明涵盖的化合物而使用的另外的步骤。
反应路线3
反应路线4
反应路线5
可例如根据如下所示的一般反应路线6-10,使用合成有机化学领域已知的合成方法或者本领域技术人员理解的基于其变体来合成上述中间体A1-A5。
反应路线6
反应路线7
反应路线8
反应路线9
反应路线10
本发明的式(I)的化合物优选具有改善的特性,特别是低毒性、低药物药物相互作用、改善的生物利用度,特别是口服给药的生物利用度、改善的代谢稳定性以及改善的溶解性。例如,本文中提供的化合物在Ang II诱导的高血压和终末器官损伤的双转基因大鼠模型中表现出高心脏保护活性。
式(I)的化合物的治疗用途、它们药理学可接受的盐、溶剂合物或水合物以及制剂和药物组合物在本发明的范围内。本发明还涉及式(I)的那些化合物作为活性成分在药物制备中的用途,并且还涉及它们的用途,以及本发明的药物组合物在与炎症、增殖、高血压、凝血、免疫功能、病理性血管发生或心脏病相关的病症和/或疾病的治疗或预防中的用途。
本发明的化合物或药物组合物可被用于心脏病的治疗或预防。所述心脏病可选自心力衰竭、冠状动脉疾病、心肌梗死、急性和慢性炎性心肌损害、适应不良的心脏肥大和心律失常。
优选地,本发明的化合物或药物组合物可被用于心律失常(包括室性心动过速和室上性心律失常)的治疗或预防。更优选地,本发明的化合物或药物组合物可被用于室上性心律失常的治疗或预防,特别是心房颤动的治疗或预防。
本发明的药物组合物包含至少一种式(I)的化合物以及任选存在的一种或多种载体物质,例如环糊精如羟丙基β-环糊精、胶束或脂质体、赋形剂和/或辅助剂。药物组合物还可以包含,例如以下物质的一种或多种:水;缓冲液,如中性缓冲盐水或磷酸缓冲盐水;乙醇;矿物油;植物油;二甲亚砜;碳水化合物,如葡萄糖、甘露糖、蔗糖或葡聚糖;甘露糖醇;蛋白质;辅助剂;多肽或氨基酸,如甘氨酸;抗氧化剂;螯合剂,如EDTA或谷胱甘肽和/或防腐剂。此外,一种或多种其他有效成分可以但不是必须地包含在本文提供的药物组合物中。例如,本发明的化合物可以有利地与以下药物联合使用:抗生素、抗真菌剂或抗病毒剂、抗组胺剂、非甾体抗炎药、缓解疾病的抗风湿药、用于治疗自身免疫病的抗炎药、细胞生长抑制药物、具有平滑肌活性调节活性的药物、抗高血压药、β-阻断剂、抗心律失常药、用于治疗心力衰竭的药物、抗血栓药、抗血小板药或上述药剂的混合物。优选地,本发明涉及组合制剂或药盒,其包含至少一种本发明的化合物和至少一种选自下列的药物:抗高血压药、β-阻断剂、抗心律失常药、用于治疗心力衰竭的药物、抗血栓药、抗血小板药、抗风湿药和/或用于治疗自身免疫病的抗炎药。
药物组合物可以配制为任何合适的给药途径,包括例如体表给药如透皮或眼部、口服、含服、阴道、直肠或胃肠外给药。本文所用的术语胃肠外包括皮下、皮内、血管内如静脉内、肌肉内、脊柱、颅内、鞘内、眼内、眼周、眼眶内、滑膜内核腹膜内注射以及任何类似的注射或输注技术。在某些实施方案中,口服使用形式的组合物是优选的。这样的形式包括例如片剂、糖锭剂(troche)、锭剂、水性或油性混悬剂、分散粉末或颗粒剂、乳剂、硬或软胶囊或者糖浆剂或酏剂。仍然在其他实施方案中,本文提供的组合物可以配制为冻干物。用于体表给药的制剂对于某些疾病状况是优选的,例如皮肤疾病状况的治疗,如灼伤或瘙痒。
口服使用的组合物还可以包含一种或多种组分如甜味剂、增香剂、着色剂和/或防腐剂以提供吸引人和可口的制品。片剂含有与适合于制备片剂的生理可接受的赋形剂混合的有效成分。此类赋形剂包括,例如惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒和崩解剂,如玉米淀粉或藻酸;粘合剂,如淀粉、明胶或阿拉伯胶;以及润滑剂,如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者它们可以通过已知技术包衣以延缓胃肠道中的崩解和吸收并由此提供较长时间段的延长作用。例如,可以使用时间延缓材料,如甘油单硬脂酸酯或甘油二硬脂酸酯。
口服使用的制剂还可以硬明胶胶囊剂的形式提供,其中将活性成分与惰性固体稀释剂如碳酸钙、磷酸钙或白陶土混合;或以软明胶胶囊剂的形式提供,其中将活性成分与水或油介质如花生油、液状石蜡或橄榄油混合。
水性混悬剂含有与适合于制备水性混悬剂的赋形剂混合的有效成分。此类赋形剂包括悬浮剂,如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散或润湿剂,如天然存在的磷脂如卵磷脂;烯化氧与脂肪酸的缩合产物,如聚氧乙烯硬脂酸酯;环氧乙烷与长链脂肪族醇的缩合产物,如十七聚环氧乙烷十六烷醇(heptadecaethyleneoxycetanol);环氧乙烷与衍生自脂肪和己糖醇的偏酯的缩合产物,如聚氧乙烯山梨醇一油酸酯;环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物,如聚乙烯脱水山梨糖醇聚乙烯一油酸酯。水性混悬剂还可以包含一种或多种防腐剂,例如乙基或正丙基对羟基苯甲酸酯,一种或多种着色剂,一种或多种增香剂,以及一种或多种甜味剂如蔗糖或糖精。
油性混悬剂可以通过将有效成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油,或者悬浮于矿物油如液状石蜡中来配制。油性混悬剂可以含有增稠剂,如蜂蜡、硬石蜡或鲸蜡醇。可以添加诸如以上所列的甜味剂和/或增香剂以提供可口的口服制品。此类混悬剂可以通过加入抗氧化剂如抗坏血酸来保存。
适合于制备水性混悬剂的分散粉末和颗粒剂通过加入水来提供与分散或湿润剂、悬浮剂和一种或多种防腐剂混合的有效成分。适合的分散剂或润湿剂和助悬剂的实例为上文提及的那些。还可以存在额外的赋形剂,如甜味剂、调味和着色剂。
药物组合物可以为水包油乳剂的形式。油相可以为植物油,如橄榄油或花生油;矿物油,如液状石蜡;或其混合物。合适的乳化剂包括天然存在的树胶,如阿拉伯树胶或黄芪树胶;天然存在的磷脂,如大豆卵磷脂;和衍生自脂肪酸和己糖醇、酐的酯或偏酯,如脱水山梨糖醇一油酸酯;以及衍生自脂肪酸和己糖醇的偏酯与环氧乙烷的缩合产物,如聚氧乙烯脱水山梨糖醇一油酸酯。乳剂还可以包含一种或多种甜味和/或增香剂。
糖浆剂和酏剂可以用甜味剂如甘油、丙二醇、山梨醇或蔗糖配制。此类制剂还可以包含一种或多种缓和剂(demulcent)、防腐剂、增香剂和/或着色剂。
化合物可以配制为用于局部或体表给药,例如体表施用于皮肤或粘膜,例如眼中。用于体表给药的制剂通常包含与体表媒介物,其与活性物质组合,具有或不具有额外的任选组分。合适的体表媒介物和额外组分是本领域公知的,而且明显的是媒介物的选择取决于递送的特定物理形式和模式。体表媒介物包括水;有机溶剂,例如醇,如乙醇或异丙醇或甘油;二元醇,如丁二醇、异二醇或丙二醇;脂肪族醇,如羊毛脂;水与有机溶剂的混合物和诸如醇和甘油的有机溶剂的混合物;基于脂质的物质,如脂肪酸、酰基甘油,包括油,如矿物油和天然或合成来源的脂肪、磷酸甘油酯、鞘脂和蜡;基于蛋白的物质,如胶原和明胶;基于硅氧烷的物质,非挥发性和挥发性;以及基于烃的物质,如微海绵(microsponge)和聚合物基质。组合物还可以包含一种或多种适合于提高施用的制剂的稳定性或效果的组分,如稳定剂、悬浮剂、乳化剂、粘度调节剂、胶凝剂、防腐剂、抗氧化剂、皮肤穿透增强剂、增湿剂和缓释材料。此类组分的实例描述于Martindale--The Extra Pharmacopoeia(Pharmaceutical Press,London 1993)和Martin(ed.),Remington’s PharmaceuticalSciences。制剂可以包括微囊剂如羟甲基纤维素或明胶-微囊剂、脂质体、白蛋白微球剂、微乳剂、纳米微粒或纳米囊。
体表制剂可以制备为多种物理形式,包括例如固体、糊剂、乳膏剂、泡沫剂、洗剂、凝胶剂、散剂、水性液体、乳剂、喷雾剂、滴眼剂和皮肤贴剂。此类形式的物理外观和粘度可以通过制剂中存在的乳化剂和粘度调节剂的量来控制。固体通常是致密且不可流动的,并且通常配制为条状或棒状;固体可以是不透明或透明的,并且可以任选地含有溶剂、乳化剂、增湿剂、软化剂、芳香剂、染料/色料、防腐剂和增加或增强最终产品的效力的其他有效成分。乳膏剂和洗剂通常互相类似,主要是它们的粘度不同;洗剂和乳膏剂可以是不透明、半透明或澄清的,并且通常含有乳化剂、溶剂和粘度调节剂以及增湿剂、软化剂、芳香剂、染料/色料、防腐剂和增加或增强最终产品的效力的其他有效成分。凝胶可以制备为各种粘度,从粘稠或高粘度至稀薄或低粘度。这些制剂和洗剂及乳膏剂一样,也可以含有溶剂、乳化剂、增湿剂、软化剂、芳香剂、染料/色料、防腐剂和增加或增强最终产品的效力的其他有效成分。液体比乳膏剂、洗剂或凝胶更稀薄,通常不含乳化剂。液体体表产品通常含有溶剂、乳化剂、增湿剂、软化剂、芳香剂、染料/色料、防腐剂和增加或增强最终产品的效力的其他有效成分。
用于体表制剂的合适乳化剂包括但不限于离子型乳化剂、鲸蜡硬脂醇、非离子型乳化如聚氧乙烯油基醚、PEG-40硬脂酸酯、鲸蜡硬脂醇醚-12、鲸蜡硬脂醇醚-20、鲸蜡硬脂醇醚-30、鲸蜡硬脂醇醚醇、PEG-100硬脂酸酯和甘油硬脂酸酯。合适的粘度调节剂包括但不限于保护胶体或非离子型树胶,如羟基乙基纤维素、黄原胶、硅酸镁铝、二氧化硅、微晶蜡、蜂蜡、石蜡和鲸蜡醇棕榈酸酯。凝胶组合物可以通过加入胶凝剂而形成,如壳聚糖、甲基纤维素、乙基纤维素、聚乙烯醇、聚季铵、羟基乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、卡波姆或氨化甘草酸盐。合适的表面活性剂包括但不限于非离子型、两性、离子型和阴离子型表面活性剂。例如聚二甲基硅氧烷共聚醇、聚山梨酯20、聚山梨酯40、聚山梨酯60、聚山梨酯80、月桂酰胺DEA、椰油酰胺DEA和椰油酰胺MEA、油基甜菜碱、亚油酰胺基丙基丙二醇磷脂二甲基氯化铵(cocamidopropyl phosphatidyl PG-dimonium chloride)和月桂醇聚醚硫酸铵中的一种或多种可以用于体表制剂。
合适的防腐剂包括但不限于抗微生物剂,如羟苯甲酯、羟苯丙酯、山梨酸、苯甲酸和甲醛;以及物理稳定剂和抗氧化剂,如维生素E、抗坏血酸钠/抗坏血酸和棓酸丙酯。合适的增湿剂包括但不限于乳酸和其他羟基和它们的盐、甘油、丙二醇和丁二醇。合适的软化剂包括羊毛脂醇、羊毛脂、羊毛脂衍生物、胆固醇、凡士林、异硬脂醇新戊酸酯(isostearylneopentanoate)和矿物油。合适的芳香剂和色料(color)包括但不限于FD&C Red No.40和FD&C Yellow No.5。可以包含于体表制剂中的其他合适的额外成分包括但不限于研磨剂;吸附剂;防结块剂;消泡剂;抗静电剂;收敛药如金缕梅、醇和草药提取物如春黄菊提取物;粘合剂/赋形剂;缓冲剂;螯合剂;成膜剂;调节剂;推进剂;乳浊剂、pH调节剂和防护剂。
用于凝胶制剂的合适体表媒介物的实例为:羟丙基纤维素(2.1%);70/30异丙基醇/水(90.9%);丙二醇(5.1%);和聚山梨酯80(1.9%)。用于泡沫制剂的合适体表媒介物的实例为:鲸蜡醇(1.1%);硬脂醇(0.5%);夸特宁52(1.0%);丙二醇(2.0%);乙醇95PGF3(61.05%);去离子水(30.05%);P75烃推进剂(4.30%)。所有的百分比为重量百分比。
体表组合物的通常递送模式包括利用手指的施用;利用物理施药器(applicator)的施用,如织物、拭子、棒或刷子;喷施,包括雾、气雾剂或泡沫喷施;滴管施用;喷洒;浸泡;和漂洗。也可以使用控释媒介物,并且组合物可以配制为作为透皮贴剂的透皮给药。
药物组合物可以配制为吸入制剂,包括喷雾、雾和气雾剂。此类制剂特别地用于治疗哮喘或其他呼吸疾病状况。对于吸入制剂,本文提供的化合物可以通过任何本领域技术人员已知的吸入方法来递送。此类吸入方法和装置包括但不限于定量雾化吸入器(metereddose inhaler),其具有诸如CFC或HFA的推进剂或者生理和环境可接受的推进剂。其他合适的装置为呼吸操作吸入器、多剂量干粉吸入器和气雾剂雾化吸入器。用于本发明方法的气雾剂制剂通常包含推进剂、表面活性剂和共溶剂,并且可以填充于通过合适的计量阀关闭的常规气雾剂容器。
吸入组合物可以包含液体或粉末组合物,其含有适合于雾化和支气管内使用的有效成分;或者包含通过气雾剂单位分配定量计量给予的气雾剂组合物。合适的液体组合物包含水性药学可接受的吸入溶剂中的有效成分,如等渗盐水或抑菌水。溶液通过泵或挤压操作喷雾分配器(squeeze-actuated nebulized spray dispenser)给予,或者通过导致或允许必要计量的液体组合物吸入患者的肺中的任何其他常规方式给予。其中载体为液体的用于例如鼻喷或鼻滴给药的合适制剂包含有效成分的水性或油性溶液。
其中载体为固体的适合于鼻给药的制剂或组合物包含粒径例如为20-500微米的粗固体,其以给予鼻吸药(snuff)的方式给予,即从装有粉末的容器通过鼻道快速吸入鼻中。作为示例,合适的粉末组合物包括有效成分的粉末制品,其与乳糖或支气管内给药可接受的其他惰性粉末完全互相混合。粉末组合物可以通过气雾剂分配器给予或装在易碎胶囊中,其可以由患者插入刺穿胶囊并将粉末吹入适合于吸入的稳定流的装置。
药物组合物还可以制备为例如用于直肠给药的栓剂形式。此类组合物可以通过将药物与合适的无刺激赋形剂混合来制备,所述无刺激赋形剂在常温下是固体但是在直肠温度下是液体,并因此在直肠中熔化以释放药物。合适的赋形剂包括例如可可脂和聚乙二醇。
药物组合物可以配制为缓释制剂,例如即在给药后产生调节剂的缓慢释放的胶囊制剂。此类制剂通常可以利用本领域已知的技术制备,并通过例如口服、直肠或皮下植入来给予,或者通过植入期望靶位点来给予。用于此类制剂中的载体是生物相容的,并且可以是生物可降解的;所述制剂优选提供调节剂释放的相对恒定的水平。缓释制剂中所含的调节剂的量取决于例如植入位点、释放的速率和预期持续时间以及要治疗或预防的疾病状况的性质。
对于心脏损伤特别是心律失常的治疗,本发明的生物学活性化合物的剂量可以在大限度内变化,并且可以调节至个体的需求。本发明的活性化合物通常以有效量,例如治疗有效量给药。优选的剂量为每天约0.1mg至约140mg每千克体重,每天约0.5mg至约7g每名患者。每日剂量可以作为单剂量给予,或者以多个剂量给予。可以与载体物质组合以产生单剂型的有效成分的量会根据治疗的宿主和特定给药模式而变化。剂量单位形式通常含有约1mg至约500mg的有效成分。
然而应当理解,任何特定患者的具体剂量水平会取决于各种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄速率、药物组合物即用于治疗患者的其他药物、以及进行治疗的特定疾病的严重性。
本发明的优选化合物会具有一定的药理特性。此类特性包括但不限于口服生物利用度,从而上文所讨论的优选口服剂型可以在体内提供化合物的治疗有效水平。
本文提供的n-3PUFA衍生物优选地口服或胃肠外给药于诸如人的患者,并因此存在于所述患者的至少一种体液或组织中。因此,本发明还提供用于治疗患者的方法,所述患者患有与炎症、增殖、高血压、凝血、免疫功能、病理性血管发生或心脏病(包括心律失常)相关的病症或疾病。本文所用的术语“治疗”涵盖任意类型的缓解疾病的治疗,包括症状治疗,即在症状开始后的治疗。然而,缓解疾病的治疗可涉及在症状开始前给药,以至少延迟症状,或者降低症状开始后的严重性。缓解疾病的治疗还可以是治疗性的(即在症状开始后),以降低症状的严重性和/或持续时间。症状开始后的治疗还可简单地涉及停止疾病的进展(稳定疾病)。在某些实施方案中,理想地,但不是必须地,将本文中提供的n-3PUFA衍生物预防性地(即在疾病和/或症状开始前)给药,以实际地预防疾病和/或症状。应理解,术语“预防”和“预防性”在本发明的上下文中只是描述将本发明的化合物在症状开始前给药。预防性给药可以是在明显与本文中讨论的疾病相关的症状开始前给药:当个体表现出某些情况(所述情况可指示形成可用本发明的n-3PUFA衍生物之一治疗的病症或疾病之一的倾向)时,本文中提供的n-3PUFA衍生物可例如向个体预防性给药。这样的指示性情况为例如高血压或糖尿病。这样的预防性治疗被称作初级预防。在另一实施方案中,当个体之前患有可用本发明的n-3PUFA衍生物治疗的病症或疾病但目前未表现出任何症状时,可向所述个体预防性给药本文中提供的n-3PUFA衍生物。这样的预防性治疗被称作次级预防。为了初级或次级预防的目的而接受n-3PUFA衍生物的患者被认为是需要这样的治疗。可以使用本文所述剂量的患者可以包括但不限于灵长类特别是人,驯化的伴随动物如狗、猫、马以及家畜如牛、猪、绵羊。
本领域技术人员会理解,多种病症和疾病会受益于本发明的n-3PUFA衍生物的给药,其中最显著的是心脏病。
在一个实例中,患有心律失常的患者口服接受两个10mg的每日剂量的本文中公开的n-3PUFA衍生物。在6个月的治疗期内,所述患者的疾病未进展。
在另一实例中,之前患有心律失常的患者口服接受单个5mg的每日剂量的本文中公开的n-3PUFA衍生物。在6个月的治疗期内,患者保持无疾病。
与增殖有关的疾病状况和疾病的实例包括肿瘤或赘生物,其中细胞增殖是失控且进行性的。一些此类失控的增殖细胞是良性的,但是其他的则是“恶性的”,并且可能导致生物的死亡。恶性肿瘤或“癌症”与良性生长的区别在于除了表现出侵入性细胞增殖以外,它们可以侵入周围的组织并转移。而且,恶性肿瘤的特征在于它们表现出更大的分化丧失(“更大的去分化”),以及相对于彼此和它们周围组织更大的组织结构上的丧失。这种特性又称为“退行发育”。可以通过本发明治疗的肿瘤还包括实体相肿瘤/恶性肿瘤即癌,局部晚期肿瘤和人软组织肉瘤。癌包括源自上皮细胞的恶性肿瘤,其渗入(侵入)周围组织并导致包括淋巴转移在内的转移癌。腺癌是源自腺组织的癌症,或者形成可识别的腺结构。另一大类的癌症包括肉瘤,其是细胞包埋于如胚性结缔组织的原纤维或均质物质中的肿瘤。本发明还允许治疗骨髓或淋巴系统的癌症,包括白血病、淋巴瘤和通常不呈现为肿瘤块(mass)但是分布于血管或淋巴网状内皮细胞的其他癌症。可以根据本发明治疗的癌症或肿瘤细胞包括例如乳腺癌;结肠癌;肺癌和前列腺癌;胃肠癌,包括食管癌、胃癌、结肠直肠癌、与结肠直肠赘生物有关的息肉、胰腺癌和胆囊癌;肾上腺皮质癌;产生ACTH的肿瘤;膀胱癌;脑癌,包括内在脑肿瘤(intrinsic brain tumor)、成神经细胞瘤、星形细胞脑肿瘤、神经胶质瘤和中枢神经系统的转移性肿瘤细胞侵入;尤文肉瘤;头颈癌,包括口癌和喉癌;肾癌,包括肾细胞癌;肝癌;肺癌包括小细胞肺癌和非小细胞肺癌;恶性腹膜积液;恶性胸膜积液;皮肤癌,包括恶性黑素瘤、人皮肤角质形成细胞的肿瘤形成、鳞状细胞癌、基底细胞癌和血管外皮肉瘤;间皮瘤;卡波西肉瘤;骨癌,包括骨瘤和肉瘤如纤维肉瘤和骨肉瘤;女性生殖道的癌症,包括子宫癌、子宫内膜癌、卵巢癌、卵巢(生殖细胞)癌和卵泡中的实体瘤、阴道癌、外阴癌和宫颈癌;乳腺癌(小细胞和导管);阴茎癌;成视网膜细胞瘤;睾丸癌;甲状腺癌;滋养细胞肿瘤(trophoblastic neoplasm);和肾胚胎瘤。
与炎症和免疫功能有关的疾病状况和疾病的实例包括炎性病症如急性期反应、局部和全身炎症和由其他任何类型疾病导致的炎症、由以下疾病示例炎性疾病导致的病因或发病机理以及免疫病症,如感觉过敏、自身免疫病症、移植中的移植排斥、移植毒性、肉芽肿性炎症/组织重塑、重症肌无力、免疫抑制、免疫复合物病、抗体的过量产生和产生不足以及脉管炎。特别地,此类疾病状况和疾病的实例包括炎性肠疾病包括克罗恩病和溃疡性结肠炎(Stadnicki等人,Am.J.Physiol.Gastrointest Liver Physiol.2005,289(2),G361-6;Devani等人,Am.J.Gastroenerol 2002,97(8),2026-32;Devani等人,Dig.Liv.Disease2005,37(9),665-73);肠易激综合征;小肠结肠炎;肝病;胰腺炎;肾炎;膀胱炎(间质膀胱炎);葡萄膜炎(uveitis);视网膜炎;青光眼;中耳炎;牙周炎(peridontitis);炎性皮肤病症,如银屑病、湿疹、特应性疾病、皮炎、瘙痒、青少年或成人发作类风湿性关节炎和痛风性关节炎(Cassim等人,Pharmacol.Ther.2002,94,1-34;Sharma等人,Exp.ToxicPathol.1994,46,421-433;Brechter等人,Arthr.Rheum.2007,56(3),910-923);关节强硬性脊椎炎;成人发作或儿科(全身发作儿科先天关节炎)斯蒂尔病(Still′s disease);银屑病关节炎;骨关节炎和与灼伤有关的水肿;扭伤或骨折;脑水肿;闭合性脑外伤(closedhead injury);血管性水肿;脉管炎;糖尿病血管病变;I型糖尿病;糖尿病肾病;糖尿病神经病;糖尿病视网膜病;后毛细血管抗性或与胰岛素(insulit)有关的糖尿病综合征(如高血糖、利尿、蛋白尿和增加的亚硝酸盐和激肽释放酶尿排泄);胆囊疾病;用于治疗胃肠道或子宫痉挛的平滑肌松弛药;多发性硬化;癫痫;肌萎缩性侧索硬化症;阿尔茨海默病;中风;帕金森病;全身炎症反应综合征(SIRS);局部缺血-再灌注损伤和动脉粥样硬化(Raidoo等人,Immunopharmacol 1997,36(2-3),153-60;McLean等人,Cardiovasc.Res.2000,48,194-210);败血性休克;抗低血容量和/或抗低血压剂;头痛,包括丛集性头痛;偏头痛,包括预防和急性用途;闭合性头颅伤;癌症;败血症;牙龈炎;骨质疏松;良性前列腺增生;膀胱活动过度(hyperactive bladder);纤维化疾病,如肺纤维化、肾纤维化、肝纤维化、进行性硬化和克罗恩病中的复发狭窄形成(Goldstein等人,J.Biol.Chem.1984,259(14),9263-8;Ricupero等人,J.Biol.Chem.2000,275(17),12475-80;Romero等人,J.Biol.Chem.2005,15,14378-14384);哮喘中呼吸途径的病症;特应性或非特应性哮喘;职业性哮喘;运动诱发的支气管收缩;支气管炎;尘肺,包括铝尘肺、煤肺(anhracosis)、石棉肺、石末沉着病、鸵鸟毛尘肺(ptilosis)、铁沉着病、矽肺、烟尘肺和棉尘病;慢性阻塞性肺疾病,包括肺气肿、成人呼吸窘迫综合征、肺炎、过敏性鼻炎、血管舒缩鼻炎和胸膜炎;自身炎性疾病,如家族性地中海热(FMF)、肿瘤坏死因子受体相关周期综合征(TRAPS)、新生儿发病多系统炎性疾病(NOMID);家族性冷自发炎症综合征(familial cold autoinflammatory syndrome,FCAS),包括家族性冷荨麻疹(FCU)、化脓性关节炎坏疽性脓皮病痤疮(pyogenic arthritispyoderma gangrenosum acne,PAPA)综合征和Muckle-Wells病。
与病理性血管发生相关的病症和疾病的实例包括如上文所述的肿瘤形成和转移、年龄相关的黄斑变性和糖尿病性视网膜病变。
与心脏病相关的病症和疾病的实例包括心力衰竭、冠状动脉疾病、心肌梗死、急性和慢性炎性心肌损害、适应不良的心脏肥大和心律失常(包括室性心动过速、恶性室性心动过速和心房颤动)、扩张性心肌病、心肌炎、高血压心脏病、炎症性心肌病。
优选地,预防和/或治疗任一上述病症或疾病的方法包括向有此需要的个体给药至少有效量的本发明的n-3PUFA类似物或本发明的药物组合物。另外,预防或治疗所述病症或病症的方法可特征在于意图通过任一上述给药途径(优选口服或通过注射)给药本发明的活性n-3PUFA类似物或组合物。
本发明的n-3PUFA类似物还可用作研究工具。例如,本发明的突变型蛋白缀合物可用作诊断剂或治疗诊断剂,其中,为了如本文中公开的治疗目的,可将这样的诊断剂用于诊断可通过本发明的n-3PUFA类似物处理的疾病或病症。例如,为了用作研究工具,可将本发明的n-3PUFA类似物通过同位素、荧光或发光标记物或者任意其它亲和性标记物进行标记。例如,本发明的这些标记的化合物可用于体内、体外和原位定位受体(例如在组织切片中通过放射性自显影),以及作为正电子发射断层扫描(PET)成像、单光子发射计算机断层扫描(SPECT)等的放射性示踪剂以在活个体或其他材料(例如组织样品)中表征那些受体。这样的用途以及它们各自的条件是本领域技术人员已知的。
本发明的n-3PUFA类似物的活性可例如在适合的体外和/或体内测定法中进行测定。例如,本发明的n-3PUFA类似物的生物学活性可使用本领域技术人员已知的Kang和Leaf建立的细胞模型(Proc Natl Acad Sci U S A,1994.91(21):p.9886-90.)来测定。
附图简述
图1:本发明的n-3PUFA类似物的实施例及其与二十碳五烯酸(EPA)和17,18-环氧二十碳四烯酸(17,18-EEQ)相比对所建立的体外心律失常模型(使用自发性搏动的新生大鼠心肌细胞(NRCM))的效力。如所表明的,细胞在基线条件下的自发性搏动通过实施例类似物的施用而降低。
以下实施例用于更完整地描述使用上述发明的方式,以及示例用于实施本发明的各个方面的最佳模式。应当理解,这些实施例不意图限制本发明的范围而是用于示例性目的。
实施例
在以下实施例中提供制备式(I)的化合物的具体实施例。除非另外说明,所有原料和试剂为标准市售等级,并且可在未进一步纯化下使用,或者可由这样的原料通过常规方法容易地制备。有机合成领域的技术人员会认识到,原料和反应条件可变化,包括为了制备本发明涵盖的化合物而使用的另外的步骤。优选的方法包括但不限于下文描述的那些方法。就所描述的合成路线所引用的各参考文献通过援引加入本文。
实施例1
中间体10的制备
步骤A.叔丁基二苯基((15-((四氢-2H-吡喃-2-基)氧基)十五-5-炔-1-基)氧基)甲硅烷(3)的合成:
将n-BuLi (己烷中2.5M,1eqiv)滴加至-78℃的1(1eqiv)在无水THF和新鲜蒸馏的HMPA (3:1)中的溶液。将反应物在-78℃下搅拌30min,并在0℃下搅拌2h。将反应物再冷却至-78℃,并缓慢加入在干燥THF中的2(1.2eqiv)。在-78℃下40min和在室温下过夜(14h)后,将反应用饱和NH4Cl溶液终止,加入水,并将反应物用EtOAc萃取两次。将合并的有机萃取物用水洗涤两次,用Na2SO4干燥,过滤并在真空下浓缩。通过SiO2柱色谱法(使用2%EtOAc/己烷)纯化,得到无色油形式的3(89%)。
1H NMR(500MHz,CDCl3)δ7.70–7.63(m,4H),7.47–7.30(m,6H),4.61–4.54(m,1H),3.92–3.82(m,1H),3.78–3.70(m,1H),3.67(t,J=6.2Hz,1H),3.56–3.45(m,1H),3.44–3.33(m,1H),2.22–2.07(m,2H),1.90–1.39(m,10H),1.39–1.23(m,9H),1.04(s,9H),0.92–0.81(m,2H);13C NMR(125MHz,CDCl3)δ135.80(4),134.26(2),129.76(2),127.84(4),99.08,80.67,80.22,67.90,63.73,62.57,31.99,31.05,30.01,29.75,29.73,29.41,29.39,29.13,27.12(3),26.48,25.82,25.77,19.97,19.47,19.02,18.81.
步骤B.15-((四氢-2H-吡喃-2-基)氧基)十五-5-炔-1-醇(4)的合成:
向3在干燥THF中的溶液加入四正丁基氟化铵(TBAF,在THF中1.0M溶液,1.3equiv)。39h后,将THF蒸发,将残渣在水中悬浮,并用Et2O萃取两次。将有机萃取物用MgSO4干燥,过滤并真空浓缩。将残渣使用Teledyne IscoRf色谱系统纯化,以得到无色油形式的醇4(61%)。
1H NMR(500MHz,CDCl3)δ4.57(dd,J=4.5,2.8Hz,1H),3.91–3.83(m,1H),3.72(dt,J=9.5,6.9Hz,1H),3.67(t,J=6.4 Hz,2H),3.54–3.44(m,1H),3.37(dt,J=9.5,6.7Hz,1H),2.19(tt,J=6.9,2.4Hz,2H),2.13(tt,J=7.1,2.4Hz,2H),1.89-1.77(m,1H),1.77–1.40(m,13H),1.40–1.24(m,10H);13C NMR(125MHz,CDCl3)δ98.98,80.75,79.96,67.86,62.50(2),32.03,30.93,29.90,29.61,29.26(2),29.01,26.39,25.67,25.60(2),19.83,18.90,18.73.
步骤C.15-(四氢-2H-吡喃-2-基氧基)十五-5(Z)-烯-1-醇(5)的合成:
向在双颈瓶中在H2(1atm)下的Ni(OAc)2(0.6equiv)在无水乙醇中的悬浮液中一次性加入NaBH4(0.8equiv)。25min后,加入纯蒸馏的乙二胺(EDA,3equiv),随后加入4在无水EtOH中的溶液。2h后,将反应混合物通过硅胶垫过滤。将垫用EtOAc洗涤。将合并的有机滤液浓缩,以得到无色油形式的烯烃5(98%)。
TLC:20%EtOAc/己烷,Rf~0.35.1H NMR(500MHz,CDCl3)δ5.41–5.31(m,2H),4.59–4.56(m,1H),3.89–3.85(m,1H),3.73(dt,J=9.7,6.9Hz,1H),3.65(t,J=6.5Hz,2H),3.53–3.47(m,1H),3.38(dt,J=9.7,6.9Hz,1H),2.06(dt,J=7.0,6.5Hz,2H),2.01(dt,J=7.0,6.5Hz,2H),1.87–1.79(m,1H),1.75–1.68(m,1H),1.64–1.48(m,9H),1.46–1.38(m,2H),1.38–1.24(m,11H);13C NMR(125MHz,CDCl3)δ130.5,129.6,99.0,67.9,62.8(2),62.5,32.6,30.9,29.9,29.8(2),29.7,29.5,27.4,27.2,26.4,26.1,25.6,19.8.
步骤D.2-(15-叠氮基十五-10(Z)-烯基氧基)四氢-2H-吡喃(6)的合成:
向-25℃的三苯基膦(TPP,1.2equiv)在干燥THF中的溶液滴加偶氮二甲酸二异丙酯(DIAD,1.2equiv)。十分钟后,将醇5在干燥THF中的溶液在相同温度下滴加,以形成黄色悬浮液。30min后,将反应混合物温热至0℃,然后滴加叠氮磷酸二苯酯(DPPA,1.2equiv)。将反应混合物温热至室温并搅拌。16h后,将反应混合物用H2O终止,并用Et2O萃取三次。将合并的醚萃取物用Na2SO4干燥,过滤并在真空下浓缩。将粗产物通过SiO2柱色谱法(使用2%EtOAc/己烷作为洗脱剂)纯化,以得到淡黄色油形式的6(>97%)。将分析样品使用制备型TLC进一步纯化,以得到无色油形式的6。
TLC:20%EtOAc/己烷,Rf~0.8.1HNMR(400MHz,CDCl3)δ5.43–5.28(m,2H),4.59–4.56(m,1H),3.91–3.84(m,1H),3.77–3.69(m,1H),3.54–3.46(m,1H),3.41–3.35(m,1H),3.27(t,J=6.8Hz,2H),2.10–1.95(m,4H),1.88–1.78(m,1H),1.76–1.68(m,1H),1.65–1.48(m,6H),1.46–1.38(m,2H),1.38–1.24(m,14H);13C NMR(100MHz,CDCl3)δ130.9,129.0,99.0,67.8,62.4,51.5,31.0,29.9,29.8,29.7,29.6(2),29.5,28.6,27.4,26.9,26.8,26.4,25.7,19.9.
步骤E.15-(四氢-2H-吡喃-2-基氧基)十五-5(Z)-烯-1-胺(7)的合成:
向室温下上述粗品叠氮化物6在THF中的溶液一次性加入三苯基膦(TPP,1.3equiv)。2h后,加入H2O,并将反应物在室温下搅拌。12h后,将反应混合物用EtOAc稀释,随后用盐水稀释,并将双相混合物用EtOAc萃取三次。将合并的有机萃取物用Na2SO4干燥,过滤并在真空下浓缩。将粗品产物在Et2O中研磨,并通过烧结漏斗过滤。将滤液真空浓缩,并将粗品7在未进一步纯化下在下一步骤中使用。TLC:5%MeOH/CH2Cl2,Rf~0.1。
步骤F.N1-甲基-N2-(15-(四氢-2H-吡喃-2-基氧基)十五-5(Z)-烯基)草酰胺(9)的合成:
根据之前的文献1,将在绝对无水乙醇中的上述粗品胺7和8(1.2equiv)在85℃下于密封管中加热。15h后,将反应混合物真空浓缩,并将粗品产物通过SiO2柱色谱法(使用25%EtOAc/己烷)纯化,得到白色固体形式的9(70%),mp 69.9-70.2℃。
TLC:50%EtOAc/己烷,Rf~0.65.1H NMR(500MHz,CDCl3)δ7.56–7.46(br s,2H),5.42–5.28(m,2H),4.59–4.56(m,1H),3.91–3.84(m,1H),3.72(dt,J=9.6,6.9Hz,1H),3.54–3.46(m,1H),3.37(dt,J=9.6,6.7Hz,1H),3.30(app q,J=6.9Hz,2H),2.91(d,J=5.5Hz,3H),2.04(dt,J=7.5,7.0Hz,2H),1.98(app q,J=7.0,2H),1.88–1.78(m,1H),1.76–1.68(m,1H),1.64–1.47(m,7H),1.44–1.22(m,15H);13C NMR(125MHz,CDCl3)δ160.8,159.9,130.9,129.1,99.1,67.9,62.6,39.8,31.0,29.9(2),29.8,29.7(2),29.5,29.0,27.5,27.1,26.9,26.5,26.4,25.7,19.9.
步骤G.N1-(15-羟基十五-5(Z)-烯基)-N2-甲基草酰胺(10)的合成:
向9在甲醇中的溶液加入对甲苯磺酸(PTSA,0.07eqiv)。2h后,将溶剂真空蒸发,并将残渣在EtOAc中再溶解。使粗品产物通过短的硅胶垫(使用EtOAc作为洗脱剂),得到白色固体形式的10(>95%),mp 115.4-115.7℃。
TLC:50%EtOAc/己烷,Rf~0.25.1H NMR(400MHz,CDCl3)δ7.45(br s,2H),5.42–5.28(m,2H),3.71–3.55(m,2H),3.31(app q,J=6.8Hz,2H),2.91(d,J=5.2Hz,3H),2.12–1.91(m,4H),1.61–1.52(m,6H),1.44–1.23(m,12H);13C NMR(125MHz,CDCl3)δ160.8,159.9,130.9,129.1,63.3,39.8,33.0,29.8,29.7,29.6(2),29.4,29.0,27.4,27.1,26.9,26.4,25.9.
实施例2
实施例化合物C41的制备
步骤A.N1-(15-溴十五-5(Z)-烯基)-N2-甲基草酰胺(11)的合成:
在氩气气氛下,向TPP(745mg,1.2equiv)在CH2Cl2(80mL)中的溶液加入共同中间体10(740mg,2.37mmol,1equiv)在CH2Cl2(40mL)中的溶液,随后一次性加入四溴化碳(CBr4,1.2equiv,942mg)。24h后,将反应混合物在真空下浓缩,并将残渣通过硅胶柱色谱法(使用20-25%EtOAc/己烷)纯化,得到白色固体形式的11(597mg,67%),mp 77.5-77.6℃。
TLC:50%EtOAc/己烷,Rf~0.7.1H NMR(400MHz,CDCl3)δ7.45(br s,2H),5.42–5.27(m,2H),3.41(t,J=6.8Hz,2H),3.31(app q,J=6.8Hz,2H),2.91(d,J=5.6Hz,3H),2.09–1.96(m,4H),1.85(app quintet,J=7.2Hz,2H),1.62–1.52(m,2H),1.47–1.37(m,4H),1.37–1.23(m,10H);13C NMR(100MHz,CDCl3)δ160.8,159.9,130.9,129.1,39.8,34.3,33.0,29.9,29.6(2),29.5,29.0,28.9,28.4,27.4,27.1,26.9,26.4.
步骤B.15-(2-(甲基氨基)-2-氧代乙酰氨基)十五-10(Z)-烯基膦酸二甲酯(12)的合成:
将11(375mg,1.1mmol)和亚磷酸三甲酯[P(OMe)3](16mL)在干燥THF(16mL)中的溶液在密封管中于120℃下加热。3d后,将THF在真空中蒸发,并将P(OMe)3在减压下蒸馏。将粗品12(240mg,54%)在未进一步纯化下进行下一步反应。将分析样品通过制备型TLC纯化。
TLC:50%EtOAc/己烷,Rf~0.2.1H NMR(500MHz,CDCl3)δ7.48(br s,2H),5.39–5.26(m,2H),3.72(d,JP,H=10.5Hz,6H),3.30(app q,J=7.0Hz,2H),2.90(d,J=5.0Hz,3H),2.04(app q,J=7.5Hz,2H),1.98(app q,J=7.5Hz,2H),1.81–1.67(m,2H),1.63–1.51(m,4H),1.43–1.21(m,14H);31P NMR(202MHz,CD3OD;rel 85%H3PO4)δ36.48(s).
步骤C.15-(2-(甲基氨基)-2-氧代乙酰氨基)十五-10(Z)-烯基膦酸二钠(C41)的合成:
根据之前的文献2,将TMSBr(10equiv,0.5mL)滴加至0℃的12(150mg,0.371mmol)在无水CH2Cl2(10mL)中的溶液。75min后,将反应物用甲醇(5mL)终止,在真空中浓缩,并将残渣用CH2Cl2(2×10mL)研磨。将残渣(mp 130.6-130.7℃)在Na2CO3水溶液(0.01M,pH 10)中溶解。向溶液中加入Bio-RadTMSM-2Bio-Beads(20-50目,5g)。轻微搅拌30min后,将珠在烧结漏斗上收集,并用水(20mL)洗涤。然后使用甲醇将C41从所述Bio-Beads脱去。将甲醇蒸发得到白色粉末形式的C41(48mg,30%),mp 240℃(dec)。
C41的游离酸:1H NMR(500MHz,CD3OD)δ8.58(br s,3H),5.44–5.24(m,2H),3.26(app q,J=6.5Hz,2H),2.82(s,1H),2.81(s,2H),2.12–1.98(m,4H),1.88–1.72(m,2H),1.71–1.50(m,4H),1.47–1.24(m,14H);31P NMR(202MHz,CD3OD;rel 85%H3PO4)δ31.37(s).
C41:1H NMR(500MHz,CD3OD)δ5.43–5.28(m,2H),3.26(t,J=7.0
Hz,2H),2.82(s,3H),2.14–1.95(m,4H),1.88–1.71(m,2H),1.69–1.42(m,4H),1.42–1.24(m,14H).
实施例2A
实施例化合物C52和C53的制备
在氩气气氛下,向搅拌的室温下的膦酸二甲基酯12(1.0mmol,0.418g)在干燥CH3CN(10mL)和CH2Cl2(2mL)中的溶液加入特戊酰氧甲基碘化物(POM-I;购自EnamineLLC,Princeton Corporate Plaza,7Deer Park Drive,Ste.M-3,Monmouth Jct.,NJ 08852USA)(5.0mmol,0.76mL)。2天后,大部分起始膦酸酯被消耗(TLC分析:5%MeOH/CH2Cl2)。将挥发物真空蒸发,并将粗品产物通过SiO2快速柱色谱法(使用CH2Cl2中1-2%MeOH梯度)纯化,以得到油形式的纯单-POM酯C53(20mg,4%)和含一些杂质的二-POM酯C52。使用制备型TLC(5%MeOH/CH2Cl2)的第二次纯化得到油形式的二-POM酯C52(21mg,3%)。
C52.TLC:Rf~0.5,5%MeOH/CH2Cl2;1H NMR(400MHz,CDCl3)δ7.46(br s,2H),5.64(d,JH-P=13.1Hz,4H),5.40–5.23(m,2H),3.28(app q,J=7.0Hz,2H),2.88(d,J=5.2Hz,3H),2.02(app q,J=6.9Hz,2H),1.97(app q,J=6.9Hz,2H),1.84–1.74(m,2H),1.64–1.49(m,4H),1.40–1.17(m,14H),1.21(s,18H);13C NMR(101MHz,CDCl3)δ176.86,160.53,159.64,130.57,128.83,81.24(d,2JC-O-P=6.2Hz),39.52,38.70,30.40(d,2JC-C-P=18.0Hz),29.64,29.40,29.27,29.21,29.02(4JC-P=1.4Hz),28.78,27.20,26.84,26.82,26.65,26.23(d,1JC-P=84.0Hz),26.12,21.91(d,3JC-P=5.4Hz).
C53.TLC:Rf~0.4,5%MeOH/CH2Cl2;1H NMR(500MHz,CDCl3)δ7.48(br s,2H),5.68(d,JH-P=13.2Hz,2H),5.43–5.27(m,2H),3.74(d,JH-P=11.2Hz,3H),3.32(app q,J=6.9Hz,2H),2.92(d,J=5.2Hz,3H),2.06(app q,J=6.9Hz,2H),2.00(app q,J=6.9Hz,2H),1.83–1.76(m,2H),1.64–1.51(m,4H),1.44–1.20(m,14H),1.21(s,9H);13C NMR(101MHz,CDCl3)δ177.00,160.55,159.67,130.59,128.84,81.66(d,2JC-O-P=6.0Hz),51.81(d,,2JC-O-P=7.2Hz),39.53,38.72,30.49(d,2JC-C-P=17.5Hz),29.66,29.42,29.28,29.22,29.04(d,4JC-P=1.3Hz),28.79,27.20,26.90,26.83,26.66,25.83(d,1JC-P=139.4Hz),26.14,22.10(d,3JC-P=5.4Hz).
实施例3
实施例化合物C38的制备
步骤A.N1-(15-氰基十五-5(Z)-烯基)-N2-甲基草酰胺(13)的合成:
向溴化物11(550mg,1.47mmol)在DMSO(30mL)中的溶液一次性加入KCN(500mg,5equiv)。在室温下24h后,将反应混合物用水(60mL)稀释,并用EtOAc(20mL×3)萃取。将合并的有机萃取物用水(25mL×2)、然后用盐水(30mL)洗涤。将萃取物用无水Na2SO4干燥,过滤然后真空浓缩。将残渣通过SiO2柱色谱法(使用20-25%EtOAc/己烷)纯化,得到白色粉末形式的13(490mg,99%),mp 88.8-88.9℃。
TLC:50%EtOAc/己烷,Rf~0.55.1H NMR(400MHz,CDCl3)δ7.43(br s,2H),5.44-5.23(m,2H),3.31(app q,J=6.8Hz,2H),2.91(d,J=5.2Hz,3H),2.34(t,J=7.2Hz,2H),2.09–1.96(m,4H),1.71–1.61(m,2H),1.61–1.49(m,4H),1.49–1.36(m,4H),1.36–1.22(m,8H);13C NMR(100MHz,CDCl3)δ160.8,159.9,130.8,129.1,120.1,39.8,29.8,29.6,29.5,29.4,29.0,28.9,28.8,27.4,27.1,26.9,26.4,25.6,17.3.
步骤B.N1-16-氨基-16-(羟基亚胺基)十六-5(Z)-烯基-N2-甲基草酰胺(14)的合成:
根据之前的文献3,将腈13(100mg,0.311mmol)、NH2OH·HCl(108mg,5equiv)和Na2CO3(181mg,5.5equiv)在无水甲醇(2mL)中的溶液在密封管中于84℃下加热。2天后,将反应混合物冷却至室温,过滤并真空浓缩。将残渣用EtOAc(60mL×3)、然后用水(70mL)研磨。将白色固体残渣(76mg,69%)在未进一步纯化下于下一步反应中使用。分析样品通过制备型TLC(5%MeOH/CH2Cl2,Rf~0.35)纯化,mp 118.1-118.5℃。
1H NMR(400MHz,CD3OD)δ5.35(td,J=5.9,4.6Hz,2H),3.25(t,J=7.1Hz,2H),2.82(s,3H),2.12–1.98(m,6H),1.90(s,1H),1.56(app quintet,J=7.3Hz,4H),1.44–1.26(m,16H);13C NMR(100MHz,CD3OD)δ161.2,160.4,156.5,130.1,129.1,39.19,30.61,29.63,29.43,29.38,29.25,29.12,28.97,28.67,27.14,26.94,26.85,26.58,25.08.
步骤C.N1-甲基-N2-(15-(2-氧化-3H-1,2,3,5-氧杂噻二唑-4-基)十五-5(Z)-烯-1-基)草酰胺(C38)的合成:
根据之前的文献3,将吡啶(43.6μL,2.6equiv)、然后是SOCl2(20μL,1.3equiv)在CH2Cl2(1mL)中的溶液加入0℃的14(74mg,0.21mmol)在THF(4mL)中的溶液。1小时40min后,将所有挥发物真空移除,并将残渣用水(10mL)稀释,并用EtOAc(15mL×5)萃取。将合并的有机萃取物用Na2SO4干燥,过滤,浓缩,并通过制备型TLC(10%MeOH/CH2Cl2)纯化,以得到白色固体形式的C38(55mg,63%),mp 92.7-92.9℃。
TLC:5%MeOH/CH2Cl2,Rf~0.6.1H NMR(500MHz,CDCl3)δ8.38(s,1H),7.50(s,2H),5.41–5.28(m,2H),3.41–3.21(m,2H),2.91(d,J=5.2Hz,3H),2.62(t,J=7.7Hz,2H),2.06(app q,J=7.0Hz,4H),2.01(app q,J=7.0Hz,4H),1.69(app quintet,J=7.7Hz,2H),1.63–1.55(m,3H),1.46–1.13(m,9H);13C NMR(100MHz,CDCl3)δ160.72,159.91,152.89,130.89,129.19,39.95,29.43,29.32,29.21,29.12,29.04,28.97,28.88,27.08(2),26.88,26.58,26.53,23.95.
实施例4
实施例化合物C42的制备
步骤A.N1-(15-碘十五-5(Z)-烯-1-基)-N2-甲基草酰胺(15)的合成:
在0℃下,向10(1.80g,5.76mmol)、TPP(1.66g,1.1equiv)和咪唑(784mg,2equiv)在干燥THF(180mL)中的溶液加入I2(1.75g,1.2equiv)。使反应物温热至室温,并搅拌。15小时后,将反应物用饱和NaHSO3溶液终止,并用水洗涤两次。将水相用EtOAc(20mL×2)再萃取。将合并的有机萃取物用Na2SO4干燥,过滤并在真空下浓缩。将残渣通过SiO2柱色谱法(使用20-25%EtOAc/己烷)纯化,以得到白色固体形式的15(1.77g,70%),mp81.7℃。
TLC:50%EtOAc/己烷,Rf~0.65.1H NMR(CDCl3,500MHz)δ7.43(br s,2H),5.42–5.27(m,2H),3.31(app q,J=6.9Hz,2H),3.19(t,J=7.0Hz,2H),2.91(d,J=5.2Hz,3H),2.05(dt,J=7.5,7.0Hz,2H),2.00(app q,J=7.0Hz,2H),1.82(app quintet,J=7.2Hz,2H),1.63–1.48(m,2H),1.44–1.22(m,14H);13C NMR(125MHz,CDCl3)δ160.81,159.94,130.87,129.12,39.82,33.80,30.75,29.93,29.67,29.63,29.50,29.06,28.78,27.48,27.11,26.94,26.44,7.68.
步骤B.15-(2-(甲基氨基)-2-氧代乙酰氨基)十五-10(Z)-烯-1-磺酸钠(C42)的合成:
将碘化物15(200mg,0.46mmol)、Na2SO3(231mg,4equiv)、乙醇(95%,3mL)、环己烯(0.93mL,20equiv)和水(1.5mL)在85℃下于密封管中加热。4天后,将反应混合物冷却至室温,真空浓缩,在H2O中溶解,并如对于C41所述的通过吸附至Bio-Rad SM-2Bio-Beads,得到灰白色固体形式的C42(51mg,27%),mp 202-210℃(dec)。
1H NMR(500MHz,DMSO-d6)δ8.86–8.55(m,2H),5.45–5.18(m,2H),3.18–2.99(m,2H),2.65(d,J=5.9Hz,3H),2.34(t,J=8.0Hz,2H),2.05–1.87(m,4H),1.60–1.35(m,4H),1.35–1.10(m,14H);13C NMR(100MHz,DMSO-d6)δ161.26,160.51,130.34,129.85,52.20(2),39.23,29.81,29.70,29.58,29.59,29.32,29.10,28.98,27.28,27.07,26.94,25.78.
实施例5
实施例化合物C43的制备
N1-(15-((2-乙酰氨基苯并[d]噻唑-7-基)氧基)十五-5(Z)-烯-1-基)-N2-甲基草酰胺(C43)的合成:
将包含碘化物15(200mg,0.458mmol)、N-(4-羟基苯并[d]噻唑-2-基)乙酰胺4(122mg,1equiv)和K2CO3(95mg,1.5equiv)的密封管在85℃下加热。6h后,将反应物冷却至室温,用EtOAc(15mL)和水(15mL)稀释,并用EtOAc(15mL×3)萃取。将合并的有机萃取物用Na2SO4干燥,过滤并在真空下浓缩。将残渣在Teledyne IscoRf色谱系统(1.2g SiO2柱,用50-60%EtOAc/己烷洗脱)上纯化,得到褐色固体形式的C43(68mg,29%)。将褐色固体在EtOH(1mL)中溶解,并在室温下超声5分钟。在静置和在高真空下干燥后,类似物C43以白色固体的形式沉淀。
TLC:50%EtOAc/己烷,Rf~0.2.1H NMR(CDCl3,500MHz)δ11.33(br s,1H),7.85(brs,1H),7.59(br s,1H),7.40(d,J=8.0Hz,1H),7.24(app t,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),5.40–5.26(m,2H),4.13(t,J=6.5Hz,2H),3.32(app q,J=7.0Hz,2H),2.89(d,J=5.0Hz,3H),2.24(s,3H),2.04(app q,J=7.0Hz,2H),1.97(app q,J=7.0Hz,2H),1.88–1.79(m,2H),1.62–1.51(m,2H),1.49–1.34(m,4H),1.34–1.17(m,10H);13C NMR(125MHz,CDCl3)δ169.20,160.87,160.15,158.24,151.58,138.33,133.73,130.96,129.07,125.00,113.63,108.24,69.00,39.85,29.83,29.80,29.70,29.65,29.50,29.48,29.02,27.44,27.07,26.90,26.53,26.35,23.59.
实施例6
实施例化合物C48的制备
步骤A.
将16(12mmol)和17(10mmol)在无水EtOH(100mL)中的溶液在回流下加热。12h后,将反应混合物冷却至室温,并真空浓缩至大约20%的初始体积(当18开始以灰白色固体的形式沉淀时)。将固体通过过滤收集,并在未进一步纯化下于下一步骤中使用。
TLC:EtOAc/己烷(2:1),Rf~0.5;1H NMR(400MHz,CDCl3)δ2.26(s,1H),2.90(d,J=5.2Hz,3H),4.06–4.13(m,2H),7.44(br s,1H),7.68(br s,1H).
步骤B.
在氩气气氛下,向Pd(PPh3)4(3mol%,350mg)和CuI(5mol%,100mg)在Et3N(40mL)中的溶液加入1,2-二碘苯(10mmol,3.3g)和5-己炔-1-醇(10mmol,980mg)在Et3N(10mL)中的溶液。将反应物加热至60℃,持续12h,然后冷却至室温,并通过硅藻土垫过滤。将滤液真空浓缩,并将残渣使用Teledyne IscoRf色谱系统[40g SiO2柱,用EtOAc/己烷(1:2)洗脱]纯化,得到淡黄色油形式的19(1.5g,50%)。
TLC:EtOAc/己烷(1:2),Rf~0.2.1H NMR(500MHz,CDCl3)δ1.73–1.81(m,2H),1.82–1.88(m,2H),2.55(t,J=7.0Hz,2H),3.76(t,J=7.0Hz,2H),6.98(dd,J=7.0,8.0Hz,1H),7.29(dd,J=7.0,8.0Hz,1H),7.42(d,J=7.5Hz,1H),7.84(d,J=8.0Hz,1H).
步骤C.
在氩气气氛下,将Et3N(16.6mmol,2.3mL)和醇19(1.66mmol,500mg)顺序加入至18(1.66mmol,232mg)、Pd(PPh3)2Cl2(3mol%,35mg)和CuI(5mol%,16mg)在干燥CH3CN(15mL)中的溶液。在50℃下加热12h后,将反应物冷却至室温,并通过硅藻土垫过滤。将滤液真空浓缩,并将残渣使用Teledyne IscoRf色谱系统[40g SiO2柱,用EtOAc/己烷(2:1)洗脱]纯化,得到淡黄色油形式的20(362mg,70%)。
TLC:EtOAc/己烷(2:1),Rf~0.15.1H NMR(500MHz,CDCl3)d 1.68–1.78(m,2H)1.80–1.88(m,2H),2.53(t,J=7.0Hz,2H),2.92(d,J=5.0Hz,3H),3.76(t,J=6.5Hz,2H),4.40(d,J=6.0Hz,2H),7.18–7.28(m,2H),7.36–7.44(m,2H),7.62(br s,1H),8.24(br s,1H).
步骤D.
将二炔20(100mg)和PtO2(10mg)在干燥MeOH(10mL)中的混合物在Parr氢化装置中于H2气氛(50psi)下摇动。12h后,将反应混合物通过硅藻土垫过滤,并将滤液真空浓缩,得到白色固体形式的粗品21,将其在未进一步纯化下于下一步骤中使用。
步骤E.
将PPh3(0.38mmol,100mg)一次性加入至0℃的21(0.32mmol,100mg)和CBr4(0.48mmol,160mg)在CH2Cl2(5mL)中的溶液。在室温下搅拌12小时后,将溶剂真空蒸发,并将残渣使用Teledyne IscoRF色谱系统[24g SiO2柱,用EtOAc/己烷(2:1)洗脱]纯化,得到白色固体形式的溴化物22(98mg,80%)。
TLC:EtOAc/己烷(4:1),Rf~0.7.1H NMR(400MHz,CDCl3)δ1.35–1.50(m,4H),1.54–1.62(m,2H),1.80–1.90(m,4H),2.58(dd,J=8.0,8.0Hz,2H),2.65(dd,J=8.0,8.0Hz,2H),2.91(d,J=5.2Hz,3H),3.38(dd,J=7.2,7.2Hz,2H),3.40(J=7.2,7.2Hz,2H),7.10–7.16(m,4H),7.42(br s,1H),7.47(br s,1H);13C NMR(100MHz,CDCl3)δ26.4,28.3,29.0,30.0,30.8,31.2,32.7,32.9,34.2,39.7,126.3,126.5,129.3,129.5,138.8,140.4,160.0,160.7.
步骤F.
将溴化物22(0.54mmol,200mg)和P(OMe)3(16.2mmol,1.9mL)的混合物在回流下于密封管中加热48小时,然后冷却至室温,并将过量的P(OMe)3在真空下移除。将残渣通过PTLC(使用EtOAc/己烷/MeOH(2:1:0.3))纯化,得到白色固体形式的膦酸二甲酯23(195mg,88%)。
TLC:EtOAc/己烷/MeOH(2:1:0.3),Rf~0.3.1H NMR(400MHz,CDCl3)δ1.32–1.42(m,4H),1.50–1.76(m,6H),1.78–1.88(m,2H),2.53–2.58(m,2H),2.60–2.65(m,2H),2.89(d,J=5.2Hz,3H),3.36(dd,J=6.8,6.8Hz,2H),3.71(d,JP-H=10.4Hz,6H),7.08–7.12(m,4H),7.56(br s,2H).
步骤G.
在氩气气氛下,将TMSBr(2mmol,260uL)滴加至粗品二酯23(0.19mmol,80mg)在干燥CH2Cl2(3mL)中的溶液。3h后,将反应物用MeOH(2mL)终止。搅拌另外1h后,将所有挥发物真空移除,并加入饱和Na2CO3溶液(0.5M),以达到pH~10。向所述溶液中加入Bio-RadTMSM-2Bio-Beads(20-50目,5g)。轻微搅拌30min后,将珠在烧结漏斗上收集,并用水(20mL)洗涤。然后使用甲醇和EtOAc将化合物从所述Bio-Beads脱去。将有机洗涤物蒸发得到灰白色固体形式的C48(37mg,45%),mp>300℃(dec)。
1H NMR(400MHz,CD3OD)δ1.34–1.66(m,10H),1.74–1.84(m,2H),2.58(dd,J=8.0,8.0Hz,2H),2.63(dd,J=8.0,8.0Hz,2H),2.81(s,3H),3.26–3.34(m,2H),7.02–7.12(m,4H);13C NMR(100MHz,CD3OD)δ24.4(d,JC-P=4.0Hz),24.9,29.3,29.5,30.5,30.6,31.3,31.6(d,JC-P=17.4Hz),32.4,39.1,125.4,125.6,128.7,129.0,138.9,140.3,160.3,161.0;31P NMR(162MHz,CD3OD;ref 85%H3PO4)δ24.4.
实施例7
实施例化合物C49的制备
步骤A.
紧密按照上述为了得到同系物18所使用的操作制备粗品24,将其在未进一步纯化下使用。
步骤B.
在0℃下,于氩气气氛下,将NaH(在矿物油中60wt%,714mmol,2.85g)一次性加入乙二胺(35mL)中。将反应物在室温下搅拌1h,然后在60℃下搅拌1h。冷却至室温后,滴加醇25(17.85mmol,2.84mL)。加入完成后,将反应混合物再加热至60℃。1h后,将反应混合物冷却至0℃,并用1N HCl终止。将有机层用乙醚(3×100mL)萃取。将合并的醚萃取物真空浓缩,并将残渣使用Teledyne IscoRf色谱系统[40g SiO2柱,用EtOAc/己烷(1:5)洗脱]纯化,得到淡黄色油形式的26(1.4g,56%)。
步骤C.
如对于19的合成所述的进行用于生成27的交叉偶联。
步骤D.
按照为了制备20所使用的操作,将碘化物27和乙炔24转化为28,得到淡黄色固体形式。
TLC:EtOAc/己烷(2:1),Rf~0.1.1H NMR(400MHz,CDCl3)δ1.32–1.42(m,4H),1.46–1.66(m,6H),2.46(t,J=6.8Hz,2H),2.72(t,J=6.8Hz,2H),2.90(d,J=5.2Hz,3H),3.58(dd,J=5.2,13.2Hz,2H),3.64(t,J=6.4Hz,2H),7.15–7.22(m,2H),7.34–7.40(m,2H),7.46(br s,1H),7.90(br s,1H).
步骤E.
按照为了制备21所使用的操作,将二炔28转化为29,得到白色固体。
TLC:EtOAc/己烷(2:1),Rf~0.15.1H NMR(400MHz,CDCl3)δ1.25–1.40(m,10H),1.50–1.65(m,8H),2.54–2.59(m,2H),2.60–2.65(m,2H),2.90(d,J=5.2Hz,3H),3.30–3.38(m,2H),3.60–3.68(m,2H),7.08–7.14(m,4H),7.45(br s,2H).
步骤F.
按照为了制备22所使用的操作,将醇29转化为30,得到白色固体。
TLC:EtOAc/己烷(2:1),Rf~0.75.1H NMR(400MHz,CDCl3)δ1.22–1.48(m,12H),1.50–1.70(m,6H),1.80–1.90(m,2H),2.52–2.68(m,4H),2.89(d,J=4.8Hz,3H),3.26–3.46(m,4H),7.08–7.16(m,4H),7.53(br s,2H);13C NMR(100MHz,CDCl3)δ26.4,28.4,28.6,29.0,29.5,29.6,29.7,29.9,31.5,32.3,32.9,33.0,34.3,39.8,126.0,126.2,129.3,129.4,139.7,140.7,159.9,160.8.
步骤G.
按照为了制备23所使用的操作,将溴化物30转化为31,得到白色固体。
TLC:EtOAc/己烷/MeOH(1:1:0.2),Rf~0.2.1HNMR(400MHz,CDCl3)δ1.20–1.80(m,20H),2.56–2.70(m,4H),2.93(s,3H),3.30–3.42(m,2H),3.76(d,JP-H=10.0Hz,6H),7.08–7.18(m,4H),7.52(br s,2H).
步骤H.
按照为了制备C48所使用的操作,将膦酸二甲酯31转化为二钠盐C49,获得白色固体,mp>300℃(dec)。
1HNMR(400MHz,CD3OD)δ1.25–1.40(m,10H),1.45–1.65(m,10H),2.56–2.66(m,4H),2.80(s,3H),3.25–3.30(m,2H),7.02–7.12(m,4H);13C NMR(100MHz,CD3OD)δ24.1(d,JC-P=4.2Hz),24.8,28.4,28.7,28.8,29.2,29.3,29.4,30.1,31.3,31.4(d,JC-P=17.4Hz),31.8,32.2,38.9,125.4,125.5,128.8,128.9,139.5,140.1,160.2,161.0;31P NMR(162MHz,CD3OD)d 24.6.
实施例8
实施例化合物C50的制备
N1-(16-苯磺酰氨基-16-氧代十六-5(Z)-烯-1-基)-N2-甲基草酰胺C50的合成:
根据之前的文献5制备16-(2-(甲基氨基)-2-氧代乙酰氨基)十六-11(Z)-烯酸32。在氩气气氛下,将(Z)-16-(2-(甲基氨基)-2-氧代乙酰氨基)十六-11-烯酸32(30mg,0.091mmol)和苯磺酰胺33(13mg,0.091mmol)放入干燥圆底烧瓶的5mL无水DMF中。将二甲基氨基吡啶(DMAP,13mg,0.12,1.2equiv)和1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(16mg,0.12mmol;EDCI.HCl)以固体形式加入。在室温下搅拌12h后,将反应混合物用水(20mL)稀释,并将合并的水层用EtOAc(3×20mL)萃取,将有机层用水(2X 10mL)和盐水(10mL)洗涤。将合并的有机萃取物用Na2SO4干燥,在减压下浓缩,并将残渣通过PTLC(使用100%EtOAc作为洗脱剂)纯化,得到白色固体形式的酰胺(35mg,84%)。
TLC:100%EtOAc,Rf:0.30.1H NMR(CDCl3,500MHz):δ8.05(d,J=7.5Hz,2H),7.85(bs,1H,NH),7.65(bs,1H,NH),7.60(t,J=7.5Hz,1H),7.55(t,J=7.5Hz,2H),5.26-5.42(m,2H),3.28_3.35(m,2H),2.90(s,3H),2.36(t,2H,J=7.3Hz),1.97-2.08(m,4H),1.51-1.64(m,4H),1.22-1.42(m,14H).mp:72℃-73℃.
实施例9
实施例化合物C44的制备
(Z)-N1-(15-((2-羟基苯基)硫基)十五-5-烯-1-基)-N2-甲基草酰胺C44的合成:
向(Z)-N1-(15-碘十五-5-烯-1-基)-N2-甲基草酰胺(15)(400mg,0.92mmol)和KHCO3(1.2equiv,1.10mmol,111mg)在无水DMF(3.5mL)中的悬浮液中滴加2-巯基苯酚(1equiv,116mg)。将反应物在室温下搅拌。注意:反应物在下一天从白色悬浮液变成澄清的溶液。在反应通过TLC分析评价为完成后,将反应用水终止,用乙酸乙酯(3×30mL)萃取,用无水Na2SO4干燥,过滤并在真空下浓缩。将粗品产物使用Teledyne IscoRf色谱系统(12g SiO2柱,用15-20%EtOAc/己烷洗脱)纯化,得到淡黄色固体形式的标题苯酚(317mg,79%)。
TLC:50%EtOAc/己烷,Rf≈0.65.1H NMR(CDCl3,500MHz)δ7.46(dd,J=7.5,1.5Hz,2H),7.45–7.39(brs,1H),7.29–7.22(m,1H),6.98(dd,J=8.3,1.3Hz,1H),6.87(td,J=7.5,1.3Hz,1H),6.78(s,1H),5.42–5.26(m,2H),3.31(q,J=6.9Hz,2H),2.91(d,J=5.2Hz,3H),2.72–2.65(m,2H),2.10–1.91(m,5H),1.62–1.49(m,5H),1.44–1.23(m,12H);13C NMR(125MHz,CDCl3)δ160.69,159.81,156.99,135.93,130.95,130.72,128.96,120.74,119.37,114.78,39.68,36.85,29.77,29.73,29.52,29.51,29.34,29.19,28.91,28.67,27.32,26.96,26.79,26.28.mp:62.4-62.7℃.
参考文献
1.Meddad-Belhabich,N.;Aoun,D.;Djimdé,A.;Redeuilh,C.;Dive,G.;Massicot,F.;Chau,F.;Heymans,F.;Lamouri,A.Design of new potent and selective secretoryphospholipase A2 inhibitors.6-Synthesis,structure–activity relationships andmolecular modeling of1-substituted-4-[4,5-dihydro-1,2,4-(4H)-oxadiazol-5-one-3-yl(methyl)]-function alized aryl piperazin/one/dione derivatives.Bioorg.Med.Chem.2010,18,3588–3600.
2.Borbas,K.E.;Ling Kee,H.;Holten,D.;Lindsey,S.J.A compact water-soluble porphyrin bearing an iodoacetamido bioconjugatablesite.Org.Biomol.Chem.,2008,6,187–194.
3.Ellingboe,J.W.;Lombardo,L.J.;Alessi,T.R.;Nguyen,T.T.;Guzzo,F.;Guinosso,C.J.;Bullington,J.;Browne,E.N.C.;Bagli,J.F.Antihyperglycemicactivity of novel naphthalenylmethyl-3H-1,2,3,5-oxathiadiazole 2-oxides.J.Med.Chem.1993,36,2485–2493.
4.Thiel,O.R.;Bernard,C.;King,T.;Dilmeghani-Seran,M.;Bostick,T.;Larsen,R.D.;Margaret M.Faul,M.M.J.Org.Chem.2008,73,3508–3515.
5.Falck,J.R.;Wallukat,G.;Puli,N.;Goli,M.;Arnold,C.;Konkel,A.;Rothe,M.;Fischer,R.;Müller,D.N.;Schunck,W.H.17(R),18(S)-epoxyeicosatetraenoic acid,a potent eicosapentaenoic acid(EPA)derived regulator of cardiomyocytecontraction:structure-activity relationships and stableanalogues.J.Med.Chem.2011,54,4109-4118.
6.Y.Hamada等人/Bioorg.Med.Chem.Lett.18:1649-1653,2008。
实施例10
选择的本发明实施例化合物的生物学活性的测定
物质和方法:
所测试的所有化合物的结构示于图1。所述化合物包括如实施例2-9中所述合成的类似物。EPA和17,18-EEQ(购自Cayman Chemical)用作对照。使用前,将要测试的化合物制备为在乙醇中的1000倍储备溶液。
为了测定新化合物的生物学活性,使用建立的细胞模型(Kang,J.X.和A.Leaf,Effects of long-chain polyunsaturated fatty acids on the contraction ofneonatal rat cardiac myocytes.Proc Natl Acad Sci U S A,1994.91(21):p.9886-90.)。自发性搏动的新生大鼠心肌细胞(NRCM)是用于研究测试化合物的抗心律失常作用的模型系统。细胞响应于心律失常物质的无规律且异步的搏动用作体内心脏纤维颤动的体外等同,其可通过合成的17,18-EEQ类似物/测试化合物逆转。
如之前所述进行NRCM的分离和培养(Wallukat,G;Wollenberger,A.BiomedBiochim Acta.1987;78:634–639;Wallukat G,Homuth V,Fischer T,Lindschau C,Horstkamp B,Jupner A,Baur E,Nissen E,Vetter K,Neichel D,Dudenhausen JW,HallerH,Luft FC.J Clin Invest.1999;103:945-952)。简言之,将新生Wistar大鼠(1-2天龄)根据Community of Health Service of the City of Berlin的推荐处死,并用0.2%的粗胰蛋白酶溶液从切碎的心室分离心肌细胞。然后将分离的细胞在用加湿空气平衡的Falcon烧瓶底部(12.5cm2),于2.5ml的Halle SM 20-I培养基中作为单层培养。培养基含有10%热失活的FCS和2μmol/l的氟脱氧尿苷(Serva,Heidelberg,Germany),后者抑制非肌肉细胞的增殖。将NRCM(2.4x 106个细胞/烧瓶)在37℃下于培养箱中培养。5-7天后,NRCM形成自发搏动细胞簇。每个簇中的细胞表现出同步的收缩,搏动速率为120-140次/分钟。在实验的当天,用新鲜的含血清培养基代替培养基。两小时后,在37℃下利用装有加热台的倒置显微镜监测搏动速率。为了测定基础速率,选择6-8个单独簇并计数15sec的收缩数目。然后,向培养物中加入要测试的化合物,并在5min后再监测相同簇的搏动速率。基于单独簇的基础搏动速率与化合物诱导的搏动速率之间的差异,计算变时效应(Δ搏动/min)并表示为平均值±SE值。N表示监测的簇的数目,通常来自至少三个独立的NRCM簇。
结果:
这些实验的结果示于图1。将所测试的所有化合物以30nM的终浓度加入至NRCM中,并且在孵育5分钟后进行测量;除了EPA,其以3.3μM的终浓度使用,并且在孵育30分钟后监测效力。在相同条件下,溶媒对照(0.1%乙醇)显示对自发性搏动速率无作用。
如图1所总结的,所测试的合成类似物表现出与EPA和17,18-EEQ类似的负变时效应。因此,可将羧基用不同的羧酸生物等排体(C38、C41、C42、C43、C44、C49、C50、C52)代替而不改变这些合成类似物的负变时效应。由于C44表现出最低的活性(-7.5±4.5;n=12),其似乎具有效力最低的羧酸生物等排体。
C38、C41、C42、C43、C44、C50和C52提供权利要求1的通式(IV)的化合物的实例。这些化合物中双键的位置与之前的构效关系研究一致,所述研究表明11,12-双键对于17,18-EEQ及其激动剂的生物学活性是关键的(Falck JR,Wallukat G,Puli N,Goli M,Arnold C,Konkel A,Rothe M,Fischer R,Müller DN,Schunck WH.17(R),18(S)-epoxyeicosatetraenoic acid,a potent eicosapentaenoic acid(EPA)derivedregulator of cardiomyocyte contraction:structure-activity relationships andstable analogues.J Med Chem.2011年6月23日;54(12):4109-18)。C48和C49包含在那些分子部分中的芳香环结构,所述结构别样地具有11,12-双键。C48和C49的负变时效应表明权利要求1中通式(III)的化合物也是有生物活性的。
Claims (21)
1.通式(I)的化合物:
P-E-I (I)
或其药学上可接受的盐,
其中
P为由通式(II)表示的基团:
–(CH2)n-B-(CH2)k-X (II)
其中
B表示碳-碳键;-O-;或-S-;
n为3-8的整数;并且
k为0;
X表示基团:
其中
R1表示羟基基团、C1-C6烷氧基、—NHCN、—NH(C1-C6烷基)、—NH(C3-C6环烷基)、—NH(芳基)或—O(C1-C6亚烷基)O(C=O)R11;
R11为C1-C6烷基,其任选地被一个或多个氟原子或氯原子取代;或者C3-C6环烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;
R2表示-NHR3;单糖或二糖或者其衍生物,其经所述糖的1-O-、3-O-或6-O-位通过酯键连接至-C(O);或者
R2选自:
其中
R3表示(SO2R30);(OR31);或-C1-C6亚烷基(SO2R32);
R30为C1-C6烷基或芳基,其中所述C1-C6烷基任选地被下列基团取代:-NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,C1-C6烷基羰基氧基-,C1-C6烷氧基羰基氧基-,C1-C6烷基羰基硫基-,C1-C6烷基氨基羰基-,二(C1-C6)烷基氨基羰基-,一个、两个或三个氟原子或氯原子,或者羟基;并且其中所述芳基任选地被独立地选自下列基团中的一个、两个或三个取代基取代:C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、氟原子或氯原子、羟基、氨基、—NH(C1-C6烷基)和—N(C1-C6)二烷基;
R31为C1-C6烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;或者C3-C6环烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;
R32为C1-C6烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;或者C3-C6环烷基,其任选地被一个或多个氟原子、氯原子或者羟基取代;
R24、R25和R26各自独立地表示氢原子;—C(=O)C11-C21烷基;或—C(=O)C11-C21烯基;
R27表示—OH;—O(CH2)2NH2、—OCH2-[CH(NH2)(CO2H)]、或—O(CH2)2N(CH3)3;
R4表示
h为0、1或2;
R5表示氢原子;氟原子或氯原子;-CF3;-C(=O)OR51;–NHC(=O)R52;-C(=O)NR53R54;或者–S(O2)OH;
R51表示氢原子;C1-C6烷基;或者C3-C6环烷基;其中所述C1-C6烷基或者所述C3-C6环烷基任选地被下列基团取代:-NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,—NH(C1-C6)亚烷基-C1-C6烷氧基,一个、两个或三个氟原子或氯原子,羟基或C1-C6烷氧基;
R52、R53和R54各自独立地表示C1-C6烷基,其任选地被一个或多个氟原子或氯原子取代;C3-C6环烷基,其任选地被一个或多个氟原子或氯原子取代;或者芳基,其任选地被独立地选自下列基团中的一个、两个或三个取代基取代:C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷硫基、氟原子或氯原子、羟基、氨基、—NH(C1-C6烷基)、—N(C1-C6)二烷基和氧代取代基;
R6和R7各自独立地表示羟基;-O(C1-C6)烷基、-O(C2-C6)烯基、-O(C1-C6)亚烷基O(C=O)(C1-C6)烷基或-O(C1-C6)亚烷基O(C=O)(C2-C6)烯基;其中所述C1-C6烷基和所述C2-C6烯基可被下列基团取代:NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,C1-C6烷基羰基氧基-,C1-C6烷氧基羰基氧基-,C1-C6烷基羰基硫基-,C1-C6烷基氨基羰基-,二(C1-C6)烷基氨基羰基-,或者一个、两个或三个氟原子或氯原子;或者
R6表示羟基并且R7表示基团:
R8和R8'各自独立地表示氢原子;C1-C6烷基;–C(=O)C1-C6烷基;–C(=O)C3-C6环烷基;–C(=O)芳基;或者–C(=O)杂芳基;其中所述C1-C6烷基、所述C3-C6环烷基、所述芳基或者所述杂芳基可被一个、两个或三个选自下列基团中的取代基取代:氟原子或氯原子、羟基、-NH2、—NH(C1-C6)烷基、—N(C1-C6)二烷基、—NH(C1-C6)亚烷基-C1-C6烷氧基和C1-C6烷氧基;
R9表示C1-C6烷基或芳基;其中所述C1-C6烷基任选地被下列基团取代:-NH2,—NH(C1-C6)烷基,—N(C1-C6)二烷基,—NH(C1-C6)亚烷基-C1-C6烷氧基,一个、两个或三个氟原子或氯原子,羟基,C1-C6烷氧基,芳基,芳基氧基,—C(═O)-芳基,—C(═O)C1-C6烷氧基;并且其中所述芳基任选地被独立地选自下列基团中的一个、两个或三个取代基取代:C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、氟原子或氯原子、羟基、氨基、—NH(C1-C6烷基)、—N(C1-C6)二烷基和氧代取代基;
g为1或2;
X1表示氧原子;硫原子;或NH;
X2表示氧原子;硫原子;NH;或N(CH3);
E为由通式(IV)表示的基团:
其中
R12和R13表示氢原子;
I为–(CH2)m-Y,其中
m为3-6的整数;
Y表示基团:
其中
R40、R41、R43和R44各自独立地表示氢原子;
R42和R45各自独立地表示-C1-C6烷基。
2.权利要求1的化合物,其中B表示碳-碳键;或者,其中B表示-O-;或者,其中B表示S。
3.权利要求1的化合物,其中R1表示羟基或C1-C6烷氧基基团。
4.权利要求1的化合物,其中R2表示-NHR3。
5.权利要求4的化合物,其中R3表示(SO2R30)。
6.权利要求5的化合物,其中R30为芳基。
8.权利要求1的化合物,其中h为0。
9.权利要求1的化合物,其中R9表示芳基。
10.权利要求1的化合物,其中g为2。
11.权利要求1的化合物,其中R5表示氢原子。
12.权利要求1的化合物,其中R8表示氢原子;并且R8'表示–C(=O)C1-C6烷基。
13.权利要求1的化合物,其中R6和R7各自独立地表示羟基;-O(C1-C6)烷基或-O(C1-C6)亚烷基O(C=O)(C1-C6)烷基。
14.权利要求1的化合物,其中m为3。
15.权利要求1的化合物,其中R42和R45各自为甲基。
17.药物组合物,其包含至少一种权利要求1-16中任一项的化合物以及任选存在的载体物质和/或辅助剂。
18.至少一种权利要求1-16中任一项的化合物在制备用于治疗患者的受益于ω-3(n-3)多不饱和脂肪酸(PUFA)衍生物的给药的病症或疾病的药物中的用途。
19.权利要求18的用途,其中所述患者患有心血管疾病或者过去患有心血管疾病。
20.权利要求19的用途,其中所述心血管疾病为室性心律失常或心房纤维性颤动。
21.权利要求20的用途,其中所述药物用于在一天中向所述患者给药至少0.5mg的所述至少一种化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461930031P | 2014-01-22 | 2014-01-22 | |
US61/930,031 | 2014-01-22 | ||
CN201580005451.7A CN106061942B (zh) | 2014-01-22 | 2015-01-21 | 新型cyp-类二十烷酸衍生物 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201580005451.7A Division CN106061942B (zh) | 2014-01-22 | 2015-01-21 | 新型cyp-类二十烷酸衍生物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110950786A true CN110950786A (zh) | 2020-04-03 |
Family
ID=52446335
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911170917.5A Pending CN110950786A (zh) | 2014-01-22 | 2015-01-21 | 新型cyp-类二十烷酸衍生物 |
CN201580005451.7A Active CN106061942B (zh) | 2014-01-22 | 2015-01-21 | 新型cyp-类二十烷酸衍生物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201580005451.7A Active CN106061942B (zh) | 2014-01-22 | 2015-01-21 | 新型cyp-类二十烷酸衍生物 |
Country Status (21)
Country | Link |
---|---|
US (1) | US11130772B2 (zh) |
EP (1) | EP3097076B1 (zh) |
JP (1) | JP6577951B2 (zh) |
KR (1) | KR102392893B1 (zh) |
CN (2) | CN110950786A (zh) |
AU (1) | AU2015208416B2 (zh) |
BR (1) | BR112016016139B1 (zh) |
CA (1) | CA2934964C (zh) |
CY (1) | CY1122591T1 (zh) |
DK (1) | DK3097076T3 (zh) |
ES (1) | ES2738701T3 (zh) |
HR (1) | HRP20191315T1 (zh) |
HU (1) | HUE044703T2 (zh) |
LT (1) | LT3097076T (zh) |
MX (1) | MX368689B (zh) |
PL (1) | PL3097076T3 (zh) |
PT (1) | PT3097076T (zh) |
RS (1) | RS59218B1 (zh) |
RU (1) | RU2730512C2 (zh) |
SI (1) | SI3097076T1 (zh) |
WO (1) | WO2015110262A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3313816B1 (en) * | 2015-07-22 | 2023-05-24 | OMEICOS Therapeutics GmbH | Metabolically robust analogs of cyp-eicosanoids for the treatment of cardiac disease |
BR112018070194A2 (pt) * | 2016-04-01 | 2019-01-29 | Max Delbrueck Centrum Fuer Molekulare Medizin | composto e composição para uso |
US20190117597A1 (en) * | 2016-04-01 | 2019-04-25 | Omeicos Therapeutics Gmbh | Analogs of cyp-eicosanoids for use in treating or preventing a disorder associated with neovascularization and/or inflammation |
JP7080826B2 (ja) * | 2016-05-16 | 2022-06-06 | ザ ボード オブ リージェンツ オブ ザ ユニバーシティー オブ テキサス システム | カチオン性スルホンアミドアミノ脂質および両親媒性両性イオンアミノ脂質 |
EP4436562A1 (en) | 2021-11-26 | 2024-10-02 | OMEICOS Therapeutics GmbH | Synthetic eicosanoid analogues for the treatment and prevention of diseases associated with increased gdf15 plasma concentration |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102066412A (zh) * | 2008-02-05 | 2011-05-18 | 自然环境研究会 | 由类二十烷酸介导的疾病和病症的治疗 |
CN102348678A (zh) * | 2009-01-13 | 2012-02-08 | 分子医学马克斯德尔布吕克中心 | 新的类二十烷酸衍生物 |
WO2012138706A1 (en) * | 2011-04-06 | 2012-10-11 | Mcw Research Foundation, Inc. | Epoxyeicosatrienoic acid analogs and methods of making and using the same |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5753702A (en) | 1996-05-22 | 1998-05-19 | University Of Vermont | Arachidonic acid metabolite, 16-hete |
US6395781B1 (en) | 1998-02-26 | 2002-05-28 | Mcw Research Foundation | 20-HETE antagonists and agonists |
WO2002059072A2 (en) | 2001-01-02 | 2002-08-01 | New York Medical College | 12-hydroxy-eicosatrienoic acid analogs and methods of use thereof |
WO2004080389A2 (en) * | 2003-03-07 | 2004-09-23 | Taisho Pharmaceutical Co., Ltd. | Hydroxyeicosadienamide compounds |
US20080015184A1 (en) * | 2004-06-14 | 2008-01-17 | 3M Innovative Properties Company | Urea Substituted Imidazopyridines, Imidazoquinolines, and Imidazonaphthyridines |
US20080306155A1 (en) | 2004-09-16 | 2008-12-11 | Roman Richard J | Method for treating renal disease |
US20080095711A1 (en) | 2006-08-31 | 2008-04-24 | Falck John R | Modulators of Pulmonary Hypertension |
US7550617B2 (en) | 2006-10-02 | 2009-06-23 | Medical College Of Georgia Research Institute | Compositions and methods for the treatment of renal and cardiovascular disease |
CN102725261B (zh) | 2009-11-25 | 2014-07-30 | 赛托麦蒂克斯有限公司 | 花生四烯酸类似物及用其进行镇痛治疗的方法 |
-
2015
- 2015-01-21 KR KR1020167022894A patent/KR102392893B1/ko active IP Right Grant
- 2015-01-21 HU HUE15702370 patent/HUE044703T2/hu unknown
- 2015-01-21 PL PL15702370T patent/PL3097076T3/pl unknown
- 2015-01-21 RU RU2016133336A patent/RU2730512C2/ru active
- 2015-01-21 EP EP15702370.6A patent/EP3097076B1/en active Active
- 2015-01-21 JP JP2016548269A patent/JP6577951B2/ja active Active
- 2015-01-21 SI SI201530839T patent/SI3097076T1/sl unknown
- 2015-01-21 CN CN201911170917.5A patent/CN110950786A/zh active Pending
- 2015-01-21 US US15/113,139 patent/US11130772B2/en active Active
- 2015-01-21 CA CA2934964A patent/CA2934964C/en active Active
- 2015-01-21 WO PCT/EP2015/000105 patent/WO2015110262A1/en active Application Filing
- 2015-01-21 MX MX2016009507A patent/MX368689B/es active IP Right Grant
- 2015-01-21 RS RSP20190960 patent/RS59218B1/sr unknown
- 2015-01-21 CN CN201580005451.7A patent/CN106061942B/zh active Active
- 2015-01-21 PT PT15702370T patent/PT3097076T/pt unknown
- 2015-01-21 AU AU2015208416A patent/AU2015208416B2/en active Active
- 2015-01-21 LT LTEP15702370.6T patent/LT3097076T/lt unknown
- 2015-01-21 BR BR112016016139-4A patent/BR112016016139B1/pt active IP Right Grant
- 2015-01-21 DK DK15702370.6T patent/DK3097076T3/da active
- 2015-01-21 ES ES15702370T patent/ES2738701T3/es active Active
-
2019
- 2019-07-22 HR HRP20191315TT patent/HRP20191315T1/hr unknown
- 2019-08-07 CY CY20191100843T patent/CY1122591T1/el unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102066412A (zh) * | 2008-02-05 | 2011-05-18 | 自然环境研究会 | 由类二十烷酸介导的疾病和病症的治疗 |
CN102348678A (zh) * | 2009-01-13 | 2012-02-08 | 分子医学马克斯德尔布吕克中心 | 新的类二十烷酸衍生物 |
WO2012138706A1 (en) * | 2011-04-06 | 2012-10-11 | Mcw Research Foundation, Inc. | Epoxyeicosatrienoic acid analogs and methods of making and using the same |
Non-Patent Citations (2)
Title |
---|
FALCK J. R.等: ""14,15-Epoxye icosa-5,8,11-trienoic Acid ( 14,15-EET ) Surrogat es Containing Epoxide Bioisosteres: Influence upon Vascular Relaxation and Sol uble Epoxide Hydrolase Inhibition"", 《J. MED. CHEM.》 * |
FALCK J. R.等: ""17(R ),18( S )-Epoxyeicosatetraenoic Acid, a Potent Eicosapentaenoic Acid (EPA) Derived Regulator of Cardiomyocyte Contraction: Structure Activity Relati onships and Stable Analogues"", 《J. MED. CHEM.》 * |
Also Published As
Publication number | Publication date |
---|---|
HUE044703T2 (hu) | 2019-11-28 |
MX2016009507A (es) | 2017-03-15 |
CA2934964C (en) | 2022-03-01 |
CA2934964A1 (en) | 2015-07-30 |
WO2015110262A1 (en) | 2015-07-30 |
DK3097076T3 (da) | 2019-07-29 |
PL3097076T3 (pl) | 2019-10-31 |
AU2015208416B2 (en) | 2017-11-30 |
MX368689B (es) | 2019-10-11 |
RU2730512C2 (ru) | 2020-08-24 |
LT3097076T (lt) | 2019-08-26 |
RU2016133336A3 (zh) | 2018-08-10 |
SI3097076T1 (sl) | 2019-10-30 |
EP3097076A1 (en) | 2016-11-30 |
JP2017505313A (ja) | 2017-02-16 |
BR112016016139A2 (zh) | 2017-08-08 |
CY1122591T1 (el) | 2021-01-27 |
AU2015208416A1 (en) | 2016-08-11 |
US11130772B2 (en) | 2021-09-28 |
EP3097076B1 (en) | 2019-05-08 |
KR102392893B1 (ko) | 2022-04-29 |
BR112016016139B1 (pt) | 2023-04-25 |
CN106061942B (zh) | 2019-11-15 |
JP6577951B2 (ja) | 2019-09-18 |
US20170008918A1 (en) | 2017-01-12 |
KR20160111988A (ko) | 2016-09-27 |
ES2738701T3 (es) | 2020-01-24 |
RS59218B1 (sr) | 2019-10-31 |
PT3097076T (pt) | 2019-07-30 |
HRP20191315T1 (hr) | 2019-10-18 |
CN106061942A (zh) | 2016-10-26 |
RU2016133336A (ru) | 2018-02-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110950786A (zh) | 新型cyp-类二十烷酸衍生物 | |
KR101618166B1 (ko) | 신규한 아이코사노이드 유도체 | |
KR100798499B1 (ko) | 약리학적으로 활성인 화합물의 세포 내 전달을 위한양이온성 지질로서 유용한 l-카르니틴 또는 알카노일l-카르니틴의 에스테르 | |
CN108349880B (zh) | 用于治疗心脏疾病的cyp类花生酸代谢稳健类似物 | |
JP2021534215A (ja) | 病的症状の治療における使用のための芳香族分子 | |
US20170183297A1 (en) | Omega-3 analogues | |
JP7032323B2 (ja) | N-ホルミルペプチド受容体モジュレーターとしてのフェニル尿素誘導体 | |
AU2013350311B2 (en) | Omega-3 analogues | |
JP5849336B2 (ja) | アデニル酸シクラーゼの活性調節剤 | |
AU2012298567B2 (en) | New ligands for targeting of S1P receptors for in vivo imaging and treatment of diseases | |
WO2020249120A1 (zh) | 氨基硫醇类化合物作为脑神经或心脏保护剂的用途 | |
JP2021534212A (ja) | 病的状態の治療における使用のための芳香族分子 | |
US20240208942A1 (en) | Metap-2 inhibitors, pharmaceutical compositions and therapeutic methods thereof | |
EP3632893A1 (en) | Vinylarene derivative and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200403 |
|
WD01 | Invention patent application deemed withdrawn after publication |