CN101044117A - 用于治疗缺血性损伤的4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-烷氧基-7-乙炔基-3-氰喹啉 - Google Patents
用于治疗缺血性损伤的4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-烷氧基-7-乙炔基-3-氰喹啉 Download PDFInfo
- Publication number
- CN101044117A CN101044117A CNA2005800360383A CN200580036038A CN101044117A CN 101044117 A CN101044117 A CN 101044117A CN A2005800360383 A CNA2005800360383 A CN A2005800360383A CN 200580036038 A CN200580036038 A CN 200580036038A CN 101044117 A CN101044117 A CN 101044117A
- Authority
- CN
- China
- Prior art keywords
- arbitrary
- compound
- amino
- patient
- chloro
- 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims description 44
- 208000037906 ischaemic injury Diseases 0.000 title description 3
- -1 2,4-dichloro-5-methoxyphenyl Chemical group 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 230000008728 vascular permeability Effects 0.000 claims abstract description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 208000014674 injury Diseases 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
- 230000008733 trauma Effects 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 47
- 208000006011 Stroke Diseases 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 17
- 230000000302 ischemic effect Effects 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 206010021143 Hypoxia Diseases 0.000 claims description 10
- 206010061216 Infarction Diseases 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- 230000007574 infarction Effects 0.000 claims description 10
- 201000006474 Brain Ischemia Diseases 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 230000000324 neuroprotective effect Effects 0.000 claims description 8
- 230000007213 cerebrovascular event Effects 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 230000000926 neurological effect Effects 0.000 claims description 6
- 230000001154 acute effect Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 208000018875 hypoxemia Diseases 0.000 claims description 5
- 206010002660 Anoxia Diseases 0.000 claims description 4
- 241000976983 Anoxia Species 0.000 claims description 4
- 230000007953 anoxia Effects 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 206010019196 Head injury Diseases 0.000 claims description 3
- 208000010496 Heart Arrest Diseases 0.000 claims description 3
- 206010028923 Neonatal asphyxia Diseases 0.000 claims description 3
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 claims description 3
- 230000001037 epileptic effect Effects 0.000 claims description 3
- 208000033300 perinatal asphyxia Diseases 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- 230000001629 suppression Effects 0.000 claims description 2
- 230000007954 hypoxia Effects 0.000 claims 1
- 239000006207 intravenous dosage form Substances 0.000 claims 1
- 230000006378 damage Effects 0.000 abstract description 11
- 208000027418 Wounds and injury Diseases 0.000 abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 14
- 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 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 208000028867 ischemia Diseases 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000007937 lozenge Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 208000005189 Embolism Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 102000001332 SRC Human genes 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- 108010058765 Oncogene Protein pp60(v-src) Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 230000002490 cerebral 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
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 150000003459 sulfonic acid esters Chemical class 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 3
- 238000001238 wet grinding Methods 0.000 description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 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 2
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108060006706 SRC Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000006287 biotinylation Effects 0.000 description 2
- 238000007413 biotinylation Methods 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 229960002424 collagenase Drugs 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000007774 longterm Effects 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
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000862 numbness Toxicity 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 210000003200 peritoneal cavity Anatomy 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 108010087686 src-Family Kinases Proteins 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- BKQFOYCEUMVWOW-UHFFFAOYSA-N 2-iodo-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1I BKQFOYCEUMVWOW-UHFFFAOYSA-N 0.000 description 1
- VNVGDKQKDQGFAR-UHFFFAOYSA-N 3-(chloromethoxy)aniline Chemical class NC1=CC=CC(OCCl)=C1 VNVGDKQKDQGFAR-UHFFFAOYSA-N 0.000 description 1
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 101150012716 CDK1 gene Proteins 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 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
- 208000003164 Diplopia Diseases 0.000 description 1
- 206010013887 Dysarthria Diseases 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018985 Haemorrhage intracranial Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 1
- 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 1
- 201000009906 Meningitis Diseases 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000862969 Stella Species 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 206010042441 Sudden visual loss Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 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
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 230000002802 cardiorespiratory effect Effects 0.000 description 1
- 235000019994 cava Nutrition 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 239000013530 defoamer Substances 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 208000037902 enteropathy Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 210000000630 fibrocyte Anatomy 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000003906 hydrocephalus Diseases 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 238000011859 neuroprotective therapy Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000009023 proprioceptive sensation Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 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
- 230000009467 reduction Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 210000005227 renal system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000003566 sealing material Substances 0.000 description 1
- 230000036362 sensorimotor function Effects 0.000 description 1
- 238000009958 sewing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 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 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及式(I)化合物:其中:R为甲基或乙基;R’及R”独立为1-3个碳原子的烷基,或R’及R”连同其所连接的氮一起可形成5或6元饱和环,所述环可视情况包含选自NR″′、O或S(O)n的额外杂原子;n为0-2;且R″′为氢或1-3个碳原子的烷基;和其医药上可接受的盐,以及其用于抑制由疾病、损伤或其他创伤造成的血管通透性的用途。
Description
技术领域
本发明涉及4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-烷氧基-7-乙炔基-3-氰喹啉且涉及使用所述化合物治疗缺血损伤的方法。
背景技术
在美国,中风是第三个主要死亡原因且是造成残疾的重要原因,每年出现大约750,000例中风。缺血性中风占此数量的约80%,其中原发性脑出血中风占约15-20%。至今为止,针对急性缺血脑梗塞的唯一经认可有效治疗是借助静脉内投与t-PA(重组组织纤维蛋白溶酶原激活剂)的血栓溶解疗法。此疗法的有效性极为有限。其必须在症状开始发作三小时窗内给与,而大多数患者是在实质延迟后寻求及/或接受治疗。此外,利用t-PA治疗具有导致脑出血(一种潜在的破坏性并发症)增加的风险。必须在治疗之前消除出血且在利用t-PA治疗期间及之后必须小心控制并监测血压。目前,没有有效用于治疗缺血中风、出血中风或脑瘤的神经保护疗法。人们极需要用于治疗中风及其他与血管通透性有关的病状的新治疗。
发明内容
具体实施方式
根据本发明一个方面,提供具有以下结构式的化合物:
其中:
R为甲基或乙基;
R’及R”独立为1-3个碳原子的烷基,或R’及R”连同其所连接的氮一起可形成5或6元饱和环,所述环可视情况包括选自NR、O或S(O)n的额外杂原子;
n为0-2;
及
R为氢或1-3个碳原子的烷基;及其医药上可接受的盐。
在本发明某些较佳实施例中,R’及R”连同其所连接的氮一起形成N-(C1-C3)-烷基哌嗪、哌啶、哌嗪或吗啉。
在本发明一些较佳实施例中,R为甲基。
在本发明其他较佳实施例中,R’及R”连同其所连接的氮一起形成N-(C1-C3)-烷基哌嗪、哌嗪或吗啉环。
当R’及R”连同其所连接的氮一起形成N-(C1-C3)-烷基哌嗪时,其较佳形成N-甲基哌嗪。
在本发明再其他较佳实施例中,R’及R”皆为甲基。
医药上可接受的盐是那些衍生自有机及无机酸者,例如:乙酸、乳酸、羧酸、柠檬酸、肉桂酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、草酸、丙酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、乙醇酸、丙酮酸、甲磺酸、乙磺酸、甲苯磺酸、水杨酸、苯甲酸、及类似习知医药上可接受的酸。
由NR’R”所定义视情况包含一个选自NR、O或S(O)n的额外杂原子的五或六元饱和环包括(但不限于)吡咯烷、吡唑烷、咪唑烷、哌啶、哌嗪、吗啉、硫吗啉、1-氧代-1-硫吗啉及1,1-二氧代-1-硫吗啉。
本发明的特定化合物包括:
4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[4-(二甲基氨基)丁-1-炔基]-6甲氧基-3-氰喹啉;
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[4-(4-甲基哌嗪-1-基)丁-1-炔基]-3-氰喹啉;
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(4-吗啉-4-基丁-1-炔基)-3-氰喹啉;
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(4-哌嗪-1-基丁-1-炔基)-3-氰喹啉;及
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[4-(4-甲基哌嗪-1-基)丁-1-炔基]-3-氰喹啉、及其医药上可接受的盐。
本发明的其他方面包括含有本文所述化合物及至少一种医药上可接受的载剂或赋形剂的医药组合物及使用这些化合物治疗缺血损伤的方法。
本发明化合物是如下文所述制备。本发明化合物是自以下制备:(a)市售起始材料(b)可如文献程序中所述制备的习知起始材料或(c)本文方案及试验性程序中所述的新中间体。
反应是在适于所用试剂及材料且适用于所实施转化的溶剂中实施。熟悉有机合成项技术者应了解,分子上存在的各种官能团必须符合所建议的化学转化。当并未规定时,采用熟悉该项技术者所明了的合成步骤顺序、保护基团的选择和去保护条件。此外,在某些情况下,起始材料上的取代基可能与某些反应条件不相容。与给定取代基有关的限制对熟悉该项技术者显而易见。反应是在惰性气氛(若适宜)下进行。
如方案1中所绘示制备式I化合物。式1(其中R为Me)的化合物可容易地自
1a、即3-氰基-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-喹啉基三氟甲烷磺酸酯制得。
1a的制备已报告于文献Berger,D.等人的Bioorg.Med.Chem.Lett.(12,2761(2002))及美国专利第6521618号(2003年2月18日)中,其整体内容以引用的方式并入本文中。
将
1a利用3-丁炔-1-醇在钯催化剂(较佳四(三苯基膦)钯)连同碘化铜的存在下在溶剂系统(例如三乙基胺及二氧杂环乙烷)中在高温(较佳95-100℃)下处理,获得式
2化合物。式
2化合物与甲烷磺酰氯在溶剂系统(例如N,N-二甲基甲酰胺及四氢呋喃)中在降低温度(较佳0℃)下反应,给出对应的甲磺酸盐。中间体甲磺酸盐通常并不分离,而是直接用式R″R′NH的适宜胺处理来获得式I化合物。可使用其他离去基团(例如甲苯磺酸根)作为甲磺酸根基团的替代物。
除
1a之外,可使用其他起始材料获得式I(其中R为Me)的化合物,所述起始材料包括
1b(4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-碘-6-甲氧基-3-氰喹啉)及
1c(7-溴-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-3-氰喹啉)。
式I(其中R为Et)的化合物可容易地自4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-碘-3-氰喹啉
1d起始获得。
方案1
式I化合物的替代途径绘示于方案2中。将式
1a-d的化合物利用式
3的胺在钯催化剂(较佳二氯双(三苯基膦)钯(II))连同碘化铜及三苯基膦的存在下在溶剂系统(例如三乙基胺及N-甲基吡咯烷酮)中在高温(较佳70℃)下处理,获得式I化合物。或者,式
1a-d化合物与式
3胺的反应可在三乙基胺及N,N-二甲基甲酰胺的溶剂系统中或者在碱(例如碳酸钾)的存在下在甲醇及四氢呋喃的溶剂系统中实施。
方案2
在若干标准药理学测试中评价本发明化合物,所述测试展示本发明化合物抑制Src激酶且用于预防血管通透性。
Src激酶分析
重组人类Src酶是从PanVera(P3044)获得。使用对应于Cdk1的残基6-20的生物素化肽作为底物(生物素-KVEKIGEGTYGVVYK-COOH)。使用铕/APC检测形式(LANCE,Perkin Elmer)实施均相荧光共振能量转移激酶分析。将Src酶(10ng)与生物素化肽(最终浓度为2μM)、50mM Hepes(pH 7.5)、10mM MgCl2、20μg/ml BSA、0.001%Brij-35(Sigma)、100μM ATP、1%DMSO混合。将激酶反应在37℃下培育70分钟。利用EDTA在最终浓度为30mM EDTA/25mM Hepes(pH 7.5)/10μg/ml BSA下终止所述反应。将所述混合物与Eu-标记的抗磷酸酪氨酸抗体PT66(Perkin Elmer,AD0068)及链霉亲和素Surelight-APC(Perkin Elmer,CR130-100)在50mM Hepes(pH 7.5)/20μg/ml BSA中组合,并根据制造商的说明书培育30分钟。使用665nm荧光强度监测所述激酶反应的程度。给定化合物的多项记录表明其经历多次测试。本发明代表性化合物的结果列于下表1中。
非贴壁依赖性Src转化成纤维细胞增殖分析
使用经质粒(其含有CMV启动子控制的v-Src/Hu c-Src融合基因,其中插入人类c-Src催化域代替v-Src基因中的v-Src催化域)稳定转化的大鼠2成纤维细胞来测量src依赖性悬浮生长。第1天,在超低群集板(Costar编号3474)的每一孔中种10,000个细胞。或者,在经Sigmacote(Sigma)处理、70%乙醇冲洗、在通风橱中干燥后的超低群集盘(Costar 3474)中种5000个细胞。第2天添加化合物自10微摩尔浓度至0.009微摩尔浓度的连续两倍稀释液,第5天添加MTS试剂(Promega)(100微升MTS/培养基混合物+100微升已经在细胞上的培养基),并在490nm处测量吸光度。根据以下分析结果可获得如下增殖IC50(微摩尔浓度单位):%抑制=(490nm样品吸光度值-空白值)/(490nm无化合物对照品吸光度值-空白值)×100%。给定化合物的多项记录表明其经历多次测试。本发明代表性化合物的结果列于下表1中。
表1.Src酶及细胞活性的抑制
实例 | R | NR’R” | Src酶IC50nM | Src细胞IC50nM |
1 | Me | NMe2 | 5.0,4.7 | 252,240 |
2 | Me | N-Me-哌嗪 | 3.5,4.2 | 71,70,77 |
3 | Me | 吗啉 | 4.0,4.1 | 206,183 |
4 | Me | 哌嗪 | 5.9,4.8 | 435,605 |
5 | Et | N-Me-哌嗪 | 6.5,2.8 | 96,183,154,103 |
实例2的静脉内投与在短暂性局部缺血模型中提供神经保护
在短暂性局部缺血的模型中测试实例2。使用管腔内缝合方法使Wistar大鼠经受90分钟的脑中动脉(MCA)栓塞,随后再灌注48小时,如Longa等人在Stroke 1989,20:84中所述。缺血开始发作后4小时,动物接受作为单次i.v推注存于5%右旋糖、0.9%pH为4.5-5.0的乳酸中的实例2化合物(3mg/kg、10mg/kg或30mg/kg)。再灌注后,在48小时内针对神经功能缺陷评价动物。MCA栓塞后48小时时将动物处死,然后测量梗塞面积。10及30mg/kg剂量的实例2明显将中风诱发的神经缺陷的恢复率分别提高35%和53%(占对照的百分比)(统计误差:10-12%)。10mg/kg及30mg/kg的实例2观察到梗塞脑组织体积在统计上明显减少,此表明梗塞体积减少32%及40%(占对照的百分比)(统计误差;7-10%)。
实例2的静脉内投与在永久局部缺血模型中提供神经保护并提高长期神经恢复
在脑中动脉永久性栓塞、无再灌注的模型中测试实例2,实质上如Chen等人在Stroke,1986,17:738中所述。这是一个比短暂性局部缺血更严苛的模型。脑中动脉电凝后2小时时,以10mg/kg静脉内投与媒剂或实例2,随后在诱发中风后4、24及26小时时静脉内投与3次10mg/kg的附加剂量。在一项研究中,中风后48小时时估计被破坏的脑组织。在第二项研究中,根据触觉和本体感觉肢体放置(实质上如DeRyck等人在Brain Res.1992,573:44中所述)在中风后三周的时间过程内以三天时间间隔对动物进行感觉运动功能测试。在用实例2治疗的动物中,发现诱发中风后48小时时梗塞体积实质上明显减少24%。此外,实例2明显改善此中风模型中所诱发的神经缺陷的长期感觉运动恢复率。
实例2的静脉内投与在出血性中风模型中提供神经保护
在通过胶原酶的纹状体内输注所诱发的脑出血大鼠模型(实质上如Rosenberg等人在Stroke,1990,20:801中所述)中测试实例2。在此模型中,输注至尾状核中的胶原酶对血管基膜中的胶原造成蛋白水解破坏并诱发颅内出血及水肿,在24-48小时时达到高峰。诱发出血性中风后4小时时将实例2以10mg/kg或30mg/kg的剂量作为单次i.v注射投与。24小时后测定脑水含量作为水肿的量度。结果表明,实例2在两个测试剂量下使出血后脑水肿分别明显降低18%及24%。
由于疾病、损伤或其他创伤造成的血管通透性可出现在各个组织及器官(包括中枢神经系统、心肺系统、肠胃系统及肾脏系统的器官)中。本发明化合物可用于抑制有疾病、损伤或其他创伤造成的血管通透性。具体而言,可抑制脑血管事件后大脑和脊柱组织中的血管通透性。血管通透性是脑血管事件后血管渗漏及/或水肿的主要原因且通常导致神经病症及残疾。脑血管事件包括(但不限于)短暂性和急性缺血事件,其可根据本发明进行治疗。急性事件包括(但不限于)中风、头部创伤、脊柱创伤、普通缺氧症、低氧(包括胎儿低氧)、低血糖症、低血压以及内陷、高灌注及低氧程序期间所看到的类似损伤。中风包括(但不限于)局部及全脑缺血、短暂性脑缺血发作及其他伴随脑缺血的脑血管问题。本发明也可用于各种脑血管事件,其包括脑出血、由颅内或外动脉的栓塞或血栓形成造成的梗塞、围产期窒息、心脏停搏及癫痫持续状态,尤其当流向大脑的血液被终止一段时间时。与血管渗漏有关的脑血管事件还包括感染,其包括(但不限于)与神经炎症有关通过血管泄漏传播伤害周围组织的脑炎及脑膜炎。系统疾病(例如糖尿病、多发性硬化、肾脏疾病及动脉粥样硬化)也可导致血管通透性增加。本发明化合物还用于抑制由中枢神经系统以外的局部组织/器官缺血(低氧)事件(包括但不限于心肌缺血及缺血性肠病)引起的血管通透性。
本发明化合物为患者提供神经保护。本文所用的神经保护是指保护神经细胞对抗细胞死亡或细胞凋亡。细胞死亡或细胞凋亡程度的一个量度是梗塞体积;坏死或死亡脑组织的体积。成像技术和患者的临床状况可用于估计缺血事件后的梗塞体积。与在类似缺血事件中在没有本发明药剂的情况下所具有的典型梗塞体积相比,本发明化合物减少患者的梗塞体积。
本发明化合物防止、降低或抑制与血管通透性有关的神经变性及/或神经毒性,所述神经变性及/或神经毒性导致包括(但不限于)以下的症状:视觉损害(例如突然视力丧失或复视)、言语或语言损害(例如失语症或构音障碍)、记忆损害、轻度认知损害至痴呆范围内的认知损害或机能障碍、及运动损害(包括但不限于麻木、失去肌肉控制、虚弱、无感觉或麻痹)。因上文所阐述的损伤或疾病产生的神经缺陷(例如上文所阐述的那些)可根据本发明抑制或预防。因此,本发明提供治疗、预防、抑制或缓解哺乳动物、较佳人类中与上文所列举的血液渗漏或通透性有关的状况,所述方法包括为需要其的哺乳动物、且具体而言人类患者提供医药有效量、且具体而言血管通透性抑制量的本发明化合物。
本发明还涵盖用于治疗或调节血管通透性的医药组合物,所述医药组合物包括至少一种式I化合物、其混合物及或其医药上的盐、且因此医药上可接受的载剂。所述组合物是根据容许医药程序制备,例如Remingtons Pharmaceutical Sciences(第17版,编者Alfonoso R.Gennaro,Mack Publishing Company,Easton,PA(1985))中所述。医药上可接受的载剂是那些与调配物中其他成份相容且生物上可接受的载剂。
在制备溶液、悬浮液、乳液、糖浆及酏剂(包括静脉内溶液)中可使用液体载剂。可将本发明的活性成份溶解或悬浮于医药上可接受的液体载剂(例如水、有机溶剂或二者的混合物)中。所述液体载剂可包含其他适宜医药添加剂,例如增溶剂、乳化剂、缓冲剂、防腐剂、甜味剂、调味剂、悬浮剂、增稠剂、着色剂、粘度调节剂、稳定剂、通透调节剂、抗氧化剂及消泡剂。
用于口服、静脉内及非经肠投与的液体载剂的适宜实例包括水(尤其包含上述者,例如纤维素衍生物、较佳羧甲基纤维素钠溶液)、盐水、右旋糖溶液、右旋糖-盐水及右旋糖-水溶液、醇(包括一元醇及多元醇在内,例如乙二醇)及其衍生物。液体载剂是以无菌形式用于非经肠和静脉内投与。在某些情况中,可通过添加HCl、氢氧化钠及磷酸调节液体调配物的pH。较佳地,本发明组合物是为存于等渗生理上相容的缓冲系统中的无菌溶液或悬浮液的液体医药组合物。
本发明的液体医药组合物可通过(例如)肌内、腹膜腔内、静脉内或皮下注射投与。本发明的医药组合物较佳通过腹膜腔内或静脉内注射投与患者。最佳地,所述组合物是通过(例如)静脉内推注、静脉内i.v.滴注、重复的缓慢推注投与或输注投与静脉内。
口服投与可为液体或固体组合物形式。本发明化合物也可以纯净形式或与传统医药载剂组合经口或非经肠投与。可接受的固体载剂可包括一种或多种物质,其可作为矫味剂、润滑剂、增溶剂、悬浮剂、填充剂、助流剂、压缩助剂、粘结剂或锭剂崩解剂或密封材料。对于粉末而言,所述载剂是与微细活性成份混合的微细固体。就锭剂而言,将所述活性成份与具有所需压缩性质的载剂以适宜比例混合并压制为期望形状及尺寸。粉末和锭剂较佳包含高达99%的活性成份。适宜固体载剂包括(例如)磷酸钙、硬脂酸镁、滑石粉、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素纳、聚乙烯吡咯烷、低熔点蜡和离子交换树脂。
较佳地,所述医药组合物呈单位剂型,例如,锭剂、胶囊、粉末、悬浮液、乳液、颗粒、栓剂、安瓿或药丸。在所述形式中,将所述组合物细分成包含适宜量活性成份的单位剂量;所述单位剂型可为经包装组合物,例如袋装粉末、冻干粉末或安瓿瓶或小瓶中的块状物、或小瓶、安瓿瓶、预充式注射器或含有液体的药囊。所述单位剂型可为(例如)胶囊或锭剂自身,或其可为适宜量的任何呈带装形式的所述组合物。
提供给患者的剂量应视所投与药物、投与目的(例如预防或治疗)、及所述患者的状况、投与方式等而有所不同。“治疗有效量”是足以治愈或改善疾病或损伤症状的量。通常,单一剂量(或剂型)应包含约1mg/kg至约30mg/kg、且更佳约1mg/kg至约10mg/kg的本发明化合物。预计一些患者将接受若干剂量。用于治疗特定病例的剂量必须由主治医生主观地确定。所涉及的变量包括特定状况及患者的大小、年龄和响应模式。
本发明提供优于先前习知中风及与血管通透性有关的其他状况治疗的优点。具体而言,尽管较佳在缺血性损伤后尽可能早地治疗患者,但当损伤后6-18小时且甚至缺血性损伤后长达约18-24小时投与本发明化合物,也可有效预防一些患者中神经变性或神经缺陷的发展。而且,可持续治疗且缺血性损伤后持续或重复投与本发明化合物长达约72小时或更长时间可改善患者的预后。
本文所用的提供是指直接投与本发明化合物或组合物,或投与将在体内形成等效量活性化合物或物质的前药、衍生物或类似物。
本发明包括式I化合物的前药。本文所用“前药”是指一种在活体内通过代谢方法(例如,通过水解)可转化成式I化合物的化合物。各种形式的前药已为该项技术所习知,如在以下文献中所讨论:Bundgaard(编者)的Design of Prodrugs,Elsevier(1985);Widder等人(编者)的Methods in Enzymology,第4卷,Academic Press(1985);Krogsgaard-Larsen等人(编者)的“Design and Application of Prodrugs,Textbook of DrugDesign and Development,第5章,113-191(1991);Bundgaard等人,Journal of DrugDelivery Reviews,8:1-38(1992),Bundgaard,J.of Pharmaceutical Sciences,77:285 et seq.(1988);以及Higuchi与Stella(编者)的Prodrugs as Novel Drug Delivery Systems,American Chemical Society(1975)。
将结合以下特定实例更全面地阐述本发明,但不应将所述实例视为限制本发明的范围。
参考实例1
2-氰基-N-(2,4-二氯-5-甲氧基苯基)乙酰胺
在N2下将2,4-二氯-5-甲氧基苯胺(5.00g,26mmol)及氰基乙酸(2.28g,26.8mmol)在50mL四氢呋喃中混合,直到形成溶液为止。将所述溶液加热回流并滴加1,3-二异丙基碳化二亚胺(4.2mL,26.8mmol)。30分钟后,TLC检查(5%存于CH2Cl2中的MeOH)表明所述反应完成。将混合物在冰浴中冷却至约15℃。通过过滤收集固体并用四氢呋喃洗涤。将滤液缓慢倾倒于水中并搅拌30分钟。通过过滤收集白色固体,用水洗涤,接着溶于500mL乙酸乙酯中。将溶液经Na2SO4干燥并在真空中浓缩,获得5.9g(88%)白色固体2-氰基-N-(2,4-二氯-5-甲氧基苯基)乙酰胺,mp 180-181℃;MS 257.0,259.0(M-H)-。
C10H8Cl2N2O2的分析:
计算值:C,46.36;H,3.11;N,10.81。
实验值:C,46.25;H,3.10;N,10.85。
参考实例2
2-氰基-N-(2,4-二氯-5-甲氧基苯基)-3-[(3-碘-4-甲氧基苯基)氨基]-丙-2-烯酰胺
在N2下向of 2-氰基-N-(2,4-二氯-5-甲氧基苯基)乙酰胺(5.00g,19.30mol)存于400mL异-丙醇的悬浮液中添加3-碘-对-甲氧基苯胺(5.80g,23.16mmol)。将所述混合物加热回流以获得一透明黄色溶液。向所述溶液中逐滴添加原甲酸三乙酯(8.60mL,52.11mmol)并使反应混合物在回流下加热过夜。添加额外的10mL原甲酸三乙酯并使混合物在回流下加热过夜。将所述混合物冷却至室温,并通过过滤收集白色固体,用异-丙醇洗涤并在约40℃下在降低压力下干燥过夜。通过悬浮在热乙酸乙酯中随后添加冰己烷来纯化,获得8.50g(85%)黄色固体2-氰基-N-(2,4-二氯-5-甲氧基苯基)-3-[(3-碘-4-甲氧基苯基)氨基]丙-2-烯酰胺,mp 289-290℃;MS(ES)m/z516.7(M-H)-。
C18H14Cl2IN3O3的分析:
计算值:C,41.73;H,2.72;N,8.11。
实验值:C,40.88;H,2.64;N,7.90。
参考实例3
4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-碘-6-甲氧基-3-氰喹啉
向2-氰基-N-(2,4-二氯-5-甲氧基苯基)-3-[(3-碘-4-甲氧基-苯基)氨基]丙-2-烯酰胺(720mg,1.39mmol)存于40mL乙腈的悬浮液中添加0.2mL甲醇。将混合物加热回流并经由注射器逐滴添加磷酰氯(1.24mL,13.9mmol)。使所述溶液在回流下加热过夜。24小时后,将混合物在冰浴中冷却且固体通过过滤收集,用冰乙腈(40mL)洗涤并然后悬浮于四氢呋喃(100mL)中。向乙腈滤液和四氢呋喃悬浮液二者中添加浓缩氢氧化铵(2×50mL)并将混合物搅拌1小时。添加水(2×800ml)并再搅拌2小时。将所得固体合并,用热水洗涤并在降低压力下于约40℃下干燥过夜,获得200mg(29%)黄色固体4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-碘-6-甲氧基-3-氰喹啉,mp253-254℃;1H NMR(400MHz,DMSO-d6)δ3.86(s,3H),4.00(s,3H),7.33(s,1H),7.74(s,1H),7.86(s,1H),8.39(s,1H),8.43(s,1H),9.61(s,1H);MS(ES)m/z 500.0,502.1(M+H)+。
C18H12Cl2IN3O2-H2O的分析:
理论值:C,41.72,H,2.72,N,8.11
实验值:C,41.80;H,2.52;N,7.87。
参考实例4
1-乙氧基-2-碘-4-硝基苯
将2-碘-4-硝基酚(21g,79.2mmol)[Kometani,T.;等人,Tetrahedron Lett.(1985).26(17).2043]、碘乙烷(9mL,0.48mol)及碳酸钾(40.7g,0.3mol)存于100mL N,N-二甲基甲酰胺中的悬浮液于70℃下加热3小时。将反应冷却至室温并添加乙酸乙酯。将无机盐滤出并用乙酸乙酯洗涤。将有机材料用水(3X)及盐水洗涤、经硫酸镁干燥并过滤。将滤液浓缩后出现固体。将所述固体用己烷洗涤,获得5.2g白色晶体1-乙氧基-2-碘-4-硝基苯。将滤液浓缩获得额外的11.3g合意产物,mp 81-83℃;1H NMR(400MHz,DMSO-d6)δ1.42(t,3H),4.26(q,2H),7.18(d,1H),8.26(dd,1H),8.55(d,1H)。
C8H8INO3的分析:
理论值:C,32.79,H,2.75,N,4.78。
实验值:C,32.71;H,2.58;N,4.53。
参考实例5
(4-乙氧基-3-碘苯基)胺
将铁(3.81g,70mmol)及氯化铵(5.47g,102mmol)存于80mL乙醇及25mL水中的悬浮液加热回流。分批添加1-乙氧基-2-碘-4-硝基苯(5.0g,20mmol)并将反应于回流下加热1小时。将热混合物通过硅藻土过滤,用热乙醇洗涤。将滤液在真空中浓缩并用乙酸乙酯和水处理。将有机层萃取、用盐水洗涤、经硫酸镁干燥并过滤。在真空中去除溶剂,获得5.1g浅褐色油状物(4-乙氧基-3-碘苯基)胺;1H NMR(400MHz,DMSO-d6)δ1.30(s,3H),3.89(q,2H),4.82(bs,2H),6.53(dd,1H),6.72(d,1H),7.11(d,1H);MS(ES)m/z 263.9(M+H)+。
C8H10INO的分析:
理论值:C,36.52,H,3.83,N,5.32。
实验值:C,36.84,H,3.71,N,4.96。
参考实例6
2-氰基-N-(2,4-二氯-5-甲氧基苯基)-3-[(4-乙氧基-3碘苯基)氨基]丙烯酰胺
在N2下向2-氰基-N-(2,4-二氯-5-甲氧基苯基)乙酰胺(5.44g,21.0mmol)存于350mL异-丙醇中的悬浮液添加(4-乙氧基-3-碘苯基)-胺(5.0g,19.30mmol)。将此混合物加热至回流并逐滴添加原甲酸三乙酯(8.53mL,51.30mmol)并将反应混合物在回流下加热过夜。将所述混合物冷却至室温,并通过过滤收集黄色固体、用异-丙醇洗涤并于约40℃下在降低压力下干燥过夜,获得5.46g(54%)黄色固体2-氰基-N-(2,4-二氯-5-甲氧基苯基)-3-[(4-乙氧基-3-碘苯基)氨基]丙-2-烯酰胺,mp>245℃;MS(El)m/z531.01(M)+。
C19H16Cl2IN3O3的分析:
计算值:C,42.88;H,3.03;N,7.90。
实验值:C,42.99;H,2.97;N,7.74。
参考实例7
4-[(2.4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-碘-3-氰喹啉
将2-氰基-N-(2,4-二氯-5-甲氧基苯基)-3-[(4-乙氧基-3-碘-苯基)氨基]丙-2-烯酰胺(2.0g,3.76mmol)存于100mL甲苯中的悬浮液加热至回流并经由注射器逐滴添加磷酰氯(3.5mL,37.6mmol)。将所述悬浮液于回流下加热6小时并缓慢添加额外的磷酰氯(3.5mL,37.6mmol),获得黑色溶液。72小时后,将混合物冷却至室温,将固体滤出并用甲苯和乙醚洗涤。使浅褐色固体在降低压力下于约40℃下干燥过夜,获得1.47g(76%)黄色固体4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-碘-3-氰喹啉,mp 213-215℃;1H NMR(300MHz,DMSO-d6)δ1.48(t,3H,J=6.9Hz),4.32(q,2H,J=6.9Hz),3.88(s,3H),7.53(s,1H),7.87(s,1H),8.06(s,1H),8.49(s,1H),9.02(s,1H),11.14(bs,1H);MS(ES)m/z 514.1(M+H)+。
C19H14Cl2IN3O2-4.0HCl的分析:
理论值:C,34.58,H,2.75,N,6.37
实验值:C,34.79;H,2.60;N,6.13。
参考实例8
4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-(4-羟基丁-1-烯基)-6-甲氧基-3-氰喹啉
将3-氰基-4-[(2,4-二氯-5-甲氧基苯基)苯胺基]-6-甲氧基-7-喹啉基三氟甲烷磺酸酯(2.0g,3.8mmol)、3-丁炔-1-醇(0.44mL,0.56mmol)、四(三苯基膦)钯(0.22g,0.19mmol)及碘化铜(45mg,0.24mmol)存于12mL三乙基胺及30mL 1,4-二氧杂环乙烷混合物中的混合物于95-100℃下加热2小时并然后冷却至室温。添加乙酸乙酯和水。通过过滤去除固体,在热乙醚中湿磨、过滤并干燥,获得0.65g(38%)4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-(4-羟基丁-1-炔基)-6-甲氧基-3-氰喹啉,mp 230-232℃;1HNMR(DMSO-d6)5 2.65(t,2H,J=6.9Hz),3.62(q,2H,J=6.9,6.0Hz),3.86(s,3H),3.98(s,3H),4.96(t,1H,J=6.0Hz),7.39(s,1H),7.76(s,1H),7.89(s,2H),8.44(s,1H),9.97(bs,1H);MS(ES)m/z 442.0(M+H)+;HRMS 442.07198(M+H)+;HPLC-93%。
参考实例9
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-(4-羟基丁-1-烯基)-3-氰喹啉
将4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-碘-3-喹啉-甲腈(0.6g,1.2mmol)、3-丁炔-1-醇(0.13mL,1.7mmol)、四(三苯基-膦)钯(68mg,0.058mmol)及碘化铜(15mg,0.076mmol)存于4mL三乙基胺和10mL 1,4-二氧杂环乙烷混合物中的混合物于95℃下加热3小时并然后冷却至室温。添加乙酸乙酯和水。将有机层萃取、经硫酸镁干燥、过滤并浓缩。添加乙醚并将固体过滤且用热乙醚(3X)洗涤。将固体和滤液合并并通过色谱法使用0至10%甲醇和二氯甲烷的梯度进行纯化。将所获得黄色固体在热乙醚中湿磨、过滤并干燥,获得0.16g(31%)4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-(4-羟基丁-1-炔基)-3-喹啉-甲腈,mp 220-222℃;1H NMR(DMSO-d6)δ1.44(t,3H,J=6.8Hz),2.65(t,2H,J=6.8Hz),3.63(dt,2H,J=6.9,5.8Hz),3.86(s,3H),4.25(q,2H,J=6.8Hz),4.95(t,1H,J=5.8Hz),7.39(s,1H),7.77(s,1H),7.87(s,2H),8.44(s,1H),9.75(bs,1H);MS(ES)m/z 456.1(M+H)+;HRMS 456.08763(M+H)+;HPLC-98%。
实例1
4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[4-(二甲基氨基)丁-1-烯基]-6-甲氧基-3-氰喹啉
于0℃下向4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-(4-羟基丁-1-炔基)-6-甲氧基-3-氰喹啉(0.3g,0.68mmol)和三乙基胺(0.47mL,3.4mmol)存于3mLN.N-二甲基甲酰胺和15mL四氢呋喃的混合物中逐滴添加甲烷磺酰氯(0.16mL,2.0mmol)。将混合物搅拌1.25小时并添加二甲基胺(2.0mL,2.0M存于四氢呋喃中的溶液)。将反应于室温下搅拌过夜。添加额外的3.0mL三乙基胺并将所述反应于室温下搅拌过夜。将混合物浓缩并用乙酸乙酯及水稀释。将有机层萃取、经硫酸镁干燥、过滤并浓缩。残余物通过色谱法使用0至10%存于二氯甲烷中的甲醇梯度来纯化。将产物在热乙醚中湿磨、过滤并干燥,获得62mg(20%)黄色固体4-[(2,4-二氯-5-甲氧基-苯基)氨基]-7-[4-(二甲基氨基)丁-1-炔基]-6-甲氧基-3-氰喹啉,mp 177-179℃;1H NMR(DMSO-d6)δ2.22(s,6H),2.56(t,2H,J=6.8Hz),2.65(t,2H,J=6.8Hz),3.86(s,3H),3.96(s,3H),7.38(s,1H),7.76(s,1H),7.88(s,2H),8.43(s,1H),9.82(bs,1H);MS(ES)m/z 469.1(M+H)+。
C24H22Cl2N4O2-1.5HCl的分析
理论值:C,58.07,H,5.08,N,11.29。
实验值:C,58.46,H,4.82,N,10.99。
实例2
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[4-(4-甲基哌嗪-1-基)丁-1-烯基]-
3-氰喹啉
按照合成实例1所用的相同程序,获得90mg(25%)黄色固体4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[4-(4-甲基-哌嗪-1-基)丁-1-炔基]-3-氰喹啉,mp165-167℃;1H NMR(DMSO-d6)δ2.17(s,3H),2.35(bs,4H),2.50(bs,4H),2.60-2.68(m,4H),3.86(s,3H),3.96(s,3H),7.34(s,1H),7.74(s,1H),7.83(s,1H),7.88(s,1H),8.43(s,1H),9.83(bs,1H),MS(ES)m/z 524.2(M+H)+。
C27H27Cl2N5O2-1.5H2O的分析
理论值:C,58.80,H,5.48,N,12.70。
实验值:C,58.89,H,5.19,N,12.38。
实例2的替代制备:
将3-氰基-4-[(2,4-二氯-5-甲氧基苯基)苯胺基]-6-甲氧基-7-喹啉基三氟甲烷磺酸酯(2.5g,4.8mmol)、1-丁-3-烯基-4-甲基-哌嗪(1.8g,11.8mmol)[Vaillancourt,V.A.等人WO2002002558A1]、双(三苯基膦)二氯化钯(170mg,0.22mmol)、碳酸钾(3.31g,0.024mol)三苯基膦(25mg,0.9mmol)及碘化铜(45mg,0.22mmol)存于6mL甲醇和30mL四氢呋喃混合物中的混合物于60℃下加热4小时小时并然后冷却至室温。添加乙酸乙酯和水。将有机层萃取、经硫酸镁亁燥、过滤并浓缩。通过色谱法使用0至10%存于二氯甲烷中的甲醇、随后20%甲醇-二氯甲烷/1%NH4OH的梯度作为溶剂系统来纯化残余物,获得2.2g(88%)4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[4-(4-甲基哌嗪-1-基)丁-1-炔基]-3-氰喹啉。
实例2的第二种替代制备
将4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-碘-6-甲氧基-3-喹啉-甲腈(0.2g,0.4mmol)、1-丁-3-烯基-4-甲基哌嗪(0.21g,1.4mmol)[Vaillancourt,V.A.等人,WO2002002558A1]、双(三苯基膦)二氯化钯(14mg,0.02mmol)、三苯基膦(21mg,0.08mmol)和碘化铜(5mg,0.02mmol)存于2mL三乙基胺及1mL N-甲基-吡咯烷酮混合物中的混合物于70℃下加热4小时并然后冷却至室温。添加乙酸乙酯和水。将有机层萃取、经硫酸镁亁燥、过滤并浓缩。通过色谱法使用0至10%存于二氯甲烷中的甲醇、随后15%甲醇-二氯甲烷/1%NH4OH的梯度作为溶剂系统来纯化残余物,获得78mg(37%)4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[4-(4-甲基-哌嗪-1-基)丁-1-炔基]-3-氰喹啉。
实例3
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(4-吗啉-4-基丁-1-烯基)-3-氰喹啉
按照合成实例1所用的相同程序,获得150mg(43%)黄色固体4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(4-吗啉-4-基丁-1-炔基)-3-氰喹啉,mp 140-142℃;1HNMR(DMSO-d6)δ2.50(t,4H,J=4.4Hz),2.58-2.73(m,4H),3.60(t,4H,J=4.4Hz),3.87(s,3H),3.98(s,3H),7.39(s,1H),7.77(s,1H),7.87(s,1H),7.89(s,1H),8.45(s,1H),9.82(bs,1H);MS(ES)m/z 511.0(M+H)+。
C26H24Cl2N4O3的分析
理论值:C,61.06,H,4.73,N,10.96。
实验值:C,60.89,H,4.74,N,10.82。
实例4
4-[(2.4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(4-哌嗪-1-基丁-1-炔基)-3-氰喹啉
按照合成实例1所用的相同程序。通过柱色谱纯化后,获得120mg包含产物的混合物。将混合物进一步通过HPLC使用5至95%乙腈/水(0.02%TFA)梯度纯化,获得15mg(5%)黄色固体4-[(2,4-二氯-5-甲氧基-苯基)氨基]-6-甲氧基-7-(4-哌嗪-1-基丁-1-炔基)-3-氰喹啉,mp 188-190℃;1H NMR(DMSO-d6)δ2.85(t,2H,J=6.8Hz),3.03(bs,6H),3.32(bs,4H),3.89(s,3H),3.98(s,3H),7.35(s,1H),7.77(s,1H),7.89(s,1H),7.92(s,1H),8.52(s,1H),8.81(bs,1H),10.01(bs,1H);MS(ES)m/z 510.1(M+H)+。
C26H25Cl2N5O2-3TFA/1H2O的分析
理论值:C,44.18,H,3.48,N,8.06。
实验值:C,44.07,H,3.22,N,8.06。
实例5
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[4-(4-甲基哌嗪-1-基)丁-1-烯基]-
3-氰喹啉
根据合成实例1所用的相同程序,获得45mg(24%)黄色固体4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[4-(4-甲基-哌嗪-1-基)丁-1-炔基]-3-氰喹啉,mp158-160℃;1H NMR(DMSO-d6)δ1.43(t,3H,J=6.8Hz),2.19(s,3H),2.38(bs,4H),2.50(bs,4H),2.60-2.67(m,4H),3.86(s,3H),4.22(q,2H,J=6.8Hz),7.36(s,1H),7.74(s,1H),7.84(s,1H),7.88(s,1H),8.42(s,1H),9.78(bs,1H);MS(ES)m/z 538.2(M+H)+;HRMS538.17726(M+H)+;HPLC纯度为99%。
Claims (27)
2、如权利要求1所述的化合物,其中R’及R”均为甲基。
3、如权利要求1所述的化合物,其中R’及R”连同其所连接的氮一起形成N-(C1-C3)-烷基哌嗪、哌嗪或吗啉环。
4、如权利要求3所述的化合物,其中所述N-(C1-C3)烷基哌嗪环是N-甲基-哌嗪。
5、如权利要求1至4中任一权利要求所述的化合物,其中R为甲基。
6、如权利要求1所述的化合物,其中所述化合物选自:
4-[(2,4-二氯-5-甲氧基苯基)氨基]-7-[4-(二甲基氨基)丁-1-炔基]-6-甲氧基-3-氰喹啉;
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[4-(4-甲基哌嗪-1-基)丁-1-炔基]-3-氰喹啉;
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(4-吗啉-4-基丁-1-炔基)-3-氰喹啉;
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-(4-哌嗪-1-基丁-1-炔基)-3-氰喹啉;和
4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-乙氧基-7-[4-(4-甲基哌嗪-1-基)丁-1-炔基]-3-氰喹啉;
和其医药上可接受的盐。
7、一种医药组合物,其包括如权利要求1至6中任一权利要求所述的化合物及其医药上可接受的盐以及至少一种医药上可接受的载剂或赋形剂。
8、一种医药组合物,其包括血管通透性抑制量的如权利要求1至6中任一权利要求所述的化合物及其医药上可接受的盐以及至少一种医药上可接受的载剂或赋形剂。
9、如权利要求7或8所述的组合物,其为静脉内剂型。
10、一种在患者脑血管缺血事件后提供神经保护的方法,所述方法包括提供治疗有效量的权利要求1至6中任一权利要求所述的化合物。
11、一种在患者脑血管缺血事件后抑制神经缺陷的方法,所述方法包括提供治疗有效量的权利要求1至6中任一权利要求所述的化合物。
12、一种在患者脑血管缺血事件后减少梗塞体积的方法,所述方法包括投与治疗有效量的如权利要求1至6中任一权利要求所述的化合物。
13、一种抑制遭受脑血管事件的患者中的脑血管的缺血后血管通透性的方法,所述方法包括投与治疗有效量的权利要求1至6中任一权利要求所述的化合物。
14、如权利要求10至13中任一权利要求所述的方法,其中所述化合物是在所述缺血事件后约6至约24小时之间投与。
15、如权利要求10至14中任一权利要求所述的方法,其中所述治疗有效量介于约1mg/kg至约30mg/kg之间。
16、如权利要求10至15中任一权利要求所述的方法,其包括静脉内投与式I化合物。
17、如权利要求10至16中任一权利要求所述的方法,其中所述患者是人类。
18、如权利要求10至17中任一权利要求所述的方法,其中所述缺血事件是短暂性的。
19、如权利要求10至17中任一权利要求所述的方法,其中所述缺血事件是急性的。
20、如权利要求19所述的方法,其中所述缺血事件是中风、头部创伤、脊柱创伤、普通缺氧症(anoxia)或低氧(hypoxia)。
21、如权利要求10至20中任一权利要求所述的方法,其中所述缺血事件发生在脑出血、围产期窒息、心脏停搏或癫痫持续状态期间。
22、一种权利要求1至6中任一权利要求所述的化合物在制造医药中的用途,所述医药用于在患者脑血管缺血事件后提供神经保护、在患者脑血管缺血事件后抑制神经缺陷、在患者脑血管缺血事件后减少梗塞体积以及抑制遭受脑血管事件的患者中的脑血管的缺血后血管通透性。
23、如权利要求22所述的用途,其中所述患者是人类。
24、如权利要求22或权利要求23所述的用途,其中所述缺血事件是短暂性的。
25、如权利要求22或权利要求23所述的用途,其中所述缺血事件是急性的。
26、如权利要求25所述的用途,其中所述缺血事件是中风、头部创伤、脊柱创伤、普通缺氧症或低氧。
27、如权利要求22至26中任一权利要求所述的用途,其中所述缺血事件是发生在脑出血、围产期窒息、心脏停搏或癫痫持续状态期间。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62128004P | 2004-10-22 | 2004-10-22 | |
US60/621,280 | 2004-10-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101044117A true CN101044117A (zh) | 2007-09-26 |
Family
ID=35784691
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2005800360383A Pending CN101044117A (zh) | 2004-10-22 | 2005-10-21 | 用于治疗缺血性损伤的4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-烷氧基-7-乙炔基-3-氰喹啉 |
Country Status (24)
Country | Link |
---|---|
US (1) | US20060116375A1 (zh) |
EP (1) | EP1802581B1 (zh) |
JP (1) | JP2008517924A (zh) |
KR (1) | KR20070085413A (zh) |
CN (1) | CN101044117A (zh) |
AT (1) | ATE391122T1 (zh) |
AU (1) | AU2005299822A1 (zh) |
BR (1) | BRPI0516995A (zh) |
CA (1) | CA2581807A1 (zh) |
CR (1) | CR9072A (zh) |
DE (1) | DE602005005843T2 (zh) |
DK (1) | DK1802581T3 (zh) |
EC (1) | ECSP077385A (zh) |
ES (1) | ES2303287T3 (zh) |
HK (1) | HK1104555A1 (zh) |
IL (1) | IL182547A0 (zh) |
MX (1) | MX2007004833A (zh) |
NO (1) | NO20071708L (zh) |
PL (1) | PL1802581T3 (zh) |
PT (1) | PT1802581E (zh) |
RU (1) | RU2007111704A (zh) |
SI (1) | SI1802581T1 (zh) |
WO (1) | WO2006047262A1 (zh) |
ZA (1) | ZA200703275B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102952037A (zh) * | 2012-11-18 | 2013-03-06 | 大连九信生物化工科技有限公司 | 一种2-氰基-n-(2,4-二氯-5-甲氧苯基)乙酰胺的合成方法 |
CN103848785A (zh) * | 2012-12-04 | 2014-06-11 | 上海医药集团股份有限公司 | 一类氘代3-氰基喹啉类化合物、其药用组合物、制备方法及其用途 |
CN114436851A (zh) * | 2022-01-17 | 2022-05-06 | 常州大学 | 一种n,n-二甲基苄胺及其衍生物的制备方法 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200829555A (en) * | 2006-11-10 | 2008-07-16 | Astrazeneca Ab | Chemical compounds |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6002008A (en) * | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
US6297258B1 (en) * | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
US6521618B2 (en) * | 2000-03-28 | 2003-02-18 | Wyeth | 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors |
TWI275390B (en) * | 2002-04-30 | 2007-03-11 | Wyeth Corp | Process for the preparation of 7-substituted-3- quinolinecarbonitriles |
TW200423938A (en) * | 2003-02-21 | 2004-11-16 | Wyeth Corp | 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury |
-
2005
- 2005-10-21 MX MX2007004833A patent/MX2007004833A/es active IP Right Grant
- 2005-10-21 CA CA002581807A patent/CA2581807A1/en not_active Abandoned
- 2005-10-21 BR BRPI0516995-0A patent/BRPI0516995A/pt not_active IP Right Cessation
- 2005-10-21 AT AT05820982T patent/ATE391122T1/de not_active IP Right Cessation
- 2005-10-21 JP JP2007538054A patent/JP2008517924A/ja not_active Withdrawn
- 2005-10-21 CN CNA2005800360383A patent/CN101044117A/zh active Pending
- 2005-10-21 DE DE602005005843T patent/DE602005005843T2/de active Active
- 2005-10-21 SI SI200530255T patent/SI1802581T1/sl unknown
- 2005-10-21 RU RU2007111704/04A patent/RU2007111704A/ru not_active Application Discontinuation
- 2005-10-21 AU AU2005299822A patent/AU2005299822A1/en not_active Abandoned
- 2005-10-21 EP EP05820982A patent/EP1802581B1/en not_active Not-in-force
- 2005-10-21 US US11/255,556 patent/US20060116375A1/en not_active Abandoned
- 2005-10-21 PL PL05820982T patent/PL1802581T3/pl unknown
- 2005-10-21 PT PT05820982T patent/PT1802581E/pt unknown
- 2005-10-21 DK DK05820982T patent/DK1802581T3/da active
- 2005-10-21 ES ES05820982T patent/ES2303287T3/es active Active
- 2005-10-21 KR KR1020077011472A patent/KR20070085413A/ko not_active Application Discontinuation
- 2005-10-21 WO PCT/US2005/037839 patent/WO2006047262A1/en active Application Filing
-
2007
- 2007-03-30 NO NO20071708A patent/NO20071708L/no not_active Application Discontinuation
- 2007-04-11 EC EC2007007385A patent/ECSP077385A/es unknown
- 2007-04-12 IL IL182547A patent/IL182547A0/en unknown
- 2007-04-20 ZA ZA200703275A patent/ZA200703275B/xx unknown
- 2007-04-20 CR CR9072A patent/CR9072A/es not_active Application Discontinuation
- 2007-11-27 HK HK07112929A patent/HK1104555A1/xx not_active IP Right Cessation
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102952037A (zh) * | 2012-11-18 | 2013-03-06 | 大连九信生物化工科技有限公司 | 一种2-氰基-n-(2,4-二氯-5-甲氧苯基)乙酰胺的合成方法 |
CN103848785A (zh) * | 2012-12-04 | 2014-06-11 | 上海医药集团股份有限公司 | 一类氘代3-氰基喹啉类化合物、其药用组合物、制备方法及其用途 |
CN114436851A (zh) * | 2022-01-17 | 2022-05-06 | 常州大学 | 一种n,n-二甲基苄胺及其衍生物的制备方法 |
CN114436851B (zh) * | 2022-01-17 | 2023-08-22 | 常州大学 | 一种n,n-二甲基苄胺及其衍生物的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
BRPI0516995A (pt) | 2008-09-30 |
CA2581807A1 (en) | 2006-05-04 |
AU2005299822A1 (en) | 2006-05-04 |
ES2303287T3 (es) | 2008-08-01 |
NO20071708L (no) | 2007-07-13 |
HK1104555A1 (en) | 2008-01-18 |
ATE391122T1 (de) | 2008-04-15 |
EP1802581A1 (en) | 2007-07-04 |
JP2008517924A (ja) | 2008-05-29 |
PT1802581E (pt) | 2008-06-03 |
ZA200703275B (en) | 2008-08-27 |
SI1802581T1 (sl) | 2008-08-31 |
DK1802581T3 (da) | 2008-06-30 |
PL1802581T3 (pl) | 2008-09-30 |
ECSP077385A (es) | 2007-05-30 |
US20060116375A1 (en) | 2006-06-01 |
DE602005005843D1 (de) | 2008-05-15 |
KR20070085413A (ko) | 2007-08-27 |
WO2006047262A1 (en) | 2006-05-04 |
EP1802581B1 (en) | 2008-04-02 |
IL182547A0 (en) | 2007-09-20 |
DE602005005843T2 (de) | 2009-05-14 |
MX2007004833A (es) | 2007-05-16 |
RU2007111704A (ru) | 2008-11-27 |
CR9072A (es) | 2007-09-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1177833C (zh) | 取代的间二氮杂萘衍生物 | |
CN110062754B (zh) | 作为选择性Janus激酶抑制剂的氨基吡唑类化合物 | |
AU2008265600B2 (en) | Methods and compositions for stimulating neurogenesis and inhibiting neuronal degeneration using isothiazolopyrimidinones | |
CN106536480A (zh) | 吡咯烷‑2,5‑二酮衍生物、药物组合物及用作ido1抑制剂的方法 | |
KR101158568B1 (ko) | 신경발생을 자극 및 신경 퇴화를 억제하는 방법 및 조성물 | |
MX2012009541A (es) | Derivados de ciclobutano y metilciclobutano como inhibidores de janus cinasa. | |
JP2010531849A (ja) | オレキシン受容体アンタゴニストとしてのイミダゾ[1,2−c]ピリミジン−2−イルメチルピペリジン誘導体 | |
CN103874699A (zh) | 吡唑并[4,3-c]吡啶衍生物作为激酶抑制剂 | |
JP2010508324A (ja) | プロテインキナーゼモジュレーターとしての3−アミノカルボニル置換縮合ピラゾロ誘導体 | |
WO2018084321A1 (ja) | Egfr阻害及び腫瘍治療に有用な新規化合物 | |
EP2164328B1 (en) | Therapeutic pyrazoloquinoline urea derivatives | |
EA020609B1 (ru) | ИМИДАЗО[1,2-а]ПИРИДИН-2-ИЛФЕНИЛ ПРОИЗВОДНЫЕ ДЛЯ ЛЕЧЕНИЯ РАКА | |
JP2023554282A (ja) | 置換ピペリジノ化合物及び関連する治療方法 | |
CN101044117A (zh) | 用于治疗缺血性损伤的4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-烷氧基-7-乙炔基-3-氰喹啉 | |
WO2012155339A1 (zh) | 4-苯胺-6-丁烯酰胺-7-烷醚喹唑啉衍生物及其制备方法和用途 | |
JP2020529465A (ja) | キナーゼ阻害剤として有用な置換ピラゾロピリミジン | |
US20040229880A1 (en) | 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury | |
CN1167698C (zh) | 用作神经激肽受体拮抗剂的n-三唑基甲基哌嗪衍生物 | |
WO2010096395A1 (en) | Amides as kinase inhibitors | |
CN107459521B (zh) | Flt3激酶的新型抑制剂及其用途 | |
CN105732583A (zh) | 一种治疗脑胶质母细胞瘤的靶向化合物 | |
CN103965119A (zh) | 含有锌结合基的不可逆egfr酪氨酸激酶抑制剂 | |
WO2016115869A1 (zh) | Flt3激酶的新型抑制剂及其用途 | |
CN111039947A (zh) | 一类蛋白受体激酶抑制剂的制备和应用 | |
CN1046273C (zh) | 用作记忆增强剂的3-芳基-4-烷基及4,5-二烷基-4h-1,2,4-三唑 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20070926 |
|
C20 | Patent right or utility model deemed to be abandoned or is abandoned |