JP2018080113A - Treatment agent of cerebral infarction - Google Patents
Treatment agent of cerebral infarction Download PDFInfo
- Publication number
- JP2018080113A JP2018080113A JP2015107763A JP2015107763A JP2018080113A JP 2018080113 A JP2018080113 A JP 2018080113A JP 2015107763 A JP2015107763 A JP 2015107763A JP 2015107763 A JP2015107763 A JP 2015107763A JP 2018080113 A JP2018080113 A JP 2018080113A
- Authority
- JP
- Japan
- Prior art keywords
- cerebral infarction
- group
- compound
- agent
- test
- 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
- 206010008118 cerebral infarction Diseases 0.000 title claims abstract description 110
- 208000026106 cerebrovascular disease Diseases 0.000 title claims abstract description 80
- 238000011282 treatment Methods 0.000 title claims abstract description 33
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000003527 fibrinolytic agent Substances 0.000 claims abstract description 8
- 229960000103 thrombolytic agent Drugs 0.000 claims abstract description 8
- 230000001154 acute effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 11
- 206010008111 Cerebral haemorrhage Diseases 0.000 abstract description 5
- 230000007246 mechanism Effects 0.000 abstract description 2
- 125000004663 dialkyl amino group Chemical group 0.000 abstract 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 50
- 229940125904 compound 1 Drugs 0.000 description 41
- 241000700159 Rattus Species 0.000 description 30
- 238000004519 manufacturing process Methods 0.000 description 26
- 239000013641 positive control Substances 0.000 description 26
- 239000003981 vehicle Substances 0.000 description 25
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 24
- 239000000126 substance Substances 0.000 description 21
- 201000006474 Brain Ischemia Diseases 0.000 description 19
- 206010008120 Cerebral ischaemia Diseases 0.000 description 19
- 210000003657 middle cerebral artery Anatomy 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 208000007536 Thrombosis Diseases 0.000 description 18
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 230000001052 transient effect Effects 0.000 description 15
- 206010060860 Neurological symptom Diseases 0.000 description 14
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 13
- 229950009041 edaravone Drugs 0.000 description 13
- -1 alkali metal salts Chemical class 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 210000003462 vein Anatomy 0.000 description 9
- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 0 CCCN(C)C* Chemical compound CCCN(C)C* 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 206010002091 Anaesthesia Diseases 0.000 description 6
- 230000037005 anaesthesia Effects 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 210000000269 carotid artery external Anatomy 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 208000006011 Stroke Diseases 0.000 description 5
- 238000000692 Student's t-test Methods 0.000 description 5
- 235000010724 Wisteria floribunda Nutrition 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 210000004004 carotid artery internal Anatomy 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- RIMUHDOEPYXAMV-UHFFFAOYSA-N 5-pyridin-4-ylpyridine-2-carbaldehyde Chemical compound C1=NC(C=O)=CC=C1C1=CC=NC=C1 RIMUHDOEPYXAMV-UHFFFAOYSA-N 0.000 description 4
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000004809 Teflon Substances 0.000 description 4
- 229920006362 Teflon® Polymers 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 229960002725 isoflurane Drugs 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- VYCADPDVDFTZFI-UHFFFAOYSA-N 5-bromo-2-(1,3-dioxolan-2-yl)pyridine Chemical compound N1=CC(Br)=CC=C1C1OCCO1 VYCADPDVDFTZFI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102000010909 Monoamine Oxidase Human genes 0.000 description 3
- 108010062431 Monoamine oxidase Proteins 0.000 description 3
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 3
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- WVILRWXMXUGYBA-UHFFFAOYSA-M [4-(2-methoxy-2-oxoethyl)phenyl]methyl-triphenylphosphanium;bromide Chemical compound [Br-].C1=CC(CC(=O)OC)=CC=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WVILRWXMXUGYBA-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001555 benzenes Chemical class 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 210000001168 carotid artery common Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 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
- 229940079593 drug Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000001361 intraarterial administration Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000001603 reducing effect Effects 0.000 description 3
- 238000010825 rotarod performance test Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- YVHSDJASEWOYSL-UHFFFAOYSA-N 2-(1,3-dioxolan-2-yl)-5-pyridin-3-ylpyridine Chemical compound O1C(OCC1)C1=CC=C(C=N1)C=1C=NC=CC=1 YVHSDJASEWOYSL-UHFFFAOYSA-N 0.000 description 2
- MJNVZYZJBIOUKW-UHFFFAOYSA-N 5-[6-(1,3-dioxolan-2-yl)pyridin-3-yl]pyrimidine Chemical compound O1C(OCC1)C1=CC=C(C=N1)C=1C=NC=NC=1 MJNVZYZJBIOUKW-UHFFFAOYSA-N 0.000 description 2
- JITDPKPBUMNTIB-UHFFFAOYSA-N 5-pyrimidin-5-ylpyridine-2-carbaldehyde Chemical compound N1=CN=CC(=C1)C=1C=CC(=NC=1)C=O JITDPKPBUMNTIB-UHFFFAOYSA-N 0.000 description 2
- 206010008088 Cerebral artery embolism Diseases 0.000 description 2
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229960003318 alteplase Drugs 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000001269 cardiogenic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 201000010849 intracranial embolism Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
- LOQRRKHPHDUDME-UHFFFAOYSA-N 2-(1,3-dioxolan-2-yl)-5-pyridin-4-ylpyridine Chemical compound O1C(OCC1)C1=CC=C(C=N1)C1=CC=NC=C1 LOQRRKHPHDUDME-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
- WZEVKZAFLJJHAM-UHFFFAOYSA-N 2-[4-[2-(5-pyridin-3-ylpyridin-2-yl)ethyl]phenyl]acetohydrazide Chemical compound N1=CC(=CC=C1CCC1=CC=C(C=C1)CC(=O)NN)C=1C=NC=CC=1 WZEVKZAFLJJHAM-UHFFFAOYSA-N 0.000 description 1
- CBCYYYHTVSKUAZ-UHFFFAOYSA-N 2-[4-[2-(5-pyridin-4-ylpyridin-2-yl)ethyl]phenyl]acetohydrazide Chemical compound N1=CC(=CC=C1CCC1=CC=C(C=C1)CC(=O)NN)C1=CC=NC=C1 CBCYYYHTVSKUAZ-UHFFFAOYSA-N 0.000 description 1
- WZFPTULXUSYJBO-UHFFFAOYSA-N 2-[4-[2-(5-pyrimidin-5-ylpyridin-2-yl)ethyl]phenyl]acetohydrazide Chemical compound N1=CN=CC(=C1)C=1C=CC(=NC=1)CCC1=CC=C(C=C1)CC(=O)NN WZFPTULXUSYJBO-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
- HRZQYNVEQATAEI-UHFFFAOYSA-N 3-bromo-2-(1,3-dioxolan-2-yl)pyridine Chemical compound Brc1cccnc1C1OCCO1 HRZQYNVEQATAEI-UHFFFAOYSA-N 0.000 description 1
- ZQVLPMNLLKGGIU-UHFFFAOYSA-N 5-bromopyridine-2-carbaldehyde Chemical compound BrC1=CC=C(C=O)N=C1 ZQVLPMNLLKGGIU-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 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
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010063648 Cerebral artery stenosis Diseases 0.000 description 1
- 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 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 108010057987 Desmodus rotundus salivary plasminogen activator alpha 1 Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- 238000012276 Endovascular treatment Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 229920001499 Heparinoid Polymers 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 241001484259 Lacuna Species 0.000 description 1
- 208000004552 Lacunar Stroke Diseases 0.000 description 1
- 206010051078 Lacunar infarction Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 241000384016 Rattus morotaiensis Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 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
- 108090000190 Thrombin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 108050006955 Tissue-type plasminogen activator Proteins 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 1
- 229960003856 argatroban Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000013172 carotid endarterectomy Methods 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229950001282 desmoteplase Drugs 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 description 1
- 229960004253 dexmedetomidine Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000011038 discontinuous diafiltration by volume reduction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000002554 heparinoid Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940106780 human fibrinogen Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical class CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229950003837 ozagrel Drugs 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011251 protective drug Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- HZFPPBMKGYINDF-UHFFFAOYSA-N pyrimidin-5-ylboronic acid Chemical compound OB(O)C1=CN=CN=C1 HZFPPBMKGYINDF-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000012216 screening Methods 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
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- NCNYJCOBUTXCBR-IPZCTEOASA-M sodium;(e)-3-[4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate Chemical compound [Na+].C1=CC(/C=C/C(=O)[O-])=CC=C1CN1C=NC=C1 NCNYJCOBUTXCBR-IPZCTEOASA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 210000001321 subclavian vein Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 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
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000013151 thrombectomy Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K31/435—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本発明は、特定の構造を有するベンゼン誘導体であるＶＡＰ−１阻害剤を含む脳梗塞処置剤に関する。 The present invention relates to a cerebral infarction treatment agent containing a VAP-1 inhibitor which is a benzene derivative having a specific structure.
脳卒中の患者数は２０２０年頃には日本国内で３００万人に達すると推定され、また、一旦発症すると後遺症を残す可能性が高く、福祉および医療経済面でも大きな課題となっている。脳卒中にはいくつかの種類があり、脳の血管がつまる脳梗塞と、脳の血管が破れて出血する「脳出血」や「くも膜下出血」に大別される。脳梗塞は、一般に、脳動脈の閉塞または狭窄により脳虚血が生じ、脳組織が酸素または栄養の不足のため壊死または壊死に近い状態になることを特徴とする疾患である。脳梗塞には、脳内小動脈病変が原因の「ラクナ梗塞」、頸部ないし頭蓋内の比較的大きな動脈のアテローム硬化が原因の「アテローム血栓性脳梗塞」、心疾患による「心原性脳塞栓症」等の病型が含まれる。 The number of stroke patients is estimated to reach 3 million in Japan around 2020, and once it develops, there is a high possibility of remaining sequelae, which is a major issue in welfare and medical economics. There are several types of strokes, which can be broadly divided into cerebral infarction, where the blood vessels in the brain are clogged, and “cerebral hemorrhage” and “subarachnoid hemorrhage”, where the blood vessels in the brain are broken and bleed. Cerebral infarction is a disease characterized in that cerebral ischemia generally occurs due to cerebral artery occlusion or stenosis, and brain tissue becomes necrotic or nearly necrotic due to lack of oxygen or nutrients. Cerebral infarction includes “lacuna infarction” caused by intracerebral small artery lesions, “atherothrombotic cerebral infarction” caused by atherosclerosis of relatively large arteries in the neck or skull, “cardiogenic brain” caused by heart disease Disease types such as “embolism” are included.
急性期の脳梗塞に対しては、組織プラスミノーゲン活性化因子（tissue plasminogen activator：ｔＰＡまたはｔ−ＰＡ）による血栓溶解治療が第一選択である。プラスミノーゲンは、血管内に出来た血栓を強力に溶解する酵素である。脳の動脈に生じた血栓により脳梗塞が起こった後にｔＰＡを投与することにより、血栓を溶解し、血液の流れを回復させる治療が行われている（血栓溶解療法）。ｔＰＡ治療により自立して生活できるまで回復する患者は４０−５０％と報告されている。しかしながら、発症からｔＰＡ投与までの時間が長く経過した場合には、脳出血を引き起こすことがあり、現状は発症後４.５時間以内の患者にしか使用できない。また、最近、発症から6時間以内の治療可能な患者に機械的血栓回収療法により血栓を除去する血管内治療を行うことも実施されつつある。いずれにしても更なる治療改善率および適応時間の拡大が臨床現場から強く望まれており、脳内出血のリスクを軽減し、かつ治療対象を広げる新たな治療法を開発することは極めて重要である。 For acute cerebral infarction, thrombolytic treatment with tissue plasminogen activator (tPA or t-PA) is the first choice. Plasminogen is an enzyme that strongly dissolves blood clots formed in blood vessels. A treatment that dissolves the thrombus and restores the blood flow by administering tPA after a cerebral infarction has occurred due to a thrombus generated in a cerebral artery has been performed (thrombolytic therapy). It has been reported that 40-50% of patients recover by tPA treatment until they can live independently. However, if a long time elapses from onset to tPA administration, cerebral hemorrhage may be caused, and the present situation can be used only for patients within 4.5 hours after onset. Recently, endovascular treatment for removing a thrombus by mechanical thrombectomy is being performed on a treatable patient within 6 hours of onset. In any case, there is a strong desire from the clinical site to further improve the treatment improvement rate and the adaptation time, and it is extremely important to develop a new treatment method that reduces the risk of intracerebral hemorrhage and expands the treatment target. .
ＶＡＰ−１（Vascular adhesion protein-1）は、ＳＳＡＯ（セミカルバジド感受性アミンオキシダーゼ）とも呼ばれるタンパク質である。膜結合型のＶＡＰ−１は血管内皮表面に存在し、遊離型のＳＳＡＯは血清中に存在する。前者は白血球（炎症に関連する顆粒球、炎症や免疫に関連するリンパ球や単球）との接着分子の機能を持ち、主に炎症に関連し、後者はアミンオキシダーゼ活性により生体内のアミンの解毒を担う。糖尿病、アトピー性皮膚炎、乾癬、肥満、動脈硬化、心疾患等の患者の血清および種々の組織においてＶＡＰ−１／ＳＳＡＯ活性の増加が見られる。そのため、過剰になったＶＡＰ−１／ＳＳＡＯの機能をＶＡＰ−１／ＳＳＡＯ阻害剤により抑制し、正常化することにより、これらの疾患を処置することが期待されている。 VAP-1 (Vascular adhesion protein-1) is a protein called SSAO (semicarbazide sensitive amine oxidase). Membrane-bound VAP-1 is present on the surface of vascular endothelium and free SSAO is present in serum. The former functions as an adhesion molecule with leukocytes (granulocytes related to inflammation, lymphocytes and monocytes related to inflammation and immunity), and the latter is mainly related to inflammation. Responsible for detoxification. Increased VAP-1 / SSAO activity is seen in the serum and various tissues of patients with diabetes, atopic dermatitis, psoriasis, obesity, arteriosclerosis, heart disease and the like. Therefore, it is expected to treat these diseases by suppressing and normalizing the excessive function of VAP-1 / SSAO with a VAP-1 / SSAO inhibitor.
脳梗塞に関連して、血漿ＶＡＰ−１活性が高い脳卒中の患者は、神経症状の予後が悪いことが報告されている（非特許文献１）。また、自己血栓または栓子により脳虚血を生じさせた脳梗塞モデルラットにおいて、ＶＡＰ−１阻害剤が神経保護効果を示すことが報告されている（非特許文献１および２）。 In relation to cerebral infarction, it has been reported that stroke patients with high plasma VAP-1 activity have a poor prognosis of neurological symptoms (Non-patent Document 1). In addition, it has been reported that a VAP-1 inhibitor exhibits a neuroprotective effect in a cerebral infarction model rat in which cerebral ischemia is caused by self-thrombosis or an obturator (Non-patent Documents 1 and 2).
ＶＡＰ−１阻害活性を有するベンゼン、チオフェンまたはチアゾール誘導体が知られており、ＶＡＰ−１関連疾患の予防または治療に使用し得ることが示唆されている（特許文献１および２）。 Benzene, thiophene or thiazole derivatives having VAP-1 inhibitory activity are known, and it has been suggested that they can be used for prevention or treatment of VAP-1-related diseases (Patent Documents 1 and 2).
本発明者らは、鋭意研究の末、特定の構造を有するベンゼン誘導体であるＶＡＰ−１阻害剤が脳梗塞の処置に特に有効であることを見出し、本発明を完成した。 As a result of intensive studies, the present inventors have found that a benzene derivative having a specific structure, a VAP-1 inhibitor, is particularly effective in the treatment of cerebral infarction, and completed the present invention.
従って、本発明は、以下の通りである。
［１］式（Ｉ）
ｍは１または２の整数であり、
ｎは２または３の整数であり、
Ａは、
からなる群から選択される］、
の化合物またはその医薬上許容され得る塩を含む、脳梗塞処置剤（本明細書において、本発明の脳梗塞処置剤と称する）。
［２］Ａが、
［３］Ａが、
［４］Ｒがメチルである、［３］に記載の脳梗塞処置剤。
［５］急性期の脳梗塞を処置するための、［１］ないし［４］のいずれかに記載の脳梗塞処置剤。
［６］１種またはそれ以上のさらなる薬剤と、同時に、連続的に、または異なる時点で対象に投与するための、［１］ないし［５］のいずれかに記載の脳梗塞処置剤。
［７］さらなる薬剤が他の脳梗塞処置剤である、［６］に記載の脳梗塞処置剤。
［８］さらなる薬剤が血栓溶解剤である、［６］または［７］に記載の脳梗塞処置剤。
［９］血栓溶解剤がｔＰＡである、［８］に記載の脳梗塞処置剤。
［１０］式（Ｉ）
ｍは１または２の整数であり、
ｎは２または３の整数であり、
Ａは、
からなる群から選択される］、
の化合物またはその医薬上許容され得る塩。
［１１］
[1] Formula (I)
m is an integer of 1 or 2,
n is an integer of 2 or 3,
A is
Selected from the group consisting of],
Or a pharmaceutically acceptable salt thereof, a cerebral infarction treatment agent (referred to herein as the cerebral infarction treatment agent of the present invention).
[2] A is
[3] A is
[4] The cerebral infarction treatment agent according to [3], wherein R is methyl.
[5] The cerebral infarction treatment agent according to any one of [1] to [4] for treating acute cerebral infarction.
[6] The agent for treating cerebral infarction according to any one of [1] to [5], which is administered to a subject simultaneously with one or more additional agents at the same time, sequentially, or at different time points.
[7] The agent for treating cerebral infarction according to [6], wherein the further agent is another agent for treating cerebral infarction.
[8] The cerebral infarction treatment agent according to [6] or [7], wherein the further agent is a thrombolytic agent.
[9] The cerebral infarction treatment agent according to [8], wherein the thrombolytic agent is tPA.
[10] Formula (I)
m is an integer of 1 or 2,
n is an integer of 2 or 3,
A is
Selected from the group consisting of],
Or a pharmaceutically acceptable salt thereof.
[11]
本発明の脳梗塞処置剤は、特定の構造を有するベンゼン誘導体である化合物またはその医薬上許容され得る塩を含む。これらの化合物または塩は、ＶＡＰ−１阻害剤であり、脳出血のリスクのある血栓溶解剤とは異なるメカニズムで、また、適用時間の制限なく、脳梗塞を処置し得る。 The agent for treating cerebral infarction of the present invention contains a compound which is a benzene derivative having a specific structure or a pharmaceutically acceptable salt thereof. These compounds or salts are VAP-1 inhibitors and can treat cerebral infarction by a different mechanism than thrombolytic agents at risk for cerebral hemorrhage and without limitation of application time.
本明細書の上記および下記の記載において、本発明の範囲に含まれるべき種々の定義の適切な例および説明を、以下に詳細に説明する。 In the foregoing and following description of this specification, suitable examples and descriptions of various definitions that are to be included within the scope of the present invention are described in detail below.
式（Ｉ）において、ピリジン環上の置換基Ａの位置は、その任意の適切な位置であり、特に限定されない。
本発明に関して、「Ｃ１−Ｃ６アルキル」は、１から６個の炭素原子を有する直鎖または分枝鎖のアルキル、例えば１から４個の炭素原子を有する直鎖または分枝鎖のアルキルであり、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ペンチル、ｔｅｒｔ−ペンチルおよびヘキシルが含まれる。
In the formula (I), the position of the substituent A on the pyridine ring is any appropriate position, and is not particularly limited.
In the context of the present invention, “C 1 -C 6 alkyl” means a linear or branched alkyl having 1 to 6 carbon atoms, for example a linear or branched alkyl having 1 to 4 carbon atoms. And includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl.
本発明のある実施態様では、本発明の脳梗塞処置剤は、
本発明に関して、「医薬上許容され得る塩」は、医薬上許容され得る通常の塩であり、非毒性であれば特に限定されず、無機または有機塩基との塩、酸付加塩などが挙げられる。無機または有機塩基との塩には、アルカリ金属塩（例、ナトリウム塩、カリウム塩など）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩など）、アンモニウム塩、およびアミン塩（例、トリエチルアミン塩、Ｎ−ベンジル−Ｎ−メチルアミン塩など）などが挙げられ、酸付加塩には、鉱酸（例、塩酸、臭化水素酸、ヨウ化水素酸、リン酸、メタリン酸、硝酸および硫酸）から誘導される塩、および有機酸（例、酒石酸、酢酸、クエン酸、リンゴ酸、乳酸、フマル酸、マレイン酸、安息香酸、グリコール酸、グルコン酸、コハク酸およびアリールスルホン酸（例、ｐ−トルエンスルホン酸））から誘導される塩などが挙げられる。 In the context of the present invention, “pharmaceutically acceptable salts” are ordinary pharmaceutically acceptable salts, and are not particularly limited as long as they are non-toxic, and include salts with inorganic or organic bases, acid addition salts, and the like. . Salts with inorganic or organic bases include alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts, and amine salts (eg, triethylamine) Salts, N-benzyl-N-methylamine salts, etc., and acid addition salts include mineral acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid). ) And organic acids (eg, tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, maleic acid, benzoic acid, glycolic acid, gluconic acid, succinic acid and aryl sulfonic acids (eg, p) -Salts derived from toluenesulfonic acid)).
本発明の式（Ｉ）の化合物およびその医薬上許容され得る塩は、公知の参考文献、例えば国際公開第２００９／０９６６０９号または国際公開第２００９／１４５３６０号に基づいて、あるいは、本明細書に記載の製造例に準じて、製造することができる。 The compounds of formula (I) of the present invention and pharmaceutically acceptable salts thereof are based on known references such as WO 2009/096609 or WO 2009/145360, or It can be produced according to the production examples described.
本発明に関して、「脳梗塞」は、脳虚血に起因する脳の損傷およびそれに関連する症状を意味し、ラクナ梗塞、アテローム血栓性脳梗塞および心原性脳塞栓症を含むが、これらに限定されず、神経障害、高次機能障害、感情障害等の脳梗塞の後遺症を包含する。脳虚血の原因としては、脳血栓、脳栓塞、血管攣縮、低血圧、低酸素血症などが挙げられるが、これらに限定されない。 In the context of the present invention, “cerebral infarction” means brain damage and associated symptoms resulting from cerebral ischemia, including but not limited to lacunar infarction, atherothrombotic cerebral infarction and cardiogenic cerebral embolism. It includes the aftereffects of cerebral infarction such as neuropathy, higher order dysfunction, and emotional disorder. Causes of cerebral ischemia include, but are not limited to, cerebral thrombus, cerebral embolism, vasospasm, hypotension, hypoxemia and the like.
本発明に関して、「脳梗塞処置剤」は、脳梗塞を処置するために対象に投与される医薬を意味する。「脳梗塞を処置する」は、脳梗塞を軽減、減退および／または治癒すること、あるいは、その進行を遅延または停止することを意味する。 In the context of the present invention, a “cerebral infarction treatment agent” means a medicament that is administered to a subject to treat cerebral infarction. “Treating a cerebral infarction” means reducing, reducing and / or healing the cerebral infarction, or delaying or stopping its progression.
本発明の脳梗塞処置剤の投与対象は、哺乳動物（例、ヒト、マウス、ラット、ブタ、イヌ、ネコ、ウマ、ウシなどの哺乳動物、特にヒト）である。 The administration target of the agent for treating cerebral infarction of the present invention is a mammal (eg, mammals such as humans, mice, rats, pigs, dogs, cats, horses, cows, particularly humans).
本発明の脳梗塞処置剤は、任意の経路により投与することができ、例えば、経口、皮下、経皮、経粘膜、静脈内、動脈内、筋肉内、腹腔内、鼻腔内、硬膜下、直腸、胃腸経由、吸入などの投与経路で、全身的または局所的に投与し得る。脊髄投与および硬膜外投与、または脳室への投与も可能である。本発明の脳梗塞処置剤が投与される様式は、処置に当たる医師が適宜決定すればよい。本発明の脳梗塞処置剤を投与するのに１つ以上の経路を用いることができ、ある経路が、別の経路よりも迅速でより効果的な反応を提供してもよい。記載された投与の経路は単なる例示であり、これらに限定されるものではない。 The agent for treating cerebral infarction of the present invention can be administered by any route, for example, oral, subcutaneous, transdermal, transmucosal, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal, subdural, Administration may be systemic or local via the route of administration, such as rectal, gastrointestinal, or inhalation. Spinal and epidural administration or administration to the ventricles is possible. The manner in which the agent for treating cerebral infarction of the present invention is administered may be appropriately determined by a doctor who performs treatment. One or more routes can be used to administer the cerebral infarction treating agent of the present invention, and one route may provide a quicker and more effective response than another route. The routes of administration described are merely exemplary and are not intended to be limiting.
本発明の脳梗塞治療剤は、急性期の脳梗塞を処置するために投与され得る。「急性期」とは、脳梗塞の発症から１４日以内の期間を意味する。本発明の脳梗塞処置剤は、哺乳動物、特にヒトの対象が脳梗塞を発症した後、例えば、対象が脳梗塞を発症した後に速やかに、例えば、３時間以内、４.５時間以内、６時間以内、１２時間以内または２４時間以内に投与される。 The therapeutic agent for cerebral infarction of the present invention can be administered to treat acute cerebral infarction. “Acute” means a period of 14 days or less from the onset of cerebral infarction. The therapeutic agent for cerebral infarction of the present invention can be used immediately after a mammal, particularly a human subject, has developed cerebral infarction, for example, within 3 hours, within 4.5 hours, 6 It is administered within hours, within 12 hours or within 24 hours.
本発明によれば、哺乳動物、特にヒトの対象に投与される本発明の脳梗塞処置剤の用量は、合理的な期間にわたって対象に所望の反応を及ぼすのに十分であるべきである。当業者は、用量は、用いられる個々の化合物の活性、対象の種、年齢、性別、体重、並びに、脳梗塞の状態および重篤度を含む種々の要因に依存することを理解するであろう。用量はまた、投与の経路、タイミングおよび回数、並びに、個々の化合物および所望の生理学的効果に伴い得る有害な副作用の存在、性質および程度にも依存するであろう。当業者は、脳梗塞の状態および重篤度によっては、複数回の投与を必要とする長期の治療が必要であり得ることを理解するであろう。適切な用量および投与計画は、当業者に公知の通常の範囲で見出される技術により決定することができる。 According to the present invention, the dose of the cerebral infarction treatment agent of the present invention administered to a mammal, particularly a human subject, should be sufficient to exert the desired response on the subject over a reasonable period of time. One skilled in the art will appreciate that the dosage will depend on a variety of factors including the activity of the particular compound used, the species of the subject, age, sex, weight, and cerebral infarction status and severity. . The dose will also depend on the route, timing and frequency of administration, as well as the presence, nature and extent of adverse side effects that may accompany the individual compound and the desired physiological effect. One skilled in the art will appreciate that depending on the state and severity of cerebral infarction, long-term treatments that require multiple administrations may be necessary. Appropriate doses and dosing schedules can be determined by techniques found in the usual ranges known to those skilled in the art.
本発明の脳梗塞処置剤は、式（Ｉ）の化合物またはその医薬上許容され得る塩の重量で、例えば、約０.００１〜約１００ｍｇ／ｋｇ体重／日の用量、約０.００５ｍｇ〜約５０ｍｇ／ｋｇ体重／日の用量、または、約０.０１ｍｇ〜約２５ｍｇ／ｋｇ体重／日の用量約０.１ｍｇ〜約１０ｍｇ／ｋｇ体重／日の用量で、１日当たり単回投与または２回、３回、４回もしくはそれ以上の回数で投与し得、あるいは、持続的に投与することもできる。 The agent for treating cerebral infarction of the present invention is, for example, a dose of about 0.001 to about 100 mg / kg body weight / day, about 0.005 mg to about 0.005 mg / day, by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Single dose or twice daily at a dose of 50 mg / kg body weight / day, or a dose of about 0.01 mg to about 25 mg / kg body weight / day, a dose of about 0.1 mg to about 10 mg / kg body weight / day, It can be administered three, four or more times, or can be administered continuously.
本明細書で用いる用語「約」は、数値の±３０％、好ましくは±２０％、より好ましくは±１０％までの誤差を意味し得る。 The term “about” as used herein may mean an error of up to ± 30%, preferably ± 20%, more preferably ± 10% of a numerical value.
本発明の脳梗塞処置剤は、医薬組成物の形態であり得る。医薬組成物は、活性成分として、脳梗塞を処置するのに十分な量の式（Ｉ）の化合物またはその医薬上許容され得る塩、および、医薬上許容され得る担体を含む。医薬上許容され得る担体は、医薬として通常用いられる任意のものであってよく、これは物理化学的な検討事項（例えば、溶解度、および当該化合物に対する反応性の欠如）および投与の経路によって限定される場合を除き、特に限定されない。 The agent for treating cerebral infarction of the present invention can be in the form of a pharmaceutical composition. The pharmaceutical composition comprises as active ingredients an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof sufficient to treat cerebral infarction and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be any of those commonly used as pharmaceuticals, limited by physicochemical considerations (eg, solubility and lack of reactivity to the compound) and route of administration. Unless otherwise specified, there is no particular limitation.
本発明の脳梗塞処置剤が医薬組成物である場合、式（Ｉ）の化合物またはその医薬上許容され得る塩の量は、組成物の処方によって変化し得、例えば、０.００００１〜１０.０重量％、０.００１〜５重量％または０.００１〜１重量％である。 When the agent for treating cerebral infarction of the present invention is a pharmaceutical composition, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof can vary depending on the formulation of the composition, for example, 0.0001 to 10. 0 wt%, 0.001 to 5 wt% or 0.001 to 1 wt%.
本発明の脳梗塞処置剤の投与形態は特に限定されず、脳梗塞の処置を達成するために種々の形態で投与することができる。式（Ｉ）の化合物またはその医薬上許容され得る塩を単独でまたは医薬上許容され得る担体または希釈剤などの添加剤と組み合わせて製剤化し、本発明の脳梗塞処置剤として経口または非経口投与することができる。製剤の特性および性質は、活性成分として用いる化合物の溶解度および化学的特性、選択された投与経路および標準的な薬学的プラクティスによって決定される。経口投与に用いる製剤としては、固体剤形（例、カプセル、錠剤、散剤）または液体形態（例、溶液または懸濁液）などが挙げられる。非経口投与に用いる製剤としては、無菌溶液または懸濁液の形態である注射、点滴などが挙げられる。固体経口製剤は、通常の賦形剤などを含み得る。液体経口製剤は、種々の芳香剤、着色剤、保存剤、安定化剤、可溶化剤または懸濁剤などを含み得る。非経口製剤は、例えば、無菌の水性または非水性の溶液または懸濁液であり、特定の種々の保存剤、安定化剤、緩衝化剤、可溶化剤または懸濁化剤などを含み得る。必要に応じて、種々の等張化剤を添加してもよい。 The administration form of the agent for treating cerebral infarction of the present invention is not particularly limited, and can be administered in various forms in order to achieve treatment of cerebral infarction. The compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated alone or in combination with an additive such as a pharmaceutically acceptable carrier or diluent, and is orally or parenterally administered as a cerebral infarction treatment agent of the present invention. can do. The properties and properties of the formulation are determined by the solubility and chemical properties of the compound used as the active ingredient, the chosen route of administration and standard pharmaceutical practice. Examples of the preparation used for oral administration include solid dosage forms (eg, capsules, tablets, powders) or liquid forms (eg, solutions or suspensions). Examples of the preparation used for parenteral administration include injection and infusion in the form of a sterile solution or suspension. The solid oral preparation may contain usual excipients and the like. Liquid oral preparations may contain various fragrances, colorants, preservatives, stabilizers, solubilizers or suspending agents and the like. Parenteral preparations are, for example, sterile aqueous or non-aqueous solutions or suspensions and may contain various various preservatives, stabilizers, buffers, solubilizers or suspending agents and the like. Various isotonic agents may be added as necessary.
本発明の脳梗塞処置剤は、本発明の効果を阻害しない限り、他の薬剤を含んでいてもよい。本発明の脳梗塞処置剤および他の薬剤を含む製剤、および、本発明の脳梗塞処置剤を含む製剤と他の薬剤を含む製剤を含むキットまたはパックは、本発明に含まれる。キットまたはパックは、投与のための指示書を含み得る。 The agent for treating cerebral infarction of the present invention may contain other drugs as long as the effects of the present invention are not inhibited. A preparation containing the agent for treating cerebral infarction and other agents of the present invention, and a kit or pack containing a preparation containing the agent for treating cerebral infarction of the present invention and other agents are included in the present invention. The kit or pack may contain instructions for administration.
本発明の脳梗塞処置剤は、本発明の効果を阻害しない限り、他の薬剤と組み合わせて、同時に、連続的に、または異なる時点で対象に投与することができる。本発明の脳梗塞処置剤と他の薬剤を、同一の製剤中または分離した別の製剤中で投与し得る。投与経路は、同一であっても異なっていてもよい。 The therapeutic agent for cerebral infarction of the present invention can be administered to a subject in combination with other drugs at the same time, continuously or at different time points as long as the effects of the present invention are not inhibited. The agent for treating cerebral infarction of the present invention and other agents can be administered in the same preparation or in separate preparations. The route of administration may be the same or different.
他の薬剤または薬学的に活性な化合物としては、例えば、血栓溶解剤（例、ｔＰＡ、ｒｔＰＡ（アルテプラーゼ）、デスモテプラーゼ（desmoteplase）、ウロキナーゼ、オザグレルナトリウム、アスピリン）、選択的トロンビン阻害薬（例、アルガトロバン）、ヘパリン、低分子ヘパリン、ヘパリノイド、脳保護薬（例、エダラボン）、高張グリセロール、高張マンニトールなどが挙げられるが、これらに限定されない。さらに、本発明の脳梗塞処置剤の投与を、機械的血栓回収療法、開頭外減圧療法、緊急頸動脈内膜剥離術、急性期再開通療法、急性期頸部頸動脈血行再建術（血管形成術／ステント留置術）などの外科的療法と組み合わせてもよい。 Other drugs or pharmaceutically active compounds include, for example, thrombolytic agents (eg, tPA, rtPA (alteplase), desmoteplase, urokinase, ozagrel sodium, aspirin), selective thrombin inhibitors (eg, argatroban) , Heparin, low molecular weight heparin, heparinoid, cerebral protective drugs (eg, edaravone), hypertonic glycerol, hypertonic mannitol and the like. Furthermore, administration of the treatment agent for cerebral infarction of the present invention comprises mechanical thrombus recovery therapy, extracranial decompression therapy, emergency carotid endarterectomy, acute phase recanalization therapy, acute phase carotid artery revascularization (angiogenesis) May be combined with surgical therapy such as surgery / stent placement).
さらなる態様において、本発明は、脳梗塞の処置用医薬を製造するための、式（Ｉ）の化合物またはその医薬上許容され得る塩の使用を提供する。式（Ｉ）の化合物およびその医薬上許容され得る塩はＶＡＰ−１阻害剤であり、ＶＡＰ−１関連疾患の予防または処置用医薬の製造に、特に脳梗塞の処置用医薬の製造に有用である。 In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cerebral infarction. The compounds of formula (I) and their pharmaceutically acceptable salts are VAP-1 inhibitors and are useful in the manufacture of a medicament for the prevention or treatment of VAP-1-related diseases, in particular in the manufacture of a medicament for the treatment of cerebral infarction. is there.
さらなる態様において、本発明は、脳梗塞の処置方法であって、それを必要とする対象に治療上有効量の式（Ｉ）の化合物またはその医薬上許容され得る塩を投与することを含む方法を提供する。 In a further aspect, the invention provides a method of treating cerebral infarction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. I will provide a.
以下、本発明を実施例（製造例および試験例）により、さらに詳細に説明するが、これは本発明を限定するものではない。 EXAMPLES Hereinafter, although an Example (manufacturing example and test example) demonstrates this invention further in detail, this does not limit this invention.
製造例１：２−｛４−［２−（３,４'−ビピリジン−６−イル）エチル］フェニル｝アセトヒドラジド
第１工程
５−ブロモピリジン−２−カルボアルデヒド（４.９７ｇ、２６.９ｍｍｏｌ）のトルエン（５０ｍＬ）溶液にエチレングリコール（８.３４ｇ、１３４ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物（５１.２ｍｇ、０.２７ｍｍｏｌ）を加えた。発生する水を検水管で分離しながら、１３時間加熱還流した。反応液を室温まで冷却し、飽和炭酸水素ナトリウム水溶液を加えて攪拌、静置した。有機層を分離し、水層を酢酸エチル（５０ｍＬ）で２回抽出した。有機層を合わせ、飽和食塩水（１００ｍＬ）で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（富士シリシア BW-300SP １２０ｇ、酢酸エチル：ヘキサン＝２：３）で精製し、黄色粉末として、５−ブロモ−２−（１,３−ジオキソラン−２−イル）ピリジン（５.２４ｇ、２２.８ｍｍｏｌ、収率８５％）を得た。
Production Example 1: 2- {4- [2- (3,4'-bipyridin-6-yl) ethyl] phenyl} acetohydrazide First Step 5-Bromopyridine-2-carbaldehyde (4.97 g) , 26.9 mmol) in toluene (50 mL) were added ethylene glycol (8.34 g, 134 mmol) and p-toluenesulfonic acid monohydrate (51.2 mg, 0.27 mmol). The generated water was refluxed for 13 hours while being separated by a test tube. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred and allowed to stand. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (50 mL). The organic layers were combined and washed with saturated brine (100 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP 120 g, ethyl acetate: hexane = 2: 3) to give 5-bromo-2- (1,3-dioxolan-2-yl) pyridine as a yellow powder. (5.24 g, 22.8 mmol, 85% yield).
第２工程
ブロモ−２−（１,３−ジオキソラン−２−イル）ピリジン（２.０８ｇ、９.００ｍｍｏｌ）、ピリジン−４−イルボロン酸（１.２８ｇ、１０.４ｍｍｏｌ）、酢酸パラジウム（１０１ｍｇ、１.３μｍｏｌ）、トリフェニルホスフィン（７０８ｍｇ、２.７０ｍｍｏｌ）、炭酸ナトリウム（１.９１ｇ、１８.０ｍｍｏｌ）、ジオキサン（５０ｍＬ）、水（５０ｍＬ）の混合物を２５時間加熱還流した。室温まで冷却後、水（５０ｍＬ）を加え、酢酸エチル（１５０ｍＬ）で３回抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（富士シリシア BW-300SP １２０ｇ、ジクロロメタン：メタノール＝３０：１→１０：１）で精製し、淡黄色固体として６−（１,３−ジオキソラン−２−イル）−３,４'−ビピリジン（１.９７ｇ、８.６０ｍｍｏｌ、収率９６％）を得た。
Second Step Bromo-2- (1,3-dioxolan-2-yl) pyridine (2.08 g, 9.00 mmol), Pyridin-4-ylboronic acid (1.28 g, 10.4 mmol), Palladium acetate (101 mg, A mixture of 1.3 μmol), triphenylphosphine (708 mg, 2.70 mmol), sodium carbonate (1.91 g, 18.0 mmol), dioxane (50 mL) and water (50 mL) was heated to reflux for 25 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted 3 times with ethyl acetate (150 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP 120 g, dichloromethane: methanol = 30: 1 → 10: 1) to give 6- (1,3-dioxolan-2-yl) -3 as a pale yellow solid. , 4′-bipyridine (1.97 g, 8.60 mmol, yield 96%) was obtained.
第３工程
６−（１,３−ジオキソラン−２−イル）−３,４'−ビピリジン（９６１ｇ、４.２１ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物（６４０ｇ、３.３７ｍｍｏｌ）、アセトニトリル（２５ｍＬ）、水（５ｍＬ）の混合物を８０℃で８時間攪拌した。室温まで冷却後、飽和炭酸水素ナトリウム水溶液（２５ｍＬ）、水（２５ｍＬ）を加え、ジクロロメタンで３回抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（富士シリシア BW-300SP １００ｇ、アセトン）で精製し、黄色固体として３,４'−ビピリジン−６−カルボアルデヒド（５２５ｍｇ、２.８５ｍｍｏｌ、収率６８％）を得た。
第４工程
［４−（２−メトキシ−２−オキソエチル）ベンジル］（トリフェニル）ホスホニウムブロミド（９０６ｍｇ、１.７９ｍｍｏｌ）のテトラヒドロフラン（７ｍＬ）懸濁液に０℃でｔ−ブトキシカリウム（２１６ｍｇ、１.７９ｍｍｏｌ）を加え、１５分間攪拌した。３,４'−ビピリジン−６−カルボアルデヒド（３００ｍｇ、１.６３ｍｍｏｌ）を加え、３０分間攪拌した。反応液に水（１０ｍＬ）を加えて酢酸エチルで３回抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮し、メチル｛４−［２−（３,４'−ビピリジン−６−イル）エテニル］フェニル｝アセテートとトリフェニルホスフィンオキシドとの混合物（５８０ｍｇ）を得た。
Fourth Step [4- (2-Methoxy-2-oxoethyl) benzyl] (triphenyl) phosphonium bromide (906 mg, 1.79 mmol) in tetrahydrofuran (7 mL) at 0 ° C. with t-butoxypotassium (216 mg, 1 .79 mmol) was added and stirred for 15 minutes. 3,4'-bipyridine-6-carbaldehyde (300 mg, 1.63 mmol) was added and stirred for 30 minutes. Water (10 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a mixture (580 mg) of methyl {4- [2- (3,4'-bipyridin-6-yl) ethenyl] phenyl} acetate and triphenylphosphine oxide. Obtained.
第５工程
前工程で得られたメチル｛４−［２−（３,４'−ビピリジン−６−イル）エテニル］フェニル｝アセテートとトリフェニルホスフィンオキシドとの混合物を酢酸エチル−エタノール混合溶媒（１：１、３０ｍＬ）に溶解し、１０％パラジウム炭素（５０％含水、４００ｍｇ）を加え、室温、常圧水素添加した。反応液をセライト濾過し、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（富士シリシア BW-300SP ６０ｇ、酢酸エチル）で精製し、メチル｛４−［２−（３,４'−ビピリジン−６−イル）エチル］フェニル｝アセテート（２１８ｍｇ、０.６６ｍｍｏｌ、２工程通算収率４０％）を得た。
Fifth Step A mixture of methyl {4- [2- (3,4'-bipyridin-6-yl) ethenyl] phenyl} acetate obtained in the previous step and triphenylphosphine oxide was mixed with an ethyl acetate-ethanol mixed solvent (1 : 1 and 30 mL), 10% palladium carbon (containing 50% water, 400 mg) was added, and hydrogenation was performed at room temperature and normal pressure. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP 60 g, ethyl acetate), and methyl {4- [2- (3,4′-bipyridin-6-yl) ethyl] phenyl} acetate (218 mg, 0.2%). 66 mmol and the total yield of 2 steps was 40%).
第６工程
メチル｛４−［２−（３,４'−ビピリジン−６−イル）エチル］フェニル｝アセテート（２１８ｍｇ、０.６６ｍｍｏｌ）のメタノール（２０ｍＬ）溶液にヒドラジン一水和物（３３４ｍｇ、６.６７ｍｍｏｌ）を加え、５０℃で１９時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（富士シリシア BW-300SP ５０ｇ、ジクロロメタン：メタノール＝３０：１）で精製した。目的物を含む分画を濃縮して得られた結晶を酢酸エチル−ジイソプロプルエーテル混合液（１：１、５ｍＬ）にて懸濁洗浄した。濾過、減圧乾燥し、白色固体として表題化合物（１５０ｍｇ、０.４５ｍｍｏｌ、収率６８％）を得た。
1H-NMR(CDCl3): 8.83 (d, J = 2.4 Hz, 1H), 8.69 (dd, J = 4.4 Hz, 1.8 Hz, 2H), 7.82 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.50 (dd, J = 4.4 Hz, 1.8 Hz, 2H), 7.29 - 7.13 (m, 5H), 6.58 (brs, 1H), 3.83 (brs, 2H), 3.53 (s, 2H), 3.19 - 3.05 (m, 4H)
高分解能MS（ESI）：実測値 355.1515 [M+Na]+ 理論値 355.1529 [M+Na]+
Step 6 Methyl {4- [2- (3,4'-bipyridin-6-yl) ethyl] phenyl} acetate (218 mg, 0.66 mmol) in methanol (20 mL) in hydrazine monohydrate (334 mg, 6 .67 mmol) was added and the mixture was stirred at 50 ° C. for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP 50 g, dichloromethane: methanol = 30: 1). Crystals obtained by concentrating the fraction containing the desired product were suspended and washed with an ethyl acetate-diisopropyl ether mixture (1: 1, 5 mL). Filtration and drying under reduced pressure gave the title compound (150 mg, 0.45 mmol, yield 68%) as a white solid.
1 H-NMR (CDCl 3 ): 8.83 (d, J = 2.4 Hz, 1H), 8.69 (dd, J = 4.4 Hz, 1.8 Hz, 2H), 7.82 (dd, J = 8.4 Hz, 2.4 Hz, 1H) , 7.50 (dd, J = 4.4 Hz, 1.8 Hz, 2H), 7.29-7.13 (m, 5H), 6.58 (brs, 1H), 3.83 (brs, 2H), 3.53 (s, 2H), 3.19-3.05 ( m, 4H)
High resolution MS (ESI): Measured value 355.1515 [M + Na] + Theoretical value 355.1529 [M + Na] +
製造例２：２−｛４−［２−（３,３'−ビピリジン−６−イル）エチル］フェニル｝アセトヒドラジド
第１工程
製造例１の第２工程と類似の方法により、５−ブロモ−２−（１,３−ジオキソラン−２−イル）ピリジン（２.０３ｍｇ、８.８２ｍｍｏｌ）とピリジン−３−イルボロン酸（１.２５ｇ、１０.２ｍｍｏｌ）から、淡黄色固体として６−（１,３−ジオキソラン−２−イル）−３,３'−ビピリジン（１.７８ｇ、７.８１ｍｍｏｌ、収率８９％）を得た。
Production Example 2: 2- {4- [2- (3,3′-bipyridin-6-yl) ethyl] phenyl} acetohydrazide First Step According to a method similar to the second step of Production Example 1, From 5-bromo-2- (1,3-dioxolan-2-yl) pyridine (2.03 mg, 8.82 mmol) and pyridin-3-ylboronic acid (1.25 g, 10.2 mmol) as a pale yellow solid, 6 -(1,3-Dioxolan-2-yl) -3,3'-bipyridine (1.78 g, 7.81 mmol, 89% yield) was obtained.
第２工程
製造例１の第２工程と類似の方法により、６−（１,３−ジオキソラン−２−イル）−３,３'−ビピリジン（１.７７ｇ、７.７５ｍｍｏｌ）から黄色固体として、３,４'−ビピリジン−６−カルボアルデヒド（７９７ｍｇ、４.３２ｍｍｏｌ、収率５６％）を得た。
Second Step By a method similar to the second step of Production Example 1, from 6- (1,3-dioxolan-2-yl) -3,3′-bipyridine (1.77 g, 7.75 mmol) as a yellow solid, 3,4'-bipyridine-6-carbaldehyde (797 mg, 4.32 mmol, yield 56%) was obtained.
第３工程〜第５工程
製造例１の第４〜第６工程と類似の方法により、［４−（２−メトキシ−２−オキソエチル）ベンジル］（トリフェニル）ホスホニウムブロミド（７７８ｍｇ、１.５４ｍｍｏｌ）と３,４'−ビピリジン−６−カルボアルデヒド（２５８ｍｇ、１.５４ｍｍｏｌ）から白色固体として表題化合物（３３５ｍｇ、０.９４ｍｍｏｌ、収率６１％）を得た。
1H-NMR(CDCl3): 8.85 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.64 (dd, J = 4.7 Hz, 1.7 Hz, 1H), 7.88 (ddd, J = 7.7 Hz, 2.0 Hz, 1.7 Hz, 1H), 7.79 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.41(dd, J = 7.7 Hz, 4.7 Hz, 1H), 7.25 (d, J = 12.2 Hz, 2H), 7.19 (d, J = 12.2 Hz, 2H), 6.60 (brs, 1H), 3.84 (brs, 2H), 3.55 (s, 2H), 3.20 - 3.06 (m, 4H)
高分解能MS（ESI）：実測値 355.1522 [M+Na]+ 理論値 355.1529 [M+Na]+
1 H-NMR (CDCl 3 ): 8.85 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.64 (dd, J = 4.7 Hz, 1.7 Hz, 1H), 7.88 ( ddd, J = 7.7 Hz, 2.0 Hz, 1.7 Hz, 1H), 7.79 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.41 (dd, J = 7.7 Hz, 4.7 Hz, 1H), 7.25 (d, J = 12.2 Hz, 2H), 7.19 (d, J = 12.2 Hz, 2H), 6.60 (brs, 1H), 3.84 (brs, 2H), 3.55 (s, 2H), 3.20-3.06 (m, 4H)
High resolution MS (ESI): Measured value 355.1522 [M + Na] + Theoretical value 355.1529 [M + Na] +
製造例３：２−｛４−［２−（５−ピリミジン−５−イルピリジン−２−イル）エチル］フェニル｝アセトヒドラジド
第１工程
製造例１の第２工程と類似の方法により、５−ブロモ−２−（１,３−ジオキソラン−２−イル）ピリジン（２.０６ｇ、８.９５ｍｍｏｌ）、ピリミジン−５−イルボロン酸（１.２８ｇ、１０.３ｍｍｏｌ）から、淡黄色固体として５−［６−（１,３−ジオキソラン−２−イル）ピリジン−３−イル］ピリミジン（１.２４ｇ、５.４１ｍｍｏｌ、収率６０％）を得た。
Production Example 3: 2- {4- [2- (5-pyrimidin-5-ylpyridin-2-yl) ethyl] phenyl} acetohydrazide First step By a method similar to the second step of Production Example 1 , 5-bromo-2- (1,3-dioxolan-2-yl) pyridine (2.06 g, 8.95 mmol), pyrimidin-5-ylboronic acid (1.28 g, 10.3 mmol) as a pale yellow solid 5- [6- (1,3-dioxolan-2-yl) pyridin-3-yl] pyrimidine (1.24 g, 5.41 mmol, 60% yield) was obtained.
第２工程
製造例１の第２工程と類似の方法により、５−［６−（１,３−ジオキソラン−２−イル）ピリジン−３−イル］ピリミジン（１.２４ｇ、５.４１ｍｍｏｌ）から、黄色固体として５−ピリミジン−５−イルピリジン−２−カルボアルデヒド（４５３ｍｇ、２.４５ｍｍｏｌ、４５％）を得た。
Second Step By a method similar to the second step of Production Example 1, from 5- [6- (1,3-dioxolan-2-yl) pyridin-3-yl] pyrimidine (1.24 g, 5.41 mmol), 5-Pyrimidin-5-ylpyridine-2-carbaldehyde (453 mg, 2.45 mmol, 45%) was obtained as a yellow solid.
第３工程〜第５工程
製造例１の第４〜第６工程と類似の方法により、［４−（２−メトキシ−２−オキソエチル）ベンジル］（トリフェニル）ホスホニウムブロミド（９００ｍｇ、１.７８ｍｍｏｌ）と５−ピリミジン−５−イルピリジン−２−カルボアルデヒド（３００ｍｇ、１.６２ｍｍｏｌ）から、白色固体として表題化合物（１６２ｍｇ、０.４９ｍｍｏｌ、収率５２％）を得た。
1H-NMR(CDCl3): 9.25 (s, 1H), 8.95 (s, 2H), 8.79 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.0 Hz, 2.2 Hz, 1H), 7.34 - 7.10 (m, 5H), 6.58 (brs, 1H), 3.83 (brs, 2H), 3.53 (s, 2H),3.20 - 3.06 (m, 4H)
高分解能MS（ESI）：実測値 356.1461 [M+Na]+ 理論値 356.1482 [M+Na]+
1 H-NMR (CDCl 3 ): 9.25 (s, 1H), 8.95 (s, 2H), 8.79 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.0 Hz, 2.2 Hz, 1H), 7.34-7.10 (m, 5H), 6.58 (brs, 1H), 3.83 (brs, 2H), 3.53 (s, 2H), 3.20-3.06 (m, 4H)
High resolution MS (ESI): Measured value 356.1461 [M + Na] + Theoretical value 356.1482 [M + Na] +
試験例１：ＳＳＡＯ阻害活性評価、ＭＡＯ−Ａ／Ｂ阻害活性評価
国際公開第２００９／１４５３６０号（特許文献２）に記載の方法により、製造例１〜３の化合物、試験例２の被験物質についてＳＳＡＯ（ＶＡＰ−１）阻害活性およびヒトモノアミンオキシダーゼ（ＭＡＯ）−Ａ／Ｂ阻害活性を測定した。測定結果を下表に示す。
試験例２：ラット一過性局所脳虚血モデルを用いた薬効スクリーニング試験
試験物質
媒体として生理食塩液（ｐＨ４.０）を、被験物質として化合物１、化合物２、製造例１溶液（各０.２ｍｇ／ｍＬ）を、陽性対照物質としてエダラボン（田辺三菱製薬株式会社、販売名：ラジカット（登録商標）注３０ｍｇ）を使用した。
Physiological saline solution (pH 4.0) as a test substance medium, Compound 1, Compound 2, and Production Example 1 solution (each 0.2 mg / mL) as test substances, Edaravone (Mitsubishi Tanabe Pharma Corporation, sold as a positive control substance) Name: Radicut (registered trademark) Note 30 mg) was used.
ラット一過性局所脳虚血モデルの作製
一過性局所脳虚血モデルの作製には、８週齢、体重２６０〜３５０ｇの雄性ラット（系統：Ｃｒｌ：ＣＤ（ＳＤ）、供給源：日本チャールス・リバー株式会社）を使用した。ラットをイソフルラン（マイラン製薬株式会社）の２％吸入による麻酔下にて、仰臥位に固定した。右総頸動脈、外頸動脈および内頸動脈を露出し、中大脳動脈（ＭＣＡ）を閉塞するために総頸動脈および外頸動脈を縫合糸で結紮した。予めシリコン（ヘレウスクルツァージャパン株式会社）コーティングし、１９ｍｍの長さに切断した４号のナイロン糸（栓子）を外頸動脈と内頸動脈の分岐部より挿入し、ＭＣＡを閉塞した。ＭＣＡ閉塞後２時間に栓子を抜き、ＭＣＡの血流を再開させた。ＭＣＡ閉塞手術後、ベンジルペニシリンカリウム（Meiji Seika ファルマ株式会社）を２００００ｕｎｉｔｓ／ｋｇの用量で筋肉内投与した。ＭＣＡ閉塞後３０分に閉塞側の対側前肢の屈曲を確認した。
Preparation of rat transient focal cerebral ischemia model For preparation of transient focal cerebral ischemia model, male rats (line: Crl: CD (SD), 8 weeks old, body weight 260-350 g, source: Charles Japan) -River Corporation) was used. Rats were fixed in the supine position under anesthesia with 2% inhalation of isoflurane (Mylan Pharmaceutical Co., Ltd.). The right common carotid artery, external carotid artery and internal carotid artery were exposed and the common carotid artery and external carotid artery were ligated with sutures to occlude the middle cerebral artery (MCA). The nylon (No. 4) nylon thread (obturator) previously coated with silicon (Heraeus Kurzer Japan Co., Ltd.) and cut to a length of 19 mm was inserted from the bifurcation of the external carotid artery and the internal carotid artery to occlude the MCA. The obturator was withdrawn 2 hours after the MCA occlusion to resume MCA blood flow. After MCA occlusion surgery, benzylpenicillin potassium (Meiji Seika Pharma Co., Ltd.) was intramuscularly administered at a dose of 20000 units / kg. 30 minutes after the MCA occlusion, the bending of the contralateral forelimb on the occlusion side was confirmed.
試験物質の投与
一過性局所脳虚血モデル作製手術の当日、ＭＣＡ再開通前３分およびＭＣＡ再開通後２時間に、媒体群（１０匹）には生理食塩液（ｐＨ４.０）を５ｍＬ／ｋｇの容量で尾静脈内に投与し、化合物１群、化合物２群および製造例１群（各１０匹）には、それぞれ化合物１、化合物２および製造例１を１回あたり１ｍｇ／５ｍＬ／ｋｇの投与量で尾静脈内に２回投与した。また、陽性対照群はＭＣＡ再開通前３分およびＭＣＡ再開通後３０分に、陽性対照物質（エダラボン、田辺三菱製薬株式会社、販売名：ラジカット（登録商標）注３０ｍｇ）を１回あたり３ｍｇ／２ｍＬ／ｋｇの用量で尾静脈内に２回投与した。
Administration of test substance On the day of the transient local cerebral ischemia model preparation operation, 3 minutes before resuming MCA and 2 hours after resuming MCA, 5 mL of physiological saline (pH 4.0) was given to the vehicle group (10 animals). / Kg is administered into the tail vein, and the compound 1, the compound 2 group and the production example 1 group (each 10 animals) are respectively supplied with compound 1, compound 2 and production example 1 at 1 mg / 5 mL / It was administered twice into the tail vein at a dose of kg. In the positive control group, the positive control substance (Edaravone, Mitsubishi Tanabe Pharma Corporation, trade name: Radicut (registered trademark) Note 30 mg) was applied at 3 mg /
脳梗塞巣体積の算出
ＭＣＡ閉塞後２４時間に動物を断頭し、全脳を摘出して厚さ２ｍｍの脳切片を作製した。脳切片を１ｗ／ｖ％２,３,５−トリフェニルテトラゾリウムクロリド（ナカライテスク株式会社）により染色し、写真撮影を行った。得られた写真を画像解析し、脳梗塞巣面積を実測値で求め、その値より脳梗塞巣体積を算出した。
Calculation of cerebral infarction volume The animal was decapitated 24 hours after MCA occlusion, and the whole brain was removed to prepare a 2 mm thick brain slice. The brain sections were stained with 1 w /
統計学的解析
脳梗塞巣体積について、媒体群と化合物１群および陽性対照群と被験物質群の比較は Dunnett の多重比較検定にて、媒体群と陽性対照群の比較は Student のt検定にて行った。各検定では、解析ソフトSAS 9.1.3［EXSUS Version 7.7.1、SAS Institute Japan株式会社（株式会社CACエクシケア）］を用いた。有意水準は５％（両側）とし、１％および５％に分けて表示した。
Statistical analysis For cerebral infarction volume, Dunnett's multiple comparison test was used for comparison between vehicle group and compound 1 group, and positive control group and test substance group, and comparison between vehicle group and positive control group was performed using Student's t test. went. In each test, analysis software SAS 9.1.3 [EXSUS Version 7.7.1, SAS Institute Japan Co., Ltd. (CAC Excicare)] was used. The significance level was 5% (both sides), and it was divided into 1% and 5%.
結果
本試験の結果を図１に示す。媒体群、化合物１群、化合物２群、製造例１群および陽性対照群の脳梗塞巣体積は、それぞれ３４４.０±３６.３ｍｍ３（平均値±標準偏差、以下同じ）、２８７.７±４２.９ｍｍ３、３０５.２±４１.２ｍｍ３、２７３.２±５７.９ｍｍ３および２７３.７±５６.６ｍｍ３であった。化合物１および製造例１群の脳梗塞巣体積は、媒体群と比較して統計学的に有意な縮小が認められた。化合物１群、化合物２群および製造例１群の脳梗塞巣体積は、陽性対照群と比較して統計学的に有意な縮小は認められなかった。陽性対照群の脳梗塞巣体積は、媒体群と比較して低い値を示し、統計学的に有意な差が認められた。以上の結果より、化合物１および製造例１は脳梗塞巣体積縮小作用を有することが示唆される。
Results The results of this test are shown in FIG. The cerebral infarct volume of the vehicle group, the compound 1 group, the compound 2 group, the production example 1 group and the positive control group was 344.0 ± 36.3 mm 3 (mean value ± standard deviation, the same applies hereinafter), 287.7 ± 42.9mm 3, 305.2 ± 41.2mm 3, was 273.2 ± 57.9mm 3 and 273.7 ± 56.6mm 3. A statistically significant reduction was observed in the cerebral infarct volume of Compound 1 and Production Example 1 group compared to the vehicle group. As for the cerebral infarct volume of the compound 1 group, the compound 2 group and the production example 1 group, no statistically significant reduction was observed as compared with the positive control group. The cerebral infarct volume in the positive control group was lower than that in the vehicle group, and a statistically significant difference was observed. From the above results, it is suggested that Compound 1 and Production Example 1 have a cerebral infarct volume reducing action.
試験例３：ラット一過性局所脳虚血モデルを用いた用量反応性検討試験
試験物質
媒体として生理食塩液（ｐＨ６.０）を、被験物質として化合物１の３濃度（０.００５、０.０５、０.５ｍｇ／ｍＬ）を、陽性対照物質としてエダラボン（田辺三菱製薬株式会社、販売名：ラジカット（登録商標）注３０ｍｇ）を使用した。
ラット一過性局所脳虚血モデルの作製
試験例２と同様の試験方法でラット一過性局所脳虚血モデルを作製した。
Test Example 3: Dose-response study using rat transient focal cerebral ischemia model
Saline (pH 6.0) as the test substance medium, 3 concentrations of compound 1 (0.005, 0.05, 0.5 mg / mL) as the test substance, and edaravone (Mitsubishi Tanabe Pharma Corporation) as the positive control substance , Trade name: Radicut (registered trademark) Note 30 mg).
Preparation of rat transient focal cerebral ischemia model A rat transient focal cerebral ischemia model was prepared by the same test method as in Test Example 2.
試験物質の投与
一過性局所脳虚血モデル作製手術の当日、ＭＣＡ再開通前３分およびＭＣＡ再開通後２時間に、媒体群（１０匹）には生理食塩液（ｐＨ６.０）を、低用量群、中用量群および高用量群（各１０匹）には化合物１をそれぞれ０.０１、０.１および１ｍｇ／２ｍＬ／ｋｇの投与量で尾静脈内に投与した。また、化合物１［投与量：１ｍｇ／ｋｇ／回（高用量）］およびエダラボン（田辺三菱製薬株式会社、販売名：ラジカット（登録商標）注３０ｍｇ、３ｍｇ／ｋｇ／回、再開通直前、再開通後３０分の２回投与）の併用投与並びにエダラボン投与（３ｍｇ／ｋｇ／回、再開通直前、再開通後３０分の２回投与）も尾静脈内に行った。
Administration of test substance On the day of transient local cerebral ischemia model preparation operation, 3 minutes before resuming MCA and 2 hours after resuming MCA, vehicle group (10 animals) was given physiological saline (pH 6.0), In the low dose group, medium dose group and high dose group (each 10 mice), Compound 1 was administered into the tail vein at doses of 0.01, 0.1 and 1 mg / 2 mL / kg, respectively. In addition, Compound 1 [dosage: 1 mg / kg / dose (high dose)] and edaravone (Mitsubishi Tanabe Pharma Corporation, trade name: Radicut (registered trademark) Note 30 mg, 3 mg / kg / dose, immediately before recommencement, recommencement 2 times administration for 30 minutes later) and edaravone administration (3 mg / kg / time, immediately before resumption, twice administration for 30 minutes after resumption) were also carried out in the tail vein.
脳梗塞巣体積の算出
試験例２と同様の試験方法で脳梗塞巣体積を算出した。
統計学的解析
脳梗塞巣体積について、媒体群と低用量群、中用量群および高用量群との間ではDunnett の多重比較検定にて、媒体群と陽性対照群の間並びに化合物１（高用量）およびエダラボンの併用（以下、併用）群と陽性対照群の間では Student のt検定にて比較した。比較には、解析ソフトSAS 9.1.3［EXSUS Version 7.7.1、SAS Institute Japan 株式会社（株式会社CACエクシケア）］を用いた。有意水準は５％（両側）とし、１％および５％に分けて表示した。
Calculation of cerebral infarct volume The cerebral infarct volume was calculated by the same test method as in Test Example 2.
Statistical analysis Regarding the volume of cerebral infarction, Dunnett's multiple comparison test was performed between the vehicle group and the low-dose group, the medium-dose group, and the high-dose group. ) And edaravone (hereinafter referred to as combination) group and positive control group were compared by Student's t-test. For the comparison, analysis software SAS 9.1.3 [EXSUS Version 7.7.1, SAS Institute Japan Co., Ltd. (CAC Excicare)] was used. The significance level was 5% (both sides), and it was divided into 1% and 5%.
結果
本試験の結果を図２に示す。媒体群、低用量群、中用量群、高用量群、陽性対照群および併用群の脳梗塞巣体積は、それぞれ３５８.０±４０.７ｍｍ３（平均値±標準偏差、以下同じ）、３２２.１±１９.６ｍｍ３、２９３.６±２９.７ｍｍ３、２５９.７±８０.０ｍｍ３、２６３.０±５０.７ｍｍ３および２６２.０±５２.２ｍｍ３であった。化合物１は用量依存的かつ中用量群および高用量群で媒体群と比較して有意な脳梗塞巣体積縮小を示した。高用量群と併用群の間および併用群と陽性対照群の間で脳梗塞巣体積に有意差は認められなかった。
Results The results of this test are shown in FIG. The volume of cerebral infarction in the vehicle group, the low dose group, the medium dose group, the high dose group, the positive control group, and the combination group was 358.0 ± 40.7 mm 3 (mean ± standard deviation, the same applies hereinafter), 322. 1 ± 19.6mm 3, 293.6 ± 29.7mm 3, 259.7 ± 80.0
試験例４：ラット一過性局所脳虚血モデルを用いた行動薬理学的評価試験
試験物質
被験物質として、化合物１（０.５ｍｇ／ｍＬ）を使用した。媒体および陽性対照物質は試験例３と同様の物質を使用した。
ラット一過性局所脳虚血モデルの作製
試験例２と同様の試験方法でラット一過性局所脳虚血モデルを作製した。
Test Example 4: Behavioral pharmacological evaluation test using a rat transient focal cerebral ischemia model
Compound 1 (0.5 mg / mL) was used as a test substance test substance. As the medium and the positive control substance, the same substances as in Test Example 3 were used.
Preparation of rat transient focal cerebral ischemia model A rat transient focal cerebral ischemia model was prepared by the same test method as in Test Example 2.
試験物質の投与
化合物１（投与量：１ｍｇ／２ｍＬ／ｋｇ）は、モデル作製日に３回（再開通直前、再開通後２時間および８時間）、ＭＣＡ閉塞・再開通後１〜６日に２回（９時および２１時）尾静脈内に投与した。陽性対照物質（エダラボン、田辺三菱製薬株式会社、販売名：ラジカット（登録商標）注３０ｍｇ）は、モデル作製日に２回（再開通直前、再開通後３０分）、ＭＣＡ閉塞・再開通後１〜６日には化合物１同様に尾静脈内に投与した。
Test substance administration compound 1 (dose: 1 mg / 2 mL / kg) was administered 3 times on the model preparation day (immediately before resumption, 2 hours and 8 hours after resumption), 1-6 days after MCA occlusion / resumption. Two doses (9 o'clock and 21 o'clock) were administered via the tail vein. The positive control substance (Edaravone, Mitsubishi Tanabe Pharma Corporation, trade name: Radicut (registered trademark) Note 30 mg) is twice on the model production day (immediately before reopening, 30 minutes after reopening), 1 after MCA occlusion / reopening. On day 6 it was administered via the tail vein as in Compound 1.
神経症状スコアの評価
神経症状の評価はBedersonらの方法（Bederson J.B., Pitts L.H., Tsuji M. Nishimura M.C., Davis R.L., Bartkowski H. Rat middle cerebral artery occlusion: Evaluation of the model and development of a neurologic examination. Stroke. 1986; 17: 472-476）を参考にＭＣＡ閉塞・再開通後３、７および１４日（以下、それぞれ３、７、１４日後）に実施した。観察は午前中に実施した。
Evaluation of neurological symptom score Evaluation of neurological symptom was performed by Bederson et al. (Bederson JB, Pitts LH, Tsuji M. Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: Evaluation of the model and development of a neurologic examination. Stroke. 1986; 17: 472-476) was performed on
ロータロッドテスト
ロータロッドテストはモデル作製前１日または２日並びに３、７および１４日後に実施した。なお、３、７および１４日後は、神経症状観察後にロータロッドテストを実施した。回転速度を８回／分に設定したロータロッドを用いて、回転棒上の滞在時間（秒）を測定した。最長測定時間は１２０秒間とした。なお、モデル作製前１〜３日のうち続けて２日、回転棒上に滞在できるように動物の訓練を行い、回転棒上に１２０秒間滞在できるラットをモデル作製に供した。
Rotarod test The rotarod test was performed 1 or 2 days before model creation and 3, 7 and 14 days later. In addition, after 3, 7 and 14 days, a rotarod test was performed after neurological symptoms were observed. Using a rotarod whose rotational speed was set to 8 times / min, the residence time (seconds) on the rotating rod was measured. The longest measurement time was 120 seconds. The animals were trained so that they could stay on the rotating rod for 2 consecutive days from 1 to 3 days before the model creation, and rats that could stay on the rotating rod for 120 seconds were used for model creation.
統計学的解析
各観察日の神経症状スコアについて、各群間の比較をSteel-Dwass検定にて行った。各測定日の回転棒上の滞在時間については、各群間の比較をTukey-Kramer検定にて行った。
Statistical analysis The neurological symptom score on each observation day was compared with each other by the Steel-Dwass test. About the residence time on the rotating bar on each measurement day, the comparison between each group was performed by Tukey-Kramer test.
結果
本試験の結果を図３〜４に示す。３、７、１４日後の神経症状スコアは、媒体群ではそれぞれ２.９±０.３（平均値±標準偏差、以下同じ）、２.９±０.３および２.８±０.４、化合物１群ではそれぞれ２.８±０.４、２.５±０.７および２.１±０.７、陽性対照群ではそれぞれ２.７±０.５、２.５±０.７および２.１±０.７であった。３、７、１４日後の回転棒上の滞在時間は、媒体群ではそれぞれ１１.５±９.１秒、１４.２±１０.１秒および１７.０±１０.９秒であり、化合物１群ではそれぞれ１７.９±１９.０秒、３２.３±２３.８秒および５５.０±４４.０秒であり、陽性対照群ではそれぞれ１７.７±２６.２秒、３１.６±３１.０秒および５４.５±３９.７秒であった。化合物１群はＭＣＡ閉塞・再開通後１４日に陽性対照群と同程度かつ媒体群と比較して有意な神経症状スコアの低下（図３）および回転棒上の滞在時間の延長（図４）を示した。
Results The results of this test are shown in FIGS. The neurological symptom scores after 3, 7, and 14 days were 2.9 ± 0.3 (mean ± standard deviation, the same applies hereinafter) in the vehicle group, 2.9 ± 0.3, and 2.8 ± 0.4, respectively. The compound 1 group has 2.8 ± 0.4, 2.5 ± 0.7 and 2.1 ± 0.7, respectively, and the positive control group has 2.7 ± 0.5, 2.5 ± 0.7 and respectively. 2.1 ± 0.7. The residence time on the rotating bar after 3, 7 and 14 days was 11.5 ± 9.1 seconds, 14.2 ± 10.1 seconds and 17.0 ± 10.9 seconds for the media group, respectively. The groups are 17.9 ± 19.0 seconds, 32.3 ± 23.8 seconds and 55.0 ± 44.0 seconds, respectively, and the positive control groups are 17.7 ± 26.2 seconds and 31.6 ± respectively. 31.0 seconds and 54.5 ± 39.7 seconds. Compound 1 group had a significant decrease in neurological symptom score (Fig. 3) and prolonged stay on the rotating bar (Fig. 4) to the same extent as the positive control group 14 days after MCA occlusion / reopening showed that.
試験例５：ラット自己血栓モデルを用いた薬効薬理試験
試験物質
媒体として生理食塩液（ｐＨ６.０）を、被験物質として化合物１（０.５ｍｇ／ｍＬ）を、血栓溶解剤としてｒｔＰＡ（アルテプラーゼ、協和発酵キリン株式会社、販売名：アクチバシン（登録商標）注６００万）を使用した。
Test Example 5: Pharmacokinetic test using rat self-thrombosis model
Physiological saline (pH 6.0) as a test substance medium, Compound 1 (0.5 mg / mL) as a test substance, rtPA (Alteplase, Kyowa Hakko Kirin Co., Ltd., trade name: Activacin (registered trademark) as a thrombolytic agent Note 6 million) was used.
ラット自己血栓モデル作製
自己血栓モデルの作製には、８週齢、体重１８０〜２６０ｇの雄性ラット（系統：Ｓｌｃ：Ｗｉｓｔａｒ、供給源：日本エスエルシー株式会社）を使用した。
血栓の作製において、１.５〜２.０％イソフルラン吸入麻酔下で採血用動物の鎖骨下静脈から約２ｍＬ採血し、採血直後の血液に日本薬局方トロンビン１５０単位およびヒトフィブリノゲン末４０ｍｇを血液と混和させた。混和後、直ちにポリエチレンチューブ（PE8040、外径：０.８０ｍｍ、内径：０.４０ｍｍ、株式会社夏目製作所）に充填し、３７℃に設定したインキュベータ内に２４時間静置した。使用直前に血栓の形状を実体顕微鏡下で確認し、２５ｍｍに切断して使用した。
Preparation of rat self-thrombosis model For preparation of a self-thrombosis model, male rats (strain: Slc: Wistar, source: Nippon SLC Co., Ltd.), 8 weeks old, weighing 180 to 260 g were used.
In the preparation of a thrombus, about 2 mL of blood was collected from the subclavian vein of the animal for blood collection under 1.5 to 2.0% isoflurane inhalation anesthesia, and 150 units of Japanese Pharmacopoeia thrombin and 40 mg of human fibrinogen powder were added to the blood immediately after blood collection. Mixed. Immediately after mixing, it was filled into a polyethylene tube (PE8040, outer diameter: 0.80 mm, inner diameter: 0.40 mm, Natsume Seisakusho Co., Ltd.), and left in an incubator set at 37 ° C. for 24 hours. Immediately before use, the shape of the thrombus was confirmed under a stereomicroscope and cut into 25 mm.
ラットを小動物実験用簡易吸入麻酔装置［NARCOBIT-E（II型）、株式会社夏目製作所］を用いて１.５〜２.０％イソフルラン吸入麻酔下で仰臥位に固定し、頸部正中切開にて右総頸動脈、外頸動脈、内頸動脈を露出し、外頸動脈を糸で結紮した。血栓を充填したテフロンチューブ（SLW-AWG32、内径：０.２０３ｍｍ、外径：０.３５５ｍｍ、株式会社ハギテック）を右外頸動脈から右内頸動脈を介して中大脳動脈の起始部まで挿入し、血栓を注入した。血栓注入後、チューブを抜き、頸部を縫合し、麻酔から解放した。 Rats were fixed in a supine position under 1.5-2.0% isoflurane inhalation anesthesia using a simple inhalation anesthesia device for small animal experiments [NARCOBIT-E (Type II), Natsume Seisakusho Co., Ltd.], and a midline neck incision was made. The right common carotid artery, external carotid artery, and internal carotid artery were exposed, and the external carotid artery was ligated with a thread. Insert a Teflon tube filled with a thrombus (SLW-AWG32, inner diameter: 0.203 mm, outer diameter: 0.355 mm, Hagitec Co., Ltd.) from the right external carotid artery to the origin of the middle cerebral artery via the right internal carotid artery. And injected a thrombus. After thrombus injection, the tube was removed, the neck was sutured and released from anesthesia.
試験物質の投与
ラットを１.５〜２.０％イソフルラン吸入麻酔下にて仰臥位に固定し、頸部の縫合を解き、テフロンチューブを内頸動脈内に挿入し、そのテフロンチューブを介して血栓注入後２時間にインフュージョンポンプ（テルフュージョンシリンジポンプ３５型TE-351、テルモ株式会社）を用いてｒｔＰＡ（投与量：２００,０００ＩＵ／０.５ｍＬ／ラット）または生理食塩液（投与容量：０.５ｍＬ／ラット）を２ｍＬ／ｈの投与速度で１５分かけて投与した。なお、投与中には体温低下を防ぐため、３７.０℃に設定した小動物体温保持装置（BWT-100、バイオリサーチセンター株式会社）の上に動物を載せた。
The rat to which the test substance was administered was fixed in the supine position under 1.5-2.0% isoflurane inhalation anesthesia, the neck was sutured, a Teflon tube was inserted into the internal carotid artery, and the Teflon tube was passed through the Teflon tube. Two hours after the thrombus injection, rtPA (dose: 200,000 IU / 0.5 mL / rat) or physiological saline (dose volume: terffusion syringe pump 35 type TE-351, Terumo Corporation) was used. 0.5 mL / rat) was administered at a dose rate of 2 mL / h over 15 minutes. During the administration, the animal was placed on a small animal body temperature maintaining device (BWT-100, Bioresearch Center Co., Ltd.) set at 37.0 ° C. in order to prevent a decrease in body temperature.
ｒｔＰＡ投与（血栓注入後２時間、動脈内投与）下あるいは非投与（血栓注入後２時間、生理食塩液動脈内投与）下において化合物１を尾静脈内に投与した。化合物１（投与量：１ｍｇ／２ｍＬ／ｋｇ）は４回（ｒｔＰＡあるいは生理食塩液の投与直前、投与後２時間、８時間および１４時間）尾静脈内に投与した。 Compound 1 was administered into the tail vein under rtPA administration (2 hours after thrombus injection, intraarterial administration) or non-administration (2 hours after thrombus injection, saline intraarterial administration). Compound 1 (dose: 1 mg / 2 mL / kg) was administered into the tail vein four times (immediately before administration of rtPA or physiological saline, 2 hours, 8 hours and 14 hours after administration).
神経症状の評価
神経症状の評価はW. E. Hoffmanらの方法（William E. Hoffman, Eberhard Kochs, Christian Werner, Chinamma Thomas, and Ronald F. Albrecht, Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Anesthesiology 75: 328-332, 1991）を参考に血栓注入後２４時間に行った。
Evaluation of neurological symptoms The evaluation of neurological symptoms was performed by WE Hoffman et al. (William E. Hoffman, Eberhard Kochs, Christian Werner, Chinamma Thomas, and Ronald F. Albrecht, Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Anesthesiology 75: 328 -332, 1991) for 24 hours after thrombus injection.
統計学的解析
神経症状スコアでは、媒体群とｒｔＰＡ群の間、媒体群と化合物１群の間並びに媒体群と化合物１およびｒｔＰＡの併用（以下、併用）群の間でWilcoxon検定を行った。併用群とｒｔＰＡ群および化合物１群との間でSteel検定を行った。各検定では、SAS 9.3（SAS Institute社）を用いた。なお、検定はいずれも片側で行った。有意水準は５％とし、１および５％に分けて表示した。
Statistical analysis In the neurological symptom score, the Wilcoxon test was performed between the vehicle group and the rtPA group, between the vehicle group and the compound 1 group, and between the vehicle group and the combined use of the compound 1 and rtPA (hereinafter, combined use) group. Steel test was performed between the combination group, the rtPA group and the compound 1 group. In each test, SAS 9.3 (SAS Institute) was used. All tests were performed on one side. The significance level was 5%, and was divided into 1 and 5%.
結果
本試験の結果（死亡例は除く）を図５に示す。媒体群、ｒｔＰＡ群、化合物１群および併用群の神経症状スコアは、それぞれ１０.０±２.７（平均値±標準偏差、以下同じ）、７.５±３.１、７.６±３.３および６.４±３.８であった。ｒｔＰＡ非投与下での化合物１投与およびｒｔＰＡ投与下での化合物１投与により、媒体と比較して有意な神経症状スコアの低下が認められた（図５）。
Results The results of this test (excluding deaths) are shown in FIG. The neurological symptom scores of the vehicle group, the rtPA group, the compound 1 group and the combination group are 10.0 ± 2.7 (mean ± standard deviation, the same applies hereinafter), 7.5 ± 3.1, 7.6 ± 3, respectively. .3 and 6.4 ± 3.8. Compound 1 administration without rtPA administration and Compound 1 administration with rtPA administration significantly reduced the neurological symptom score compared to the vehicle (FIG. 5).
Claims (11)
ｍは１または２の整数であり、
ｎは２または３の整数であり、
Ａは、
からなる群から選択される］、
の化合物またはその医薬上許容され得る塩を含む、脳梗塞処置剤。 Formula (I)
m is an integer of 1 or 2,
n is an integer of 2 or 3,
A is
Selected from the group consisting of],
Or a pharmaceutically acceptable salt thereof.
ｍは１または２の整数であり、
ｎは２または３の整数であり、
Ａは、
からなる群から選択される］、
の化合物またはその医薬上許容され得る塩。 Formula (I)
m is an integer of 1 or 2,
n is an integer of 2 or 3,
A is
Selected from the group consisting of],
Or a pharmaceutically acceptable salt thereof.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015107763A JP2018080113A (en) | 2015-05-27 | 2015-05-27 | Treatment agent of cerebral infarction |
| TW105116596A TW201707701A (en) | 2015-05-27 | 2016-05-27 | Pharmaceutical composition for treating cerebral infarction |
| PCT/JP2016/002598 WO2016189881A1 (en) | 2015-05-27 | 2016-05-27 | Pharmaceutical composition for treating cerebral infarction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015107763A JP2018080113A (en) | 2015-05-27 | 2015-05-27 | Treatment agent of cerebral infarction |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2018080113A true JP2018080113A (en) | 2018-05-24 |
Family
ID=56121145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015107763A Pending JP2018080113A (en) | 2015-05-27 | 2015-05-27 | Treatment agent of cerebral infarction |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP2018080113A (en) |
| TW (1) | TW201707701A (en) |
| WO (1) | WO2016189881A1 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI437986B (en) | 2008-01-31 | 2014-05-21 | R Tech Ueno Ltd | Thiazole derivative and use thereof as vap-1 inhibitor |
| TWI490214B (en) | 2008-05-30 | 2015-07-01 | 艾德克 上野股份有限公司 | Benzene or thiophene derivative and use thereof as vap-1 inhibitor |
| WO2010026272A1 (en) * | 2008-09-03 | 2010-03-11 | Universitat Autònoma De Barcelona | Methods and compositions for the treatment and diagnosis of haemorrhagic conversion |
| CN102499914A (en) * | 2011-11-22 | 2012-06-20 | 陶英亮 | Drug for treating strokes |
-
2015
- 2015-05-27 JP JP2015107763A patent/JP2018080113A/en active Pending
-
2016
- 2016-05-27 WO PCT/JP2016/002598 patent/WO2016189881A1/en active Application Filing
- 2016-05-27 TW TW105116596A patent/TW201707701A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW201707701A (en) | 2017-03-01 |
| WO2016189881A1 (en) | 2016-12-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2368155T3 (en) | DERIVATIVES OF CYCLIC AMIDAS AND ITS PRODUCTION AND USE IN THE FORM OF ANTITROMBÓTIC AGENTS. | |
| USRE43481E1 (en) | Diazepan derivatives or salts thereof | |
| JP4316794B2 (en) | Isoquinoline derivatives and pharmaceuticals | |
| JP6262225B2 (en) | Oxabicycloheptanes and oxabicycloheptanes for the treatment of reperfusion injury | |
| WO2011118672A1 (en) | Plasma kallikrein inhibitor | |
| US20080058312A1 (en) | Modulators of hepatocyte growth factor/c-Met activity | |
| JP2021523887A (en) | Factor XIIa inhibitor | |
| CA3144113A1 (en) | Method for treating idiopathic pulmonary fibrosis | |
| JP2003522733A (en) | Alkenyl and alkynyl compounds as factor Xa inhibitors | |
| WO2006137510A1 (en) | Agent for reduction of bleeding in cerebrovascular disorder | |
| JP2009521472A (en) | Thrombin receptor antagonist as prevention of complications of cardiopulmonary surgery | |
| JP5081890B2 (en) | Combination drugs of antithrombotic drugs and pyrazolone derivatives | |
| JPH04503524A (en) | Medications for preventing or limiting reperfusion injury | |
| JP2023506496A (en) | Compounds and their use for the treatment of α1-antitrypsin deficiency | |
| CN105384739A (en) | Pyrazolo[3,4-c]pyridine derivative | |
| CN120693326A (en) | Use of certain 1,4-oxazepane-2-carboxamides as DPP1 inhibitors | |
| JP3858279B2 (en) | Preventive / therapeutic agent for thromboxane A2-related diseases | |
| JP2018080113A (en) | Treatment agent of cerebral infarction | |
| CN114671856B (en) | Polysubstituted uracil derivative and use thereof | |
| KR20120038982A (en) | Otamixaban for treatment of elderly and renal impaired non-st elevation myocardial infarction patients | |
| CN113387909B (en) | Medical application of 2, 3-epoxysuccinyl derivative | |
| CN115427043A (en) | Medical application of FXIa inhibitor compound or salt thereof | |
| EP0369035A1 (en) | Agent for treating pancreatitis or the like | |
| US20230122967A1 (en) | Novel compounds as inhibitors of pcsk9 | |
| CN111356677A (en) | Tetrahydroisoquinoline derivatives, and preparation method and application thereof |