CN1289249A - 1,3,4-噁二唑酮衍生物 - Google Patents
1,3,4-噁二唑酮衍生物 Download PDFInfo
- Publication number
- CN1289249A CN1289249A CN99802411A CN99802411A CN1289249A CN 1289249 A CN1289249 A CN 1289249A CN 99802411 A CN99802411 A CN 99802411A CN 99802411 A CN99802411 A CN 99802411A CN 1289249 A CN1289249 A CN 1289249A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- methyl
- oxadiazole
- trifluoromethyl
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- WTSXVIMLKCKWIW-UHFFFAOYSA-N 3h-1,3,4-oxadiazol-2-one Chemical class O=C1NN=CO1 WTSXVIMLKCKWIW-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 17
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 17
- 239000012453 solvate Substances 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 101
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- -1 4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenyl (dimethylamino) Chemical class 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 23
- 239000011575 calcium Substances 0.000 claims description 22
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 21
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 18
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 15
- GWVLAXGYZUVAGV-UHFFFAOYSA-N n,n-dimethylmethanamine;methanesulfonic acid Chemical class C[NH+](C)C.CS([O-])(=O)=O GWVLAXGYZUVAGV-UHFFFAOYSA-N 0.000 claims description 15
- 102000004257 Potassium Channel Human genes 0.000 claims description 13
- 108020001213 potassium channel Proteins 0.000 claims description 13
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 12
- 208000006011 Stroke Diseases 0.000 claims description 12
- 229910052791 calcium Inorganic materials 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 150000001450 anions Chemical class 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 208000028867 ischemia Diseases 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 9
- 206010010904 Convulsion Diseases 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 208000020431 spinal cord injury Diseases 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 208000019695 Migraine disease Diseases 0.000 claims description 7
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 7
- 206010046543 Urinary incontinence Diseases 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 230000036461 convulsion Effects 0.000 claims description 7
- 206010015037 epilepsy Diseases 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 7
- 206010027599 migraine Diseases 0.000 claims description 7
- 230000035945 sensitivity Effects 0.000 claims description 7
- 230000009529 traumatic brain injury Effects 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229960004194 lidocaine Drugs 0.000 claims description 5
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 5
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- ZJEZSISCHHJCIO-UHFFFAOYSA-N methyl 4-(dimethylamino)butanoate Chemical compound COC(=O)CCCN(C)C ZJEZSISCHHJCIO-UHFFFAOYSA-N 0.000 claims description 3
- YHOXRVURMRBHDX-UHFFFAOYSA-N diethyl(methyl)azanium;methanesulfonate Chemical class CS([O-])(=O)=O.CC[NH+](C)CC YHOXRVURMRBHDX-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 102000016469 Large-Conductance Calcium-Activated Potassium Channels Human genes 0.000 abstract description 3
- 108010092555 Large-Conductance Calcium-Activated Potassium Channels Proteins 0.000 abstract description 3
- 208000035475 disorder Diseases 0.000 abstract 1
- ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical class O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 24
- 239000000203 mixture Substances 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000001819 mass spectrum Methods 0.000 description 16
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 16
- 239000003814 drug Substances 0.000 description 14
- 238000004364 calculation method Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 10
- 239000000376 reactant Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 210000000170 cell membrane Anatomy 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000002902 bimodal effect Effects 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 108091006146 Channels Proteins 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 210000001168 carotid artery common Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940093499 ethyl acetate Drugs 0.000 description 5
- 230000028161 membrane depolarization Effects 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 241001597008 Nomeidae Species 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 229960004203 carnitine Drugs 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000002102 hyperpolarization Effects 0.000 description 4
- VDNVVLOBNHIMQA-UHFFFAOYSA-N iberiotoxin Chemical compound C1SSCC(C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(O)=O)NC(=O)C(CCCNC(N)=N)NC(=O)C1NC(=O)C(CCCCN)NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCCNC(N)=N)NC(=O)C(CC(O)=O)NC(=O)C(C(C)C)NC(=O)CNC(=O)C(CC=1C=CC=CC=1)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CCCCN)NC1=O)CSSCC1NC(=O)C(C(C)C)NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(NC(=O)C(CCC(O)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(CO)NC1=O)CSSCC1NC(=O)C(CC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(O)=O)NC(=O)C(C(C)O)NC(=O)C(NC(=O)C1NC(=O)CC1)CC1=CC=CC=C1 VDNVVLOBNHIMQA-UHFFFAOYSA-N 0.000 description 4
- 108010068927 iberiotoxin Proteins 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000001035 methylating effect Effects 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- 101100381997 Danio rerio tbc1d32 gene Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 101100381999 Mus musculus Tbc1d32 gene Proteins 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000012752 auxiliary agent Substances 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 3
- 230000005595 deprotonation Effects 0.000 description 3
- 238000010537 deprotonation reaction Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000010291 membrane polarization Effects 0.000 description 3
- 210000003657 middle cerebral artery Anatomy 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 210000000287 oocyte Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102000034573 Channels Human genes 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010022998 Irritability Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical class CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- VGEREEWJJVICBM-UHFFFAOYSA-N phloretin Chemical compound C1=CC(O)=CC=C1CCC(=O)C1=C(O)C=C(O)C=C1O VGEREEWJJVICBM-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 208000012201 sexual and gender identity disease Diseases 0.000 description 2
- 208000015891 sexual disease Diseases 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000024891 symptom Diseases 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
- 239000000080 wetting agent Substances 0.000 description 2
- ZWTDXYUDJYDHJR-UHFFFAOYSA-N (E)-1-(2,4-dihydroxyphenyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one Natural products OC1=CC(O)=CC=C1C=CC(=O)C1=CC=C(O)C=C1O ZWTDXYUDJYDHJR-UHFFFAOYSA-N 0.000 description 1
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- GWOYTRDTYUBKTJ-UHFFFAOYSA-N 2-(bromomethyl)-4-chloro-1-methoxybenzene Chemical compound COC1=CC=C(Cl)C=C1CBr GWOYTRDTYUBKTJ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- OXOWTLDONRGYOT-UHFFFAOYSA-M 4-(dimethylamino)butanoate Chemical compound CN(C)CCCC([O-])=O OXOWTLDONRGYOT-UHFFFAOYSA-M 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 102100023073 Calcium-activated potassium channel subunit alpha-1 Human genes 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 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
- 206010057671 Female sexual dysfunction Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101001049859 Homo sapiens Calcium-activated potassium channel subunit alpha-1 Proteins 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- YQHMWTPYORBCMF-UHFFFAOYSA-N Naringenin chalcone Natural products C1=CC(O)=CC=C1C=CC(=O)C1=C(O)C=C(O)C=C1O YQHMWTPYORBCMF-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920006266 Vinyl film Polymers 0.000 description 1
- 241000269370 Xenopus <genus> Species 0.000 description 1
- 241000269368 Xenopus laevis Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- IFVTZJHWGZSXFD-UHFFFAOYSA-N biphenylene Chemical group C1=CC=C2C3=CC=CC=C3C2=C1 IFVTZJHWGZSXFD-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000000621 bronchi 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
- XQPRBTXUXXVTKB-UHFFFAOYSA-M caesium iodide Chemical compound [I-].[Cs+] XQPRBTXUXXVTKB-UHFFFAOYSA-M 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 210000000080 chela (arthropods) Anatomy 0.000 description 1
- JWMLCCRPDOIBAV-UHFFFAOYSA-N chloro(methylsulfanyl)methane Chemical compound CSCCl JWMLCCRPDOIBAV-UHFFFAOYSA-N 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000004387 flavanoid group Chemical group 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical class CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000012423 maintenance Methods 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
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000012241 membrane hyperpolarization Effects 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- WMUQLHIITDJQHZ-UHFFFAOYSA-N methoxymethanesulfonic acid Chemical compound COCS(O)(=O)=O WMUQLHIITDJQHZ-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- DQHUNQPOBFLPAH-UHFFFAOYSA-N n-benzyl-2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-n-phenylacetamide Chemical compound CC1=C(Cl)C(C(F)(F)F)=NN1CC(=O)N(C=1C=CC=CC=1)CC1=CC=CC=C1 DQHUNQPOBFLPAH-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000036403 neuro physiology Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 108010083133 potassium channel protein I(sk) Proteins 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000011471 prostatectomy Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明提供了新颖的具有通式(Ⅰ)结构的噁二唑酮衍生物,其中A、B、D和R是如本文所定义的,或其无毒的药学上可接受的盐或溶剂化物,可用于治疗对大电导钙活化的钾通道打开敏感的病症。
Description
发明领域
本发明涉及新颖的1,3,4-噁二唑-2(3H)-酮化合物的衍生物,该化合物是大电导钙活化的钾(BK)通道调节剂,因此可用于神经元细胞的保护和由细胞膜极化与电导功能障碍引起的疾病。本发明也提供了使用该新颖的取代的噁二唑酮的治疗方法,还提供了它们的药物组合物。
发明背景
目前在美国和欧洲,中风被认为是导致成人病残和死亡的第三大病因。在过去的十年里,已经实现了若干用于减少中风引起的脑损伤的治疗方法,包括AMPA/红藻氨酸盐抑制剂、N-甲基-D-天冬氨酸盐(NMDA)和腺苷再摄取抑制剂。本发明的目的是提供新颖的调节钾通道的化合物,特别是调节大电导钙活化的钾(BK)通道,将可用于减少中风发作的局部缺血状态中的神经元损伤。
钾通道在细胞膜电位的调节和细胞兴奋性的调节中起到关键性作用。钾通道本身受电压、细胞代谢、钙离子和受体介导的过程的调节[Cook,N.S.《药理科学趋势》9,pp.21-28(1988);Quast,U.和Cook,N.S.《药理科学趋势》10,pp.431-435(1989)]。钙活化的钾(KCa)通道是一组不同的离子通道,它们分享对细胞内钙离子活性的依赖性。KCa通道的活性受细胞内[Ca2+]、膜电位和磷酸化作用的调节。根据其在对称K+溶液中的单通道电导,KCa通道分为三个子类:大电导(BK)>150pS;中电导50-150pS;小电导<50pS(“pS”代表电导单位,皮西门子(picosiemen))。大电导钙活化的钾(BK)通道存在于很多可兴奋的细胞内,包括神经元、心肌细胞和各种类型的平滑肌细胞[Singer,J.J.和Walsh,J.V.《Pflügers Archiv.》408,pp.98-111(1987);Baró,I.和Escande,D.《Pflügers Archiv.》414(增刊1),pp.S168-S170(1989);Ahmed,F.等《英国药理学杂志》83,pp.227-233(1984)]。
钾离子在控制大多数可兴奋细胞内的静息膜电位上和保持跨膜电位接近约-90mV的K+平衡电位(Ek)上起到决定性作用。有报道揭示,钾通道的打开使细胞膜电位向平衡钾膜电位(Ek)靠近,导致细胞的超极化[Cook,N.S.《药理科学趋势》9,pp.21-28(1988)]。超极化的细胞对潜在有害的去极化刺激的反应性降低。既受电压调节也受细胞内Ca2+调节的BK通道起到限制去极化和钙进入的作用,特别是可以有效阻断有害刺激。因此,通过打开BK通道而使细胞超极化,可以保护局部缺血状态下的神经元细胞。
S.Trivedi等在《生物化学与生物物理学研究通讯》(1995),213,No.2,pp.404-409中讨论了钾通道在人膀胱平滑肌运动中的作用。
已经报道了一些具有BK打开活性的合成的和天然来源的化合物。利用脂类双层工艺,从燕麦-普通燕麦中提取的燕麦吡喃酮已被鉴定是一种BK通道打开剂(国际专利中请WO 93/08800,1993年5月13日公开)。利用外部药贴,已经在Xenopus laevis有髓鞘神经纤维内发现黄烷类根皮素可影响Ca2+活化的钾通道的打开[Koh,D-S.等《神经科学快报》165,pp.167-170(1994)]。
其中
R1是烷基、环烷基或芳烷基;
R2是氢或R1;
R3是氢或C1-4烷基;
Y和Z独立地是O或S;
或者(2)如果m=2,那么是亚烷基、亚烷基醚、亚烷基硫醚、二亚苯基或萘。该化合物是有机聚合物的抗氧化剂。
1993年3月24日公开的EPO 0-533276-A1涉及式(ⅱ)化合物: (ⅱ)
其中P或Q之一是邻位取代的苯基,另一个是取代的苄基。式(ⅱ)化合物是杀螨剂和杀虫剂。
A.E.Wilder Smith在《Arzneim.Forsch.》(1967)67,No.17,pp.768-772中公开了式(ⅲ)化合物的制备和研究: (ⅲ)
其中X是H或Cl,n是1或2。该化合物具有抑制结核菌的性质。式(ⅲ)化合物不包括在羟基对位的取代。
J.L.Romine等在1998年2月5日公开的国际专利申请WO98/04135中描述了一系列式(ⅳ)的二苯基杂环: (ⅳ)
其中Het是杂环部分,尤其选自噁二唑酮。该化合物可用作大电导钙活化的钾通道调节剂,其中还描述了制备本发明化合物的原料,其中Het是1,3,4-噁二唑-2(3H)-酮,m=1,n=0,Rc是氯,Rd是三氟甲基,Ra=Rb=Re是氢。
这些参考文献都没有教导或提示本发明的新颖化合物。
发明概述
本发明提供了新颖的1,3,4-噁二唑酮衍生物,具有下列通式结构: Ⅰ
其中A、B、D和R是如下定义的,
或其无毒的药学上可接受的盐或溶剂化物。本发明也提供了包含所述衍生物的药物组合物,还提供了治疗对钾通道打开活性敏感的病症的方法,例如局部缺血、中风、惊厥、癫痫、哮喘、过敏性肠综合征、偏头痛、外伤性脑损伤、脊髓损伤、性功能障碍和尿失禁。
发明的详细说明
本发明提供了3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮的新颖衍生物,所述酮是一种有效的大电导钙活化的K+通道(BK通道)打开剂,该新颖的衍生物具有下列通式结构: Ⅰ
其中
A是一条直接的键或-CH2O-;
B是-条直接的键或氧;
D是-(CH2)n-或-CH2CHOHCH2-;
n是1至4的整数;
R1、R2和R3各自独立地是氢或C1-4烷基;
或其无毒的药学上可接受的盐或溶剂化物。
本发明也提供了哺乳动物病症的治疗或预防方法,该病症是以大电导钙活化的K+通道(BK通道)的打开为介导的,该方法包括将治疗有效量的式Ⅰ化合物或其无毒的药学上可接受的盐对所述哺乳动物给药。优选地,式Ⅰ化合物可用于治疗局部缺血、中风、癫痫、惊厥、哮喘、过敏性肠综合征、偏头痛、外伤性脑损伤、脊髓损伤、性功能障碍、尿失禁和其他对BK通道活化活性敏感的病症。
这里和权利要求书中所用术语“C1-4烷基”(除非上下文中另有指示)指直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基。优选地,这些基团含有1至2个碳原子。
这里和权利要求书中所用术语“无毒的药学上可接受的盐”和“相反阴离子”意在包括与无机酸及有机酸所形成的无毒的酸加成盐和相反阴离子。适合的酸盐和/或适合的酸的相反阴离子意在包括无机酸盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐等,和有机酸盐和/或酸的相反阴离子,例如甲酸盐、乙酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、抗坏血酸盐、乳酸盐、富马酸盐、甲磺酸盐和酒石酸盐,它们已用来形成碱性胺和叔胺的盐。
由于本发明化合物可能具有不对称碳原子,因此本发明意在包括外消旋物以及这里和权利要求书中所述式Ⅰ化合物的各对映异构体形式,例如降肉碱和肉碱的(D)、(L)和(DL)型。
一般来说,本发明的药学上可接受的盐是其中的相反阴离子不显著参与盐的毒性或药理活性的那些。在某些情况下,它们具有药物制剂所需的物理性质,例如溶解度、无吸湿性、与形成片剂有关的可压缩性和与出于药学目的而可能使用的其他成分的相容性。盐是用常规方法制备的:使式Ⅰ化合物与所选择的酸混合,优选地利用一种过量的常用惰性溶剂而使它们在溶液中接触,溶剂例如水、乙醚、二噁烷、二氯甲烷、异丙醇、甲醇、乙醇、乙酸乙酯和乙腈。盐也可以通过置换作用制备,或者在一定条件下用离子交换树脂进行处理,其中式Ⅰ物质的盐的适当离子被另一种离子置换,反应在可以进行所需物质的分离的条件下进行,例如从溶液中沉淀或用溶剂萃取,或者从离子交换树脂上洗脱或保留在树脂上。
包括其药学上可接受的盐在内的某些本发明化合物能够以溶剂化的形式存在,包括水合的形式,例如一水合物、二水合物、半水合物、三水合物、四水合物等。产物可以是真正的溶剂化物,而在其他情况下,产物可以仅保留偶然的溶剂,或者是溶剂化物加某种偶然溶剂的混合物。本领域技术人员应当这样理解,溶剂化物的形式等价于未溶剂化的形式,也涵盖在本发明的范围内。
在本发明的方法中,术语“治疗有效量”指组合物的每种活性组分的总量足以给患者带来有意义的益处,即治愈以大电导钙活化的K+通道打开剂为特征的急性状态或提高其治愈率。当适用于单独给药的单独活性成分时,该术语指的是单独的该成分。当适用于组合时,该术语指的是产生治疗效果的各活性成分总量,而与是否联合、连续或同时给药无关。这里和权利要求书中所用术语“治疗”指预防或改善与细胞膜极化与电导功能障碍有关的疾病、组织损伤和/或症状。
另一方面,本发明提供了WO98/04135中所述的3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮的水溶性前体药物。这里所用的术语前体药物表示一种活性药物的衍生物,它在给药后转化回活性药物。更确切地说,它指的是1,3,4-噁二唑-2(3H)-酮化合物的衍生物,它们可以是活性药物和/或能够进行酯部分或亚甲氧基酯部分的水解或酯的裂解,从而释放出活性的游离药物。生理学上可水解的基团充当前体药物,通过在体内水解得到母体药物本身,因此,本发明的水溶性前体药物是母体药物的给药所优选的。
另一方面,本发明提供了哺乳动物病症的治疗方法或预防方法,该病症是以大电导钙活化的K+通道(BK通道)的打开为介导的,该方法包括将治疗有效量的式Ⅰ化合物或其无毒的药学上可接受的盐、溶剂化物或水合物对所述哺乳动物给药。优选地,式Ⅰ化合物可用于治疗局部缺血、中风、惊厥、癫痫、哮喘、过敏性肠综合征、偏头痛、外伤性脑损伤、脊髓损伤和尿失禁,通过增加生殖器、尤其是海绵体的血流还可用于治疗男性性功能障碍(勃起障碍,例如由糖尿病、脊髓损伤、根治前列腺切除术、精神性病因或任何其他原因导致)和女性性功能障碍,以及其他对BK通道活化活性敏感的病症。最优选地,式Ⅰ化合物可用于脑缺血/中风的治疗。
另一方面,本发明提供了药物组合物,它包含至少一种式Ⅰ化合物结合药物助剂、载体或稀释剂。
式Ⅰ化合物可以通过不同操作进行制备,例如实施例、反应流程及其变例中所阐述的那些,它们对本领域技术人员来说是显而易见的。各种式Ⅰ的前体药物化合物可以有利地从式Ⅱ活性药物物质进行制备,后者本身是通过WO98/04135和实施例1中所述的一般操作进行制备的,它们在反应流程1至5中所阐述的方法中用作原料。
反应流程1阐述了式Ⅴ的1,3,4-噁二唑-2-(3H)-酮衍生物的制备。将式Ⅱ化合物用光气和催化量的相转移试剂(例如氯化苄基三苯基鏻)在甲苯中进行处理,并在密封试管内加热,得到式Ⅲ的氯甲酸酯,然后用适当取代的N,N-二烷基氨基醇在惰性有机溶剂(例如二氯甲烷)中进行处理,得到式Ⅳ的碳酸酯化合物。当需要制备式Ⅴ化合物时,将式Ⅳ的氨基化合物用甲基化试剂(例如甲磺酸甲酯)进行季铵化,通过本领域技术人员熟知的标准操作得到式Ⅴ的季胺。
反应流程2
当需要制备其中n是1至4的式Ⅷ化合物时,将式Ⅱ化合物用碱(例如氢化钠)进行去质子化,然后用所需的N,N-二烷基氨基酰氯进行酰化,得到式Ⅶ的酯,将其有利地用烷基化试剂(例如甲磺酸甲酯)进行季铵化,得到式Ⅷ的季胺。
反应流程3阐述了式Ⅻ化合物的制备,其中R1、R2、R3和n定义同上。将式Ⅱ化合物用碱(例如氢化钠)进行去质子化,然后用氯甲基甲基硫醚进行烷基化,得到式Ⅸ的硫代甲基甲基醚。将式Ⅸ化合物用氯化剂(例如磺酰氯)进行处理,得到式Ⅹ的氯甲基醚,然后用所需的N,N-二烷基氨基酸在碱(例如碳酸铯)的存在下进行处理,得到相应的式Ⅺ的甲氧基酯。当需要制备式Ⅻ化合物时,将式Ⅺ的胺用甲基化试剂(例如甲磺酸甲酯)进行季铵化,得到式Ⅻ的季胺。
式ⅩⅢ化合物的制备是易于进行的,方法是将式Ⅹ的氯甲基醚用肉碱在碱(例如碳酸铯)的存在下进行处理,然后将所得产物用甲基化试剂(例如甲磺酸甲酯)进行处理,得到式ⅩⅢ的季胺。
反应流程5
反应流程5阐述了式ⅩⅦ化合物的制备,其中R1、R2、R3和n定义同上。将式Ⅱ化合物用碱(例如氢化钠)进行去质子化,然后用丁基硫代碳酸碘甲基酯(iodomethyl butyl carbononothioate)进行烷基化,得到式ⅩⅣ的甲氧基硫代碳酸酯。将式ⅩⅣ中间体用氯化剂(例如磺酰氯)进行处理,得到式ⅩⅤ的氯甲酸酯,然后用所需的N,N-二烷基氨基醇进行处理,得到相应的式ⅩⅥ的甲氧基碳酸酯。随后可以将式ⅩⅥ化合物用甲基化试剂(例如甲磺酸甲酯)进行烷基化,得到式ⅩⅦ的季胺。
其中A是一条直接的键或-CH2O-;B是一条直接的键或氧;D是-(CH2)n-或-CH2CHOHCH2-,其中n是1至4;并且R1和R2是氢或C1-4烷基;或其无毒的药学上可接受的盐或溶剂化物。更优选地,A是一条直接的键或-CH2O-;B是一条直接的键;D是-(CH2)n-,其中n是1、2或3;并且R1和R2是甲基或乙基。最优选地,A是-CH2O-;B是一条直接的键;D是-(CH2)n-,其中n是2或3;并且R1和R2是甲基;或其无毒的药学上可接受的盐或溶剂化物。
其中A是一条直接的键或-CH2O-;B是一条直接的键或氧;D是-(CH2)n-或-CH2CHOHCH2-,其中n是1至4;R1、R2和R3是氢或C1-4烷基;是相反阴离子;或其无毒的药学上可接受的盐或溶剂化物。更优选地,A是一条直接的键或-CH2O-;B是一条直接的键;D是-(CH2)n-,其中n是1、2或3;R1、R2和R3是甲基;
是氯、溴、硫酸根、磷酸根或甲磺酸根。最优选地,A是-CH2O-;B是一条直接的键;D是-(CH2)n-,其中n是3;R1、R2和R3是甲基;
是甲磺酸根;或其无毒的药学上可接受的盐或溶剂化物。
在另一种实施方式中,本发明包括药物组合物,它包含至少一种式Ⅰ化合物结合药物助剂、载体或稀释剂。
在另一种实施方式中,本发明涉及哺乳动物病症的治疗或预防方法,该病症对钾通道的打开有应答,该方法包括将治疗有效量的式Ⅰ化合物或其无毒的药学上可接受的盐、溶剂化物或水合物对所述哺乳动物给药。
在另一种实施方式中,本发明涉及用于治疗哺乳动物局部缺血、惊厥、癫痫、哮喘、过敏性肠综合征、偏头痛、外伤性脑损伤、脊髓损伤、雄性及雌性性功能障碍、尿失禁、尤其是中风的方法,该方法包括将治疗有效量的式Ⅰ化合物或其无毒的药学上可接受的盐、溶剂化物或水合物对所述哺乳动物给药。
生物活性
钾(K+)通道是结构和功能各异的K+选择性通道蛋白质,它们在细胞内是无所不在的,这说明它们在调节一些关键细胞功能上具有重要作用[Rudy,B.《神经科学》25,pp.729-749(1988)]。作为广泛分布的一类,K+通道的分布因该种类的各成员或各种类而异[Gehlert,D.R.等《神经科学》52,pp.191-205(1993)]。一般来说,细胞内、特别是神经元和肌细胞这样的可兴奋的细胞内K+通道的活化导致细胞膜超极化,或者在去极化细胞的情况下,导致再极化。除了充当内源性膜电压箝以外,K+通道还能够对重要的细胞事件作出反应,例如细胞内ATP浓度的改变或细胞内钙(Ca2+)浓度的改变。K+通道在调节大量细胞功能中的核心作用使它们成为治疗研究的特别重要的目标[Cook,N.S.,《钾通道:结构、分类、功能和治疗潜力》,Ellis Horwood,Chinchester(1990)]。有一类K+通道,即大电导Ca2+活化的K+通道(BK或BK通道)受到跨膜电压、细胞内Ca2+和各种其他因素的调节,例如通道蛋白质的磷酸化状态[Latorre,R.等《生理学年鉴》51,pp.385-399(1989)]。BK通道的大而单一的通道电导(通常>150pS)和对K+的高度特异性说明,少量通道可能对膜电导和细胞可兴奋性产生深刻影响。另外,随着细胞内Ca2+的增加,打开的概率也增加,这说明BK通道参与了Ca2+依赖性现象的调节,例如分泌和肌肉收缩[Asano,M.等《药理实验与治疗学杂志》267,pp.1277-1285(1993)]。
BK通道打开剂通过增加这些通道的打开概率来发挥它们的细胞作用[McKay,M.C.等《神经生理学杂志》71,pp.1873-1882(1994);Olesen,S.-P.《Exp.Opin.Invest.Drugs》3,pp.1181-1188(1994)]。增加各BK通道的打开共同导致细胞膜、特别是去极化细胞的超极化,这是由全细胞BK介导的电导的显著增加而引起的。
在电压箝条件下评价实施例1化合物打开BK通道和增加全细胞向外的(K+)BK介导电流的能力,方法是测定它们增加非洲爪蟾属卵母细胞内异源表达的克隆哺乳动物(mSlo或hSlo)BK介导的向外电流的能力[Butler,A.等《科学》261,pp.221-224(1993);Dworetzky,S.I.等《分子脑研究》27,pp.189-193(1994)]。所用两种BK构成物代表结构上几乎相同的同源蛋白质,而且在我们的试验里已证实具有相同的药理作用。为了从天然(背景,非BK)电流中分离BK电流,使用超高浓度(50nM)特异性的和有效的BK通道阻滞毒素iberiotoxin(IBTX)[Galvez,A.等《生物学和化学杂志》265,pp.11083-11090(1990)]。测定BK通道电流对总向外电流的相对贡献,方法是从在所有其他实验条件(对照、药物和洗液)下得到的电流中减去在IBTX存在下剩余的电流(非BK电流)。肯定的是化合物在试验浓度下不影响卵母细胞内非BK的天然电流。浓度为1μM的实施例1化合物在至少5个卵母细胞内显示,与对照组IBTX敏感的电流相比,使BK电流增加了126%。利用标准双电极电压箝工艺[Stuhmer,W.等《酶学方法》207,pp.319-339(1992)]完成了记录;电压箝方案由持续500-750ms的去极化步骤组成,在20mV步骤中的保持电位为-60mV至+140mV。实验介质(改性Barth溶液)的组成为(mM);NaCl(88),NaHCO3(2.4),KCl(1.0),HEPES(10),MgSO4(0.82),Ca(NO3)2(0.33),CaCl2(0.41);pH7.5。
如下进行快速筛选,以测定前体药物水解和释放药物(实施例1化合物)的能力。在蒸馏水或乙腈或PEG-400中制备前体药物的1mg/ml储备溶液。在本项测定中使用来自新鲜采集的大鼠或人血液的血浆。在37℃下向1ml血浆中加入10μl前体药物的储备溶液,轻轻地混合。混合后立即取出100μl血浆,用300μl乙腈淬灭(零时间样本)。30分钟时同样采集样本,立即淬灭。淬灭过的样本离心,得到澄清的上清液,供分析之用。储备溶液、T=0和T=30样本用HPLC测定法进行分析,从前体药物中分离出药物。根据前体药物和药物在这些样本中的相对峰面积,将不同的前体药物鉴定为快、中和慢释放剂。例如,在该模型中,将实施例13化合物以1mg/ml的浓度溶解在PEG-400中,以10ug/ml在新鲜大鼠血浆内、在37℃下培养。培养后5分钟分析溶液,指示实施例13化合物向实施例1化合物的转化。
为了测定本发明化合物减少由神经元缺血所致细胞损失的能力,通过左中脑动脉(MCA)和普通颈动脉(CCA)的永久性阻塞诱发标准病灶性脑缺血,同时使Wistar大鼠右CCA阻塞一小时。利用A.Tamura等《脑血流与代谢杂志》1,pp.53-60(1981)的颞下方法及其改进[K.Osborne等《神经学、神经外科学与精神病学杂志》50,pp.402-410(1987)和S.Menzies等《神经外科学》31,pp.100-107(1992)]进行手术。
在病灶性中风模型中评价实施例13化合物,该模型涉及Wistar大鼠左MCA与CCA的永久性阻塞(MCAO与CCAO)和右CCA的暂时性阻塞。该操作导致可靠的大体积新生皮层梗塞,后者是利用MCAO后24小时通过脑的不含活体染剂的连续切片测量的。本试验中,将化合物在阻塞后两小时通过i.v.或i.p.途径给药。例如在该模型中,在中脑动脉阻塞后两小时将实施例13化合物通过静脉内以单一大丸剂给药(1mg/kg),与载体处理的(水)对照组相比显著减少了约17%的皮层梗塞体积。
上述体外和体内试验结果证明,本发明新颖的1,3,4-噁二唑-2(3H)-酮化合物可用于由细胞膜极化与电导功能障碍引起的人病症的治疗,优选地适用于局部缺血、中风、惊厥、癫痫、哮喘、过敏性肠综合征、偏头痛、外伤性脑损伤、脊髓损伤、性功能障碍、尿失禁和其他对BK通道活化活性敏感的病症的治疗。最优选地,式Ⅰ化合物可用于脑缺血/中风的治疗。
式Ⅰ化合物或其药物组合物可用于病症或其他与BK通道有关的病症的治疗、缓解或消除。这样的病症包括局部缺血、中风、惊厥、癫痫、哮喘、过敏性肠综合征、偏头痛、外伤性脑损伤、脊髓损伤、性功能障碍、尿失禁和其他对钾通道打开剂敏感的病症。
在用于治疗时,式Ⅰ的药理活性化合物通常作为药物组合物进行给药,后者利用标准和常规工艺包含至少一种该化合物作为必要的活性成分(或之一),以及固体或液体药学上可接受的载体,和可选的药学上可接受的助剂及赋形剂。
药物组合物包括适用于口服、胃肠外(包括皮下、肌内、皮内和静脉内)、支气管或鼻给药的剂型。因此,如果使用了固体载体,那么制剂可以被压成片剂、以粉末或颗粒的形式放入硬胶囊、或者是糖锭或锭剂的形式。固体载体可以含有常规的赋形剂,例如黏合剂、填充剂、压片润滑剂、崩解剂、润湿剂等。如果需要的话,片剂可以用常规工艺包衣。如果使用了液体载体,那么制剂可以是糖浆、乳液、软胶囊、无菌注射用赋形剂、含水或非水的混悬液的形式,或者是干燥产物,在使用前与水或其他适当载体重新配制。液体制剂可以含有常规的添加剂,例如悬浮剂、乳化剂、润湿剂、非水载体(包括食用油)、防腐剂、以及矫味剂和/或着色剂。对胃肠外给药来说,载体通常包含无菌水,至少大部分是,不过也可以使用盐水溶液、葡萄糖溶液等。也可以使用可注射的混悬液,在这种情况下可以使用常规的悬浮剂。还可以向胃肠外剂型中加入常规的防腐剂、缓冲剂等。特别有用的是将式Ⅰ化合物直接以胃肠外制剂给药。药物组合物按照常规工艺制备,这些工艺适合于含有适量活性成分、即按照本发明的式Ⅰ化合物的所需制剂。例如参见《雷明顿药物科学》Mack出版公司,Easton,PA,第17版,1985。
式Ⅰ化合物达到治疗效果的剂量将不仅取决于患者年龄、体重与性别和给药方式等因素,而且取决于所需钾通道活化活性的程度和所用特定化合物针对特定疾病的功效。当然,特定化合物的治疗和剂量可以以单位剂型给药,单位剂型将因此由本领域技术人员进行调整,以反映相对活性水平。关于所用特定剂量(和每天的给药次数)的决定是在医师的指导下,可以通过滴定法改变剂量以适应本发明的具体情况,从而达到所需的治疗效果。
式Ⅰ化合物或其药物组合物对患有或可能患有本文所述的任何疾病的哺乳动物、包括人的适用剂量以活性成分计,约为0.1ng/kg至10mg/kg体重。对胃肠外给药来说,剂量可以在0.1ng/kg至1.0mg/kg体重的范围内,此为静脉内给药。活性成分将优选地连续给药,或者在一天内分一至四次以等剂量给药。不过,通常给以小剂量,逐渐增加剂量,直到确定在治疗条件下对宿主的最佳剂量。
不过不言而喻的是,化合物的实际给药量将由医师根据相关环境而决定,包括所治疗的疾病、用以给药的化合物的选择、所选择的给药途径、个体患者的年龄、体重与反应、和患者症状的严重性。
以举例说明方式给出下列实施例,而绝不被解释为对发明的限制,因为发明的很多变例在发明的含义内都是可能的。
具体实施方式的说明
下列实施例中,所有温度以摄氏度给出。熔点是在Gallenkamp毛细管熔点仪上记录的,温度未经校正。质子磁共振(1H NMR)是在Bruker AC300上记录的。所有光谱是在所示溶剂中测定的,化学位移是以向下偏离内标四甲基硅烷(TMS)的δ单位报告的,质子内偶联常数是以赫兹(Hz)报告的。分裂方式表示如下:s单峰,d双峰,t三重峰,q四重峰,m多重峰,br宽峰,dd双峰的双峰,bd宽的双峰,dt三重峰的双峰,bs宽的单峰,dq四重峰的双峰。使用溴化钾(KBr)的红外(IR)光谱是在PerkinElmer781分光光度计上测定的,测定范围4000cm-1至400cm-1,对聚苯乙烯膜的1601cm-1吸收进行校正,以厘米倒数(cm-1)报告。低分辨质谱(MS)和表观分子量(MH+)或(M-H)-是在Finnigen TSQ7000上测定的。高分辨质谱是在Kratos MS50以FAB模式测定的,并使用碘化铯/甘油作为内参。元素分析是以重量百分比报告的。
下列实施例阐述原料、中间体的制备操作和按照本发明的产物的制备方法。对本领域技术人员来说也应当显而易见的是,这里所公开的原料和方法的适当替换将得到下面所阐述的实施例,它们也涵盖在本发明的范围之内。
实施例1
3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮
步骤A:5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮
在N2下,将4-(三氟甲基)苯甲酸酰肼(商业上可从MaybridgeChemicals得到)(59,24.5mmol)溶于THF(250ml)/三乙胺(2.7ml,26mmol),加入1,1’-羰基二咪唑(4.2g,26mmol)。溶液在24℃下搅拌18小时,浓缩,将残余物溶于乙酸乙酯,用1NHCl溶液、饱和NaHCO3溶液和盐水洗涤,然后干燥(MgSO4)。浓缩,得到5g(89%)标题化合物,将样本从二乙醚/己烷中重结晶:mp214-216℃.MS m/z231(MH+).1R(KBr)3280,1778,1608,1420,1318,1170,1114cm-1;1H NMR(DMSO-d6)δ7.87(2H,d,J=8.3Hz),7.96(2H,d,J=8.3Hz),12.77(1H,br.s);分析计算值:C9H5F3N2O2·0.64H2O:C,46.74;H,2.24;N,12.11.
实测值:C,47.07;H,2.10;N,12.34.
步骤B:3-[(5-氯-2-甲氧基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮
在氮下,向CH3CN(300ml)中加入5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(H)-酮(11.75g,51mmol)和5-氯-2-甲氧基苄基溴[N.Meanwell等《生物有机与医药化学快报》6,pp.1641-1646(1996)](12.0g,51mmol)和11.2g(81mmol)碳酸钾,加入碘化钾(0.2g,1.2mmol)。溶液回流16小时,冷却,倒入水(1500ml)中,剧烈搅拌。过滤沉淀,得到一固体,从CH3CN中重结晶,得到15.2g(78%)标题化合物。mp144-145℃.MS(ESl)m/z385(MH+).IR(KBr)3440,1782,1492,1324,1248,1168cm-1;1H NMR(300MHz,DMSO)δ3.79(3H,s),4.91(2H,s),7.07(1H,d,J=8.8Hz),7.35-7.38(2H,m),7.88(2H,d,J=8.4Hz),7.96(2H,d,J=8.2Hz);分析计算值:C17H12ClF3N2O3·0.1H2O:C,52.81;H,3.19;N,7.25.
实测值:C,53.03;H,3.20;N,7.31.
步骤C:3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮
将3-[(5-氯-2-甲氧基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(15.2g,39.6mmol)与盐酸吡啶(19.7g,0.17mol)混合,在225℃下加热2小时。将热的溶液倒入800ml1NHCl中,混合物搅拌10分钟。收集固体,用1NHCl洗涤,在80℃真空下干燥,得到13.1g灰白色固体。从乙腈中重结晶,得到10.8g标题化合物,为松散针状物,mp217-218℃.MS m/z:371(MH+).IR(KBr)3354,1762,1500,1324,1068cm-1;1H NMR(DMSO-d6)δ4.98(2H,s),6.84(1H,d,J=8.7Hz),7.20(1H,dd,J=8.7Hz,2.6Hz),7.30(1H,d,J=2.5Hz),7.89(2H,d,J=8.6Hz),7.97(1H,d,J=8.6Hz),10.11(1H,br.s);分析计算值:C16H10ClF3N2O3:C,51.84;H,2.72;N,7.56.
实测值:C,51.88;H,2.58;N,7.57.
实施例2
3-[[5-氯-2-[[[[2-(二甲氨基)乙基]氧]羰基]氧]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮
步骤A:4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基氯甲酸酯
在密封的试管内,将3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(1g,2.69mmol)与BnPh3PCl(25mg)在光气(15ml)的1.9摩尔甲苯溶液中的混悬液一边搅拌一边在120℃下加热过夜。除去过量光气后,将甲苯溶液旋转蒸发至干,得到氯甲酸酯产物,为白色半固体(1.18g)。
步骤B:3-[[5-氯-2-[[[[2-(二甲氨基)乙基]氧]羰基]氧]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮
一边搅拌一边向步骤A的氯甲酸酯(0.6g,0.15mmol)的无水CH2Cl2(5ml)冷(0℃)溶液中滴加纯2-(二甲氨基)乙醇(0.41g,0.45mmol)。使所得混合物温度升至室温,保持2-3小时。将CH2Cl2在室温下旋转蒸发,使残余物在乙醚和5%NaHCO3之间分布。分离醚层,用盐水洗涤,然后干燥(MgSO4)。蒸发溶剂得到产物,为浅黄色油(0.613g)。使粗产物与无水HCl在乙醚中反应,得到3-[[5-氯-2-[[[[2-(二甲氨基)乙基]氧]羰基]氧]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮相应的盐酸盐。mp160-163℃;MS m/z486(MH+).
实施例3
2-[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]氧]乙基]三甲基铵甲磺酸酯
将粗的3-[[5-氯-2-[[[[2-(二甲氨基)乙基]氧]羰基]氧]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮溶于1∶1乙醚-EtOAc中,加入纯甲磺酸甲酯(2eqt.)。混合物在室温下搅拌过夜。过滤收集沉淀出来的固体,用乙醚洗涤,然后在真空中干燥,得到标题化合物,为白色固体:mp190-195℃(dec.);IR(KBr,cm-1)1193,1318,1765,1777;1H NMR(CDCl3)δ2.76(s,3H),3.51(s,9H),4.19(m,2H),4.75(m,2H),4.89(s,2H),7.17(d,J=8.6Hz,1H),7.25(s,1H),7.38(dd,J=8.6and2.5Hz,1H),7.54(d,J=2.5Hz,1H),7.71(d,J=8.4Hz,1H),7.91(d,J=8.1Hz,1H);MS m/z500(M+).
实施例4-11的制备的一般操作
下面描述用于制备式Ⅶa-c和Ⅷa-c化合物的一般操作,这在反应流程2中也有阐述。式Ⅵa-c酰氯的制备方法是使相应的酸与草酰氯和催化量的DMF在CH2Cl2中反应。分离出式Ⅵa-c酰氯的HCl盐,使用时无需进一步纯化。一边搅拌一边向实施例1化合物(1eqt.)与NaH(2eqt.)在无水乙醚中的混悬液中加入相应的式Ⅵ酰氯(1.2eqt.),混合物搅拌3-4小时。反应混合物用乙醚和EtOAc稀释,用5%NaHCO3、水、盐水洗涤,然后干燥(MgSO4)。将溶剂旋转蒸发,使残余物从乙醚-己烷中重结晶,得到式Ⅶa-c化合物。向式Ⅶa-c化合物的1∶1乙醚-EtOAc溶液中加入纯甲磺酸甲酯,混合物在室温下搅拌过夜。过滤沉淀出来的白色固体,用乙醚洗涤,然后在真空中干燥,得到相应的纯式Ⅷa-c化合物。
实施例4
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基(二甲氨基)乙酸酯(Ⅶa,n=1)mp112-113℃;MS m/z:456(MH+).分析计算值:C20H17ClF3N3O4:C,52.70;H,3.76;N,9.22.
实测值:C,52.51;H,3.66;N,9.10.
实施例5
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基-3-(二乙氨基)丙酸酯(Ⅶb,n=2)mp179-181℃;MS m/z:498(MH+).分析计算值:C23H23ClF3N3O4·HCl:C,51.70;H,4.53;N,7.86.
实测值:C,51.46;H,4.67;N,7.71.
实施例6
4-氯-2-[ [5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基-4-(二甲氨基)丁酸酯(Ⅶc,n=3)mp162-164℃;分析计算值:C22H21ClF3N3O4·HCl:C,50.78;H,4.26;N,8.08.
实测值:C,49.51;H,4.35;N,7.80.
实施例7
[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]甲基]三甲基铵甲磺酸酯(Ⅷa,n=1)mp230-232℃;MS m/z:470(M+).分析计算值:C21H20ClF3N3O4.CH3SO3:C,46.69;H,4.10;N,7.42.
实测值:C,46.06;H,4.06;N,7.21.
实施例8
2-[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]乙基]二乙基甲基铵甲磺酸酯(Ⅷb,n=2)mp>260℃
实施例9
3-[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]丙基]三甲基铵甲磺酸酯(Ⅷc,n=3)mp>260℃;MS m/z:498(M+).分析计算值:C23H24CF3N3O4SO3:C,48.53;H,4.58;N,7.07.
实测值:C,48.61;H,4.58;N,7.03.
实施例10
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1.3.4-噁二唑-3-基]甲基]苯基(甲氨基)乙酸酯mp186-188℃(dec.).
实施例11
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基-3-氨基丙酸酯mp184-185℃(dec.).
实施例12
[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲基-4-(二甲氨基)丁酸酯(Ⅺc,n=3)
步骤A:3-[[5-氯-2-(甲基硫代甲氧基)苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(Ⅸ)
在氮下,一边搅拌一边向氢化钠(0.77g,60%矿物油分散系,19.4mmol)在HMPA(15ml)中的混悬液中滴加3-[(5-氯-2-羟基苯基)甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(6.0g,16.2mmol)的无水HMPA(50ml)溶液。所得黄色溶液搅拌30分钟,然后滴加纯氯甲基甲基硫醚(1.49ml,17.8mmol)。反应混合物在室温下搅拌过夜,产物用乙酸乙酯(500ml)萃取。EtOAc层用饱和NaHCO3、水、盐水洗涤,然后干燥(MgSO4)。将EtOAc旋转蒸发,得到黄色半固体,从乙酸乙酯/己烷中重结晶,得到标题化合物,为白色晶体(4.4g,70%)。1H NMR(CDCl3)δ2.28(s,3H),5.00(s,2H),5.22(s,2H),6.92(d,J=8.5Hz,1H),7.3(m,2H),7.74(d.J=8.4Hz,2H),7.96(d,J=8.3Hz,2H).IR(KBr,cm-1):1779,1608,1494,1328,1238,1176,1126.分析计算值:C18H14ClF3N2O3S:C,50.18;H,3.28;N,6.50.
实测值:C,50.19;H,3.32;N,6.52.
步骤B:3-[[5-氯-2-(氯甲氧基)苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(Ⅹ)
在氮下,一边搅拌一边向步骤A化合物(3.5g,8.12mmol)的CH2Cl2(40ml)溶液中滴加纯磺酰氯(0.78ml,9.75mmol)。反应混合物在室温下搅拌4小时。TLC指示反应完全。旋转蒸发除去过量试剂和CH2Cl2后,产物在真空下干燥,得到标题化合物,为灰白色固体(3.4g,100%)。MS m/z:419(MH+).1H NMR(CDCl3)δ5.0(s,2H),5,94(s,2H),7.18(d,J=9.2Hz,1H),7.38(m,2H),7.74(d,J=8.4Hz,2H),7.96(d,J=8.3Hz,2H).1R(KBr, cm-1):1773,1611,1572,1487,1325,1163,1128.分析计算值:C17H11Cl2F3N2O3·0.25H2O:C,48.19;H,2.76;N,6.61.
实测值:C,48.04;H,2.68;N,6.53.
步骤C:[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲基-4-(二甲氨基)丁酸酯(Ⅺc,n=3)
一边搅拌一边向Cs2CO3(1.306g,4.01mmol)与盐酸4-(二甲氨基)丁酸盐酸化物(0.352g,2.1mmol)在丙酮(20ml)中的混悬液中加入步骤B的氯甲氧基化合物(0.8g,1.91mmol)。反应混合物在室温下搅拌过夜。TLC指示反应完全。将丙酮旋转蒸发,加入盐水溶液。过滤收集黄色沉淀,用水洗涤,然后风干。粗的固体从乙酸乙酯/己烷中重结晶,得到标题化合物Ⅺc,为白色固体(0.64g,65%)。mp115-117℃;1H NMR(DMSO-d6)δ1.49(m,2H),2.02(t,J=7.0Hz,2H),2.25(t,J=7.3Hz,2H),3.32(s,6H),4.92(s,2H),5.79(s,2H),7.24(d,J=8.8Hz,1H),7.43(dd,J=2.6Hz,8.8Hz,1H),7.50(d,J=2.6Hz,1H),7.90(d,J=8.5Hz,2H),7.98(d,J=8.3Hz,2H).IR(KBr,cm-1):1776,1764,1607,1492,1416,1324,1121.分析计算值:C23H23ClF3N3O5·0.5H2O:C,52.83;H,4.63;N,8.04.实测值:C,53.00;H,4.70;N,8.04.
实施例13
3-[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]丙基]三甲基铵甲磺酸酯(Ⅻc,n=3)
将实施例12化合物(Ⅺc)(0.95g,1.85mmol)溶于乙酸乙酯(10ml),滴加纯甲磺酸甲酯(0.32ml,3.7mmol)。反应混合物在室温下搅拌过夜。收集白色沉淀,用乙醚研制进行纯化,得到标题化合物,为白色固体(0.95g,82%)。从乙醇/乙醚中重结晶,得到白色晶体:mp156-158℃;MS m/z:528(MH+).1H NMR(DMSO-d6)δ1.91(m,2H),2.27(s,3H),2.43(t,J=7.1Hz,2H),3.01(s,9H),3.22(m,2H),4.91(s,2H),5.81(s,2H),7.24(d,J=8.9Hz,1H),7.43(dd,J=2.7Hz,8.8Hz,1H),7.49(d,J=2.6Hz,1H),7.90(d,J=8.5Hz,2H),7.98(d,J=8.4Hz,2H);分析计算值:C24H26ClF3N3O5·CH3SO3:C,48.12;H,4.68;N,6.73.
实测值:C,48.15;H,4.74;N,6.71.
实施例14
[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]甲基]三甲基铵甲磺酸酯(Ⅻa,n=1)
向实施例12步骤B化合物Ⅹ(0.49,0.95mmol)、Cs2CO3(0.342g,1.05mmol)与N,N-二甲基甘氨酸(0.108g,1.05mmol)的混合物中加入丙酮(20ml)。反应混合物在室温下搅拌过夜。将丙酮旋转蒸发,然后加入盐水。收集化合物Ⅺa(n=1)的白色沉淀,将其溶于乙腈,加入纯甲磺酸甲酯(0.053ml)。反应混合物在室温下搅拌2天。蒸发溶剂,加入乙醚。收集沉淀,从乙腈/乙醚中重结晶进行纯化,得到标题化合物,为白色固体(0.13g,23%两步)。mp:100-104℃.MS m/z:500(M+).1H NMR(DMSO-d6)δ2.27(s,3H),3.33(s,9H),4.60(s,2H),5.09(s,2H),5.48(s,2H),7.24(d,J=8.9Hz,1H),7.52(dd,J=2.6Hz,8.8Hz,1H),7.60(d,J=2.6Hz,1H),7.90(d,J=8.6Hz,2H),7.97(d,J=8.3Hz,2H).分析计算值:C22H22ClF3N3O5·CH3SO3·1.5H2O:
C,44.34;H,4.53;N,6.74.
实测值:C,44.35;H,4.28;N,6.46.
实施例15
盐酸[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲基-3-(二乙氨基)丙酸酯(Ⅺb,n=2)
向实施例12步骤B化合物Ⅹ(0.4g,0.95mmol)、Cs2CO3(0.622g,1.91mmol)与盐酸3-(二乙氨基)丙酸(0.108g,1.05mmol)的混合物中加入丙酮(20ml)。反应混合物在室温下搅拌3天。将丙酮旋转蒸发,向残余物中加入盐水。收集沉淀出来的白色固体(0.38g,75%)。一边搅拌一边向粗产物(0.16g,0.30mmol)的乙酸乙酯溶液中加入1NHCl的乙醚溶液(0.36ml,0.36mmol),在室温下保持3小时。过滤收集标题化合物Ⅺb的盐酸盐(0.11g,64%):mp165-167℃(dec.);MS m/z:528(MH+).1H NMR(DMSO-d6)δ1.16(t,J=7.2Hz,6H),2.93(t,J=7.8Hz,2H),3.01-3.10(m,4H),3.19-3.25(m,2H),4.93(s,2H),5.84(s,2H),7.27(d,J=8.8Hz,1H),7.44(dd,J=2.6Hz,8.8Hz,1H),7.51(d,J=2.6Hz,1H),7.91(d,J=8.5Hz,2H),8.00(d,J=8.3Hz,2H),10.5(s,br,1H).分析计算值:C24H25ClF3N3O5·HCl:C,51.08;H,4.64;N,7.45.
实测值:C,46.94;H,4.42;N,6.76.
实施例16
3-[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]-2-羟基丙基]三甲基铵甲磺酸酯(ⅩⅢ)
一边搅拌一边向实施例12步骤B化合物Ⅹ(0.4g,0.95mmol)与Cs2CO3(0.342g,1.05mmol)在丙酮(20ml)中的混悬液中加入(L)-降肉碱[Colucci,W.J.;Turnbull,Jr.,S.P.;Gandour,R.D.《分析生物化学》162,pp.459-462(1987)](0.155g,1.05mmol)。反应混合物在室温下搅拌2小时。将丙酮旋转蒸发,加入水,然后用乙醚萃取。萃取液然后用水、盐水洗涤,干燥(MgSO4)。蒸发乙醚,得到浅黄色泡沫状固体,然后将其溶于乙醚,加入0.1ml甲磺酸甲酯。反应混合物在室温下搅拌过夜。收集沉淀出来的固体,用乙酸乙酯/乙醚研制,得到标题化合物,为灰白色固体(0.2g,33%两步)。mp:98-101℃.MS m/z:544(M+).1H NMR(DMSO-d6)δ2.30(s,3H),2.52-2.58(m,2H),3.10(s,9H),3.34-3.41(m,2H),4.43(m,1H),4.94(s,2H),5.73(d,J=6.2Hz,1H),5.81(d.J=5.5Hz,1H),5.64(d,J=6.6Hz,1H),7.27(d,J=8.8Hz,1H),7.44(dd,J=2.7Hz,8.8Hz,1H),7.49(d,J=2.6Hz,1H),7.91(d,J=8.5Hz,2H),7.99(d,J=8.3Hz,2H);IR(KBr,cm-1):3307,1764,1751,1490,1417,1324,1194,1123,1065.分析计算值:C24H26ClF3N3O6·CH3SO3·0.75H2O:
C,45.95;H,4.70;N,6.43.
实测值:C,45.88;H,4.69;N,6.13.
实施例17
2-[[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]氧]乙基]三甲基铵甲磺酸酯(ⅩⅦa,n=1)
步骤A:3-[[2-[[[(丁硫基)羰基]氧]甲氧基]-5-氯苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(ⅩⅣ)
在氮下,一边搅拌一边向式Ⅱ化合物(1.11g,3mmol)的无水HMPA(6ml)冷(0℃)溶液中加入氢化钠(60%,矿物油中,144mg,3.6mmol),然后使温度升至室温。30分钟后,将所得黄色溶液冷却至0℃,然后滴加纯0-碘代甲基-S-丁基硫代碳酸酯(O-iodomethyl-S-butylcarbonothioate)[Folkman,M.和Lund,F.《合成》pp.1159,(1990)](1.0g,3.6mmol)。使所得混合物温度升至室温,搅拌过夜。向反应混合物中加入饱和盐水,过滤沉淀出来的白色固体,用水彻底洗涤。将粗的湿固体溶于1∶1∶1EtOAc-CH2Cl2-THF,然后干燥(MgSO4)。过滤,蒸发溶剂,得到一白色固体(1.76g),从乙醚中重结晶,得到纯ⅩⅣ(693mg,62%)。
步骤B:[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲基氯甲酸酯(ⅩⅤ)
在氮下,一边搅拌一边向步骤A化合物(258mg,0.5mmol)的无水CH2Cl2(2ml)溶液中加入纯磺酰氯(80μl,1mmol)。所得混合物在室温下搅拌2小时。将反应混合物在室温下旋转蒸发至干,然后保持在高真空下,得到所需式ⅩⅤ的氯甲酸酯,为白色固体(0.23g)。
步骤C:3-[[5-氯-2-[[[[[2-(二甲氨基)乙基]氧]羰基]氧]甲氧基]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮(ⅩⅥa,n=1)
一边搅拌一边向步骤B的式ⅩⅤ化合物(0.23g)的无水CH2Cl2(5ml)溶液中加入纯的无水2-(二甲氨基)乙醇(134mg),混合物搅拌过夜。反应混合物用CH2Cl2稀释,然后用5%NaHCO3猝灭。分离有机层,用水、盐水洗涤,然后干燥(MgSO4)。蒸发CH2Cl2,得到标题化合物,为浅黄色油(0.21g)。
步骤D:2-[[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]氧]乙基]三甲基铵甲磺酸酯(ⅩⅦa,n=1)
将步骤C粗产物(0.2g)溶于1∶1乙醚-EtOAc(5ml),用甲磺酸甲酯(2eqt.)处理。混合物在室温下搅拌过夜,过滤沉淀出来的白色固体,用乙醚洗涤,然后在真空中干燥,得到标题化合物,为白色固体(94mg):mp145-150℃(dec.);1H NMR(CDCl3)δ2.76(s,3H),3.45(s,9H),4.16(m,2H),4.71(m,2H),4.96(s,2H),5.79(s,2H),6.98(d,J=8.4Hz,1H),7.31-7.34(m,2H),7.75(d,J=8.4 Hz,2H),7.97(d,J=8.2Hz,2H);MS m/z530(M+).
Claims (16)
2、权利要求1的化合物,其中A是一条直接的键,B是一条直接的键,D是-(CH2)n-。
3、权利要求2的化合物,选自:
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基(二甲氨基)乙酸酯;
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基-3-(二乙氨基)丙酸酯;
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基-4-(二甲氨基)丁酸酯;
[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]甲基]三甲基铵甲磺酸酯;
2-[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]乙基]二乙基甲基铵甲磺酸酯;
3-[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]丙基]三甲基铵甲磺酸酯;
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基(甲氨基)乙酸酯;和
4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯基-3-氨基丙酸酯;
或其无毒的药学上可接受的盐、相反阴离子或溶剂化物。
4、权利要求1的化合物,其中A是一条直接的键,B是氧,D是-(CH2)n-。
5、权利要求4的化合物,选自:
3-[[5-氯-2-[[[[2-(二甲氨基)乙基]氧]羰基]氧]苯基]甲基]-5-[4-(三氟甲基)苯基]-1,3,4-噁二唑-2(3H)-酮;和
2-[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]羰基]氧]乙基]三甲基铵甲磺酸酯;
或其无毒的药学上可接受的盐、相反阴离子或溶剂化物。
6、权利要求1的化合物,其中A是-CH2O-,B是一条直接的键,D是-(CH2)n-。
7、权利要求6的化合物,选自:
[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲基-4-(二甲氨基)丁酸酯;
3-[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]丙基]三甲基铵甲磺酸酯;
[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]甲基]三甲基铵甲磺酸酯;和
盐酸[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲基-3-(二乙氨基)丙酸酯;
或其无毒的药学上可接受的盐、相反阴离子或溶剂化物。
8、权利要求7的化合物,它是3-[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]丙基]三甲基铵甲磺酸酯。
9、权利要求1的化合物,其中A是-CH2O-,B是一条直接的键,D是-CH2CHOHCH2-。
10、权利要求9的化合物,它是3-[[[[4-氯2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]-2-羟基丙基]三甲基铵甲磺酸酯。
11、权利要求1的化合物,其中A是-CH2O-,B是氧,D是-(CH2)n-。
12、权利要求11的化合物,它是2-[[[[[4-氯-2-[[5-[4-(三氟甲基)苯基]-2,3-二氢-2-氧代-1,3,4-噁二唑-3-基]甲基]苯氧基]甲氧基]羰基]氧]乙基]三甲基铵甲磺酸酯。
13、用于治疗对大电导钙活化的钾通道打开剂敏感的病症的药物组合物,它包含治疗有效量的如权利要求1所定义的化合物,以及药学上可接受的载体或稀释剂。
14、治疗哺乳动物对大电导钙活化的钾通道打开敏感的病症的方法,它包括将治疗有效量的如权利要求1所定义的化合物对所述哺乳动物给药。
15、权利要求14的方法,其中所述的病症是局部缺血、中风、惊厥、癫痫、哮喘、过敏性肠综合征、偏头痛、外伤性脑损伤、脊髓损伤、性功能障碍和尿失禁。
16、权利要求15的方法,其中所述的病症是中风。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US7296698P | 1998-01-29 | 1998-01-29 | |
US60/072,966 | 1998-01-29 | ||
US10227498P | 1998-09-29 | 1998-09-29 | |
US60/102,274 | 1998-09-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1289249A true CN1289249A (zh) | 2001-03-28 |
CN1150175C CN1150175C (zh) | 2004-05-19 |
Family
ID=26753969
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB998024112A Expired - Fee Related CN1150175C (zh) | 1998-01-29 | 1999-01-15 | 1,3,4-噁二唑酮衍生物 |
Country Status (27)
Country | Link |
---|---|
US (1) | US6034113A (zh) |
EP (1) | EP1051173A4 (zh) |
JP (1) | JP2002527352A (zh) |
KR (1) | KR20010077838A (zh) |
CN (1) | CN1150175C (zh) |
AR (1) | AR010712A1 (zh) |
AU (1) | AU735704B2 (zh) |
BG (1) | BG104706A (zh) |
BR (1) | BR9913010A (zh) |
CA (1) | CA2318830A1 (zh) |
CO (1) | CO5090837A1 (zh) |
EE (1) | EE04089B1 (zh) |
GE (1) | GEP20032914B (zh) |
HU (1) | HUP0102025A3 (zh) |
ID (1) | ID26909A (zh) |
IL (1) | IL137518A0 (zh) |
LT (1) | LT4838B (zh) |
LV (1) | LV12559B (zh) |
NO (1) | NO317102B1 (zh) |
NZ (1) | NZ505409A (zh) |
PL (1) | PL342060A1 (zh) |
RU (1) | RU2202548C2 (zh) |
SK (1) | SK10852000A3 (zh) |
TR (1) | TR200002019T2 (zh) |
TW (1) | TW550075B (zh) |
UA (1) | UA58579C2 (zh) |
WO (1) | WO1999038510A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104710379A (zh) * | 2015-03-09 | 2015-06-17 | 华南理工大学 | 一种bms-191011的合成方法 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU736599B2 (en) * | 1998-01-29 | 2001-08-02 | Bristol-Myers Squibb Company | Amino acid derivatives of diaryl 1,3,4-oxadiazolone |
US6297241B1 (en) | 1999-01-29 | 2001-10-02 | Bristol-Myers Squibb Company | Carbamate derivatives of diaryl 1,3,4-oxadiazolone |
EP1150978A4 (en) * | 1999-01-29 | 2002-06-12 | Bristol Myers Squibb Co | CARBAMATE DERIVATIVES OF 1,3,4-OXADIAZOLONES |
US6326388B1 (en) * | 1999-12-21 | 2001-12-04 | Celgene Corporation | Substituted 1,3,4-oxadiazoles and a method of reducing TNF-alpha level |
CA2438868A1 (en) | 2001-02-20 | 2002-09-19 | Valentin K. Gribkoff | Modulators of kcnq potassium channels and use thereof in treating migraine and mechanistically related diseases |
JP4073786B2 (ja) * | 2001-04-16 | 2008-04-09 | 田辺三菱製薬株式会社 | 高コンダクタンス型カルシウム感受性kチャネル開口薬 |
US6909027B1 (en) * | 2001-08-13 | 2005-06-21 | Perry Robins | Method of forming an in-situ film dressing and the composition of the film-forming material |
US7119246B2 (en) * | 2002-06-25 | 2006-10-10 | Perry Robins | Method of treating acne |
EP4356912A2 (en) | 2012-05-16 | 2024-04-24 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions |
JP5855599B2 (ja) * | 2013-04-30 | 2016-02-09 | テックフィールズ バイオケム カンパニー リミテッド | 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ |
JP6165816B2 (ja) * | 2015-10-01 | 2017-07-19 | テックフィールズ バイオケム カンパニー リミテッド | 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ |
CN110545809A (zh) * | 2017-02-24 | 2019-12-06 | 奥维德医疗公司 | 治疗发作性疾病的方法 |
CN110987847B (zh) * | 2019-12-11 | 2021-02-19 | 苏州今蓝纳米科技有限公司 | 1,3,4-噁二唑衍生物在检测酸以及数据加密和储存中的应用 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH583213A5 (zh) * | 1973-05-21 | 1976-12-31 | Ciba Geigy Ag | |
IT1251488B (it) * | 1991-09-17 | 1995-05-15 | Mini Ricerca Scient Tecnolog | Ossa(tia)diazol- e triazol-oni(tioni) ad attivita' acaricida ed insetticida |
US5234947A (en) * | 1991-11-07 | 1993-08-10 | New York University | Potassium channel activating compounds and methods of use thereof |
US5547966A (en) * | 1993-10-07 | 1996-08-20 | Bristol-Myers Squibb Company | Aryl urea and related compounds |
TW467902B (en) * | 1996-07-31 | 2001-12-11 | Bristol Myers Squibb Co | Diphenyl heterocycles as potassium channel modulators |
AU736599B2 (en) * | 1998-01-29 | 2001-08-02 | Bristol-Myers Squibb Company | Amino acid derivatives of diaryl 1,3,4-oxadiazolone |
-
1999
- 1999-01-15 SK SK1085-2000A patent/SK10852000A3/sk unknown
- 1999-01-15 HU HU0102025A patent/HUP0102025A3/hu unknown
- 1999-01-15 RU RU2000122733/04A patent/RU2202548C2/ru not_active IP Right Cessation
- 1999-01-15 WO PCT/US1999/000910 patent/WO1999038510A1/en not_active Application Discontinuation
- 1999-01-15 BR BR9913010-6A patent/BR9913010A/pt not_active IP Right Cessation
- 1999-01-15 KR KR1020007008227A patent/KR20010077838A/ko not_active Application Discontinuation
- 1999-01-15 EE EEP200000447A patent/EE04089B1/xx not_active IP Right Cessation
- 1999-01-15 AU AU22308/99A patent/AU735704B2/en not_active Ceased
- 1999-01-15 NZ NZ505409A patent/NZ505409A/en unknown
- 1999-01-15 CA CA002318830A patent/CA2318830A1/en not_active Abandoned
- 1999-01-15 PL PL99342060A patent/PL342060A1/xx unknown
- 1999-01-15 ID IDW20001421A patent/ID26909A/id unknown
- 1999-01-15 GE GEAP19995472A patent/GEP20032914B/en unknown
- 1999-01-15 US US09/232,033 patent/US6034113A/en not_active Expired - Fee Related
- 1999-01-15 CN CNB998024112A patent/CN1150175C/zh not_active Expired - Fee Related
- 1999-01-15 EP EP99902290A patent/EP1051173A4/en not_active Withdrawn
- 1999-01-15 UA UA2000085059A patent/UA58579C2/uk unknown
- 1999-01-15 IL IL13751899A patent/IL137518A0/xx unknown
- 1999-01-15 TR TR2000/02019T patent/TR200002019T2/xx unknown
- 1999-01-15 JP JP2000529243A patent/JP2002527352A/ja active Pending
- 1999-01-27 AR ARP990100312A patent/AR010712A1/es not_active Application Discontinuation
- 1999-01-27 TW TW088101231A patent/TW550075B/zh not_active IP Right Cessation
- 1999-01-28 CO CO99004746A patent/CO5090837A1/es unknown
-
2000
- 2000-07-14 LT LT2000068A patent/LT4838B/lt not_active IP Right Cessation
- 2000-07-26 NO NO20003825A patent/NO317102B1/no not_active IP Right Cessation
- 2000-08-03 LV LVP-00-103A patent/LV12559B/en unknown
- 2000-08-22 BG BG104706A patent/BG104706A/xx unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104710379A (zh) * | 2015-03-09 | 2015-06-17 | 华南理工大学 | 一种bms-191011的合成方法 |
Also Published As
Publication number | Publication date |
---|---|
NO317102B1 (no) | 2004-08-09 |
JP2002527352A (ja) | 2002-08-27 |
AU735704B2 (en) | 2001-07-12 |
KR20010077838A (ko) | 2001-08-20 |
AU2230899A (en) | 1999-08-16 |
IL137518A0 (en) | 2001-07-24 |
LT2000068A (en) | 2001-03-26 |
CO5090837A1 (es) | 2001-10-30 |
AR010712A1 (es) | 2000-07-12 |
GEP20032914B (en) | 2003-03-25 |
TW550075B (en) | 2003-09-01 |
CA2318830A1 (en) | 1999-08-05 |
RU2202548C2 (ru) | 2003-04-20 |
EP1051173A1 (en) | 2000-11-15 |
SK10852000A3 (sk) | 2002-02-05 |
HUP0102025A2 (hu) | 2001-11-28 |
BG104706A (en) | 2001-04-30 |
NO20003825D0 (no) | 2000-07-26 |
LV12559B (en) | 2001-04-20 |
NO20003825L (no) | 2000-07-26 |
EP1051173A4 (en) | 2002-07-31 |
US6034113A (en) | 2000-03-07 |
ID26909A (id) | 2001-02-15 |
LT4838B (lt) | 2001-08-27 |
TR200002019T2 (tr) | 2000-11-21 |
CN1150175C (zh) | 2004-05-19 |
PL342060A1 (en) | 2001-05-21 |
BR9913010A (pt) | 2001-05-08 |
EE200000447A (et) | 2001-12-17 |
NZ505409A (en) | 2003-08-29 |
EE04089B1 (et) | 2003-08-15 |
UA58579C2 (uk) | 2003-08-15 |
LV12559A (en) | 2000-11-20 |
HUP0102025A3 (en) | 2002-01-28 |
WO1999038510A1 (en) | 1999-08-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1116287C (zh) | 用作钾通道调节剂的二苯基杂环化合物 | |
CN1289249A (zh) | 1,3,4-噁二唑酮衍生物 | |
CN1136278A (zh) | 双膦酸盐与生长激素促分泌素的组合 | |
CN88101642A (zh) | 哌嗪基-杂环化合物 | |
CN1106805A (zh) | 磺酰胺类内皮素拮抗剂 | |
EP1056754B1 (en) | Phosphate derivatives of diaryl 1,3,4-oxadiazolone | |
CN1202106A (zh) | 选择性的β3肾上腺素能激动剂 | |
CN1276783A (zh) | 2-苯氧基苯胺衍生物 | |
CN1139572C (zh) | Nmda(n-甲基-d-天冬氨酸)拮抗剂 | |
CN1133636C (zh) | 二芳基1,3,4-噁二唑酮的氨基甲酸酯衍生物 | |
CN1265652A (zh) | 用作速激肽受体拮抗剂的2-酰基氨基丙胺化合物 | |
AU736712B2 (en) | Benzoate derivatives of diaryl 1,3,4-oxadiazolone | |
US5977150A (en) | Amino acid derivatives of diaryl 1,3,4-oxadiazolone | |
CN1764660A (zh) | 新型噁唑衍生物,它们的制造和作为药物制剂的用途 | |
CN1289495C (zh) | 新的哌啶基-烷基氨基-哒嗪酮衍生物、其制备方法以及包含所述化合物的药物组合物 | |
US6297241B1 (en) | Carbamate derivatives of diaryl 1,3,4-oxadiazolone | |
CN1533278A (zh) | 萘并噻嗪正变构的ampa受体调节物(paarm) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |