CN115068472A - 吲哚嗪类化合物、或其药学上可接受的盐在制备治疗trpm2功能异常疾病药物中的应用 - Google Patents
吲哚嗪类化合物、或其药学上可接受的盐在制备治疗trpm2功能异常疾病药物中的应用 Download PDFInfo
- Publication number
- CN115068472A CN115068472A CN202110267928.6A CN202110267928A CN115068472A CN 115068472 A CN115068472 A CN 115068472A CN 202110267928 A CN202110267928 A CN 202110267928A CN 115068472 A CN115068472 A CN 115068472A
- Authority
- CN
- China
- Prior art keywords
- use according
- trpm2
- indolizine
- indolizine compound
- halogen
- 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
- -1 indolizine compound Chemical class 0.000 title claims abstract description 32
- 102000003615 TRPM2 Human genes 0.000 title claims abstract description 23
- 101150095096 TRPM2 gene Proteins 0.000 title claims abstract description 23
- 150000003839 salts Chemical class 0.000 title claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 16
- 201000010099 disease Diseases 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 230000004064 dysfunction Effects 0.000 title claims abstract description 11
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 7
- 208000028867 ischemia Diseases 0.000 claims description 7
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 230000010410 reperfusion Effects 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
- 230000002490 cerebral effect Effects 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000036407 pain Effects 0.000 claims description 4
- 208000020431 spinal cord injury Diseases 0.000 claims description 4
- 208000020925 Bipolar disease Diseases 0.000 claims description 3
- 208000004296 neuralgia Diseases 0.000 claims description 3
- 208000021722 neuropathic pain Diseases 0.000 claims description 3
- 230000036542 oxidative stress Effects 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 206010008132 Cerebral thrombosis Diseases 0.000 claims description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 208000027753 pain disease Diseases 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 206010008118 cerebral infarction Diseases 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 6
- 150000002478 indolizines Chemical class 0.000 abstract description 5
- 230000000144 pharmacologic effect Effects 0.000 abstract description 5
- 206010061296 Motor dysfunction Diseases 0.000 abstract description 2
- 230000007488 abnormal function Effects 0.000 abstract description 2
- 210000005036 nerve Anatomy 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 12
- 108091006146 Channels Proteins 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- SRNWOUGRCWSEMX-UHFFFAOYSA-N Adenosine diphosphate ribose Natural products C1=NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COP(O)(=O)OP(O)(=O)OCC1OC(O)C(O)C1O SRNWOUGRCWSEMX-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 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 5
- SRNWOUGRCWSEMX-KEOHHSTQSA-N ADP-beta-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-KEOHHSTQSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 5
- 201000006474 Brain Ischemia Diseases 0.000 description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 210000000269 carotid artery external Anatomy 0.000 description 4
- 210000004004 carotid artery internal Anatomy 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 230000001052 transient effect Effects 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 210000001168 carotid artery common Anatomy 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229950009041 edaravone Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003722 extracellular fluid Anatomy 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 210000003657 middle cerebral artery Anatomy 0.000 description 3
- 230000001095 motoneuron effect Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- FYKNTVQRXPNYDG-UHFFFAOYSA-N 1-phenacylpyrrole-2-carbaldehyde Chemical compound O=C(CN1C(=CC=C1)C=O)C1=CC=CC=C1 FYKNTVQRXPNYDG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 108010062580 Concanavalin A Proteins 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 206010072005 Spinal pain Diseases 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FKJSFKCZZIXQIP-UHFFFAOYSA-N 2-bromo-1-(4-bromophenyl)ethanone Chemical compound BrCC(=O)C1=CC=C(Br)C=C1 FKJSFKCZZIXQIP-UHFFFAOYSA-N 0.000 description 1
- FLAYZKKEOIAALB-UHFFFAOYSA-N 2-bromo-1-(4-chlorophenyl)ethanone Chemical compound ClC1=CC=C(C(=O)CBr)C=C1 FLAYZKKEOIAALB-UHFFFAOYSA-N 0.000 description 1
- XQJAHBHCLXUGEP-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(=O)CBr)C=C1 XQJAHBHCLXUGEP-UHFFFAOYSA-N 0.000 description 1
- KRVGXFREOJHJAX-UHFFFAOYSA-N 2-bromo-1-(4-methylphenyl)ethanone Chemical compound CC1=CC=C(C(=O)CBr)C=C1 KRVGXFREOJHJAX-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- NXDWETXHSKDTCJ-UHFFFAOYSA-N CC(C=C1)=CC=C1C(C1=CC(C(OC)=O)=CC2=CC=CN12)=O Chemical compound CC(C=C1)=CC=C1C(C1=CC(C(OC)=O)=CC2=CC=CN12)=O NXDWETXHSKDTCJ-UHFFFAOYSA-N 0.000 description 1
- XBQXUEIWGQTANX-UHFFFAOYSA-N COC(C1=CC2=CC=CN2C(C(C(C=C2)=CC=C2Cl)=O)=C1)=O Chemical compound COC(C1=CC2=CC=CN2C(C(C(C=C2)=CC=C2Cl)=O)=C1)=O XBQXUEIWGQTANX-UHFFFAOYSA-N 0.000 description 1
- TZVWFCMWLIGESK-UHFFFAOYSA-N COC(C1=CC2=CC=CN2C(C(C(C=C2)=CC=C2OC)=O)=C1)=O Chemical compound COC(C1=CC2=CC=CN2C(C(C(C=C2)=CC=C2OC)=O)=C1)=O TZVWFCMWLIGESK-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 108091005462 Cation channels Proteins 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 101100370896 Homo sapiens TRPM2 gene Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241001089723 Metaphycus omega Species 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940125400 channel inhibitor Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000009193 crawling Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 102000045119 human TRPM2 Human genes 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000019948 ion homeostasis Effects 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000013307 optical fiber Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000003462 vein Anatomy 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
- A61K31/435—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Psychiatry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Psychology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本申请公开了一种吲哚嗪类化合物、或其药学上可接受的盐在制备治疗TRPM2功能异常疾病中的应用。本申请中，吲哚嗪类化合物具有通式(I)所示结构，吲哚嗪类化合物具有显著减少脑梗死体积，并显著降低神经运动功能障碍评分，具有良好的药理活性和药用前景，为吲哚嗪类化合物开辟了新的应用领域，尤其是在制备TRPM2功能异常疾病药物应用方面。
Description
技术领域
本发明实施例涉及化学药物应用领域，特别涉及吲哚嗪类化合物、或其药学上可接受的盐在制备治疗TRPM2功能异常疾病药物中的应用。
背景技术
TRPM2(Transient Receptor Potential Melastatin 2)是瞬时受体电位离子通道家族中可渗透同型四聚体非选择性阳离子通道，广泛表达于人体各个部位的细胞中，如：脑、心脏、血管、肾、内皮细胞、平滑肌细胞和免疫细胞等。细胞外信号如氧化应激、肿瘤坏死因子-α(TNF-α)、淀粉样蛋白β-肽(Aβ)和伴刀豆球蛋白A(ConA)都能导致细胞内腺苷二磷酸核糖(adenosine diphosphate ribose，ADPR)的产生，而ADPR作为已经被证实的TRPM2内源性配体，其含量的增加将激活TRPM2通道，引起Na+、K+、Zn2+和Ca+等阳离子流入胞内，对细胞内的离子稳态造成影响。
近年来，对TRPM2通道功能的深入研究已发现其介导了许多重要的生理及病理功能：1)参与发热的退温调控以及调控小鼠对外界温度的适应性(Song K等，Science，2016；Tan CH等，Nature，2016)；2)介导多种重要的免疫和炎症反应，例如介导抗肿抗瘤药物引发的肺部炎症(Yonezawa R等，Free Radic Biol Med，2016)；3)调控钙离子内流、细胞因子和趋化因子释放以及活性氧(reactive oxygen species，ROS)水平，介导帕金森症、阿尔茨海默氏症、肌萎缩侧索硬化症、脊髓损伤和疼痛等神经系统疾病的发生发展(Hermosura MC等，Proc Natl Acad Sci U S A，2008；
M等，J Recept Signal Transduct Res，2012；Ostapchenko VG等，J Neurosci，2015)；4)参与调节胰岛素分泌和血糖水平，介导糖尿病的发生(Uchida K等，Diabetes，2011)；5)通过其自身表达水平的调控，在乳腺癌、膀胱癌、神经母细胞瘤、前列腺癌等多种恶性肿瘤的发生发展中发挥功能(Hopkins MM等，Int JOncol，2015；Cao QF等，Cancer Biother Radiopharm，2015；Chen SJ等，Am J PhysiolCell Physiol，2013；Zeng X等，Prostate Cancer Prostatic Dis，2010)。
综上，TRPM2通道参与调控多种病理生理功能，是多种疾病的潜在治疗靶点；且研究表明多种涉及该通道的疾病都是由于通道的过度激活所导致，因此研发该通道的抑制剂，对于进一步阐明通道功能、确证其作为多种疾病的治疗靶点及针对该靶点的药物研发，具有十分重要的作用。
发明内容
如本文所用的，术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如硝酸，磷酸，碳酸等；所述的有机酸诸如丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，葡糖酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺，二乙醇胺，三乙醇胺，N-甲基葡糖胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明实施方式的目的在于提供一种吲哚嗪类化合物、或其药学上可接受的盐在制备治疗TRPM2功能异常疾病药物中的应用。
为解决上述技术问题，本发明的实施方式第一方面提供了一种吲哚嗪类化合物、或其药学上可接受的盐在制备治疗治疗TRPM2功能异常疾病药物中的应用，所述吲哚嗪类化合物具有通式(I)所示结构：
式中，R1、R2、R3、R4或R5分别独立地为氢、卤素、C1～4烷基或C1～4烷氧基；优选地，R1、R2、R4和R5为氢；且R3为氢、卤素、C1～4烷基或C1～4烷氧基；所述卤素优选为氟、氯、溴或碘，更优选为氯或溴；所述C1～4烷基优选为甲氧基、乙氧基、丙氧基、丁氧基或异丙氧基，更优选为甲基、乙基或正丙基，所述C1～4烷氧基优选为甲氧基、乙氧基、丙氧基、丁氧基或异丙氧基，更优选为甲氧基或乙氧基。
在一些优选的方案中，所述吲哚嗪类化合物选自下述任一种化合物：
在一些优选的方案中，所述TRPM2功能异常疾病包括脊髓损伤或疼痛、心脑血管疾病、阿尔茨海默症、神经性疼痛、帕金森病、双相性精神障碍或肌萎缩侧索硬化症；所述心脑血管疾病优选为由缺血/再灌注引起的氧化应激所导致；更优选地，所述心脑血管疾病包括中风、脑血栓或脑卒中。
本发明的实施例第二方面提供了制备所述吲哚嗪类化合物的方法，所述方法包括步骤(1)：在碱性条件下，M1与丙炔酸甲酯进行如下反应即得所述吲哚嗪类化合物；
式中，R1、R2、R3、R4或R5分别独立地为氢、卤素、C1～4烷基或C1～4烷氧基；优选地，R1、R2、R4和R5为氢；且R3为氢、卤素、C1～4烷基或C1～4烷氧基；所述卤素优选为氟、氯、溴或碘，更优选为氯或溴；所述C1～4烷基优选为甲氧基、乙氧基、丙氧基、丁氧基或异丙氧基，更优选为甲基、乙基或正丙基，所述C1～4烷氧基优选为甲氧基、乙氧基、丙氧基、丁氧基或异丙氧基，更优选为甲氧基或乙氧基。
在一些优选的方案中，在步骤(1)中所述反应在极性溶剂中进行，优选为在N,N-二甲基甲酰胺中进行；
在步骤(1)中所述反应在氮气气氛中进行；
在步骤(1)中，所述碱为弱碱，优选为碳酸钠或碳酸钾，例如碳酸钾；
在步骤(1)中，所述反应的温度为70℃～90℃，例如80℃；
在步骤(1)中，所述反应的时间为5～9小时，例如7小时；
在步骤(1)中，所述反应还包括萃取、干燥和减压蒸馏除去溶剂。
在一些优选的方案中，在步骤(1)中，所述萃取为一次使用交替使用乙酸乙酯和水萃取；
在步骤(1)中，所述干燥为用无水硫酸钠干燥；
所述步骤(1)后还包括步骤(2)：将步骤(1)所得产物纯化。
在一些优选的方案中，所述纯化为柱层析纯化。
在一些优选的方案中，所述反应包括步骤：在氮气保护的条件下，将M1、丙炔酸甲酯和碳酸钾溶解在无水N,N-二甲基甲酰胺中，80℃下反应5～9小时，薄层色谱监测原料反应完全后，冷却至室温，反应液用乙酸乙酯和萃取，水相乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析纯化即得所述吲哚嗪类化合物。
在一些优选的方案中，M1经如下反应制得：
式中，R1、R2、R3、R4或R5分别独立地为氢、卤素、C1～4烷基或C1～4烷氧基；优选地，R1、R2、R4和R5为氢；且R3为氢、卤素、C1～4烷基或C1～4烷氧基；所述卤素优选为氟、氯、溴或碘，更优选为氯或溴；所述C1～4烷基优选为甲氧基、乙氧基、丙氧基、丁氧基或异丙氧基，更优选为甲基、乙基或正丙基，所述C1～4烷氧基优选为甲氧基、乙氧基、丙氧基、丁氧基或异丙氧基，更优选为甲氧基或乙氧基。
在一些优选的方案中，制备M1的反应在极性溶剂中进行。
在一些优选的方案中，制备M1的反应在碱性条件下进行。
在一些优选的方案中，M1经如下反应制得：在氮气保护的条件下，将吡咯-2-甲醛和碳酸钾溶解在无水乙腈中，然后分批次加入α-溴代酮，完全加入后，升温至60℃反应过夜，薄层色谱监测原料完全反应完全后，冷却至室温，过滤除去碳酸钾，滤液减压蒸馏除去溶剂，所得粗产物经硅胶柱层析纯化即得所述M1。
本发明的实施方式第三方面提供了一种治疗TRPM2功能异常疾病的方法，所述方法包括步骤：向TRPM2功能异常疾病患者施用有效剂量的上述吲哚嗪类化合物或其药学上可接受的盐。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明实施方式相对于现有技术而言，至少具有下述优点：
(1)本发明为吲哚嗪类化合物开辟了新的应用领域，尤其是在制备TRPM2功能异常疾病药物应用方面。
(2)本发明中的产品吲哚嗪类化合物具有显著减少脑梗死体积，并显著降低神经运动功能障碍评分，具有良好的药理活性和药用前景。
(3)本发明中的产品吲哚嗪类化合物为治疗脊髓损伤或疼痛、心脑血管疾病、阿尔茨海默症、神经性疼痛、帕金森病、双相性精神障碍或肌萎缩侧索硬化症等疾病提供了新方法。
附图说明
一个或多个实施例通过与之对应的附图中的图片进行示例性说明，这些示例性说明并不构成对实施例的限定。
图1是根据本发明实施例6中吲哚嗪类化合物对TRPM2通道的电流抑制作用示意图；
图2是根据本发明实施例6中C57BL/6小鼠进行短暂性大脑中动脉阻塞模型(tMACO)造模后，吲哚嗪类化合物和阳性对照药(依达拉奉)对小鼠脑组织缺血侧TTC染色结果示意图；
图3是根据本发明实施例6中小鼠脑组织的梗死体积示意图；
图4是根据本发明实施例6中各组模型小鼠缺血再灌注24小时后进行神经运动功能障碍评分结果示意图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合实施例对本发明的各实施方式进行详细的阐述。然而，本领域的普通技术人员可以理解，在本发明各实施方式中，为了使读者更好地理解本申请而提出了许多技术细节。但是，即使没有这些技术细节和基于以下各实施方式的种种变化和修改，也可以实现本申请所要求保护的技术方案。
实施例1：5-苯甲酰亚胺-7-羧酸甲酯(I-1)的制备
步骤(1)：在氮气保护的条件下，将吡咯-2-甲醛(0.95g，10.0mmol)和碳酸钾(1.66g，12.0mmol)溶解在50mL无水乙腈中，然后分批次加入2-溴-1-苯基乙烷-1-酮(2.3g，12.0mmol)，完全加入后，升温至60摄氏度反应过夜。薄层色谱监测原料完全反应完全后，冷却至室温，过滤除去碳酸钾，滤液减压蒸馏除去溶剂，所得粗产物经硅胶柱层析纯化得到的产物1-(2-氧代-2-苯基乙基)-1H-吡咯-2-甲醛为白色固体。
步骤(2)：在氮气保护的条件下，将上一步所得的化合物1-(2-氧代-2-苯基乙基)-1H-吡咯-2-甲醛(852mg,4.0mmol)、丙炔酸甲酯(403mg,4.8mmol)和碳酸钾(662mg，4.8mmol)溶解在25mL无水N，N-二甲基甲酰胺中，80摄氏度下反应过夜，薄层色谱监测原料反应完全后，冷却至室温，反应液用乙酸乙酯100mL和50mL萃取，水相用乙酸乙酯萃取两次(50mL×2)，合并乙酸乙酯相，无水硫酸钠干燥，减压蒸馏除去溶剂，所得粗产物经硅胶柱层析纯化得黄色固体(I-1，78％)。1H NMR(500MHz,CDCl3):δ8.91(d,J＝2.0Hz,1H),8.45(d,J＝1.0Hz,1H),7.81(dd,J＝8.0,1.0Hz,2H),7.74(d,J＝1.5Hz,1H),7.64(t,J＝7.5Hz,1H),7.53(t,J＝7.5Hz,2H),7.08(dd,J＝4.0,3.0Hz,1H),7.01(dd,J＝4.0,0.5Hz,1H),3.89(s,3H)；HRMS(EI):m/z预测值C17H13NO3(M)+279.0895，检测值279.0905。
实施例2：5-(4-甲基苯甲酰)吲哚嗪-7-羧酸甲酯(I-2)的制备。
根据实施例1的方法，用2-溴-1-(对甲苯基)乙烷-1-酮(2.5g，12.0mmol)代替2-溴-1-苯基乙烷-1-酮，得黄色固体(I-2，76％)。1H NMR(500MHz,CDCl3):δ8.83(d,J＝2.0Hz,1H),8.44(d,J＝1.0Hz,1H),7.73(t,J＝8.5Hz,2H),7.71(d,J＝2.0Hz,1H),7.34(d,J＝8.0Hz,2H),7.07(dd,J＝4.0,3.0Hz,1H),6.99(dd,J＝4.0,0.5Hz,1H),3.90(s,3H),2.48(s,3H)；HRMS(EI):m/z预测值C18H15NO3(M)+293.1052，检测值293.1062。
实施例3：5-(4-氯苯甲酰)吲哚嗪-7-羧酸甲酯(I-3)的制备。
根据实施例1的方法，用2-溴-1-(对氯苯基)乙烷-1-酮(2.8g，12.0mmol)代替2-溴-1-苯基乙烷-1-酮，得黄色固体(I-3，82％)。1H NMR(500MHz,CDCl3):δ8.89(d,J＝2.0Hz,1H),8.46(d,J＝1.0Hz,1H),7.76(d,J＝8.5Hz,2H),7.70(d,J＝1.5Hz,1H),7.52(d,J＝8.5Hz,2H),7.09(dd,J＝4.0,3.0Hz,1H),7.02(d,J＝4.5Hz,1H),3.88(s,3H)；HRMS(EI):m/z预测值C17H12ClNO3(M)+313.0506，检测值m/z 313.0515.
实施例4：5-(4-甲氧基苯甲酰)吲哚嗪-7-羧酸甲酯(I-4)的制备。
根据实施例1的方法，用2-溴-1-(对甲氧苯基)乙烷-1-酮(2.7g，12.0mmol)代替2-溴-1-苯基乙烷-1-酮，得黄色固体(I-4，87％)。1H NMR(500MHz,CDCl3):δ8.68(d,J＝2.0Hz,1H),8.41(s,1H),7.85(d,J＝9.0Hz,2H),7.65(d,J＝1.0Hz,1H),7.04(dd,J＝4.0,3.0Hz,1H),7.01(d,J＝9.0Hz,2H),6.97(d,J＝4.0Hz,1H),3.91(s,3H),3.90(s,3H)；HRMS(EI):m/z预测值C18H15NO4(M)+309.1001，检测值309.1009。
实施例5：5-(4-溴苯甲酰)吲哚嗪-7-羧酸甲酯(I-5)的制备。
根据实施例1的方法，用2-溴-1-(对溴苯基)乙烷-1-酮(3.3g，12.0.0mmol)代替2-溴-1-苯基乙烷-1-酮，得黄色固体(I-5，65％)。1H NMR(500MHz,CDCl3):δ8.90(d,J＝2.0Hz,1H),8.46(s,1H),7.70(d,J＝1.5Hz,1H),7.68(s,4H),7.09(dd,J＝4.0,2.5Hz,1H),7.02(d,J＝4.0Hz,1H),3.90(s,3H)；HRMS(EI):m/z预测值C17H12BrNO3(M)+357.0001，检测值357.0010。
实施例6：生物学评价
本发明的吲哚嗪类化合物对TRPM2通道具有抑制作用，采用全细胞膜片钳技术(Whole-cell patch)测定其药理活性测定，其相应的步骤如下。
1.细胞准备：
稳定表达人源TRPM2通道的的HEK293细胞，用含有10％牛血清，50units/mL青霉素，50mg/mL链霉素的DMEM/F-12培养基，于5％CO2及37摄氏度条件下进行孵育。
2.电生理测试：
测试前的细胞保存于细胞外液(147mM NaCl,2mM KCl,1mM MgCl2,2mM CaCl2,10mMHEPES,13mM glucose,pH 7.4)。电极充满电极内液(147mM NaCl,0.05mM EGTA,1mM MgCl2,10mM HEPES,0.5mM ADPR,pH＝7.3)，电阻保持在3～5MΩ。
通过电极向细胞内给予ADPR，测试用于激活TRPM2的ADPR浓度为500μM；待检测到平稳电流，在细胞外液给予相应浓度的化合物灌流，时间至少为60秒，记录电流大小的变化，记录方式为电压斜坡模式记录，500毫秒时间内电压从-100mV变化到+100mV，正常钳制电压为0mV，每5秒为一个ramp；最后，将细胞外液置换为pH＝5.0的溶液，以阻断TRPM2电流。电生理代表性电流如图1所示：
表1：吲哚嗪类化合物对TRPM2抑制的IC50数据
实施例6：吲哚嗪类化合物I-1对缺血/再灌注损伤的保护活性研究
1)小鼠短暂性局灶性脑缺血大脑中动脉栓塞(tMCAO)模型制备
22～25g雄性C57BL/6小鼠进行异氟烷吸入式气体麻醉后，将激光多普勒血流仪光纤探头用胶水固定于动物颅骨上，用于监测大脑中动脉(MCA)供血皮层脑血流。仰卧位固定小鼠，颈部正中去毛，75％酒精常规消毒，取颈正中约1.5cm切口，切开颈部皮肤，沿胸锁骨乳突肌内缘分离肌肉和筋膜；钝性分离右侧颈动脉鞘，暴露右侧颈总动脉(CCA)、颈外动脉(ECA)及颈内动脉(ICA)；手术范围暴露满意后，用动脉夹暂时夹闭CCA和ICA，在ECA近心端用显微手术剪剪切一小口，将尼龙单丝缝合线由该小口沿ECA插入，顺着ICA方向轻轻推入至颅内约11.5±0.5mm，堵住大脑中动脉起点。根据脑血流仪监测数据血流数据，只选择血流值降至基础值20％的动物。缺血90分钟后，轻轻抽出单丝缝合线，扎紧动脉残端，检查手术创口，彻底止血后，局部洒少量青霉素粉末预防感染，逐层缝合皮下组织及皮肤，完成缺血再灌注损伤模型。手术过程中采用加热板维持动物体温。手术完成后将缝合好的小鼠放入保温保湿箱中，直至小鼠恢复活动。假手术组动物采用相同手术过程，但不进行中动脉堵塞。
2)动物分组及给药方案
清洁级雄性C57BL/6小鼠随机分成3组，分别为假手术组、阳性对照药依达拉奉组(3mg/kg)，化合物I-1的3mg/kg剂量组。小鼠建模再灌注3h后分别进行尾静脉注射依达拉奉和I-1，假手术组注射等体积生理盐水，I-1和依达拉奉均用0.9％生理盐水溶液溶解。在缺血再灌注24小时后进行小鼠神经功能评分及TTC染色，TTC染色结果见图2。
3)脑梗死体积测定
小鼠缺血再灌注24h后，断头取脑，冠状面均匀切成厚度约2mm的脑片，脑片置于0.25％的2,3,5-氯化三苯基四氮唑(TTC)溶液中，37摄氏度避光孵育30分钟，染色后于4％多聚甲醛中性缓冲液(pH 7.4)固定过夜。微距相机拍摄，Image J图像分析软件计算并统计脑梗死体积，测得结果见图3。梗死体积百分数计算公式为：(左侧未梗面积之和-右侧未梗面积之和)/左侧未梗面积之和×l00％。
4)神经功能检测
根据五级四分法评分标准，对各组小鼠进行死亡率统计以及神经运动功能障碍评分，测得结果见图4。神经功能评分标准为：0分：无神经功能缺损症状；1分：提尾时脑缺血对侧前肢不能完全伸展；2分：实验动物向脑缺血对侧转圈；3分：实验动物爬行时倒向脑缺血对侧；4分：实验动物不能独立行走，意识丧失。
5)活性结果评价
本发明所述吲哚嗪类化合物I-1可明显减小tMCAO造成的小鼠脑梗死体积，并显著降低tMCAO引起的神经运动功能障碍评分，与等浓度的阳性对照药物依达拉奉具有相似的药理活性。
本领域的普通技术人员可以理解，上述各实施方式是实现本发明的具体实施例，而在实际应用中，可以在形式上和细节上对其作各种改变，而不偏离本发明的精神和范围。
Claims (10)
1.吲哚嗪类化合物，或其药学上可接受的盐在制备治疗TRPM2功能异常疾病药物中的应用，所述吲哚嗪类化合物具有通式(I)所示结构：
式中，R1、R2、R3、R4或R5分别独立地为氢、卤素、C1～4烷基或C1～4烷氧基；优选地，R1、R2、R4和R5为氢；且R3为氢、卤素、C1～4烷基或C1～4烷氧基。
2.根据权利要求1所述的应用，其特征在于，所述卤素为氟、氯、溴或碘；
和/或，所述C1～4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
和/或，所述C1～4烷氧基为甲氧基、乙氧基、丙氧基、丁氧基或异丙氧基。
3.根据权利要求1所述的应用，其特征在于，所述卤素为氯或溴；
和/或，所述C1～4烷基为甲基；
和/或，所述C1～4烷氧基为甲氧基。
4.根据权利要求1任一项所述的应用，其特征在于，R1、R2、R4和R5为氢；且
R3为氢、卤素、C1～4烷基或C1～4烷氧基。
5.根据权利要求1任一项所述的应用，其特征在于，所述吲哚嗪类化合物选自下述任一种化合物：
6.根据权利要求1～5任一项所述的应用，其特征在于，所述TRPM2功能异常疾病包括脊髓损伤或疼痛、心脑血管疾病、阿尔茨海默症、神经性疼痛、帕金森病、双相性精神障碍或肌萎缩侧索硬化症。
7.根据权利要求6所述的应用，其特征在于，所述心脑血管疾病由缺血/再灌注引起的氧化应激所导致。
8.根据权利要求6或7所述的应用，其特征在于，所述心脑血管疾病包括中风、脑血栓或脑卒中。
9.根据权利要求1～7任一项所述的应用，其特征在于，制备所述吲哚嗪类化合物的步骤包括：在碱性条件下，M1与丙炔酸甲酯进行如下反应即得所述吲哚嗪类化合物；
10.根据权利要求6所述的应用，其特征在于，所述反应在极性溶剂中进行，优选为在N,N-二甲基甲酰胺中进行；
和/或，所述反应在氮气气氛中进行；
和/或，所述碱为弱碱，优选为碳酸钠或碳酸钾，例如碳酸钾；
和/或，所述反应的温度为70℃～90℃，例如80℃；
和/或，所述反应时间为5～9小时，例如7小时；
和/或，所述反应还包括萃取、干燥和减压蒸馏除去溶剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110267928.6A CN115068472A (zh) | 2021-03-11 | 2021-03-11 | 吲哚嗪类化合物、或其药学上可接受的盐在制备治疗trpm2功能异常疾病药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110267928.6A CN115068472A (zh) | 2021-03-11 | 2021-03-11 | 吲哚嗪类化合物、或其药学上可接受的盐在制备治疗trpm2功能异常疾病药物中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115068472A true CN115068472A (zh) | 2022-09-20 |
Family
ID=83240980
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110267928.6A Pending CN115068472A (zh) | 2021-03-11 | 2021-03-11 | 吲哚嗪类化合物、或其药学上可接受的盐在制备治疗trpm2功能异常疾病药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115068472A (zh) |
-
2021
- 2021-03-11 CN CN202110267928.6A patent/CN115068472A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101769999B1 (ko) | Ｎｍｄａ 수용체 조절제 및 그의 용도 | |
| KR101059639B1 (ko) | 치환된 베타-페닐-알파-하이드록시 프로파노산, 그의 합성 방법 및 사용 | |
| JP2926046B2 (ja) | 水安定型ｌ−アスコルビン酸誘導体とその製造方法及びこれを含有する美白化粧料組成物 | |
| JPS63313729A (ja) | 置換２―アミノベンゾチアゾール類を含有する脳血管疾患治療剤 | |
| CN104053439A (zh) | 1-(5,6-二氯-1h-苯并[d]咪唑-2-基)-1h-吡唑-4-羧酸的葡甲胺盐制剂 | |
| KR100397721B1 (ko) | 벤조피란및치료제로서의그의용도 | |
| JP2016514151A (ja) | ガドフォスベセット三ナトリウム一水和物の製造方法 | |
| CN101454309A (zh) | 焦谷氨酸衍生物的合成和用途 | |
| CN109081801A (zh) | 酸性氨基酸修饰的吲哚乙醇衍生物,其合成，活性和应用 | |
| CN115991698B (zh) | 一种杂环化合物及其制备方法与应用 | |
| CN115068472A (zh) | 吲哚嗪类化合物、或其药学上可接受的盐在制备治疗trpm2功能异常疾病药物中的应用 | |
| ES2593578T3 (es) | Derivado de butilftalida y método de preparación y uso del mismo | |
| CN105531270B (zh) | (+)－5－(3，4－二氟苯基)－5－[(3－甲基－2－氧吡啶－1(2h)－基)甲基]咪唑烷－2，4－二酮及含有该化合物的药物 | |
| AU2022234499A1 (en) | Fused ring heterocyclic compound and application thereof, and pharmaceutical composition containing same and application thereof | |
| CN115724857A (zh) | 一种芳杂环类化合物、含其的药物组合物及其应用 | |
| JP2024505912A (ja) | 連環を含むｔｙｋ２阻害剤化合物 | |
| CN112010928B (zh) | 乙基pak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 | |
| CA2928701A1 (en) | Nmda receptor modulators and prodrugs, salts, and uses thereof | |
| CN114249721B (zh) | 长春胺peg衍生物与在制备治疗糖尿病周围神经病变、糖尿病足及肺纤维化药物中的应用 | |
| CN114380868B (zh) | 一种金属铱化合物及其制备方法和应用 | |
| CN107459553B (zh) | 左旋维c-2-氧乙酰-pak,其合成,活性和应用 | |
| CN115073449A (zh) | 稠环杂环化合物及应用、含有其的药物组合物及应用 | |
| CN112010936B (zh) | 乙基grpak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 | |
| CN108929320A (zh) | 3r-吲哚甲基-6r-恶唑烷酮修饰的哌嗪-2,5-二酮，其合成，活性和应用 | |
| CN107459556B (zh) | 左旋维c-2-氧乙酰-pakpak，其合成，活性和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20240308 Address after: Room 105, Building 8, Shiyuan New Village, Xihu District, Hangzhou City, Zhejiang Province, 310012 Applicant after: Yang Wei Country or region after: China Applicant after: ZHEJIANG University Address before: 310058 Yuhang Tang Road, Xihu District, Hangzhou, Zhejiang 866 Applicant before: ZHEJIANG University Country or region before: China |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20241014 Address after: Room 105, Building 8, Shiyuan New Village, Xihu District, Hangzhou City, Zhejiang Province, 310012 Applicant after: Yang Wei Country or region after: China Applicant after: Hangzhou Shengnuo Hongjian Biotechnology Co.,Ltd. Address before: Room 105, Building 8, Shiyuan New Village, Xihu District, Hangzhou City, Zhejiang Province, 310012 Applicant before: Yang Wei Country or region before: China Applicant before: ZHEJIANG University |