CN118084903A - Beta-carboline hydrogen sulfide donor derivative and preparation method and application thereof - Google Patents
Beta-carboline hydrogen sulfide donor derivative and preparation method and application thereof Download PDFInfo
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- CN118084903A CN118084903A CN202410215114.1A CN202410215114A CN118084903A CN 118084903 A CN118084903 A CN 118084903A CN 202410215114 A CN202410215114 A CN 202410215114A CN 118084903 A CN118084903 A CN 118084903A
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- Prior art keywords
- indole
- ethyl
- pyridine
- carboxylic acid
- carboxamide
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- -1 Beta-carboline hydrogen sulfide Chemical compound 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 81
- 230000002107 myocardial effect Effects 0.000 claims abstract description 11
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 11
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical class SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 5
- 230000004792 oxidative damage Effects 0.000 claims abstract description 4
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 claims description 192
- LSGKMZLPZFPAIN-UHFFFAOYSA-N 1h-indole-3-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=CNC2=C1 LSGKMZLPZFPAIN-UHFFFAOYSA-N 0.000 claims description 54
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 7
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 6
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 5
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 238000011001 backwashing Methods 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 239000000284 extract Substances 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- VFHUJFBEFDVZPJ-UHFFFAOYSA-N 1h-indole-2-carboxamide Chemical compound C1=CC=C2NC(C(=O)N)=CC2=C1 VFHUJFBEFDVZPJ-UHFFFAOYSA-N 0.000 claims 1
- 125000006494 2-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 58
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 10
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 abstract description 9
- 229910000037 hydrogen sulfide Inorganic materials 0.000 abstract description 8
- 230000004224 protection Effects 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000007789 gas Substances 0.000 abstract description 3
- 230000009441 vascular protection Effects 0.000 abstract description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 abstract 1
- 210000004165 myocardium Anatomy 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 229940126214 compound 3 Drugs 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 10
- 238000011160 research Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 150000003573 thiols Chemical class 0.000 description 5
- 230000001960 triggered effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 3
- 210000004413 cardiac myocyte Anatomy 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- QYNVGXKRERVLCV-UHFFFAOYSA-N 2-fluorobenzenecarbothioic s-acid Chemical group OC(=S)C1=CC=CC=C1F QYNVGXKRERVLCV-UHFFFAOYSA-N 0.000 description 2
- OUGRJASIBYFPRJ-UHFFFAOYSA-N 2-methoxybenzenecarbothioic s-acid Chemical group COC1=CC=CC=C1C(O)=S OUGRJASIBYFPRJ-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000000916 dilatatory effect Effects 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 208000007201 Myocardial reperfusion injury Diseases 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008065 myocardial cell damage Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000002751 oxidative stress assay Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a beta-carboline hydrogen sulfide donor derivative, a preparation method and application thereof. The synthesis method of the beta-carboline hydrogen sulfide donor derivative is simple, firstly hydroxylamine oxysulfonic acid is used for reacting with substituted thiobenzoic acid to obtain an intermediate, then the intermediate is condensed with different beta-carboline compounds to obtain the beta-carboline hydrogen sulfide donor with double effects, the compounds have remarkable activity of resisting myocardial cell oxidative damage, beta-carboline with myocardial protection and hydrogen sulfide gas with vascular protection can be released under the action of mercaptan, damaged cardiac muscle can be protected simultaneously from two aspects, the influence on normal cells is small, and a new thought and method are provided for treating ischemic heart diseases.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a beta-carboline hydrogen sulfide donor derivative, a preparation method and application thereof.
Background
Research shows that myocardial ischemia and myocardial necrosis are caused by cardiovascular diseases such as myocardial infarction, coronary heart disease and the like. Timely restoration of blood flow is a major therapeutic approach to improving myocardial ischemia, however reperfusion itself can further exacerbate myocardial cell injury, initiate apoptosis, increase infarct size, and lead to arrhythmia and even death. Thus, myocardial ischemia/reperfusion injury (Myocardial ischemia-reperfusion injury, MIRI) has become an important cause of death due to myocardial ischemia.
The novel hydrogen sulfide (H 2 S) gas signal molecule plays a wide physiological and pathological role in vivo, such as dilating blood vessels, reducing blood pressure, inhibiting oxidative stress, regulating inflammation, protecting blood vessels and the like. H 2 S has effects of dilating blood vessel, lowering blood pressure, and promoting proliferation of vascular endothelial cells. Research shows that H 2 S can obviously improve various cardiovascular diseases such as arrhythmia, cardiac hypertrophy, myocardial fibrosis, heart failure and the like. In vitro studies have shown that H 2 S donors can reduce cardiomyocyte death caused by hypoxia/reoxygenation injury; in MIRI, H 2 S can protect myocardial cells and significantly reduce infarct size. With the continuous and deep research of H 2 S as an important endogenous gas signal molecule of a human body, the research of an H 2 S donor also has greatly progressed, but no H 2 S donor medicine is marketed at present. NaHS and Na 2 S are the first typical class of H 2 S donors that release large amounts of H 2 S in a short period of time, but such inorganic donors are unpleasant in smell, unstable in nature, and too short in half-life to be effective in treating disease. The existing chemical fragments of the organic hydrogen sulfide donor after releasing H 2 S almost have no myocardial protection effect, so that the chemical structure of the donor molecule has lower use efficiency, and millimoles of the organic donor are needed to reach the micromole concentration of H 2 S for exerting biological effect, thereby generating the problems of toxicity, solubility, interaction with other components of organisms and the like. Therefore, how to improve the chemical structure utilization efficiency of the H 2 S donor and reduce the dosage is a problem to be solved in the design of the novel H 2 S donor.
Carbolines are heterocyclic compounds in which the pyridine ring is fused to the pyrrole ring of the indole. The research shows that the beta-carboline has remarkable in-vivo and in-vitro myocardial protection activity, but the vascular protection activity is not reported. Patent number 202010151142.3 reports that the compound is stable in solution and has obvious protective activity for resisting myocardial hypoxia reoxygenation injury, especially myocardial ischemia reperfusion injury. And the beta-carboline with myocardial protection activity and hydrogen sulfide with cardiovascular protection function are coupled to play the dual protection function of myocardial and cardiovascular at the same time, so that the dosage is reduced, the use efficiency of the chemical structure is improved, and a new thought is provided for the drug development of ischemic heart diseases.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide the beta-carboline hydrogen sulfide donor derivative, and the preparation method and the application thereof
The method is realized by the following technical scheme:
the first object of the invention is to provide a beta-carboline hydrogen sulfide donor derivative, which has a structural formula shown in a formula (1):
Wherein R 1 is proton, alkyl, phenyl, aralkyl; r 2 is proton, alkyl, benzyl, substituted benzyl; r 3 is proton, alkyl, methoxy, hydroxyl, nitro, amino, halogen; r 4 is proton, alkyl, methoxy, hydroxy, nitro, amino, halogen.
Preferably, the alkyl group referred to in structure (1) refers to a straight or branched saturated aliphatic group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
Preferably, R 1 is proton, methyl, ethyl; r 2 is proton, methyl, benzyl, o-fluorobenzyl, p-fluorobenzyl, o-chlorobenzyl, p-trifluoromethylbenzyl, o-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, p-methoxybenzyl; r 3 is proton, methyl, methoxy or hydroxy; r 4 is proton, methyl, methoxy, hydroxyl.
Preferably, the beta-carboline hydrogen sulfide donor derivative is any one of the following compounds:
compound 3: n- (benzoylthio) -1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxamide;
Compound 4: n- (benzoylthio) -1-ethyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxamide;
compound 5: n- (benzoylthio) -1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide;
compound 6: n- (benzoylthio) -1-ethyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide;
compound 7: n- (benzoylthio) -1-ethyl-9- (4-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxamide;
Compound 8: n- (benzoylthio) -1-methyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxamide;
Compound 9: n- (benzoylthio) -1-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide;
compound 10: n- (benzoylthio) -1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide;
Compound 11: n- (benzoylthio) -1-ethyl-9-methyl-pyrido [3,4-b ] indole-3-carboxamide;
Compound 12: n- (benzoylthio) -1-ethyl-9- (4-methylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide;
compound 13: n- (benzoylthio) -1-ethyl-9- (2-methylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide;
Compound 14: n- (benzoylthio) -1-ethyl-9- (2-methoxybenzyl) -pyrido [3,4-b ] indole-3-carboxamide;
Compound 15: n- (benzoylthio) -1-ethyl-9- (4-trifluoromethylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide;
Compound 16: n- (benzoylthio) -1-ethyl-9- (2-trifluoromethylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide;
compound 17: n- (benzoylthio) -1-ethyl-9- (2-chlorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide;
Compound 18: n- (benzoylthio) -1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide;
Compound 19: 1-ethyl-6-hydroxy-9- (4-fluorobenzyl) -N- (2-methoxybenzoylthio) -pyrido [3,4-b ] indole-3-carboxamide;
Compound 20: 1-ethyl-6-methyl-9- (4-fluorobenzyl) -N- (2-fluorobenzoylthio) -pyrido [3,4-b ] indole-3-carboxamide.
The second object of the present invention is to provide a preparation method of the aforementioned β -carboline hydrogen sulfide donor derivative, comprising the following steps:
the first step: weighing KOH, dissolving in water, stirring at room temperature, adding the compound 1 and hydroxylamine oxysulfonic acid, stirring for reaction, extracting with dichloromethane, and spin-drying to obtain an intermediate 2;
And a second step of: weighing intermediate 2, dissolving in dry DMF, adding compound 2, HATU and DIEA, stirring at room temperature for reaction, adding pure water, extracting with ethyl acetate, mixing the extracts, backwashing with saturated saline solution, spin-drying the organic layer to obtain crude product, and purifying by normal phase silica gel column chromatography to obtain compound 3-20.
The compound 1 is substituted thiobenzoic acid, and has a structural formula as follows: Wherein R 4 is proton, alkyl, methoxy, hydroxyl, nitro, amino, halogen;
The compound 2 is 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-methyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxylic acid, 1-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9-methyl-pyridine [3,4-b ] indole-carboxylic acid, 1-ethyl-9-indole-3-ethyl-4-b ] indole-carboxylic acid, 1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-carboxylic acid, 1-ethyl-9- (2-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-trifluoromethylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (2-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-6-hydroxy-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-6-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Further, the invention provides a synthetic route of the beta-carboline hydrogen sulfide donor compound, which comprises the following steps:
Furthermore, the invention also provides a synthetic route and a preparation method of the compound 3, wherein the synthetic route is as follows:
the preparation method comprises the following steps:
the first step: weighing KOH, dissolving in water, stirring at room temperature, adding hydroxylamine oxysulfonic acid and thiobenzoic acid, stirring for reaction, extracting with dichloromethane, and spin-drying to obtain an intermediate 2;
And a second step of: weighing intermediate 2, dissolving in dry DMF, adding 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid, HATU and DIEA, stirring at room temperature for reaction, adding pure water, extracting with ethyl acetate, combining the extracts, backwashing with saturated saline solution, spin-drying the organic layer to obtain a crude product, and purifying by normal phase silica gel column chromatography to obtain a compound 3.
Preparation of the Compound 4-N- (benzoylthio) -1-ethyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxylic acid;
Preparation of the Compound 5-N- (benzoylthio) -1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxylic acid;
Preparation of the Compound 6-N- (benzoylthio) -1-ethyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid;
preparation of the Compound 7-N- (benzoylthio) -1-ethyl-9- (4-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid;
Preparation of Compound 8-N- (benzoylthio) -1-methyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-methyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxylic acid;
Preparation of the Compound 9-N- (benzoylthio) -1-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid;
Preparation of Compound 10-N- (benzoylthio) -1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid;
Preparation of Compound 11-N- (benzoylthio) -1-ethyl-9-methyl-pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9-methyl-pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of Compound 12-N- (benzoylthio) -1-ethyl-9- (4-methylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-methylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of Compound 13-N- (benzoylthio) -1-ethyl-9- (2-methylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (2-methylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of Compound 14-N- (benzoylthio) -1-ethyl-9- (2-methoxybenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (2-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of Compound 15-N- (benzoylthio) -1-ethyl-9- (4-trifluoromethylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-trifluoromethylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of Compound 16-N- (benzoylthio) -1-ethyl-9- (2-trifluoromethylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (2-trifluoromethylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of Compound 17-N- (benzoylthio) -1-ethyl-9- (2-chlorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (2-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of the Compound 18-N- (benzoylthio) -1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of Compound 19-1-ethyl-6-hydroxy-9- (4-fluorobenzyl) -N- (2-methoxybenzoylthio) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, thiobenzoic acid was replaced with o-methoxythiobenzoic acid and 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-6-hydroxy-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
Preparation of the Compound 20-1-ethyl-6-methyl-9- (4-fluorobenzyl) -N- (2-fluorobenzoylthio) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, thiobenzoic acid was replaced with o-fluorothiobenzoic acid and 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-6-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
The third purpose of the invention is to provide an application of the beta-carboline hydrogen sulfide donor derivative in preparing a medicament for resisting myocardial oxidative damage.
Further, the invention discloses application of the beta-carboline hydrogen sulfide donor derivative in preparation of ischemic heart disease medicines.
Drawings
Fig. 1: synthetic route for compound 3.
Detailed Description
The following detailed description of the invention is provided in further detail, but the invention is not limited to these embodiments, any modifications or substitutions in the basic spirit of the present examples, which still fall within the scope of the invention as claimed.
EXAMPLE 1 preparation of the Compound 3-N- (benzoylthio) -1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxamide
A: 2.2mmol of KOH 122mg was weighed, dissolved in 5mL of water and placed in a 20mL eggplant-shaped bottle, stirred at room temperature for 5min, then 147mg of hydroxylamine oxysulfonic acid 1.3mmol and 60mg of thiobenzoic acid 0.44mmol were added, and the reaction was continued for 10min and monitored by TLC. After 2h, the reaction is terminated, and the white solid is obtained by extraction and spin-drying with dichloromethane, namely the intermediate 2 (s-acyl thiohydroxylamine) is obtained, and the yield is 67%.
B: 0.4mmol of intermediate 2 was weighed 100mg and placed in a 25mL eggplant-shaped bottle, dissolved in 9mL of dry DMF, added with 128mg of 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid, 128mg of 0.45mmol of HATU 190mg,0.8mmol of DIEA 108mg, and reacted at room temperature. The reaction condition is detected by TLC, the reaction is stopped after 4 hours, 10mL of pure water is added, ethyl acetate is used for extraction, the extract liquid is combined, the saturated saline water is used for backwashing for times, the organic layer is concentrated to obtain a crude product, and the crude product is purified by normal phase silica gel column chromatography to obtain a white solid, namely the compound 3 (N- (benzoyl thio) -1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxamide) with the yield of 12 percent.
Example 2
Preparation of the Compound 4-N- (benzoylthio) -1-ethyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxylic acid in 15% yield.
Example 3
Preparation of the Compound 5-N- (benzoylthio) -1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxylic acid in 36% yield.
Example 4
Preparation of the Compound 6-N- (benzoylthio) -1-ethyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid in 19% yield.
Example 5
Preparation of the Compound 7-N- (benzoylthio) -1-ethyl-9- (4-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid in 24% yield.
Example 6
Preparation of Compound 8-N- (benzoylthio) -1-methyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-methyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxylic acid in 21% yield.
Example 7
Preparation of the Compound 9-N- (benzoylthio) -1-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid in 21% yield.
Example 8
Preparation of Compound 10-N- (benzoylthio) -1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid in 19% yield.
Example 9
Preparation of Compound 11-N- (benzoylthio) -1-ethyl-9-methyl-pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9-methyl-pyridine [3,4-b ] indole-3-carboxylic acid, 31%.
Example 10
Preparation of Compound 12-N- (benzoylthio) -1-ethyl-9- (4-methylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-methylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 24%.
Example 11
Preparation of Compound 13-N- (benzoylthio) -1-ethyl-9- (2-methylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (2-methylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 27%.
Example 12
Preparation of Compound 14-N- (benzoylthio) -1-ethyl-9- (2-methoxybenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (2-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 42%.
Example 13
Preparation of Compound 15-N- (benzoylthio) -1-ethyl-9- (4-trifluoromethylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-trifluoromethylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 36%.
Example 14
Preparation of Compound 16-N- (benzoylthio) -1-ethyl-9- (2-trifluoromethylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (2-trifluoromethylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 11%.
Example 15
Preparation of Compound 17-N- (benzoylthio) -1-ethyl-9- (2-chlorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (2-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 17%.
Example 16
Preparation of the Compound 18-N- (benzoylthio) -1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 15%.
Example 17
Preparation of Compound 19-1-ethyl-6-hydroxy-9- (4-fluorobenzyl) -N- (2-methoxybenzoylthio) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, thiobenzoic acid was replaced with o-methoxythiobenzoic acid and 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-6-hydroxy-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 22%.
Example 18
Preparation of the Compound 20-1-ethyl-6-methyl-9- (4-fluorobenzyl) -N- (2-fluorobenzoylthio) -pyrido [3,4-b ] indole-3-carboxamide
Referring to the preparation of compound 3, thiobenzoic acid was replaced with o-fluorothiobenzoic acid and 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid was replaced with 1-ethyl-6-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 15%.
The structural formulas of the compounds of examples 1-18 are shown in Table 1:
TABLE 1
Test example 1
MTT method for detecting toxicity of thiol-triggered hydrogen sulfide donor compound based on beta-carboline structure, the compound is carried out as follows:
The toxicity of the example compounds on H9c2 cells was investigated using the MTT method. Cells (10000 cells/well) were seeded in 96-well plates, test compounds (2.5, 5, 10, 20, 40 and 80. Mu. Mol/L) were added respectively at 37℃and after 24h incubation 3- (4, 5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT, sigma) was added to a final concentration of 0.5mg/mL per well and after further incubation for 4h the medium was removed and 150. Mu. LDMSO was added per well. Absorbance was measured at 570nm with a microplate reader, all measurements being performed at least 3 times under the same conditions. The half-inhibitory concentration value (IC 50) was calculated using GRAPHPAD PRISM.
The experimental results are shown in a second table;
TABLE 2 influence of thiol-triggered Hydrogen sulfide donor Compounds (μmol/L) based on beta-carboline Structure on H9c2 component on myocardial cell survival (%)
According to the thiol-triggered hydrogen sulfide donor compound 3-20 based on the beta-carboline structure, except that the compounds 3 and 13 show certain toxicity at the concentration higher than 10 mu M, the cell survival rate of the rest compounds is almost close to or higher than 100%, which indicates that the safety is good.
2.H 2O2 -induced cardiomyocyte oxidative stress assay
H9c2 cells were incubated in 96-well plates and after 24H the medium was removed. 100. Mu.L of complete medium containing 0, 5, 10, 20, 40, 80. Mu. Mol/L of test compound and 50. Mu L H 2O2 (1.5 mM) were added to each well, the final concentration was 0.3mM, and after further incubation of the cells for 30min, the viability of H9c2 cells was examined by MTT method.
The test results are shown in Table III;
TABLE 3 influence of thiol-triggered Hydrogen sulfide donor compound (μmol/L) pretreatment based on beta-carboline structure on H9c2 cardiomyocyte H/R injured cell viability
According to the test results, the thiol-triggered hydrogen sulfide donor compounds 5, 9, 10, 11 and 13-20 based on the beta-carboline structure have remarkable protection effects on oxidative damage induced by H 2O2, wherein the activities of the compounds 5, 18, 19 and 20 are most remarkable, the cell activity can be remarkably improved from about 60% to more than 90%, and a new thought is provided for drug development of ischemic heart diseases.
Claims (6)
1. The beta-carboline hydrogen sulfide donor derivative is characterized by having a structural formula as shown in formula (1):
Wherein R 1 is proton, alkyl, phenyl, aralkyl; r 2 is proton, alkyl, benzyl, substituted benzyl; r 3 is proton, alkyl, methoxy, hydroxyl, nitro, amino, halogen; r 4 is proton, alkyl, methoxy, hydroxy, nitro, amino, halogen.
2. The β -carboline hydrogen sulfide donor derivative according to claim 1, wherein R 1 is proton, methyl, ethyl; r 2 is proton, methyl, benzyl, o-fluorobenzyl, p-fluorobenzyl, o-chlorobenzyl, p-trifluoromethylbenzyl, o-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, p-methoxybenzyl; r 3 is proton, methyl, methoxy or hydroxy; r 4 is proton, methyl, methoxy, hydroxyl.
3. A β -carboline hydrogen sulfide donor derivative according to claim 1, wherein the β -carboline hydrogen sulfide donor derivative is N- (benzoylthio) -1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (4-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-methyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (4-methylbenzyl) -pyridine [3,4-b ] indole-carboxamide, N- (benzoylthio) -1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9-methyl-pyrido [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (4-methylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (2-methoxybenzyl) -pyrido [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (4-trifluoromethylbenzyl) -pyrido [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (2-trifluoromethylbenzyl) -1-ethyl-9- (2-trifluoromethyl) -pyrido [3,4-b ] indole-3-carboxamide,
Any of N- (benzoylthio) -1-ethyl-9- (2-chlorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide, N- (benzoylthio) -1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxamide, 1-ethyl-6-hydroxy-9- (4-fluorobenzyl) -N- ((2-methoxybenzoyl) thio) -pyrido [3,4-b ] indole-3-carboxamide, 1-ethyl-6-methyl-9- (4-fluorobenzyl) -N- ((2-fluorobenzoyl) thio) -pyrido [3,4-b ] indole-3-carboxamide.
4. A process for the preparation of a β -carboline hydrogen sulfide donor derivative according to any one of claims 1 to 3, comprising the steps of:
A. weighing KOH, dissolving in water, stirring at room temperature, adding hydroxylamine oxysulfonic acid and the compound 1, stirring for reaction, extracting with dichloromethane, and spin-drying to obtain an intermediate 2;
B. dissolving the intermediate 2 in dry DMF, adding the compound 2, HATU and DIEA, stirring at room temperature for reaction, adding pure water, extracting with ethyl acetate, mixing the extracts, backwashing with saturated saline solution, spin-drying the organic layer to obtain a crude product, and purifying by normal phase silica gel column chromatography to obtain a product;
the compound 1 is substituted thiobenzoic acid, and has a structural formula as follows: Wherein R 4 is proton, alkyl, methoxy, hydroxyl, nitro, amino, halogen;
The compound 2 is 1-ethyl-9H-pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-fluorobenzyl) -pyrido [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-methyl-9-benzyl-pyridine [3,4-b ] indole-3-carboxylic acid, 1-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9-methyl-pyridine [3,4-b ] indole-carboxylic acid, 1-ethyl-9-indole-3-ethyl-4-b ] indole-carboxylic acid, 1-methyl-9- (4-chlorobenzyl) -pyridine [3,4-b ] indole-carboxylic acid, 1-ethyl-9- (2-methoxybenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-trifluoromethylbenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (2-chlorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-6-hydroxy-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid, 1-ethyl-6-methyl-9- (4-fluorobenzyl) -pyridine [3,4-b ] indole-3-carboxylic acid.
5. Use of a β -carboline hydrogen sulfide donor derivative according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of myocardial cell oxidative damage.
6. Use of a β -carboline hydrogen sulfide donor derivative according to any one of claims 1 to 3 for the preparation of a medicament for ischemic heart disease.
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