CN117447375A - 胍类化合物及其制备方法和用途 - Google Patents
胍类化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN117447375A CN117447375A CN202210844227.9A CN202210844227A CN117447375A CN 117447375 A CN117447375 A CN 117447375A CN 202210844227 A CN202210844227 A CN 202210844227A CN 117447375 A CN117447375 A CN 117447375A
- Authority
- CN
- China
- Prior art keywords
- compound
- sci
- virus
- alkanoyl
- mmol
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 Guanidine compound Chemical class 0.000 title claims description 92
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title abstract description 6
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 title abstract description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 106
- 239000003814 drug Substances 0.000 claims abstract description 26
- 241000711573 Coronaviridae Species 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 206010035664 Pneumonia Diseases 0.000 claims abstract description 9
- 206010057190 Respiratory tract infections Diseases 0.000 claims abstract description 6
- 208000025721 COVID-19 Diseases 0.000 claims abstract description 5
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims abstract 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 241001678559 COVID-19 virus Species 0.000 claims description 27
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 241000700605 Viruses Species 0.000 claims description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 208000006454 hepatitis Diseases 0.000 claims description 10
- 231100000283 hepatitis Toxicity 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 230000009385 viral infection Effects 0.000 claims description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 7
- 241000315672 SARS coronavirus Species 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 6
- 208000001528 Coronaviridae Infections Diseases 0.000 claims description 6
- 241000725619 Dengue virus Species 0.000 claims description 6
- 241001115402 Ebolavirus Species 0.000 claims description 6
- 241000711549 Hepacivirus C Species 0.000 claims description 6
- 241000724675 Hepatitis E virus Species 0.000 claims description 6
- 208000037262 Hepatitis delta Diseases 0.000 claims description 6
- 241000724709 Hepatitis delta virus Species 0.000 claims description 6
- 241000709721 Hepatovirus A Species 0.000 claims description 6
- 241001115401 Marburgvirus Species 0.000 claims description 6
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 244000309467 Human Coronavirus Species 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- 241000700721 Hepatitis B virus Species 0.000 claims description 4
- 241000711467 Human coronavirus 229E Species 0.000 claims description 4
- 241000482741 Human coronavirus NL63 Species 0.000 claims description 4
- 241001428935 Human coronavirus OC43 Species 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- 208000036142 Viral infection Diseases 0.000 claims description 4
- 208000020329 Zika virus infectious disease Diseases 0.000 claims description 4
- 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 claims description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940126543 compound 14 Drugs 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 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 claims description 4
- 201000009240 nasopharyngitis Diseases 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 208000024891 symptom Diseases 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- BFWYZZPDZZGSLJ-UHFFFAOYSA-N 4-(aminomethyl)aniline Chemical compound NCC1=CC=C(N)C=C1 BFWYZZPDZZGSLJ-UHFFFAOYSA-N 0.000 claims description 3
- ODHCTXKNWHHXJC-UHFFFAOYSA-N 5-oxoproline Chemical compound OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 3
- 206010003757 Atypical pneumonia Diseases 0.000 claims description 3
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 150000001371 alpha-amino acids Chemical class 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 230000000840 anti-viral effect Effects 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000005518 carboxamido group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- 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 claims description 2
- 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 claims description 2
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 claims description 2
- CSEWAUGPAQPMDC-UHFFFAOYSA-N 2-(4-aminophenyl)acetic acid Chemical compound NC1=CC=C(CC(O)=O)C=C1 CSEWAUGPAQPMDC-UHFFFAOYSA-N 0.000 claims description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 229940126657 Compound 17 Drugs 0.000 claims description 2
- 208000001490 Dengue Diseases 0.000 claims description 2
- 206010012310 Dengue fever Diseases 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- 206010061192 Haemorrhagic fever Diseases 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 241000712431 Influenza A virus Species 0.000 claims description 2
- 241000713196 Influenza B virus Species 0.000 claims description 2
- 241000713297 Influenza C virus Species 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 2
- 208000001455 Zika Virus Infection Diseases 0.000 claims description 2
- 241000907316 Zika virus Species 0.000 claims description 2
- 208000035332 Zika virus disease Diseases 0.000 claims description 2
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 229960004050 aminobenzoic acid Drugs 0.000 claims description 2
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940050390 benzoate Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 2
- 229940125797 compound 12 Drugs 0.000 claims description 2
- 208000025729 dengue disease Diseases 0.000 claims description 2
- 239000012634 fragment Substances 0.000 claims description 2
- 229930195712 glutamate Natural products 0.000 claims description 2
- 229940049906 glutamate Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 206010022000 influenza Diseases 0.000 claims description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 2
- 229960000310 isoleucine Drugs 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims description 2
- 229940049953 phenylacetate Drugs 0.000 claims description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 claims description 2
- 241000712461 unidentified influenza virus Species 0.000 claims description 2
- 239000004474 valine Substances 0.000 claims description 2
- 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 claims 2
- 239000002253 acid Substances 0.000 claims 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-M 4-aminobenzenesulfonate Chemical compound NC1=CC=C(S([O-])(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-M 0.000 claims 1
- 241001109669 Human coronavirus HKU1 Species 0.000 claims 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 16
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 2
- 239000003443 antiviral agent Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 101
- 230000015572 biosynthetic process Effects 0.000 description 89
- 238000003786 synthesis reaction Methods 0.000 description 89
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 84
- 239000007787 solid Substances 0.000 description 65
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000003756 stirring Methods 0.000 description 37
- 239000002904 solvent Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 31
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000004698 Polyethylene Substances 0.000 description 18
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 230000002401 inhibitory effect Effects 0.000 description 17
- 238000002390 rotary evaporation Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000001035 drying Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 12
- 239000002207 metabolite Substances 0.000 description 12
- HLRWVDNGCCHKSI-UHFFFAOYSA-N 4-[[n,n'-bis[(2-methylpropan-2-yl)oxycarbonyl]carbamimidoyl]amino]benzoic acid Chemical compound CC(C)(C)OC(=O)NC(=NC(=O)OC(C)(C)C)NC1=CC=C(C(O)=O)C=C1 HLRWVDNGCCHKSI-UHFFFAOYSA-N 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 238000003384 imaging method Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000007821 HATU Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- BMBANPOHPFKVTA-UHFFFAOYSA-N benzamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NC(=O)C1=CC=CC=C1 BMBANPOHPFKVTA-UHFFFAOYSA-N 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229960001997 adefovir Drugs 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- 230000009545 invasion Effects 0.000 description 4
- PXPIXLVXGYQMFM-UHFFFAOYSA-N phenyl 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=CC=C1 PXPIXLVXGYQMFM-UHFFFAOYSA-N 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 238000009987 spinning Methods 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 101710114810 Glycoprotein Proteins 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108060004795 Methyltransferase Proteins 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 241000566242 Ochrotomys Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 101710167605 Spike glycoprotein Proteins 0.000 description 3
- YILCBSAIBMIFQA-UHFFFAOYSA-N benzyl n-[(4-aminophenyl)methyl]carbamate Chemical compound C1=CC(N)=CC=C1CNC(=O)OCC1=CC=CC=C1 YILCBSAIBMIFQA-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- ASKRTLBFSMARDB-SNVBAGLBSA-N (4-nitrophenyl) [(3r)-oxolan-3-yl] carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)O[C@H]1COCC1 ASKRTLBFSMARDB-SNVBAGLBSA-N 0.000 description 2
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- IOXOZOPLBFXYLM-UHFFFAOYSA-N 2-(4-nitrophenyl)ethanamine Chemical compound NCCC1=CC=C([N+]([O-])=O)C=C1 IOXOZOPLBFXYLM-UHFFFAOYSA-N 0.000 description 2
- XHJAOEKASUFHHN-UHFFFAOYSA-N 5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=C=NC=C[CH]1 XHJAOEKASUFHHN-UHFFFAOYSA-N 0.000 description 2
- WGOIHPRRFBCVBZ-UHFFFAOYSA-N 5-oxopyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCC(=O)N1 WGOIHPRRFBCVBZ-UHFFFAOYSA-N 0.000 description 2
- 241000008904 Betacoronavirus Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 102100031673 Corneodesmosin Human genes 0.000 description 2
- 101710139375 Corneodesmosin Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical group Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 2
- 241000566236 Ochrotomys nuttalli Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000006278 bromobenzyl group Chemical group 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamic acid amide Natural products NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000000120 cytopathologic effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000008299 semisolid dosage form Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 230000029812 viral genome replication Effects 0.000 description 2
- OHYMUFVCRVPMEY-SSDOTTSWSA-N (2r)-5-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound COC(=O)CC[C@H](C(O)=O)NC(=O)OC(C)(C)C OHYMUFVCRVPMEY-SSDOTTSWSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- XDPCNPCKDGQBAN-SCSAIBSYSA-N (3r)-oxolan-3-ol Chemical compound O[C@@H]1CCOC1 XDPCNPCKDGQBAN-SCSAIBSYSA-N 0.000 description 1
- WKBQQWDVVHGWDB-UHFFFAOYSA-N 1,3-thiazol-5-ylmethanol Chemical compound OCC1=CN=CS1 WKBQQWDVVHGWDB-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- ZXYKUPPWJMOKGE-UHFFFAOYSA-N 2-[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]acetic acid Chemical compound CC(C)(C)OC(=O)NC1=CC=C(CC(O)=O)C=C1 ZXYKUPPWJMOKGE-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GRASQZGKZFJLDB-UHFFFAOYSA-N 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride Chemical compound CC1=NN=C(C(Cl)=O)O1 GRASQZGKZFJLDB-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 1
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000004172 Cathepsin L Human genes 0.000 description 1
- 108090000624 Cathepsin L Proteins 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241001533413 Deltavirus Species 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 101710204837 Envelope small membrane protein Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000638154 Homo sapiens Transmembrane protease serine 2 Proteins 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 101710145006 Lysis protein Proteins 0.000 description 1
- 101710085938 Matrix protein Proteins 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 101710127721 Membrane protein Proteins 0.000 description 1
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 1
- 101710141454 Nucleoprotein Proteins 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 102100031989 Transmembrane protease serine 2 Human genes 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 238000009529 body temperature measurement Methods 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- GNPOLJYMEXUGCG-UHFFFAOYSA-N n-methyl-1-(2-propan-2-yl-1,3-thiazol-4-yl)methanamine;dihydrochloride Chemical compound Cl.Cl.CNCC1=CSC(C(C)C)=N1 GNPOLJYMEXUGCG-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- BRHMYHXNUGVBCU-UHFFFAOYSA-M potassium;5-methyl-1,3,4-oxadiazole-2-carboxylate Chemical compound [K+].CC1=NN=C(C([O-])=O)O1 BRHMYHXNUGVBCU-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 230000009467 reduction 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
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药领域,公开了一类含胍基结构的化合物,其制备方法,含有它们的药物组合物,其药物制剂,及其作为抗病毒药物的用途。所述的含胍基结构的化合物如通式I所示。本发明的胍类药物作为冠状病毒的抑制剂,可治疗和/或预防、缓解由2019新型冠状病毒感染引起的呼吸道感染、肺炎(COVID‑19)等相关疾病。
Description
技术领域
本发明属于医药领域,具体地涉及一类胍类化合物及其制备方法和在抗病毒中的应用。
背景技术
病毒性感染是威胁人类健康的主要疾病之一。冠状病毒是一类单股正链RNA病毒,分为四个属:α、β、γ、δ,可引起人和动物呼吸道、消化道和神经系统等疾病。严重急性呼吸系统综合征冠状病毒2(Severe acute respiratory syndrome coronavirus 2,SARS-CoV-2),简称新冠病毒,属于β属冠状病毒,于2019年末首次发现,是一种具有包膜的正链单链RNA病毒,其结构和基因序列与引发非典型性肺炎(SARS)和中东呼吸综合征(MERS)的病毒极为相似,同属β冠状病毒属,包括单链RNA、刺突糖蛋白(S蛋白)、包膜蛋白(E蛋白)、膜蛋白(M蛋白)、核衣壳蛋白(N蛋白)等结构。SARS-CoV-2主要通过2条途径实现对人体宿主细胞的感染:(1)SARS-CoV-2中的刺突糖蛋白(S蛋白)与宿主细胞表面的血管紧张素转化酶2(ACE2)相结合,通过内吞作用进入宿主细胞内形成核内体,在组织蛋白酶L等作用下被激活,释放RNA,经RNA依赖的RNA聚合酶(RdRp)作用进行病毒复制;(2)SARS-CoV-2中的刺突糖蛋白在宿主细胞表面被跨膜丝氨酸蛋白酶2(TMPRSS2)裂解,暴露融合肽区,诱导病毒与细胞膜融合,促使病毒基因组入侵细胞,经RdRp进行病毒复制。
SARS-CoV-2具有极强的呼吸道传染性,其感染人体后可引起发热、乏力和咳嗽,严重情况下可导致肺炎(简称新冠肺炎,COVID-19)、肾功能衰竭甚至死亡。截止至2022年5月,SARS-CoV-2已造成全球5亿多人感染,超过600万人死亡,对全球公共健康形成巨大挑战,已成为威胁人类生命健康的最大敌人。因此,开发针对SARS-CoV-2冠状病毒的靶向、高效、低毒的药物,以满足国内外SARS-CoV-2冠状病毒感染患者的临床需求,及时有效地保护人类健康,拯救人类生命,具有重大的社会意义。
综上所述,本领域迫切需要开发针对SARS-CoV-2病毒侵入和复制的抑制剂用于治疗由新冠病毒感染引起的相关疾病。
发明内容
发明目的:本发明的目的是提供一种可有效抑制冠状病毒侵入和/或复制的化合物及其在冠状病毒感染引起的相关疾病中的用途。本发明的另一个目的在于公开该类化合物的制备方法,该方法可操作性强且较为高效。
技术方案:本发明技术方案的第一方面在于:提供一种由下述通式(I)表示的可抑制冠状病毒侵入和/或复制的化合物或其药学上可接受的盐或其结晶水合物或其溶剂化物或其前药:
其中,
X选自-CH2-、-NH-、O、S;
n=0,1,2,3,4;
L选自甲酰基、磺酰基、亚硫酰基、甲酰胺基、甲酰氧基、取代或未取代的氨基甲酰基、取代或未取代的氨基磺酰基、取代或未取代的氨基甲酰氧基、取代或未取代的氨基甲酰胺基,其中,所述取代基独立地选自氢、C1-C4烷基;
R选自氢、C1-C6烷基、取代或未取代的C1-C6羧基、取代或未取代的C5-C10芳基、取代或未取代的C1-C8饱和或不饱和杂环基、 其中,所述取代基独立地选自C1-C6烷基或烷氧基、C1-C4烯基、羟基、氨基、硝基、氰基、三氟甲基、卤素,所述卤素为F、Cl、Br、I;所述杂环至少包含一个杂原子,所述杂原子为N、O、S;R1选自氢、C1-10烷基、C1-10烷酰基、氨基C1-10烷酰基、C1-6烷氨基C1-6烷酰基、C1-6烷氧基C1-6烷酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连;R2选自氢、C1-10烷基、C1-10烷酰基、氨基C1-10烷酰基、C1-6烷氨基C1-6烷酰基、C1-6烷氧基C1-6烷酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连。
进一步地,所述取代基独立的选自甲基、乙基、异丙基、叔丁基、羟基、氨基、三氟甲基、卤素,所述卤素为F、Cl、Br、I;所述杂环至少包含一个杂原子,所述杂原子为N、O、S;R1选自氢、甲基、乙基、异丙基、叔丁基、乙酰基、丙酰基、正丁酰基、异丁酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连;R2选自氢、C1-10烷基、C1-10烷酰基、氨基C1-10烷酰基、C1-6烷氨基C1-6烷酰基、C1-6烷氧基C1-6烷酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连。优选地,所述α-氨基酸选自丙氨酸、缬氨酸、异亮氨酸、色氨酸、苯丙氨酸。
更进一步地,R优选自以下结构片段之一:
更优选地,所述化合物选自下述化合物:
本发明同时涉及通式(I)化合物在药学上可接受的盐的形式,和/或溶剂化物。
通式(I)化合物盐的例子包括盐酸盐、硫酸盐、氢溴酸盐、氢氟酸盐、氢碘酸盐、胺基磺酸盐、磷酸盐、甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、萘磺酸盐、萘二磺酸盐、醋酸盐、丙酸盐、酒石酸盐、丙二酸盐、富马酸盐、乳酸盐、琥珀酸盐、樟脑磺酸盐、柠檬酸盐、草酸盐、马来酸盐、苹果酸盐、丙酮酸盐、三氟乙酸盐、扑酸盐、羟基马来酸盐、苯乙酸盐、苯甲酸盐、水杨酸盐、谷氨酸盐、抗坏血酸盐、对胺基苯磺酸盐、2-乙酰氧基苯甲酸盐、羟乙磺酸盐。
根据本发明,通式(I)化合物可以以异构体形式存在,而且通常所述的本发明“化合物”包括该化合物的异构体。
通式(I)化合物可以存在双键的顺反异构,不对称中心具有S构型或R构型,本发明包括所有可能的立体异构体以及两种或多种异构体的混合物。如果存在顺反异构体,本发明涉及顺式形式和反式形式以及这些形式的混合物,如果需要单一异构体可根据常规方法分离或通过立体选择合成制备。
本发明技术方案的第二方面在于提供了第一方面所述化合物的制备方法,包括但不限于以下合成路线:
(1)化合物SCI-1、SCI-2、SCI-4的合成路线:
将对氨基苯甲酸的氨基转化为Boc保护的胍基得化合物1,将对/间硝基苯乙胺与含羧酸的化合物缩合得化合物2,化合物2经氢气还原得化合物3,化合物1与化合物3缩合得化合物4,化合物4在酸性条件下脱除Boc保护基得到化合物SCI-1,SCI-2,SCI-4。
反应条件:(a)甲醇,60℃,16h;(b)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),三乙胺,二氯甲烷,r.t.,12h;(c)氢气,5%Pd-C,甲醇,r.t.,4h;(d)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),三乙胺,二氯甲烷,r.t.,12h;(e)2N HCl,二氯甲烷,r.t.,6h。
(2)化合物SCI-3的合成路线:
将化合物1与Cbz保护的对羟基苯乙胺缩合得化合物5,化合物5经氢气还原脱除Cbz保护基得化合物6,化合物6与5-羧基吡咯烷酮缩合得化合物7,化合物7在酸性条件下脱除Boc保护基得到化合物SCI-3。
反应条件:(a)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),四氢呋喃,r.t.,4h;(b)氢气,5%Pd-C,甲醇,r.t.,4h;(c)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU),二异丙基乙胺,N,N-二甲基甲酰胺,r.t.,6h;(d)2N HCl,二氯甲烷,r.t.,6h。
(3)化合物SCI-5、SCI-7、SCI-14、SCI-18的合成路线:
将Boc保护的对氨基苯乙酸与苄溴反应得化合物8,化合物8经三氟乙酸脱除Boc保护基得化合物9,化合物9与化合物1缩合得化合物10,化合物10经氢气还原脱除苄基得化合物11,化合物11与含氨基或羟基的化合物12缩合得化合物13,化合物13在酸性条件下脱除Boc保护基得到化合物SCI-5、SCI-7、SCI-14、SCI-18。
反应条件:(a)溴苄,碳酸铯,DMF,0℃–r.t.,1h;(b)三氟醋酸,二氯甲烷,r.t.,1.5h;(c)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),三乙胺,二氯甲烷,r.t.,12h;(d)氢气,5%Pd-C,四氢呋喃,甲醇,r.t.,12h;(e)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),三乙胺,N,N-二甲基甲酰胺,r.t.,5h;(f)2N HCl,乙酸乙酯,r.t.,2h。(4)化合物SCI-6、SCI-8~SCI-13、SCI-15~SCI-17的合成路线:
将对氨基苄胺与氯甲酸苄酯反应得化合物14,化合物14与化合物1缩合得化合物15,化合物15经氢气还原脱除Cbz保护基得化合物16,化合物16与含羧基或酰氯或磺酰氯或羧酸活性酯的化合物17缩合得化合物18,化合物18在酸性条件下
脱除Boc保护基得到化合物SCI-6、SCI-8~SCI-13、SCI-15~SCI-17。
反应条件:(a)氯甲酸苄酯,三乙胺,二氯甲烷,0℃–r.t.,1h;(b)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),二氯甲烷,r.t.,12h;(c)氢气,5%Pd-C,四氢呋喃,甲醇,r.t.,2h;(d)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),三乙胺,N,N-二甲基甲酰胺,r.t.,5h;(e)三氟醋酸,二氯甲烷,r.t.,1.5h。
本发明技术方案的第三方面涉及以第一方面所述化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔黏膜、眼、肺和呼吸道、皮肤、引道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;润湿剂可以是水、乙醇、异丙醇等;黏合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯糖浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成份本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成份本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为了将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以像药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物或药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来说,本发明化合物的每天的合适剂量范围为0.001~150mg/kg体重,优选为0.1~100mg/kg体重,更优选为1~60mg/kg体重,最优选为2~30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其他治疗手段的给药方案。
本发明的化合物或组合物可以单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明技术方案的第四方面涉及第一方面所述化合物或组合物用于制备抗病毒药物的用途,及治疗由病毒感染引起的相关疾病的药物的用途。
所述的病毒包括非典型性肺炎病毒或严重急性呼吸系统综合征冠状病毒(Severeacute respiratory syndrome coronavirus,SARS-CoV)、严重急性呼吸系统综合征冠状病毒2或2019新型冠状病毒(SARS-CoV-2)、中东呼吸综合征冠状病毒(Middle Eastrespiratory syndrome coronavirus,MERS-CoV)、人冠状病毒OC43(Human coronavirusOC43)、人冠状病毒229E(Human coronavirus229E)、人冠状病毒NL63(Human coronavirusNL63)、人冠状病毒HKUl(Human coronavirus HKUl)、甲型流感病毒、乙型流感病毒、丙型流感病毒、甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、丁型肝炎病毒(HDV)、戊型肝炎病毒(HEV)、登革热病毒(DENV)、寨卡病毒(Zika)、马尔堡病毒(MBV)、埃博拉病毒(EBV),以及以上病毒的所有变异株。
所述由病毒感染引起的相关疾病包括:SARS-CoV-2引起的新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19)及其并发症,人冠状病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症,人流感病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症,甲型肝炎病毒引起的甲型肝炎及其并发症,乙型肝炎病毒引起的乙型肝炎及其并发症,丙型肝炎病毒引起的丙型肝炎及其并发症,丁型肝炎病毒引起的丁型肝炎及其并发症,戊型肝炎病毒引起的戊型肝炎及其并发症,登革热病毒引起的登革热及其并发症,寨卡病毒引起的感染及其并发症,马尔堡病毒、埃博拉病毒引起的出血热及其并发症。
本发明具有如下优点和有益效果:
本发明的化合物可高效地抑制SARS-CoV-2病毒,对GD108,Alpha(B.1.1.7),Beta(B.1.351),Delta(B.1.617.2),Omicron(B.1.1.529)等多种新冠病毒变异株均具有高抑制活性,EC50值小,体内模型中可有效抑制新冠病毒复制,且毒副作用低,在病毒感染性疾病治疗领域,尤其在新冠肺炎治疗领域有良好的应用前景。
附图说明
附图是用来提供对本发明的进一步阐述,并且构成说明书的一部分,与下面的具体实施方式一起用于解释本发明,但并不构成对本发明的限制;
图1 SCI-1、SCI-2、SCI-3抑制新冠病毒(GD108)的细胞显微成像
图2 SCI-4、SCI-5、SCI-6、SCI-7抑制新冠病毒(GD108)的细胞显微成像
图3 SCI-8、SCI-9、SCI-10、SCI-11抑制新冠病毒(GD108)的细胞显微成像
图4 SCI-12、SCI-13、SCI-14、SCI-15、SCI-16、SCI-17抑制新冠病毒(GD108)的细胞显微成像
图5 SCI-5、SCI-18抑制新冠病毒(GD108)的细胞显微成像
图6 SCI-5在不同浓度下抑制新冠病毒(GD108)的细胞显微成像
图7 SCI-5在不同浓度下抑制新冠病毒Alpha突变株的细胞显微成像
图8 SCI-5在不同浓度下抑制新冠病毒Beta突变株的细胞显微成像
图9 SCI-5在不同浓度下抑制新冠病毒Delta突变株的细胞显微成像
图10 SCI-5和瑞德西韦对新冠病毒不同变异株的抑制活性
图11 SCI-5和代谢产物M1、M2对新冠病毒(Delta)的抑制活性
图12 SCI-5对Vero-E6细胞的毒性
图13 SCI-5对金黄地鼠体重的影响
图14 SCI-5处理的金黄地鼠GD108病毒模型的肺病理切片
图15 SCI-5处理的金黄地鼠Delta病毒模型的肺病理切片
具体实施方式
(所述实施例用来说明本发明,而不是来限定本发明)
本发明的权利要求书特别陈述了本发明的新特征。在下文陈述了利用本发明原理的示例性实施方式。通过参考以下内容可以更好地理解本发明的特征和优点。
尽管本文描述了本申请的优选实施方式,但是这些实施方式仅作为示例提供。应该理解本文所述的本申请实施方式的变体也可用于实施本申请的技术方案。本领域普通技术人员应理解,可出现多种变体、变化和替换而不脱离本申请的范围。应理解本申请各个方面的保护范围由权利要求书决定,并且这些权利要求范围内的方法和结构以及其等价的方法和结构均在本申请权利要求书涵盖的范围之内。
实施例1:化合物SCI-1的合成
(1)(Z)-4-(2,3-二(叔丁氧羰基)胍基)苯甲酸(1)的合成
将对氨基苯甲酸(5.48g,40mmol)加入100mL甲醇中,剧烈搅拌下加入N,N′-二-Boc-1H-1-胍基吡唑(12.4g,40mmol),加毕,60℃加热搅拌过夜,析出大量白色固体,冷却至室温,抽滤,冷甲醇洗涤滤饼,干燥得白色固体13.0g,收率86%。1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),11.25(s,1H),10.17(s,1H),7.90(d,J=8.6Hz,2H),7.66(d,J=8.6Hz,2H),1.46(s,18H).MS m/z=380.2[M+H]+.
(2)N-(4-硝基苯乙基)-5-氧代吡咯烷-2-甲酰胺(2a)的合成
将2-(4-硝基苯)乙胺(284mg,2.2mmol),5-羧基吡咯烷酮(406mg,2.0mmol),EDCI(460mg,2.4mmol),DMAP(48.8mg,0.4mmol),三乙胺(606mg,6.0mmol)加入10mL二氯甲烷中,室温搅拌过夜,旋蒸除去溶剂,硅胶柱层析分离(PE:EA=1:1),得白色固体258mg,收率42.4%。1H NMR(400MHz,DMSO-d6)δ8.16(d,J=8.4Hz,2H),8.05(t,J=5.5Hz,1H),7.76(s,1H),7.50(d,J=8.5Hz,2H),3.91(dd,J=8.5,4.4Hz,1H),3.36(p,J=6.9Hz,2H),2.87(t,J=7.0Hz,2H),2.32–2.13(m,1H),2.08(td,J=9.6,6.5Hz,2H),1.82–1.63(m,1H).MS m/z=278.1[M+H]+.
(3)N-(4-氨基苯乙基)-5-氧代吡咯烷-2-甲酰胺(3a)的合成
将2a(200mg,0.72mmol),5%Pd-C(20mg)加入10mL甲醇中,氢气置换3次,室温搅拌4h,反应完毕后,硅藻过滤,浓缩滤液得灰白色固体175mg,收率98.3%。1H NMR(400MHz,DMSO-d6)δ8.01–7.92(m,1H),7.76(s,1H),6.84(d,J=8.2Hz,2H),6.49(d,J=8.2Hz,2H),4.89(s,2H),3.93(dd,J=8.2,4.1Hz,1H),3.18(d,J=7.5Hz,2H),2.53(s,2H),2.29–2.16(m,1H),2.14–1.99(m,2H),1.87–1.74(m,1H).MS m/z=248.1[M+H]+.
(4)(E)-N-(4-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺基)苯基)乙基)-5-氧代吡咯烷-2-甲酰胺(4a)的合成
将中间体1(126mg,0.33mmol),3a(75mg,0.3mmol),EDCI(70mg,0.36mmol),DMAP(7.0mg,0.06mmol),三乙胺(61mg,0.61mmol)加入10mL二氯甲烷中,室温搅拌过夜,旋蒸除去溶剂,硅胶柱层析分离(PE:EA=1:1),得白色固体86mg,收率46.6%。1H NMR(400MHz,CDCl3)δ11.60(s,1H),10.41(s,1H),8.72(s,1H),7.72(d,J=8.6Hz,2H),7.55(d,J=14.1Hz,4H),7.09(d,J=8.3Hz,3H),7.02–6.96(m,1H),4.00(dd,J=8.7,4.7Hz,1H),3.53–3.43(m,2H),2.78(t,J=6.6Hz,2H),2.43–2.03(m,4H),1.54(s,9H),1.48(s,9H).MS m/z=609.3[M+H]+.
(5)N-(4-(4-胍基苯甲酰胺基)苯乙基)-5-氧代吡咯烷-2-甲酰胺盐酸盐(SCI-1)的合成
将4a(50mg,0.082mmol)加入2mL二氯甲烷溶液中,搅拌下加入等体积的4N盐酸二氧六环溶液(2mL),室温搅拌6h,旋干溶剂,加入乙醚,抽滤,得白色固体24.0mg,收率71.6%。1H NMR(400MHz,Methanol-d4)δ8.05(d,J=8.4Hz,2H),7.62(d,J=8.3Hz,2H),7.42(d,J=8.4Hz,2H),7.24(d,J=8.3Hz,2H),4.18–4.04(m,1H),3.46(t,J=6.9Hz,2H),2.82(t,J=7.2Hz,2H),2.47–2.18(m,3H),2.03–1.86(m,1H).MS m/z=409.2[M+H]+.
实施例2:化合物SCI-2的合成
(1)N-(3-硝基苯乙基)-5-氧代吡咯烷-2-甲酰胺(2b)的合成
合成方法同化合物2a,白色固体,收率29.2%。1H NMR(400MHz,DMSO-d6)δ8.08(dd,J=4.3,2.2Hz,2H),8.03(t,J=5.7Hz,1H),7.75(s,1H),7.71–7.66(m,1H),7.59(dd,J=8.8,7.6Hz,1H),3.90(dd,J=8.6,4.4Hz,1H),3.39(dq,J=13.4,6.5Hz,2H),2.88(td,J=6.8,3.5Hz,2H),2.25–2.11(m,1H),2.10–2.01(m,2H),1.74–1.67(m,1H).MS m/z=278.1[M+H]+.
(2)N-(3-氨基苯乙基)-5-氧代吡咯烷-2-甲酰胺(3b)的合成
合成方法同化合物3a,白色固体,收率99.5%。1H NMR(400MHz,DMSO-d6)δ7.97(d,J=5.9Hz,1H),7.73(d,J=5.2Hz,1H),6.88(d,J=7.4Hz,1H),6.35(d,J=5.3Hz,2H),6.30(t,J=6.6Hz,1H),4.94(s,2H),3.91(d,J=7.7Hz,1H),3.19(q,J=7.0Hz,2H),2.51(s,2H),2.20–1.98(m,3H),1.79(dq,J=10.7,5.3,4.4Hz,1H).MS m/z=248.1[M+H]+.
(3)(E)-N-(3-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺基)苯乙基)-5-氧代吡咯烷-2-甲酰胺(4b)的合成
将中间体1(270mg,0.71mmol),3b(160mg,0.65mmol),EDCI(150mg,0.78mmol),DMAP(13.1mg,0.13mmol),三乙胺(131.3mg,1.3mmol)加入10mL二氯甲烷中,室温搅拌过夜,旋蒸除去溶剂,硅胶柱层析分离(PE:EA=1:1),得白色固体180mg,收率41.6%。1H NMR(400MHz,CDCl3)δ11.61(s,1H),10.44(s,1H),8.67(s,1H),7.78(d,J=8.6Hz,2H),7.61(d,J=27.8Hz,2H),7.49(d,J=53.1Hz,2H),7.27(s,2H),6.96(d,J=6.8Hz,2H),4.05(dd,J=9.2,3.9Hz,1H),3.73–3.63(m,1H),3.30(dd,J=13.0,7.1Hz,1H),2.80(q,J=5.9Hz,2H),2.48–2.38(m,1H),2.25(dt,J=16.5,10.3Hz,1H),2.13(dq,J=12.6,4.6Hz,1H),1.55(s,9H),1.49(s,9H).MS m/z=609.3[M+H]+.
(4)N-(3-(4-胍基苯甲酰胺基)苯乙基)-5-氧代吡咯烷-2-甲酰胺盐酸盐(SCI-2)的合成
合成方法同SCI-1,白色固体,收率89.5%。1H NMR(400MHz,CD3OD)δ8.04(d,J=8.0Hz,2H),7.61(s,1H),7.49(d,J=7.4Hz,1H),7.41(d,J=8.0Hz,2H),7.30(t,J=7.7Hz,1H),7.08–6.99(m,1H),4.14(s,1H),3.48(t,J=6.7Hz,2H),2.85(t,J=6.6Hz,2H),2.45–2.19(m,3H),2.03–1.90(m,1H).MS m/z=409.2[M+H]+.
实施例3:化合物SCI-3的合成
(1)4-(2-((苄氧羰基)氨基)乙基)苯基(Z)-4-(2,3-双(叔丁氧羰基)胍基)苯甲酸酯(5)的合成
将1(1.1g,3mmol),苄基N-[2-(4-羟基苯基)乙基]氨基甲酸酯(895mg,3.3mmol),EDCI(682.4mg,3.6mmol),DMAP(72.0mg,0.6mmol)加入20mL四氢呋喃中,室温搅拌4h,旋蒸除去溶剂,硅胶柱层析分离(PE:EA=1:1),得白色固体1.4g,收率76.4%。1H NMR(400MHz,CDCl3)δ11.59(s,1H),10.60(s,1H),8.20–8.09(m,2H),7.82–7.72(m,2H),7.39–7.25(m,5H),7.25–7.15(m,2H),7.15–7.05(m,2H),5.07(s,2H),4.75(s,1H),3.50–3.35(m,2H),2.87–2.71(m,2H),1.51(s,18H).MS m/z=633.3[M+H]+.
(2)4-(2-氨基乙基)苯基(Z)-4-(2,3-双(叔丁氧羰基)胍基)苯甲酸酯(6)的合成
将5(500mg,0.79mmol),5%Pd-C(50mg)加入10mL甲醇中,氢气置换3次,室温搅拌4h,反应完毕后,硅藻过滤,浓缩滤液得灰白色固体377mg,收率95.6%。1H NMR(400MHz,CDCl3)δ10.61(s,1H),8.14(d,J=8.9Hz,2H),7.79(d,J=8.9Hz,2H),7.23(d,J=6.9Hz,2H),7.13(d,J=6.9Hz,2H),3.05–2.93(m,2H),2.77(t,J=6.8Hz,2H),1.52(s,18H).MS m/z=499.2[M+H]+.
(3)4-(2-(5-氧代吡咯烷-2-甲酰胺)乙基)苯基(Z)-4-(2,3-双(叔丁氧羰基)胍基)苯甲酸酯(7)的合成
将6(249mg,0.5mmol)、5-羧基吡咯烷酮(65mg,0.5mmol)、二异丙基乙胺(129mg,1mmol)加入无水DMF中,室温搅拌下加入HATU(228mg,0.6mmol),继续搅拌6h,TLC监测反应完全。加水,PE+EA混合溶剂(VPE:VEA=2:1)萃取3次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干溶剂,柱层析纯化得白色固体232mg,收率76.1%。1H NMR(400MHz,CDCl3)δ11.58(s,1H),10.61(s,1H),8.13(d,J=8.5Hz,2H),7.79(d,J=8.5Hz,2H),7.21(d,J=8.1Hz,2H),7.11(d,J=8.2Hz,2H),6.74(s,1H),6.58(s,1H),4.13–4.05(m,1H),3.59–3.45(m,2H),2.85(t,J=6.8Hz,2H),2.50–2.38(m,1H),2.38–2.20(m,2H),2.15–2.05(m,1H),1.52(s,18H).MS m/z=610.3[M+H]+.
(4)4-(2-(5-氧代吡咯烷-2-甲酰胺)乙基)苯基4-胍基苯甲酸酯(SCI-3)的合成
将7(50mg,0.082mmol)加入2mL二氯甲烷溶液中,搅拌下加入等体积的4N盐酸二氧六环溶液(2mL),室温搅拌6h,旋干溶剂,加入乙醚,抽滤,得白色固体28mg,收率82.8%。1HNMR(400MHz,CD3OD)δ8.17(d,J=8.5Hz,2H),7.38(d,J=8.5Hz,2H),7.24(d,J=8.2Hz,2H),7.07(d,J=8.2Hz,2H),4.09–3.98(m,1H),3.69–3.64(m,2H),3.52–3.47(m,2H),3.45–3.37(m,2H),2.79(t,J=7.1Hz,2H).MS m/z=410.2[M+H]+.
实施例4:化合物SCI-4的合成
(1)(S)-4-((叔丁氧基羰基)氨基)-5-((4-硝基苯乙基)氨基)-5-氧代戊酸甲酯(2c)的合成
将N-Boc-D-谷氨酸-5-甲酯(775mg,3mmol),2-(4-硝基苯)乙胺(662mg,3.3mmol),EDCI(682.4mg,3.6mmol),DMAP(72.0mg,0.6mmol),三乙胺(900mg,9.0mmol)加入20mL二氯甲烷中,室温搅拌4h,旋蒸除去溶剂,硅胶柱层析分离(PE:EA=1:1),得白色固体320mg,收率26.4%。1H NMR(400MHz,DMSO-d6)δ8.12(d,J=8.7Hz,2H),7.89(t,J=5.6Hz,1H),7.49(d,J=8.7Hz,2H),6.90–6.77(m,1H),3.88–3.79(m,1H),3.55(s,3H),3.41(dq,J=13.5,6.7Hz,2H),2.86(t,J=6.8Hz,2H),2.16(t,J=7.9Hz,2H),1.81–1.70(m,1H),1.66–1.60(m,1H),1.36(s,9H).MS m/z=410.2[M+H]+.
(2)(S)-5-((4-氨基苯乙基)氨基)-4-((叔丁氧基羰基)氨基)-5-氧代戊酸甲酯(3c)的合成
合成方法同化合物3a,黄色油状物,收率98.0%。1H NMR(400MHz,CDCl3)δ6.96(d,J=8.4Hz,2H),6.62(d,J=8.3Hz,2H),6.29(s,1H),5.27(d,J=8.1Hz,1H),4.13–3.98(m,1H),3.67(s,3H),3.52–3.32(m,2H),2.68(t,J=7.1Hz,2H),2.43(dt,J=16.8,7.3Hz,1H),2.32(dt,J=16.7,7.0Hz,1H),2.07(dtd,J=14.5,7.3,5.3Hz,1H),1.85(ddt,J=14.2,8.2,7.0Hz,1H),1.42(s,9H).MS m/z=380.2[M+H]+.
(4)(S,Z)-5-((4-(4-(2,3-双(叔丁氧基羰基)胍基)苯甲酰氨基)苯乙基)氨基)-4-((叔丁氧羰基)氨基)-5-氧代戊酸甲酯(4c)的合成
将中间体1(2.3g,6.2mmol),3c(2.0mg,5.2mmol),EDCI(1.5g,7.8mmol),DMAP(126.5mg,1.0mmol),三乙胺(1.57g,15.5mmol)加入50mL二氯甲烷中,室温搅拌过夜,旋蒸除去溶剂,硅胶柱层析分离(PE:EA=1:1),得白色固体3.3g,收率86.0%。1H NMR(400MHz,CDCl3)δ11.61(s,1H),10.51(s,1H),8.17(s,1H),7.80(d,J=8.7Hz,2H),7.66(d,J=8.6Hz,2H),7.58(d,J=8.4Hz,2H),7.16(d,J=8.4Hz,2H),6.40–6.34(m,1H),5.31–5.24(m,1H),4.10(dd,J=11.8,4.6Hz,1H),3.66(s,3H),3.49(dq,J=9.3,6.9Hz,2H),2.78(t,J=6.9Hz,1H),2.46–2.40(m,1H),2.35–2.3(m,1H),2.12–2.04(m,1H),1.90–1.82(m,1H),1.54(s,9H),1.50(s,9H),1.42(s,9H).MS m/z=741.4[M+H]+.
(5)(S)-4-氨基-5-((4-(4-胍基苯甲酰氨基)苯乙基)氨基)-5-氧代戊酸三氟醋酸盐(SCI-4)的合成
将4c(74mg,0.1mmol)加入2mL甲醇和水的混合溶液(V甲醇:V水=2:1)中,搅拌下加入一水合氢氧化锂(12mg,0.31mmol)的水溶液,室温搅拌1h,旋蒸除去大部分溶剂,加水,用稀盐酸(1N)调节pH至5-6,乙酸乙酯(50mL×3)萃取,合并有机层,干燥,浓缩,得无色油状物40mg,收率55.1%。
将上述产物(40mg)溶于3mL二氯甲烷溶液中,缓慢滴加1.5mL三氟醋酸溶液,室温搅拌过夜,旋干溶剂,加入10mL乙醚,抽滤,得白色固体27mg,收率98.0%。1H NMR(400MHz,CD3OD)δ8.03(d,J=8.5Hz,2H),7.63(d,J=8.5Hz,2H),7.42(d,J=8.6Hz,2H),7.27(d,J=8.5Hz,2H),3.85(t,J=6.3Hz,1H),3.62–3.58(m,1H),3.48–3.42(m,1H),2.84(p,J=6.7Hz,2H),2.42–2.33(m,2H),2.08–2.03(m,2H),1.18(t,J=7.0Hz,2H).MS m/z=427.2[M+H]+.
实施例5:化合物SCI-5的合成
(1)2-(4-((叔丁氧基羰基)氨基)苯基)乙酸苄酯(8)的合成
将4-(Boc-氨基)苯乙酸(5.0g,19.9mmol),碳酸铯(7.78g,13.88mmol)加入无水DMF中,室温搅拌20min,逐滴加入溴苄(2.6ml,21.89mmol),室温继续搅拌1h,TLC监测反应完全。加水,析出大量固体,抽滤得粗品。石油醚打浆1h得白色结晶型固体5.53g,收率81.1%。1H NMR(500MHz,DMSO-d6)δ9.32(s,1H),7.37(m,7H),7.15(d,J=8.1Hz,2H),5.11(s,2H),3.65(s,2H),1.48(s,9H).MS m/z=342.2[M+H]+.
(2)2-(4-氨基苯基)乙酸苄酯三氟醋酸盐(9)的合成
将中间体8(5.53g,16.2mmol)溶于8mL无水二氯甲烷中,室温下逐滴加入等体积(8mL)的三氟醋酸,室温搅拌1.5h,TLC监测(PE:EA=2:1)无原料剩余,旋蒸除去有机溶剂,加入乙醚,抽滤,得白色固体3.9g,收率100%,未经纯化直接投入下一步。MS m/z=242.1[M+H]+.
(3)(Z)-2-(4-(4-(2,3-二(叔丁氧基羰基)胍基)苯甲酰胺基)苯基)乙酸苄酯(10)的合成
中间体1(1.21g,3.2mmol)、中间体9(1.5g,3.2mmol)、DIPEA(4.13ml,32mmol)加入无水DMF中,室温搅拌下加入HATU(1.28g,3.36mmol),继续搅拌2h,TLC监测反应完全。加水,PE+EA混合溶剂(VPE:VEA=2:1)萃取3次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干溶剂得白色固体1.67g,收率86.5%,未经纯化直接投入下一步。1H NMR(500MHz,DMSO-d6)δ11.32(s,1H),10.17(s,2H),8.01–7.89(m,2H),7.83–7.64(m,4H),7.40–7.31(m,5H),7.29–7.21(m,2H),5.11(s,2H),3.70(s,2H),1.52(s,9H),1.47–1.36(s,9H).MS m/z=603.3[M+H]+.
(4)(Z)-2-(4-(4-(2,3-二(叔丁氧基羰基)胍基)苯甲酰胺基)苯基)乙酸(11)的合成
将中间体10(1.65g,2.74mmol)溶于无水甲醇中,加入少量无水THF助溶,搅拌下加入165mg Pd-C(10%W),H2置换3次,室温搅拌过夜,TLC监测反应完,。硅藻土过滤除去Pd-C,旋干溶剂,柱层析纯化(EA=1%-3%)得白色固体1.04g,收率74.3%。1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.16(s,2H),7.95(d,J=8.8Hz,2H),7.70(d,J=8.6Hz,4H),7.23(d,J=8.8Hz,2H),3.53(s,2H),1.47(s,18H).MS m/z=513.2[M+H]+.
(5)(2R,3S,4R,5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-4-羟基-2-(羟甲基)2-(4-(4-((Z)-2,3-二(叔丁氧基羰基)胍基)苯甲酰氨基)苯基)乙酸四氢呋喃-3-基(13a)的合成
将中间体11(1.04g,2.0mmol),EDCI(0.585g,3mmol),DMAP(0.05g,0.4mmol)加入无水DMF中,逐滴加入三乙胺(0.85mL,6.0mmol),室温搅拌均匀后,加入中间体12a(0.621g,2.1mmol),维持室温继续反应5h,TLC监测反应基本完全,加水,PE+EA混合溶剂(VPE:VEA=2:1)萃取3次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干溶剂得淡黄色固体(粗品),柱层析纯化[MeOH:(VDCM+VEA=1:1)=2%-3%]得白色固体364mg,收率22.8%。1H NMR(400MHz,CD3OD)δ7.93(d,J=8.9Hz,2H),7.84(s,1H),7.75(d,J=8.3Hz,2H),7.66(d,J=8.6Hz,2H),7.39(d,J=8.7Hz,2H),7.01(d,J=4.6Hz,1H),6.93(d,J=4.6Hz,1H),5.40(dd,J=5.9,3.0Hz,1H),5.20(d,J=5.9Hz,1H),4.39(d,J=3.0Hz,1H),3.85–3.76(m,4H),1.54(d,J=26.4Hz,18H).MS m/z=786.3[M+H]+.
(6)(2R,3S,4R,5R)-5-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-4-羟基-2-(羟甲基)2-(4-(4-胍基苯甲酰氨基)苯基)乙酸四氢呋喃-3-基酯盐酸盐(SCI-5)的合成
将中间体13a(1.2g,1.5mmol)溶于10mL无水EA中,室温下逐滴加入4MHCl的1,4-二氧六环溶液,析出大量固体,继续加入4M HCl的1,4-二氧六环溶液,固体溶解,维持室温继续搅拌24h,重新析出白色固体,TLC监测(PE:EA=2:1)无原料剩余,抽滤,EA洗涤滤饼,得目标产物盐酸盐粗品。经制备液相分离,收集产物,旋蒸除去大部分水,冻干得白色粉末状固体,加入乙腈+THF=2:1,70℃加热搅拌1h,趁热过滤,热乙腈洗涤滤饼,干燥得白色固体0.6g,收率67.1%。1H NMR(400MHz,CD3OD)δ8.04(d,J=8.6Hz,2H),7.85(s,1H),7.67(d,J=8.6Hz,2H),7.51–7.33(m,4H),7.01(d,J=4.6Hz,1H),6.95(d,J=4.7Hz,1H),5.40(dd,J=5.9,2.9Hz,1H),5.19(d,J=5.9Hz,1H),4.38(d,J=3.0Hz,1H),3.86–3.70(m,4H).MS m/z=586.2[M+H]+.
实施例6:化合物SCI-6的合成
(1)(4-氨基苄基)氨基甲酸苄酯(14)的合成
将4-氨基苄胺(1.0g,8.2mmol)和三乙胺(1.24g,7.3mmol)溶于40mL二氯甲烷溶液中,0℃下缓慢加入氯甲酸苄酯(736.7mg,7.3mmol),加毕,升至室温继续搅拌1h,将反应液加入到水(120mL)中,乙酸乙酯萃取,分出有机层,干燥,浓缩,得白色固体0.9g,收率43.1%,不经纯化直接投下一步。MS m/z=257.1[M+H]+.
(2)(E)-(4-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺基)苄基)氨基甲酸苄酯(15)的合成
将1(1.33g,3.5mmol),EDCI(808.3mg,4.2mmol),DMAP(43mg,0.35mmol)加入30mL二氯甲烷溶液中,搅拌下加入14(900mg,3.5mmol),室温搅拌12h,将反应液加入到水(120mL)中,二氯甲烷萃取,分出有机层,干燥,浓缩,得白色固体1.7g,收率92.1%,不经纯化直接投下一步。MS m/z=618.3[M+H]+.
(3)(E)-N-(4-(氨基甲基)苯基)-4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺(16)的合成
将15(1.7g,2.7mmol)加入20mL四氢呋喃和甲醇的混合溶液中(四氢呋喃4mL,甲醇16mL),搅拌下加入5%的钯碳(345mg),室温搅拌2h,TLC监测反应完成,硅藻土过滤除去钯碳,旋干滤液,加入乙酸乙酯(5mL),析出大量固体,抽滤,石油醚洗涤滤饼,干燥得灰白色固体1.03g,收率77.5%。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),7.91(d,J=8.5Hz,2H),7.66(d,J=7.8Hz,4H),7.26(d,J=8.3Hz,2H),3.66(s,2H),1.43(s,18H).MS m/z=484.2[M+H]+.
(4)(E)-N-(4-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺基)苄基)-6-氟-3-羟基吡嗪-2-甲酰胺(18a)的合成
将16(96mg,0.2mmol),17a(38mg,0.24mmol),EDCI(58mg,0.3mmol),DMAP(5mg,0.04mmol)加入无水DMF中,逐滴加入三乙胺(0.85mL,6.0mmol),室温反应5h,TLC监测反应基本完全,加水,PE+EA混合溶剂(VPE:VEA=2:1)萃取3次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干溶剂,柱层析纯化得白色固体68mg,收率56.0%。1H NMR(500MHz,CDCl3)δ12.69(s,1H),11.62(s,1H),10.56(s,1H),8.32(d,J=60.6Hz,2H),8.09–7.54(m,9H),4.61(s,2H),2.97(s,9H),2.87(s,9H).MS m/z=624.3[M+H]+.
(5)6-氟-N-(4-(4-胍基苯甲酰氨基)苄基)-3-羟基吡嗪-2-甲酰胺三氟醋酸盐(SCI-6)的合成
将18a(42.5mg,0.068mmol)溶于2mL无水二氯甲烷中,室温下逐滴加入等体积(2mL)的三氟醋酸,室温搅拌1.5h,TLC监测无原料剩余,旋蒸除去有机溶剂,加入乙醚,析出大量白色固体,抽滤,得化合物,白色固体24.8mg,收率86.1%。1H NMR(400MHz,CD3OD)δ8.21(s,1H),8.04(d,J=8.5Hz,2H),7.65(d,J=6.7Hz,2H),7.51–7.30(m,4H),4.58(s,2H).MSm/z=424.1[M+H]+.
实施例7:化合物SCI-7的合成
(1)(R,E)-4-(2,3-二(叔丁氧羰基)胍基)-N-(4-(2-((3-甲基-1-(4,4,5,5-四甲基-1,3,2-二氧代硼烷)-2-基)丁基)氨基)-2-氧代乙基)苯基)苯甲酰胺(13b)合成
将11(51mg,0.1mmol)、12b(25g,0.1mmol)、三乙胺(20mg,0.2mmol)加入无水DMF中,室温搅拌下加入HATU(46mg,0.12mmol),继续搅拌6h,TLC监测反应完全。加水,PE+EA混合溶剂(VPE:VEA=2:1)萃取3次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,旋干溶剂,柱层析纯化得白色固体61mg,收率86.2%。1H NMR(500MHz,CDCl3)δ11.61(s,1H),10.48(s,1H),8.57(s,1H),7.77(d,J=8.4Hz,2H),7.67(d,J=8.2Hz,2H),7.60(d,J=8.4Hz,2H),7.17(d,J=8.2Hz,2H),6.75(s,1H),4.30(t,J=6.7Hz,1H),3.64(s,2H),1.55(s,9H),1.50(s,9H),1.38–1.34(m,3H),1.22(s,12H),0.84(dd,J=11.6,6.6Hz,6H).MS m/z=708.4[M+H]+.
(2)(R)-(1-(2-(4-(4-胍基苯甲酰胺基)苯基)乙酰氨基)-3-甲基丁基)硼酸三氟醋酸盐(SCI-7)的合成
合成方法同SCI-6,白色固体,收率68.8%。1H NMR(500MHz,CD3OD)δ8.05(s,2H),7.69(s,2H),7.38(d,J=41.4Hz,4H),3.76(s,2H),2.59(s,1H),1.68(s,1H),1.31(s,2H),0.92(s,6H).MS m/z=426.2[M+H]+.
实施例8:化合物SCI-8的合成
(1)2,5-二氧代吡咯啉-1-基(噻唑-5-甲基)碳酸酯(17b)的合成
将5-羟甲基噻唑(46mg,0.4mmol)和三乙胺(81mg,0.8mmol)加入5mL乙腈溶液中,搅拌下加入DSC(153mg,0.6mmol),室温反应1h,旋蒸除去溶剂,得粗产物86mg,收率84.0%,不经纯化直接投下一步。
(2)噻唑-5-基甲基(E)-(4-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰氨基)苄基)氨基甲酸酯(18b)的合成
将17b(34mg,0.13mmol),三乙胺(27mg,0.27mmol)和16(70mg,0.15mmol)加入二氯甲烷溶液中,室温搅拌5h,旋干溶剂,柱层析纯化得白色固体61mg,收率86.2%。1H NMR(400MHz,CDCl3)δ11.61(s,1H),10.48(s,1H),8.79(s,1H),8.25(s,1H),7.86(s,1H),7.76(d,J=8.6Hz,2H),7.63(dd,J=8.4,2.8Hz,4H),7.24(d,J=8.2Hz,2H),5.33(s,2H),4.41–4.26(m,2H),1.54(s,9H),1.49(s,9H).MS m/z=625.2[M+H]+.
(3)噻唑-5-基甲基(4-(4-胍基苯甲酰氨基)苄基)氨基甲酸酯三氟醋酸盐(SCI-8)的合成
合成方法同SCI-6,白色固体,收率92.4%。1H NMR(500MHz,CD3OD)δ8.99(s,1H),8.03(d,J=8.3Hz,2H),7.90(s,1H),7.64(d,J=8.1Hz,2H),7.42(d,J=8.4Hz,2H),7.29(d,J=8.0Hz,2H),5.35(s,2H),4.29(s,2H).MS m/z=425.1[M+H]+.
实施例9:化合物SCI-9的合成
(1)4-硝基苯基((2-异丙基噻唑-4-基)甲基)甲胺碳酸酯(17c)的合成
将N-甲基-2-异丙基-4-噻唑甲胺二盐酸盐(121mg,0.5mmol)和三乙胺(101mg,1.0mmol)加入5mL二氯甲烷溶液中,搅拌下加入对硝基苯基氯甲酸酯(121mg,0.6mmol),室温反应3h,旋蒸除去溶剂,柱层析纯化得白色固体121mg,收率72.8%。1H NMR(400MHz,CDCl3)δ8.27–8.11(m,2H),7.30(dd,J=15.1,9.0Hz,2H),7.03(d,J=29.8Hz,1H),4.66(d,J=28.1Hz,2H),3.38–3.30(m,1H),3.14(d,J=38.3Hz,3H),1.40(s,3H),1.39(s,3H).MSm/z=336.1[M+H]+.
(2)(E)-4-(2,3-二(叔丁氧羰基)胍基)-N-(4-((3-((2-异丙基噻唑-4-基)甲基)-3-甲基脲基)甲基)苯基)苯甲酰胺(18c)的合成
将17c(44mg,0.13mmol),三乙胺(10mg,0.39mmol)和16(63mg,0.13mmol)加入DMF溶液中,80℃加热搅拌12h,旋干溶剂,柱层析纯化得白色固体36mg,收率40.4%。1H NMR(400MHz,CD3OD)δ7.90(d,J=8.3Hz,2H),7.72(d,J=8.2Hz,2H),7.61(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),7.10(s,1H),4.53(s,2H),4.35(s,2H),2.95(d,J=2.8Hz,3H),1.51(s,18H),1.32–1.28(m,7H).MS m/z=680.3[M+H]+.
(3)4-胍基-N-(4-((3-((2-异丙基噻唑-4-基)甲基)-3-甲基脲基)甲基)苯基)苯甲酰胺三氟醋酸盐酸盐(SCI-9)的合成
合成方法同SCI-6,白色固体,收率86.0%。1H NMR(500MHz,CD3OD)δ8.04(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),7.41(d,J=8.5Hz,2H),7.32(d,J=8.3Hz,2H),7.13(s,1H),4.56(s,2H),4.38(s,2H),2.99(s,3H),1.36(s,3H),1.35(s,3H).MS m/z=480.2[M+H]+.
实施例10:化合物SCI-10的合成
(1)(R)-4-硝基苯基(四氢呋喃-3-基)碳酸酯(17d)的合成
将(R)-(-)-3-羟基四氢呋喃(26mg,0.3mmol)和三乙胺(61mg,0.6mmol)加入5mL二氯甲烷溶液中,搅拌下加入对硝基苯基氯甲酸酯(80mg,0.4mmol),室温反应3h,旋蒸除去溶剂,柱层析纯化得白色固体26mg,收率34.3%。1H NMR(400MHz,Chloroform-d)δ8.28(d,J=9.2Hz,2H),7.38(d,J=9.2Hz,2H),5.36–5.34(m,1H),4.06–3.85(m,4H),2.29–2.20(m,2H).MS m/z=254.1[M+H]+.
(2)(R)-四氢呋喃-3-基(E)-(4-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺基)苄基)氨基甲酸酯(18d)的合成
将上述产物17d(26mg,0.1mmol),三乙胺(30mg,0.3mmol)和16(48mg,0.1mmol)加入二氯甲烷溶液中,室温搅拌12h,饱和食盐水洗涤,无水硫酸钠干燥,旋干溶剂,得白色固体44mg,收率73.6%,不经纯化直接投下一步。MS m/z=598.3[M+H]+.
(3)(R)-四氢呋喃-3-基(4-(4-胍基苯甲酰氨基)苄基)氨基甲酸酯三氟醋酸盐(SCI-10)的合成
合成方法同SCI-6,白色固体,收率92.8%。1H NMR(500MHz,CD3OD)δ8.03(d,J=8.2Hz,2H),7.73–7.59(m,2H),7.42(d,J=8.1Hz,2H),7.30(d,J=7.9Hz,2H),5.21(s,1H),4.27(s,2H),3.84(dd,J=31.5,11.3Hz,4H),2.18(d,J=21.2Hz,1H),2.02(s,1H).MS m/z=398.2[M+H]+.
实施例11:化合物SCI-11的合成
(1)(E)-4-(2,3-二(叔丁氧羰基)胍基)-N-(4-(((5-(三氟甲基)吡啶)-2-磺酰胺基)甲基)苯基)苯甲酰胺(18e)的合成
将16(33.8mg,0.07mmol),三乙胺(21mg,0.21mmol)和17e(20mg,0.08mmol)加入二氯甲烷溶液中,室温搅拌2h,饱和食盐水洗涤,无水硫酸钠干燥,旋干溶剂,得白色固体24mg,收率49.5%,不经纯化直接投下一步。MS m/z=693.2[M+H]+.
(2)4-胍基-N-(4-(((5-(三氟甲基)吡啶)-2-磺胺基)甲基)苯基)苯甲酰胺三氟醋酸盐(SCI-11)的合成
合成方法同SCI-6,白色固体,收率88.9%。1H NMR(500MHz,CD3OD)δ8.91(s,1H),8.34–8.15(m,1H),8.07–7.92(m,3H),7.52(d,J=7.1Hz,2H),7.42(d,J=7.9Hz,2H),7.20(d,J=7.1Hz,2H),4.28(s,2H).MS m/z=493.1[M+H]+.
实施例12:化合物SCI-12的合成
(1)(S,E)-4-(2,3-二(叔丁氧羰基)胍基)-N-(4-((3-甲基-2-(2-氧代四氢嘧啶-1(2H)-基)丁酰胺基)甲基)苯基)苯甲酰胺(18f)的合成
将17f(25mg,0.06mmol)、三乙胺(18.8mg,0.18mmol)和HATU(38mg,0.1mmol)加入无水二氯甲烷溶液中,室温搅拌下加入16(30mg,0.1mmol),继续搅拌4h,TLC监测反应完全。旋干溶剂,柱层析纯化得白色固体25mg,收率60.5%。1H NMR(400MHz,CDCl3)δ11.62(s,1H),7.94(s,1H),7.82(d,J=8.6Hz,2H),7.71(d,J=8.4Hz,2H),7.62–7.55(m,2H),7.22(d,J=8.3Hz,2H),4.52–4.21(m,2H),3.39–3.30(m,1H),3.25(t,J=5.8Hz,3H),2.32(dt,J=12.3,6.5Hz,1H),1.88(q,J=5.9Hz,2H),1.81(q,J=6.0Hz,1H),1.54(s,9H),1.50(s,9H),0.96(d,J=6.5Hz,3H),0.89(d,J=6.7Hz,3H).MS m/z=666.4[M+H]+.
(2)(S)-4-胍基-N-(4-((3-甲基-2-(2-氧代四氢嘧啶-1(2H)-基)丁酰胺基)甲基)苯基)苯甲酰胺三氟醋酸盐(SCI-12)的合成
合成方法同SCI-6,白色固体,收率86.4%。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),10.03(s,1H),8.29(d,J=6.2Hz,1H),8.00(d,J=8.1Hz,2H),7.62(s,6H),7.33(d,J=8.1Hz,2H),7.16(d,J=8.2Hz,2H),6.29(s,1H),4.41(d,J=11.0Hz,1H),4.16(dq,J=20.9,7.5,5.6Hz,2H),3.99(d,J=7.2Hz,1H),3.35(s,1H),3.05(s,3H),1.69(s,2H),0.78(dd,J=10.0,6.4Hz,6H).MS m/z=466.2[M+H]+.
实施例13:化合物SCI-13的合成
(1)(E)-N-(4-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺基)苄基)-5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-甲酰胺(18g)的合成
将16(22.5mg,0.21mmol)溶于5mL无水THF中,冰浴下缓慢加入17g(14.3mg,0.07mmol),室温下搅拌4h,加水,乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,旋蒸除去溶剂,得白色固体17.5mg,收率45.2%,不经纯化直接投下一步。MS m/z=640.2[M+H]+.
(2)(E)-N-(4-(4-胍基)苯甲酰胺基)苄基)-5-氟-2,4-二氧代-3,4-二氢嘧啶-1(2H)-甲酰胺三氟醋酸盐(SCI-13)的合成
合成方法同SCI-6,白色固体,收率89.2%。1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),10.22(s,1H),10.04(s,1H),9.50(t,J=5.9Hz,1H),8.37(d,J=7.5Hz,1H),8.11–7.92(m,2H),7.70(d,J=8.6Hz,6H),7.44–7.16(m,4H),4.43(d,J=5.9Hz,2H).MS m/z=440.1[M+H]+.
实施例14:化合物SCI-14的合成
(1)4-((E)-2,3-二(叔丁氧羰基)胍基)-N-(4-(2-(((1S,2R)-2-羟基-2,3-二氢-1H-茚-1-基)氨基)-2-氧代乙基)苯基)苯甲酰胺(13c)的合成
将12c(15mg,0.1mmol)、三乙胺(20mg,0.2mmol)和HATU(46mg,0.12mmol)加入无水二氯甲烷溶液中,室温搅拌下加入11(51mg,0.1mmol),继续搅拌4h,TLC监测反应完全。旋干溶剂,柱层析纯化得白色固体56mg,收率87.0%。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.41(s,1H),7.82(s,2H),7.63(d,J=8.4Hz,2H),7.54(s,2H),7.28(s,1H),7.20(d,J=10.4Hz,4H),6.28(d,J=11.6Hz,1H),5.40–5.32(m,1H),4.58(s,1H),3.65(s,2H),3.12(dd,J=16.4,5.1Hz,1H),2.88(s,1H),1.56(s,9H),1.47(s,10H).MS m/z=644.3[M+H]+.
(2)4-胍基-N-(4-(2-(((1S,2R)-2-羟基-2,3-二氢-1H-茚-1-基)氨基)-2-氧代乙基)苯基)苯甲酰胺三氟醋酸盐(SCI-14)的合成
合成方法同SCI-6,白色固体,收率78.8%。1H NMR(400MHz,CD3OD)δ8.12–7.94(m,2H),7.65(dd,J=8.4,1.5Hz,2H),7.38(tt,J=6.4,1.5Hz,4H),7.25–7.11(m,4H),5.28(d,J=5.2Hz,1H),4.53(ddt,J=5.2,3.4,1.8Hz,1H),3.66(d,J=6.5Hz,2H),3.46(qd,J=7.0,1.4Hz,2H).MS m/z=444.2[M+H]+.
实施例15:化合物SCI-15的合成
(1)2,5-二氧代吡咯啉-1-基((3S,3aR,6aS)-六氢呋喃[2,3-b]并呋喃-3基)碳酸酯(17h)的合成
将(3S,3aR,6aS)-六氢呋喃[2,3-b]呋喃-3-醇(100mg,0.77mmol)和三乙胺(233mg,2.3mmol)加入5mL二氯甲烷溶液中,搅拌下加入N,N'-二琥珀酰亚胺基碳酸酯(295mg,1.15mmol),室温反应过夜,旋蒸除去溶剂,柱层析纯化得黄色固体160.3mg,收率77.1%。1H NMR(500MHz,CDCl3)δ5.78(d,J=5.2Hz,1H),5.28(dt,J=8.2,6.1Hz,1H),4.15(dd,J=10.2,6.2Hz,1H),4.06(td,J=8.4,2.4Hz,1H),3.98(dd,J=10.1,6.0Hz,2H),3.16(tdd,J=7.7,5.0,2.2Hz,1H),2.88(s,4H),2.20–2.16(m,1H),2.07–1.96(m,1H).MS m/z=272.1[M+H]+.
(2)(3S,3aR,6aS)-六氢呋喃[2,3-b]呋喃-3-基(4-(4-((E)-2,3-二(叔丁氧羰基)胍基)苯甲酰氨基)苄基)氨基甲酸酯(18h)的合成
将16(60mg,0.12mmol),17h(40.4mg,0.15mmol)和三乙胺(62uL,0.36mmol)加入3mL二氯甲烷溶液中,室温反应6h,饱和食盐水洗涤,无水硫酸钠干燥,旋蒸除去溶剂,得淡黄色固体70.1mg,收率88.3%,不经纯化直接投下一步。MS m/z=640.3[M+H]+.
(3)(3S,3aR,6aS)-六氢呋喃[2,3-b]呋喃-3-基(4-(4-胍基苯甲酰氨基)苄基)氨基甲酸酯三氟醋酸盐(SCI-15)的合成
合成方法同SCI-6,黄色固体,收率82.0%。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),10.08(s,1H),8.00(d,J=8.2Hz,2H),7.85(t,J=6.2Hz,1H),7.67(d,J=8.5Hz,6H),7.33(d,J=8.3Hz,2H),7.20(d,J=8.2Hz,2H),5.55(d,J=5.2Hz,1H),4.99(q,J=6.7Hz,1H),4.13(d,J=6.2Hz,2H),3.89(dd,J=9.4,6.2Hz,1H),3.85–3.78(m,1H),3.73(dt,J=14.6,7.1Hz,1H),3.57(dd,J=9.4,6.2Hz,1H),3.00–2.90(m,1H),1.93–1.86(m,1H),1.73(p,J=9.7Hz,1H).MS m/z=440.2[M+H]+.
实施例16:化合物SCI-16的合成
(1)5-甲基-1,3,4-噁二唑-2-甲酰氯(17i)的合成
将5-甲基-1,3,4-恶二唑-2-羧酸钾(100mg,0.6mmol),DMF(0.1mL)加入3mL乙腈中,冰浴下缓慢滴加草酰氯(56uL,0.66mmol),加毕,室温搅拌1h,旋干溶剂,得粗产物,直接投入下一步。
(2)(E)-N-(4-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺基)苄基)-5-甲基-1,3,4-恶二唑-2-甲酰胺(18i)的合成
将16(30mg,0.06mmol),三乙胺(18.2mg,0.18mmol)加入3mL二氯甲烷中,缓慢加入中间体17i,室温搅拌2h,旋干溶剂,柱层层析纯化,白色固体25.3mg,收率68.6%。1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.79(d,J=8.4Hz,2H),7.70–7.60(m,4H),7.47(t,J=6.0Hz,1H),7.37–7.28(m,2H),4.60(d,J=6.0Hz,2H),2.61(s,3H),1.60–1.46(m,18H).MSm/z=594.3[M+H]+.
(3)N-(4-(4-胍基苯甲酰氨基)苄基)-5-甲基-1,3,4-恶二唑-2-甲酰胺三氟醋酸盐(SCI-16)的合成
合成方法同SCI-6,淡黄色固体,收率95.9%。1H NMR(500MHz,CD3OD)δ8.16–7.97(m,2H),7.80–7.65(m,2H),7.50–7.28(m,4H),4.59(s,2H),2.65(s,3H).MS m/z=394.2[M+H]+.
实施例17:化合物SCI-17的合成
(1)N-(4-(肉桂酰胺甲基)苯基)-4-((E)-2,3-二(叔丁氧羰基)胍基)苯甲酰胺(18j)的合成
将17j(11.1mg,0.07mmol)、三乙胺(18.8mg,0.18mmol)和HATU(38mg,0.1mmol)加入无水二氯甲烷溶液中,室温搅拌下加入16(30mg,0.06mmol),继续搅拌6h,TLC监测反应完全。旋干溶剂,柱层析纯化得白色固体22mg,收率57.9%。1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.84(d,J=7.9Hz,2H),7.64(dd,J=16.4,8.7Hz,5H),7.53–7.45(m,2H),7.39–7.28(m,5H),4.53(d,J=5.5Hz,1H),1.54(s,9H),1.47(s,9H).MS m/z=614.3[M+H]+.
(2)N-(4-(肉桂酰胺甲基)苯基)-4-胍基苯甲酰胺三氟醋酸盐(SCI-17)的合成
合成方法同SCI-6,白色固体,收率92.0%。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),10.09(s,1H),8.57(t,J=6.0Hz,1H),8.08–7.93(m,2H),7.74–7.62(m,6H),7.57–7.50(m,2H),7.48–7.30(m,6H),7.29–7.21(m,2H),6.67(d,J=15.8Hz,1H),4.34(d,J=5.9Hz,2H).MS m/z=414.2[M+H]+.
实施例18:化合物SCI-18的合成
(1)((3aR,4R,6R,6aR)-4-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-6-羟甲基-2,2-二甲基四氢呋喃[3,4-d][1,3]二氧代-4-基)-甲腈(12d)的合成
将12a(291mg,1.0mmol)和2,2-二甲氧基丙烷(521mg,5.0mmol)加入10mL丙酮溶液中,搅拌下缓慢滴加浓硫酸(72uL,1.3mmol),室温搅拌30min,升至40℃反应2h,降至室温,加入饱和碳酸氢钠水溶液调节PH>7,搅拌15min,乙酸乙酯萃取3次,收集有机相,无水硫酸钠干燥,旋蒸除去溶剂,得白色固体320mg,收率96.0%,不经纯化直接投下一步。MS m/z=331.1[M+H]+.
(2)((3aR,4R,6R,6aR)-6-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-6-氰基-2,2-二甲基四氢呋喃[3,4-d][1,3]二氧代-4-基)甲基2-(4-(4-((E)-2,3-二(叔丁氧羰基)胍基)苯甲酰氨基)苯基)乙酸酯(13d)的合成
将上述产物12d(66mg,0.2mmol)、11(102mg,0.2mmol)、EDCI(58mg,0.3mmol)、HOBT(27mg,0.2mmol)、DMAP(5mg,0.04mmol)和三乙胺(61mg,0.6mmol)和加入无水THF溶液中,室温搅拌6h,TLC监测反应完全。旋干溶剂,柱层析纯化得白色固体256mg,收率62.1%。1H NMR(400MHz,CDCl3)δ11.61(s,1H),10.49(s,1H),8.23(s,1H),8.01(s,1H),7.94(s,1H),7.79(d,J=8.7Hz,2H),7.64(d,J=8.7Hz,2H),7.55(d,J=8.5Hz,2H),7.16(d,J=8.5Hz,2H),6.81(d,J=4.6Hz,1H),6.68(d,J=4.7Hz,1H),6.22(s,2H),5.26(d,J=6.7Hz,1H),4.81(dd,J=6.6,3.9Hz,1H),4.66–4.57(m,1H),4.46(dd,J=12.1,3.6Hz,1H),4.26(dd,J=12.1,5.3Hz,1H),3.56(s,2H),1.75(s,2H),1.54(s,9H),1.49(s,9H),1.39(s,3H).MS m/z=826.3[M+H]+.
(3)(E)-N-(4-(4-(2,3-二(叔丁氧羰基)胍基)苯甲酰胺基)苄基)-6-氟-3-羟基吡嗪-2-甲酰胺盐酸盐(SCI-18)的合成
合成方法同SCI-1,白色固体,收率72.6%。1H NMR(400MHz,CD3OD)δ8.05–7.96(m,2H),7.83(s,1H),7.54(d,J=8.5Hz,2H),7.43–7.36(m,2H),7.18(d,J=8.5Hz,2H),6.94(d,J=4.6Hz,1H),6.81(d,J=4.7Hz,1H),4.61(d,J=5.3Hz,1H),4.50–4.24(m,3H),4.07(t,J=5.6Hz,1H),3.61(s,1H).MS m/z=586.2[M+H]+.药理实验
本发明化合物的部分药理学试验及结果如下:
实验例1:本发明化合物对新型冠状病毒的抑制作用研究
测定本发明化合物对新型冠状病毒(SARS-CoV-2)的抑制活性:将密度为2×105/mL的Vero细胞铺于96孔板,每孔100μL,过夜贴壁培养。用DMEM培养基将本发明化合物配置成10mM浓度,分别用不同浓度的本发明化合物预处理Vero-E6细胞1小时(100μl/孔),然后加入病毒(MOI=0.05)作用1小时(100μl/孔),弃药物-病毒混合物,重新加入含本发明化合物的DMEM培养基(200μl/孔,2%FBS)进一步培养细胞,48小时后观察药物作用后的细胞病变情况(CPE),通过定量实时RT-PCR对细胞上清液中的病毒拷贝数进行定量评估,计算化合物对病毒复制的抑制率。实验分组如下:空白对照组:未被病毒感染的Vero-E6细胞;药物溶剂对照组:Vero-E6细胞培养基中加入终浓度为1/1000的DMSO;病毒感染对照组:不加化合物的病毒感染的Vero-E6细胞;阳性药物对照组:瑞德西韦(工作浓度4μM)处理的病毒感染的Vero-E6细胞;药物毒性实验组:不同浓度的本发明化合物处理的病毒感染的Vero-E6细胞。结果表明,化合物SCI-1,SCI-3和SCI-5对SARS-CoV-2病毒具有显著抑制活性,如图1~图5和表1所示。其中,SCI-5对SARS-CoV-2病毒的多种变异株(GD108,Alpha,Beta,Delta,Omicron)均具有良好的抑制活性,结果如图6~图10和表2所示。
表1化合物对SARS-CoV-2病毒(GD108)的抑制活性
表2 SCI-5对SARS-CoV-2病毒不同变异株的抑制活性
病毒变异株 | SCI-5EC50(μM) | 瑞德西韦EC50(μM) |
GD108 | 0.72 | 1.26 |
Alpha(B.1.1.7) | 0.78 | 0.69 |
Beta(B.1.351) | 1.21 | 1.14 |
Delta(B.1.617.2) | 1.43 | 1.84 |
Omicron(B.1.1.529) | 0.56 | 0.45 |
实验例2:SCI-5及其活性代谢产物对新型冠状病毒的抑制作用研究
SCI-5属于前药,在体内代谢产生M1和M2两个活性代谢产物(表3),发挥抗病毒作用。本实验例测定了SCI-5、M1和M2对SARS-CoV-2的抑制活性,测定方法同实验例1。
结果表明,SCI-5对SARS-CoV-2病毒Delta变异株的抑制活性高于M1或M2,并高于M1与M2的联合用药(表3和图11),表明SCI-5的前药设计相比于联合用药具有显著的优势。
表3 SCI-5和M1、M2对SARS-CoV-2病毒Delta变异株的抑制活性
实验例3:SCI-5的半数毒性浓度测定
在本实验例中,通过CCK8试剂盒分析确定SCI-5对Vero-E6细胞的半数毒性浓度(CC50)。
结果显示,SCI-5在浓度为10μM时对Vero-E6细胞的抑制率为7.5%,浓度为40μM时抑制率为30.3%(图12),这提示SCI-5的CC50大于40μM,安全性较高。
实验例4:SCI-5在大鼠体内的药代动力学评价
测定SCI-5在大鼠体内的药代动力学:将SCI-5用0.5%CMC配制为5、10mg/mL用于灌胃给药,SCI-5(100mg/mL,DMSO溶液)用生理盐水配制成1、2mg/mL溶液用于静脉注射,配制成4、10mg/mL溶液用于皮下和肌肉注射。小鼠24只,分为8组,每组3只。灌胃组给药前禁食,其它各组给药前自由进食、饮水。小鼠灌胃(50、100mg/10mL/kg)皮下和肌肉注射SCI-5(20、50mg/5mL/kg)后5、15、30min、1、2、4、6、8、24h眼眶连续取血;小鼠静脉注射SCI-5(10、20mg/10mL/kg)后2、5、15、30min、1、2、4、6、8、24h眼眶连续取血。
在全血20μL中加入含内标(普萘洛尔,0.2μg/mL)的乙腈80μL,混旋后离心(14000rpm×5min)两次,取上清液1μL进行LC-MS/MS分析。LC-MS/MS条件为:色谱柱:ZorbaxC18(50mm×2.1mm,3.5μm);柱温:38℃;流动相:甲醇/水(含0.1%甲酸)梯度;流速:0.35mL/min。
药代动力学参数如表4所示。结果表明,小鼠灌服SCI-5(50、100mg/kg)后原形药含量均低于0.05μM,代谢产物M1和M2的Tmax≥4h,药物浓度均低于2μM,代谢产物M1血药浓度略高于M2。皮下和肌注后原形药和代谢产物的Tmax均在5-30min,Cmax为M1>原形药≈M2;代谢产物M2体内清除较慢,除肌注高剂量组外,AUC为M2>M1>>原形药(代谢产物AUC至少是原形药的5倍)。静脉注射SCI-5(10、20mg/kg)后,原形药清除较快(t1/2β<1h),药后4-8h血药浓度低于0.05μM。代谢产物的Tmax均在2-5min,Cmax>7μM,具有剂量倍数关系,且代谢产物M1的Cmax约为M2的2倍;代谢产物的t1/2β随剂量增加均明显延长(t1/2β为1-4h);AUC为M2>M1>>原形药(代谢产物AUC至少是原形药的3.6倍)。
表4 SCI-5在小鼠体内的药代动力学参数
实验例5:SCI-5的大鼠体内药效学研究
以金黄地鼠为研究对象评价SCI-5的体内药效学。金黄地鼠流行株(GD108)攻毒评价分组为:模型对照组(n=6)、阳性药对照组-瑞德西韦(n=6)、SCI-5低剂量组20mg/kg(n=6)、SCI-5高剂量组50mg/kg(n=6),共24只;金黄地鼠Delta变异株攻毒评价分组为:模型对照组(n=6)、阳性药对照组-瑞德西韦(n=6)、SCI-5低剂量组20mg/kg(n=6)、SCI-5高剂量组50mg/kg(n=6),共24只。攻毒方式为滴鼻,攻毒剂量为1×105PFU/只,给药方式和剂量为:对照组:肌肉注射生理盐水;阳性药对照组-瑞德西韦:肌肉注射46mg/kg/天,等摩尔剂量;SCI-5低剂量组:肌肉注射SCI-5 20mg/kg/天;SCI-5高剂量组:肌肉注射SCI-5 50mg/kg/天。每日称重、测体温、采鼻咽拭子,比较体重、体温和体征,以及鼻拭子病毒载量的变化,连续给药5日后进行解剖。解剖后取左叶肺用10%中性福尔马林固定,HE染色检测肺病理改变,评估SCI-5疗效。
结果显示,SCI-5相对于阳性对照瑞德西韦,引起大鼠体重下降的程度较轻(图13),表明SCI-5具有更好的安全性。病理切片结果显示,SCI-5处理的大鼠GD108模型和Delta模型的肺部感染程度均有明显下降,具有和瑞德西韦相当的效果(图14和图15)。
Claims (9)
1.如通式(I)所示的化合物或其药学上可接受的盐或其结晶水合物或其溶剂化物或其前药:
其中,
X选自-CH2-、-NH-、O、S;
n=0,1,2,3,4;
L选自甲酰基、磺酰基、亚硫酰基、甲酰胺基、甲酰氧基取代或未取代的氨基甲酰基、取代或未取代的氨基磺酰基、取代或未取代的氨基甲酰氧基、取代或未取代的氨基甲酰胺基,其中,所述取代基独立地选自氢、C1-C4烷基;
R选自氢、C1-C6烷基、取代或未取代的C1-C6羧基、取代或未取代的C5-C10芳基、取代或未取代的C1-C8饱和或不饱和杂环基、 其中,所述取代基独立地选自C1-C6烷基或烷氧基、C1-C4烯基、羟基、氨基、硝基、氰基、三氟甲基、卤素,所述卤素为F、Cl、Br、I;所述杂环至少包含一个杂原子,所述杂原子为N、O、S;R1选自氢、C1-10烷基、C1-10烷酰基、氨基C1-10烷酰基、C1-6烷氨基C1-6烷酰基、C1-6烷氧基C1-6烷酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连;R2选自氢、C1-10烷基、C1-10烷酰基、氨基C1-10烷酰基、C1-6烷氨基C1-6烷酰基、C1-6烷氧基C1-6烷酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连。
2.根据权利要求1所述的化合物或其药学上可接受的盐或其结晶水合物或其溶剂化物或其前药,其特征在于:
其中,
X选自-CH2-、-NH-、O、S;
n=0,1,2,3,4;
L选自甲酰基、磺酰基、亚硫酰基、甲酰胺基、甲酰氧基、取代或未取代的氨基甲酰基、取代或未取代的氨基磺酰基、取代或未取代的氨基甲酰氧基、取代或未取代的氨基甲酰胺基,其中,所述取代基独立地选自氢、C1-C4烷基;
R选自氢、C1-C6烷基、取代或未取代的C1-C6羧基、取代或未取代的C5-C10芳基、取代或未取代的C1-C8饱和或不饱和杂环基、 其中,所述取代基独立地选自C1-C6烷基或烷氧基、C1-C4烯基、羟基、氨基、硝基、氰基、三氟甲基、卤素,所述卤素为F、Cl、Br、I;所述杂环至少包含一个杂原子,所述杂原子为N、O、S;R1选自氢、C1-10烷基、C1-10烷酰基、氨基C1-10烷酰基、C1-6烷氨基C1-6烷酰基、C1-6烷氧基C1-6烷酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连;R2选自氢、C1-10烷基、C1-10烷酰基、氨基C1-10烷酰基、C1-6烷氨基C1-6烷酰基、C1-6烷氧基C1-6烷酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连;
进一步地,所述取代基独立的选自甲基、乙基、异丙基、叔丁基、羟基、氨基、三氟甲基、卤素,所述卤素为F、Cl、Br、I;所述杂环至少包含一个杂原子,所述杂原子为N、O、S;R1选自氢、甲基、乙基、异丙基、叔丁基、乙酰基、丙酰基、正丁酰基、异丁酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连;R2选自氢、甲基、乙基、异丙基、叔丁基、乙酰基、丙酰基、正丁酰基、异丁酰基、α-氨基酸,所述α-氨基酸的羧基与呋喃环上的羟基以酯键相连。优选地,所述α-氨基酸选自丙氨酸、缬氨酸、异亮氨酸、色氨酸、苯丙氨酸;
更进一步地,R优选自以下结构片段之一:
3.根据权利要求1-2任一项所述的化合物或其药学上可接受的盐或其结晶水合物或其溶剂化物或其前药,其特征在于,所述化合物选自如下:
4.权利要求1或2所述的化合物及其酸式盐的制备方法,其特征在于,包括以下步骤:
(1)化合物SCI-1、SCI-2、SCI-4的合成路线:
将对氨基苯甲酸的氨基转化为Boc保护的胍基得化合物1,将对/间硝基苯乙胺与含羧酸的化合物缩合得化合物2,化合物2经氢气还原得化合物3,化合物1与化合物3缩合得化合物4,化合物4在酸性条件下脱除Boc保护基得到化合物SCI-1,SCI-2,SCI-4;
(2)化合物SCI-3的合成路线:
将化合物1与Cbz保护的对羟基苯乙胺缩合得化合物5,化合物5经氢气还原脱除Cbz保护基得化合物6,化合物6与5-羧基吡咯烷酮缩合得化合物7,化合物7在酸性条件下脱除Boc保护基得到化合物SCI-3;
(3)化合物SCI-5、SCI-7、SCI-14、SCI-18的合成路线:
将Boc保护的对氨基苯乙酸与苄溴反应得化合物8,化合物8经三氟乙酸脱除Boc保护基得化合物9,化合物9与化合物1缩合得化合物10,化合物10经氢气还原脱除苄基得化合物11,化合物11与含氨基或羟基的化合物12缩合得化合物13,化合物13在酸性条件下脱除Boc保护基得到化合物SCI-5、SCI-7、SCI-14、SCI-18;
(4)化合物SCI-6、SCI-8~SCI-13、SCI-15~SCI-17的合成路线:
将对氨基苄胺与氯甲酸苄酯反应得化合物14,化合物14与化合物1缩合得化合物15,化合物15经氢气还原脱除Cbz保护基得化合物16,化合物16与含羧基或酰氯或磺酰氯或羧酸活性酯的化合物17缩合得化合物18,化合物18在酸性条件下脱除Boc保护基得到化合物SCI-6、SCI-8~SCI-13、SCI-15~SCI-17。
5.根据权利要求4所述的制备方法,其特征在于,所述的酸式盐为盐酸盐、硫酸盐、氢溴酸盐、氢氟酸盐、氢碘酸盐、胺基磺酸盐、磷酸盐、甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、萘磺酸盐、萘二磺酸盐、醋酸盐、丙酸盐、酒石酸盐、丙二酸盐、富马酸盐、乳酸盐、琥珀酸盐、樟脑磺酸盐、柠檬酸盐、草酸盐、马来酸盐、苹果酸盐、丙酮酸盐、三氟乙酸盐、扑酸盐、羟基马来酸盐、苯乙酸盐、苯甲酸盐、水杨酸盐、谷氨酸盐、抗坏血酸盐、对胺基苯磺酸盐、2-乙酰氧基苯甲酸盐、羟乙磺酸盐。
6.一种药物组合物,其特征在于,所述药物组合物由权利要求1-3中任意一项所述的化合物或其药学上可接受的盐或其立体异构体,和药学上可接受的载体。
7.权利要求1~3任一项所述的化合物或其药学上可接受的盐及权利要求6所述的药物组合物在制备抗病毒药物或治疗由病毒感染引起的相关疾病的药物中的用途。
8.根据权利要求7的用途,其特征在于,所述的病毒选自:
非典型性肺炎病毒或严重急性呼吸系统综合征冠状病毒(Severe acute respiratorysyndrome coronavirus,SARS-CoV)、严重急性呼吸系统综合征冠状病毒2或2019新型冠状病毒(SARS-CoV-2)、中东呼吸综合征冠状病毒(Middle East respiratory syndromecoronavirus,MERS-CoV)、人冠状病毒OC43(Human coronavirus OC43)、人冠状病毒229E(Human coronavirus229E)、人冠状病毒NL63(Human coronavirus NL63)、人冠状病毒HKU1(Human coronavirus HKUl)、甲型流感病毒、乙型流感病毒、丙型流感病毒、甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、丁型肝炎病毒(HDV)、戊型肝炎病毒(HEV)、登革热病毒(DENV)、寨卡病毒(Zika)、马尔堡病毒(MBV)、埃博拉病毒(EBV),以及以上病毒的所有变异株。
9.根据权利要求7的用途,其特征在于,所述由病毒感染引起的相关疾病选自:SARS-CoV-2引起的新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19)及其并发症,人冠状病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症,人流感病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症,甲型肝炎病毒引起的甲型肝炎及其并发症,乙型肝炎病毒引起的乙型肝炎及其并发症,丙型肝炎病毒引起的丙型肝炎及其并发症,丁型肝炎病毒引起的丁型肝炎及其并发症,戊型肝炎病毒引起的戊型肝炎及其并发症,登革热病毒引起的登革热及其并发症,寨卡病毒引起的感染及其并发症,马尔堡病毒、埃博拉病毒引起的出血热及其并发症。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210844227.9A CN117447375A (zh) | 2022-07-18 | 2022-07-18 | 胍类化合物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210844227.9A CN117447375A (zh) | 2022-07-18 | 2022-07-18 | 胍类化合物及其制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117447375A true CN117447375A (zh) | 2024-01-26 |
Family
ID=89586100
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210844227.9A Pending CN117447375A (zh) | 2022-07-18 | 2022-07-18 | 胍类化合物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117447375A (zh) |
-
2022
- 2022-07-18 CN CN202210844227.9A patent/CN117447375A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100520737B1 (ko) | 아스파틸 프로테아제 억제제의 전구약물로서 술폰아미드유도체 | |
KR20220143919A (ko) | 뉴클레오시드 유사체 또는 뉴클레오시드 유사체를 함유하는 조합제제의 항바이러스적 응용 | |
PT1302468E (pt) | Processos e intermediários para o fabrico de compostos inibidores de protease retroviral | |
KR20010033595A (ko) | 아스파틸 프로테아제 억제제의 전구약물 | |
CN102838523A (zh) | 抗肠病毒71(ev71)戊内酰胺类化合物及其制备方法和用途 | |
JP2002511491A (ja) | パパインスーパーファミリーのシステインプロテアーゼの阻害による寄生虫病の治療 | |
CN103130710B (zh) | 抗肠病毒71(ev71)己内酰胺醛类化合物及其制备方法和用途 | |
ES2426234T3 (es) | Derivado de amida tiazol, procedimiento de preparación y usos del mismo | |
ES2743199T3 (es) | Derivados de indanona, sales farmacéuticamente aceptables o isómeros ópticos de los mismos, método de preparación para los mismos y composiciones farmacéuticas que los contienen como ingrediente activo para prevenir o tratar enfermedades virales | |
ES2628730T3 (es) | Inhibidores de proteasa | |
KR20060114374A (ko) | 치료용 조합물 | |
WO2023025319A1 (zh) | 一种新型的胞苷衍生物及其药物组合物和用途 | |
CN105348345A (zh) | 一种含有硫普罗宁结构的前药、其制备方法、药物组合物及其用途 | |
US20040092539A1 (en) | Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them | |
CN115710297A (zh) | 一种新型核苷酸衍生物类及其药物组合物和用途 | |
CN114699419A (zh) | PLpro蛋白抑制剂在治疗或预防新型冠状病毒感染的药物中的应用 | |
SK18182000A3 (sk) | Kryštalický efavirenz | |
EP1480941B1 (en) | Urea derivatives as hiv aspartyl protease inhibitors | |
CN117447375A (zh) | 胍类化合物及其制备方法和用途 | |
JPH02218654A (ja) | 安息香酸誘導体、それらの製造方法およびそれらを含有する薬剤 | |
WO2005111006A1 (en) | Ritonavir analogous compound useful as retroviral protease inhibitor, preparation of the ritonavir analogous compound and pharmaceutical composition for the ritonavir analogous compound. | |
CN101538311B (zh) | α-氨基酰环酰亚胺类肽金属蛋白酶抑制剂及其应用 | |
US12083092B2 (en) | Antiviral 1,3-di-oxo-indene compounds | |
CN114805141A (zh) | 4-胍基苯甲酸芳基酯类化合物及其在抗SARS-CoV-2病毒中的用途 | |
CN105777829B (zh) | 一种含有类核苷结构的前药、其制备方法、药物组合物及其用途 |
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 |