CN113582935A - Inflammatory corpuscle nucleotide-binding oligomerization domain-like receptor protein 3 inhibitor and preparation method and application thereof - Google Patents
Inflammatory corpuscle nucleotide-binding oligomerization domain-like receptor protein 3 inhibitor and preparation method and application thereof Download PDFInfo
- Publication number
- CN113582935A CN113582935A CN202110993643.0A CN202110993643A CN113582935A CN 113582935 A CN113582935 A CN 113582935A CN 202110993643 A CN202110993643 A CN 202110993643A CN 113582935 A CN113582935 A CN 113582935A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- sodium
- pharmaceutically acceptable
- reacting
- 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 11
- 230000002757 inflammatory effect Effects 0.000 title abstract description 10
- 239000002773 nucleotide Substances 0.000 title abstract description 8
- 125000003729 nucleotide group Chemical group 0.000 title abstract description 8
- 238000006384 oligomerization reaction Methods 0.000 title abstract description 8
- 102000005962 receptors Human genes 0.000 title abstract description 8
- 108020003175 receptors Proteins 0.000 title abstract description 8
- 239000003112 inhibitor Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 102000003777 Interleukin-1 beta Human genes 0.000 claims abstract description 31
- 108090000193 Interleukin-1 beta Proteins 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 12
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 5
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 4
- 230000028327 secretion Effects 0.000 claims abstract description 3
- -1 cyclopropanoyl Chemical group 0.000 claims description 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 23
- WNRZHQBJSXRYJK-UHFFFAOYSA-N carboxyamidotriazole Chemical compound NC1=C(C(=O)N)N=NN1CC(C=C1Cl)=CC(Cl)=C1C(=O)C1=CC=C(Cl)C=C1 WNRZHQBJSXRYJK-UHFFFAOYSA-N 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 12
- 239000002798 polar solvent Substances 0.000 claims description 12
- 239000012312 sodium hydride Substances 0.000 claims description 12
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- NXEDTZGUAGKMJS-UHFFFAOYSA-N ethyl 4-chlorobenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(Cl)C=C1 NXEDTZGUAGKMJS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 229940126062 Compound A Drugs 0.000 claims description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- HCJTYESURSHXNB-UHFFFAOYSA-N propynamide Chemical compound NC(=O)C#C HCJTYESURSHXNB-UHFFFAOYSA-N 0.000 claims description 3
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 3
- 229960005055 sodium ascorbate Drugs 0.000 claims description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- MANVMTSCCSAYSN-UHFFFAOYSA-N acetonitrile;2-methylpropan-2-ol Chemical compound CC#N.CC(C)(C)O MANVMTSCCSAYSN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000013024 sodium fluoride Nutrition 0.000 claims description 2
- 239000011775 sodium fluoride Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 10
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 abstract description 7
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 238000002965 ELISA Methods 0.000 abstract description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 3
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 abstract 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 5
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 5
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000011161 development Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 210000002303 tibia Anatomy 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 108090000426 Caspase-1 Proteins 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 2
- FDOLAMRYHDWRIS-UHFFFAOYSA-N (4-methylpiperazin-1-yl)methanone Chemical compound CN1CCN([C]=O)CC1 FDOLAMRYHDWRIS-UHFFFAOYSA-N 0.000 description 1
- HUUSXLKCTQDPGL-UHFFFAOYSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylurea Chemical compound CC(C)(O)C1=COC(S(=O)(=O)NC(=O)NC=2C=3CCCC=3C=C3CCCC3=2)=C1 HUUSXLKCTQDPGL-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- LIHUTSFYFGCWQP-UHFFFAOYSA-N 2-cyano-n-methylacetamide Chemical compound CNC(=O)CC#N LIHUTSFYFGCWQP-UHFFFAOYSA-N 0.000 description 1
- ZEZSIOCMLBVHIU-UHFFFAOYSA-N 2h-triazol-4-ylcarbamic acid Chemical compound OC(=O)NC1=CNN=N1 ZEZSIOCMLBVHIU-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- 102100032814 ATP-dependent zinc metalloprotease YME1L1 Human genes 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 208000011594 Autoinflammatory disease Diseases 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 102100035904 Caspase-1 Human genes 0.000 description 1
- 206010051288 Central nervous system inflammation Diseases 0.000 description 1
- 206010050685 Cytokine storm Diseases 0.000 description 1
- 206010013700 Drug hypersensitivity Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 108010034143 Inflammasomes Proteins 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 108091008099 NLRP3 inflammasome Proteins 0.000 description 1
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- FLISRKMOMNUNEF-UHFFFAOYSA-N [4-(azidomethyl)-2,6-dichlorophenyl]-(4-chlorophenyl)methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1=C(Cl)C=C(CN=[N+]=[N-])C=C1Cl FLISRKMOMNUNEF-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005354 acylalkyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 210000005093 cutaneous system Anatomy 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 206010052015 cytokine release syndrome Diseases 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000005311 drug allergy Diseases 0.000 description 1
- 102000038037 druggable proteins Human genes 0.000 description 1
- 108091007999 druggable proteins Proteins 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 210000002745 epiphysis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- KJLLKLRVCJAFRY-UHFFFAOYSA-N mebutizide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(C(C)C(C)CC)NC2=C1 KJLLKLRVCJAFRY-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound which is shown in a formula I and can inhibit the secretion of inflammatory corpuscle nucleotide combined oligomerization structural domain-like receptor protein 3(NLRP3) and interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) and a preparation method thereof. ELISA experiments show that the compounds can obviously inhibit the activity of NLRP3 and reduce the expression of IL-1 beta, which is a downstream inflammatory factor of NLRP 3. Further experiments showed that some of the compounds were IL-activated1 beta/TNF-alpha has selective inhibitory effect. The compound shown in the formula I is expected to become a novel anti-inflammatory drug and a drug for treating autoimmune diseases.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method and application of 1, 2, 3-triazole micromolecule compounds, in particular to a novel micromolecule medicine capable of inhibiting inflammatory corpuscle nucleotide from being combined with oligomerization domain-like receptor protein 3(NLRP3) and interleukin-1 beta (IL-1 beta).
Background
The following discussion is presented in the context of a description of the invention to aid in understanding the invention, but is not to be construed as prior art to the invention. All cited publications are incorporated herein by reference in their entirety.
It is well known that inflammation and immunity are closely related to the development of various diseases, such as SARS-CoV-2 induced fatal cytokine storm leading to multiple organ failure and death (Filipou and Karagianis, 2020). Many autoimmune diseases are caused by the homeostatic disturbance of inflammatory factors such as interleukin-1 beta (IL-1 beta), tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), etc., and the interaction between innate immunity and adaptive immunity eventually leads to the damage of body tissues (Vernino, 2020, Bertholt and Sibilia, 2019). TNF-alpha plays a central role in the pathogenesis of psoriasis (Boehncke and)
2015) (ii) a Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disease characterized by systemic, cutaneous, musculoskeletal and central nervous system inflammation, and excessive release of pro-inflammatory cytokines of myeloid origin is critical in causing systemic and tissue inflammation leading to disease symptoms (bookehri and Hoffman, 2019).
Inflammatory small-body nucleotide binding oligomerization domain-like receptor protein 3(NLRP3) is a key regulator in these processes and also an important drug target protein for anti-inflammatory and other related diseases (Green et al, 2018, Dinarello, 2018). NLRP3 promotes self-cleavage of caspase-1 precursor (pro-caspase-1) after activation by several pathogens and damage-associated molecules (PAMPs and DAMPs), thereby accelerating cleavage of IL-1 β precursor and extracellular release of IL-1 β (Hoyle et al, 2020, Swanson et al, 2019). Currently, monoclonal antibodies against the corresponding cytokines are mostly used for clinical treatment of these autoimmune diseases. However, monoclonal antibody preparations belong to biomacromolecule preparations and have the disadvantages of great development difficulty and high transportation and storage costs. In addition, prolonged use of monoclonal antibody preparations may also cause side effects such as drug resistance or allergy in the body. The search for effective small molecules to reduce the safety of IL-1 β or TNF- α remains a common academic goal (Ecker et al, 2015, Wolska-Washer and Robak, 2019).
Some small molecules have activity in inhibiting the release of IL-1 β or other cytokines. For example MCC950, which shows excellent activity in human monocytes with an IC50 value of 8.1nM, but was found to be hepatotoxic in phase II clinical trials (Mangan et al, 2018, Green et al, 2018). Therefore, there is still a need to find a safe and effective small drug molecule for reducing NLRP3 inflammation. Carboxyamidotriazole (CAI) as an oral broad spectrum anticancer drug with a credible safety in phase III clinical trials (Bonnefond et al, 2018, Das, 2018, Yang et al, 2008) (Berlin et al, 2002, Omuro et al, 2018, Winters et al, 2005, Hussain et al, 2003, Si et al, 2020), was identified as an important inhibitor of IL-1 β release mediated by NLRP3 inflammasome both in vitro and in vivo (Shi et al, 2019, Chen et al, 2017, Si et al, 2020, Ju et al, 2012, Guo et al, 2012). In addition to IL-1 β, the anti-inflammatory activity of CAI has also been shown to inhibit secretion of other inflammatory cytokines such as TNF- α (Guo et al, 2008, Lu et al, 2020). CAI, however, is less selective in inhibiting IL-1 β and TNF- α release (Stephenson et al, 2020). It has now been demonstrated that TNF- α inhibitors are associated with a risk of immunosuppression, which may lead to severe side effects such as severe infection or tumor recurrence in patients (Singh et al, 2020, Holmer and Singh, 2019, Radner and aletha, 2015, Askling et al, 2011). Therefore, the development of selective IL-1 beta small molecule inhibitors as anti-inflammatory agents, the treatment of autoimmune diseases and the improvement of the safety of the drugs are of great significance.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method and application of a novel small molecule drug capable of inhibiting the combination of an inflammasome nucleotide and an oligomerization domain-like receptor protein 3 so as to solve the technical problem that a similar compound is lacked in the prior art;
another technical problem to be solved by the present invention is that the compounds described in the background of the invention have low activity and poor stability;
the invention also provides application of the compound serving as an inflammatory corpuscle nucleotide binding oligomerization domain-like receptor protein 3 inhibitor and an interleukin-1 beta inhibitor in anti-inflammatory drugs and autoimmune drugs.
The invention provides a compound shown in formula I and pharmaceutically usable salts thereof:
wherein:
R1independently selected from: amide, cyano, ester, acyl, substituted amide;
R2independently selected from: hydrogen, amino, alkylated amino,
Wherein R is3Independently selected from: hydrogen, C1-C6Alkanoyl, cyclopropanoyl, furoyl, tetrahydrofurfuryl, benzoyl, 3-bromopropionamido, 4-bromobutyramido;
R4independently selected from: hydrogen, C1-C6Alkanoyl, cyclopropanoyl, furoyl, tetrahydrofurfuryl, benzoyl, 3-bromopropionamido, 4-bromobutyramido.
Further, the following is preferred:
R1independently selected from:
R2independently selected from:
still further, the following compounds and pharmaceutically usable salts thereof are preferred:
the invention provides a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, including a diluent.
Meanwhile, the invention provides application of the compound or pharmaceutically usable salts thereof and the pharmaceutical composition in preparing medicines for preparing small molecular inhibitors of inflammatory corpuscle nucleotide binding oligomerization domain-like receptor protein 3, interleukin-1 beta and tumor necrosis factor-alpha inhibitors.
Preferably, the compound or the pharmaceutically acceptable salt thereof and the pharmaceutical composition are drugs for anti-tumor or tumor chemoradiotherapy sensitization.
Meanwhile, the invention provides a preparation method of the compound, which comprises the following steps:
1) reacting carboxyamidotriazole with methyl iodide and sodium hydride in a polar solvent to obtain a compound A;
2) reacting carboxyamidotriazole with ethyl p-chlorobenzenesulfonate and sodium hydride in a polar solvent to obtain a compound A;
3) reacting the compound B with potassium carbonate and a cyano compound to obtain a compound C;
4) reacting the compound C with methyl iodide and sodium hydride in a polar solvent to obtain a compound D;
5) reacting the compound C with ethyl p-chlorobenzenesulfonate and sodium hydride in a polar solvent to obtain a compound D;
6) the compound E is obtained by carboxyamidotriazole and acyl chloride under the catalysis of concentrated sulfuric acid;
7) the compound B and propynamide react in a polar mixed solvent under the catalysis of copper sulfate pentahydrate and sodium ascorbate to obtain a compound F.
Wherein the compound has the following structure:
preferably, the reaction in step 1)2)4)5) is carried out under nitrogen protection and heating conditions.
Preferably, the reaction of step 6) is carried out at low temperature. More preferably, the reaction temperature is 0 ℃.
Preferably, the reaction in the step 7) is carried out in a polar mixed solvent, and the volume ratio of the mixed solvent is 1: 2: 1.
Preferably, the reaction in step 3) is carried out under basic conditions, and bases include, but are not limited to, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium fluoride, potassium carbonate, sodium bicarbonate, and cesium carbonate. More preferably, it is potassium carbonate.
Preferably, the reaction of step 1)2)4)5) is carried out in a polar solvent, including but not limited to N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, methyl ethyl ketone, 1, 4-dioxane, t-butanol, water. More preferably, it is N, N-dimethylformamide.
Preferably, the reaction of step 7) is carried out in a mixed polar solvent, including but not limited to N, N-dimethylformamide, dimethyl sulfoxide, tert-butanol acetonitrile, acetone, methyl ethyl ketone, 1, 4-dioxane, water. More preferably, it is water/dichloromethane/tert-butanol.
Technical terms related to the above technical solutions, unless specifically explained, will follow the following definitions.
The term "alkyl" refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms, thus, for example, the term "C" as used herein1-C6Alkyl "refers to an alkyl having at least 1 and at most 6. Examples of such branched or straight chain alkyl groups for use in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like.
The term "optionally substituted" or "substituted" refers to groups bearing 1-2 different substituents and may be respectively lower alkyl, lower aryl, lower aralkyl, lower cycloalkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, polyhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroaryralkyl, lower heteroaralkoxy, azido, amino, halogen, lower alkylthio, oxy, lower acylalkyl, lower carboxylate, carboxylic acid, amide, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower acylaminoalkylaryl, lower amidinoaryl, lower acylaminoaryl, lower aralkylamino, lower acylaminoaryl, lower heteroarylalkyl, sulfonyl, lower amidinoaryl, lower heteroarylalkyl, or lower heteroaryl, or lower heteroarylalkyl, or lower heteroaryl, or lower heteroarylalkyl, or lower heteroaryl, or lower heteroarylalkyl, or lower heteroaryl, Lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkyl, lower ureidoalkyl, cyano, lower alkoxyalkyl, lower polyhaloalkyl, lower aralkoxyalkyl.
Detailed Description
The compounds and preparations of the present invention are better illustrated by the following examples. These examples should not be construed as limitations of the present invention, and variations of these compounds, now known or later developed, should also be considered within the scope of the present invention and claimed.
Hereinafter, specific embodiments of the present invention will be described in detail. Well-known structures or functions may not be shown in detail in a following embodiment in order not to obscure the unnecessary detail.
Approximating language, as used herein in the following examples, may be applied to identify quantitative representations that could permissibly vary in number without resulting in a change in the basic function. Accordingly, a numerical value modified by a language such as "about", "left or right" is not limited to the precise numerical value itself. In some embodiments, "about" indicates that the value allowed for correction varies within plus or minus ten percent (+ -10%), for example, "about 100" indicates that any value between 90 and 110 is possible. Further, in the expression "about a first value to a second value", both the first and second values are corrected at about the same time. In some cases, the approximating language may be related to the precision of a measuring instrument.
Unless defined otherwise, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Example 11- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -5- (methylamino) -1H-1, 2, 3-triazole-4-carboxamide (A1)
Carboxyamidotriazole (300mg, 0.71mmol), sodium hydride (34mg, 0.85mmol) and methyl iodide (151mg, 1.06mmol) were added to N, N-dimethylformamide under nitrogen. The reaction solution was stirred at 60 ℃ for 4 hours. The reaction was stopped, cooled to room temperature, 5mL of ethyl acetate was added, washed three times with water, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent petroleum ether: ethyl acetate 1: 1) to give a white solid (0.241g, 77.7%).1H NMR(400MHz， DMSO-d6)δ7.78(d，J＝8.6Hz，2H)，7.68(d，J＝8.7Hz，2H)，7.62(s，1H)，7.39(s， 2H)，7.22(s，1H)，6.51(q，J＝5.4Hz，1H)，5.70(s，2H)，2.97(d，J＝5.4Hz，3H).
Referring to the procedure of example 1, the following compounds can be prepared:
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-(dimethylamino)-1H-1，2，3-triazole-4- carboxamide(A2)
1H NMR(400MHz，DMSO-d6)δ7.84(s，1H)，7.78(d，J＝8.7Hz，2H)，7.68(d，J＝ 8.7Hz，2H)，7.53(s，2H)，7.48(s，1H)，5.59(s，2H)，2.72(s，6H).
example 21- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -5- (ethylamino) -1H-1, 2, 3-triazole-4-carboxamide (A3)
Carboxyaminotriazole (425mg, 1.0mmol), sodium hydride (48mg, 1.2mmol) and ethyl p-chlorobenzenesulfonate (300mg, 1.5mmol) were added to N, N-dimethylformamide under nitrogen. The reaction solution was stirred at room temperature for 12 hours. The reaction was stopped, 5mL of ethyl acetate was added, washed three times with water, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent petroleum ether: ethyl acetate 2: 1) to give a white solid (0.309g, 68.5%).1H NMR(400MHz，DMSO-d6)δ7.77 (d，J＝8.6Hz，2H)，7.68(d，J＝8.7Hz，2H)，7.66(s，1H)，7.40(s，2H)，7.24(s，1H)， 6.33(t，J＝6.3Hz，1H)，5.66(s，2H)，3.42(p，J＝7.0Hz，2H)，1.02(t，J＝7.1Hz，3H).
Example 35-amino-1- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -N-methyl-IH-1, 2, 3-triazole-4-carboxamide (C1)
Will (a) to4- (azidomethyl) -2, 6-dichlorophenyl) (4-chlorophenyl) methanone (681mg, 2mmol), 2-cyano-N-methylacetamide (255mg, 2.6mmol), and potassium carbonate (1161mg, 8.4mmol) in dimethyl sulfoxide (1mL) was stirred overnight. To the reaction mixture was added 5mL of ethyl acetate, which was washed three times with water, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent, petroleum ether: ethyl acetate 2: 1) to give a white solid (0.723g, 82.7%).1H NMR(400 MHz，DMSO-d6)δ8.11(q，J＝4.8Hz，1H)，7.78(d，J＝8.6Hz，2H)，7.67(d，J＝8.6 Hz，2H)，7.46(s，2H)，6.51(s，2H)，5.54(s，2H)，2.74(d，J＝4.7Hz，3H)。
Referring to the procedure of example 2, the following compounds can be prepared:
5-Amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-N，N-dimethyl-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ7.77(d，J＝8.6Hz，2H)，7.68(d，J＝8.5Hz，2H)， 7.47(s，2H)，6.72(s，2H)，5.54(s，2H)，2.97(s，3H).
5-Amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-N-ethyl-1H-1，2，3-triazole- 4-carboxamide
1H NMR(400MHz，DMSO-d6)δ8.18(t，J＝5.9Hz，1H)，7.76(d，J＝8.6Hz，2H)， 7.66(d，J＝8.6Hz，2H)，7.45(s，2H)，6.51(s，2H)，5.52(s，2H)，3.23(p，J＝7.0Hz， 2H)，1.08(t，J＝7.1Hz，3H).
5-Amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-N-(2-hydroxyethyl)-1A-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ8.01(t，J＝5.8Hz，1H)，7.77(d，J＝8.6Hz，2H)，7.67(d，J＝8.6Hz，2H)，7.46(s，2H)，6.54(s，2H)，5.54(s，2H)，4.76(t，J＝5.5Hz， 1H)，3.48(q，J＝6.1Hz，2H)，3.30(q，J＝6.1Hz，2H).
(5-Amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3-triazol-4- yl)(pyrrolidin-1-yl)methanone
1H NMR(400MHz，DMSO-d6)δ7.77(d，J＝8.7Hz，2H)，7.67(d，J＝8.7Hz，2H)， 7.47(s，2H)，6.72(s，2H)，5.55(s，2H)，3.97(t，J＝6.8Hz，2H)，3.47(t，J＝6.9Hz， 2H)，1.93(p，J＝6.8Hz，2H)，1.80(p，J＝6.7Hz，2H).
(5-Amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3-triazol-4- yl)(piperidin-1-yl)methanone
1H NMR(400MHz，DMSO-d6)δ7.77(d，J＝8.7Hz，2H)，7.68(d，J＝8.8Hz，2H)， 7.49(s，2H)，6.71(s，2H)，5.54(s，2H)，4.29(s，2H)，3.57(s，2H)，1.64(s，2H)，1.54(s， 4H).
(5-Amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3-triazo1-4-y1)(4- methylpiperazin-1-yl)methanone
1H NMR(400MHz，DMSO-d6)δ7.77(d，J＝8.4Hz，2H)，7.68(d，J＝8.4Hz，2H)， 7.49(s，2H)，6.75(s，2H)，5.55(s，2H)，4.35(s，2H)，3.60(s，2H)，2.36(s，4H)，2.20(s， 3H).
5-Amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3-triazole-4-carbonitrile
1H NMR(400MHz，DMSO-d6)δ7.78(d，J＝8.6Hz，2H)，7.68(d，J＝8.6Hz，2H)， 7.51(s，2H)，7.34(s，2H)，5.52(s，2H).
1-(5-Amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3-triazol-4-y1)ethan- 1-one
1H NMR(400MHz，DMSO-d6)δ7.79(d，J＝8.6Hz，2H)，7.68(d，J＝8.6Hz，2H)， 7.59(s，2H)，5.78(s，2H)，2.51(s，3H).
Methyl 5-amino-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3-triazole-4- carboxylate
1H NMR(400MHz，DMSO-d6)δ7.77(d，J＝8.6Hz，2H)，7.67(d，J＝8.6Hz，2H)， 7.47(s，2H)，6.80(s，2H)，5.55(s，2H)，3.79(s，3H).
example 41- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -N-methyl-5- (methylamino) -1H-1, 2, 3-triazole-4-carboxamide (D1)
Carboxyamidotriazole 5-amino-1- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -N-methyl-1H-1, 2, 3-triazole-4-carboxamide (300mg, 0.69mmol), sodium hydride (33mg, 0.82mmol) and iodomethane (147mg, 1.04mmol) were added to N, N-dimethylformamide under nitrogen. The reaction solution was stirred at 60 ℃ for 4 hours. The reaction was stopped, cooled to room temperature, 5mL of ethyl acetate was added, washed three times with water, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent petroleum ether: ethyl acetate 1: 1) to give a white solid (0.340g, 75.3%).1H NMR(400MHz，DMSO- d6)δ8.21(q，J＝4.6Hz，1H)，7.78(d，J＝8.6Hz，2H)，7.68(d，J＝8.6Hz，2H)，7.39 (s，2H)，6.44(q，J＝5.4Hz，1H)，5.68(s，2H)，2.97(d，J＝5.4Hz，3H)，2.74(d，J＝4.7 Hz，3H).
Referring to the procedure of example 4, the following compounds can be prepared:
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-(dimethylamino)-N-methyl-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ8.48(q，J＝4.5Hz，1H)，7.77(d，J＝8.6Hz， 2H)，7.68(d，J＝8.6Hz，2H)，7.52(s，2H)，5.59(s，2H)，2.77(d，J＝4.7Hz，3H)，2.72 (s，6H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-N，N-dimethyl-5-(methylamino)-1H- 1，2，3-triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ7.78(d，J＝8.7Hz，2H)，7.68(d，J＝8.7Hz， 2H)，7.42(s，2H)，6.64(q，J＝5.2Hz，1H)，5.62(s，2H)，3.29(s，3H)，2.98(s，3H)，2.82(d，J＝5.2Hz，3H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-N-ethyl-5-(methylamino)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ8.28(t，J＝5.9Hz，1H)，7.78(d，J＝8.6Hz，2H)， 7.68(d，J＝8.7Hz，2H)，7.39(s，2H)，6.46(q，J＝5.4Hz，1H)，5.69(s，2H)，3.24(qd， J＝7.1，5.8Hz，2H)，2.97(d，J＝5.4Hz，3H)，1.09(t，J＝7.2Hz，3H).
example 51- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -5- (ethylamino) -N-methyl-1H-1, 2, 3-triazole-4-carboxamide (D5)
5-amino-1- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -N-methyl-1H-1, 2, 3-triazole-4-carboxamide (425mg, 0.97mmol), sodium hydride (47mg, 1.2mmol) and ethyl p-chlorobenzenesulfonate (291mg, 1.5mmol) were added to N, N-dimethylformamide under nitrogen. The reaction solution was stirred at room temperature for 12 hours. The reaction was stopped, 5mL of ethyl acetate was added, washed three times with water, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent petroleum ether: ethyl acetate 2: 1) to give a white solid (0.330g, 71.1%).1H NMR(400MHz，DMSO-d6)δ 7.77(d，J＝8.6Hz，2H)，7.68(d，J＝8.7Hz，2H)，7.66(s，1H)，7.40(s，2H)，7.24(s， 1H)，6.33(t，J＝6.3Hz，1H)，5.66(s，2H)，3.42(p，J＝7.0Hz，2H)，1.02(t，J＝7.1 Hz，3H).
Referring to the procedure of example 5, the following compounds can be prepared:
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-N-ethyl-5-(ethylamino)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ8.31(t，J＝5.9Hz，1H)，7.77(d，J＝8.7Hz，2H)，7.68(d，J＝8.7Hz，2H)，7.40(s，2H)，6.29(t，J＝6.3Hz，1H)，5.65(s，2H)，3.41(p， J＝7.0Hz，2H)，3.25(p，J＝7.1Hz，2H)，1.09(t，J＝7.1Hz，3H)，1.02(t，J＝7.1Hz， 3H).
example 61- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -5-propionamide-1H-1, 2, 3-triazole-4-carboxamide (E1)
CAI (300mg, 0.71mmol) was dispersed in 2.5mL propionyl chloride and stirred in an ice bath for half an hour. 2 drops of concentrated sulfuric acid are added dropwise, and ice bath stirring is continued. After half an hour the ice bath was removed and stirred at room temperature overnight. The reaction was stopped and saturated sodium bicarbonate solution was added to neutral pH. 5mL of ethyl acetate was added, washed three times with water, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent petroleum ether: ethyl acetate 2: 1) to give a white solid (0.364g, 76.0%).1H NMR(400MHz， DMSO-d6)δ10.21(s，1H)，7.93(s，1H)，7.77(d，J＝8.3Hz，2H)，7.68(d，J＝8.3Hz， 2H)，7.52(d，J＝22.2Hz，3H)，5.56(s，2H)，2.38(dd，J＝7.6Hz，2H)，1.06(t，J＝7.6 Hz，3H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-(N-propionylpropionamido)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.69(s，1H)，10.42(s，1H)，7.76(d，J＝8.7Hz，2H)， 7.69(d，J＝8.7Hz，2H)，7.51(s，2H)，5.63(s，2H)，2.67(q，J＝7.4Hz，2H)，2.39(q，J ＝7.5Hz，2H)，1.07(t，J＝7.5HZ，3H)，1.03(t，J＝7.4HZ，3H).
5-Butyramido-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3-triazole-4- carboxamide
1H NMR(400MHz，DMSO-d6)δ10.23(s，1H)，7.93(s，1H)，7.77(d，J＝8.6Hz， 2H)，7.68(d，J＝8.7Hz，2H)，7.54(s，1H)，7.48(s，2H)，5.56(s，2H)，2.33(t，J＝7.3 Hz，2H)，1.59(sext，J＝7.4Hz，2H)，0.91(t，J＝7.4Hz，3H).
5-(N-butyrylbutyramido)-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.70(s，1H)，10.44(s，1H)，7.6(d，J＝8.6Hz， 2H)，7.69(d，J＝8.7Hz，2H)，7.49(s，2H)，5.63(s，2H)，1.24(m，14H).
5-(3-Bromopropanamido)-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.56(s，1H)，7.94(s，1H)，7.78(d，J＝8.6Hz，2H)， 7.68(d，J＝8.7Hz，2H)，7.57(s，1H)，7.51(s，2H)，5.55(s，2H)，3.87(t，J＝6.3Hz， 2H)，2.92(t，J＝6.3Hz，2H).
5-(4-Bromobutanamido)-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.32(s，1H)，7.92(s，1H)，7.77(d，J＝8.6Hz，2H)， 7.68(d，J＝8.7Hz，2H)，7.54(s，1H)，7.50(s，2H)，5.57(s，2H)，3.71(t，J＝6.6Hz， 2H)，2.54(t，J＝6.6Hz，2H)，2.02(p，J＝6.6Hz，2H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzy1)-5-isobutyramido-1H-1，2，3-triazole-4- carboxamide
1H NMR(400MHz，DMSO-d6)δ10.16(s，1H)，7.93(s，1H)，7.77(d，J＝8.6Hz，2H)，7.68(d，J＝8.7Hz，2H)，7.46(s，2H)，5.56(s，2H)，2.65(hept，J＝6.7Hz，1H)， 1.10(d，J＝6.9Hz，6H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-(N-isobutyrylisobutyramido)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.77(s，1H)，10.37(s，1H)，7.76(d，J＝8.6Hz， 2H)，7.69(d，J＝8.6Hz，2H)，7.48(s，2H)，5.64(s，2H)，3.07(hept，J＝6.8Hz，1H)， 2.66(hept，J＝6.8Hz，1H)，1.10(d，J＝6.7Hz，6H)，1.08(d，J＝6.7Hz，6H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-pivalamido-1H-1，2，3-triazole-4- carboxamide
1H NMR(400MHz，DMSO-d6)δ9.66(s，1H)，7.92(s，1H)，7.77(d，J＝8.6Hz，2H)， 7.68(d，J＝8.7Hz，2H)，7.51(s，1H)，7.45(s，2H)，5.57(s，2H)，1.19(s，9H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-(N-pivaloylpivalamido)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.20(s，1H)，9.87(s，1H)，7.75(d，J＝8.7Hz，2H)，7.68(d，J＝8.8Hz，2H)，7.47(s，2H)，5.65(s，2H)，1.24(s，9H)，1.21(s，9H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-(2-ethylbutanamido)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.26(s，1H)，7.92(s，1H)，7.75(d，J＝8.6Hz，2H)， 7.68(d，J＝8.7Hz，2H)，7.51(s，1H)，7.43(s，2H)，5.57(s，2H)，2.31(m，1H)，1.57(m， 2H)，1.45(m，2H)，0.87(m，6H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-(2-ethyl-N-(2- ethylbutanoyl)butanamido)-1H-1，2，3-triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.86(s，1H)，10.48(s，1H)，7.75(d，J＝8.8Hz， 2H)，7.69(d，J＝8.9Hz，2H)，7.44(s，2H)，5.66(s，2H)，2.81(m，1H)，2.31(m，1H)， 1.57(m，4H)，1.44(m，4H)，0.86(m，12H).
1-(3，5-Dichloro-4-(4-chlorobenzoyl)benzyl)-5-(furan-2-carboxamido)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.02(dd，J＝1.8，0.8Hz，1H)，7.98 (s，1H)，7.76(d，J＝8.7Hz，2H)，7.69(d，J＝8.8Hz，2H)，7.58(s，1H)，7.49(s，2H)， 7.39(dd，J＝3.6，0.8Hz，1H)，6.75(dd，J＝3.5，1.7Hz，1H)，5.65(s，2H).
5-Benzamido-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3-triazole-4- carboxamide
1H NMR(400MHz，DMSO-d6)δ10.63(s，1H)，8.01(s，1H)，7.96(d，J＝7.4Hz， 2H)，7.75(d，J＝8.6Hz，2H)，7.68(d，J＝8.6Hz，2H)，7.64(d，J＝7.4Hz，1H)，7.56 (m，3H)，7.48(s，2H)，5.68(s，2H).
5-(Cyclopropanecarboxamido)-1-(3，5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1，2，3- triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ10.56(s，1H)，7.95(s，1H)，7.77(d，J＝8.7Hz， 2H)，7.68(d，J＝8.8Hz，2H)，7.57(s，1H)，7.45(s，2H)，5.55(s，2H)，4.03(q，J＝7.1 Hz，1H)，0.85(m，4H).
5-(N-(cyclopropanecarbonyl)cyclopropanecarboxamido)-1-(3，5-dichloro-4-(4- chlorobenzoyl)benzyl)-1H-1，2，3-triazole-4-carboxamide
1H NMR(400MHz，DMSO-d6)δ11.11(s，1H)，10.76(s，1H)，7.77(d，J＝8.6Hz， 2H)，7.69(d，J＝8.7Hz，2H)，7.48(s，2H)，5.64(s，2H)，2.43(s，1H)，1.88(s，1H)， 0.87(m，8H).
Example 71- (3, 5-dichloro-4- (4-chlorobenzoyl) benzyl) -1H-1, 2, 3-triazole-4-carboxamide (F1)
Prepared from (4- (azidomethyl) -2, 6-dichlorophenyl) (4-chlorophenyl) methanone (300mg, 0.88mmol), propynamide (74mg, 1.06mmol) with copper sulfate pentahydrate (23mg, 0.09mmol) and sodium ascorbate (52mg, 0.3mmol) in 16mL of dichloromethane/t-butanol/water (1/2/1) v/v/v. After stirring at room temperature for 2 hours, the reaction was stopped. Washed with water three times, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Separation by column chromatography (eluent petroleum ether: ethyl acetate 1: 2) gave a white solid (0.322g, 89.7%).1H NMR(400MHz，DMSO-d6)δ8.74(s，1H)，7.95(s，1H)， 7.79(d，J＝8.6Hz，2H)，7.69(s，2H)，7.67(d，J＝8.7Hz，2H)，7.56(s，1H)，5.77(s， 2H).
Example 8 Elisa test for IL-1. beta. content
1. Experimental reagent:
2. the experimental steps are as follows:
2.1 BMDM cell isolation and culture
2.1.1 after killing the mice by removing the neck, submerging the mice in 75% alcohol for 3-5 min;
2.1.2 separating the skin and muscle of the leg of the mouse by scissors and tweezers in a clean bench, separating the tibia and the femur, and soaking the tibia and the femur in 75% alcohol and a culture medium containing double antibodies for 3min respectively;
2.1.3 cutting off epiphyses at two ends of femur and tibia, sucking sterile PBS by using a 1ml syringe to wash bone marrow into a 50ml centrifuge tube, and washing each bone by using 5ml PBS;
2.1.4 bone marrow cell suspension was filtered through a 300 mesh screen into a 50ml centrifuge tube. Centrifuging at 4 deg.C for 5min at 1500g, discarding supernatant, adding 1ml erythrocyte lysate to lyse erythrocyte, suspending with 3 ml BMDM culture medium after 2min, and centrifuging again;
2.1.5 adding 10m1BMDM culture medium to resuspend the cells, and incubating in an incubator for 3 hours in a 10cm large dish;
2.1.6 Collection of nonadherent bone marrow cells in 15m1 centrifuge tubes, cell counting after centrifugation at 1X105Density plates in 96-well plates, medium change on day 3, and day 6 are available for experiments.
2.2 stimulation of inflammation
Day 6 morning, add 50ng/mL lipopolysaccharide solution to 96-well plates and stimulate for three hours.
2.3 administration of drugs
The compound was added to each well at a final concentration of 20. mu.M and incubated for 30 minutes
2.4 stimulation of ATP
A final concentration of 5mM ATP solution was added to further stimulate NLRP3 inflammation.
2.5 taking cell supernatant, and detecting the content of IL-1 beta according to the operation of an ELISA kit instruction.
Table one: inhibition rate of compound induced interleukin-1 beta expression
ELISA results showed that compounds other than compounds XIX, XX, XXII, XXIV, XXVIII, XXX, XXXII, XXXIV, inhibited IL-1. beta. to a different extent. Wherein the activity of the compounds VIII, XXV and XXXI is better than that of CAI.
Comparing the activity of each compound, the preliminary structure-activity relationship indicates that R2The monoacylation is carried out on the active structure of this class of compounds.
EXAMPLE 9 TNF-alpha content Elisa test
1. Experimental reagent:
2. the experimental steps are as follows:
2.1 RAW264.7 cell culture
Cells were plated at 2X105The density in 96 plate, cultured for 3 hours.
2.2 administration of drugs
Compounds were added to each well at a final concentration of 20 μ M and incubated for 30 minutes.
2.3 stimulation of inflammation
Cells were stimulated with a final concentration of 50ng/mL lipopolysaccharide solution for three hours
2.4 taking cell supernatant, and detecting the content of TNF-alpha according to the operation of an ELISA kit instruction.
Table two: inhibition rate of compound induced tumor necrosis factor-alpha expression
ELISA results showed that compounds other than compound XIV and XXIV inhibit TNF- α to different extents. Most of the compounds inhibit TNF-alpha less than CAI, which contributes to the selective inhibition of IL-1 beta by the compounds.
Example 10 selectivity of Compounds for IL-1 beta
Table three: selectivity index (selectivity index) of a compound for IL-1 beta
The selectivity of a compound for IL-1 β is expressed as the ratio of the inhibition of IL-1 β by the compound to the inhibition of TNF- α. Many compounds are selective over CAI (0.82). Wherein the selectivity index of compounds XXVI and XXXI is as high as more than ten, which shows that the selectivity of the compounds on IL-1 beta is greatly improved.
EXAMPLE 11 IC of representative Compounds on IL-1 beta inhibition50
Table four: IC for IL-1 beta inhibition by representative compoundss0(μM)
The results show that representative compounds have stable inhibitory activity against IL-1 beta.
Thus, the compounds of formula I all inhibit IL-1 β release to varying degrees. Representative compounds XXVI, XXXI therein greatly improve selectivity for IL-1 β inhibition while maintaining activity comparable to CAI. The compound shown in the formula I is expected to become a new anti-inflammatory drug or an autoimmune drug.
Claims (11)
1. A compound having the structure of formula I:
wherein:
R1independently selected from: amide, cyano, ester, acyl, substituted amide;
R2independently selected from: hydrogen, amino, alkylated amino,
Wherein R is3Independently selected from: hydrogen, C1-C6Alkanoyl, cyclopropanoyl, furoyl, tetrahydrofurfuryl, benzoyl, 3-bromopropionamido, 4-bromobutyramido;
R4independently selected from: hydrogen, C1-C6Alkanoyl, cyclopropanoyl, furoyl, tetrahydrofurfuryl, benzoyl, 3-bromopropionamido, 4-bromobutyramido.
2. The compound according to claim 1, and pharmaceutically acceptable salts thereof, wherein:
wherein,
R1independently selected from:
R2independently selected from:
3. the compound according to claim 2, and pharmaceutically acceptable salts thereof, selected from:
4. a process for the preparation of a compound according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof, comprising the steps of:
1) reacting carboxyamidotriazole with methyl iodide and sodium hydride in a polar solvent to obtain a compound A;
2) reacting carboxyamidotriazole with ethyl p-chlorobenzenesulfonate and sodium hydride in a polar solvent to obtain a compound A;
3) reacting the compound B with potassium carbonate and a cyano compound to obtain a compound C;
4) reacting the compound C with methyl iodide and sodium hydride in a polar solvent to obtain a compound D;
5) reacting the compound C with ethyl p-chlorobenzenesulfonate and sodium hydride in a polar solvent to obtain a compound D;
6) the compound E is obtained by carboxyamidotriazole and acyl chloride under the catalysis of concentrated sulfuric acid;
7) reacting the compound B with propynamide in a polar mixed solvent under the catalysis of copper sulfate pentahydrate and sodium ascorbate to obtain a compound F;
wherein the compound has the following structure:
5. the method of claim 4, wherein:
the reaction in the step 1)2)4)5) is carried out under the protection of nitrogen and under the heating condition.
Step 6) the reaction is carried out at low temperature. More preferably, the reaction temperature is 0 ℃.
The reaction in the step 7) is carried out in a polar mixed solvent, and the volume ratio of the mixed solvent is 1: 2: 1.
6. The method of claim 4, wherein:
the reaction in step 3) is carried out under alkaline conditions, and bases include but are not limited to sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium fluoride, potassium carbonate, sodium bicarbonate and cesium carbonate; preferably: potassium carbonate.
7. The method of claim 4, wherein:
step 1)2)4)5) in a polar solvent, including but not limited to N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, methyl ethyl ketone, 1, 4-dioxane, tert-butanol, water; preferably: n, N-dimethylformamide.
8. The method of claim 4, wherein:
step 7) the reaction is carried out in a mixed polar solvent, including but not limited to N, N-dimethylformamide, dimethyl sulfoxide, tert-butanol acetonitrile, acetone, methyl ethyl ketone, 1, 4-dioxane, water; preferably: water/dichloromethane/tert-butanol.
9. A composition comprising a compound of formula I as described in any one of claims 1-3, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
10. Use of a compound according to claims 1-3, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the inhibition of IL-1 β secretion.
11. Use of the compound of claim 10 and pharmaceutically acceptable salts thereof for the manufacture of autoimmune diseases and anti-inflammatory agents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110993643.0A CN113582935A (en) | 2021-08-27 | 2021-08-27 | Inflammatory corpuscle nucleotide-binding oligomerization domain-like receptor protein 3 inhibitor and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110993643.0A CN113582935A (en) | 2021-08-27 | 2021-08-27 | Inflammatory corpuscle nucleotide-binding oligomerization domain-like receptor protein 3 inhibitor and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113582935A true CN113582935A (en) | 2021-11-02 |
Family
ID=78240098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110993643.0A Pending CN113582935A (en) | 2021-08-27 | 2021-08-27 | Inflammatory corpuscle nucleotide-binding oligomerization domain-like receptor protein 3 inhibitor and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113582935A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023025264A1 (en) * | 2021-08-27 | 2023-03-02 | 中国医学科学院放射医学研究所 | 1,2,3-triazolopyrimidine compound, preparation method therefor and use thereof |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6057346A (en) * | 1994-12-12 | 2000-05-02 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibition of retroviral LTR promoters by calcium response modifiers |
| CN101164538A (en) * | 2006-10-16 | 2008-04-23 | 中国医学科学院基础医学研究所 | Application of carboxyamido-triazoles compound and its salt in preparing medicine for treating painful diseases and/or inflammatory diseases |
| CN101618036A (en) * | 2008-06-30 | 2010-01-06 | 中国医学科学院基础医学研究所 | Novel medicinal application of carboxyl aminotriazole and acceptable salts of the carboxyl aminotriazole |
| CN102595904A (en) * | 2009-09-04 | 2012-07-18 | 巧妙疗法股份有限公司 | Novel compositions and processes for preparing 5-amino or substituted amino 1,2,3-triazoles and triazole orotate formulations |
| US20160168158A1 (en) * | 2013-09-06 | 2016-06-16 | Hoffmann-La Roche Inc. | Novel triazolo[4,5-d]pyrimidine derivatives |
| CN107652293A (en) * | 2017-09-26 | 2018-02-02 | 中国药科大学 | Imidazopyridazines IRAK4 inhibitor and its preparation method and application |
| CN107890467A (en) * | 2017-11-24 | 2018-04-10 | 中国医学科学院基础医学研究所 | Application of the medicine of interfering energy metabolism in pancreas cancer recurrence |
| CN111253327A (en) * | 2018-12-03 | 2020-06-09 | 中国医学科学院基础医学研究所 | Application of carboxyamidotriazole compound or salt thereof in preparation of medicines for treating NLRP3 inflammatory-body-activation-related diseases |
| CN112358451A (en) * | 2021-01-11 | 2021-02-12 | 广东银珠医药科技有限公司 | Synthetic method of carboxyamidotriazole |
| US20210188897A1 (en) * | 2019-12-05 | 2021-06-24 | Sparx Therapeutics, Inc. | Neuroactive steroids and compositions and methods thereof |
-
2021
- 2021-08-27 CN CN202110993643.0A patent/CN113582935A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6057346A (en) * | 1994-12-12 | 2000-05-02 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibition of retroviral LTR promoters by calcium response modifiers |
| CN101164538A (en) * | 2006-10-16 | 2008-04-23 | 中国医学科学院基础医学研究所 | Application of carboxyamido-triazoles compound and its salt in preparing medicine for treating painful diseases and/or inflammatory diseases |
| CN101618036A (en) * | 2008-06-30 | 2010-01-06 | 中国医学科学院基础医学研究所 | Novel medicinal application of carboxyl aminotriazole and acceptable salts of the carboxyl aminotriazole |
| CN102595904A (en) * | 2009-09-04 | 2012-07-18 | 巧妙疗法股份有限公司 | Novel compositions and processes for preparing 5-amino or substituted amino 1,2,3-triazoles and triazole orotate formulations |
| US20160168158A1 (en) * | 2013-09-06 | 2016-06-16 | Hoffmann-La Roche Inc. | Novel triazolo[4,5-d]pyrimidine derivatives |
| CN107652293A (en) * | 2017-09-26 | 2018-02-02 | 中国药科大学 | Imidazopyridazines IRAK4 inhibitor and its preparation method and application |
| CN107890467A (en) * | 2017-11-24 | 2018-04-10 | 中国医学科学院基础医学研究所 | Application of the medicine of interfering energy metabolism in pancreas cancer recurrence |
| CN111253327A (en) * | 2018-12-03 | 2020-06-09 | 中国医学科学院基础医学研究所 | Application of carboxyamidotriazole compound or salt thereof in preparation of medicines for treating NLRP3 inflammatory-body-activation-related diseases |
| US20210188897A1 (en) * | 2019-12-05 | 2021-06-24 | Sparx Therapeutics, Inc. | Neuroactive steroids and compositions and methods thereof |
| CN112358451A (en) * | 2021-01-11 | 2021-02-12 | 广东银珠医药科技有限公司 | Synthetic method of carboxyamidotriazole |
Non-Patent Citations (1)
| Title |
|---|
| 夏然，等: "《药物生产与合成技术研究》", 30 June 2020, 天津科学技术出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023025264A1 (en) * | 2021-08-27 | 2023-03-02 | 中国医学科学院放射医学研究所 | 1,2,3-triazolopyrimidine compound, preparation method therefor and use thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5739169A (en) | Aromatic compounds for inhibiting immune response | |
| JP5754040B2 (en) | Modulator of TNFα signaling | |
| CZ2002642A3 (en) | N-Heterocyclic derivatives functioning as inhibitors of dinitrogen dioxide and pharmaceutical preparations containing thereof | |
| EA015251B1 (en) | Quinazoline derivatives and their use in the treatment of thrombocythemia | |
| TW200306818A (en) | Indolylmaleimide derivatives | |
| BG65837B1 (en) | New crystalline and amorphous form af a triazolo(4,5-d) pyrimidine compound | |
| CN118557580A (en) | JAK1 pathway inhibitors for the treatment of cytokine-related disorders | |
| US9962383B2 (en) | Compounds, compositions and methods of agelastatin alkaloids | |
| JPS60142932A (en) | Indene derivative useful as antagonist against thrombocyte activating factor | |
| JP2013506716A (en) | Methods for treating diseases using proanthocyanidin oligomers such as crofelemer | |
| US5547970A (en) | Use of leflunomide for inhibiting tumor necrosis factor alpha | |
| WO2023025264A1 (en) | 1,2,3-triazolopyrimidine compound, preparation method therefor and use thereof | |
| JP6289659B2 (en) | Pentacyclic triterpene structure-modifying compounds and their preparation and applications | |
| CN113582935A (en) | Inflammatory corpuscle nucleotide-binding oligomerization domain-like receptor protein 3 inhibitor and preparation method and application thereof | |
| JP2006513185A (en) | Process for the preparation of substantially pure polymorphs of N-pyrazolyl-N'-naphthyl-urea | |
| EP2021003A2 (en) | Imidazoazephinone compounds | |
| EP2217242A1 (en) | Methods of use | |
| WO2022192731A1 (en) | Compositions and methods for treating anemia associated with a ribosomal disorder | |
| CN113004253B (en) | Di- (benzimidazole) -1,2, 3-triazole derivative, preparation method thereof and application thereof in inflammatory skin diseases | |
| US20160251330A1 (en) | Chromene derivatives as inhibitors of tcr-nck interaction | |
| EP2220087A1 (en) | Enantiomerically enriched imidazoazepinone compounds | |
| CN112358517B (en) | Benzimidazole derivative BI305 and preparation method and application thereof | |
| CN112999227B (en) | Medicament containing di- (benzimidazole) -1,2, 3-triazole derivative | |
| CN112375112B (en) | Benzimidazole derivative BI361 and preparation method and application thereof | |
| KR20050059132A (en) | Novel crystals |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20211102 |
|
| WD01 | Invention patent application deemed withdrawn after publication |