CN117384150A - 噻唑烷酮类免疫蛋白酶体抑制剂及其制法和药物用途 - Google Patents
噻唑烷酮类免疫蛋白酶体抑制剂及其制法和药物用途 Download PDFInfo
- Publication number
- CN117384150A CN117384150A CN202210782937.3A CN202210782937A CN117384150A CN 117384150 A CN117384150 A CN 117384150A CN 202210782937 A CN202210782937 A CN 202210782937A CN 117384150 A CN117384150 A CN 117384150A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- alkyl
- reaction
- phenyl
- 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 31
- 229940126097 immunoproteasome inhibitor Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- -1 thiazolidine ketone compound Chemical class 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 6
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
- KPPVNWGJXFMGAM-UUILKARUSA-N (e)-2-methyl-1-(6-methyl-3,4-dihydro-2h-quinolin-1-yl)but-2-en-1-one Chemical compound CC1=CC=C2N(C(=O)C(/C)=C/C)CCCC2=C1 KPPVNWGJXFMGAM-UUILKARUSA-N 0.000 claims description 4
- 238000010976 amide bond formation reaction Methods 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 238000013268 sustained release Methods 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 239000007787 solid Substances 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- 238000004896 high resolution mass spectrometry Methods 0.000 description 40
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 34
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 26
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 23
- 238000003818 flash chromatography Methods 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 229940117953 phenylisothiocyanate Drugs 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 238000009987 spinning Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- 239000007795 chemical reaction product Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 11
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 10
- 210000004072 lung Anatomy 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- KKASGUHLXWAKEZ-UHFFFAOYSA-N 1-isothiocyanatopropane Chemical compound CCCN=C=S KKASGUHLXWAKEZ-UHFFFAOYSA-N 0.000 description 4
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229960002591 hydroxyproline Drugs 0.000 description 4
- 238000003119 immunoblot Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000004770 neurodegeneration Effects 0.000 description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 4
- SIAVMDKGVRXFAX-UHFFFAOYSA-N 4-carboxyphenylboronic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C=C1 SIAVMDKGVRXFAX-UHFFFAOYSA-N 0.000 description 3
- WJTFHWXMITZNHS-UHFFFAOYSA-N 5-bromofuran-2-carbaldehyde Chemical compound BrC1=CC=C(C=O)O1 WJTFHWXMITZNHS-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 239000007771 core particle Substances 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000003207 proteasome inhibitor Substances 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 description 3
- OYKDNXIKMAQMJG-UHFFFAOYSA-N pyridin-3-yl thiocyanate Chemical compound N#CSC1=CC=CN=C1 OYKDNXIKMAQMJG-UHFFFAOYSA-N 0.000 description 3
- 239000012679 serum free medium Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- ZAZPDOYUCVFPOI-UHFFFAOYSA-N 2-methylpropylboronic acid Chemical compound CC(C)CB(O)O ZAZPDOYUCVFPOI-UHFFFAOYSA-N 0.000 description 2
- QRTAOOSYSVHQGT-UHFFFAOYSA-N 5-(4-bromophenyl)furan-2-carbaldehyde Chemical compound C1=CC(Br)=CC=C1C1=CC=C(C=O)O1 QRTAOOSYSVHQGT-UHFFFAOYSA-N 0.000 description 2
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 229940090044 injection Drugs 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 2
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 1
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- SLYRGJDSFOCAAI-UHFFFAOYSA-N 1,3-thiazolidin-2-one Chemical class O=C1NCCS1 SLYRGJDSFOCAAI-UHFFFAOYSA-N 0.000 description 1
- FCEKLQPJGXIQRY-UHFFFAOYSA-N 1-isothiocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1N=C=S FCEKLQPJGXIQRY-UHFFFAOYSA-N 0.000 description 1
- WVBNZZHGECFCSH-UHFFFAOYSA-N 2,4-dichloro-1-isothiocyanatobenzene Chemical compound ClC1=CC=C(N=C=S)C(Cl)=C1 WVBNZZHGECFCSH-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical compound C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-UHFFFAOYSA-N 0.000 description 1
- VPSARXNVXCRDIV-UHFFFAOYSA-N 3-(4-boronophenyl)propanoic acid Chemical compound OB(O)C1=CC=C(CCC(O)=O)C=C1 VPSARXNVXCRDIV-UHFFFAOYSA-N 0.000 description 1
- VMSZFBSYWXMXRF-UHFFFAOYSA-N 3-isothiocyanatopyridine Chemical group S=C=NC1=CC=CN=C1 VMSZFBSYWXMXRF-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- ASOXJGFTNRPKEN-UHFFFAOYSA-N 4-borono-2-methoxybenzoic acid Chemical compound COC1=CC(B(O)O)=CC=C1C(O)=O ASOXJGFTNRPKEN-UHFFFAOYSA-N 0.000 description 1
- JDRMYOQETPMYQX-UHFFFAOYSA-M 4-methoxy-4-oxobutanoate Chemical compound COC(=O)CCC([O-])=O JDRMYOQETPMYQX-UHFFFAOYSA-M 0.000 description 1
- PHNDZBFLOPIMSM-UHFFFAOYSA-N 4-morpholin-4-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCOCC1 PHNDZBFLOPIMSM-UHFFFAOYSA-N 0.000 description 1
- GFBVUFQNHLUCPX-UHFFFAOYSA-N 5-bromothiophene-2-carbaldehyde Chemical compound BrC1=CC=C(C=O)S1 GFBVUFQNHLUCPX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- BMGMQYRPZOGZFU-YFKPBYRVSA-N [(1r)-1-amino-3-methylbutyl]boronic acid Chemical compound CC(C)C[C@H](N)B(O)O BMGMQYRPZOGZFU-YFKPBYRVSA-N 0.000 description 1
- UBVOLHQIEQVXGM-UHFFFAOYSA-N [4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid Chemical compound CC(C)(C)OC(=O)NC1=CC=C(B(O)O)C=C1 UBVOLHQIEQVXGM-UHFFFAOYSA-N 0.000 description 1
- SAZUGELZHZOXHB-UHFFFAOYSA-N acecarbromal Chemical compound CCC(Br)(CC)C(=O)NC(=O)NC(C)=O SAZUGELZHZOXHB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229940040609 bleomycin injection Drugs 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- JDRMYOQETPMYQX-UHFFFAOYSA-N butanedioic acid monomethyl ester Natural products COC(=O)CCC(O)=O JDRMYOQETPMYQX-UHFFFAOYSA-N 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000512 collagen gel Substances 0.000 description 1
- 229940096422 collagen type i Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- XYRYDVSXZCBWQD-UHFFFAOYSA-N fluorobenzene;isothiocyanic acid Chemical compound N=C=S.FC1=CC=CC=C1 XYRYDVSXZCBWQD-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002496 gastric effect Effects 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
- 239000001963 growth medium Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000005980 lung dysfunction Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 1
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical compound COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 1
- 229950004616 tribromoethanol Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (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)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域，公开了通式(I)所示新的噻唑烷酮类化合物及其立体异构体和生理上可接受的盐，所述化合物的制备方法，含有所述化合物的药物制剂，以及所述化合物在治疗与免疫蛋白酶体相关疾病中的临床应用。
Description
技术领域
本发明属于药物化学领域，涉及通式(I)新的噻唑烷酮类化合物及其立体异构体和它们的生理上可接受的盐。这些化合物在与免疫蛋白酶体相关的疾病的治疗过程中的用途，还涉及其用于治疗的方法，以及含有所述化合物的药物组合物。
背景技术
泛素-蛋白酶体通路是真核细胞中蛋白质降解的主要途径，在蛋白质量控制、抗原提呈、信号转导、细胞周期的控制、细胞分化和凋亡等生理过程中发挥着重要作用。作为泛素-蛋白酶体通路的催化中心，蛋白酶体是治疗肿瘤、炎症、自身免疫性疾病和神经退行性疾病等的潜在靶点。目前已有三个蛋白酶体抑制剂硼替佐米、卡非佐米、艾莎佐米先后作为抗肿瘤药物经美国FDA批准上市；此外，蛋白酶体抑制剂作为自身免疫性疾病治疗药物亦正在临床研究中。
20S核心颗粒是蛋白酶体进行蛋白降解的催化中心。真核细胞的20S核心颗粒为四层环状结构，两个外层由七个α亚基组成，两个内层则由7个β亚基构成，其中只有β1、β2和β5具有催化活性。组成型蛋白酶体(constitutive proteasome,cCP)的催化亚基β1c、β2c和β5c是蛋白水解的主要场所。细胞应激反应会促使免疫系统表达免疫蛋白酶体(immunoproteasome,iCP)，其催化亚基分别为β1i、β2i和β5i。现有的蛋白酶体抑制剂大多都同时与cCP及iCP的20S核心颗粒的多个催化亚基发生可逆或不可逆的结合作用，存在嗜中性白血球减少症、血小板减少、胃肠反应、周围神经病变、低血压、肺功能紊乱和心脏毒性等副作用。cCP在大多数细胞中都表达，且参与了许多正常的生理功能，因此，抑制cCP可能造成全身毒性。而iCP在正常细胞中表达水平不高，研究已证实其表达与炎性肠病、类风湿性关节炎等自身免疫性疾病以及多发性骨髓瘤等都密切相关。因此，选择性抑制免疫蛋白酶体是更合理的药物设计策略。
本发明旨在提供一种新的噻唑烷酮类化合物，其具有高的免疫蛋白酶体抑制活性，可用于治疗肿瘤、炎症、自身免疫性疾病、神经退行性疾病等与免疫蛋白酶体相关的疾病。
发明内容
本发明的目的在于提供一种通式(I)所示新的噻唑烷酮类化合物。
本发明的另一目的在于提供一种制备通式(I)所示新的噻唑烷酮类化合物的方法。
本发明的又一目的在于提供通式(I)所示新的噻唑烷酮类化合物在抑制免疫蛋白酶体中的用途，以及治疗与免疫蛋白酶体有关的疾病中的用途。
为了完成本发明的目的，本发明采用的技术方案在于在于提供通式(I)所示的化合物及其立体异构体或其生理上可接受的盐：：
其中，
R1选自C1-C6烷基、(CH2)nLR4；其中，n为1，2或3，L选自O，S，N或COO，R4选自C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自取代或未取代的苯基、萘基、吡啶基，取代基选自单取代或多取代的卤素、C1-C3烷基、C1-C3烷氧基、C1-C3烷胺基、吗啉基、CF3；
R3选自羧基、硼酸基、硼酸酯基、(CH2)mCOOH、CONH(CHR5)COOH、CONH(CHR5)B(OH)2、NHCO(CH2)mCOOH，其中m为1，2或3，R5选自H、C1-C6烷基、苄基；
X选自O或S。
本发明的又一技术方案在于提供通式(IA)所示的化合物及其立体异构体或其生理上可接受的盐：
其中，
R1选自C1-C6直链烷基、(CH2)nLR4；其中，n为1或2，L选自O，S，N或COO，R4为C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自苯基、氟取代的苯基、吡啶基。
本发明的又一技术方案在于提供通式(IB)所示的化合物及其立体异构体或其生理上可接受的盐：
其中，
R1选自C1-C6直链烷基、(CH2)nLR4；其中，n为1或2，L选自O，S，N或COO，R4为C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自苯基、氟取代的苯基、吡啶基。
本发明的又一技术方案在于提供通式(IC)所示的化合物及其立体异构体或其生理上可接受的盐：
其中，
R1选自C1-C6直链烷基、(CH2)nLR4；其中，n为1或2，L选自O，S，N或COO，R4为C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自苯基、氟取代的苯基、吡啶基；
R5选自H、C1-C6烷基、苄基；
R6选自COOH、B(OH)2。
本发明的又一技术方案在于提供通式(ID)所示的化合物及其立体异构体或其生理上可接受的盐：
其中，
R1选自C1-C6直链烷基、(CH2)nLR4；其中，n为1或2，L选自O，S，N或COO，R4为C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自苯基、氟取代的苯基、吡啶基；
m为1，2或3。
本发明的又一技术方案在于提供所示的化合物及其立体异构体或其生理上可接受的盐，其特征在于，所述的化合物选自：
/>
本发明的又一技术方案在于提供通式(I)所示的化合物制备方法，其特征在于，包括以下步骤：
式II化合物与式III化合物在室温下反应生成式IV化合物，式IV化合物与溴乙酸反应生成式V化合物；式VI化合物与式VII化合物经偶联反应生成式VIII化合物；式IX化合物与式VII化合物经偶联反应生成式X化合物；式V化合物与式XI化合物经缩合反应生成式XII化合物；式V化合物与式VIII化合物经缩合反应，或式V化合物与式VIII化合物经缩合反应、酰胺键形成反应、水解反应，或式V化合物与式X化合物经缩合反应、脱保护反应、酰胺键形成反应、水解反应,或式XII化合物经偶联反应，或式XII化合物经偶联、水解反应生成式I目标化合物；
其中，R1、R2、R3、X及m的定义同权利要求1～6任意一项。
为了制成药剂，可将通式(I)化合物按已知方法与合适的制药载体物质、芳香剂、调味剂和颜料用已知的方法混合，并被制成片剂或包衣的片剂，或者将其与其它的附加物质悬浮或溶解在水或油中。
本发明还涉及一种含有药物有效剂量的如通式(I)所述的化合物和药学上可接受的载体的药物组合物。
药理学研究表明，本发明的通式(I)化合物具有抑制免疫蛋白酶体的活性，可用于治疗与免疫蛋白酶体活性相关的疾病，如炎症，肿瘤，自身免疫性疾病，神经退行性疾病等。
本发明化合物可用口服方法或非肠胃道用药。口服用药可以是片剂、胶囊剂、包衣剂，非经肠用药剂型有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂，例如淀粉，明胶，阿拉伯胶，硅石，聚乙二醇，液体剂型所用的溶剂例如有水，乙醇，丙二醇，植物油类如玉米油，花生油，橄榄油等。含有本发明化合物的制剂中还可有其他助剂，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂，色素等。
有益技术效果：
实现选择性抑制是目前免疫蛋白酶体抑制剂研究面临的主要挑战之一。本发明化合物具有选择性抑制免疫蛋白酶体的特点和优势，并在体内外实验中表现出显著的抗肺纤维化作用，有望为与免疫蛋白酶体相关的肿瘤、炎症、自身免疫性疾病、神经退行性疾病等疾病，尤其是特发性肺纤维化提供新的安全有效的治疗手段。
附图说明：
图1.化合物在40μM时对RAW264.7细胞TNF-α释放的抑制作用。
图2.化合物对肺成纤维细胞胶原收缩的影响。Nint：尼达尼布。
图3.化合物对COL1A1表达含量的影响。Nint：尼达尼布。
图4.NGL-20-30体内抗肺纤维化活性。Nint：尼达尼布。
具体实施方式
以下结合实施例对发明作进一步的说明，但这些实施例并不限制本发明的范围。
化合物的结构是通过核磁共振(NMR)或质谱(MS)或高分辨质谱(HRMS)来确定的。NMR位移(δ)以百万分之一(ppm)的单位给出。m.p.是以℃给出的熔点，温度未加校正。快速柱层析用Isco CombiFlash Rf快速纯化仪完成。NMR测定是用JEOL ECZ-400S和INOVA-500MHz，测定溶剂为DMSO-D6，内标为TMS，化学位移是以ppm作为单位给出。MS的测定用Agilent LC/MSD TOF液质联用仪。
实施例1：NGL-17-11
a)将2-甲氧基乙胺(209μL，2.4mmol)加入至10mL苯基异硫氰酸酯(239μL，2mmol)的乙腈溶液中，室温搅拌，TLC监测反应完全后，旋除溶剂，加入乙酸乙酯溶解所得物，1MHCl洗，旋除乙酸乙酯，干燥备用。
b)将上述产物(376mg，1.79mmol)、乙酸钠(176mg，2.15mmol)、10mL乙醇依次加入50mL圆底烧瓶中，于室温搅拌下加入溴乙酸(299mg，2.15mmol)，升温至回流反应24h，旋除溶剂，乙酸乙酯稀释反应液，饱和碳酸氢钠、饱和氯化钠洗，旋除乙酸乙酯，残余物通过快速柱层析纯化。
c)将5-溴-2-呋喃甲醛(350mg，2mmol)，对羧基苯硼酸(398mg，2.4mmol)，碳酸钾(829mg，6mmol)，Pd(PPh3)4(116mg，0.1mmol)加入schelenk管中，氮气置换气体三次，加入3mL甲苯、3mL乙醇、1mL水,90℃反应12h，加10mL水稀释反应液，硅藻土过滤，旋除有机溶剂，加1M HCl至固体析出完全，过滤得到白色固体，干燥备用。
d)将上述b)反应产物(100mg，0.4mmol)、上述c)反应产物(69mg，0.32mmol)、吡咯烷(26μL，0.32mmol)、5mL乙醇加入50mL圆底瓶中，回流反应4h，旋除溶剂，所得残余物通过快速柱层析纯化，所得固体经乙醇-水重结晶，得黄色固体19mg，收率13.2％。m.p.:279-280℃。1H NMR(400MHz,DMSO-d6)δ7.92(d,J＝8.5Hz,2H),7.73(d,J＝8.5Hz,2H),7.62(s,1H),7.52–7.46(m,2H),7.39(d,J＝3.7Hz,1H),7.31–7.26(m,1H),7.18(d,J＝3.7Hz,1H),7.13–7.09(m,2H),4.09(t,J＝5.8Hz,2H),3.70(t,J＝5.8Hz,2H),3.31(s,3H).HR-MS:m/z＝449.11557[M+H]+,calcd for C24H21O5N2S:449.11657.
实施例2：NGL-17-15
制备方法与实施例1类似，不同之处在于，用正丙胺替代实施例1中的2-甲氧基乙胺。得红色固体31mg，收率20.8％。m.p.:276-278℃。1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),7.91(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.61(s,1H),7.51-7.45(m,2H),7.38(d,J＝3.7Hz,1H),7.32–7.25(m,1H),7.17(d,J＝3.7Hz,1H),7.13–7.08(m,2H),3.88(t,J＝7.2Hz,2H),1.81-1.70(m,2H),0.94(t,J＝7.4Hz,3H).HR-MS:m/z＝433.12042[M+H]+,calcd for C24 H21 O4 N2 S:433.12165.
实施例3：NGL-17-16
制备方法与实施例1类似，不同之处在于，用1-萘胺替代实施例1中的2-甲氧基乙胺、用丙基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得红色固体53mg，收率39.2％。m.p.:266-269℃。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),8.03–7.95(m,2H),7.88–7.84(m,3H),7.66–7.51(m,6H),7.35(d,J＝3.7Hz,1H),7.26(dd,J＝7.3,1.1Hz,1H),7.15(d,J＝3.7Hz,1H),4.03(t,J＝7.2Hz,2H),1.95-1.83(m,2H),1.03(t,J＝7.4Hz,3H).HR-MS:m/z＝483.13724[M+H]+,calcd for C28H23O4N2S:483.13730.
实施例4：NGL-17-21
制备方法与实施例1类似，不同之处在于，用异丙胺替代实施例1中的2-甲氧基乙胺。得黄色固体42mg，收率28.2％。m.p.:256-258℃。1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝8.5Hz,2H),7.69(d,J＝8.5Hz,2H),7.55(s,1H),7.52–7.45(m,2H),7.36(d,J＝3.7Hz,1H),7.32–7.26(m,1H),7.15(d,J＝3.7Hz,1H),7.12–7.08(m,2H),4.97–4.87(m,1H),1.53(d,J＝6.9Hz,6H).HR-MS:m/z＝433.12076[M+H]+,calcd for C24H21O4N2S:433.12165.
实施例5：NGL-17-22
制备方法与实施例1类似，不同之处在于，用N,N-二甲基乙二胺替代实施例1中的2-甲氧基乙胺。得黄色固体68mg，收率44.9％。m.p.:>300℃。1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),9.76(s,1H),7.93(d,J＝8.5Hz,2H),7.74(d,J＝8.5Hz,2H),7.65(s,1H),7.55–7.48(m,2H),7.41(d,J＝3.7Hz,1H),7.34–7.28(m,1H),7.22(d,J＝3.7Hz,1H),7.19–7.15(m,2H),4.26(t,J＝5.8Hz,2H),3.53(brs,2H),2.92(s,6H).HR-MS:m/z＝462.14734[M+H]+,calcd for C25H24O4N3S:462.14820.
实施例6：NGL-17-23
制备方法与实施例1类似，不同之处在于，用对甲氧基苯胺替代实施例1中的2-甲氧基乙胺、用丙基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体23mg，收率16.4％。m.p.:246-249℃。1H NMR(400MHz,DMSO-d6)δ7.94(d,J＝8.5Hz,2H),7.75(d,J＝8.5Hz,2H),7.59(s,1H),7.39(d,J＝3.7Hz,1H),7.16(d,J＝3.7Hz,1H),7.05(s,4H),3.87(t,J＝7.3Hz,2H),3.83(s,3H),1.80-1.70(m,2H),0.94(t,J＝7.4Hz,3H).HR-MS:m/z＝463.13156[M+H]+,calcd for C25H23O5N2S:463.13222.
实施例7：NGL-17-28
制备方法与实施例1类似，不同之处在于，用2-萘胺替代实施例1中的2-甲氧基乙胺、用丙基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体18mg，收率11.3％。m.p.:278-280℃。1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),8.06–7.95(m,3H),7.69(overlap,3H),7.61(overlap,3H),7.59–7.50(m,2H),7.35(d,J＝3.7Hz,1H),7.30(dd,J＝8.6,2.1Hz,1H),7.16(d,J＝3.7Hz,1H),3.94(t,J＝7.2Hz,2H),1.81–1.71(m,2H),0.98(t,J＝7.4Hz,3H).HR-MS:m/z＝483.13675[M+H]+,calcd for C28H23O4N2S:483.13730.
实施例8：NGL-17-30
制备方法与实施例1类似，不同之处在于，用甲胺盐酸盐替代实施例1中的2-甲氧基乙胺。得红色固体116mg，收率73.5％。m.p.:>300℃。1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),7.91(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.61(s,1H),7.51–7.45(m,2H),7.38(d,J＝3.7Hz,1H),7.31–7.25(m,1H),7.17(d,J＝3.7Hz,1H),7.13–7.09(m,2H),3.35(s,3H).HR-MS:m/z＝405.08963[M+H]+,calcd for C22H17O4N2S:405.09035.
实施例9：NGL-17-33
制备方法与实施例1类似，不同之处在于，用环戊胺替代实施例1中的2-甲氧基乙胺。得黄色固体63mg，收率43.7％。m.p.:>300℃。1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,2H),7.57(s,1H),7.51-7.45(m,2H),7.37(d,J＝3.7Hz,1H),7.31-7.26(m,1H),7.15(d,J＝3.7Hz,1H),7.12–7.08(m,2H),5.11-5.01(m,1H),2.25(brs,2H),1.91(brs,4H),1.62(brs,2H).HR-MS:m/z＝459.13876[M+H]+,calcd for C26H23O4N2S:459.13730.
实施例10：NGL-17-45
制备方法与实施例1类似，不同之处在于，用2-(硫代甲基)乙胺替代实施例1中的2-甲氧基乙胺。得黄色固体76mg，收率54.5％。m.p.:262-263℃。1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),7.91(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.62(s,1H),7.51–7.45(m,2H),7.38(d,J＝3.7Hz,1H),7.31–7.26(m,1H),7.18(d,J＝3.7Hz,1H),7.13–7.08(m,2H),4.11(t,J＝6.8Hz,2H),2.90(t,J＝6.8Hz,2H),2.16(s,3H).HR-MS:m/z＝465.09332[M+H]+,calcd for C24H21O4N2S2:465.09373.
实施例11：NGL-17-46
制备方法与实施例1类似，不同之处在于，用正丙胺替代实施例1中的2-甲氧基乙胺、用2,4-二氯苯基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体55mg，收率42.2％。m.p.:270-272℃。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),7.94(d,J＝8.5Hz,2H),7.80(d,J＝2.4Hz,1H),7.71(d,J＝8.5Hz,2H),7.68(s,1H),7.57(dd,J＝8.5,2.4Hz,1H),7.40(d,J＝3.7Hz,1H),7.27(d,J＝8.5Hz,1H),7.22(d,J＝3.7Hz,1H),3.90(t,J＝7.2Hz,2H),1.84-1.74(m,2H),0.95(t,J＝7.4Hz,3H).HR-MS:m/z＝501.04309[M+H]+,calcd forC24H19O4N2Cl2S:501.04371.
实施例12：NGL-17-47
制备方法与实施例1类似，不同之处在于，用异丁胺替代实施例1中的2-甲氧基乙胺。得黄色固体71mg，收率49.7％。m.p.:296-298℃。1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),7.91(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.61(s,1H),7.51-7.45(m,2H),7.39(d,J＝3.7Hz,1H),7.31-7.25(m,1H),7.17(d,J＝3.7Hz,1H),7.11–7.06(m,2H),3.75(d,J＝7.4Hz,2H),2.31-2.22(m,1H),0.95(d,J＝6.7Hz,6H).HR-MS:m/z＝447.13657[M+H]+,calcd for C25H23O4N2S:447.13730.
实施例13：NGL-17-48
制备方法与实施例1类似，不同之处在于，用甘氨酸乙酯盐酸盐替代实施例1中的2-甲氧基乙胺。得红色固体21mg，收率14.7％。m.p.:216-219℃。1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),7.93(d,J＝8.5Hz,2H),7.74(d,J＝8.5Hz,2H),7.70(s,1H),7.52-7.45(m,2H),7.41(d,J＝3.7Hz,1H),7.32-7.27(m,1H),7.23(d,J＝3.7Hz,1H),7.09–7.05(m,2H),4.69(s,2H),4.21(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H).HR-MS:m/z＝477.11069[M+H]+,calcd for C25H21O6N2S:477.11148.
实施例14：NGL-17-49
制备方法与实施例1类似，不同之处在于，用4-(4-吗啉基)苯胺替代实施例1中的2-甲氧基乙胺、用丙基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得红色固体30mg，收率23.2％。m.p.:>300℃。1H NMR(400MHz,DMSO-d6)δ13.06(s,1H),7.90(d,J＝8.5Hz,2H),7.70(d,J＝8.5Hz,2H),7.52(s,1H),7.32(d,J＝3.7Hz,1H),7.10(d,J＝3.7Hz,1H),7.02(d,J＝9.0Hz,2H),6.96(d,J＝9.0Hz,2H),3.82(t,J＝7.3Hz,2H),3.75(t,J＝4.8Hz,4H),3.13(t,J＝4.8Hz,4H),1.76–1.64(m,2H),0.89(t,J＝7.4Hz,3H).HR-MS:m/z＝518.17358[M+H]+,calcd for C28H28O5N3S:518.17442.
实施例15：NGL-18-2
制备方法与实施例1类似，不同之处在于，用甘氨酸甲酯盐酸盐替代实施例1中的2-甲氧基乙胺。得黄色固体38mg，收率27.4％。m.p.:264-265℃。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),7.92(d,J＝8.2Hz,2H),7.74(d,J＝8.2Hz,2H),7.70(s,1H),7.52-7.45(m,2H),7.40(d,J＝3.7Hz,1H),7.32-7.27(m,1H),7.23(d,J＝3.7Hz,1H),7.09–7.05(m,2H),4.72(s,2H),3.75(s,3H).HR-MS:m/z＝463.09525[M+H]+,calcd for C24H19O6N2S:463.09583.
实施例16：NGL-18-25
制备方法与实施例1类似，不同之处在于，用正丙胺替代实施例1中的2-甲氧基乙胺、用2-(N,N-二甲基)异硫氰酸苯酯替代实施例1中的苯基异硫氰酸酯。得红色固体72mg，收率45.9％。m.p.:183-185℃。1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),7.91(d,J＝8.1Hz,2H),7.70(d,J＝8.1Hz,2H),7.58(s,1H),7.37(d,J＝3.7Hz,1H),7.24–7.17(m,1H),7.14(d,J＝3.7Hz,1H),7.08(d,J＝8.0Hz,1H),7.05-6.99(m,1H),6.97–6.92(m,1H),3.91(t,J＝7.3Hz,2H),2.69(s,6H),1.86-1.72(m,2H),0.95(t,J＝7.4Hz,3H).HR-MS:m/z＝476.16321[M+H]+,calcd for C26H26O4N3S:476.16385.
实施例17：NGL-18-33
制备方法与实施例1类似，不同之处在于，用正丙胺替代实施例1中的2-甲氧基乙胺、用3-吡啶基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体65mg，收率40.5％。m.p.:279-281℃。1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),8.50(dd,J＝4.6,1.6Hz,1H),8.37(d,J＝2.5Hz,1H),7.92(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.66(s,1H),7.59–7.55(m,1H),7.54–7.49(m,1H),7.39(d,J＝3.7Hz,1H),7.20(d,J＝3.7Hz,1H),3.89(t,J＝7.3Hz,2H),1.82-1.70(m,2H),0.95(t,J＝7.4Hz,3H).HR-MS:m/z＝434.11667[M+H]+,calcd for C23H20O4N3S:434.11690.
实施例18：NGL-19-4
制备方法与实施例1类似，不同之处在于，用正丙胺替代实施例1中的2-甲氧基乙胺、用3-甲氧基-4-羧基苯硼酸替代实施例1中的对羧基苯硼酸。得黄色固体102mg，收率55.1％。m.p.:222-223℃。1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),7.67(d,J＝7.9Hz,1H),7.63(s,1H),7.45–7.39(m,2H),7.37(d,J＝3.7Hz,1H),7.34(dd,J＝7.9,1.5Hz,1H),7.28–7.23(m,1H),7.19(d,J＝3.7Hz,1H),7.16(d,J＝1.5Hz,1H),7.03(dd,J＝7.5,1.7Hz,2H),3.93–3.82(m,2H),3.49(s,3H),1.81–1.69(m,2H),0.94(t,J＝7.5Hz,3H).HR-MS:m/z＝463.13318[M+H]+,calcd for C25H23O5N2S:463.13222.
实施例19：NGL-19-17
制备方法与实施例1类似，不同之处在于，用3-吡啶基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体42mg，收率29.2％。m.p.:290-292℃。1H NMR(400MHz,DMSO-d6)δ8.50(dd,J＝4.6,1.6Hz,1H),8.38(dd,J＝2.6,0.8Hz,1H),7.92(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.67(s,1H),7.58(ddd,J＝8.1,2.6,1.6Hz,1H),7.53(ddd,J＝8.1,4.6,0.8Hz,1H),7.40(d,J＝3.7Hz,1H),7.21(d,J＝3.7Hz,1H),4.10(t,J＝5.8Hz,2H),3.71(t,J＝5.8Hz,2H),3.31(s,3H).HR-MS:m/z＝450.11313[M+H]+,calcd forC23H20O5N3S:450.11182.
实施例20：NGL-19-22
制备方法与实施例1类似，不同之处在于，用2-(硫代甲基)乙胺替代实施例1中的2-甲氧基乙胺、用3-吡啶基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体93mg，收率66.5％。m.p.:252-254℃。1H NMR(400MHz,DMSO-d6)δ13.13(s,1H),8.50(dd,J＝4.5,1.7Hz,1H),8.38(d,J＝2.4Hz,1H),7.92(d,J＝8.3Hz,2H),7.73(d,J＝8.3Hz,2H),7.68(s,1H),7.63–7.56(m,1H),7.55–7.50(m,1H),7.40(d,J＝3.7Hz,1H),7.22(d,J＝3.7Hz,1H),4.13(t,J＝6.8Hz,2H),2.91(t,J＝6.8Hz,2H),2.16(s,3H).HR-MS:m/z＝466.09061[M+H]+,calcd for C23H20O4N3S2:466.08897.
实施例21：NGL-19-30
制备方法与实施例1类似，不同之处在于，用正丙胺替代实施例1中的2-甲氧基乙胺、用5-溴噻吩-2-甲醛替代实施例1中的5-溴-2-呋喃甲醛、用3-吡啶基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体63mg，收率41.2％。m.p.:201-203℃。1H NMR(400MHz,DMSO-d6)δ8.46(dd,J＝4.4,1.8Hz,1H),8.34(dd,J＝2.4,1.0Hz,1H),8.08(d,J＝0.6Hz,1H),7.96(d,J＝8.6Hz,2H),7.84(s,1H),7.83–7.81(m,2H),7.72(dd,J＝4.0,0.6Hz,1H),7.54–7.46(m,2H),3.93–3.83(m,2H),1.80-1.70(m,2H),0.94(t,J＝7.4Hz,3H).HR-MS:m/z＝450.09366[M+H]+,calcd for C23H20O3N3S2:450.09406.
实施例22：NGL-19-32
制备方法与实施例1类似，不同之处在于，用正丙胺替代实施例1中的2-甲氧基乙胺、用(S)-2-((叔丁氧羰基)氨基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)丙酸替代实施例1中的对羧基苯硼酸、用3-吡啶基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体44mg，收率22.4％。m.p.:159-161℃。1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.45(d,J＝4.6Hz,1H),8.32(s,1H),7.57(s,1H),7.55-7.43(m,4H),7.23(d,J＝7.9Hz,2H),7.16–7.05(m,3H),4.11-4.02(m,1H),3.83(t,J＝7.3Hz,2H),3.01(dd,J＝13.9,4.6Hz,1H),2.87–2.74(m,1H),1.77–1.63(m,2H),1.27(s,9H),0.90(t,J＝7.4Hz,3H).HR-MS:m/z＝577.21063[M+H]+,calcd for C30H33O6N4S:577.21153.
实施例23：NGL-19-39
制备方法与实施例1类似，不同之处在于，用2-(硫代甲基)乙胺替代实施例1中的2-甲氧基乙胺、用邻甲苯异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体48mg，收率34.6％。m.p.:264-267℃。1H NMR(400MHz,DMSO-d6)δ13.06(s,1H),7.89(d,J＝8.7Hz,2H),7.69(d,J＝8.7Hz,2H),7.63(s,1H),7.38(d,J＝3.7Hz,1H),7.35–7.28(m,2H),7.20(dd,J＝7.4,1.4Hz,1H),7.17(d,J＝3.7Hz,1H),7.01(dd,J＝7.7,1.3Hz,1H),4.14(t,J＝6.9Hz,2H),2.94(t,J＝6.9Hz,2H),2.16(overlap,6H).HR-MS:m/z＝479.10840[M+H]+,calcd for C25H23O4N2S2:479.10938.
实施例24：NGL-19-44
制备方法与实施例1类似，不同之处在于，用2-(硫代甲基)乙胺替代实施例1中的2-甲氧基乙胺、用邻氟苯异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体72mg，收率53.2％。m.p.:266-267℃。1H NMR(400MHz,DMSO-d6)δ7.89(d,J＝8.1Hz,2H),7.71–7.65(m,3H),7.41–7.29(m,4H),7.27–7.19(m,2H),4.13(t,J＝6.8Hz,2H),2.92(t,J＝6.8Hz,2H),2.15(s,3H).HR-MS:m/z＝483.08350[M+H]+,calcd for C24H20O4N2FS2:483.08430.
实施例25：NGL-19-45
制备方法与实施例1类似，不同之处在于，用2-(硫代甲基)乙胺替代实施例1中的2-甲氧基乙胺、用2-(三氟甲基)苯基异硫代氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体67mg，收率52.4％。m.p.:266-267℃。1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.91(d,J＝8.5Hz,2H),7.86–7.77(m,2H),7.73–7.68(m,3H),7.51-7.45(m,1H),7.40(d,J＝3.7Hz,1H),7.35(d,J＝7.9Hz,1H),7.23(d,J＝3.7Hz,1H),4.11(t,J＝7.0Hz,2H),2.90(t,J＝7.0Hz,2H),2.13(s,3H).HR-MS:m/z＝533.08008[M+H]+,calcd for C25H20O4N2F3S2:533.08111.
实施例26：NGL-20-2
a)将NGL-18-33(100mg，0.23mmol)、甘氨酸甲酯盐酸盐(29mg，0.23mmol)、HATU(87mg 0.23mmol)、DIEA(89mg，0.69mmol)和5mL DMF加入50mL圆底烧瓶中，室温搅拌过夜，旋除溶剂，加入乙酸乙酯溶解所得物，1M HCl洗，旋除乙酸乙酯，所得残余物通过快速柱层析纯化，将所得产物、2mL甲醇加入50mL圆底烧瓶中，于搅拌下滴加2mL 1M LiOH水溶液，室温搅拌2h，旋除溶剂，所得残余物通过快速柱层析纯化，得黄色固体25mg，收率22.2％。m.p.:296-299℃。1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.93(t,J＝5.9Hz,1H),8.50(dd,J＝4.6,1.6Hz,1H),8.39–8.36(m,1H),7.88(d,J＝8.5Hz,2H),7.71(d,J＝8.5Hz,2H),7.66(s,1H),7.58(ddd,J＝8.0,2.6,1.6Hz,1H),7.52(dd,J＝8.0,4.6Hz,1H),7.38(d,J＝3.7Hz,1H),7.21(d,J＝3.7Hz,1H),3.94(d,J＝5.9Hz,2H),3.89(t,J＝7.2Hz,2H),1.82–1.69(m,2H),0.95(t,J＝7.4Hz,3H).HR-MS:m/z＝491.13898[M+H]+,calcd forC25H23O5N4S:491.13837.
实施例27：NGL-20-3
制备方法与实施例26类似，不同之处在于，用苯丙氨酸甲酯盐酸盐替代实施例26中的甘氨酸甲酯盐酸盐。得黄色固体31mg，收率23.2％。m.p.:196-199℃。1H NMR(400MHz,DMSO-d6)δ8.77(d,J＝8.1Hz,1H),8.50(d,J＝4.5Hz,1H),8.37(s,1H),7.78(d,J＝8.0Hz,2H),7.71–7.62(m,3H),7.61–7.48(m,2H),7.37–7.26(m,5H),7.20(t,J＝6.9Hz,2H),4.67–4.54(m,1H),3.88(t,J＝7.4Hz,2H),3.21(dd,J＝13.7,4.5Hz,1H),3.08(dd,J＝13.7,10.5Hz,1H),1.81-1.70(m,2H),0.94(t,J＝7.3Hz,3H).HR-MS:m/z＝581.18451[M+H]+,calcd for C32H29O5N4S:581.18532.
实施例28：NGL-20-6
制备方法与实施例1类似，不同之处在于，用正丙胺替代实施例1中的2-甲氧基乙胺、用4-(2-羧基乙基)苯硼酸替代实施例1中的对羧基苯硼酸、用3-吡啶基异硫氰酸酯替代实施例1中的苯基异硫氰酸酯。得黄色固体99mg，收率63.0％。m.p.:222-223℃。1H NMR(400MHz,DMSO-d6)δ8.50(dd,J＝4.7,1.6Hz,1H),8.36(d,J＝2.5Hz,1H),7.63(s,1H),7.60–7.49(m,4H),7.26(d,J＝8.1Hz,2H),7.19–7.15(m,2H),3.88(t,J＝7.3Hz,2H),2.85(t,J＝7.6Hz,2H),2.56(t,J＝7.6Hz,2H),1.81-1.70(m,2H),0.94(t,J＝7.5Hz,3H).HR-MS:m/z＝462.14847[M+H]+,calcd for C25H24O4N3S:462.14820.
实施例29：NGL-20-8
a)将正丙胺(197μL，2.4mmol)加入至10mL 3-吡啶基异硫氰酸酯(223μL，2mmol)的乙腈溶液中，室温搅拌，TLC监测反应完全后，旋除溶剂，加入乙酸乙酯溶解所得物，1M HCl洗，旋除乙酸乙酯，干燥备用。
b)将上述产物(305mg，1.56mmol)、乙酸钠(154mg，1.87mmol)、10mL乙醇依次加入50mL圆底烧瓶中，于室温搅拌下加入溴乙酸(260mg，1.87mmol)，升温至回流反应24h，旋除溶剂，乙酸乙酯稀释反应液，饱和碳酸氢钠、饱和氯化钠洗，旋除乙酸乙酯，所得残余物通过快速柱层析纯化。
c)将5-溴-2-呋喃甲醛(350mg，2mmol)，4-(N-Boc-氨基)苯硼酸(569mg，2.4mmol)，碳酸钾(829mg，6mmol)，Pd(PPh3)4(116mg，0.1mmol)加入schelenk管中，氮气置换气体三次，加入3mL甲苯、3mL乙醇、1mL水,90℃反应12h，加10mL水稀释反应液，硅藻土过滤，旋除有机溶剂，所得残余物通过快速柱层析纯化。
d)将上述b)反应产物(570mg，2.43mmol)、上述c)反应产物(556mg，1.94mmol)、吡咯烷(159μL，1.94mmol)、10mL乙醇加入50mL圆底瓶中，回流反应4h，旋除溶剂，所得残余物通过快速柱层析纯化。
e)将上述d)反应产物、12mL无水二氯甲烷加入100mL圆底烧瓶中，于搅拌下室温滴加三氟乙酸3mL，室温反应2h，TLC检测反应完全，旋除溶剂，所得残余物通过快速柱层析纯化。
f)将上述e)反应产物(100mg，0.25mmol)、丁二酸单甲酯(33mg，0.25mmol)、HATU(95mg 0.25mmol)、DIEA(97mg，0.75mmol)和5mL DMF加入50mL圆底烧瓶中，室温搅拌过夜，旋除溶剂，加入乙酸乙酯溶解所得物，1M HCl洗，旋除乙酸乙酯，所得残余物通过快速柱层析纯化，将所得产物、2mL甲醇加入50mL圆底烧瓶中，于搅拌下滴加2mL 1M LiOH水溶液，室温搅拌2h，旋除溶剂，所得残余物通过快速柱层析纯化，得黄色固体20mg，收率15.8％。m.p.:219-220℃。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.17(s,1H),8.48(dd,J＝4.7,1.6Hz,1H),8.37(d,J＝2.5Hz,1H),7.63(overlap,3H),7.58–7.47(m,4H),7.15(d,J＝3.7Hz,1H),7.11(d,J＝3.7Hz,1H),3.88(t,J＝7.3Hz,2H),2.62–2.53(m,4H),1.81-1.71(m,2H),0.94(t,J＝7.4Hz,3H).HR-MS:m/z＝505.15494[M+H]+,calcd for C26H25O5N4S:505.15402.
实施例30：NGL-20-10
制备方法a)-e)与实施例29类似，不同之处在于f)：
f)将上述e)反应产物(100mg，0.25mmol)、DIEA(97mg，0.75mmol)和5mL DMF加入50mL圆底烧瓶中，于冰浴下滴加丙二酸甲酯酰氯(54μL，0.25mmol)，滴毕移至室温反应2h。旋除溶剂，所得残余物通过快速柱层析纯化，将所得产物、2mL甲醇加入50mL圆底烧瓶中，于搅拌下滴加2mL 1M LiOH水溶液，室温搅拌2h，旋除溶剂，所得残余物通过快速柱层析纯化，得黄色固体40mg，收率32.6％。m.p.:171-173℃。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.48(dd,J＝4.7,1.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.67–7.48(m,7H),7.21–7.05(m,2H),3.88(t,J＝7.3Hz,2H),3.38(s,2H),1.82-1.70(m,2H),0.94(t,J＝7.4Hz,3H).HR-MS:m/z＝491.13898[M+H]+,calcd for C25H23O5N4S:491.13837.
实施例31：NGL-20-11
制备方法与实施例26类似，不同之处在于，用亮氨酸甲酯盐酸盐替代实施例26中的甘氨酸甲酯盐酸盐。得黄色固体50mg，收率39.7％。m.p.:161-163℃。1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),8.69(d,J＝7.9Hz,1H),8.49(dd,J＝4.6,1.6Hz,1H),8.37(d,J＝2.6Hz,1H),7.89(d,J＝8.5Hz,2H),7.70(d,J＝8.5Hz,2H),7.66(s,1H),7.57(ddd,J＝8.0,2.6,1.6Hz,1H),7.51(dd,J＝8.0,4.6Hz,1H),7.37(d,J＝3.7Hz,1H),7.20(d,J＝3.7Hz,1H),4.49–4.41(m,1H),3.88(t,J＝7.2Hz,2H),1.85–1.66(m,4H),1.65–1.57(m,1H),0.99–0.86(m,9H).HR-MS:m/z＝547.20166[M+H]+,calcd for C29H31O5N4S:547.20097.
实施例32：NGL-20-13
制备方法与实施例26类似，不同之处在于，用脯氨酸甲酯盐酸盐替代实施例26中的甘氨酸甲酯盐酸盐。得黄色固体81mg，收率66.3％。m.p.:199-201℃。1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.52–8.45(m,1H),8.36(d,J＝2.6Hz,1H),7.72–7.60(m,3H),7.59–7.48(m,3H),7.42–7.30(m,2H),7.20(d,J＝3.6Hz,1H),4.45–4.33(m,1H),3.89(t,J＝7.2Hz,2H),3.63–3.46(m,2H),2.34-2.23(m,1H),2.00-1.82(m,3H),1.81-1.70(m,2H),0.95(t,J＝7.4Hz,3H).HR-MS:m/z＝531.16949[M+H]+,calcd for C28H27O5N4S:531.16967.
实施例33：NGL-20-14
制备方法与实施例26类似，不同之处在于，用(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟乙酸盐替代实施例26中的甘氨酸甲酯盐酸盐。得黄色固体240mg，收率70.5％。m.p.:125-127℃。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.47(d,J＝4.4Hz,1H),8.38(d,J＝2.5Hz,1H),7.94(d,J＝8.2Hz,2H),7.75(d,J＝8.2Hz,2H),7.67(s,1H),7.60-7.55(m,1H),7.51(dd,J＝8.0,4.4Hz,1H),7.42(d,J＝3.7Hz,1H),7.21(d,J＝3.7Hz,1H),4.13(d,J＝8.3Hz,1H),3.89(t,J＝7.2Hz,2H),2.70(t,J＝7.8Hz,1H),2.25(t,J＝11.4Hz,1H),2.11-2.02(m,1H),1.91-1.80(m,3H),1.80–1.71(m,2H),1.68(d,J＝14.0Hz,1H),1.47(d,J＝9.9Hz,1H),1.40(t,J＝7.2Hz,2H),1.33(s,3H),1.25(s,3H),0.94(overlap,9H),0.86(s,3H).HR-MS:m/z＝681.32556[M+H]+,calcd for C38H46O5N4BS:681.32765.
实施例34：NGL-20-17
a)将正丙胺(197μL，2.4mmol)加入至10mL 3-吡啶基异硫氰酸酯(223μL，2mmol)的乙腈溶液中，室温搅拌，TLC监测反应完全后，旋除溶剂，加入乙酸乙酯溶解所得物，1M HCl洗，旋除乙酸乙酯，干燥备用。
b)将上述产物(305mg，1.56mmol)、乙酸钠(154mg，1.87mmol)、10mL乙醇依次加入50mL圆底烧瓶中，于室温搅拌下加入溴乙酸(260mg，1.87mmol)，升温至回流反应24h，旋除溶剂，乙酸乙酯稀释反应液，饱和碳酸氢钠、饱和氯化钠洗，旋除乙酸乙酯，所得残余物通过快速柱层析纯化。
c)将上述b)反应产物(384mg，1.63mmol)、5-(4-溴苯基)-2-呋喃甲醛(410mg，1.63mmol)、吡咯烷(134μL，1.63mmol)、10mL乙醇加入50mL圆底瓶中，回流反应4h，旋除溶剂，所得残余物通过快速柱层析纯化。
d)将上述c)反应产物(558mg，1.2mmol)，联硼酸频那醇酯(333mg，1.31mmol)，醋酸钾(353mg，3.6mmol)，PdCl2(dppf)(26mg，0.036mmol)加入schelenk管中，氮气置换气体三次，加入8mL二氧六环,90℃反应12h，加10mL水稀释反应液，硅藻土过滤，旋除有机溶剂，所得残余物通过快速柱层析纯化。所得固体乙醇/水重结晶，得黄色固体232mg，收率37.5％。m.p.:125-127℃。1H NMR(400MHz,DMSO-d6)δ8.49(dd,J＝4.5,1.7Hz,1H),8.37(d,J＝2.5Hz,1H),7.68–7.60(m,5H),7.58–7.49(m,2H),7.32(d,J＝3.7Hz,1H),7.18(d,J＝3.7Hz,1H),3.88(t,J＝7.2Hz,2H),1.82-1.70(m,2H),1.32(s,12H),0.94(t,J＝7.4Hz,3H).HR-MS:m/z＝516.21191[M+H]+,calcd for C28H31O4N3BS:516.21228.
实施例35：NGL-20-18
将NGL-20-14(100mg，0.15mmol)、异丁基硼酸(45mg，0.45mmol)、2mL甲醇加入50mL圆底烧瓶中，于搅拌下加入2mL2N盐酸水溶液，室温搅拌24h，旋除溶剂，旋除有机溶剂，所得残余物通过快速柱层析纯化，所得固体乙醇/水重结晶，得黄色固体40mg，收率48.8％。m.p.:252-254℃。1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.42(d,J＝4.6Hz,1H),8.34(s,1H),7.92(d,J＝8.0Hz,2H),7.69(d,J＝8.0Hz,2H),7.63(s,1H),7.53(d,J＝7.4Hz,1H),7.49–7.39(m,1H),7.37(d,J＝3.7Hz,1H),7.18(d,J＝3.7Hz,1H),3.88(s,2H),1.85–1.67(m,4H),1.54–1.37(m,3H),0.93(overlap,10H).HR-MS:m/z＝529.20734[M-OH]+,calcdfor C28H30O4N4BS:529.20753.
实施例36：NGL-20-19
a)将正丙胺(197μL，2.4mmol)加入至10mL 3-吡啶基异硫氰酸酯(223μL，2mmol)的乙腈溶液中，室温搅拌，TLC监测反应完全后，旋除溶剂，加入乙酸乙酯溶解所得物，1M HCl洗，旋除乙酸乙酯，干燥备用。
b)将上述产物(305mg，1.56mmol)、乙酸钠(154mg，1.87mmol)、10mL乙醇依次加入50mL圆底烧瓶中，于室温搅拌下加入溴乙酸(260mg，1.87mmol)，升温至回流反应24h，旋除溶剂，乙酸乙酯稀释反应液，饱和碳酸氢钠、饱和氯化钠洗，旋除乙酸乙酯，所得残余物通过快速柱层析纯化。
c)将上述b)反应产物(384mg，1.63mmol)、5-(4-溴苯基)-2-呋喃甲醛(410mg，1.63mmol)、吡咯烷(134μL，1.63mmol)、10mL乙醇加入50mL圆底瓶中，回流反应4h，旋除溶剂，所得残余物通过快速柱层析纯化。
d)将上述c)反应产物(100mg，0.21mmol)，联硼酸频那醇酯(61mg，0.24mmol)，醋酸钾(35mg，0.36mmol)，PdCl2(dppf)(5mg，0.0063mmol)加入schelenk管中，氮气置换气体三次，加入4mL二氧六环,90℃反应12h，加10mL水稀释反应液，硅藻土过滤，旋除有机溶剂，所得残余物通过快速柱层析纯化。
e)将上述d)反应产物(90mg，0.17mmol)、异丁基硼酸(53mg，0.52mmol)、2mL甲醇加入50mL圆底烧瓶中，于搅拌下加入2mL 2N盐酸水溶液，室温搅拌24h，旋除溶剂，旋除有机溶剂，所得残余物通过快速柱层析纯化，所得固体乙醇/水重结晶，得黄色固体31mg，收率42.1％。m.p.:218-220℃。1H NMR(400MHz,DMSO-d6)δ8.50(dd,J＝4.7,1.6Hz,1H),8.37(dd,J＝2.6,0.8Hz,1H),8.16(overlap,2H),7.79(d,J＝8.4Hz,2H),7.64(s,1H),7.58(overlap,3H),7.51(ddd,J＝8.1,4.7,0.8Hz,1H),7.27(d,J＝3.7Hz,1H),7.18(d,J＝3.7Hz,1H),3.89(t,J＝7.2Hz,2H),1.82-1.70(m,2H),0.95(t,J＝7.4Hz,3H).HR-MS:m/z＝434.13324[M+H]+,calcd for C22H21O4N3BS:434.13403.
实施例37：NGL-20-29
制备方法与实施例36类似，不同之处在于，用2-甲氧基乙胺替代实施例36中的正丙胺。得黄色固体78mg，收率46.9％。m.p.:206-208℃。1H NMR(400MHz,DMSO-d6)δ8.50(dd,J＝4.7,1.6Hz,1H),8.37(d,J＝2.6Hz,1H),8.17(s,2H),7.79(d,J＝7.9Hz,2H),7.65(s,1H),7.58(overlap,3H),7.52(dd,J＝8.0,4.7Hz,1H),7.28(d,J＝3.7Hz,1H),7.19(d,J＝3.7Hz,1H),4.10(t,J＝5.8Hz,2H),3.71(t,J＝5.8Hz,2H),3.31(overlap,3H).HR-MS:m/z＝450.12921[M+H]+,calcd for C22H21O5N3BS:450.12895.
实施例38：NGL-20-30
制备方法与实施例36类似，不同之处在于，用2-(硫代甲基)乙胺替代实施例36中的正丙胺。得黄色固体96mg，收率39.0％。m.p.:225-228℃。1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝4.6Hz,1H),8.38(d,J＝2.5Hz,1H),8.17(overlap,2H),7.80(d,J＝7.8Hz,2H),7.66(s,1H),7.59(overlap,3H),7.52(dd,J＝8.1,4.6Hz,1H),7.28(d,J＝3.8Hz,1H),7.20(d,J＝3.8Hz,1H),4.12(t,J＝7.0Hz,2H),2.91(t,J＝7.0Hz,2H),2.16(s,3H).HR-MS:m/z＝466.10641[M+H]+,calcd for C22H21O4N3BS2:466.10610.
药理实验
实验例1：本发明的化合物对蛋白酶体β5i、β5c亚基的抑制作用
方法：
蛋白酶体分别从白细胞(i20S)或红细胞(c20S)制备而得。将蛋白酶体加入到蛋白酶体底物Ac-ANW-AMC或Ac-WLA-AMC的50mM Hepes pH 7.5、1mM DTT、10mM EDTA、0.035％SDS、0.1％BSA缓冲液中。蛋白酶体的最终反应浓度为10nM，蛋白酶体底物的最终反应浓度为10μM。加入不同浓度的化合物，在室温及激发光345nm和发射光445nm的条件下连续记录30分钟的反应进程，观察化合物对酶的抑制情况。IC50值由Graphpad Prism 8软件处理而得。
结果：
结果如表1所示。
表1.化合物对蛋白酶体β5i、β5c亚基的抑制作用
β5i抑制率：40μM下测定；
ND：未测定。
实验例2：部分化合物对RAW264.7细胞TNF-α释放的抑制作用
方法：
将处于生长期的RAW264.7细胞用胰蛋白酶处理，收获后悬浮于培养基中。以2.5×104个细胞/孔的密度将细胞接种于96孔板中，200μL/孔，在37℃，5％CO2的环境下孵育过夜，弃去原培养液。加入含1μg/mL的LPS(ACMEC,AL8880)无血清培养基180μL/孔。阴性对照组加入等体积的无血清培养基180μL/孔。加入代测化合物20μL/孔，孵育48h，空白组和阴性对照组加入20μL DMSO。取上清100μL，使用Mouse TNF-αELISA Kit(Absin,abs520010)按照试剂盒说明书检测TNF-α。
结果：如图1所示。
实验例3：NGL-20-30抑制TGF-β1诱导的肺成纤维细胞胶原收缩
方法：
将人肺成纤维细胞系MRC-5悬液与3mg/mL I型鼠尾胶原(CORNING,354236)按2:1的比例混合在无血清培养基中。将密度为2×105/mL的细胞悬液接种于24孔板中。使胶原凝胶在37℃下凝固1h，将凝胶边缘从孔壁上剥离，然后加入1mL培养基。孵育48小时后，对凝胶进行拍照，并使用ImageJ软件(US National Institutes of Health)测量凝胶面积。
结果：如图2所示。
实验例4：NGL-20-30抑制COL1A1的表达含量
方法：
使用RIPA裂解缓冲液(Beyotime Technology)从培养的细胞中提取蛋白质。使用BCA蛋白检测试剂盒(Beyotime Technology)测定蛋白浓度。蛋白提取物经10％SDS-PAGE分离，电转到PVDF膜上，进行免疫印迹分析。免疫印迹图像由化学发光成像系统(Tanon，上海，北京)获得。
结果：如图3所示。
实验例5：NGL-20-30体内抗肺纤维化活性
方法：
a.步骤
小鼠隔夜禁食，使用三溴乙醇麻醉小鼠，气管内注射50μL博来霉素(3U/kg)完成造模(记为第1天)。造模完成后将动物随机分组并在第3天给药，每天灌胃给药至第21天。到达时间点后麻醉小鼠，取材称重，其中左侧肺大叶置于4％多聚甲醛中用于形态学检测，右肺用于蛋白及羟脯氨酸含量检测。
b.分组
Sham组为未注射博来霉素的正常对照组、Model组为未给药的模型组、Nint组为一天一次尼达尼布(50mg/kg)治疗组、20-30组为一天一次NGL-20-30(30mg/kg)治疗组。
c.药物配制
取处方量化合物加至30％PEG400+0.5％Tween80+5％丙二醇+水至全量
d.形态学检测
取材后的小鼠左侧肺大叶，经4％多聚甲醛固定、脱水、石蜡包埋后，切成厚度为4μm的肺组织切片。之后进行HE与Masson染色。在200倍镜下观察并进行图像采集。
e.羟脯氨酸含量检测
羟脯氨酸含量通过羟脯氨酸测定试剂盒(南京建成生物工程研究所)进行测定。取肺组织50mg，加入碱性水解液1mL,95℃恒温煮沸20min。将pH调至6.0-6.8，活性炭吸附上清液3-4mL,3500rpm离心10min后，取上清液1mL，按试剂盒说明书进行测定。
f.Western blotting
使用RIPA裂解缓冲液(Beyotime Technology)从肺组织中提取蛋白质。使用BCA蛋白检测试剂盒(Beyotime Technology)测定蛋白浓度。蛋白提取物经10％SDS-PAGE分离，电转到PVDF膜上，进行免疫印迹分析。免疫印迹图像由化学发光成像系统(Tanon)获得。
g.免疫荧光检测
肺组织石蜡切片经脱蜡、水化后，依次使用0.5％Triton X-100处理15分钟、SuperBlocking缓冲液处理30分钟，之后与相应的抗体在4℃下孵育过夜。PBS洗涤3次后，在室温下用二抗(山羊抗兔Alexa 647)染色2小时，用DAPI染色细胞核，之后用盖玻片覆盖切片。免疫荧光图像由共聚焦显微镜(Olympus)采集。结果：如图4所示。
Claims (12)
1.一种由下述通式(I)表示的噻唑烷酮类化合物及其立体异构体或其生理上可接受的盐，
其中，
R1选自C1-C6烷基、(CH2)nLR4；其中，n为1，2或3，L选自O，S，N或COO，R4选自C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自取代或未取代的苯基、萘基、吡啶基，取代基选自单取代或多取代的卤素、C1-C3烷基、C1-C3烷氧基、C1-C3烷胺基、吗啉基、CF3；
R3选自羧基、硼酸基、硼酸酯基、(CH2)mCOOH、CONH(CHR5)COOH、CONH(CHR5)B(OH)2、NHCO(CH2)mCOOH，其中m为1，2或3，R5选自H、C1-C6烷基、苄基；
X选自O或S。
2.根据权利要求1所述的化合物，其特征在于，所述的化合物是通式(IA)所示化合物及其立体异构体或其生理上可接受的盐：
其中，
R1选自C1-C6直链烷基、(CH2)nLR4；其中，n为1或2，L选自O，S，N或COO，R4为C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自苯基、氟取代的苯基、吡啶基。
3.根据权利要求1所述的化合物，其特征在于，所述的化合物是通式(IB)所示化合物及其立体异构体或其生理上可接受的盐：
其中，
R1选自C1-C6直链烷基、(CH2)nLR4；其中，n为1或2，L选自O，S，N或COO，R4为C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自苯基、氟取代的苯基、吡啶基。
4.根据权利要求1所述的化合物，其特征在于，所述的化合物是通式(IC)所示化合物及其立体异构体或其生理上可接受的盐：
其中，
R1选自C1-C6直链烷基、(CH2)nLR4；其中，n为1或2，L选自O，S，N或COO，R4为C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自苯基、氟取代的苯基、吡啶基；
R5选自H、C1-C6烷基、苄基；
R6选自COOH、B(OH)2。
5.根据权利要求1所述的化合物，其特征在于，所述的化合物是通式(ID)所示化合物及其立体异构体或其生理上可接受的盐：
其中，
R1选自C1-C6直链烷基、(CH2)nLR4；其中，n为1或2，L选自O，S，N或COO，R4为C1-C3烷基，当L为N时，R4为单烷基或双烷基取代；
R2选自苯基、氟取代的苯基、吡啶基；
m为1，2或3。
6.具有如下结构的化合物及其立体异构体或其生理上可接受的盐，其特征在于，所述化合物选自：
7.权利要求1～6所述化合物的制备方法，其特征在于，包括以下步骤：
式II化合物与式III化合物在室温下反应生成式IV化合物，式IV化合物与溴乙酸反应生成式V化合物；式VI化合物与式VII化合物经偶联反应生成式VIII化合物；式IX化合物与式VII化合物经偶联反应生成式X化合物；式V化合物与式XI化合物经缩合反应生成式XII化合物；式V化合物与式VIII化合物经缩合反应，或式V化合物与式VIII化合物经缩合反应、酰胺键形成反应、水解反应，或式V化合物与式X化合物经缩合反应、脱保护反应、酰胺键形成反应、水解反应,或式XII化合物经偶联反应，或式XII化合物经偶联、水解反应生成式I目标化合物；
其中，R1、R2、R3、X及m的定义同权利要求1～6任意一项。
8.一种药物组合物，其特征在于，药物组合物含有有效剂量的如权利要求1～6任一项所述的化合物或其生理上可接受的盐和在药学上可接受的载体。
9.根据权利要求8所述的药物组合物，其特征在于，所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
10.权利要求1～6任一项所述的化合物或其生理上可接受的盐在制备免疫蛋白酶体抑制剂中的用途。
11.权利要求1～6任一项所述的化合物或其生理上可接受的盐用于制备预防或治疗免疫蛋白酶体相关疾病的药物中的应用。
12.根据权利要求11所述的应用，所述的疾病选自肿瘤、炎症、自身免疫性疾病、神经退行性疾病。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210782937.3A CN117384150A (zh) | 2022-07-05 | 2022-07-05 | 噻唑烷酮类免疫蛋白酶体抑制剂及其制法和药物用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210782937.3A CN117384150A (zh) | 2022-07-05 | 2022-07-05 | 噻唑烷酮类免疫蛋白酶体抑制剂及其制法和药物用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117384150A true CN117384150A (zh) | 2024-01-12 |
Family
ID=89437870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210782937.3A Pending CN117384150A (zh) | 2022-07-05 | 2022-07-05 | 噻唑烷酮类免疫蛋白酶体抑制剂及其制法和药物用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117384150A (zh) |
-
2022
- 2022-07-05 CN CN202210782937.3A patent/CN117384150A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI516263B (zh) | 經取代之５－氟－１ｈ－吡唑并吡啶類及其用途 | |
| US10717736B2 (en) | Pyrrole amides as alpha V integrin inhibitors | |
| CA2494700C (en) | Calcium receptor modulating compound and use thereof | |
| JP6395731B2 (ja) | ブロモドメイン阻害剤として有用なカルバゾール化合物 | |
| CN107428758B (zh) | 丙烯酸类衍生物、其制备方法及其在医药上的用途 | |
| KR20190093205A (ko) | 단백질 표적화에 사용하기 위한 티에노피롤 유도체, 조성물, 방법 및 이의 용도 | |
| KR101126383B1 (ko) | 3환계 화합물 | |
| EP3538526A1 (en) | Cyclobutane- and azetidine-containing mono and spirocyclic compounds as alpha v integrin inhibitors | |
| US10548883B2 (en) | Benzotriazole-derived α and β-unsaturated amide compound used as TGF-β RI inhibitor | |
| JP6498705B2 (ja) | 代謝障害の治療に用いるためのジヒドロピリジノンｍｇａｔ２阻害剤 | |
| JP6449919B2 (ja) | テトラゾロン置換のジヒドロピリジノンｍｇａｔ２阻害剤 | |
| CN110418796A (zh) | 托法替尼(tofacitinib)的葡萄糖苷酸前药 | |
| WO2004048379A1 (ja) | キサンチン化合物 | |
| KR102291444B1 (ko) | 디히드로피리디논 mgat2 억제제 | |
| JP2017532338A (ja) | 癌を治療する方法 | |
| JP2010521513A (ja) | アザ−ピリドピリミジノン誘導体 | |
| JP2016533364A (ja) | 癌を処置する方法 | |
| WO2012031563A1 (zh) | 杂环氨基小檗胺衍生物、其制备方法和应用 | |
| CN113227093A (zh) | 结晶螺环化合物、包含该化合物的剂型、用于疾病治疗的方法和再结晶方法 | |
| EA031679B1 (ru) | Производные тетрагидрохинолина в качестве ингибиторов бромодомена | |
| JP7152078B2 (ja) | ホウ酸塩ベースの薬物およびその使用 | |
| CN111108083B (zh) | 氨基亚甲基环己烷1,3-二酮化合物的用途 | |
| CN117384150A (zh) | 噻唑烷酮类免疫蛋白酶体抑制剂及其制法和药物用途 | |
| CN117242061A (zh) | 用于治疗艰难梭菌的二氮杂卓衍生物 | |
| CN117285485A (zh) | 一种双磺酰胺类衍生物及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |