CN110483437B - Five-membered ring-containing compound and preparation and application thereof - Google Patents
Five-membered ring-containing compound and preparation and application thereof Download PDFInfo
- Publication number
- CN110483437B CN110483437B CN201810455868.9A CN201810455868A CN110483437B CN 110483437 B CN110483437 B CN 110483437B CN 201810455868 A CN201810455868 A CN 201810455868A CN 110483437 B CN110483437 B CN 110483437B
- Authority
- CN
- China
- Prior art keywords
- intermediate product
- alkyl
- following structure
- compound
- compound shown
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 158
- 238000002360 preparation method Methods 0.000 title claims description 7
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 19
- 206010013774 Dry eye Diseases 0.000 claims abstract description 18
- 210000002865 immune cell Anatomy 0.000 claims abstract description 11
- 239000003112 inhibitor Substances 0.000 claims abstract description 10
- 239000003889 eye drop Substances 0.000 claims abstract description 5
- 239000013067 intermediate product Substances 0.000 claims description 225
- -1 methoxy, ethoxy, hydroxyl Chemical group 0.000 claims description 85
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 53
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 51
- 239000000047 product Substances 0.000 claims description 41
- 238000006460 hydrolysis reaction Methods 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- 229910052757 nitrogen Chemical group 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 230000007062 hydrolysis Effects 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- 238000007112 amidation reaction Methods 0.000 claims description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 239000011593 sulfur Chemical group 0.000 claims description 16
- 238000006722 reduction reaction Methods 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000004185 ester group Chemical group 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000012292 cell migration Effects 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 238000007259 addition reaction Methods 0.000 claims description 4
- 230000002862 amidating effect Effects 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000005905 alkynylation reaction Methods 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 2
- 238000004073 vulcanization Methods 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 230000005012 migration Effects 0.000 abstract description 5
- 238000013508 migration Methods 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 208000024891 symptom Diseases 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 52
- 239000000243 solution Substances 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 230000015572 biosynthetic process Effects 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 33
- 238000001035 drying Methods 0.000 description 31
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 31
- 239000002253 acid Substances 0.000 description 29
- 238000010791 quenching Methods 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 230000000171 quenching effect Effects 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 18
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007821 HATU Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000003513 alkali Substances 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 10
- 230000002441 reversible effect Effects 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 150000001266 acyl halides Chemical class 0.000 description 8
- 230000009435 amidation Effects 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 230000001590 oxidative effect Effects 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000009987 spinning Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 239000007800 oxidant agent Substances 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 150000002431 hydrogen Chemical group 0.000 description 4
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 208000005494 xerophthalmia Diseases 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YOLVBJUSDXESQT-LSLKUGRBSA-N (2S)-2-amino-N-(1-diphenoxyphosphorylethyl)propanamide Chemical compound C=1C=CC=CC=1OP(=O)(C(C)NC(=O)[C@@H](N)C)OC1=CC=CC=C1 YOLVBJUSDXESQT-LSLKUGRBSA-N 0.000 description 2
- BLSRGJPGRJBHQK-BUSXIPJBSA-N (2s)-2-amino-1-(2-diphenoxyphosphorylpyrrolidin-1-yl)propan-1-one Chemical compound C[C@H](N)C(=O)N1CCCC1P(=O)(OC=1C=CC=CC=1)OC1=CC=CC=C1 BLSRGJPGRJBHQK-BUSXIPJBSA-N 0.000 description 2
- JMVFRBIAXHMBPB-KKFHFHRHSA-N (3s)-3-amino-4-(2-diphenoxyphosphorylpyrrolidin-1-yl)-4-oxobutanamide Chemical compound NC(=O)C[C@H](N)C(=O)N1CCCC1P(=O)(OC=1C=CC=CC=1)OC1=CC=CC=C1 JMVFRBIAXHMBPB-KKFHFHRHSA-N 0.000 description 2
- ZASXCTCNZKFDTP-UHFFFAOYSA-N 1-ethynyl-3-methoxybenzene Chemical group COC1=CC=CC(C#C)=C1 ZASXCTCNZKFDTP-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 150000001924 cycloalkanes Chemical class 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- APGOHCBEJDAUOM-VYIIXAMBSA-N (2S)-2-amino-N-(1-diphenoxyphosphorylethyl)butanediamide Chemical compound C=1C=CC=CC=1OP(=O)(C(NC(=O)[C@@H](N)CC(N)=O)C)OC1=CC=CC=C1 APGOHCBEJDAUOM-VYIIXAMBSA-N 0.000 description 1
- DZODXKMLRLHQBB-ZENAZSQFSA-N (2s)-2-amino-1-(2-diphenoxyphosphorylpyrrolidin-1-yl)-3-hydroxypropan-1-one Chemical compound OC[C@H](N)C(=O)N1CCCC1P(=O)(OC=1C=CC=CC=1)OC1=CC=CC=C1 DZODXKMLRLHQBB-ZENAZSQFSA-N 0.000 description 1
- PLIQWXNVJOPJOT-UXMRNZNESA-N (2s)-2-amino-1-(2-diphenoxyphosphorylpyrrolidin-1-yl)-3-phenylpropan-1-one Chemical compound C([C@H](N)C(=O)N1C(CCC1)P(=O)(OC=1C=CC=CC=1)OC=1C=CC=CC=1)C1=CC=CC=C1 PLIQWXNVJOPJOT-UXMRNZNESA-N 0.000 description 1
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 1
- NTSKOZMSQFZPKG-ZENAZSQFSA-N (3s)-3-amino-4-(2-diphenoxyphosphorylpyrrolidin-1-yl)-4-oxobutanoic acid Chemical compound OC(=O)C[C@H](N)C(=O)N1CCCC1P(=O)(OC=1C=CC=CC=1)OC1=CC=CC=C1 NTSKOZMSQFZPKG-ZENAZSQFSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- HLSNQZQSNWFXET-UHFFFAOYSA-N 1-benzofuran-6-carbaldehyde Chemical compound O=CC1=CC=C2C=COC2=C1 HLSNQZQSNWFXET-UHFFFAOYSA-N 0.000 description 1
- XIMXGVWNPANARA-UHFFFAOYSA-N 2-amino-3,5-dichloro-4-methoxycarbonylbenzoic acid Chemical compound COC(=O)C1=C(Cl)C=C(C(O)=O)C(N)=C1Cl XIMXGVWNPANARA-UHFFFAOYSA-N 0.000 description 1
- AZVSIHIBYRHSLB-UHFFFAOYSA-N 3-furaldehyde Chemical compound O=CC=1C=COC=1 AZVSIHIBYRHSLB-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- ZFHUHPNDGVGXMS-UHFFFAOYSA-N 4-(hydroxymethyl)benzaldehyde Chemical compound OCC1=CC=C(C=O)C=C1 ZFHUHPNDGVGXMS-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010015958 Eye pain Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- NTECHUXHORNEGZ-UHFFFAOYSA-N acetyloxymethyl 3',6'-bis(acetyloxymethoxy)-2',7'-bis[3-(acetyloxymethoxy)-3-oxopropyl]-3-oxospiro[2-benzofuran-1,9'-xanthene]-5-carboxylate Chemical compound O1C(=O)C2=CC(C(=O)OCOC(C)=O)=CC=C2C21C1=CC(CCC(=O)OCOC(C)=O)=C(OCOC(C)=O)C=C1OC1=C2C=C(CCC(=O)OCOC(=O)C)C(OCOC(C)=O)=C1 NTECHUXHORNEGZ-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000004378 air conditioning Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 239000000607 artificial tear Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-N benzene-dicarboxylic acid Natural products OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000003352 cell adhesion assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
-
- 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
- C07D417/12—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 chain containing hetero atoms as chain links
Abstract
The invention provides a novel compound containing a five-membered ring, which is characterized by being a compound shown in the following structure:
Description
Technical Field
The invention relates to the field of medical chemistry, in particular to a compound containing a five-membered ring, a preparation method thereof and application thereof in treating xerophthalmia.
Background
The permanent wetting and lubrication of the eye by tears is critical to maintaining vision and eye comfort. Tears are composed of water, oil, mucus, antibodies, and some specific proteins (used to fight infection). These components are secreted by specific glands located around the eye. When there is an imbalance in the tear system, a person feels dry.
Dry eye syndrome is a common ocular surface inflammatory disease. People with dry eye may experience eye pain, photosensitivity, itching, redness and blurred vision. Dry eye syndrome has a variety of causative factors including age, sex, environment, drugs, surgery, and systemic diseases such as autoimmune diseases, diabetes, thyroid diseases, lymphoma, etc. Failure to properly diagnose and treat dry eye may lead to further complications such as infection, ocular surface keratinization, corneal ulceration, and conjunctival squamous, among others.
Thus, dry eye is a very large disease that afflicts 5-10% of the population, especially those who have been working for long periods of time before computers, and beyond. More than 30% of ophthalmologists outpatient visits today are dry eye patients. China despite its numerous dry eye patients, to date no drugs have been approved for the treatment of dry eye. The patient can only have temporary relief from the artificial tears. Therefore, there is an urgent need for drugs for treating dry eye.
The incidence and age of dry eye is directly proportional, with about 20% of people over 50 years of age having varying degrees of dry eye; gender also affects dry eye, which is much higher in women, particularly in older women, than in men, and may be associated with the secretion of sex hormones; white-collar workers are in an air-conditioning environment for a long time, and the incidence rate of xerophthalmia of the crowd is also high due to the fact that the white-collar workers use the screen for a long time. Dry eye disease is a continuous pathological process, and the disease condition continuously develops from mild condition to severe condition, and no obvious boundary exists between mild condition, moderate condition and severe condition. Despite the complex etiology of dry eye, studies have found that the pathology of dry eye, which is triggered by a variety of causes, is similar: the immune cells infiltrate the surface tissues of the eye to cause chronic inflammation and damage to the ocular surface. Currently, there are two drugs approved in the european and american markets: and (1) a cyclosporine A suspension. The drug is a very powerful immune system suppressor and thus may cause damage to the immune system. Meanwhile, because the suspension liquid is a suspension liquid, the problems of long-term storage stability, irritation to eyes of patients in use and the like exist; (2) Lifitigrast, a drug approved by FDA in the united states for 12 months in 2016, is an inhibitor of migration of immune cells, and achieves therapeutic effects by preventing immune cells from entering sites of inflammation; however, the drug is highly lipophilic and has no clinical effect in >50% of patients.
Disclosure of Invention
The invention is a novel immune cell migration inhibitor, has good hydrophilicity, and can be developed into eyedrops. Has strong capability of inhibiting the migration of immune cells, and can relieve the symptoms of most patients with dry eye syndrome.
The invention provides a compound containing a five-membered ring, which is characterized by being a compound shown in the following structure:
the compound may also be represented in the form of the following structure:
wherein R is 1 Selected from aryl, heteroaryl, alkyl, alkoxy, R 1 -X；
R 1 Selected from aryl, heteroaryl, alkyl;
x is selected from carbon, carbonyl (i.e.:
forms of (d), nitrogen, sulfur, oxygen;
y is selected from carbon, carbonyl (i.e.:
forms of (d), nitrogen, sulfur, oxygen;
the X-Y bond is selected from a single bond, a double bond or a triple bond; that is, when X is present, the linkage of X to Y is any chemical bond.
R 2 Is hydrogen, halogen or alkyl substituted on any or several of benzene rings;
R 3 is alkyl, benzyl, aryl, heteroaryl;
R 4 hydrogen, alkyl, benzyl, aryl;
A 1 selected from carbon, nitrogen;
A 2 selected from carbon, oxygen, sulfur, nitrogen;
A 3 selected from carbon, oxygen, sulfur, nitrogen;
A 4 selected from carbon, nitrogen;
A 5 selected from carbon and nitrogen.
The aryl group may be a five-membered aromatic ring and its derivatives, a six-membered aromatic ring compound and its derivatives, or an aromatic compound composed of one or more five-membered or six-membered aromatic rings and its derivatives, for example: the compounds such as benzene, naphthalene, anthracene, phenanthrene, quinoline and derivatives thereof can also be compounds shown in the following structures:
The heteroaryl may be any one or more carbon atoms of the aryl compound substituted by oxygen, sulfur or nitrogen.
The above alkyl group may be, for example, C n H 2n+1 The aliphatic hydrocarbon group represented by the chemical formula (I) - (n is a natural number), or a compound in which one or more of the hydrogens of the aliphatic hydrocarbon group are substituted with a substituent such as an aryl group, a heteroaryl group, a hydroxy group, or a halogen, or a cyclic alkyl group (e.g., a cycloalkane such as cyclopropane, cyclopentane, cyclohexane, or a derivative thereof).
The above alkoxy group may be, for example, C n H 2n+1 O- (n is a natural number) and derivatives thereof.
The benzyl group may be a compound represented by the following structure:
Further, in the present invention, the above five-membered ring-containing compound is most preferably a compound represented by the following structure:
further, the present invention provides one of the above-mentioned five-membered ring-containing compounds, which is produced by the following synthesis steps:
an intermediate product B is obtained from the terephthalic acid alkyl ester derivative A through hydrolysis reaction;
during this synthesis, one of the ester groups can be converted into a carboxyl group in any way, for example: the conventional method of acid or alkali hydrolysis, etc., and the preferred synthesis method can be: adding ether solvent, water and alkaline agent (such as hydroxide) into alkyl terephthalate derivative A, reacting at 15-35 deg.C for 0.1-10 hr, quenching with inorganic or organic acid, extracting, and spin drying. Wherein the molar ratio/mass ratio of the alkyl terephthalate derivative a to the alkaline agent is generally 1:0.1-0.5.
Carrying out amidation reaction on the intermediate product B to obtain an intermediate product C;
during this synthesis, the carboxyl group may be amidated in any way, for example: amidation is carried out directly with carboxyl and amino compound, or reaction with ammonia after carboxyl is changed into acyl halide, etc. In the present invention, it is preferable to adopt a process comprising mixing the intermediate product B and the amino derivative, reacting the mixture in a DIPEA + HATU system for 10 to 60 minutes with stirring, quenching the reaction with an acid solution, and then extracting and spin-drying the reaction product. Wherein the molar ratio of the intermediate product B to the amino derivative is 1:1-3.
Carboxylating alkyl formate on the benzene ring of the intermediate product C to obtain an intermediate product D;
during the synthesis, one of the ester groups can be converted into a carboxyl group in any way, for example: the conventional method of acid or alkali hydrolysis, etc., the preferred synthesis method may be: dissolving intermediate product C and alkaline agent (such as lithium iodide) in high boiling point organic solvent, preferably under protection of protective gas, reacting at a temperature of above 100 deg.C for 1-10 hr, cooling, spin drying, adding acid solution, extracting, and spin drying. Wherein the mass ratio of the intermediate product C to the alkaline agent is 1.
Obtaining an intermediate product E from the intermediate product D under the action of a vulcanizing agent;
in this synthesis process, any sulfurizing reagent that can change (C = O to C = S) may be used, and in the present invention, it is preferable to adopt a process in which a sulfurizing reagent (for example, lawesson' S reagent) is added to intermediate product D, and then the reaction is carried out at a reaction temperature of about 100 ℃ for 1 to 10 hours, followed by vacuum drying. Wherein the molar ratio of the intermediate product D to the vulcanizing agent is 1.5-3.
Carrying out intramolecular cyclization reaction on the intermediate product E to obtain an intermediate product F;
in this synthesis, the cyclization reaction can take place in any manner, generally under oxidative conditions. In the invention, the following process steps are preferably adopted, namely, after the intermediate product E is added with the oxidant and reacts for 3 to 10 hours at normal temperature, the mixture is extracted and dried by using acid and an extracting agent. Wherein the mass ratio of the intermediate product E to the oxidant is 1:1-10.
Performing amidation reaction on carboxyl on the intermediate product F to obtain an intermediate product G;
during this synthesis, the carboxyl group may be amidated in any way, for example: amidation is carried out directly with carboxyl and amino compound, or reaction with ammonia after carboxyl is changed into acyl halide, etc. In the present invention, it is preferable to adopt a process comprising mixing the intermediate product F with an amino derivative, reacting the mixture in a DIPEA + HATU system for 2 to 8 hours with stirring, quenching the reaction with an acid solution, and then extracting and spin-drying the reaction product. Wherein the molar ratio of the intermediate product B to the amino derivative is 1:1-3.
Carrying out hydrolysis/reduction reaction on the intermediate product G to obtain a target product;
during this synthesis, the ester or alkoxy group may be converted to a carboxyl or hydroxyl group in any manner, for example: conventional acid type, alkali type hydrolysis, reduction and the like.
Wherein the alkyl terephthalate derivative A is a compound represented by the following structure:
the intermediate product B is a compound shown in the following structure:
the intermediate product C is a compound shown in the following structure:
the intermediate product D is a compound shown in the following structure:
the intermediate E is a compound represented by the following structure:
the intermediate product F is a compound shown in the following structure:
the intermediate product G is a compound shown in the following structure:
in the above reaction process, the alkyl group denoted by alkyl group generally means a short chain alkyl group having not more than 10 carbon atoms.
The synthesis steps in the above reaction process can be carried out under the condition of no solvent or under the condition of solvent, and the solvent can be selected from: ether solvents, ketones, benzene, toluene, p-toluene, DMF, DMSO, cycloalkanes, halogenated hydrocarbons, and the like.
In the above reaction process, the extraction reagent used may be selected from esters, alcohols, ethers, ketones or aromatic reagents.
In addition, the present invention provides another method for producing a five-membered ring-containing compound, characterized by comprising the following synthesis steps:
an intermediate product B is obtained by hydrolysis reaction of an alkyl terephthalate derivative A;
during this synthesis, one of the ester groups can be converted into a carboxyl group in any way, for example: the conventional method of acid or alkali hydrolysis, etc., and the preferred synthesis method can be: adding ether solvent, water and alkaline agent (such as hydroxide) into alkyl terephthalate derivative A, reacting at 15-35 deg.C for 0.1-10 hr, quenching with inorganic or organic acid, extracting, and spin drying. Wherein the molar ratio/mass ratio of the alkyl terephthalate derivative a to the alkaline agent is generally 1:0.1-0.5.
Carrying out amidation reaction on the intermediate product B to obtain an intermediate product C with an N protecting group;
during this synthesis, the carboxyl group may be amidated in any way, generally by reacting it with an ammonia derivative under basic or catalytic conditions. The following method is preferably employed in the present invention: and mixing the intermediate product B with an ammonia derivative, reacting for 10-60 minutes under the condition of DIPEA + HATU, quenching the reaction by using an acid solution, extracting and drying. Wherein the molar ratio of the intermediate product B to the ammonia derivative is 1.5-3.
Carboxylating alkyl formate on the benzene ring of the intermediate product C to obtain an intermediate product D;
in the course of this synthesis, the ester group on the benzene ring can be converted into a carboxyl group in any manner, for example: the conventional method of acid or alkali hydrolysis, etc., and the preferred synthesis method can be: dissolving intermediate product C and alkaline agent (such as lithium iodide) in high boiling point organic solvent, preferably under protection of protective gas, reacting at a temperature of above 100 deg.C for 2-8 hr, cooling, spin drying, adding acid solution, extracting, and spin drying. Wherein the mass ratio of the intermediate product C to the alkaline agent is 1.
Obtaining an intermediate product E from the intermediate product D under the action of a vulcanizing agent;
in this synthesis process, any sulfurizing reagent that can change (C = O to C = S) may be used, and in the present invention, it is preferable to adopt a process in which a sulfurizing reagent (for example, lawesson' S reagent) is added to intermediate product D, and then the reaction is carried out at a reaction temperature of about 100 ℃ for 1 to 10 hours, followed by vacuum drying. Wherein the molar ratio of the intermediate product D to the vulcanizing agent is 1.5-3.
Carrying out intramolecular cyclization reaction on the intermediate product E to obtain an intermediate product F;
in this synthesis, the cyclization reaction can take place in any manner, generally under oxidative conditions. In the invention, the following process steps are preferably adopted, namely, after the intermediate product E is added with the oxidant and reacts for 3 to 10 hours at normal temperature, the mixture is extracted and dried by using acid and an extracting agent. Wherein the mass ratio of the intermediate product E to the oxidant is 1:1-10.
Deprotecting the amido on the intermediate product F to obtain an intermediate product G;
depending on the difference of the protecting groups, deprotection schemes for different protecting groups may be chosen. For example: when the protecting group is benzyl (Bn), deprotection thereof can be carried out under acidic conditions such as trifluoroacetic acid.
Performing substitution/addition reaction on amino on the intermediate product G to obtain an intermediate product H;
during this synthesis, the amino group on the phenyl ring can be amidated in any way, for example: directly using reagents such as carboxylic acid/anhydride/acyl halide and the like to perform amidation with amino. In the present invention, the following process steps are preferably adopted, namely, the intermediate product G and acid react for 0.5 to 5 hours at the reaction temperature of 20 to 80 ℃ under the alkaline condition, and then the intermediate product G is quenched by acid and extracted and dried by spinning. Wherein the molar ratio of the intermediate product G to the acid is 1:0.8-2.
Carrying out amidation reaction on carboxyl on a benzene ring of the intermediate product H to obtain an intermediate product I;
during this synthesis, the carboxyl group on the phenyl ring can be amidated in any way, for example: amidation is carried out directly with carboxyl and amino compound, or reaction with ammonia after carboxyl is changed into acyl halide, etc. In the present invention, it is preferable to adopt a process comprising mixing the intermediate product H with an amino derivative, reacting the mixture in a DIPEA + HATU system for 2 to 8 hours with stirring, quenching the reaction with an acid solution, and then extracting and spin-drying the reaction product. Wherein the molar ratio of the intermediate product H to the amino derivative is 1:1-3.
Carrying out hydrolysis/reduction reaction on the intermediate product I to obtain a target product;
during this synthesis, the ester or alkoxy group may be converted to a carboxyl or hydroxyl group in any manner, for example: conventional acid type, alkali type hydrolysis, reduction and the like.
Wherein the alkyl terephthalate derivative A is a compound represented by the following structure:
the intermediate product B is a compound shown in the following structure:
the intermediate product C is a compound shown in the following structure:
the intermediate product D is a compound shown in the following structure:
the intermediate product E is a compound shown in the following structure:
the intermediate product F is a compound shown in the following structure:
the intermediate product G is a compound represented by the following structure:
the intermediate product H is a compound shown in the following structure:
the intermediate product I is a compound shown in the following structure:
the amino protecting group represented by pro above may be any group susceptible to deprotection, such as: bn, cbz, boc, fmoc, alloc, teoc, pht, tos, tfa, trt, dmb, PMB, and the like.
In addition, the present invention provides a third method for producing the five-membered ring-containing compound, which comprises the following steps:
intermediate G was obtained by the second method described above
Then;
amidating the carboxyl on the intermediate product G to obtain an intermediate product H;
during this synthesis, the carboxyl group may be amidated in any way, for example: amidation is carried out directly with carboxyl and amino compound, or reaction with ammonia after carboxyl is changed into acyl halide, etc. In the present invention, it is preferable to adopt a process comprising mixing the intermediate product G with an amino derivative, reacting the mixture in a DIPEA + HATU system for 2 to 8 hours with stirring, quenching the reaction with an acid solution, and then extracting and spin-drying the reaction product. Wherein the molar ratio of the intermediate product G to the amino derivative is 1:1-3.
Performing addition/substitution reaction on amino on the intermediate product H to obtain an intermediate product I;
during this synthesis, the amino group on the phenyl ring can be amidated in any way, for example: the amidation is directly carried out with amino by using reagents such as carboxylic acid/anhydride/acyl halide and the like. In the invention, the following process steps are preferably adopted, namely, the intermediate product H and acid react for 0.5 to 5 hours at the reaction temperature of between 20 and 80 ℃ under the alkaline condition, and then the intermediate product H is quenched by acid and extracted and dried by spinning. Wherein the molar ratio of the intermediate product H to the acid is 1:0.8-2.
Carrying out hydrolysis/reduction reaction on the intermediate product I to obtain a target product;
during this synthesis, the ester or alkoxy group may be converted to a carboxyl or hydroxyl group in any manner, for example: conventional acid-base hydrolysis, reduction and the like.
Wherein, the intermediate product H is a compound shown in the following structure:
intermediate I is a compound represented by the following structure:
the present invention also provides a fourth method for producing the five-membered ring-containing compound, which comprises the following steps:
an intermediate product B is obtained by hydrolysis reaction of an alkyl terephthalate derivative A;
during this synthesis, one of the ester groups can be converted into a carboxyl group in any way, for example: the conventional method of acid or alkali hydrolysis, etc., and the preferred synthesis method can be: adding ether solvent, water and alkaline agent (such as hydroxide) into alkyl terephthalate derivative A, reacting at 15-35 deg.C for 0.1-10 hr, quenching with inorganic or organic acid, extracting, and spin drying. Wherein the molar ratio/mass ratio of the alkyl terephthalate derivative a to the alkaline agent is generally 1:0.1-0.5.
The intermediate product B reacts with hydrochloric acid-N, O-dimethylhydroxylamine to obtain an intermediate product C; the reaction process is that the intermediate product B reacts with hydrochloric acid-N, O-dimethylhydroxylamine for 0.1 to 1 hour under the alkaline condition, and then the intermediate product B is quenched by water and extracted and dried by spinning.
Opening the ring of the intermediate product C to obtain an intermediate product D containing an acetylene bond;
the reaction process is obtained by reacting the intermediate product C with a compound containing a terminal alkynyl group, preferably under catalytic conditions, followed by extraction and/or column chromatography. Wherein the molar ratio of the intermediate product C to the compound containing the terminal alkynyl is 1:1-2.
Reducing the intermediate product D to obtain an intermediate product E;
the process involves a reaction in which a triple bond (C ≡ C) is reduced to a single bond (C = C), and as the reducing agent, sodium borohydride, lithium aluminum hydride, pd/C, hydrogen, and the like, various types of reducing agents suitable for such a reaction can be used.
Hydrolyzing ester groups on the benzene ring of the intermediate product E into an intermediate product F containing carboxyl;
during the synthesis, one of the ester groups can be converted into a carboxyl group in any way, for example: the conventional method of acid or alkali hydrolysis, etc., and the preferred synthesis method can be: dissolving the intermediate product E and an alkaline agent (such as lithium iodide) in a high-boiling-point organic solvent, preferably reacting at a temperature of more than 100 ℃ for 1-10 hours under the protection of protective gas, cooling, spin-drying, adding an acid solution, and then extracting and spin-drying. Wherein the mass ratio of the intermediate product E to the alkaline agent is 1.
The intermediate product F is subjected to carbonyl vulcanization to obtain an intermediate product G;
in this synthesis process, any sulfurizing reagent that can change (C = O to C = S) may be used, and in the present invention, it is preferable to adopt a process in which a sulfurizing reagent (e.g., lawesson' S reagent, phosphorus pentasulfide, etc.) is added to intermediate product F, and then the reaction is carried out at a reaction temperature of about 100 ℃ for 5 hours or more, followed by reduced pressure drying. Wherein the molar ratio of the intermediate product F to the vulcanizing agent is 1.5-3.
Cyclizing the intermediate product G into an intermediate product H with a five-membered ring;
in this synthesis, the cyclization reaction can take place in any manner, generally under oxidative conditions. In the present invention, it is preferable to adopt a process in which an oxidizing agent is added to the intermediate product G, and after the reaction is carried out at room temperature for 3 to 10 hours, the intermediate product G is extracted with an acid and an extractant and then spin-dried. Wherein the mass ratio of the intermediate product G to the oxidant is 1:1-10.
Performing amidation reaction on carboxyl on a benzene ring of the intermediate product H to obtain an intermediate product I;
during this synthesis, the carboxyl group may be amidated in any way, for example: amidation is carried out directly with carboxyl and amino compound, or reaction with ammonia after carboxyl is changed into acyl halide, etc. In the invention, the following process steps are preferably adopted, namely, after the intermediate product H and the amino derivative are mixed, the mixture is stirred and reacted in a system of DIPEA + HATU for 2 to 8 hours, then the reaction is quenched by acid solution, and then extraction and spin drying are carried out. Wherein the molar ratio of the intermediate product H to the amino derivative is 1:1-3.
Carrying out hydrolysis/reduction reaction on the intermediate product I to obtain a target product;
during this synthesis, the ester or alkoxy group may be converted to a carboxyl or hydroxyl group in any manner, for example: conventional acid type, alkali type hydrolysis, reduction and the like.
Wherein the alkyl terephthalate derivative A is a compound represented by the following structure:
the intermediate product B is a compound shown in the following structure:
the intermediate product C is a compound shown in the following structure:
the intermediate product D is a compound shown in the following structure:
the intermediate E is a compound represented by the following structure:
the intermediate product F is a compound shown in the following structure:
the intermediate product G is a compound represented by the following structure:
the intermediate product H is a compound shown in the following structure:
the intermediate product I is a compound shown in the following structure:
the present invention also provides a fifth process for producing the above five-membered ring-containing compound, which comprises the following steps:
intermediate G was obtained by the second method described above
Then;
protecting carboxyl on a benzene ring of the intermediate product G to obtain an intermediate product H;
the mode of the intermediate product H can be adjusted according to the difference of the protecting groups, and preferably an ester group protecting scheme is adopted, specifically: the intermediate product G reacts with halogenated hydrocarbon/diazoalkane and the like, and then the solvent is removed to obtain the intermediate product. The molar ratio of intermediate product G to halohydrocarbon/diazoalkane is preferably 1:1.
Halogenating amino on the intermediate product H to obtain an intermediate product I;
the halogenated product is preferably an iodinated product, and the synthesis process is preferably as follows: the intermediate product H reacts with halide salt under the acidic oxidation condition and is obtained by extraction and spin drying (column chromatography purification is also available). Wherein the molar ratio of the intermediate product H to the halide salt is 1:1-2.
Carrying out alkynylation on the halogen on the intermediate product I to obtain an intermediate product J;
the synthesis step is that the intermediate product I and a compound with an ethynyl group at the tail end react under the action of a catalyst (cuprous iodide and the like). Wherein the molar ratio of the intermediate product I to the compound with the ethinyl end is 1:1-2.
Deprotection of carboxyl on the benzene ring of the intermediate product J to obtain an intermediate product K;
this step is a treatment which discriminates between protective groups. In the case of an ester protecting group, this is carried out by acidic or basic hydrolysis.
Amidating carboxyl on the benzene ring of the intermediate product K to obtain an intermediate product L;
during this synthesis, the carboxyl group may be amidated in any way, for example: amidation is carried out directly with carboxyl and amino compound, or reaction with ammonia after carboxyl is changed into acyl halide, etc. In the invention, the following process steps are preferably adopted, namely, after the intermediate product K is mixed with the amino derivative, the mixture is stirred and reacts in a system of DIPEA + HATU for 2 to 8 hours, then the reaction is quenched by acid solution, and then extraction and spin drying are carried out. Wherein the molar ratio of the intermediate product K to the amino derivative is 1:1-3.
Carrying out hydrolysis/reduction reaction on the intermediate product L to obtain a target product;
during this synthesis, the ester or alkoxy group may be converted to a carboxyl or hydroxyl group in any manner, for example: conventional acid type, alkali type hydrolysis, reduction and the like.
Wherein the intermediate product H is a compound shown in the following structure:
the intermediate product I is a compound shown in the following structure:
the intermediate product J is a compound shown in the following structure:
the intermediate product K is a compound shown in the following structure:
the intermediate product L is a compound shown in the following structure:
in the present invention, the carboxyl protecting group pro may be any protecting group such as an ester group, an amide, a hydrazide, etc., and it is preferably protected with an ester group as required in the subsequent synthesis step, such as: converting the carboxyl group into a group which is easily removed by methyl ester, ethyl ester, isopropyl ester, isobutyl ester, etc.
In addition, the present invention also provides compounds represented by the following structure: the following compounds are all various intermediates in the synthesis.
Wherein R is 1 Selected from aryl, heteroaryl;
R 2 is hydrogen, halogen or alkyl substituted on any or several of benzene rings;
x is selected from carbon, carbonyl, nitrogen, sulfur and oxygen;
y is selected from carbon, carbonyl, nitrogen, sulfur and oxygen;
the X-Y bond is selected from a single bond, a double bond or a triple bond;
A 1 selected from carbon, oxygen, sulfur, nitrogen;
A 2 selected from carbon, oxygen, sulfur, nitrogen;
A 3 selected from carbon, oxygen, sulfur, nitrogen;
A 4 selected from carbon, oxygen, sulfur, nitrogen;
A 5 selected from carbon, oxygen, sulfur, nitrogen.
In addition, the invention also provides application of the compound containing the five-membered ring as an immune cell migration inhibitor.
In addition, the invention also provides a medicine for treating xerophthalmia, which is characterized in that:
contains the compound containing the five-membered ring with the mass percent content of 1-1000%.
The specific manufacturing method of the medicine for treating xerophthalmia is as follows: adding sterile normal saline into the compound containing the five-membered ring, uniformly mixing, adding NaOH, and stirring to obtain a transparent solution;
to the solution obtained above, naH was added 2 PO 4 After the pH value of the saturated water solution is between 6.75 and 7.25, the solution is subjected to constant volume by using sterile normal saline;
introducing nitrogen into the solution, bubbling for 1-2 hours, and storing in a sealed and light-proof manner for later use;
wherein, the proportion of the compound containing the five-membered ring and the sterile normal saline is 1 g: 10-25 ml;
the mass ratio of the sodium hydroxide to the compound containing the five-membered ring is 1:6-15;
wherein, naOH-NaH 2 PO 4 May be replaced by any buffer system.
Action and effect:
the invention provides a novel immune cell migration inhibitor which has good hydrophilicity and can be developed into eyedrops. Has strong capability of inhibiting the migration of immune cells, and can relieve the symptoms of most patients with dry eye syndrome.
Detailed Description
Example 1 (VIP 102)
The specific reaction equation for(s) -2- (5,7-dichloro-3- ((3-hydroxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid is shown below:
step A: 2-amino-3,5-dichloro-4- (methoxycarbonyl) benzoic acid (Compound 1.1)
Weighing 1g of 2-amino-3,5-dichloro-4- (methoxycarbonyl) methyl benzoate, adding 10ml of tetrahydrofuran, 1ml of water and 0.5g of lithium hydroxide, reacting at 20 ℃ for 1 hour, adding hydrochloric acid for quenching, extracting with ethyl acetate, and then spin-drying.
And B: 3-amino-2,6-dichloro-4- ((3-methoxybenzyl) carbamoyl) benzoic acid methyl ester (Compound 1.2)
0.92g of the compound 1.1 was dissolved in 10mL of dichloromethane, 3-methoxybenzylamine (2 eq), DIPEA (5 eq) and HATU (1.5 eq) were added, the reaction was quenched with 1mol/L dilute hydrochloric acid solution under stirring for 20 minutes, extracted three times with 30mL of ethyl acetate, and the organic phases were combined, spun-dried and purified to obtain a product (0.98g, 70%). LCMS ESI (+) M/z:383.0 (M + 1).
And C: 3-amino-2,6-dichloro-4- ((3-methoxybenzyl) carbamoyl) benzoic acid (compound 1.3)
Dissolving compound 1.2 (0.98 g) and lithium iodide (0.98 g) in 10ml pyridine under nitrogen protection, stirring at 120 ℃ for 3 hours, cooling, spinning, adding 10ml 1mol/L diluted hydrochloric acid solution, extracting with 30ml ethyl acetate for 3 times, combining organic phases, and spinning without purification. LCMSISI (+) M/z:369.0 (M + 1).
Step D: 3-amino-2,6-dichloro-4- ((3-methoxybenzyl) aminomethylsulfonyl) benzoic acid (Compound 1.4)
0.82g of the compound 1.3 is dissolved in 10ml of toluene, added with Lawesson's reagent (2 eq) and stirred for 4 hours at 100 ℃, dried by spinning under reduced pressure and subjected to column chromatography to obtain 0.65g of a target product. LCMSISI (+) M/z 385.0 (M + 1).
Step E:5,7-dichloro-3- ((3-methoxybenzyl) amino) benzisothiazole-6-carboxylic acid (Compound 1.5)
0.65g of compound 1.4 is dissolved in 5ml of pyridine, and 2ml of 10% hydrogen peroxide are added. Stirring at room temperature for 4h, adding 10ml dilute hydrochloric acid solution, extracting with 30ml ethyl acetate for 3 times, combining organic phases, and spin-drying under reduced pressure. Column chromatography to obtain target product 0.5g. LCMSISI (+) M/z:383.0 (M + 1).
Step F: (s) -benzyl 2- (5,7-dichloro-3- ((3-methoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionate (compound 1.6)
0.5g of compound 1.5 was dissolved in 5ml DMF and (2 s) -benzyl 2-amino-3- (3- (methylsulfonyl) phenyl) propionate hydrochloride (2 eq) was added followed by DIPEA (10 eq), HATU (2.5 eq). Stirring at room temperature for 4h, adding 10ml dilute hydrochloric acid solution, extracting with ethyl acetate for 3 times, combining organic phases, and spin-drying. Purifying by column chromatography to obtain target product 0.45g. LCMS ESI (+) M/z:698.0 (M + 1).
Step G: (s) -2- (5,7-dichloro-3- ((3-hydroxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (compound 1.7)
Dissolving 60mg of compound 1.6 in 1ml of dichloromethane, adding boron tribromide (5 eq), reacting at 0 ℃ for 1h, adding water to quench, concentrating to remove the organic solvent, preparing in reverse phase, and freeze-drying to obtain 38mg of a product. 1 H NMR(400MHz,CD 3 OD):δ7.96(s,1H),7.87-7.85(m,2H),7.74(d,J＝7.6Hz,,1H),7.61(t,J＝8.0Hz,1H),7.21(t,J＝8.0Hz,1H),6.90(d,J＝7.2Hz,1H),6.87(s,1H),6.76(dd,J＝8.4,2.0Hz,1H),5.13(dd,J＝10.0,4.8Hz,1H),4.46(s,2H),3.50(dd,J＝14.4,5.2Hz,1H),3.19(dd,J＝14.4,10.0Hz,1H),3.11(s,3H)；LC-MS:m/z 594.0(M+H) +
Example 2 (VIP 114)
(s) -2- (3- (benzofuran-2-carboxamido) -5,7-dichlorobenzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: 3-amino-2,6-dichloro-4- ((4-methoxyphenyl) carbamoyl) benzoic acid methyl ester (Compound 2.1)
8.5g of compound 1.1 is weighed, dissolved in 100mL of dichloromethane, added with 4-methoxybenzylamine (2 eq), DIPEA (5 eq) and HATU (1.5 eq), stirred for 20 minutes, quenched with 1mol/L diluted hydrochloric acid solution, extracted three times with 300mL of ethyl acetate, the organic phases are combined, spun dry and purified by column chromatography to obtain the product (8.8 g). LCMS ESI (+) M/z:383.0 (M + 1).
And B: 3-amino-2,6-dichloro-4- ((4-methoxybenzyl) carbamoyl) benzoic acid (Compound 2.2)
Dissolving compound 2.1 (0.98 g) and lithium iodide (0.98 g) in 10ml pyridine under nitrogen protection, stirring at 120 ℃ for 3 hours, cooling, spinning, adding 10ml 1mol/L diluted hydrochloric acid solution, extracting with 30ml ethyl acetate for 3 times, combining organic phases, and spinning without purification. LCMS ESI (+) M/z:369.0 (M + 1).
And C: 3-amino-2,6-dichloro-4- ((4-methoxybenzyl) aminomethylsulfonyl) benzoic acid (Compound 2.3)
Dissolving 0.82g of compound 2.2 in 10ml of toluene, adding Lawesson reagent (2 eq) at 100 ℃, stirring for 4h, carrying out reduced pressure spin drying, and carrying out column chromatography to obtain 0.65g of a target product. LCMS ESI (+) M/z 385.0 (M + 1).
Step D:5,7-dichloro-3- ((4-methoxybenzyl) amino) benzisothiazole-6-carboxylic acid (Compound 2.4)
0.65g of compound 2.3 is dissolved in 5ml of pyridine, and 2ml of 10% hydrogen peroxide are added. Stirring at room temperature for 4h, adding 10ml dilute hydrochloric acid solution, extracting with 30ml ethyl acetate for 3 times, combining organic phases, and spin-drying under reduced pressure. Column chromatography to obtain target product 0.5g. LCMS ESI (+) M/z:383.0 (M + 1).
Step E:5,7-dichloro-3-aminobenzothiazole-6-carboxylic acid (Compound 2.5)
0.5g of Compound 2.4 was added to 10mL of trifluoroacetic acid, heated at 70 ℃ for 12 hours, and concentrated under reduced pressure and used in the next step. LCMS ESI (+) M/z:262.9 (M + 1).
Step F:3- (benzofuran-2-carboxamido) -5,7-dichlorobenzisothiazole-6-carboxylic acid (compound 2.6)
0.35g of Compound 2.5 and 0.5g of benzofuran-2-carboxylic acid are dissolved in 5ml of DMF and triethylamine (5 eq), HATU (1.5 eq) are added. Stirring at room temperature for 1h, adding 10ml dilute hydrochloric acid solution, extracting with ethyl acetate for 3 times, combining organic phases, and spin-drying. Column chromatography was used to obtain 0.5g of the desired product. LCMS ESI (+) M/z:407.0 (M + 1).
Step G: (s) -benzyl 2- (3- (benzofuran-2-carboxamido) -5,7-dichlorobenzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionate (compound 2.7)
0.5g of compound 2.6 was dissolved in DMF and (2 s) -benzyl 2-amino-3- (3- (methylsulfonyl) phenyl) propionate hydrochloride (2 eq) was added followed by DIPEA (5 eq), HATU (1.5 eq). Stirring at room temperature for 4h, adding 10ml dilute hydrochloric acid solution, extracting with ethyl acetate for 3 times, combining organic phases, and spin-drying. Purifying by column chromatography to obtain target product 0.55g. LCMS ESI (+) M/z:721.1 (M + 1).
Step H: (s) -2- (3- (benzofuran-2-carboxamido) -5,7-dichlorobenzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (compound 2.8)
50mg of compound 2.7 was dissolved in methanol (1 ml), 10mg of Pd/C (10%) was added, and the mixture was hydrogenated under normal pressure for 1 hour, filtered, spun-dried, and purified by a reverse phase column to obtain 23mg of the objective product. LCMS ESI (+) M/z:632.0 (M + 1). 1 H NMR(400MHz,CD 3 OD):δ8.54(s,1H),7.99(s,1H),7.95(s,1H),7.89-7.85(m,2H),7.77-7.75(m,2H),7.65-7.58(m,2H),7.42(t,J＝7.6Hz,,1H),5.16(dd,J＝9.6,4.8Hz,1H),3.53(dd,J＝14.4,4.8Hz,1H),3.23(dd,J＝14.0,10.0Hz,1H),3.14(s,3H)；LC-MS:m/z 632.0(M+H) + .
Example 3 (VIP 113)
(s) -2- (5,7-dichloro-3- ((4-hydroxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (S) -benzyl 2- (5,7-dichloro-3-aminobenzothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionate (Compound 3.1)
5g of Compound 2.5 0.5g of Compound 2.6 are dissolved in DMF and benzyl (2 s) -2-amino-3- (3- (methylsulfonyl) phenyl) propionate hydrochloride (2 eq) is added followed by DIPEA (5 eq), HATU (1.5 eq). Stirring at room temperature for 4h, diluting with water, extracting with chloroform for 3 times, mixing organic phases, and spin-drying. And purifying by column chromatography to obtain 5.2g of target product. LCMS ESI (+) M/z:578.1 (M + 1).
And B: (s) -2- (5,7-dichloro-3- ((4-methoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (Compound 3.2)
200mg of compound 3.1 and 500mg of 4-hydroxybenzaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5h, adding sodium bicarbonate to quench, extracting the aqueous phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 53mg of a product. LCMS ESI (+) M/z 636.1 (M + 1).
And C: (s) -2- (5,7-dichloro-3- ((4-methoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (compound 3.3)
53mg of compound 3.3 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and the mixture is stirred for 30min. After quenching with citric acid solution, the product was prepared in reverse phase as 28mg.1H NMR (400MHz, CD3OD): delta 7.95 (d, J =6.0Hz, 1H), 7.86-7.83 (M, 1.5H), 7.75-7.71 (M, 1H), 7.62-7.58 (M, 1H), 7.48 (s, 0.5H), 7.28 (d, J =8.8Hz, 1H), 7.18 (d, J =8.4Hz, 1H), 6.81 (d, J =8.4Hz, 1H), 6.76 (d, J =8.4Hz, 1H), 5.14-5.08 ((M, 1H), 4.41 (s, 2H), 3.51-3.46 (M, 1H), 3.22-3.16 (M, 1H), 3.11 (s, 3H); S ESI (+) zm/z: 8978 zm + 8978 (M, 78M + 89ft)
Example 4 (VIP 123)
(s) -2- (5,7-dichloro-3- ((2-furylmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (s) -2- (5,7-dichloro-3- ((2-furylmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (Compound 4.1)
200mg of compound 3.1 and 500mg of 2-furaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5h, adding sodium bicarbonate to quench, extracting the aqueous phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 50mg of a product. LCMS ESI (+) M/z:610.1 (M + 1).
And B: (s) -2- (5,7-dichloro-3- ((2-furylmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (compound 4.2)
50mg of compound 4.1 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and stirring is carried out for 30min. After quenching with citric acid solution, the reverse phase was prepared to give 25mg of product. LCMS ESI (+) M/z 568.1 (M + 1). 1 H-NMR(400MHz,DMSO)1H NMR(400MHz,CD3OD):δ7.94(s,1H),7.84-7.81(m,2H),7.71(d,J＝7.2Hz,,1H),7.58(t,J＝8.0Hz,1H),7.50(s,1H),6.50(d,J＝2.8Hz,1H),6.41(s,1H),5.10(dd,J＝9.6,4.8Hz,1H),4.51(s,2H),3.47(dd,J＝12.4,9.6Hz,1H),3.15(dd,J＝14.4,9.6Hz,1H),3.08(s,3H)；
Example 5 (VIP 123)
(s) -2- (5,7-dichloro-3- ((3-furylmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (s) -2- (5,7-dichloro-3- ((3-furylmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (compound 5.1).
200mg of compound 3.1 and 500mg of 3-furaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5h, adding sodium bicarbonate to quench, extracting the aqueous phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 50mg of a product. LCMS ESI (+) M/z:610.1 (M + 1).
And B: (s) -2- (5,7-dichloro-3- ((3-furylmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (compound 5.2)
50mg of compound 5.1 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and stirring is carried out for 30min. After quenching with citric acid solution, the reverse phase was prepared to give 25mg of product. LCMS ESI (+) M/z 568.1 (M + 1). 1 H NMR(400MHz,CD3OD):δ7.96(s,1H),7.87-7.84(m,2H),7.74(d,J＝8.0Hz,,1H),7.67(s,1H),7.61(t,J＝8.4Hz,1H),7.54(d,J＝3.2Hz,1H),6.51(d,J＝1.2Hz,1H),5.12(dd,J＝10.0,4.8Hz,1H),4.39(s,2H),3.49(dd,J＝12.4,9.6Hz,1H),3.19(dd,J＝14.4,9.6Hz,1H),3.11(s,3H)；LC-MS:m/z 568.0(M+H)+.
Example 6 (VIP 127)
(s) -2- (5,7-dichloro-3- ((3' -hydroxyphenylethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (s) -2- (5,7-dichloro-3- ((3' -hydroxyphenylethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (Compound 6.1)
200mg of compound 3.1 and 500mg of 3' -hydroxybenzaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5h, adding sodium bicarbonate to quench, extracting the aqueous phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 50mg of a product. LCMS ESI (+) M/z 650.1 (M + 1).
And B: (s) -2- (5,7-dichloro-3- ((3' -hydroxyphenylethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (Compound 6.2)
50mg of compound 6.1 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and stirring is carried out for 30min. After quenching with citric acid solution, the reverse phase was prepared to give 25mg of product. LCMS ESI (+) M/z:713.5 (M + 1). 1H NMR (400MHz, CD3OD): δ 7.94 (s, 1H), 7.83 (d, J =8.0Hz, 1H), 7.77 (s, 1H), 7.71 (d, J =8.0Hz, 1H), 7.58 (t, J =8.0Hz, 1H), 7.09 (t, J =8.0Hz, 1H), 6.72 (d, J =7.6Hz, 1H), 6.69 (s, 1H), 6.64 (d, J =8.0Hz, 1H), 5.10 (dd, J =9.6,4.8Hz, 1H), 3.54-3.45 (M, 3H), 3.17 (dd, J =14.0, 9.1H), 3.09 (s = 3.2H), 2.2T (7, 2H), 2H, 1H)
Example 7 (VIP 130)
(s) -2- (5,7-dichloro-3- ((6-benzofuranmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (s) -2- (5,7-dichloro-3- ((6-benzofuranmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (Compound 7.1)
200mg of compound 3.1 and 500mg of 6-benzofurancarboxaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5 hour, adding sodium bicarbonate to quench, extracting the water phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 50mg of a product. LCMS ESI (+) M/z:660.1 (M + 1).
And B, step B: (s) -2- (5,7-dichloro-3- ((6-benzofuranmethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (Compound 7.2)
50mg of compound 7.1 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and stirring is carried out for 30min. After quenching with citric acid solution, the product was prepared in reverse phase at 15mg. LCMS ESI (+) M/z 618.1 (M + 1). 1H NMR (400MHz, CD3OD): δ 7.94 (s, 1H), 7.86-7.82 (M, 2H), 7.76 (s, 1H), 7.71 (d, J =7.6Hz, 1H), 7.64-7.58 (M, 3H), 7.33 (d, J =8.0Hz, 1H), 6.84 (s, 1H), 5.10 (dd, J =10.0,4.8Hz, 1H), 4.63 (s, 2H), 3.48 (dd, J =9.2,4.8Hz, 1H), 3.17 (dd, J =14.4,6.0Hz, 1H), 3.08 (s, 3H); LC-MS M/z 618.0 (M + H) +.
Example 8 (VIP 165)
(s) -2- (5,7-dichloro-3- ((3' -hydroxyphenylethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (s) -2- (5,7-dichloro-3- ((4' -hydroxyphenylethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (Compound 8.1)
200mg of compound 3.1 and 500mg of 4' -hydroxyphenylacetaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5h, adding sodium bicarbonate to quench, extracting the aqueous phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 50mg of a product. LCMS ESI (+) M/z 650.1 (M + 1).
And B: (s) -2- (5,7-dichloro-3- ((4' -hydroxyphenylethyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (Compound 8.2)
50mg of compound 8.1 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and stirring is carried out for 30min. After quenching with citric acid solution, the reverse phase was prepared to give 25mg of product. LCMS ESI (+) M/z:713.5 (M + 1). 1H NMR (400mhz, cd3od): δ 7.94 (s, 1H), 7.83 (d, J =7.6Hz, 1h), 7.79-7.78 (M, 1H), 7.71 (d, J =7.6Hz, 1H), 7.58 (t, J =7.6Hz, 1h), 7.16 (d, J =8.4Hz, 0.5H), 7.07 (d, J =8.4hz, 1.5h), 6.73-6.68 (M, 2H), 5.10 (dd, J =10.0,5.2hz, 1h), 3.50-3.45 (M, 2.5H), 3.33-3.26 (M, 1H), 3.17 (dd, J =14.4, 10.10 Hz, 1H), 3.50-3.09 (s, 3.96H), 3.6.8 (t, 6H).
Example 9 (VIP 147)
(s) -2- (5,7-dichloro-3- ((3'4' -dimethoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (s) -2- (5,7-dichloro-3- ((3'4' -dimethoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (Compound 9.1)
200mg of compound 3.1 and 500mg of 3'4' -dimethoxyphenylacetaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5h, adding sodium bicarbonate to quench, extracting the aqueous phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 50mg of a product. LCMS ESI (+) M/z:680.1 (M + 1).
And B: (s) -2- (5,7-dichloro-3- ((3'4' -dimethoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (Compound 9.2)
50mg of compound 9.1 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and stirring is carried out for 30min. After quenching with citric acid solution, the reverse phase was prepared to give 25mg of product. 1H NMR (400MHz, CD3OD): δ 7.96 (s, 1H), 7.87-7.84 (m, 2H), 7.74 (d, J =8.0Hz, 1H), 7.60 (t, J =7.6Hz, 1H), 7.05-6.96 (m, 3H), 5.12 (dd, J =10.0,4.8Hz, 1H), 4.46 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.50 (dd, J =14.0,4.8Hz, 1H), 3.19 (dd, J =14.4,9.6Hz, 1H), 3.11 (s, 3H); LC-MS M/z 638.0 (M + H) +.
Example 10 (VIP 161)
(s) -2- (5,7-dichloro-3- (3-hydroxyphenylethyl) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: 3-amino-2,6-dichloro-4- (methoxymethylcarbamoyl) benzoic acid methyl ester (Compound 10.1)
1.34g of the compound 1.1,0.5g of hydrochloric acid-N, O-dimethylhydroxylamine and 1ml of triethylamine were dissolved in 10ml of DMF, and 1g of HATU was added thereto, followed by stirring at room temperature for 30min. Adding water for quenching, extracting by ethyl acetate to obtain a crude product, and purifying by column chromatography to obtain a product of 1.63g. LCMS ESI (+) M/z:307.1 (M + 1).
And B: 3-amino-2,6-dichloro-4- (3- (3-methoxyphenyl) propiolic acyl) benzoic acid methyl ester (Compound 10.2)
Dissolving 3g of 3-methoxy phenylacetylene in 30ml of tetrahydrofuran, adding 9ml of 2.5M butyl lithium solution at minus 78 ℃, adding 1.63g of tetrahydrofuran solution of a compound 10.1 after half an hour, heating to minus 20 ℃, adding an ammonium chloride aqueous solution, extracting a water phase by using ethyl acetate after layering, concentrating, and performing column chromatography to obtain 2.8g of a product. LCMS ESI (+) M/z:378.1 (M + 1).
And C: 3-amino-2,6-dichloro-4- (3- (3-methoxyphenyl) propionyl) benzoic acid methyl ester (Compound 10.3)
2.83g of Compound 10.2 was dissolved in 50ml of methanol, 0.3g of 10% Pd/C was added, hydrogen gas was introduced, hydrogenation was carried out at normal pressure for 2 hours, and the resulting solution was filtered and concentrated to obtain 2.8g of a product. LCMS ESI (+) M/z:382.1 (M + 1).
Step D: 3-amino-2,6-dichloro-4- (3- (3-methoxyphenyl) propionyl) benzoic acid (Compound 10.4)
2.8g of compound 10.4 are dissolved in 30ml of pyridine, and 3g of lithium iodide are added. After heating at 120 ℃ for 30 minutes, the mixture was cooled to room temperature, and 200ml of 10% hydrochloric acid was added to precipitate a solid. After filtration, recrystallization with isopropanol alcohol gives the product 2.5g.LCMS ESI (+) M/z:368.1 (M + 1).
Step E: 3-amino-2,6-dichloro-4- (3- (3-methoxyphenyl) propanethioacyl) benzoic acid (Compound 10.5)
2.5g of compound 10.5 and 5g of phosphorus pentasulfide are added to 100ml of toluene and refluxed at 100 ℃ for 12 hours. After concentration, the product was extracted with tetrahydrofuran, and the resulting solution was concentrated to give 2.5g of product (LCMS ESI (+) M/z:384.1 (M + 1)).
Step E:5,7-dichloro-3- (3-methoxyphenethyl) benzisothiazole-6-carboxylic acid (Compound 10.6)
2.5g of compound 10.5 are dissolved in 50ml of pyridine and 5ml of 30% hydrogen peroxide solution are slowly added at 0 ℃. After 30 minutes of reaction, quench with sodium sulfite solution, adjust to pH =2 with 1M hydrochloric acid and extract the aqueous phase with 3X100 ml dichloromethane. The organic phases are combined, concentrated and chromatographed to obtain 1.7g of the product. LCMS ESI (+) M/z:382.1 (M + 1).
Step F: (s) -benzyl 2- (5,7-dichloro-3- (3-methoxyphenylethyl) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionate (compound 10.7)
0.5g of compound 10.6 was dissolved in 5ml DMF and benzyl (2 s) -2-amino-3- (3- (methylsulfonyl) phenyl) propionate hydrochloride (2 eq) was added followed by DIPEA (10 eq), HATU (2.5 eq). Stirring at room temperature for 4h, adding 10ml dilute hydrochloric acid solution, extracting with ethyl acetate for 3 times, combining organic phases, and spin-drying. And purifying by column chromatography to obtain 0.45g of target product. LCMS ESI (+) M/z:697.1 (M + 1).
G: (s) -2- (5,7-dichloro-3- (3-methoxyphenylethyl) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (Compound 10.8)
Dissolving 60mg of compound 10.7 in 1ml of dichloromethane, adding boron tribromide (5 eq), reacting at 0 ℃ for 1h, adding water for quenching, concentrating to remove an organic solvent, carrying out reverse phase preparation, and freeze-drying to obtain a product 38mg.1H NMR (400MHz, CD3OD): δ 7.97 (s, 1H), 7.86 (d, J =8.0Hz, 1H), 7.74 (d, J =8.0Hz, 1H), 7.71 (s, 1H), 7.61 (t, J =8.0Hz, 1H), 7.06 (t, J =8.0Hz, 1H), 6.64-6.56 (m, 3H), 5.14 (dd, J =10.0,4.8Hz, 1H), 3.64 (t, J =7.2Hz, 2H), 3.51 (dd, J =14.4,4.8Hz, 1H), 3.19 (dd, J =14.4,10.0Hz, 1H), 3.11 (s, 3H), 3.04 (t, J = 7.0Hz, 2H); LC-MS M/z 593.0 (M + H) +.
Example 11 (VIP 165)
(s) -2- (5,7-dichloro-3- ((4-hydroxymethylbenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (s) -2- (5,7-dichloro-3- ((4-hydroxymethylbenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (Compound 11.1)
200mg of compound 3.1 and 500mg of 4-hydroxymethylbenzaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5h, adding sodium bicarbonate to quench, extracting the aqueous phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 50mg of a product. LCMS ESI (+) M/z 650.1 (M + 1).
And B: (s) -2- (5,7-dichloro-3- ((4-hydroxymethylbenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (compound 11.2)
50mg of compound 11.1 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and the mixture is stirred for 30min. After quenching with citric acid solution, the reverse phase was prepared to give 25mg of product. 1H NMR (400MHz, CD3OD): δ 7.84 (s, 1H), 7.78 (s, 1H), 7.74 (d, J =7.6Hz, 1H), 7.62 (d, J =8.0Hz, 1H), 7.49 (t, J =8.0Hz, 1H), 7.35-7.26 (m, = 4H), 5.01 (dd, J =10.0,4.8Hz, 1H), 4.51 (s, 2H), 4.41 (s, 2H), 3.38 (dd, J =14.4,4.8Hz, 1H), 3.07 (dd, J =14.0,9.6Hz, 1H), 2.99 (s, 3H); LC-MS M/z 608.0 (M + H) +.
Example 12 (VIP 176)
(s) -2- (5,7-dichloro-3- ((3-hydroxy-4-methoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: (s) -2- (5,7-dichloro-3- ((3-hydroxy-4-methoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid isopropyl ester (Compound 12.1)
200mg of compound 3.1 and 500mg of 3-hydroxy-4-methoxybenzaldehyde are added to 5ml of dichloromethane and 100ml of titanium tetraisopropoxide are added at 0 ℃. After the reaction was stirred for 12 hours, 0.1g of sodium cyanoborohydride was added. Reacting for 0.5h, adding sodium bicarbonate to quench, extracting the aqueous phase with dichloromethane, combining the organic phases, spin-drying, and performing column chromatography to obtain 50mg of a product. LCMS ESI (+) M/z:666.1 (M + 1).
And B: (s) -2- (5,7-dichloro-3- ((3-hydroxy-4-methoxybenzyl) amino) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (compound 11.2)
50mg of compound 12.1 are dissolved in 1ml of tetrahydrofuran, 0.1ml of 20% sodium hydroxide solution is added and the mixture is stirred for 30min. After quenching with citric acid solution, the reverse phase was prepared to give 25mg of product. 1H NMR (400MHz, CD3OD): δ 7.96 (s, 1H), 7.86-7.84 (m, 2H), 7.74 (d, J =7.6Hz, 1H), 7.60 (t, J =7.6Hz, 1H), 6.95-6.89 (m, 3H), 5.13 (dd, J =10.0,4.8Hz, 1H), 4.40 (s, 2H), 3.87 (s, 3H), 3.50 (dd, J =14.4,4.8Hz, 1H), 3.19 (dd, J =14.4,9.6Hz, 1H), 3.11 (s, 3H); LC-MS M/z 624.0 (M + H) +.
Example 13 (VIP 189)
(s) -2- (5,7-dichloro-3- (3-hydroxyphenylethynyl) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The specific reaction equation is as follows:
step A: 3-amino-5,7-dichlorobenzisothiazole-6-carboxylic acid methyl ester (Compound 13.1)
Compound 2.5 (100 mg) was dissolved in 5ml of THF, and 2ml of 2M TMS diazomethane toluene solution was added thereto, followed by stirring for 30min and concentration to give 105mg of product, LCMS ESI (+) M/z:277.0 (M + 1).
And B:5,7-dichloro-3-iodobenzisothiazole-6-carboxylic acid methyl ester (Compound 13.2)
105mg of compound 13.1 (100 mg) was dissolved in 2ml of 1M hydrochloric acid, 50mg of sodium nitrite solid was added at 0 ℃, stirred for 10 minutes, then 2ml of 1M sodium iodide solution was added, the temperature was raised to room temperature, and the aqueous phase was extracted with 2X5ml of ethyl acetate. The organic phase obtained is concentrated by drying and then is subjected to column chromatography to obtain a product of 45mg. LCMS ESI (+) M/z:388.0 (M + 1).
And C:5,7-dichloro-3- (3-methoxyphenylethynyl) benzisothiazole-6-carboxylic acid methyl ester (Compound 13.3)
45mg of compound 13.2, 20mg of 3-methoxyphenylacetylene, 5mg of palladium tetrakistriphenylphosphine, 1mg of cuprous iodide and 0.1ml of triethylamine were dissolved in 2ml of tetrahydrofuran, and the mixture was heated at 40 ℃ for 8 hours while substituting nitrogen. The resulting solution was concentrated and subjected to column chromatography to give 52mg of the product. LCMS ESI (+) M/z:392.0 (M + 1).
Step D:5,7-dichloro-3- (3-methoxyphenylethynyl) benzisothiazole-6-carboxylic acid (Compound 13.4)
52mg of compound 13.3 and 100mg of lithium iodide were dissolved in 2ml of pyridine, heated at 100 ℃ for 1 hour, and then poured into 20ml of 2M hydrochloric acid. Filtration gave 43mg of product. LCMS ESI (+) M/z:378.0 (M + 1).
Step E: (s) -benzyl 2- (5,7-dichloro-3- (3-methoxyphenylethynyl) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionate (compound 13.5)
43mg of compound 13.4 are dissolved in 2ml of DMF and benzyl (2 s) -2-amino-3- (3- (methylsulfonyl) phenyl) propionate hydrochloride (2 eq) is added followed by DIPEA (10 eq) and HATU (2.5 eq). Stirring at room temperature for 4h, adding 5ml dilute hydrochloric acid solution, extracting with ethyl acetate for 3 times, combining organic phases, and spin-drying. Purifying by column chromatography to obtain target product 40mg. LCMS ESI (+) M/z:693.0 (M + 1).
Step F: (s) -2- (5,7-dichloro-3- (3-hydroxyphenylethynyl) benzisothiazole-6-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (Compound 13.6)
Dissolving 40mg of compound 13.5 in 1ml of dichloromethane, adding boron tribromide (5 eq), reacting at 0 ℃ for 1h, adding water for quenching, concentrating to remove an organic solvent, carrying out reverse phase preparation, and freeze-drying to obtain a product 30mg. LCMS ESI (+) M/z:589.0 (M + 1). Sub.1H NMR (400MHz, CD3OD): δ 7.87 (s, 1H), 7.83 (s, 1H), 7.76 (d, J =8.0Hz, 1H), 7.64 (d, J =8.0Hz, 1H), 7.51 (t, J =7.6Hz, 1H), 7.19 (t, J = 8.2Hz, 1H), 7.05 (d, J =7.6Hz, 1H), 6.97 (s, 1H), 6.82 (d, J =8.0,3.2Hz, 1H), 5.04 (0dd, J =9.6,4.8Hz, 1H), 3.43-3.38 (M, 1H), 3.11 (dd, J =14.0,10.0Hz, 1H), 3.00 (ddl, 3.00H).
Cell adhesion and inhibition experiments:
t-cell adhesion assays were performed using the human T-lymphocyte cell line Jurkat (ATCC TIB-152): goat Anti-Human IgG (Fc specific) (Sigma I8885) was diluted to 10. Mu.g/ml in PBS, incubated at 4 ℃ for 12 hours in 100uL/96 well plates, the wells were decanted, blocked with 200uL 1% BSA at 37 ℃ for 90 minutes, and the plates were washed 3 times with PBS. 50uL of 1ug/mL ICAM-1 (containing 0.1% BSA,0.01% tween 20) was added per well and incubated at 37 ℃ for 3 hours. Using assay buffer (20mM HEPES pH 7.6,140mM NaCl,1mM MgCl) 2 ,1mM MnCl 2 0.2% glucose) wash plate 3 times.
Jurkat cell machine 100-G centrifugation process re-suspended the cells in 37 ℃ assay buffer (20mM HEPES pH 7.6,140mM NaCl,1mM MgCl. Sub. 2 ,1mM MnCl 2 0.2% glucose), 2. Mu.l of 1mM of BCECF-AM per mL of the cell suspension. Incubate at 37 ℃ for 30 minutes with stirring every 10 minutes during incubation. After incubation, the cells were washed with assay buffer at 37 ℃. Suspend cells to 6X10 6 Concentration in/mL.
The inhibitor was diluted to 2X final concentration in assay buffer and 50uL of compound solution and 60uL of Jurkat cells were mixed at room temperature and incubated at 37 ℃ for 30 minutes. 100 μ L/well of cells and inhibitor were added to the plate and incubated at room temperature for 1 hour. Measuring the total fluorescence ex:485 by using a fluorometer; em is 530; cutoff 530 to measure total fluorescence. Washing the plate once with the assay buffer, and measuring the fluorescence value ex:485 by using a fluorimeter; em is 530; cutoff is as follows. Drawing the result into an inhibition-concentration relation graph, and calculating the EC by using a standard method 50 . Table I shows the partial EC determined in this way 50 The value is obtained.
Table one: cell adhesion and inhibited EC 50
Experimental example: preparation
5.0g of the compound obtained in example 11 was added to 90mL of sterile physiological saline, 0.7g of NaOH was added thereto, and the mixture was stirred to obtain a transparent solution; to the above obtained solutionAdding NaH into the solution 2 PO 4 The aqueous solution is saturated until the pH of the solution is between 6.75 and 7.25. To the resulting aqueous solution, sterile physiological saline was added until the total volume reached 100.0mL. The above solution was bubbled with nitrogen for 1 hour, and the resulting solution was sealed and stored at 5 ℃ in the dark. The solution is divided into disposable eye drop bags, each containing 60mL of preparation solution. The method and specific proportions of the formulation may also be adjusted as desired, depending on the nature of the particular compound and the requirements of use.
Claims (11)
1. A compound containing a five-membered ring, characterized in that it is a compound represented by the following structure:
wherein R is 1 Is R 1 -X；
R 1 Selected from aryl, heteroaryl, wherein said aryl is selected from
Wherein R is hydrogen or a substituent group which is connected with any one or more carbon atoms on the ring and is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, hydroxyl and halogen, wherein the heteroaryl is a group which is substituted by oxygen, sulfur and nitrogen at any carbon atom in the aryl;
x is selected from carbon and carbonyl;
y is selected from carbon and nitrogen;
the X-Y bond is selected from a single bond, a double bond or a triple bond;
R 2 is hydrogen or halogen substituted on any or several benzene rings;
R 3 is composed of
R 4 Is hydrogen;
A 1 is carbon; a. The 2 Is nitrogen; a. The 3 Is sulfur; a. The 4 Is carbon; a. The 5 Is carbon.
2. The five-membered ring containing compound according to claim 1, which is represented by the following structure:
3. a compound containing a five-membered ring, characterized by being a compound represented by the following structure:
4. the method for producing a five-membered ring-containing compound according to claim 1, which comprises the following steps:
an intermediate product B is obtained by hydrolysis reaction of an alkyl terephthalate derivative A;
carrying out amidation reaction on the intermediate product B to obtain an intermediate product C;
carboxylating alkyl formate on the benzene ring of the intermediate product C to obtain an intermediate product D;
obtaining an intermediate product E from the intermediate product D under the action of a vulcanizing agent;
carrying out intramolecular cyclization reaction on the intermediate product E to obtain an intermediate product F;
performing amidation reaction on carboxyl on the intermediate product F to obtain an intermediate product G;
carrying out hydrolysis/reduction reaction on the intermediate product G to obtain a target product;
wherein the alkyl terephthalate derivative A is a compound represented by the following structure:
the intermediate product B is a compound shown in the following structure:
the intermediate product C is a compound shown in the following structure:
the intermediate product D is a compound shown in the following structure:
the intermediate product E is a compound shown in the following structure:
the intermediate product F is a compound shown in the following structure:
the intermediate product G is a compound shown in the following structure:
5. The method for producing a five-membered ring-containing compound according to claim 1, which comprises the following steps:
an intermediate product B is obtained by hydrolysis reaction of an alkyl terephthalate derivative A;
carrying out amidation reaction on the intermediate product B to obtain an intermediate product C with an N protecting group;
carboxylating alkyl formate on the benzene ring of the intermediate product C to obtain an intermediate product D;
obtaining an intermediate product E from the intermediate product D under the action of a vulcanizing agent;
performing intramolecular cyclization reaction on the intermediate product E to obtain an intermediate product F;
deprotecting the amido on the intermediate product F to obtain an intermediate product G;
performing substitution/addition reaction on amino on the intermediate product G to obtain an intermediate product H;
performing amidation reaction on carboxyl on a benzene ring of the intermediate product H to obtain an intermediate product I;
carrying out hydrolysis/reduction reaction on the intermediate product I to obtain a target product;
wherein the alkyl terephthalate derivative A is a compound represented by the following structure:
the intermediate product B is a compound shown in the following structure:
the intermediate product C is a compound shown in the following structure:
the intermediate product D is a compound shown in the following structure:
the intermediate product E is a compound shown in the following structure:
the intermediate product F is a compound shown in the following structure:
the intermediate product G is a compound shown in the following structure:
the intermediate product H is a compound shown in the following structure:
the intermediate product I is a compound shown in the following structure:
6. The method for producing a five-membered ring-containing compound according to claim 1, which comprises the following steps:
after obtaining intermediate G by the process of claim 5;
amidating the carboxyl on the intermediate product G to obtain an intermediate product H;
performing addition/substitution reaction on amino on the intermediate product H to obtain an intermediate product I;
carrying out hydrolysis/reduction reaction on the intermediate product I to obtain a target product;
wherein, the intermediate product H is a compound shown in the following structure:
intermediate I is a compound represented by the following structure:
7. The method for producing a five-membered ring-containing compound according to claim 1, which comprises the following steps:
an intermediate product B is obtained by hydrolysis reaction of an alkyl terephthalate derivative A;
the intermediate product B reacts with hydrochloric acid-N, O-dimethylhydroxylamine to obtain an intermediate product C;
opening the ring of the intermediate product C to obtain an intermediate product D containing an acetylene bond;
reducing the intermediate product D to obtain an intermediate product E;
hydrolyzing ester groups on a benzene ring of the intermediate product E into an intermediate product F containing carboxyl;
the intermediate product F is subjected to carbonyl vulcanization to obtain an intermediate product G;
cyclizing the intermediate product G into an intermediate product H with a five-membered ring;
performing amidation reaction on carboxyl on a benzene ring of the intermediate product H to obtain an intermediate product I;
carrying out hydrolysis/reduction reaction on the intermediate product I to obtain a target product;
wherein the alkyl terephthalate derivative A is a compound represented by the following structure:
the intermediate product B is a compound shown in the following structure:
the intermediate product C is a compound shown in the following structure:
the intermediate product D is a compound shown in the following structure:
the intermediate product E is a compound shown in the following structure:
the intermediate product F is a compound shown in the following structure:
the intermediate product G is a compound shown in the following structure:
the intermediate product H is a compound shown in the following structure:
the intermediate product I is a compound shown in the following structure:
8. The method for producing a five-membered ring-containing compound according to claim 1, which comprises the following steps:
after obtaining intermediate G by the process of claim 5;
protecting carboxyl on a benzene ring of the intermediate product G to obtain an intermediate product H;
halogenating amino on the intermediate product H to obtain an intermediate product I;
carrying out alkynylation on the halogen on the intermediate product I to obtain an intermediate product J;
deprotection of carboxyl on the intermediate product J benzene ring to obtain an intermediate product K;
amidating carboxyl on the benzene ring of the intermediate product K to obtain an intermediate product L;
carrying out hydrolysis/reduction reaction on the intermediate product L to obtain a target product;
wherein the intermediate product H is a compound shown in the following structure:
the intermediate product I is a compound shown in the following structure:
the intermediate product J is a compound shown in the following structure:
the intermediate product K is a compound shown in the following structure:
the intermediate product L is a compound shown in the following structure:
9. A compound containing a five-membered ring, characterized by being a compound represented by the following structure:
wherein R is 1 Selected from aryl, heteroaryl, wherein said aryl is selected from
Wherein R is hydrogen or a substituent group which is connected with any one or more carbon atoms on the ring and is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, hydroxyl and halogen, wherein the heteroaryl is a group which is substituted by oxygen, sulfur and nitrogen at any carbon atom in the aryl;
R 2 is hydrogen or halogen substituted on any or several benzene rings;
R 3 is composed of
X is selected from carbon and carbonyl;
y is selected from carbon and nitrogen;
the X-Y bond is selected from a single bond, a double bond or a triple bond;
A 1 is carbon; a. The 2 Is nitrogen; a. The 3 Is sulfur; a. The 4 Is carbon; a. The 5 Is carbon.
10. Use of a compound containing a five-membered ring according to any one of claims 1 to 3 for the preparation of an inhibitor of immune cell migration.
11. The use of claim 10, wherein the inhibitor of immune cell migration is an eye drop for the treatment of dry eye.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810455868.9A CN110483437B (en) | 2018-05-14 | 2018-05-14 | Five-membered ring-containing compound and preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810455868.9A CN110483437B (en) | 2018-05-14 | 2018-05-14 | Five-membered ring-containing compound and preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110483437A CN110483437A (en) | 2019-11-22 |
| CN110483437B true CN110483437B (en) | 2022-12-06 |
Family
ID=68543773
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810455868.9A Active CN110483437B (en) | 2018-05-14 | 2018-05-14 | Five-membered ring-containing compound and preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110483437B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6277987B1 (en) * | 1998-02-04 | 2001-08-21 | Novartis Ag | Sulfonylamino acid and sulfonylamino hydroxamic acid derivatives |
| TW200526205A (en) * | 2003-12-22 | 2005-08-16 | Ono Pharmaceutical Co | Nitrogen-containing heterocyclic compound, and medicine containing such compound as effective ingredient |
| TW200813094A (en) * | 2006-05-23 | 2008-03-16 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| CN101160309A (en) * | 2005-03-16 | 2008-04-09 | 赛诺菲-安万特 | Novel imidazo [1, 5-a] pyridine derivatives, method for preparing same and pharmaceutical compositions containing same |
| CN101668741A (en) * | 2007-01-11 | 2010-03-10 | 阿勒根公司 | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity |
| TW201734001A (en) * | 2016-01-29 | 2017-10-01 | 維它藥物公司 | Modulators of ROR-gamma |
-
2018
- 2018-05-14 CN CN201810455868.9A patent/CN110483437B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6277987B1 (en) * | 1998-02-04 | 2001-08-21 | Novartis Ag | Sulfonylamino acid and sulfonylamino hydroxamic acid derivatives |
| TW200526205A (en) * | 2003-12-22 | 2005-08-16 | Ono Pharmaceutical Co | Nitrogen-containing heterocyclic compound, and medicine containing such compound as effective ingredient |
| CN101160309A (en) * | 2005-03-16 | 2008-04-09 | 赛诺菲-安万特 | Novel imidazo [1, 5-a] pyridine derivatives, method for preparing same and pharmaceutical compositions containing same |
| TW200813094A (en) * | 2006-05-23 | 2008-03-16 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| CN101668741A (en) * | 2007-01-11 | 2010-03-10 | 阿勒根公司 | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity |
| TW201734001A (en) * | 2016-01-29 | 2017-10-01 | 維它藥物公司 | Modulators of ROR-gamma |
Non-Patent Citations (1)
| Title |
|---|
| 2105313-45-7/RN;ACS;《STN Registry数据库》;20170730;第1-6页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110483437A (en) | 2019-11-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6033835B2 (en) | Benzo [b] [1,4] oxazine derivatives as calcium-sensing receptor modulators | |
| EP0506532A1 (en) | Indole derivatives, process for their preparation and medicaments containing them | |
| CA2412368A1 (en) | Benzimidazole derivatives, preparation and therapeutic use thereof | |
| WO2004067498A2 (en) | Aryl alkyl carbamate derivatives production and use thereof in therapy | |
| CN113248524B (en) | Bisindole alkaloid compound and synthesis method and application thereof | |
| CN110483437B (en) | Five-membered ring-containing compound and preparation and application thereof | |
| EP0162776A2 (en) | Heterocyclic derivatives, process for their preparation and medicaments useful as aldose reductase inhibitors containing them | |
| Soltani Rad et al. | Synthesis of fluorene and/or benzophenone O-oxime ethers containing amino acid residues and study of their cardiovascular and antibacterial effects | |
| CN113272315B (en) | Steroid compounds and application thereof | |
| CA1300133C (en) | Benzimidazolesulfonamides and imidazopyridinesulfonamides; process for preparing the same and their use as therapeutic agents | |
| JPS58219169A (en) | Oxazoleacetic acid derivative | |
| WO2019001171A1 (en) | Phosphorus-containing compound and preparation and use thereof | |
| EP0471259A1 (en) | Phenylsulfonamid substituted pyridinealken- and aminooxyalkan-carboxylic-acid derivatives | |
| EP0915087A2 (en) | Sulfonamide substituted fused five-membered ring compounds, their use as medicaments as well as pharmaceutical compositions containing them | |
| EP0866692A1 (en) | Use of bicyclic mono- or diketone derivatives, resulting compounds, and use thereof as a drug for treating inflammation, migraine and shock | |
| JPH0372485A (en) | Staurosporine derivative | |
| DE19707656A1 (en) | Sulphonamide-substituted fused 7-ring compounds, processes for their preparation, their use as medicaments or diagnostic agents and pharmaceutical preparations containing them | |
| CA2439730A1 (en) | Benzofuran derivatives and pharmaceutical compositions containing the same | |
| CH637650A5 (en) | PROCESS FOR THE PREPARATION OF A CHROMONE CARBOXYLIC ACID. | |
| CN109134533B (en) | Phosphorus-containing compound and preparation and application thereof | |
| JPH0357915B2 (en) | ||
| JPS632274B2 (en) | ||
| EP0082040B1 (en) | 3,7a-diazacyclohepta(j,k)fluorene derivatives, their preparation and therapeutical use | |
| CH634071A5 (en) | Therapeutically active pyranoquinolones | |
| CH618977A5 (en) |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240112 Address after: 325006, Room 4020, Building B, Gene Medicine Valley North District, Ouhai District, Wenzhou City, Zhejiang Province Patentee after: Weimu Biotechnology (Zhejiang) Co.,Ltd. Address before: 314000 3rd floor, building B, 51 Wufeng Road, Xiuzhou District, Jiaxing City, Zhejiang Province Patentee before: Jiaxing Wei Mou Biological Technology Co.,Ltd. |