CN105732458B - Pyrrole amides class compound and preparation method thereof and purposes - Google Patents
Pyrrole amides class compound and preparation method thereof and purposes Download PDFInfo
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- CN105732458B CN105732458B CN201511002999.4A CN201511002999A CN105732458B CN 105732458 B CN105732458 B CN 105732458B CN 201511002999 A CN201511002999 A CN 201511002999A CN 105732458 B CN105732458 B CN 105732458B
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- ethyl
- volume ratio
- methyl
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- -1 Pyrrole amides Chemical class 0.000 title claims abstract description 486
- 150000001875 compounds Chemical class 0.000 title claims abstract description 319
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims description 50
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 31
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 31
- 230000000694 effects Effects 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 150000003839 salts Chemical group 0.000 claims abstract description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 16
- 150000002367 halogens Chemical class 0.000 claims abstract description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical group 0.000 claims abstract 9
- 239000002904 solvent Substances 0.000 claims description 163
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 126
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 91
- 238000003756 stirring Methods 0.000 claims description 71
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 69
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 62
- 239000012043 crude product Substances 0.000 claims description 61
- 239000012046 mixed solvent Substances 0.000 claims description 60
- 239000012074 organic phase Substances 0.000 claims description 51
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 49
- 239000000243 solution Substances 0.000 claims description 49
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 40
- 125000004193 piperazinyl group Chemical group 0.000 claims description 40
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 239000007787 solid Substances 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 32
- 238000001914 filtration Methods 0.000 claims description 31
- 150000008282 halocarbons Chemical class 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 25
- 238000004440 column chromatography Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 20
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 20
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 20
- HBXVLQNYPMSTEN-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]-2,5-dihydropyrrole-3-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1CC(=CC1)C(=O)O HBXVLQNYPMSTEN-UHFFFAOYSA-N 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 18
- 238000010790 dilution Methods 0.000 claims description 18
- 239000012895 dilution Substances 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 17
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 10
- 230000002159 abnormal effect Effects 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- NLXXVSKHVGDQAT-UHFFFAOYSA-N o-(oxan-2-yl)hydroxylamine Chemical compound NOC1CCCCO1 NLXXVSKHVGDQAT-UHFFFAOYSA-N 0.000 claims description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 9
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 8
- 125000005518 carboxamido group Chemical group 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 239000007821 HATU Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- CPPKAGUPTKIMNP-UHFFFAOYSA-N cyanogen fluoride Chemical compound FC#N CPPKAGUPTKIMNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 6
- 229960003750 ethyl chloride Drugs 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 238000002953 preparative HPLC Methods 0.000 claims description 6
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- 230000002062 proliferating effect Effects 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 230000003612 virological effect Effects 0.000 claims description 3
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000001980 alanyl group Chemical group 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 abstract description 5
- 108090000790 Enzymes Proteins 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 201000007270 liver cancer Diseases 0.000 abstract description 5
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- 239000013078 crystal Chemical group 0.000 abstract description 4
- 230000006196 deacetylation Effects 0.000 abstract description 4
- 238000003381 deacetylation reaction Methods 0.000 abstract description 4
- 239000012453 solvate Substances 0.000 abstract description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N epoxyketone group Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 30
- AFAZWQJKGPGEBO-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C1=CCNC1 AFAZWQJKGPGEBO-UHFFFAOYSA-N 0.000 description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
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- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 9
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 description 9
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- KEHCTXFLUIBRQS-UHFFFAOYSA-N 1-[4-[4-[(dimethylamino)methyl]phenyl]phenyl]sulfonyl-2,5-dihydropyrrole-3-carboxylic acid Chemical compound CN(C)Cc1ccc(cc1)-c1ccc(cc1)S(=O)(=O)N1CC=C(C1)C(O)=O KEHCTXFLUIBRQS-UHFFFAOYSA-N 0.000 description 3
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- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 3
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- WTCNXDDZKQIMLP-UHFFFAOYSA-N ethyl 2,5-dihydro-1h-pyrrole-3-carboxylate Chemical compound CCOC(=O)C1=CCNC1 WTCNXDDZKQIMLP-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
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Abstract
The invention discloses pyrrole amides class compound shown in a kind of formula I or its pharmaceutically acceptable salt, crystal form, hydrate or solvates: where R1Selected from (methylamino) methyl, (methylamino) ethyl etc.；R2、R3Separately or concurrently it is selected from hydrogen, hydroxyl, cyano, halogen, carboxyl, C1~C6Alkyl etc.；R4The phenyl or epoxy ketone groups replaced selected from hydroxyl, sulfydryl, amino.Noval chemical compound shown in formula I provided by the invention shows good deacetylation enzyme inhibition activity, have prevention and/or treat by histone deacetylase activity extremely caused by disease potentiality；Meanwhile noval chemical compound of the present invention has good inhibitory activity to different liver cancer cells, the prospect with clinical application.
Description
Technical Field
The invention relates to a pyrrole amide compound and a preparation method and application thereof, in particular to a pyrrole amide compound with histone deacetylase inhibitory activity and a preparation method and application thereof.
Background
Inactivation of genes that control cell growth in the body is one of the hallmarks of tumorigenesis. Epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modifications of other components in chromatin higher order structures, which alter chromatin conformation, resulting in changes in gene transcription regulation, and dysregulation of gene transcription causing cell proliferation disorders, resulting in tumor production.
Over 40 years ago, Allfrey et al recognized that histone acetylation process is closely related to eukaryotic gene transcription regulation (Allfrey VG, Faulkner R, Mirsky AE.Acetolation and methylation of histones and in the regulation of RNA synthesis [ J]ProcNatl Acad Sci USA, 1964, 51: 786-794). Transcriptional regulation of eukaryotic cells by histone acetylation is centralAnd (4) acting. Acetylation of histones occurs at the epsilon-amino group of the N-terminally evolutionarily conserved lysine residue, with modifications at H3 and H4 more prevalent than H2A and H2B, and the more important acetylation site being Lys at H39And Lys14And Lys at H45，Lys8，Lys12And Lys16. Acetylation of HAT acetylates the amino group of N-terminal lysine in histone, eliminates the positive charge in the amino group, makes the negative charge of DNA molecule favorable to the development of DNA conformation, relaxes the structure of nucleosome, facilitates the contact of transcription factor and cooperative transcription activator with DNA molecule, and makes histone acetylation activate the transcription expression of specific gene. In contrast, deacetylation of histones is detrimental to the expression of specific genes (e.g.Rb, p21, p 27). Acetylation and deacetylation of histones into a switch for specific gene expression (Thiaglinggam S, Cheng KH, Lee HJ, ethyl. histonedeacetylases: unique planes in mapping the oligomeric histone code [ J].Ann N Y Acad Sci，2003，983：84-100)。
Histone acetylation is regulated by a pair of functionally antagonistic proteases Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs). In normal cells, the pair of enzymes is in a state of dynamic equilibrium. In general, increased histone acetylation levels are associated with increased gene transcription activity, while too low acetylation levels are associated with suppressed gene expression (Forsberg EC, Bresenick EH. Histone catalysis genes and promoters: long-ranging catalysis patterns in the chromatography world [ J ]. Bioessays, 2001, 23 (9): 820-. Studies have found that HDACs are overexpressed and recruited by transcription factors, leading to abnormal suppression of specific genes, leading to tumors and other diseases; inhibition of HDAC activity results in the growth arrest and apoptosis of many cancer cells (Somech R, Izraeli S, J Simon A. Histone deacetylase inhibitors-a new tool to treat cancer [ J ]. cancer treat Rev, 2004, 30 (5): 461-. Therefore, HDACs have become the newest and most popular target in the current field of antineoplastic drug development.
HDAC inhibitors, which inhibit HDAC enzymatic activity, act by inhibiting HDAC, blocking the inhibition of gene expression due to dysfunction of HDAC recruitment, and modifying chromatin structure by altering histone acetylation, thereby modulating gene expression to treat cancer. It has obvious curative effect on treating blood system tumor and solid tumor by inducing growth arrest, differentiation or apoptosis of tumor cell. HDAC inhibitors are tumor specific and cytotoxic to proliferating and quiescent variant cells, whereas normal cells are more than 10-fold tolerant to them and do not cause growth arrest and apoptosis in normal cells. Moreover, the clinical dosage of the HDAC inhibitor is far lower than the maximum tolerance of human bodies, and the toxicity to the organisms is lower. The development and utilization of HDAC inhibitors have become a new hotspot in tumor therapy.
Currently, HDAC inhibitors that have been investigated and developed can be divided into five major classes: (1) hydroxamic acid compounds, the functional group being hydroxamic acid, and representative examples thereof include TSA, SAHA (Curtin ML, Garland RB, Heyman HR, et a1. succinimidyl hydroxamic acids as pore inhibitors of hormone deacylase [ J ]. Bioorg Medchem, 2002, 12 (20): 2919-; (2) cyclic tetrapeptides containing 2-amino-8-oxo-9, 10-epoxydecanoyl group or not containing the group, such as FK-228; (3) benzamide compound, representative MS-275, has entered clinical studies; (4) short chain fatty acids such as butyric acid and phenylbutyric acid; (5) other classes of HDAC inhibitors do not have the structural features of common HDACs, but all contain some or all of the structural subunits required for inhibiting HDAC activity.
For example, chinese patent CN 103420917a discloses a benzamide compound containing a fused ring structure, as shown in formula a, which has histone deacetylase inhibitory activity and application in treating malignant tumor and differentiation and proliferation related diseases; chinese patent CN 103288728A discloses a naphthamide derivative, shown as formula B, which can effectively treat partial diseases caused by abnormal regulation of protein kinase; chinese patent CN 103539695A discloses a substituted diphenyl ether histone deacetylase inhibitor, which is shown in formula C; chinese patent CN 103467359A discloses a cinnamamide histone deacetylase inhibitor containing indole, which is shown in formula D; chinese patent CN 102659630a discloses hydroxamic acid compounds, as shown in formula E.
Chinese patent CN 102786458A discloses a pyrrole carboxamide derivative, represented by formula F, which is used as an anti-malignant tumor drug, in particular, in the preparation of drugs for treating breast cancer, lung cancer and gastric cancer.
R1，R2，R3，R4Comprises the following steps: C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl;
R5，R6simultaneously or separately: hydrogen, C1-C6 alkyl; hydroxyl, halogen, C1-C4 alkoxy, and nitrate substituted C1-C6 alkyl.
At present, SAHA developed by Merck is a histone deacetylase inhibitor which is already on the market, is only limited to the treatment of T cell lymphoma of skin, and has no obvious curative effect on other cancers. Other developed HDAC inhibitors also have certain problems in the aspects of anticancer activity, toxic and side effects, subtype selectivity, and the like. Therefore, the development of a novel compound having histone deacetylase inhibitory activity is of great social and economic significance.
Disclosure of Invention
The invention aims to provide a pyrrole amide compound.
The invention provides a pyrrole amide compound shown in formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof:
wherein,
R1selected from (methylamino) methyl, (methylamino) ethyl, (methylamino) propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino) ethyl, (ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentaalkylpiperazinyl, or hexanalkylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R4selected from hydroxyl, sulfhydryl, amino substituted phenyl or epoxy ketone groups.
Further, in the above-mentioned case,
R1selected from (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, p-methylpiperazinyl, p-ethylpiperazinyl, p-propylpiperazinyl or p-buthylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R4selected from hydroxy, mercapto or amino substituted phenyl.
Further, the compound shown in the formula I is:
the invention also provides a preparation method of the pyrrole amide compound shown in the formula I,
when R is4When the hydroxyl is adopted, the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenylmethoxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; DCM represents dichloromethane;
R1selected from (methylamino) methyl, (methylamino) ethyl, (methylamino) propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino) ethyl, (ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentaalkylpiperazinyl, or hexanalkylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5is halogen;
the method comprises the following steps:
a. stirring a mixed solvent of a compound IM-1a, lithium hydroxide and an ether solvent/water at the temperature of 20-30 ℃ for reaction for 1-6 h, removing the organic solvent, adding water for dilution, adjusting the pH value to 3-6, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-1a to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-1a to the mixed solvent is 1: 7-20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
b. b, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent at the temperature of 0-5 ℃, adding trifluoroacetic acid, and stirring and reacting at the temperature of 20-30 ℃ for 2-12H to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 a;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 5-20 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 2-10 g/ml;
c. b, stirring the compound IM-2a obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at the temperature of 20-30 ℃ for reaction for 12-16 h, adding water for dilution, adjusting the pH value to 1-3, extracting the ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-3 a;
the molar ratio of the compound IM-2a to the sodium carbonate to the fluorenyloxycarbonyl chloride is 1: 1-5: 0.9 to 1.5; the mass-volume ratio of the compound IM-2a to the mixed solvent is 1: 10-25 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
d. c, stirring and reacting the compound IM-3a obtained in the step c, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 12 to 16 hours, adding water for dilution, extracting an ester solvent, combining organic phases, drying, filtering and concentrating the organic phase to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 a;
the molar ratio of the compound IM-3a, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1-2: 1-2: 2-4; the mass-volume ratio of the compound IM-3a to the halocarbon solvent is 1: 9-20 g/ml;
e. d, stirring the compound IM-4a obtained in the step d, piperidine and a nitrogen-containing solvent at 25-30 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM-5 a;
the mass-to-volume ratio of the compound IM-4a to piperidine is 1: 1-4 g/ml; the mass-volume ratio of the compound IM-4a to the nitrogen-containing solvent is 1: 5-20 g/ml;
f. e, stirring and reacting the compound IM-5a, triethylamine, the compound IM-6a and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 1 to 10 hours, and removing the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 a;
the mol ratio of the compound IM-5a to the triethylamine to the compound IM-6a is 1: 1-5: 1-2; the mass-volume ratio of the compound IM-5a to the halocarbon solvent is 1: 50-100 g/ml;
g. dissolving the compound TM-1a obtained in the step f in a halohydrocarbon solvent at the temperature of 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at the temperature of 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound shown in a formula I;
the mass-volume ratio of the compound TM-1a to the halocarbon solvent is 1: 50-100 g/ml; the mass-volume ratio of the compound TM-1a to trifluoroacetic acid is 1: 10-50 g/ml.
Further, in the above-mentioned case,
a. stirring a mixed solvent of the compound IM-1a, lithium hydroxide and an ether solvent/water at 25 ℃ for 2 hours, removing the organic solvent, adding water for dilution, adjusting the pH to be 5, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-1a to the lithium hydroxide is 1: 4.5-5; the mass-volume ratio of the compound IM-1a to the mixed solvent is 1: 10-12 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 2: 1;
b. b, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, and stirring and reacting at 25 ℃ for 2 hours to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 a;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 10 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 4-5 g/ml;
c. b, stirring the compound IM-2a obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at 25 ℃ for 12-16 h, adding water for dilution, adjusting the pH value to be 1, extracting by using an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-3 a;
the molar ratio of the compound IM-2a to the sodium carbonate to the fluorenyloxycarbonyl chloride is 1: 3: 1; the mass-volume ratio of the compound IM-2a to the mixed solvent is 1: 20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 5: 3;
d. c, stirring the compound IM-3a obtained in the step c, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at 25 ℃ for 12-16H, adding water for dilution, extracting an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 a;
the molar ratio of the compound IM-3a, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1.1: 1.2: 3; the mass-volume ratio of the compound IM-3a to the halocarbon solvent is 1: 9-10 g/ml;
e. d, stirring the compound IM-4a obtained in the step d, piperidine and a nitrogen-containing solvent at 25 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM-5 a;
the mass-to-volume ratio of the compound IM-4a to piperidine is 1: 2 g/ml; the mass-volume ratio of the compound IM-4a to the nitrogen-containing solvent is 1: 10 g/ml;
f. e, stirring the compound IM-5a, triethylamine, the compound IM-6a and a halohydrocarbon solvent in the step e at 25 ℃ for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 a;
the mol ratio of the compound IM-5a to the triethylamine to the compound IM-6a is 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM-5a to the halocarbon solvent is 1: 80 g/ml;
g. dissolving the compound TM-1a obtained in the step f in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound shown in a formula I;
the mass-volume ratio of the compound TM-1a to the halocarbon solvent is 1: 60-65 g/ml; the mass-volume ratio of the compound TM-1a to trifluoroacetic acid is 1: 25 g/ml.
Further, in the above-mentioned case,
R1selected from (dimethylamino) methylA group (dimethylamino) ethyl, dimethylamino propyl, diethylamino methyl, diethylamino ethyl, diethylamino propyl, dipropylamino methyl, dipropylamino ethyl, dipropylamino propyl, piperazinyl, p-methylpiperazinyl, p-ethylpiperazinyl, p-propylpiperazinyl or p-butanepiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5selected from fluorine, chlorine, bromine or iodine.
Further, in step f, the compound IM-6a is:
further, in the steps a to g, the ether solvent is one or more selected from tetrahydrofuran, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is selected from one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is selected from one or more of ethyl acetate and ethyl formate; the nitrogen-containing solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and pyridine.
The invention also provides another preparation method of the pyrrole amide compound shown in the formula I,
when R is4When the hydroxyl is adopted, the synthetic route is as follows:
wherein,
R1selected from (methylamino) methyl, (methylamino) ethyl, (methylamino) propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino) ethyl, (ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentaalkylpiperazinyl, or hexanalkylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substitutedPhenyl, piperazinyl or substituted piperazinyl;
R5、R6are each halogen;
the method comprises the following steps:
i. stirring a mixed solvent of a compound IM-5b, a compound IM-6b, sodium bicarbonate and an ether solvent/water at 25-30 ℃ for reaction for 1-10 h, removing the solvent, adding water, extracting with an ester solvent, combining organic phases, washing with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-7 b;
the molar ratio of the compound IM-5b to the compound IM-6b to the sodium bicarbonate is 1: 1-2: 1-5; the mass-volume ratio of the compound IM-5b to the mixed solvent of the ether solvent/water is 1: 20-100 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-5: 1;
ii. I, stirring and reacting a compound IM-7b obtained in the step i, a compound IM-8b, sodium carbonate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and a mixed solvent of an ether solvent/water at 50-100 ℃ under the protection of inert gas for 1-10 h, removing the solvent, adding water and a halohydrocarbon solvent for extraction, combining organic phases, washing the organic phases with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 b;
the mol ratio of the compound IM-7b to the compound IM-8b to the sodium carbonate is 1: 1-2: 1-5; the mass ratio of the compound IM-7b to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is 1: 0.05 to 0.2; the mass-volume ratio of the compound IM-7b to the mixed solvent of the ether solvent/water is 1: 20-100 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-10: 1;
iii, dissolving the compound TM-1b in the step II in an alcohol solvent, adding hydrochloric acid, stirring and reacting at 25-30 ℃ for 1-10 h, and then separating and purifying to obtain the compound shown in the formula I;
the mass-volume ratio of the compound TM-1b to the alcohol solvent is 1: 18-100 g/ml; the mass-volume ratio of the compound TM-1b to hydrochloric acid is 1: 3-20 g/ml; the concentration range of the hydrochloric acid is 0.5N-2N.
Further, in the above-mentioned case,
i. stirring a compound IM-5b, a compound IM-6b, sodium bicarbonate and a mixed solvent of an ether solvent/water at 25 ℃ for 2 hours, removing the solvent, adding water, extracting with an ester solvent, combining organic phases, washing with saturated saline water, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-7 b;
the molar ratio of the compound IM-5b to the compound IM-6b to the sodium bicarbonate is 1: 1: 2-3; the mass-volume ratio of the compound IM-5b to the mixed solvent of the ether solvent/water is 1: 20-40 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
ii. I, stirring and reacting a mixed solvent of the compound IM-7b, the compound IM-8b, sodium carbonate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and an ether solvent/water at 80 ℃ for 2 hours under the protection of inert gas, removing the solvent, adding water, extracting a halohydrocarbon solvent, combining organic phases, washing with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 b;
the mol ratio of the compound IM-7b to the compound IM-8b to the sodium carbonate is 1: 1: 2-3; the mass ratio of the compound IM-7b to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is 1: 0.08 to 0.12; the mass-volume ratio of the compound IM-7b to the mixed solvent of the ether solvent/water is 1: 20-40 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 4-6: 1;
iii, dissolving the compound TM-1b in the step II in an alcohol solvent, adding hydrochloric acid, stirring at 25 ℃ for reaction for 2 hours, and then separating and purifying to obtain a compound shown in the formula I;
the mass-volume ratio of the compound TM-1b to the alcohol solvent is 1: 18-40 g/ml; the mass-volume ratio of the compound TM-1b to hydrochloric acid is 1: 3-10 g/ml; the concentration range of the hydrochloric acid is 0.5N-2N.
Further, R1Selected from (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, p-methylpiperazinyl, p-ethylpiperazinyl, p-propylpiperazinyl or p-buthylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5、R6selected from fluorine, chlorine, bromine or iodine.
Further, in step i, the compound IM-6b is:
in step ii, said compound IM-8b is:
in the steps i to iii, the ether solvent is selected from one or more of tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is selected from one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is selected from one or more of ethyl acetate and ethyl formate; the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol and isopropanol.
The invention also provides a preparation method of the pyrrole amide compound shown in the formula I,
when R is4When the phenyl is substituted by amino, the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; LiOH represents lithium hydroxide;
R1selected from (methylamino) methyl, (methylamino) ethyl, (methylamino) propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino)Ethyl, (ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5selected from halogens;
the method comprises the following steps:
①, dissolving the compound IM-1c in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting for 2-12 h at 20-30 ℃ to obtain a reaction liquid, and concentrating the reaction liquid to obtain a yellow oily substance, namely the compound IM-2 c;
the mass-to-volume ratio of the compound IM-1c to the halocarbon solvent is 1: 5-20 g/ml; the mass-to-volume ratio of the compound IM-1c to trifluoroacetic acid is 1: 2-10 g/ml;
②, stirring the compound IM-2c, the compound IM-3c, the triethylamine and the halohydrocarbon solvent obtained in the step ① at the temperature of between 25 and 30 ℃ for reaction for 1 to 10 hours, concentrating to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound IM-4 c;
the mol ratio of the compound IM-2c to the compound IM-3c to triethylamine is 1: 1-2: 1-5; the mass-volume ratio of the compound IM-2c to the halocarbon solvent is 1: 50-100 g/ml;
③, stirring the mixed solvent of the compound IM-4c obtained in the step ②, lithium hydroxide and ether solvent/water at the temperature of 20-30 ℃ for 2-16 h to obtain reaction liquid, separating and purifying to obtain a compound IM-5 c;
the molar ratio of the compound IM-4c to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-4c to the mixed solvent is 1: 55-60 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-5: 1;
④, carrying out stirring reaction on the compound IM-5c obtained in the step ③,1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 12 to 16 hours to obtain a reaction solution, and separating and purifying to obtain the compound shown in the formula I;
the molar ratio of the compound IM-5c, 1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 0.8-2: 0.8-2: 1.5 to 4; the mass-to-volume ratio of the compound IM-5c to the halocarbon solvent is 1: 40-100 g/ml.
Further, in the above-mentioned case,
①, dissolving the compound IM-1c in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring and reacting for 2h at 25 ℃ to obtain a reaction solution, and concentrating the reaction solution to obtain a yellow oily substance, namely the compound IM-2 c;
the mass-to-volume ratio of the compound IM-1c to the halocarbon solvent is 1: 20 g/ml; the mass-to-volume ratio of the compound IM-1c to trifluoroacetic acid is 1: 8 g/ml;
②, stirring the compound IM-2c, the compound IM-3c, triethylamine and a halohydrocarbon solvent obtained in the step ① at 25 ℃ for 2 hours, concentrating to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound IM-4 c;
the mol ratio of the compound IM-2c to the compound IM-3c to triethylamine is 1: 1.1-1.2: 2.5-3; the mass-volume ratio of the compound IM-2c to the halocarbon solvent is 1: 65-70 g/ml;
③, stirring the compound IM-4c obtained in the step ②, lithium hydroxide and mixed solvent of ether solvent/water at 25 ℃ for 2-16 h to obtain reaction liquid, separating and purifying to obtain a compound IM-5 c;
the molar ratio of the compound IM-4c to the lithium hydroxide is 1: 4.5; the mass-volume ratio of the compound IM-4c to the mixed solvent is 1: 55-60 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 3: 1;
④, carrying out stirring reaction on the compound IM-5c obtained in the step ③,1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at 25 ℃ for 12-16 h to obtain a reaction solution, and separating and purifying to obtain the compound shown in the formula I;
the molar ratio of the compound IM-5c, 1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 0.8-1.2: 0.8-1.2: 1.5-2; the mass-to-volume ratio of the compound IM-5c to the halocarbon solvent is 1: 40-45 g/ml.
Further, in the above-mentioned case,
R1selected from (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, p-methylpiperazinyl, p-ethylpiperazinyl, p-propylpiperazinyl or p-buthylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxyAlkoxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butyramido, isobutylamido, tert-butyramido, pentanamido, hexanamido, methionyl, ethanamido, n-alaninyl, iso-alaninyl, n-butyramido, iso-butyramido, tert-butyramido, valeryl, hexanoyl, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5selected from fluorine, chlorine, bromine or iodine.
Further, in step ②, the compound IM-3c is:
further, in steps ① - ④, the halocarbon solvent is selected from one or more of dichloromethane, ethyl chloride, dichloroethane, chloroform and carbon tetrachloride, and the ether solvent is selected from one or more of tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether.
The invention also provides application of the pyrrole amide compound or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof in preparation of histone deacetylase inhibitor medicines.
The histone deacetylase inhibitor medicament is a medicament for preventing and/or treating diseases caused by abnormal histone deacetylase activity.
Further, the disease is any one or more of a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease, or a viral disease.
Still further, the disease is cancer.
The invention also provides a pharmaceutical composition for inhibiting the activity of histone deacetylase, which is a preparation prepared by taking the pyrrole amide compound or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
Further, the preparation comprises an oral administration preparation, a sublingual administration preparation, a buccal administration preparation, a transdermal absorption preparation or an injection preparation.
The novel compound shown in the formula I shows good deacetylase inhibitory activity, and has the potential of preventing and/or treating diseases caused by abnormal histone deacetylase activity; meanwhile, the novel compound has good inhibitory activity on different liver cancer cells, and has a prospect of clinical application.
The following compounds 1-8 with good deacetylase inhibitory activity are prepared in the invention, and are shown in table 1:
TABLE 1 Compounds 1 to 8 prepared according to the invention
Histone deacetylase plays an important role in the physiological and pathological processes of gene transcription regulation, signal transduction, growth and development, differentiation apoptosis, metabolic diseases, tumors and the like. If the activity of histone deacetylase is abnormal, a series of diseases with abnormal histone deacetylase activity can be caused. Including cell proliferative disorders, autoimmune disorders, inflammation, neurodegenerative disorders, viral disorders (for example, a review of the disorders in world patent WO2011011186 where HDAC6 inhibitors are useful).
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix, e.g., the prefix (C a-b) alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, (C1-4) alkyl refers to an alkyl group containing 1-4 carbon atoms.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
In certain embodiments of the present invention, the invention includes isotopically-labeled compounds, which are intended to be identical to those recited herein, but wherein one or more atoms are replaced by another atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopes which may be incorporated into compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e.2H,3H、13C、14C、15N、17O、18O、35And S. Compounds of formula (I) and stereoisomers thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, containing the aforementioned isotopes and/or other atomic isotopes are included within the scope of the invention.
The key intermediates and compounds in the present invention are isolated and purified by means of isolation and purification methods commonly used in organic chemistry and examples of such methods include filtration, extraction, drying, spin-drying and various types of chromatography. Alternatively, the intermediate may be subjected to the next reaction without purification.
In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The pharmaceutically acceptable auxiliary material of the invention refers to a substance contained in a dosage form except for an active ingredient.
The pharmaceutically acceptable auxiliary components have certain physiological activity, but the addition of the components does not change the dominant position of the pharmaceutical composition in the disease treatment process, but only plays auxiliary effects, and the auxiliary effects are only the utilization of the known activity of the components and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used in combination with the pharmaceutical composition of the present invention, the protection scope of the present invention should still be included.
The compound of the invention has the activities of inducing differentiation, immunoregulation, blocking cell cycle and promoting apoptosis and good HDAC subtype selectivity, aims to have better curative effect on various cancers, and simultaneously overcomes the toxic and side effects of the existing HDAC inhibitor, such as anemia, ischemic stroke, deep venous thrombosis, thrombocytopenia, emesis and the like.
The compound of the present invention has HDAC inhibitory activity, and can be used for treating diseases associated with abnormal HDAC activity, particularly liver cancer.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
In the invention, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenyloxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; DCM stands for dichloromethane.
Wherein, the raw materials: 4'- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride can be obtained by purchasing a commercially available product, or can be obtained by the following production method:
1. preparation of 1- ([1,1' -biphenyl ] -4-yl) -N, N-dimethylmethylamine
Bromobenzene (1.5g,10mmol) was dissolved in 50mL of dioxane and 10mL of water, followed by addition of sodium carbonate (2.1g,20 mmol) and dimethyl butanediol 4- (N, N-dimethylaminomethyl) phenylboronate hydrochloride (2.6g,10mmol, manufacturer: Bailingwei science Co., Ltd.), and addition of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (500 mg). The solution was replaced with nitrogen three times, and heated to 80 ℃ for 6 hours. After the reaction is finished, the organic solvent is removed from the reaction solution in vacuum, 200mL of water is added for dilution, dichloromethane is used for extraction for 3 times, organic phases are combined for drying, and the crude product is obtained through vacuum concentration. The crude product was subjected to column chromatography to give 1- ([1,1' -biphenyl ] -4-yl) -N, N-dimethylmethylamine as a white solid (1.1g, 52% yield).
MS(ESI)m/z212(M+1)+。
2. Preparation of 4'- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride
1- ([1,1' -biphenyl ] -4-yl) -N, N-dimethylmethylamine (1.1g,5.2mmol) was dissolved in dichloromethane (20ml), and chlorosulfonic acid (5.0ml) was added dropwise under ice bath. The reaction solution was warmed to room temperature and kept at room temperature for stirring for 4 hours, then poured into ice water, and the solid was collected by filtration and dried under vacuum to give 4'- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride (1.0g, 65% yield).
Example 1 preparation of N-hydroxy-1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
1. Preparation of 2, 5-dihydro-1H-pyrrole-3-carboxylic acid
Dissolving ethyl N-t-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylate (8.5g,36 mmol; manufacturer: Shaoshima technologies, Ltd.) in a mixed solution of 60mL tetrahydrofuran and 30mL water, adding lithium hydroxide (4.2g,176mmol), reacting at 25 ℃ with stirring for 2 hours, and removing the organic solvent in vacuo to obtain a residue; diluting the residue with an appropriate amount of water, adjusting the pH to 5 with 1N hydrochloric acid, precipitating a solid, and filtering to obtain a solid; the solid was washed with water and dried to give N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid (7.0g, 93% yield) as a white solid.
MS(ESI)m/z214(M+1)+。
Under an ice bath, dissolving N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid (7g,36mmol) in 70mL of dichloromethane solution, then dropwise adding 30mL of trifluoroacetic acid, stirring, slowly raising the temperature to 25 ℃, and continuing to stir for 2H to obtain a reaction solution; the reaction was concentrated to give 2, 5-dihydro-1H-pyrrole-3-carboxylic acid (4.0g, 99% yield) as a yellow oil.
MS(ESI)m/z114(M+1)+。
2. Preparation of N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid
2, 5-dihydro-1H-pyrrole-3-carboxylic acid (4.0g,35.4mmol) was dissolved in 50mL of tetrahydrofuran and 30mL of water, followed by addition of sodium carbonate (11.2g,106mmol) and fluorenyloxycarbonyl chloride (9.2g,35.4 mmol; manufacturer: Afahesa (China) chemical Co., Ltd.), and reaction with stirring at 25 ℃ overnight; after the reaction, 200mL of water was added to dilute the reaction mixture, the pH was adjusted to 1 with 2N hydrochloric acid, ethyl acetate was used for extraction, the organic phases were combined, dried and concentrated in vacuo to give N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid as a white solid (11.0g, 92% yield).
MS(ESI)m/z336(M+1)+。
3. Preparation of N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
Dissolving N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid (11.0g, 32.8mmol) in 100mL of dichloromethane, sequentially adding O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (4.2g,36mmol), HATU (15g,39.4mmol) and DIEA (12.8g,98.4 mmol; manufacturer: Bailingwei Technology Co., Ltd.), and stirring at 25 ℃ for reacting overnight to obtain a reaction solution; adding 50mL of water into the reaction solution for dilution, extracting with ethyl acetate (50mL x 2), combining ethyl acetate phases, drying, filtering and concentrating the ethyl acetate phases to obtain a crude product; the crude product was purified by column chromatography to give N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (12g, 48% yield).
MS(ESI)m/z435(M+1)+。
4. Preparation of 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
Dissolving N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -formamide (10g, 23mmol) in 100mL of DMF, adding 20mL of piperidine, stirring at 25 ℃ for reacting for 4 hours, then adding 800mL of water for diluting, extracting with ethyl acetate, and combining organic phases; the organic phase was dried, filtered and concentrated to give 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (4.5g, 92% yield).
MS(ESI)m/z213(M+1)+。
5. N-hydroxy-1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
Dissolving 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -formamide (100mg,0.5mmol) and triethylamine (66mg,0.7mmol) in dichloromethane (8mL), adding 4'- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride (177mg,0.6mmol) to the reaction solution at 25 ℃, stirring at 25 ℃ for 2 hours, and concentrating to remove the solvent to obtain a crude product; the crude product was purified by column chromatography to give N- ((tetrahydro-2H-pyran-2-yl) oxy) -1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid.
Dissolving N- ((tetrahydro-2H-pyran-2-yl) oxy) -1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-formamide (80mg,0.3mmol) in 5mL of dichloromethane solution under ice bath, then dropwise adding 2mL of trifluoroacetic acid, stirring, slowly raising to 25 ℃, continuing stirring for 2 hours, and concentrating to remove the solvent to obtain a crude product; the crude product was purified by preparative high performance liquid chromatography to give N-hydroxy-1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid (36mg, 19% yield).
MS(ESI)m/z 402(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.85(s,1H),9.95(s,1H),9.03(s,1H),8.00-7.88(m,6H),7.63(d,J＝8.0Hz,2H),6.35(s,1H),4.35(s,2H),4.23(s,4H),2.77(s,6H)。
Example 2 preparation of N-hydroxy-1- ((4- (4-methylpiperazine-N-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
The reaction mixture was purified by eluting 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (4-methylpiperazin-1-yl) phenylboronic acid pinacol ester (3.0g,10 mmol; manufacturer: welengi science and technology limited) as a raw material, following the preparation of 4'- ((dimethylamino) methyl)) - [1,1' -biphenyl ] -4-sulfonyl chloride and the analogous procedure in example 1, white solid N-hydroxy-1- ((4- (4-methylpiperazine-N-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide was prepared (29mg, 15% yield).
MS(ESI)m/z 443(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.84(s,1H),9.03(s,1H),7.91-7.84(m,4H),7.70(d,J＝8.4Hz,2H),7.13(d,J＝8.4Hz,2H),6.34(s,1H),4.20(s,4H),3.53(s,2H),3.27-3.08(m,6H),2.87(s,3H)。
Example 3 preparation of N- (2-aminophenyl) -1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
1. Preparation of ethyl 2, 5-dihydro-1H-pyrrole-3-carboxylate
Dissolving N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-ethyl formate (250mg,1.1mmol) in 5mL of dichloromethane solution in an ice bath, then dropwise adding 2mL of trifluoroacetic acid, stirring, slowly raising the temperature to 25 ℃, and continuing to stir for 2 hours to obtain a reaction solution; the reaction was then concentrated to give ethyl 2, 5-dihydro-1H-pyrrole-3-carboxylate (150mg, 99% yield) as a yellow oil.
MS(ESI)m/z 142(M+1)+。
2. Preparation of ethyl 1- (4'- ((dimethylamino) methyl) - [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxylate
Slowly adding 4'- ((dimethylamino) methyl) - [1,1' -biphenyl ] -4-sulfonyl chloride (364mg,1.2mmol) into a dichloromethane (10mL) solution of ethyl 2, 5-dihydro-1H-pyrrole-3-carboxylate (141mg,1.0mmol) and triethylamine (132mg,1.4mmol) under ice bath, slowly raising the temperature to 25 ℃, continuing to stir for reaction for 2 hours, and concentrating to obtain a crude product; the crude product was purified by column chromatography to give ethyl 1- (4'- ((dimethylamino) methyl) - [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxylate (164mg, 39% yield) as a white solid.
MS(ESI)m/z 415(M+1)+。
3. Preparation of 1- (4'- ((dimethylamino) methyl) - [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxylic acid
LiOH (40mg,1.0mmol) was added to a solution of ethyl 1- (4'- ((dimethylamino) methyl) - [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxylate (164mg,0.38mmol) in tetrahydrofuran (3mL) and water (3mL) at 25 ℃ and stirred for 2 hours to give a reaction solution; then, the pH of the reaction solution was adjusted to 5 with 1N hydrochloric acid in an ice bath, and the reaction solution was extracted with dichloromethane (10mL × 2), and the organic phases were combined; the organic phase was dried, filtered and concentrated to give 1- (4'- ((dimethylamino) methyl) - [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxylic acid (131mg, 82% yield) which was used directly in the next reaction.
MS(ESI)m/z 387(M+1)+。
4. Preparation of N- (2-aminophenyl) -1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
Dissolving 1- (4'- ((dimethylamino) methyl) - [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxylic acid (131mg, 0.34mmol) in 10mL of DMF, sequentially adding 1, 2-diaminobenzene (34mg,0.30mmol), HATU (113mg,0.30mmol) and DIEA (77mg,0.60mmol) to the solution, and reacting at 25 ℃ with stirring overnight to obtain a reaction solution; the reaction was diluted with 20mL of water, extracted with dichloromethane (50mL x 3), and the organic phases combined; drying, filtering and concentrating the organic phase to obtain a crude product; the crude product was purified by preparative high performance liquid chromatography to give N- (2-aminophenyl) -1- ((4- (4-dimethylaminomethyl-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid (23mg, 14% yield).
MS(ESI)m/z 477(M+1)+。
1HNMR(400MHz,CD3OD)δ＝9.27(br s,1H),7.97-7.92(m,4H),7.73(d,2H,J＝7.6Hz,2H),7.74(d,2H,J＝7.6Hz,2H),7.43(d,2H,J＝7.6Hz,2H),7.00-6.91(m,2H),6.69-6.64(m,2H),6.48(s,1H),4.32(s,4H),2.24(s,6H)。
Example 4 preparation of N- (2-aminophenyl) -1- ((4 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from ethyl 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxylate (141mg,1.0mmol) and 4- (4-methylpiperazin-N-phenyl) benzenesulfonyl chloride (354mg,1.2mmol), a white solid, N- (2-aminophenyl) -1- ((4 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide (26mg, 12% yield) was prepared according to the analogous procedure in example 3.
MS(ESI)m/z 518(M+1)+。
1HNMR(400MHz,CD3OD)δ＝9.25(br,1H),7.90-7.85(m,4H),7.65(d,J＝8.8Hz,2H),7.05(d,J＝8.8Hz,2H),7.00-6.92(m,2H),6.70-6.64(m,2H),6.50(s,1H),4.31(s,4H),4.23-4.04(m,8H),2.30(m,3H).
Example 5 preparation of 1- ((3 ' -fluoro-4 ' - (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -N-hydroxy-2, 5-dihydro-1H-pyrrole-3-carboxamide
1. Preparation of 1- ((4-bromophenyl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (2.1g,10mmol) was dissolved in a mixed solution of 50mL tetrahydrofuran and 50mL water, followed by the addition of p-bromobenzenesulfonyl chloride (2.6g,10 mmol). Sodium bicarbonate (2.6g,30mmol) was added. The solution was stirred at room temperature for 1 hour. After the reaction was completed, the organic solvent was removed in vacuo, the residue was diluted with an appropriate amount of water and extracted 2 times with ethyl acetate, which was dried and concentrated to give 1- ((4-bromophenyl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (3.8g, 88.2% yield).
MS(ESI)m/z 431(M+1)+。
1HNMR(400MHz,CD3OD)δ＝11.38(br,1H),7.86(d,J＝4.0Hz,2H),7.84(d,J＝4.0Hz,2H),6.42(s,1H),4.82(s,1H),4.21-4.19(m,4H),4.03-4.01(m,1H),3.49(s,1H),1.62(s,3H),1.50(s,3H).
2. N-hydroxy-1- ((3 ' -fluoro-4 ' - (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
1- ((4-bromophenyl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (431mg,1.0mmol) was dissolved in 10mL of dioxane and 2mL of water, followed by addition of sodium carbonate (212mg, 2mmol) and 1- ((3 ' -fluoro-4 ' - (4-methylpiperazin-1-yl) -phenylboronic acid pinacol ester (321mg,1.0mmol, manufacturer: Bailingwei science Co., Ltd.), addition of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (50mg), replacement of the solution with nitrogen three times, heating to 80 ℃ for reaction for 2 hours, after completion of the reaction, the reaction solution was vacuumed out of the organic solvent, diluted with 20mL of water, extraction with dichloromethane was performed 3 times, the combined organic phases were dried and concentrated in vacuo to give a crude product which was passed through a column to give N-hydroxy-1- ((3 ' -fluoro-4 ' - (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (257.00m g, 47.5% yield).
MS(ESI)m/z 544(M+1)+。
3. Preparation of 1- ((3 ' -fluoro-4 ' - (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -N-hydroxy-2, 5-dihydro-1H-pyrrole-3-carboxamide
Dissolving N-hydroxy-1- ((3 '-fluoro-4' - (4-methylpiperazin-1-yl) - [1,1 '-biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (257mg, 0.48mmol) in 5mL of methanol, adding 1N HCl solution (1.0mL) dropwise to the solution, stirring the mixture at room temperature for 2 hours, and filtering after the reaction to obtain a white solid, 1- ((3' -fluoro-4 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -N-hydroxy-2, 5-dihydro-1H-pyrrole-3-carboxamide (66mg, yield 17.3%).
MS(ESI)m/z 461(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.86(s,1H),9.20-8.80(br,1H),7.95-7.93(d,J＝8.8Hz,2H),7.88-7.86(d,J＝8.4Hz,2H),7.68-7.57(m,2H),7.24-7.20(t,J＝8.8Hz,1H),6.35(s,1H),4.21(s,4H),3.60-3.58(d,J＝8.8Hz,2H),3.51-3.49(d,J＝7.6Hz,2H),3.23(m,3H),2.83(s,3H)。
Example 6 preparation of N-hydroxy-1- ((4 '- (piperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (300mg,1.4mmol) and 1- ((4 ' - (piperazin-1-yl) phenylboronic acid pinacol ester (289mg,1.0 mmol; manufacturer: Bailingwei science and technology Co., Ltd.) a white solid, N-hydroxy-1- ((4 ' - (piperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide (56mg, 9.6% yield) was prepared according to the similar procedure in example 5.
MS(ESI)m/z 429(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.83(s,1H),8.91(br,2.5H),7.90.7.84(m,4H),7.71-7.68(d,J＝9.2Hz,2H),7.13-7.11(d,J＝8.8Hz,2H),6.35(s,1H),4.21(s,4H),3.47-3.44(m,4H),3.26(s,4H)。
Example 7 preparation of N-hydroxy-1- ((4 '- (4-ethylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (300mg,1.4mmol) and 1- ((4 ' - (4-ethylpiperazin-1-yl) pinacol ester phenylboronic acid (321mg,1.0 mmol; manufacturer: Shanghai Shuizi Yam technology Co., Ltd.) the procedure was analogous to that in example 5 to give N-hydroxy-1- ((4 ' - (4-ethylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid (36mg, 11.3% yield).
MS(ESI)m/z 457(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.84(s,1H),10.61-10.53(br,1H),9.0(s,1H),7.90-7.84(m,4H),7.71-7.69(d,J＝9.2Hz,2H),7.15-7.13(d,J＝8.8Hz,2H),6.36(s,1H),4.21(s,4H),3.98-3.95(d,J＝12.4Hz,2H),3.58-3.55(d,J＝11.6Hz,2H),3.21-3.08(m,6H),1.31-1.27(t,J＝7.2Hz,3H)。
Example 8 preparation of N-hydroxy-1- ((2-fluoro-4 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -N-hydroxy-2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (300mg,1.4mmol) and 1- ((4 ' - (4-methylpiperazin-1-yl) -phenylboronic acid pinacol ester (321mg,1.0mmol, manufacturer: bainwei technologies co., ltd.) and 3-fluoro-4-bromobenzenesulfonyl chloride (382mg,1.4mmol), the analogous procedure as in example 5 was followed to give N-hydroxy-1- ((2-fluoro-4 ' - (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -N-hydroxy-2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid (38mg, yield 11.5%)
MS(ESI)m/z 461(M+1)+。
1HNMR(400Hz,DMSO-D6)δ＝10.84(s,1H),10.57(br,1H),9.05(s,1H),7.78-7.70(m,3H),7.57-7.55(d,J＝7.6Hz,2H),7.15-7.13(d,J＝8.8Hz,2H),6.38(s,1H),4.25(s,4H),4.06-3.92(m,2H),3.50-3.49(d,J＝0.8Hz,2H),3.17-3.16(d,J＝0.8Hz,4H),2.83(s,3H)。
To illustrate the advantageous effects of the present invention, the present invention provides the following test examples:
test example 1 biological Activity assay
The HDA inhibitory activity of the compounds of the invention was tested in a substrate deacetylation assay.
A: detection of the enzyme activity of deacetylase 6 (#50076, BPS Bioscience):
the HDAC6 removes acetyl on the substrate, so that the substrate is activated, can be acted by a subsequently added color development solution and releases a fluorescent group, and the size of a fluorescent signal of the substrate reflects the activity of the HDAC 6. The IC50 detection method of the enzyme is disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as therapeutics for the Neurgenic disease Friedreich's Ataxia: A New Synthetic Route. The total reaction (100. mu.L/well) contained 0.35 ng/. mu.L of HDAC6, 20. mu.M substrate and varying concentrations of compound. After incubation at 37 ℃ for 30 minutes, the fluorescence signal was measured, and the inhibition of the compound was determined from the data obtained and plotted against the compound concentration to obtain a concentration response curve, and the IC50 values were fitted according to a four parameter model.
B: deacetylase 3 enzyme activity assay (#50003, BPS Bioscience):
the HDAC3 removes acetyl on the substrate, so that the substrate is activated, can be acted by a color developing solution and releases a fluorescent group, and the size of a fluorescent signal of the substrate reflects the activity of the HDAC 3. The IC50 detection method of the enzyme is disclosed in Chuping Xu, Elisabettasoargi Improved Histone Deacetylase Inhibitors as Therapeutics for the Neuregenerative disease Friedreich's Ataxia: A New Synthetic Route. The total reaction (100. mu.L/well) contained 0.16 ng/. mu.L of HDAC3, 10. mu.M substrate and varying concentrations of compound. The fluorescence signal was detected on-line at Ex/Em ═ 360/460. The inhibition of the compound was determined from the data obtained and plotted against compound concentration to obtain a concentration response curve, and IC50 values were fitted according to a four parameter model.
The enzymatic activity of deacetylase 6 (i.e., HDAC6) was assayed for compounds 1-8, prepared as described above, for the compounds 1-8 of the examples, and the results are shown in table 2, where the IC50 for each compound was determined according to the specification, table 2:
"+" indicates that the IC50 assay for HDAC6 was greater than 500 nM;
"+ + +" indicates that IC50 for HDAC6 was less than 300nM and greater than 100 nM;
"+ + + + +" indicates that IC50 for HDAC6 was less than 100nM
The enzymatic activity of deacetylase 3 (i.e., HDAC3) was assayed for compounds 1-8 prepared in the examples as described above and the results are shown in table 2, where the IC50 for each compound was determined according to the instructions and is shown in table 2:
"+" indicates that the IC50 assay for HDAC3 was greater than 1000 nM;
"+ + +" indicates that IC50 for HDAC3 was greater than 100nM and less than 1000 nM;
"+ + + + +" indicates that the IC50 for HDAC3 was less than 100 nM.
TABLE 2 inhibitory Activity of Compounds 1 to 8 of the present invention on HDAC6& HDAC3
| Compound (I) | Active (HDAC6) | Active (HDAC3) |
| 1 | +++ | +++ |
| 2 | +++ | +++ |
| 3 | +++ | +++ |
| 4 | +++ | +++ |
| 5 | +++ | +++ |
| 6 | +++ | +++ |
| 7 | +++ | ++ |
| 8 | ++ | ++ |
Test results show that the compounds 1-8 have good deacetylase inhibitory activity and have the potential of preventing and/or treating diseases caused by abnormal histone deacetylase activity.
Test example 2 cell assay-cell growth inhibition assay
Materials and reagents
HepG2 cell line, Hep3B cell line, Huh7 cell line and Li7 cell line were purchased from Shanghai Life sciences institute of Chinese academy of sciences; DMEM high-glucose medium and MEM medium were purchased from Hyclone; fetal bovine serum was purchased from Gibco; trypsin was purchased from Invitrogen Shanghai; the CCK-8 kit is purchased from Biyuntian Biotechnology institute (beyond time); the other consumables such as cell culture dishes were purchased from Corning China.
Cell preparation prior to Compound action
Digesting HepG2 cells, Hep3B cells, Huh7 cells and Li7 cells in logarithmic growth phase by trypsin, taking uniform cell suspension, counting, adjusting the cell density to 1500 cells/hole by using a culture medium containing 10% serum, re-inoculating the cells in a 96-hole cell culture plate, culturing the cells in a volume of 200 mu L at 37 ℃ and 5% CO2Culturing in an incubator; the culture was carried out for 24 hours and used for the experiment.
Action of the Compound
The cells cultured for 24 hours were taken out from the incubator, the culture solution in the well plate was aspirated, 200. mu.L of a compound solution prepared with a medium containing 10% fetal bovine serum was added to each well, each concentration was 5 in parallel, DMSO was set as a negative control, and the cells were cultured at 37 ℃ for 72 hours in 5% CO2 to carry out CCK-8 assay.
CCK-8 detection
Serum-free culture medium and CCK-8 solution are taken to prepare CCK-8 working solution according to the proportion of 10:1 (the process needs to be protected from light).
The cells cultured for 72 hours were removed from the incubator, the culture medium was aspirated from the well plate, and 120. mu. LCCK-8 working solution was added to each well, and 120. mu. LCCK-8 working solution was added to the cell-free well plate as a blank, and the cell-free well plate was incubated at 37 ℃ in a 5% CO2 incubator for 1 hour (this process required protection from light).
The plates were removed from the incubator and 100. mu.L of solution was pipetted into each well of a new 96-well plate and the absorbance read at 450nm (the process required protection from light).
Data processing:
tx: absorbance of the compound measured 72 hours after the compound was exposed to CCK-8
C: the absorbance of the negative control wells measured by CCK-8 after 72 hours of incubation
B: absorbance measured in blank control well, CCK-8
The compounds 1-8 prepared in the examples were run in the above assay and the results are shown in table 3, where the highest IC50 of one or more runs of each compound determined is categorized as per the instructions, table 3:
"+" indicates that the compound had an IC50 assay of greater than 10 μ M in cancer cells;
"+ +" indicates that the IC50 assay of the compound in cancer cells was less than 10. mu.M;
TABLE 3 inhibitory Activity of Compounds 1 to 8 of the present invention on different hepatocarcinoma cells
| Compound (I) | HepG2 | Huh-7 | Li-7 | Hep3B |
| 1 | ++ | ++ | ++ | ++ |
| 2 | ++ | ++ | ++ | ++ |
| 3 | ++ | ++ | ++ | ++ |
| 4 | ++ | ++ | ++ | ++ |
| 5 | ++ | ++ | ++ | ++ |
| 6 | ++ | ++ | ++ | ++ |
| 7 | ++ | ++ | ++ | ++ |
| 8 | ++ | ++ | ++ | ++ |
Test results show that the compounds 1-8 have good inhibitory activity on different liver cancer cells (HepG2, Huh-7, Li-7 and Hep3B) and have a prospect of clinical application.
In conclusion, the novel compound shown in the formula I shows good deacetylase inhibitory activity, and has the potential of preventing and/or treating diseases caused by abnormal histone deacetylase activity; meanwhile, the novel compound has good inhibitory activity on different liver cancer cells, and has a prospect of clinical application.
Claims (24)
1. A pyrrole amide compound represented by formula I or a pharmaceutically acceptable salt thereof:
wherein,
R1selected from (methylamino) methyl, (methylamino) ethyl, (methylamino) propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino) ethyl(ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R4selected from hydroxyl, sulfhydryl and phenyl substituted by amino.
2. The pyrrole amide compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein:
R1selected from (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, p-methylpiperazinyl, p-ethylpiperazinyl, p-propylpiperazinyl or p-buthylpiperazinyl;
R2、R3independently or simultaneously selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamino, n-butylAcylamino, isobutanamido, tert-butanamido, pentanamido, hexanamido, methionyl, ethanamido, n-alaninyl, isoalanyl, n-butanyl, isobutylyl, tert-butanyl, pentylamino, hexylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R4selected from hydroxy, mercapto or amino substituted phenyl.
3. The pyrrole amide compound or the pharmaceutically acceptable salt thereof according to claim 2, wherein: the compound shown in the formula I is:
4. a preparation method of pyrrole amide compounds shown in formula I is characterized in that:
the pyrrole amide compound shown in the formula I is:
when R is4When the hydroxyl is adopted, the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenylmethoxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; DCM represents dichloromethane;
R1selected from (methylamino) methyl, (methylamino) ethyl, (methylamino) propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino) ethyl, (ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentaalkylpiperazinyl, or hexanalkylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5is halogen;
the method comprises the following steps:
a. stirring a mixed solvent of a compound IM-1a, lithium hydroxide and an ether solvent/water at the temperature of 20-30 ℃ for reaction for 1-6 h, removing the organic solvent, adding water for dilution, adjusting the pH value to 3-6, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-1a to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-1a to the mixed solvent is 1: 7-20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
b. b, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent at the temperature of 0-5 ℃, adding trifluoroacetic acid, and stirring and reacting at the temperature of 20-30 ℃ for 2-12H to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 a;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 5-20 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 2-10 g/ml;
c. b, stirring the compound IM-2a obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at the temperature of 20-30 ℃ for reaction for 12-16 h, adding water for dilution, adjusting the pH value to 1-3, extracting the ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-3 a;
the molar ratio of the compound IM-2a to the sodium carbonate to the fluorenyloxycarbonyl chloride is 1: 1-5: 0.9 to 1.5; the mass-volume ratio of the compound IM-2a to the mixed solvent is 1: 10-25 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
d. c, stirring and reacting the compound IM-3a obtained in the step c, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 12 to 16 hours, adding water for dilution, extracting an ester solvent, combining organic phases, drying, filtering and concentrating the organic phase to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 a;
the molar ratio of the compound IM-3a, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1-2: 1-2: 2-4; the mass-volume ratio of the compound IM-3a to the halocarbon solvent is 1: 9-20 g/ml;
e. d, stirring the compound IM-4a obtained in the step d, piperidine and a nitrogen-containing solvent at 25-30 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM-5 a;
the mass-to-volume ratio of the compound IM-4a to piperidine is 1: 1-4 g/ml; the mass-volume ratio of the compound IM-4a to the nitrogen-containing solvent is 1: 5-20 g/ml;
f. e, stirring and reacting the compound IM-5a, triethylamine, the compound IM-6a and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 1 to 10 hours, and removing the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 a;
the mol ratio of the compound IM-5a to the triethylamine to the compound IM-6a is 1: 1-5: 1-2; the mass-volume ratio of the compound IM-5a to the halocarbon solvent is 1: 50-100 g/ml;
g. dissolving the compound TM-1a obtained in the step f in a halohydrocarbon solvent at the temperature of 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at the temperature of 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound shown in a formula I;
the mass-volume ratio of the compound TM-1a to the halocarbon solvent is 1: 50-100 g/ml; the mass-volume ratio of the compound TM-1a to trifluoroacetic acid is 1: 10-50 g/ml.
5. The method of claim 4, wherein:
a. stirring a mixed solvent of the compound IM-1a, lithium hydroxide and an ether solvent/water at 25 ℃ for 2 hours, removing the organic solvent, adding water for dilution, adjusting the pH to be 5, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-1a to the lithium hydroxide is 1: 4.5-5; the mass-volume ratio of the compound IM-1a to the mixed solvent is 1: 10-12 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 2: 1;
b. b, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, and stirring and reacting at 25 ℃ for 2 hours to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 a;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 10 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 4-5 g/ml;
c. b, stirring the compound IM-2a obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at 25 ℃ for 12-16 h, adding water for dilution, adjusting the pH value to be 1, extracting by using an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-3 a;
the molar ratio of the compound IM-2a to the sodium carbonate to the fluorenyloxycarbonyl chloride is 1: 3: 1; the mass-volume ratio of the compound IM-2a to the mixed solvent is 1: 20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 5: 3;
d. c, stirring the compound IM-3a obtained in the step c, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at 25 ℃ for 12-16H, adding water for dilution, extracting an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 a;
the molar ratio of the compound IM-3a, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1.1: 1.2: 3; the mass-volume ratio of the compound IM-3a to the halocarbon solvent is 1: 9-10 g/ml;
e. d, stirring the compound IM-4a obtained in the step d, piperidine and a nitrogen-containing solvent at 25 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM-5 a;
the mass-to-volume ratio of the compound IM-4a to piperidine is 1: 2 g/ml; the mass-volume ratio of the compound IM-4a to the nitrogen-containing solvent is 1: 10 g/ml;
f. e, stirring the compound IM-5a, triethylamine, the compound IM-6a and a halohydrocarbon solvent in the step e at 25 ℃ for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 a;
the mol ratio of the compound IM-5a to the triethylamine to the compound IM-6a is 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM-5a to the halocarbon solvent is 1: 80 g/ml;
g. dissolving the compound TM-1a obtained in the step f in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound shown in a formula I;
the mass-volume ratio of the compound TM-1a to the halocarbon solvent is 1: 60-65 g/ml; the mass-volume ratio of the compound TM-1a to trifluoroacetic acid is 1: 25 g/ml.
6. The production method according to claim 4 or 5, characterized in that:
R1selected from (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, p-methylpiperazinyl, p-ethylpiperazinyl, p-propylpiperazinyl or p-buthylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Of azaCyclic group, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5selected from fluorine, chlorine, bromine or iodine.
7. The method of claim 6, wherein: in step f, the compound IM-6a is:
8. the production method according to claim 4 or 5, characterized in that: in the steps a to g, the ether solvent is selected from one or more than two of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is selected from one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is selected from one or more of ethyl acetate and ethyl formate; the nitrogen-containing solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and pyridine.
9. A preparation method of pyrrole amide compounds shown in formula I is characterized in that:
the pyrrole amide compound shown in the formula I is:
when R is4When the hydroxyl is adopted, the synthetic route is as follows:
wherein,
R1selected from (methylamino) methyl, (methylamino) ethyl, (methylamino) propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino) ethyl, (ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentaalkylpiperazinyl, or hexanalkylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5、R6are each halogen;
the method comprises the following steps:
i. stirring a mixed solvent of a compound IM-5b, a compound IM-6b, sodium bicarbonate and an ether solvent/water at 25-30 ℃ for reaction for 1-10 h, removing the solvent, adding water, extracting with an ester solvent, combining organic phases, washing with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-7 b;
the molar ratio of the compound IM-5b to the compound IM-6b to the sodium bicarbonate is 1: 1-2: 1-5; the mass-volume ratio of the compound IM-5b to the mixed solvent of the ether solvent/water is 1: 20-100 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-5: 1;
ii. I, stirring and reacting a compound IM-7b obtained in the step i, a compound IM-8b, sodium carbonate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and a mixed solvent of an ether solvent/water at 50-100 ℃ under the protection of inert gas for 1-10 h, removing the solvent, adding water and a halohydrocarbon solvent for extraction, combining organic phases, washing the organic phases with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 b;
the mol ratio of the compound IM-7b to the compound IM-8b to the sodium carbonate is 1: 1-2: 1-5; the mass ratio of the compound IM-7b to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is 1: 0.05 to 0.2; the mass-volume ratio of the compound IM-7b to the mixed solvent of the ether solvent/water is 1: 20-100 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-10: 1;
iii, dissolving the compound TM-1b in the step II in an alcohol solvent, adding hydrochloric acid, stirring and reacting at 25-30 ℃ for 1-10 h, and then separating and purifying to obtain the compound shown in the formula I;
the mass-volume ratio of the compound TM-1b to the alcohol solvent is 1: 18-100 g/ml; the mass-volume ratio of the compound TM-1b to hydrochloric acid is 1: 3-20 g/ml; the concentration range of the hydrochloric acid is 0.5N-2N.
10. The method of claim 9, wherein:
i. stirring a compound IM-5b, a compound IM-6b, sodium bicarbonate and a mixed solvent of an ether solvent/water at 25 ℃ for 2 hours, removing the solvent, adding water, extracting with an ester solvent, combining organic phases, washing with saturated saline water, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-7 b;
the molar ratio of the compound IM-5b to the compound IM-6b to the sodium bicarbonate is 1: 1: 2-3; the mass-volume ratio of the compound IM-5b to the mixed solvent of the ether solvent/water is 1: 20-40 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
ii. I, stirring and reacting a mixed solvent of the compound IM-7b, the compound IM-8b, sodium carbonate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and an ether solvent/water at 80 ℃ for 2 hours under the protection of inert gas, removing the solvent, adding water, extracting a halohydrocarbon solvent, combining organic phases, washing with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 b;
the mol ratio of the compound IM-7b to the compound IM-8b to the sodium carbonate is 1: 1: 2-3; the mass ratio of the compound IM-7b to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is 1: 0.08 to 0.12; the mass-volume ratio of the compound IM-7b to the mixed solvent of the ether solvent/water is 1: 20-40 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 4-6: 1;
iii, dissolving the compound TM-1b in the step II in an alcohol solvent, adding hydrochloric acid, stirring at 25 ℃ for reaction for 2 hours, and then separating and purifying to obtain a compound shown in the formula I;
the mass-volume ratio of the compound TM-1b to the alcohol solvent is 1: 18-40 g/ml; the mass-volume ratio of the compound TM-1b to hydrochloric acid is 1: 3-10 g/ml; the concentration range of the hydrochloric acid is 0.5N-2N.
11. The production method according to claim 9 or 10, characterized in that:
R1selected from (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, p-methylpiperazinyl, p-ethylpiperazinyl, p-propylpiperazinyl or p-buthylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxyAlkyl, tert-butoxy, pentoxy, hexoxy, aminomethyl, aminoethyl, aminopropyl, aminobutynyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanamido, n-alaninyl, isoalaninyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5、R6selected from fluorine, chlorine, bromine or iodine.
12. The method of claim 11, wherein:
in step i, the compound IM-6b is:
in step ii, said compound IM-8b is:
13. the production method according to claim 9 or 10, characterized in that: in the steps i to iii, the ether solvent is selected from one or more of tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is selected from one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is selected from one or more of ethyl acetate and ethyl formate; the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol and isopropanol.
14. A preparation method of pyrrole amide compounds shown in formula I is characterized in that:
the pyrrole amide compound shown in the formula I is:
when R is4When the phenyl is substituted by amino, the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; LiOH represents lithium hydroxide;
R1selected from (methylamino) methyl, (methylamino) ethyl, (methylamino) propyl, (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (ethylamino) methyl, (ethylamino) ethyl, (ethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (propylamino) methyl, (propylamino) ethyl, (propylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentaalkylpiperazinyl, or hexanalkylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5selected from halogens;
the method comprises the following steps:
①, dissolving the compound IM-1c in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, stirring and reacting for 2-12 h at 20-30 ℃ to obtain a reaction liquid, and concentrating the reaction liquid to obtain a yellow oily substance, namely the compound IM-2 c;
the mass-to-volume ratio of the compound IM-1c to the halocarbon solvent is 1: 5-20 g/ml; the mass-to-volume ratio of the compound IM-1c to trifluoroacetic acid is 1: 2-10 g/ml;
②, stirring the compound IM-2c, the compound IM-3c, the triethylamine and the halohydrocarbon solvent obtained in the step ① at the temperature of between 25 and 30 ℃ for reaction for 1 to 10 hours, concentrating to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound IM-4 c;
the mol ratio of the compound IM-2c to the compound IM-3c to triethylamine is 1: 1-2: 1-5; the mass-volume ratio of the compound IM-2c to the halocarbon solvent is 1: 50-100 g/ml;
③, stirring the mixed solvent of the compound IM-4c obtained in the step ②, lithium hydroxide and ether solvent/water at the temperature of 20-30 ℃ for 2-16 h to obtain reaction liquid, separating and purifying to obtain a compound IM-5 c;
the molar ratio of the compound IM-4c to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-4c to the mixed solvent is 1: 55-60 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-5: 1;
④, carrying out stirring reaction on the compound IM-5c obtained in the step ③,1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 12 to 16 hours to obtain a reaction solution, and separating and purifying to obtain the compound shown in the formula I;
the molar ratio of the compound IM-5c, 1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 0.8-2: 0.8-2: 1.5 to 4; the mass-to-volume ratio of the compound IM-5c to the halocarbon solvent is 1: 40-100 g/ml.
15. The method of claim 14, wherein:
①, dissolving the compound IM-1c in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring and reacting for 2h at 25 ℃ to obtain a reaction solution, and concentrating the reaction solution to obtain a yellow oily substance, namely the compound IM-2 c;
the mass-to-volume ratio of the compound IM-1c to the halocarbon solvent is 1: 20 g/ml; the mass-to-volume ratio of the compound IM-1c to trifluoroacetic acid is 1: 8 g/ml;
②, stirring the compound IM-2c, the compound IM-3c, triethylamine and a halohydrocarbon solvent obtained in the step ① at 25 ℃ for 2 hours, concentrating to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound IM-4 c;
the mol ratio of the compound IM-2c to the compound IM-3c to triethylamine is 1: 1.1-1.2: 2.5-3; the mass-volume ratio of the compound IM-2c to the halocarbon solvent is 1: 65-70 g/ml;
③, stirring the compound IM-4c obtained in the step ②, lithium hydroxide and mixed solvent of ether solvent/water at 25 ℃ for 2-16 h to obtain reaction liquid, separating and purifying to obtain a compound IM-5 c;
the molar ratio of the compound IM-4c to the lithium hydroxide is 1: 4.5; the mass-volume ratio of the compound IM-4c to the mixed solvent is 1: 55-60 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 3: 1;
④, carrying out stirring reaction on the compound IM-5c obtained in the step ③,1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at 25 ℃ for 12-16 h to obtain a reaction solution, and separating and purifying to obtain the compound shown in the formula I;
the molar ratio of the compound IM-5c, 1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 0.8-1.2: 0.8-1.2: 1.5-2; the mass-to-volume ratio of the compound IM-5c to the halocarbon solvent is 1: 40-45 g/ml.
16. The production method according to claim 14 or 15, characterized in that:
R1selected from (dimethylamino) methyl, (dimethylamino) ethyl, (dimethylamino) propyl, (diethylamino) methyl, (diethylamino) ethyl, (diethylamino) propyl, (dipropylamino) methyl, (dipropylamino) ethyl, (dipropylamino) propyl, piperazinyl, p-methylpiperazinyl, p-ethylpiperazinyl, p-propylpiperazinyl or p-buthylpiperazinyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5selected from fluorine, chlorine,Bromine or iodine.
17. The method according to claim 16, wherein in step ②, the compound IM-3c is:
18. the method according to claim 14 or 15, wherein the halocarbon solvent is selected from one or more of dichloromethane, ethyl chloride, dichloroethane, chloroform and carbon tetrachloride, and the ether solvent is selected from one or more of tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, isopropyl ether and dibutyl ether in the steps ① to ③.
19. Use of the pyrrole amide compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of histone deacetylase inhibitor drugs.
20. Use according to claim 19, characterized in that: the histone deacetylase inhibitor medicament is a medicament for preventing and/or treating diseases caused by abnormal histone deacetylase activity.
21. Use according to claim 20, characterized in that: the disease is any one or more of a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease, or a viral disease.
22. Use according to claim 21, characterized in that: the disease is cancer.
23. A pharmaceutical composition for inhibiting histone deacetylase activity, comprising: the preparation is prepared by taking the pyrrole amide compounds or pharmaceutically acceptable salts thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
24. The pharmaceutical composition of claim 23, wherein: the preparation comprises an oral administration preparation, a sublingual administration preparation, a buccal administration preparation, a transdermal absorption preparation or an injection preparation.
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