CN108239082B - 一种抑制rock的化合物及其应用 - Google Patents
一种抑制rock的化合物及其应用 Download PDFInfo
- Publication number
- CN108239082B CN108239082B CN201711406484.XA CN201711406484A CN108239082B CN 108239082 B CN108239082 B CN 108239082B CN 201711406484 A CN201711406484 A CN 201711406484A CN 108239082 B CN108239082 B CN 108239082B
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- rock
- carbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 69
- 239000011435 rock Substances 0.000 title claims abstract description 34
- 230000002401 inhibitory effect Effects 0.000 title abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 230000000694 effects Effects 0.000 claims abstract description 19
- 230000002159 abnormal effect Effects 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000003112 inhibitor Substances 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 claims description 11
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 7
- 230000008602 contraction Effects 0.000 claims description 6
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 206010030043 Ocular hypertension Diseases 0.000 claims description 4
- 210000004027 cell Anatomy 0.000 claims description 4
- 210000005036 nerve Anatomy 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 230000033228 biological regulation Effects 0.000 claims description 3
- 230000008595 infiltration Effects 0.000 claims description 3
- 238000001764 infiltration Methods 0.000 claims description 3
- 230000011278 mitosis Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000008929 regeneration Effects 0.000 claims description 3
- 238000011069 regeneration method Methods 0.000 claims description 3
- 210000000329 smooth muscle myocyte Anatomy 0.000 claims description 3
- 210000004881 tumor cell Anatomy 0.000 claims description 3
- 101000669917 Homo sapiens Rho-associated protein kinase 1 Proteins 0.000 claims description 2
- 102100039313 Rho-associated protein kinase 1 Human genes 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000006907 apoptotic process Effects 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 210000004292 cytoskeleton Anatomy 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002207 metabolite Substances 0.000 abstract description 6
- 239000000651 prodrug Substances 0.000 abstract description 6
- 229940002612 prodrug Drugs 0.000 abstract description 6
- 239000012453 solvate Substances 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 3
- -1 (R) -5- (1- (1H-indazole-5-carbonyl) azetidine-2-carbonyl) -N-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridine-2-carboxamide Chemical compound 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 11
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- 206010020772 Hypertension Diseases 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000016349 Myosin Light Chains Human genes 0.000 description 6
- 108010067385 Myosin Light Chains Proteins 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 125000003282 alkyl amino group Chemical group 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 description 5
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 description 5
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000003590 rho kinase inhibitor Substances 0.000 description 3
- 108010041788 rho-Associated Kinases Proteins 0.000 description 3
- 102000000568 rho-Associated Kinases Human genes 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000012224 working solution Substances 0.000 description 3
- ZQEBQGAAWMOMAI-SSDOTTSWSA-N (2r)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1C(O)=O ZQEBQGAAWMOMAI-SSDOTTSWSA-N 0.000 description 2
- MAVGBUDLHOOROM-UHFFFAOYSA-N 1h-indazole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2NN=CC2=C1 MAVGBUDLHOOROM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 108091005975 Myofilaments Proteins 0.000 description 2
- 102100035044 Myosin light chain kinase, smooth muscle Human genes 0.000 description 2
- 108010074596 Myosin-Light-Chain Kinase Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002473 indoazoles Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 208000001286 intracranial vasospasm Diseases 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 210000003632 microfilament Anatomy 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- QSKQVZWVLOIIEV-NSHDSACASA-N ripasudil Chemical compound C[C@H]1CNCCCN1S(=O)(=O)C1=CC=CC2=CN=CC(F)=C12 QSKQVZWVLOIIEV-NSHDSACASA-N 0.000 description 2
- 229950007455 ripasudil Drugs 0.000 description 2
- 230000016160 smooth muscle contraction Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- JWJVSDZKYYXDDN-ZCFIWIBFSA-N (2r)-1-[(2-methylpropan-2-yl)oxycarbonyl]azetidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC[C@@H]1C(O)=O JWJVSDZKYYXDDN-ZCFIWIBFSA-N 0.000 description 1
- JQAOHGMPAAWWQO-MRVPVSSYSA-N (2r)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC[C@@H]1C(O)=O JQAOHGMPAAWWQO-MRVPVSSYSA-N 0.000 description 1
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 1
- KDRNOBUWMVLVFH-UHFFFAOYSA-N 2-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)prop-2-enamide Chemical compound CC(=C)C(=O)NC1CC(C)(C)NC(C)(C)C1 KDRNOBUWMVLVFH-UHFFFAOYSA-N 0.000 description 1
- LLJRXVHJOJRCSM-UHFFFAOYSA-N 3-pyridin-4-yl-1H-indole Chemical compound C=1NC2=CC=CC=C2C=1C1=CC=NC=C1 LLJRXVHJOJRCSM-UHFFFAOYSA-N 0.000 description 1
- IDDDVXIUIXWAGJ-DDSAHXNVSA-N 4-[(1r)-1-aminoethyl]-n-pyridin-4-ylcyclohexane-1-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1CC([C@H](N)C)CCC1C(=O)NC1=CC=NC=C1 IDDDVXIUIXWAGJ-DDSAHXNVSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- 150000003928 4-aminopyridines Chemical class 0.000 description 1
- DKNLJWSDGPXALN-GOSISDBHSA-N 9h-fluoren-9-ylmethyl (2r)-2-carbonochloridoylpyrrolidine-1-carboxylate Chemical compound ClC(=O)[C@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 DKNLJWSDGPXALN-GOSISDBHSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical group C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 101000740112 Homo sapiens Membrane-associated transporter protein Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- 102100037258 Membrane-associated transporter protein Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007201 Myocardial reperfusion injury Diseases 0.000 description 1
- MKOVTDFQNIQBIQ-UHFFFAOYSA-N N-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide Chemical compound C1(=CC=CC=C1)NC(=O)C1=CC=2CNCCC=2S1 MKOVTDFQNIQBIQ-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 description 1
- 229960002435 fasudil Drugs 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 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 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- OXSVZNWPIYKGIK-UHFFFAOYSA-N n-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide Chemical compound C1NCCC2=C1C=C(C(=O)NC)S2 OXSVZNWPIYKGIK-UHFFFAOYSA-N 0.000 description 1
- 210000002241 neurite Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000025915 regulation of apoptotic process Effects 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物。试验表明,本发明的化合物具有良好的ROCK抑制活性,可以有效用于与ROCK活性异常疾病的治疗。
Description
技术领域:
本发明涉及一种抑制ROCK的化合物及其在治疗与ROCK相关疾病中的应用。
背景技术:
Rho属于小分子单聚体GTPase超家族,是Ras超家族的哺乳动物基因同系物,通过其下游最主要的效应分子Rho激酶(Rho-associated coiled-coil containing proteinkinase,ROCK),来调节细胞肌动蛋白骨架的重组,从而广泛参与细胞有丝***、细胞骨架调整、平滑肌细胞收缩、神经再生、肿瘤细胞浸润、细胞凋亡的调节等一系列生物学过程。Rho/ROCK激活后可以作用于多种底物,从而产生生物学过程。最主要的两种底物是肌球蛋白轻链(MLC)和肌球蛋白轻链磷酸酶(MLCP),MLC的磷酸化水平是决定平滑肌收缩程度的一个重要因素。肌球蛋白轻链激酶(MLCK)磷酸化MLC的Ser-19位点,导致平滑肌收缩;MLCP的抑制可以使MLC的磷酸化和平滑肌的收缩进一步增强。ROCK被激活以后,本身可以将MLC磷酸化而发生肌丝收缩作用;同时也能将MLCP磷酸化,使MLCP失活,导致细胞胞浆内MLC磷酸化程度增高,间接促进肌丝收缩。
在动物模型中Rho激酶活性的抑制展现出治疗人类疾病的多种益处,包括心血管疾病如肺动脉高压、高血压、动脉粥样硬化、心脏肥大、高眼压、脑缺血、脑血管痉挛等,和中枢神经***病症如神经元变性等,以及肿瘤。研究表明ROCK表达和活性在自发性高血压大鼠中有所升高,说明其与这些动物高血压的发生具有关联(Involvement of Rho-kinasein hypertensive vascular disease:a novel therapeutic target in hypertension[J].FASEB J.,2001,15(6):1062-4)。ROCK抑制剂Y-27632可使三种大鼠高血压模型(自发性高血压、肾性高血压、醋酸脱氧皮质酮盐型高血压)中的血压显著降低,而对对照大鼠的血压作用较小(Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension[J].Nature,1997,389(6654):990-4)。也有研究表明ROCK抑制剂对肺动脉高压具有较好的作用(Acute vasodilator effects of aRho-kinase inhibitor,fasudil,in patients with severe pulmonary hypertension[J].Heart,2005:91(3):391-2)。
目前已经研究开发的ROCK抑制剂可分为五大类:(1)异喹啉类:此类化合物结构特点是具有一个异喹啉结构和哌嗪环,两者通过磺酰基相连。代表物有法苏地尔(Uehata M,Ishizaki T,Satoh H,et al.Calcium sensitization of smooth muscle mediated by aRho-associated protein kinase in hypertension[J].Nature,1997,389:990-994)、H-1152P(Tamura M,Nakao H,Yoshizaki H,et al.Development of specific Rho-kinaseinhibitors and their clinical application[J].Biochim Biophys Acta,2005,1754:245-252);(2)4-氨基吡啶类:此类化合物结构除4-氨基吡啶母核外,在分子的中心位置还含有一个环己烷或苯环结构,在环己烷的4位具有侧链结构。代表物有Y-30141(Takami A,Iwakubo M,Okada Y,et al.Design and synthesis of Rho kinase inhibitors[J].Bioorg Med Chem,2004,12:2115-2137);(3)吲唑类:此类化合物将5-氨基或5-烷氧基-1H吲唑作为骨架;(4)酰胺和脲类:此类化合物具有一个邻苯二甲酰亚胺和一个脲基构成的绞和结构。(5)其它类:其它不包含上述结构的ROCK抑制剂,代表物有Rockout(Yarrow JC,Totsukawa G,Charras GT,et al.Screening for cell migration inhibitors viaautomated microscopy reveals a Rho-kinase inhibitor[J].Chem Biol,2005,12:385-395)。
目前已上市的ROCK抑制剂药物有Asahi Kasei公司的Eril(适用于脑血管痉挛的治疗)和Kowa公司的Glanatec(适用于高眼压症和青光眼的治疗)。其中Glanatec仅在日本上市销售。因此进行开发作用于ROCK的靶向小分子药物研究,得到活性更好、选择性更高、更低毒性和副作用、更经济的ROCK抑制剂,具有十分重要的社会和经济意义。
发明内容
本发明目的之一在于提供一种具有ROCK抑制活性的化合物;
本发明提供式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物:
其中,
X选自N或CRa;
Y选自S、O或NR4;其中R4选自氢、C1-C6的烷基;
n为0、1、2、3或4;
R1选自氢、卤素、羧基、C1-C6的烷基、R5取代的C1-C6的烷基、C1-C6的烷氧基、R5取代的C1-C6的烷氧基、C3-C6的环烷基、R6取代的C3-C6的环烷基、C3-C6的杂环烷基、R6取代的C3-C6的杂环烷基、C5-C6的芳环基、R6取代的芳环基、C5-C6的杂芳环基、R6取代的杂芳环基、 其中R5选自卤素、羟基、氨基、C1-C6的烷氧基、C1-C6的烷氨基、C3-C6的环烷基、R6取代的C3-C6的环烷基、C3-C6的杂环烷基、R6取代的C3-C6的杂环烷基、C5-C6的芳环基、R6取代的芳环基、C5-C6的杂芳环基、R6取代的杂芳环基;R6选自卤素、羟基、氨基、C1-C6的烷基、C1-C6的烷氧基、C1-C6的烷氨基;R7、R8分别选自氢、C1-C6的烷基、R5取代的C1-C6的烷基、C3-C6的环烷基、R6取代的C3-C6的环烷基、C3-C6的杂环烷基、R6取代的C3-C6的杂环烷基、C5-C6的芳环基、R6取代的芳环基、C5-C6的杂芳环基、R6取代的杂芳环基;
Ra、R2、R3、R9、R10分别独立地选自氢、卤素、羟基、氨基、C1-C6的烷基、C1-C6的烷氧基、C1-C6的烷氨基;
或者R9与R10链接成环。
进一步地,X选自N或CH。
进一步地,Y选自O或S。
进一步地,n为0、1或2。
进一步地,所述式I所示化合物可进一步如式IIa所示:
其中,
R1选自氢、卤素、羧基、C1-C6的烷基、R5取代的C1-C6的烷基、C1-C6的烷氧基、R5取代的C1-C6的烷氧基、C3-C6的环烷基、R6取代的C3-C6的环烷基、C3-C6的杂环烷基、R6取代的C3-C6的杂环烷基、C5-C6的芳环基、R6取代的芳环基、C5-C6的杂芳环基、R6取代的杂芳环基;其中R5选自卤素、羟基、氨基、C1-C6的烷氧基、C1-C6的烷氨基;R6选自卤素、羟基、氨基、C1-C6的烷基、C1-C6的烷氧基、C1-C6的烷氨基。
进一步地,式IIa所示的化合物为:
进一步地,所述式I所示化合物可进一步如式IIb所示:
进一步地,式IIb所示的化合物为:
进一步地,所述式I所示化合物可进一步如式IIc所示:
进一步地,式IIc所示的化合物为:
进一步地,所述式I所示化合物可进一步如式IId所示:
进一步地,所述式IId所示化合物如式IIh所示:
其中,
R1选自氢、卤素、羧基、C1-C6的烷基、R5取代的C1-C6的烷基、C1-C6的烷氧基、R5取代的C1-C6的烷氧基、C3-C6的环烷基、R6取代的C3-C6的环烷基、C3-C6的杂环烷基、R6取代的C3-C6的杂环烷基、C5-C6的芳环基、R6取代的芳环基、C5-C6的杂芳环基、R6取代的杂芳环基;其中R5选自卤素、羟基、氨基、C1-C6的烷氧基、C1-C6的烷氨基;R6选自卤素、羟基、氨基、C1-C6的烷基、C1-C6的烷氧基、C1-C6的烷氨基。
进一步地,式IId所示的化合物为:
进一步地,所述式I所示化合物可进一步如式IIe所示:
进一步地,式IIe所示的化合物为:
进一步地,所述式I所示化合物可进一步如式IIf所示:
进一步地,式IIf所示的化合物为:
进一步地,所述式I所示化合物可进一步如式IIg所示:
进一步的,式IIg所示的化合物为:
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备ROCK抑制剂类药物中的用途。
进一步地,所述ROCK抑制剂类药物为ROCK1和/或ROCK2抑制剂类药物。
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗与ROCK活性异常相关的疾病的药物中的用途。
进一步地,所述与ROCK活性异常相关的疾病是与细胞有丝***、细胞骨架调整、平滑肌细胞收缩、神经再生、肿瘤细胞浸润、细胞凋亡相关的疾病中的任一种或几种。
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗心血管疾病、高眼压症、肺动脉高压、青光眼或癌症药物中的用途。
本发明还提供了一种药物组合物,它是以前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物为活性成分,加上药学上可接受的辅料制备而成的制剂。
试验证明,本发明公开的式I所示的新化合物,表现出了良好的ROCK抑制活性,为临床治疗与ROCK活性异常相关的疾病提供了一种新的药用可能。
ROCK抑制剂可用于治疗心血管疾病、神经***疾病、纤维化疾病、肿瘤等。例如,能够减轻心肌缺血/再灌注损伤,对抗高血压等;同时能够促进神经突起生长,促进损伤后神经功能的恢复;并且能够抑制肝脏、肺、肾脏纤维化;还有能够有效抑制肿瘤的转移。本发明通过验证式I化合物对ROCK的抑制活性,说明了其具有治疗上述多种疾病的效果。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名***命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(Ca~Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,(C1~C4)烷基是指包含1~4个碳原子的烷基。
所述C1~C6烷基是指C1、C2、C3、C4、C5、C6的烷基,即具有1~6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。C1-C6的烷氧基、C3-C6的环烷基、C3-C6的杂环烷基、C5-C6的芳环基、C5-C6的杂芳环基也具有与其基团相应的含义。例如,所述C3~C6的环烷基是指C3、C4、C5、C6的环烷基,即具有3~6个碳原子的环状烷基,例如环丙基、环丁基、环戊基、环己基等等。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明的某些实施方式中,本发明包括了同位素标记的化合物,所述同位素标记化合物是指与本文中所列化合物相同,但是其中的一个或多个原子被另一个原子取代,该原子的原子质量或质量数不同于自然界中常见的原子质量或质量数。可以引入式(I)化合物中的同位素包括氢、碳、氮、氧、硫,即2H,3H、13C、14C、15N、17O、18O、35S。含有上述同位素和/或其它原子同位素的式(I)的化合物及其立体异构体,以及该化合物、立体异构体的可药用的盐均应包含在本发明范围之内。
本发明中的关键中间体和化合物进行分离和纯化,所使用的方式是有机化学中常用的分离和纯化方法且所述方法的实例包括过滤、萃取、干燥、旋干和各种类型的色谱。可选择地,可以使中间体不经纯化即进行下一步反应。
在某些实施方式中,本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
在本发明的含义之内,“治疗”也包括复发性(relapse)预防或阶段性(phase)预防,以及急性或慢性体征、症状和/或功能失常的治疗。治疗可以是对症治疗,例如抑制症状。它可以在短期内实现,在中期内调整,或者可以说是长期治疗,例如在维持疗法里面。所述预防包括延迟和/或阻止病症、疾病或病况和/或其伴发症状的发作;防止对象染上病症、疾病或病况;或降低对象染上病症、疾病或病况的风险的方法。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1(R)-5-(1-(1H-吲唑-5-羰基)氮杂环丁烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
1.(R)-2-(2-(甲基氨基甲酰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-羰基)氮杂环丁烷-1-甲酸叔丁酯的制备
将N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(200mg,1.02mmol)、(R)-1-(叔丁氧羰基)氮杂环丁烷-2-羧酸(176mg,867μmol)和二异丙基乙胺(395mg,3.06mmol)溶于二氯甲烷(10.0mL),然后加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(388mg,1.02mmol),室温搅拌反应1小时后减压蒸除溶剂,经中压柱层析纯化后得(R)-2-(2-(甲基氨基甲酰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-羰基)氮杂环丁烷-1-甲酸叔丁酯(270mg,,711μmol,产率70%)。
MS(ESI)m/z=380(M+1)+
2.(R)-5-(氮杂环丁烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
将(R)-2-(2-(甲基氨基甲酰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-羰基)氮杂环丁烷-1-甲酸叔丁酯(130mg,343μmol)溶于二氯甲烷(9.96mL)中,加入三氟乙酸(2.04mL)后室温搅拌反应1小时。减压蒸除溶剂后得粗品(R)-5-(氮杂环丁烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(100mg,358μmol,产率105%)。
MS(ESI)m/z=280(M+1)+
3.(R)-5-(1-(1H-吲唑-5-羰基)氮杂环丁烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
将1H-吲唑-5-羧酸(57.5mg,354μmol)、(R)-5-(氮杂环丁烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(90.0mg,322μmol)和二异丙基乙胺(167mg,1.29mmol)溶于N,N-二甲基甲酰胺(3.00mL)中,然后加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(135mg,354μmol),室温搅拌反应1小时后减压蒸除溶剂,经中压柱层析和制备型高效液相纯化后得(R)-5-(1H-吲唑-5-羰基)氮杂环丁烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(31.4mg,72.7μmol,产率23%)。
MS(ESI)m/z=424(M+1)+
1H NMR(400MHz,CD3OD)δ=8.17(m,2H),7.74(m,2H),7.37(m,1H),5.49(m,1H),4.75(m,1H),4.79-4.25(m,3H),3.89(m,1H),3.80(m,1H),3.08(m,1H),2.9(s,3H),2.76(m,2H),2.18(m,1H).
实施例2(R)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
1、(2-(苯基氨基甲酰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-羰基)吡咯烷-1-甲酸(R)-(9H-芴-9-基)酯的制备
(R)-(9H-芴-9-基)甲基2-(氯羰基)吡咯烷-1-羧酸酯(500mg,1.41mmol)、N-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(364mg,1.41mmol)溶于二氯甲烷(10.0mL)中,室温搅拌反应1小时后减压蒸除溶剂,经中压柱层析纯化后得(2-(苯基氨基甲酰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-羰基)吡咯烷-1-甲酸(R)-(9H-芴-9-基)酯(530mg,917μmol,产率65%)。
MS(ESI)m/z=578(M+1)+
2、(R)-N-苯基-5-(吡咯烷-2-羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
将(2-(苯基氨基甲酰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-羰基)吡咯烷-1-甲酸(R)-(9H-芴-9-基)酯(530mg,917μmol)、哌啶(2.00mL)溶于二氯甲烷(10.0mL)中,室温搅拌反应30分钟后减压蒸除溶剂,经中压柱层析纯化后得(R)-N-苯基-5-(吡咯烷-2-羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(210mg,591μmol,产率64%)。
MS(ESI)m/z=356(M+1)+
3、(R)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
将1H-吲唑-5-羧酸(95.8mg,591μmol)、(R)-N-苯基-5-(吡咯烷-2-羰基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(210mg,591μmol)和二异丙基乙胺(153mg,1.18mmol)溶于N,N-二甲基甲酰胺(10.0mL)中,然后加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(225mg,591μmol),室温搅拌反应1小时后减压蒸除溶剂,经中压柱层析和制备型高效液相纯化后得(R)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(15.1mg,28.4μmol,产率4.8%)。
MS(ESI)m/z=500(M+1)+
1H NMR(400MHz,DMSO)δ=13.26(S,1H),10.15(m,1H),8.17(S,1H),7.99(S,1H),7.83(m,1H),7.73(m,2H),7.58(m,1H),7.51(m,1H),7.35(m,2H),7.09(m,1H),5.15(m,2H),4.72(m,1H),3.63-3.59(m,4H),2.31(m,1H),1.93-1.80(m,3H).
实施例3(R)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
以(R)-1-(叔丁氧羰基)吡咯烷-2-羧酸为原料,按实施例1中的类似步骤制得(R)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(总产率11%)。
MS(ESI)m/z=438(M+1)+
1H NMR(400MHz,CD3OD)δ=8.23(m,2H),7.68(m,2H),7.32(m,1H),5.36(m,1H),4.72(m,1H),4.70-4.20(m,3H),3.84(m,1H),3.77(m,1H),3.10(m,1H),2.92(s,3H),2.74(m,2H),2.54(m,2H),2.07(m,1H).
实施例4(S)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
以(S)-1-(叔丁氧羰基)吡咯烷-2-羧酸为原料,按实施例1中的类似步骤制得(S)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(总产率9.5%)。
MS(ESI)m/z=438(M+1)+
1H NMR(400MHz,CD3OD)δ=8.22(m,2H),7.70(m,2H),7.32(m,1H),5.35(m,1H),4.72(m,1H),4.71-4.20(m,3H),3.84(m,1H),3.77(m,1H),3.10(m,1H),2.923(s,3H),2.64(m,2H),2.56(m,2H),2.04(m,1H).
实施例5(R)-5-(1-(1H-吲唑-5-羰基)哌啶-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
以(R)-1-(叔丁氧羰基)哌啶-2-羧酸为原料,按实施例1中的类似步骤制得(R)-5-(1-(1H-吲唑-5-羰基)哌啶-2-羰基)-N-甲基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(总产率11%)。
MS(ESI)m/z=452(M+1)+
1H NMR(400MHz,CD3OD)δ=8.13(m,2H),7.72(m,2H),7.36(m,1H),5.34(m,1H),4.69(m,1H),4.62-4.23(m,3H),3.84(m,1H),3.72(m,1H),3.14(m,1H),2.93(s,3H),2.74(m,2H),2.44(m,2H),2.34(m,2H),2.08(m,1H).
实施例6(S)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺的制备
以(S)-(9H-芴-9-基)甲基2-(氯羰基)吡咯烷-1-羧酸酯为原料,按实施例2中的类似步骤制得(S)-5-(1-(1H-吲唑-5-羰基)吡咯烷-2-羰基)-N-苯基-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-甲酰胺(总产率2.4%)。
MS(ESI)m/z=500(M+1)+
1H NMR(400MHz,DMSO)δ=13.25(S,1H),10.14(m,1H),8.16(S,1H),7.98(S,1H),7.82(m,1H),7.72(m,2H),7.56(m,1H),7.50(m,1H),7.34(m,2H),7.07(m,1H),5.14(m,2H),4.70(m,1H),3.63-3.54(m,4H),2.31(m,1H),1.93-1.77(m,3H).
实施例7(R)-1-(1H-吲唑-5-羰基)-N-(噻吩-3-基甲基)吡咯烷-2-甲酰胺的制备
以(R)-1-(叔丁氧羰基)吡咯烷-2-羧酸、噻吩-3-基甲胺为原料,按实施例1中的类似步骤制得(R)-1-(1H-吲唑-5-羰基)-N-(噻吩-3-基甲基)吡咯烷-2-甲酰胺(总产率14%)。
MS(ESI)m/z=355(M+1)+
1H NMR(400MHz,CD3OD)δ=8.36(m,2H),7.88(m,2H),7.56(m,1H),7.06(m,2H),5.26(m,2H),4.32(m,1H),3.44(m,2H),3.06(m,1H),2.54(m,2H),2.07(m,1H).
为了说明本发明的有益效果,本发明提供以下试验例:
试验例1本发明的化合物生物活性
对本发明的化合物进行了ROCK2抑制活性的检测。
(1)方法
ROCK2抑制活性的检测
ROCK2能够磷酸化S6K(KRRRLASLR)多肽底物,将ATP转化成ADP。在激酶反应后,加入ADP-GloTM试剂,使激酶反应终止,并消耗完剩余的ATP。加入激酶检测试剂,它在使ADP转化成ATP的同时,ATP再被Ultra-GloTM萤光素酶转化成光发光信号,发光信号与激酶活性正相关。
按以下步骤进行ROCK2抑制活性的检测:
1.Assay Buffer:40mM Tris pH 7.5,20mM MgCl2,0.1%BSA(w/v),50μM DTT;
2.加12μL2.5x0.1μg/ml ROCK2工作液进入96孔PCR板;
3.加6μL6x化合物工作液进入96孔PCR板混匀,25℃预孵育10min;
4.加入12μL 2.5x 37.5μg/mlS6K底物和12.5μMATP混合工作液,30℃孵育60min;
5.取25μL反应混合物到一个新96孔PCR板,并加入25μL ADP-GloTM试剂混匀,25℃孵育40min终止反应;
6.取40μL终止反应混合物到一个新96孔PCR板,并加入40μL激酶检测试剂混匀,25℃孵育40min;
7.读取luminescence(冷光)信号值,计算抑制率。
(2)结果
按照上述方法对实施例制备的化合物进行ROCK2抑制活性检测,试验结果见表1,其中测定各化合物的IC50按照说明分类,表1中:
“+”表示IC50测定值大于500nM;
“++”表示IC50测定值小于500nM大于100nM;
“+++”表示IC50测定值小于100nM
表1化合物对ROCK2的抑制活性
实施例 | ROCK2 | 实施例 | ROCK2 |
1 | ++ | 2 | +++ |
3 | +++ | 4 | + |
5 | + | 6 | ++ |
7 | +++ |
试验表明,本发明实施例的化合物具有良好的ROCK抑制活性,可以有效用于与ROCK活性异常疾病的治疗。
综上所述,本发明公开的式I所示的新化合物,表现出了良好的ROCK抑制活性,为临床治疗与ROCK活性异常相关的疾病提供了一种新的药用可能。
Claims (11)
6.权利要求1-5任一项所述的化合物或其药学上可接受的盐在制备ROCK抑制剂类药物中的用途。
7.根据权利要求6所述的用途,其特征在于:所述ROCK抑制剂类药物为ROCK1和/或ROCK2抑制剂类药物。
8.权利要求1-5任一项所述的化合物或其药学上可接受的盐在制备治疗与ROCK活性异常相关的疾病的药物中的用途。
9.根据权利要求8所述的用途,其特征在于:所述与ROCK活性异常相关的疾病是与细胞有丝***、细胞骨架调整、平滑肌细胞收缩、神经再生、肿瘤细胞浸润、细胞凋亡相关的疾病中的任一种或几种。
10.权利要求8所述的用途,所述与ROCK活性异常相关的疾病是心血管疾病、高眼压症、肺动脉高压、青光眼。
11.一种药物组合物,其特征在于:它是以权利要求1-5任一项所述的化合物或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2016112179967 | 2016-12-26 | ||
CN201611217996 | 2016-12-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108239082A CN108239082A (zh) | 2018-07-03 |
CN108239082B true CN108239082B (zh) | 2021-01-05 |
Family
ID=62701123
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711406484.XA Active CN108239082B (zh) | 2016-12-26 | 2017-12-22 | 一种抑制rock的化合物及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108239082B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008036021A1 (en) * | 2006-09-20 | 2008-03-27 | Astrazeneca Ab | Tetrahydro-lh-pyrido [3,4 -b] indole derivatives as cbl receptor ligands |
CN101790527A (zh) * | 2006-07-20 | 2010-07-28 | 凯利普西斯公司 | Rho激酶的苯并噻吩抑制剂 |
WO2016109515A1 (en) * | 2014-12-30 | 2016-07-07 | Forma Therapeutics, Inc. | Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors |
-
2017
- 2017-12-22 CN CN201711406484.XA patent/CN108239082B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101790527A (zh) * | 2006-07-20 | 2010-07-28 | 凯利普西斯公司 | Rho激酶的苯并噻吩抑制剂 |
WO2008036021A1 (en) * | 2006-09-20 | 2008-03-27 | Astrazeneca Ab | Tetrahydro-lh-pyrido [3,4 -b] indole derivatives as cbl receptor ligands |
WO2016109515A1 (en) * | 2014-12-30 | 2016-07-07 | Forma Therapeutics, Inc. | Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors |
Non-Patent Citations (1)
Title |
---|
Design and synthesis of Rho kinase inhibitors(II);Masayuki Iwakubo et al.;《Bioorganic & Medicinal Chemistry》;20061012;第15卷;第350-364页;第352页Table1以及第350页摘要 * |
Also Published As
Publication number | Publication date |
---|---|
CN108239082A (zh) | 2018-07-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7264642B2 (ja) | エフェクターt細胞機能を増進するための、セレブロンを標的とする小分子 | |
EP1866286B1 (en) | Pyridine derivatives useful as inhibitors of pkc-theta | |
CN112955459A (zh) | 双环肽配体和其用途 | |
RU2606949C1 (ru) | Замещенные N-{ 3-[4-(1-метил-1Н-индол-3-ил)пиримидин-2-иламино]-4-метоксифенил} -амиды в качестве модуляторов EGFR, предназначенные для лечения рака | |
EP2773623B1 (en) | 1-(arylmethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diones and analogs and the use thereof | |
EP1878732B1 (en) | HIGHLY SELECTIVE Rho-KINASE INHIBITOR | |
CA3115088A1 (en) | Tyk2 inhibitors and uses thereof | |
BR112019014526A2 (pt) | Inibidores seletivos de jak1 | |
JP2021532077A (ja) | セレブロン系機構に対抗する二量体免疫調節化合物 | |
EP2826780B1 (en) | Thieno[2,3-d]pyridazine derivatives and therapeutic use thereof for protein kinase inhibition | |
JP2019526605A (ja) | 置換2−h−ピラゾール誘導体の結晶形、塩型及びその製造方法 | |
CA3078602A1 (en) | Epidermal growth factor receptor inhibitors | |
CN106928252B (zh) | 一种抑制rock的化合物及其制备方法与应用 | |
CN108239082B (zh) | 一种抑制rock的化合物及其应用 | |
CN108203433B (zh) | 一种rock抑制剂及其应用 | |
CN108239081B (zh) | 一种抑制rock的化合物及其应用 | |
CN113336774B (zh) | 作为trk抑制剂的取代的手性二芳基大环化合物 | |
CN114929675B (zh) | 作为粘着斑激酶抑制剂的新型金刚烷衍生物 | |
CN109134433B (zh) | 一种抑制rock的化合物及其应用 | |
CN113735830A (zh) | 一类羟肟酸衍生物及其应用 | |
EP3632912B1 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
EP3640242A1 (en) | Rock-inhibiting compound and uses thereof | |
RU2615986C1 (ru) | Замещенные метил (2-{ 4-[3-(3-метансульфониламино-2-фтор-5-хлор-фенил)-1Н-пиразол-4-ил]пиримидин-2-иламино} -этил)карбаматы, способ их получения и применения | |
EP3878841B1 (en) | Indazole kinase inhibitor and use thereof | |
BR112019025158A2 (pt) | Derivados de ácido carboxílico como inibidores das proteínas quinase |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information | ||
CB02 | Change of applicant information |
Address after: 610000 R&D Building 1001, No. 88 South Keyuan Road, Fengjiawan Industrial Park, Chengdu High-tech Zone, Sichuan Province Applicant after: Chengdu Pioneer Drug Development Co., Ltd. Address before: 610000 R&D Building 1001, No. 88 South Keyuan Road, Fengjiawan Industrial Park, Chengdu High-tech Zone, Sichuan Province Applicant before: Chengdu lead drug development corporation, Ltd. |
|
GR01 | Patent grant | ||
GR01 | Patent grant |